Introduction: In recent years, generative Artificial Intelligence models, such as ChatGPT, have been increasingly utilized in healthcare. Despite acknowledging the high potential of AI models in terms of quick access to sources and formulating a response to a clinical question, the results obtained using these models still require validation through comparison with established clinical guidelines. This study compares the responses of the AI model to eight clinical questions with the Italian Association of Medical Oncology (AIOM) guidelines for ovarian cancer. Materials and Methods: The authors used the Delphi method to evaluate responses from ChatGPT and the AIOM guidelines. An expert panel of healthcare professionals assessed responses based on clarity, consistency, comprehensiveness, usability, and quality using a 5-point Likert scale. The GRADE methodology assessed the evidence quality and the recommendations' strength. Results: A survey involving 14 physicians revealed that the AIOM guidelines consistently scored higher averages compared to the AI models with a statistically significant difference. Post-hoc tests showed that AIOM guidelines significantly differed from all AI models, with no significant difference among the AI models. Conclusions: While AI models can provide rapid responses, they must match established clinical guidelines regarding clarity, consistency, comprehensiveness, usability, and quality. These findings underscore the importance of relying on expert-developed guidelines in clinical decision-making and highlight potential areas for AI model improvement.

Black spot disease is associated with the breakdown of chitin by chitinolytic bacteria resulting in extensive black lesions across the body of crustaceans. Black spot is prevalent across most fished crustaceans worldwide. Severely infected individuals are rejected from the fishery resulting in financial loss to both fisher’s and seafood export and processing companies. Ecologically, populations with high infection rates may have increased mortalities resulting in fewer individuals surviving the population. The prevalence and severity of shell disease in the edible crab, Cancer pagurus, of various size classes, was assessed via scaled images taken from crabs sampled within the Berwickshire Marine Reserve, UK. A total of 22.4% of individuals across all size groups were found to contain black spot lesions. Male crabs were more commonly affected (26.21%), with more body parts showing lesions and a greater overall blackspot coverage (1.75%) than females (16.43% and 1% respectively). Crabs under the MLS (140mm) showed a significantly higher black spot coverage, but size did not significantly affect infection rates. Carapace and chelae were the most commonly affected areas. Compared to previous studies the Berwickshire Marine Reserve has a relatively low prevalence of black spot disease in Cancer pagurus.

Epidemiological and clinical evidence have extensively documented the role of obesity in the develop-ment of endometrial cancer. However, the effect of fatty acids on cell growth in endometrial cancer has not been widely studied. Here we reported that palmitic acid significantly inhibited cell proliferation of endometrial cancer cells and primary cultures of endometrial cancer, and reduced tumor growth in a transgenic mouse model of endometrial cancer, in parallel with increased cellular stress and apoptosis and decreased cellular adhesion and invasion. Inhibition of cellular stress by N-acetyl-L-cysteine effec-tively reversed the effects of palmitic acid on cell proliferation, apoptosis and invasive capacity in the endometrial cancer cells. Palmitic acid increased the intracellular formation of lipid droplets in a time- and dose-dependent manner. Depletion of lipid droplets by blocking DGAT1 and DGAT2 effectively increased the ability of palmitic acid to inhibit cell proliferation and induce cleaved caspase 3 activity. Collectively, this study provides new insight into the effect of palmitic acid on cell proliferation, inva-sion and the formation of lipid droplets that may have potential clinical relevance in the treatment of obesity-driven endometrial cancer

Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease due to the absence of effective therapies. A more comprehensive understanding of molecular events, encompassing the dysregulation of microRNAs (miRs) and metabolic reprogramming, holds the potential to unveil precise mechanisms underlying mCRPC. This study aims to assess the expression of selected serum exosomal miRs (miR-15a, miR-16, miR-19a-3p, miR-21, and miR-141a-3p) alongside serum metabolomic profiling and their correlation in patients with mCRPC and benign prostate hyperplasia (BPH). Blood serum samples from mCRPC patients (n=51) and BPH patients (n=48) underwent metabolome analysis through 1H-NMR spectroscopy. The expression levels of serum exosomal miRs in mCRPC and BPH patients were evaluated using quantitative real-time polymerase chain reaction (qRT‒PCR). The 1H-NMR metabolomics analysis revealed significant alterations in lactate, acetate, citrate, 3-hydroxybutyrate, and branched-chain amino acids (BCAAs, including valine, leucine, and isoleucine) in mCRPC patients compared to BPH patients. MiR-15a, miR-16, miR-19a-3p, and miR-21 exhibited a down-regulation of more than twofold in the mCRPC group. Significant correlations were predominantly observed between lactate, citrate, acetate, and miR-15a, miR-16, miR-19a-3p, and miR-21. The importance of integrating metabolome analysis of serum with selected serum exosomal miRs in mCRPC patients has been confirmed, suggesting their potential utility as clinical diagnostic markers.

Mutation analysis of circulating tumor DNA (ctDNA) has applications in monitoring of colorectal cancer (CRC) patients for recurrence. Considering the low tumor fraction of ctDNA in cell-free DNA (cfDNA) isolated from blood plasma, the sensitivity of the detection method is important. Here, plasma DNA collected at diagnosis and follow-up from 25 CRC patients was analyzed using a multiplex superRCA mutation detection assay. The assay was also performed on genomic DNA (gDNA) from tumor and normal tissue from 20 of these patients. The lower limit of detection for most sequence variants was in the range of 10^-5, while when analyzing cfDNA from plasma with a typical input of 33 ng, the practical detection limit was ~10^-4 or 0.01% mutant allele frequency (MAF). In 17 of 19 patients with identified hotspot mutations in tumor gDNA, at least one hotspot mutation could be detected in plasma DNA at the time of diagnosis. The MAF increased at subsequent time points in four of the patients who experienced a clinical relapse. Multiplex superRCA analysis of the remaining six patients did not reveal any hotspot mutations. In conclusion, multiplex superRCA assays proved suitable for monitoring CRC patients by analyzing hotspot mutations in cfDNA, and dynamic changes in MAF were observed in patients with clinical relapse.

Cervical cancer, primarily caused by high-risk human papillomavirus (HR-HPV) types 16 and 18, is a major global health concern. Persistent HR-HPV infection can progress from reversible pre-cancerous lesions to invasive cervical cancer, which is driven by the oncogenic activity of human papillomavirus (HPV) genes, particularly E6 and E7. Traditional screening methods, including cytology and HPV testing, have limited sensitivity and specificity. This review explores the ap-plication of p16/Ki-67 dual-staining cytology for cervical cancer screening. This advanced im-munocytochemical method allows for simultaneously detecting p16 and Ki-67 proteins within cervical epithelial cells, offering a more specific approach for triaging HPV-positive women. Dual staining and traditional methods are compared, demonstrating their high sensitivity and negative predictive value but low specificity. The increased sensitivity of dual staining results in higher detection rates of CIN2+ lesions, which is crucial for preventing cervical cancer progression. However, its low specificity may lead to increased false-positive results and unnecessary biopsies. The implications of integrating dual staining into contemporary screening strategies, particularly considering the evolving landscape of HPV vaccination and changes in HPV genotype prevalence are also discussed. New guidelines and further research are necessary to elucidate the long-term effects of integrating dual staining into screening protocols.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide. It is commonly diagnosed in advanced stages and therapeutic interventions are typically constrained to systemic chemotherapy, which yields only modest clinical outcomes. In this review, we examine recent developments in targeted therapy tailored to address distinct molecular pathway alteration required for PDAC. Our review delineates the principal signaling pathways and molecular mechanisms implicated in the initiation and progression of PDAC. Subsequently, we provide an overview of prevailing guidelines, ongoing investigations, and prospective research trajectories related to targeted therapeutic interventions, drawing insights from randomized clinical trials and other pertinent studies. This review focus on a comprehensive examination of preclinical and clinical data substantiating the efficacy of these therapeutic modalities, emphasizing the potential of combinatorial regimens and novel therapies to enhance the quality of life for individuals afflicted with PDAC. Lastly, the review delves into the contemporary application and ongoing research endeavors concerning targeted therapy for PDAC. This synthesis serves to bridge the molecular elucidation of PDAC with its clinical implications, the evolution of innovative therapeutic strategies, and the changing landscape of treatment approaches.

Introduction: Colorectal cancer (CRC) is a disease of colon or rectum the part of digestive system. DNA methylation is a process of gene expression by recruiting protein which involve in gene repression, or inhibiting the binding of transcription factors to DNA. MicroRNAs (miRNAs) have been attracting major interest as potential biomarker in cancer. Hereditary nonpolyposis of colorecta cancer (HNPCC) is a type of genetic change (mutation) in a family. Our aims to do a systematic review on DNA methylation and miRNAs serve as candidate clinical biomarkers in HNPCC. Materials and methods: Electronic databases (Medline, PubMed and Scopus data bases). We searched to identify publication all over the world related colorectal cancer and miRNA. Selection was based on the design (CRC, invasive CRC, Colon or rectum, HNPCC, microRNA, circulating miRNA, non-coding RNA), 87 papers from PubMed and 15 papers from Scopus were selected all over the world. CRC, target antigens, methodologies used for detection and miRNA expression were identified and summarized. Results: A total of 96 articles were searched, 87 articles from scopus and 9 articles from PubMed. 20 duplicates removed and remain 76, 52 excluded after screened the titles and abstracts; and remain 24, 10 full texts articles were excluded with reason, and 14 identifications were included in the studies. Conclusion: The findings of this systematic review showed that DNA methylation and mircroRNA in HNCC patients as a genetic mutation or a promoter in colorectal cancer.

The incidence and mortality of cervical cancer are high in Romania compared to other European countries, particularly for locally advanced cervical cancer cases, which are predominant at the time of diagnosis. Widely accepted therapeutic guidelines indicate that the treatment for locally advanced cervical cancer consists of concurrent chemoradiotherapy (total dose 85-90Gy at point A), with surgery not being necessary as it does not lead to improved survival and results in significant additional morbidity. In Romania, the treatment for locally advanced cervical cancer differs, involving lower-dose chemotherapy (total dose 60-65Gy at point A), followed by surgery which, under these circumstances, ensures better local control. In this regard, we attempted to evaluate the role and necessity of surgery in Romania, considering that in our study, residual lesions were found in 55.84% of cases on resected specimens, especially in cases with unfavorable histology (adenocarcinoma and adenosquamous carcinoma). This type of surgery was associated with significant morbidity (28.22%) in our study. The recurrence rate was 24.21% for operated patients compared to 62% for non-operated patients receiving suboptimal concurrent chemotherapy alone. In conclusion, In Romania, surgery will continue to play a predominant role until radiotherapy achieves the desired effectiveness for local control.

Radiotherapy, also known as radiation therapy, is a treatment modality based on the use of high energy rays or radioactive substances, to damage tumoral cells and halt their growth and division. It is an effective tool for treating cancer of different kinds for more than 100 years with remarkable outcomes for cancer patients. This technique is characterised by notable technological innovations and methodologies, enhanced precision and effectiveness. Initially, precision and efficacy of radiotherapy are improved by technological advancements, such as the development of linear accelerators and brachytherapy. As a result, Radiotherapy has transformed the prognosis for cancer patients enhancing survival rates and improving quality of life. Also, it offers targeted and personalized treatment with advancements in imaging techniques such as Intensity-Modulated Radiation Therapy (IMRT) and Stereotactic Body Radiation Therapy (SBRT) and innovations like Image-Guided Radiation Therapy (IGRT), Adaptive Radiotherapy (ART) and Artificial Intelligence (AI). Additionally, techniques like proton therapy result in reduced side effects and collateral damage. Although, among the challenges and future perspectives we note the issue of affordability and accessibility. Ongoing research into immunotherapy and nanotechnology and their synergy with radiation therapy shows potential for further improving treatment outcomes. In conclusion, the evolution of radiotherapy has been a transformative journey, reshaping the prognosis and outcomes for cancer patients.

PIEZO1 plays a crucial role in the human body as a mechanosensory ion channel. It has been demonstrated that PIEZO1 is important in tissue development and regulating many essential physiological processes. Studies have suggested that the PIEZO1 ion channel plays a role in invasion and progression in cancer; elevated levels of PIEZO1 have been correlated with increased migration in breast cancer cells, chemo-resistance and invasion in gastric cancer cells, and increased invasion of osteosarcoma cells. In addition, high PIEZO1 expression levels were correlated with a worse prognosis in glioma patients. On the other hand, studies in lung cancer have attributed high PIEZO1 levels to better patient outcomes. However, the clinical impact of PIEZO1 in breast cancer is not well characterized. Therefore, our goal was to determine the clinical relevance of PIEZO1 in breast cancer. Analysis of breast cancer data from The Cancer Genome Atlas (TCGA) was conducted to investigate PIEZO1 expression levels and correlation to survival, followed by validation in an independent dataset, GSE3494. We also performed gene set enrichment analysis (GSEA) and analyzed immune cell levels in breast tumors from TCGA through a CIBERSORT algorithm. Our results demonstrated that PIEZO1 expression levels are higher in hormone receptor (HR) negative than HR positive cohorts. High PIEZO1 expression is correlated with a significant decrease in survival in HR negative cohorts, suggesting that PIEZO1 could be utilized as a prognostic biomarker in HR negative breast cancer. GSEA showed that various signaling pathways associated with more invasive phenotypes and resistance to treatments, including epithelial-mesenchymal transition (EMT), hypoxia, and multiple signaling pathways, are enriched in high PIEZO1 HR negative tumors. Our results also demonstrated a decrease in CD8+ and CD4+ T cell infiltration in high PIEZO1 HR negative tumors. Further investigations are necessary to elucidate the mechanistic roles of PIEZO1 in HR negative breast cancer.

Breast cancer-related lymphedema (BCRL) affects approximately 20% of women after breast cancer therapy. Advances in treatment have increased life expectancy, thus the prevalence of BCRL will continue to rise with the number of cancer survivors. Hence the need to develop strategies to prevent this condition. We provide a systematic review of the literature on primary prevention of BCRL by prophylactic lymphatic surgery (PLS). Between June and August 2022, we conducted a search of PubMed, Google Scholar and Cochrane. In the end a total of eighteen papers were selected. The eleven studies without a control group reported only 15 of 342 patients who developed lymphedema at least six months after PLS (4.59%). The seven studies with a control group included 569 patients, 328 cases and 241 controls. Among the cases, 36 (10%) developed lymphedema. In contrast, the incidence of lymphedema in controls was 40% (98 of 241 patients). Formulation of definite recommendations in favour of PLS is hindered by low-quality studies. There is no consensus on which technique should be preferred, nor on whether adjuvant radiotherapy might affect the efficacy of PLS. Randomized controlled trials are mandatory to conceive evidence-based recommendations.

Skin cancer is a global health concern with increasing prevalence, necessitating effective early detection and classification systems. Transfer learning has emerged as a powerful tool in this domain, enhancing diagnostic accuracy. Attention mechanisms, which selectively focus on pertinent image features, play a pivotal role in transfer learning. While previous studies have highlighted their effectiveness, their applicability across different models and datasets remains understudied. This empirical study explores the impact of various attention mechanisms on the performance of transfer learning models for skin cancer detection and classification. Using five transfer learning models (DenseNet121, InceptionV3, MobileNet, VGG16, and Xception) and six attention mechanisms (Channel Attention, Global Context Attention, Guided Attention, Nonlocal Attention, Positional Attention, and Spatial Attention), we conducted 105 experiments across three datasets. Traditional metrics (accuracy, precision, recall, and f1-score) were employed for empirical validation. The results reveal a nuanced relationship between attention mechanisms, transfer learning models, and datasets. Overall, attention mechanisms exhibit the potential to enhance skin cancer classification. Spatial and channel attention mechanisms consistently outperform others, offering simplicity and effectiveness. Model-specific selection of attention mechanisms is crucial, with a trade-off between model complexity and performance evident. This study provides insights into developing efficient skin cancer classification models utilizing attention mechanisms.

Emerging research has revealed a complex bidirectional interaction between the gut microbiome and cannabis. Preclinical studies have demonstrated that the gut microbiota can significantly influence the pharmacological effects of cannabinoids. One notable finding is the ability of the gut microbiota to metabolise cannabinoids, including Δ^9-tetrahydrocannabinol (THC). This metabolic transformation can alter the potency and duration of cannabinoid effects, potentially impacting their efficacy in cancer treatment. Additionally, the capacity of gut microbiota to activate cannabinoid receptors through the production of secondary bile acids underscores its role in directly influencing the pharmacological activity of cannabinoids. While the literature reveals promising avenues for leveraging the gut microbiome-cannabis axis in cancer therapy, several critical considerations must be accounted for. Firstly, the variability in gut microbiota composition among individuals presents a challenge in developing universal treatment strategies. The diversity in gut microbiota may lead to variations in cannabinoid metabolism and treatment responses, emphasising the need for personalised medicine approaches. The growing interest in understanding how the gut microbiome and cannabis may impact cancer has created a demand for up-to-date, comprehensive reviews to inform researchers and healthcare practitioners. This review provides a timely and invaluable resource by synthesizing the most recent research findings and spotlighting emerging trends. A thorough examination of the literature on the interplay between the gut microbiome and cannabis, specifically focusing on their potential implications for cancer, is presented in this review to devise innovative and effective therapeutic strategies for managing cancer.

Background: Real-world data (RWD) related to the health status and care of cancer patients reflect the ongoing medical practice, and their analysis yields essential real-world evidence. Advanced information technologies are vital for their collection, qualification, and reuse in research projects. Methods: UNICANCER, the French federation of comprehensive cancer centres, has innovated a unique research network : Consore. This potent federated tool enables the analysis of data from millions of cancer patients across eleven French hospitals. Results: Currently operational within eleven French cancer centres, Consore employs natural language processing to structure the therapeutic management data of approximately 1.3 million cancer patients. This data originates from their electronic medical records, encompassing about 65 millions of medical records. Thanks to the structured data, which is harmonized within a common data model, and its federated search tool, Consore can create patient cohorts based on patient or tumor characteristics, and treatment modalities. This ability to derive larger cohorts is particularly attractive when studying rare cancers. Conclusions: Consore serves as a tremendous data mining instrument that propels French cancer centres into the big data era. With its federated technical architecture and unique shared data model, Consore facilitates compliance to regulations and acceleration of cancer research projects.

Human keratinocytes and melanoma can stick together to form clusters after eight days in co-culture. As in dynamic system concepts, one can consider cluster formation as the system attractor, cell seeding as the initial condition, and density change over time as a path within the basin of attraction. Herein, Cellular Automata, which is a class of Agent-Based Models, and Boolean Networks are discrete modeling methods used in population dynamics such that running the dynamics of cellular automata backward reveals an underlying network in terms of basin of attraction, also known as global dynamics. Thus, we hypothesize that one can estimate the local dynamic of an agent-based model from the basin of attraction of a boolean network. Here, we propose an approach to estimating these agent-based model rules, which consists of comparing the density states within each state transition and reaching a consensus among state transitions belonging to a basin of attraction of a boolean network. The objectives of this study are: (1) to infer a boolean network from the co-culture growth curve; (2) to estimate the rules of agent-based models; and (3) to implement spatial dynamics simulations. The binarization of the growth curve shows high population density after four days; the estimated agent-based model rules were compatible with cell proliferation and migration in agreement with literature, so we had to propose individual rules for survival and death. Spatial dynamics shows that (1) keratinocytes exhibit a higher density in neighborhoods where melanoma is present; (2) the chance of keratinocyte migration increases until the fourth day, then decreases, and the probability of survival increases substantially after four days; and (3) cells with low proliferation capacity die and free space for those with high ones. Our approach suggests that the attractor state of cell co-culture is induced mainly by an increase in keratinocyte migration and survival. Our approach has the potential to offer valuable clues about microenvironmental interactions or configurations that drive population dynamics.

This research paper presents a deep learning approach to early detection of skin cancer using image augmentation techniques. The authors propose a two-stage image augmentation technique that involves the use of geometric augmentation and generative adversarial network (GAN) to classify skin lesions as either benign or malignant. This research utilized the public HAM10000 dataset to test the proposed model. Several pre-trained models of CNN were employed, namely Xception, Inceptionv3, Resnet152v2, EfficientnetB7, InceptionresnetV2, and VGG19. Our approach achieved accuracy, precision, recall, and F1-score of 96.90%, 97.07%, 96.87%, 96.97%, respectively, which is higher than the performance achieved by other state-of-the-art methods. The paper also discusses the use of SHapley Additive exPlanations (SHAP), an interpretable technique for skin cancer diagnosis, which can help clinicians understand the reasoning behind the diagnosis and improve trust in the system. Overall, the proposed method presents a promising approach to automated skin cancer detection that could improve patient outcomes and reduce healthcare costs.

Background: The effect of rice bran arabinoxylan compound (RBAC), a plant-based immunomodulator, on the quality of life (QoL) in cancer patients and underlying physiological pathways remains unclear. Trial design: The RBAC-QoL study is a double-blind, randomised, controlled pilot feasibility study. The aim is to determine RBAC’s effects on QoL and the associated action mechanisms. Primary outcomes are the EORTC QLQ-C30 functional, symptom, and global QoL scores with inflammatory, nutritional, and cytokine parameters as secondary and exploratory outcomes. Methods: Recruitment targets adults diagnosed with solid organ tumours (≥ stage II) undergoing active treatment in several outpatient centres in New South Wales, Australia. Interventions are RBAC or matched placebo at 3g/day for 24 weeks allocated through stratified randomisation with participants, oncologists, and data collectors blinded. Data is collected from five study visits six weeks apart. The trial is ongoing. An interim intention-to-treat analysis was performed using repeated measure ANOVA with pairwise comparisons where statistical significance is observed and adjusted with covariates. Results: Global QoL scores from currently available data (n = 16; RBAC = 7, placebo = 9) were statistically different between groups (F[1,8] = 8.6, p = 0.019, eta2[g] = 0.267). Pairwise comparisons found significant differences at week 6 (p = 0.032, Cohen’s d = 1.454) and marginally at week 12 (p = 0.069, d = 1.427). Age-adjusted analysis showed a continuous upward trend in QoL improvement over time with RBAC, while the placebo group did not deviate from baseline QoL. Significant elevations of serum white blood cell count (week 18) and total protein (weeks 12 and 18) were detected in the RBAC group compared to placebo. The total protein levels correlated highly with white blood cell count (Pearson’s r = 0.539, p < 0.001) and moderately with the global QoL scores (r = 0.338, p = 0.01). No intervention-related adverse events were reported in both groups. Conclusions: RBAC improves QoL beyond placebo during active cancer treatment, possibly through the immuno-nutritional pathway. These findings are preliminary but valuable for future research. Funding and registration: Daiwa Pharmaceutical Co., Ltd, Japan; BioMedica Nutraceuticals Pty Ltd., Australia. ANZCTR Reg No: ACTRN12619000562178p.

Background: Cervical cancer prevention in regions with limited access to screening and HPV vaccination necessitates innovative approaches. This study explored the potential of a test-and-treat strategy using mRNA HPV tests to impact cervical cancer prevention in a high-prevalence HIV population. Methods: A cervical screening study was conducted at three South African hospitals involving 710 under-screened, non-pregnant women (25 to 65 years) without known cervical diseases. Cytology, HPV testing, colposcopy, and biopsies were performed concurrently. Histopathologists determined final histological diagnoses based on biopsy and LLETZ histology. mRNA-HPV-genotyping for 3 (16, 18, 45) to 8 (16, 18, 31, 33, 35, 45, 52, 58) high-risk types was performed on leftover liquid-based cytology material. The preventive potential of the test-and-treat approach was estimated based on published data, reporting the causative HPV types in cervical cancer tissue from South African women. Treatment was provided as needed. Results: HPV positivity rate more than doubled from 3-type (15.2%; 95% CI: 12.6-17.8) to 8-type mRNA (31.5%; 95% CI: 28.8-34.9) combinations, significantly higher among HIV-positive women. CIN3+ prevalence among HIV-positive women (26.4%) was double that of HIV-negative women (12.9%) (p&lt;0.01). The 6-type combination showed the best balance of sensitivity, specificity and treatment group size, and effectiveness to prevent cervical cancer. A 4-type combination (16, 18, 35, 45) could potentially prevent 77.6% (95% CI: 71.2-84.0) of cervical cancer burden by treating 20% and detecting 41.1% of CIN3 cases in the study group. Similarly, a 6-type combination (16, 18, 31, 33, 35, 45), treating 25% and including 62% of CIN3 cases, might prevent 85% of cervical cancer cases (95% CI: 79.6-90.6) among HIV-positive and negative women. Conclusion: Employing mRNA HPV tests within a test-and-treat approach holds huge promise for targeted cervical cancer prevention in under-screened populations. Testing for mRNA of the 6 highest-risk HPV types in this population and treating them all is projected to effectively prevent progression from CIN3 to invasive cervical cancer while reducing overtreatment in resource-constrained settings.

Cancer is the second major cause of disease-related dead worldwide, and its accurate early diagnosis and therapeutic intervention are fundamental for saving the patient’s life. Cancer, as a complex and heterogeneous disorder, results from disruption and alteration of a wide variety of biological entities, including genes, proteins, mRNAs, miRNAs, and metabolites that eventually emerge as clinical symptoms. Traditionally, diagnosis is based on clinical examination, blood tests for biomarkers, histopathology of biopsy, and imaging (MRI, CT, PET, US). Additionally, omics biotechnologies help to further characterize the genome, metabolome, microbiome traits of the patient that could have an impact on the prognosis and patient’s response to the therapy. The integration of all these data relies on gathering of several experts and may require considerable time, and, unfortunately, it is not without the risk of error in the interpretation and therefore in the decision. Systems biology algorithms exploit Artificial Intelligence (AI) combined with omics technologies to perform a rapid and accurate analysis and integration of patient’s big data and support the physician in making diagnosis and tailoring the most appropriate therapeutic intervention. However, AI is not free from possible diagnostic and prognostic errors in the interpretation of images or biochemical-clinical data. Here, we first describe the methods used by systems biology for combining AI with omics and then discuss the potential, challenges, limitations, and critical issues in using AI in cancer research.

Breast cancer and cardiovascular diseases (CVD) represent significant global health challenges, with CVD being the leading cause of mortality and breast cancer showing a complex pattern of incidence and mortality. We explore the intricate interplay between these two seemingly distinct medical conditions, shedding light on their shared risk factors and potential pathophysiological connections. A specific connection between hypertension (HTN), atrial fibrillation (AF), myocardial infarction (MI), and breast cancer was evaluated. HTN is explored in detail, emphasizing the role of aging, menopause, insulin resistance, and obesity as common factors linking HTN and breast cancer. Moreover, an attempt is made to identify the potential impact of antihypertensive medications and highlight the increased risk of breast cancer among those women, with a focus on potential mechanisms. A summary of key findings underscores the need for a multisystemic approach to understanding the relationship between CVD and breast cancer is also explored with a highlight for all the gaps in current research, such as the lack of clinical observational data on MI and breast cancer in humans and the need for studies specifically designed for breast cancer. This paper concludes that there should be a focus on potential clinical applications of further investigation in this field, including personalized prevention and screening strategies for women at risk. Overall, the authors attempt to provide a comprehensive overview of the intricate connections between breast cancer and cardiovascular diseases, emphasizing the importance of further research in this evolving field of cardio-oncology.

Over a century ago, low-dose-rate (LDR) brachytherapy was introduced to treat prostate cancer (PCa). Since then, it has been widely applied worldwide, including in East Asia. LDR brachythera-py has been performed in 88 institutes in Japan. Beneficial clinical outcomes of LDR brachytherapy for intermediate-to-high-risk PCa have been demonstrated in large clinical trials. These clinical outcomes were achieved through advances in methods, such as urological precise needle puncture and seed placement, and the quantitative decision-making regarding radiological parameters by radiation oncologists. Combined use of LDR brachytherapy with other therapeutical modalities, such as external beam radiation and androgen deprivation therapy, for clinical risk classification of PCa has led to better anticancer treatment efficacy. In this study, we summarized basic LDR brachytherapy findings that should remain unchanged and be passed down in urology depart-ments. We also discussed the applications of LDR brachytherapy for PCa in various clinical settings, including focal and salvage therapies. In addition, we highlighted technologies associated with brachytherapy that are under development.

Stereotactic body radiation therapy (SBRT) is a precise and conformal radiation therapy (RT) that aims to deliver a high dose of radiation to the tumor with sparing surrounding normal tissue, making it an attractive option for head and neck cancer (HNC) patients who are not suitable for traditional long course of RT with comprehensive RT target volume. Definitive SBRT for HNC has been investigated in different settings, including early stage glottis cancer, and as alternative to brachytherapy boost after external beam RT. It also used as a primary treatment option for elderly or medically unfit patients. More recently, SBRT combination with immunotherapy in the neoadjuvant setting for HNC showed promising results. Salvage or adjuvant SBRT for HNC can be used in appropriately selected cases. Future studies are warranted to determine the optimum dose and fractionation schedules in any of these indications.

Background: Pancreatic cancer (PC) is a disease with poor prognosis and survival rate. There is a pertinent need to identify the risk factors of this disease. The purpose of this study is to identify a subset of factors (a.k.a. features) as predictors of PC from the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer dataset consisting of responses to 65 questions about demographics, cancer and health history, medication usage, and smoking habits from 154,897 participants. Method: There are two challenges to selecting the subset of features that predict PC with highest probability: the problem is computationally intractable, and the PLCO dataset is highly imbalanced. We use an innovative method to use the dataset in a balanced way, without involving up- or down-sampling. We use nine feature selection methods to select the optimal subset of features from the preprocessed and balanced dataset. Results: Our preprocessed dataset consists of 32 risk factors (8 demographics, 5 cancer history, 13 health history, 2 medication usage, 4 smoking habits). Risk factors belonging to cancer and health history, followed by smoking habits, were consistently chosen by the feature selection methods. We also discuss findings in the medical sciences literature that corroborate our findings. Conclusions: The study found that risk factors belonging to cancer and health history are the most prominent ones for PC. In particular, previously diagnosed with PC is chosen as the most prominent risk factor by majority of methods. While most of our findings are consistent with the literature, some of our findings shed light on novel factors that may not have received their due attention by the research community.

Precision medicine approaches often relies on complex and integrative analysis of multiple biomarkers from “omics” data to generate insights that can help either diagnostics, prognostics or therapeutical decisions. Such insights are often made using Machine learning (ML) models that make sample classification for a particular phenotype (yes/no). Building such models is a challenge and time-consuming, requiring advanced coding skills and mathematical modelling expertise. Artificial intelligence (AI) is a methodological solution that has the potential to facilitate, optimize and scale model development. In this work, we developed an AI-based, user-friendly and code-free platform (https://digitalphenomics.com) that fully automates the development of predictive models from quantitative “omics” data. Here, we show the application of this tool with the development of cancer survival prognostics models using real-life data from breast, lung and renal cancer transcriptomes. We report and compare their sensitivity, specificity, accuracy and Receiver Operating Characteristic (ROC) curve Area Under the Curve (AUC). Further, we report the associated sets of genes (biomarkers) and their expression pattern that are predictive of cancer survival. Moreover, we made our models available as online tools to generate prognostic predictions based on the gene expression of the biomarkers. In conclusion, we demonstrated that our tool is a robust user-friendly solution to develop bespoke predictive tools from “omics” data which facilitate precision medicine introduction to the point-of-care.

Abstract: A punicalagin is a metabolic product of pomegranate fruits and peeled. We have compiled the recent literature review from different sources. The extract of pomegranate fruits and peel has been reported for health-beneficial properties in inflammation-associated chronic disease and the regulatory role in NF-KB, MAPK, IL-6/JAK/STAT3, and PI3K/AKT/mTOR signaling pathway. Punicalagin is an ellagitannin found in the peel of pomegranate (Punica granatum). It is a polyphenol with proven biological/pharmacological activities like antioxidant, hepatoprotective, an-ti-atherosclerotic, anti-cancer, anti-neurological, anti-diabetic, and anti-digestive. The extracts have a rich source of hydrolyzable tannin and anthocyanin exhibiting strong anti-neoplastic properties. Anti-cancer activities of pomegranate with reference to modulated signaling pathways in various cancer diseases have been recently reported. The punicalagin-induced redirection of the signal-transduction pathway from survival and proliferation into the cell cycle by arrested the living cells. Apoptosis senescence and autophagy and thus compromising neoplastic progression are delineated. This review is based mainly on data obtained from various sources including the in-vitro cell line model and its activities that are concerned with the effect of punicalagin activities on various cell types.

Background: A prognostic index validated for the outcomes of advanced high-grade serous ovarian cancer (HGSOC) patients with neoadjuvant chemotherapy (NACT) is still lacking. We therefore developed an ovarian neoadjuvant chemotherapy prognostic index (ONCPI) to enhance predictive accuracy. Methods: We analyzed clinicopathologic feature of advanced HGSOC patients receiving platinum-based NACT. Blood inflammatory composite markers were calculated and binary-transformed by optimal cutoffs. The omental hematoxylin and eosin (H&E) stained slides were selected for the assessment of chemotherapy response score (CRS). Logistic regression analyses and Cox proportional hazard regression model were utilized to develop a prognostic index. Results: Multivariate analysis showed that CRS and neutrophils-to-lymphocyte ratio (NLR) are independent risk factors for platinum-chemotherapy response. Meanwhile, Kaplan–Meier and Cox regression analysis revealed that CRS score was significantly correlated with PFS and OS, and NLR-high patients was associated with poor OS. We further developed an ONCPI model based on the CRS score and NLR level. Survival analysis suggested that patients with score 0 and 1 of ONCPI were significantly associated with improved PFS and OS. Conclusions: The ONCPI score emerges as a significant prognostic marker for predicting NACT outcomes in advanced HGSOC patients. Its integration into clinical practice and risk-stratified trial design is conceivable.

Preferentially expressed Antigen in Melanoma (PRAME) is a cancer testis antigen (CTA) that is selectively expressed in certain somatic tissues, predominantly in the testis and is overexpressed in various cancers. PRAME family proteins are leucine rich repeat proteins, that are localized in the nucleus and cytoplasm, with multifaceted roles in immunity, during gametogenesis and in the overall reproduction process. It is a widely studied CTA and has been associated with the prognosis and therapeutic outcome in patients with epithelial and non-epithelial tumors. PRAME has also been studied extensively as a therapeutic target. Moreover, it has been found to play a role in most of the well-known cancer hallmarks. Interestingly, the role of PRAME in tumorigenesis is paradoxical. Over the last decade, PRAME has garnered substantial interest as a target for immunotherapy. There are multiple clinical trials and pre-clinical studies targeting PRAME alone or in combination with other tumor antigens. This review article is an attempt to update our knowledge and understanding of the context-dependent oncogenic functions of PRAME in various carcinomas, and the current immunotherapeutic strategies, challenges, and perspectives on developing newer strategies to target PRAME for a better outcome.

BMAP-27 peptide known to exert cytotoxic effects against cancer cells by membrane integrity disruption. In the current investigation, we aimed to study the role of the BMAP-27 peptide in reducing colon cancer cell proliferation and inducing apoptosis. This study utilized both primary and metastatic colon cancer cell lines (SW480 and SW620). Proliferation was measured using CCK-8, and cellular damage was analyzed by lactate dehydrogenase assay. The study assessed apoptosis, cell cycle, and proliferation by measuring the expression of CASPASE3, BAX, BCL-2, TP53, CDK-6, PCNA, Wnt11, AXIN1, and CTNNB1. Additionally, in-silico studies were conducted to determine the binding affinities of BMAP-27 with APC and β-catenin proteins. BMAP-27 peptide reduced colon cancer cell proliferation, upregulated CASPASE3, BAX, TP53, AXIN1 expression, and downregulated BCL-2, CDK-6, PCNA, WNT11, CTNNB1 in both colon cancer cell lines, however, demonstrated higher activity in primary than metastatic colon cancer cells. The molecular dynamic simulation revealed substantial binding affinity of the peptide to adenomatous polyposis coli and β-catenin proteins.BMAP-27 peptide effectively inhibited the proliferation and enhanced apoptosis in the primary than in metastatic colon cancer cells. In-silico findings suggest that BMAP-27 exhibits a strong binding affinity with APC and β-catenin, highlighting its potential role as an anti-colon cancer agent.

Hydatid cyst fluid is a complex biological substance consisting primarily of water, proteins, lipids, carbohydrates, salts, enzymes, hormones, growth factors, immune modulators, and other bioactive molecules. Antigens, including antigen B (AgB) and antigen 5 family members (Ag5), have been identified in hydatid cyst fluid and have been shown to have the ability to inhibit cancer progression. The exact mechanisms by which these components exert inhibitory effects on cancer progression are not fully understood, but it is believed that they may influence multiple signaling pathways involved in cell proliferation, survival, angiogenesis, and metastasis. In vitro studies have demonstrated that treatment with hydatid cyst fluid or specific antigens can inhibit cell growth, induce apoptosis, and suppress the migration of cancer cells. Animal model studies have also demonstrated significant inhibition of tumor growth, reduction in angiogenesis, and suppression of metastasis. Limited clinical studies have shown promising outcomes, including improved overall survival and reduced recurrence rates among breast cancer patients receiving AgB immunotherapy alongside standard treatment.

Persistent Organic Pollutants (POP) such as dichlorodimethyltrichloroethane (DDT) are present and ubiquitous in the environment due to their resilient nature. DDT is a prevalent endocrine disruptor still found in detectable amounts in organisms and the environment even after its use was banned in the 1970s. Studies show that exposure to DDT can cause adverse health effects in humans and animals, impairing fertility and increasing the risk of developing cancer. The aim of this work is to provide a comprehensive overview of the available literature on the effect of DDT and its metabolites on female reproductive tract, leading to infertility and cancer. Medline and Google Scholar were systematically searched to detect all relevant animal and human studies published in the last 20 years (January 2003 to February 2023) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. In total, 38 studies were included for qualitative synthesis. This systematic search and review indicated that exposure to DDT is associated with female reproductive health decline and that DDT acts as a sufficient carcinogen instigating reproductive cancers.

Papain-like lysosomal cysteine proteases include 11 human cysteine cathepsins which act as endopeptidases and/or exopeptidases. They are involved in numerous physiological and pathological processes. Among them, only cathepsins B, H, C, and X/Z exhibit exopeptidase activity. Their activities are tightly regulated in various ways to prevent potentially hazardous effects on the cell. In this review, we focus on the structural and functional aspects of these four cysteine cathepsins and their role in neurodegeneration and cancer. Neurodegenerative disorders of aging share an endolysosomal dysfunction and accumulation and spread of oligomeric forms of neurotoxic proteins. The accumulation of various protein aggregates activates the microglia, thus inducing the activation and release of cysteine cathepsins and proinflammatory cytokines, leading to neurodegeneration. In cancer, cysteine cathepsins participate in tumor progression and metastasis. Tumor–stromal crosstalk leads to activation of the stroma and overexpression and secretion of proteolytic enzymes, triggering extracellular matrix degradation and the release of soluble factors. Activated stromal cells (i.e., macrophages, fibroblasts, mast cells) secrete additional growth factors, cytokines, and chemokines that are responsible for the regulation of processes leading to tumor progression and metastasis. Therefore, a better understanding of the role of cysteine cathepsins in neurodegeneration and cancer could lead to novel targeted therapeutic approaches.

Background: Wilms' tumor (or nephroblastoma) is a malignant and solid neoplasm that derives from the primitive renal bud. It represents the most frequent primary tumor of the urogenital tract in childhood, and treatment consists of surgery and chemo-radiotherapy. However, concerning the quality of life, the new therapeutic frontier is exploring other safer and potentially more effective options, such as minimally invasive surgery and biological drugs. Method: Literature (Pubmed) from January 2013 to March 2023 was reviewed. Results: One hundred five articles were included in the review. Conclusion: In addition to the therapeutic strategies already identified, such as classic surgery and pharmacological therapies, recent studies focus attention on the new frontiers of minimally invasive surgery, such as diagnostics using biomarkers and immunotherapy, which could represent a new therapeutic option and possibly less risky than in the past, contributing in fact to the current knowledge of the scientific panorama in terms of "tumor microenvironment" and systemic implications deriving from oncological disease.

Colorectal cancer is a common disease, both in Chile and worldwide. The most widely used chemotherapy schemes are based on 5-fluorouracil (5FU) as the foundational drug. Genetic polymorphisms have emerged as potential predictive biomarkers of response to chemotherapy, but conclusive evidence is lacking. Additionally, the interplay between hereditary variations and acquired mutations in the EGFR pathway remains unknown. This study aimed to investigate the role of genetic variants associated with 5FU-based chemotherapy on therapeutic effectiveness, considering their interaction with the EGFR pathway mutations. In a retrospective cohort of 63 patients diagnosed with metastatic colorectal cancer, a multivariate analysis revealed that liver metastases, DPYD, ABCB1 and MTHFR polymorphisms are independent indicators of a poor prognostic, irrespective of EGFR pathway mutations. BRAF V600E wild-type status and high-risk drug-metabolism polymorphisms correlated with a poor prognosis in this Chilean cohort. Additionally, findings from the genomics of drug sensitivity (GDSC) project demonstrated that cell lines with wild-type BRAF have higher IC50 values for 5-FU compared to BRAF-mutated cell lines. In conclusion, the genetic polymorphisms DPYD rs1801265, ABCB1 rs1045642 and MTHFR rs180113 may serve as useful biomarkers for predicting a poor prognosis in patients undergoing 5-fluorouracil chemotherapy, regardless of EGFR pathway mutations.

Enzalutamide is a drug used to treat PC. Docetaxel is a drug for chemotherapy for different cancers including prostate cancer (PC). The effectiveness of these drugs in treating castration-resistant prostate cancer (CRPC) is not consistent and thus, CRPC is still an incurable disease. Recent evidence showed that the bio-inhibitor of FABP5, dmrFABP5, suppressed the tumorigenicity and metastasis of the CRPC cells. In this work, we studied the possible synergic effect of dmrFABP5 combined with either Enzalutamide or Docetaxel on suppressing tumorigenicity of the PC cells. A highly significant synergic effect was observed when dmrFABP5 was used in combination with Enzalutamide on the androgen-responsive PC cells 22RV1. A highly significant synergic effect was also observed when dmrFABP5 was combined with Docetaxel on 22RV1 cells and on the highly malignant, androgen-receptor (AR)-negative DU145 cells. These combined applications exhibited a highly significant inhibitory action on the viability, migration, invasion and colony formation abilities of both 22RV1and DU145 cells. However, dmrFABP5 did not produce any suppression effect when used on FABP5-negative cell line LNCaP, although Enzalutamide can significantly suppress LNCaP cells as a single agent. Further investigations suggested that these synergistic effects were produced by interrupting the FABP5-related signal transduction pathway in PC cells.

HER2-low and ultra-low breast cancer (BC) have been recently proposed as new subcategories of HER2 BC, re-considering the immunohistochemical negative score of 0, 1+ or score of 2+/in situ hybridization (ISH) negative phenotype. In the present review we have outlined the needed criteria to exactly distinguish HER2 low and ultra-low BC. Recent clinical trials have demonstrated significant clinical benefits of novel HER2 directing antibody-drug conjugates (ADCs) in treating these group sof tumors. In particular, Trastuzumab-deruxtecan (T-Dxd), a HER2-directing ADC has been recently approved by the U.S. Food and Drug Administration as the first targeted therapy to treat HER2-low BC. Furthermore, ongoing trials, such as the DESTINY-Breast06, are currently evaluating ADCs in patients with HER2-ultra low BC. Finally we hope that new guidelines may help to codify HER2 low and ultra-low BC, increasing our knowledge of tumor biology and improving a targetable new therapeutical treatment.

Esophageal cancer is a formidable challenge in the realm of cancer treatment. Conventional methods such as surgery, chemotherapy, and immunotherapy have demonstrated limited success rates in managing this disease. In response, targeted drug therapies have emerged as a promising strategy to improve outcomes for patients. These therapies aim to disrupt specific pathways involved in the growth and development of esophageal cancer cells. This review explores various drugs used to target specific pathways, including cetuximab and monoclonal antibodies (gefitinib) that target the epidermal growth factor receptor (EGFR), trastuzumab that targets human epidermal growth factor receptor 2 (HER-2), drugs targeting the vascular endothelial growth factor receptor (VEGFR), mTOR inhibitors, and cMET inhibitors. Additionally, the article discusses the impact of drug resistance on the effectiveness of these therapies, highlighting factors such as cancer stem cells, cancer-associated fibroblasts, immune-inflammatory cells, cytokines, hypoxia, and growth factors. While drug targeting approaches do not provide a complete cure for esophageal cancer due to drug resistance and associated side effects, they offer potential for improving patient survival rates.

.Purpose: This paper presents a comparative analysis of state-of-the-art DIR algorithms in the context of head and neck squamous cell carcinoma (HNSCC) radiation therapy. Materials and Methods: We used a dataset of head and neck cancer patients within the Cancer Image Archive, which includes 31 patients with 3D CT image data from pre-treatment, mid-treatment, and post-treatment stages of radiotherapy. We applied DIR algorithms to two datasets, one for pre-treatment to mid-treatment registration and another for mid-treatment to post-treatment registration, by aligning one CT image to another CT image. To quantitatively analyze the patient data, we focused on the spinal cord, optic nerve, brain stem, cochlea, and PTV as the OAR datasets. To verify the DIR algorithm, we used two non-learning-based methods, SyN and NiftyReg, as well as three deep learning-based methods, Voxelmorph, Cyclemorph, and Transmorph. We trained a deep learning model by adjusting the ratio of the training dataset, validation dataset, and test dataset to 7:1:2. Results: The average DSCs of SyN and NiftyReg, the non-learning-based methods, were 0.74±0.06 and 0.70±0.12, respectively. The deep learning-based methods, Voxelmorph, Cyclemorph, and Transmorph, had average DSCs of 0.72±0.08, 0.68±0.11, and 0.69±0.13, respectively. The deep learning DIR algorithm produced transformed outputs of OAR/PTV in a shorter time than other models, including commercial and conventional mathematical algorithms (At Inference(sec/images), Voxelmorph: 0.36, Cyclemorph: 0.3, Transmorph: 5.1, SyN: 140, NiftyReg: 40.2). Conclusions: In conclusion, our study provides a comprehensive comparison of commercial DIR algorithms with traditional and deep learning-based DIR methods. Our results demonstrate that commercial DIR algorithms outperform traditional DIR methods in terms of accuracy and efficiency. However, we also show that deep learning-based DIR methods have the potential to achieve similar performance to commercial algorithms with proper training and optimization. Our findings suggest that both commercial and deep learning-based DIR methods have their respective advantages and limitations, and the choice of method should depend on the specific requirements of the clinical application. Overall, our study contributes to ongoing efforts to improve the accuracy and efficiency of DIR methods for better patient outcomes.

Oral mucosa is a key player in the cancer patient and during cancer treatment. The increasing prevalence of cancer and cancer therapy associated side effects are behind the major role that oral mucosa plays in the oncological patient. Oral mucositis is a debilitating severe complication caused by early toxicity of chemo and/or radiotherapy that can restrict treatment outcome possibilities, even challenging patient’s survival. It has been referred to as the most feared cancer treatment complication. Predictive variables as to who and to what extent will be affected are still unclear. Additionally, oral mucositis is one of the sources of the increasing economic burden of cancer, not only for patients and their families but also for institutions and governments. All efforts should be implemented in the search for new approaches to minimize the apparently ineluctable outburst of oral mucositis along the cancer treatment. New perspectives derived from different approaches in explaining the interrelation between oral mucositis and oral microbiome or the similarities with genitourinary mucosa may help elucidate the biomolecular pathways and mechanisms behind oral mucosa cancer-therapy related toxicity and what is more important its management in order to minimize treatment side effects and to provide enhanced cancer support.

APE1 is an essential endodeoxyribonuclease of the base excision repair pathway that maintains genome stability. It was identified as a pivotal factor favoring tumor progression and chemo-resistance through the control of gene expression by a redox-based mechanism. APE1 is overex-pressed and serum-secreted in different cancers, representing a prognostic and predictive factor, and a promising non-invasive biomarker. Strategies directly targeting APE1 funtions led to the identification of inhibitors showing a potential therapeutic value, which some of them are cur-rently in clinical trials. Interestingly, evidence indicates novel roles of APE1 in RNA metabolism still not fully understood, including its activity in processing damaged RNA in chemoresistant phenotypes, regulating oncomiRs maturation, and oxidized-RNA decay. Recent data point out a control role of APE1 in the expression and sorting of oncomiRs, within secreted extracellular vesicles (EVs). This review is focused on giving a portrait of the pros and cons of the last two decades of research aiming at the identification of inhibitors of the redox or the DNA-repair functions of APE1 for the definition of novel targeted therapies for cancer. We will discuss the new perspectives in cancer therapy coming from the unexpected finding of the APE1 role in miRNA processing for personalized therapy.

Breast cancer is a complex and heterogeneous disease that displays diverse molecular subtypes and clinical outcomes. Although it is known that the location of tumors can affect their biological behavior, the underlying mechanisms are not fully understood. In our previous study, we found a differential methylation profile and membrane potential between left (L) and right (R)-sided breast tumors. In this current study, we aimed to identify the ion channels responsible for this phenomenon and determine any associated phenotypic features. To achieve this, experiments were conducted in mammary tumors in mice, human patient samples, and with data from public datasets. The results revealed that L-sided tumors have a more depolarized state than R-ones. We identified a 6-ion channel-gene signature (CACNA1C, CACNA2D2, CACNB2, KCNJ11, SCN3A, and SCN3B) associated with side: L-tumors exhibit lower expression levels than R-ones. Additionally, in silico analyses show that the signature correlates inversely with DNA methylation writers and with key biological processes involved in cancer progression, such as proliferation and stemness. The signature also correlates inversely with patients’ survival rates. In an in vivo mouse model, we confirmed that KI67 and CD44 markers were increased in L-sided tumors and similar tendency for KI67 was found in patient L-tumors. Overall, this study provides new insights into the potential impact of anatomical location on breast cancer biology and highlights the need for further investigation into possible differential treatment options.

Recent data suggest that K-Ras4B (hereafter K-Ras) can drive cancer cell stemness via calmodulin (CaM)-dependent, non-canonical Wnt-signalling. Here we examined whether another Ca2+-binding protein, the CaM-related centrin1, binds to K-Ras and could mediate some K-Ras functions that were previously ascribed to CaM. While CaM and centrin1 appear to distinguish between peptides that were derived from their classical targets, they both bind to K-Ras in cells. Cellular BRET-data suggest that CaM engages more with K-Ras than centrin1 and that the interaction with the C-terminal membrane anchor of K-Ras is sufficient for this. Surprisingly, binding of neither K-Ras nor its membrane anchor alone to CaM or centrin1 is sensitive to inhibition of prenylation. In support of an involvement of the G-domain of K-Ras in cellular complexes with these Ca2+-binding proteins, we find that oncogenic K-RasG12V displays increased engagement with both CaM and centrin1. This is abrogated by addition of the D38A effector-site mutation, suggesting that K-RasG12V is held together with CaM or centrin1 in complexes with effectors. When treated with CaM-inhibitors the BRET-interaction of K-RasG12V with centrin1 was also disrupted in the low micromolar range, comparable to that with CaM. While CaM predominates in regulating functional membrane anchorage of K-Ras, it has a very similar co-distribution with centrin1 on mitotic organelles. Given these results, a significant overlap of the CaM- and centrin1-dependent functions of K-Ras is suggested.

The paradigm of drug delivery via nano- and microcarriers is one of the leading ideas that enable overcoming the limitations of traditional chemotherapy. The trend toward more complex drug carriers capable of multifunctionality is observed in the literature. To date, prospects of stimuli-responsive systems to control the cargo release in the lesion nidus are widely accepted. Both endogenous and exogenous stimuli are employed for this purpose, however, endogenous pH is one of the most common triggers. Unfortunately, scientists face difficulties in the implementation of this idea since a range of biological barriers, drug bioavailability issues, and challenges in the synthesis of carriers with required properties have arisen. Here, we discuss fundamental strategies of pH-responsive drug delivery as well as limits in its application and reveal the main problems, weak sides, and reasons for poor clinical results. Also, we have made an attempt to formulate the profiles of "ideal" drug carrier in the frame of different strategies and considered recently published studies through the lens of these profiles. This approach enables the identification of current trends and promising vectors in the development of pH-responsive drug delivery systems, as well as challenges to be resolved in the next generation of carriers.

Cervical cancer is a significant global health concern, with human papillomavirus (HPV) infection being a crucial risk factor. Photodynamic therapy (PDT) is an attractive, minimally invasive treatment for HPV-related cervical lesions, which uses photosensitizers and light to selectively de-stroy abnormal cells. We aim to provide an overview of the various sorts of dyes that are utilized in PDT for decreasing the incidence and mortality of cervical cancer. Besides, the article discusses ongoing clinical trials for PDT in low-grade squamous intraepithelial neoplasia (LSIL) and high-grade squamous intraepithelial lesions (HSIL), as well as preclinical approaches for PDT in cervical cancer using various dyes. Moreover, it highlights potential dyes for PDT, examine them in in-silico condition, their pros and cons and also the solutions for enhancing their anticancer com-patibility. We also display that PDT is a promising therapeutic strategy for the diagnosis and treatment of HPV-associated cervical lesions. Moreover, it shows that using different classes of dyes improves the anticancer effects of PDT. Finally, among all dyes which are used in PDT, Fullerene demonstrated high tendency to over expressed receptors in cervical cancer cells and seems to be a proper candidate for be used in PDT more than before, but further research is necessary to assess its long-term efficacy and safety.

Growing evidence indicates the involvement of a genetic component for CaP susceptibility and clinical severity. Somatic mutations of TP53 have been associated with 50% of diverse human cancers. Studies have also reported the role of germ line mutations and single nucleotide poly-morphisms (SNPs) of TP53 as possible risk factors for cancer development. In this single De-partment of Defense institutional retrospective study, we identified common SNPs in the TP53 gene in AA and CA men and performed association analyses for functional TP53 SNPs with clinico-pathological features of CaP. The CPDR Oncoarray database on blood derived genomic DNA from 321 men treated by radical prostatectomy at WRNMMC were used to examine clini-co-pathological associations with TP53 SNPs. The SNP genotyping analysis on the final cohort of 308 patients (212 AA; 95 CA) identified 74 SNPs in the TP53 gene region with a minor allele fre-quency (MAF) of at least 1%. Two SNPs were non-synonymous in the exonic region of TP53: rs1800371 (Pro47Ser) and rs1042522 (Arg72Pro). The Pro47Ser variant, had a minor allele frequency of 0.01 in AA, however, was not detected in CA. Arg72Pro was the most common SNP with a minor allele frequency of 0.50 (0.41 in AA; 0.68 in CA). Additionally, Arg72Pro was associated with time to biochemical recurrence (BCR) after statistical adjustment for patient age at diagnosis, self-reported race, and Gleason score (p= 0.046; HR = 1.52). The present study demonstrated ancestral differences in allele frequencies of TP53 Arg72Pro and Pro47Ser SNPs in AA and CA CaP, providing a valuable framework for the interrogating CaP disparity among AA and CA men.

Human Papillomavirus (HPV) self-sampling has the potential to increase cervical cancer screening (CCS) and reduce the cervical cancer burden in Medically Underserved Women (MUW). However, interventions promoting self-sampling are limited. We examined the effectiveness of an intervention study in increasing CCS among MUW. We conducted a quasi-experimental intervention study. Face-to-face verbal approach was to recruit MUW (n=85, mean age 48.57±11.02) living in a small city in the US. Behavioral intervention based on reframing, reprioritizing, and reforming (3R model) was used to educate the women about CCS in a group format. The women completed pre-and post-intervention assessments and followed-up interviews. The primary outcome was CCS uptake. Mixed methods analyses were conducted using a t-test for the primary outcome, PROCESS for mediation analysis, and NVivo for interview data. Majority of women (75%) completed self-testing. High-risk HPV prevalent among the women was 11%, and of those, 57% followed-up with physicians for care. We found that the significant increase in the women’s post-intervention screening behaviors was mediated by the increase in knowledge (Indirect Effect [IE] = .1314; 95% CI, .0104, .4079) and attitude (IE = .2167; 95% CI, .0291, .6050) scores, (p&lt;0.001). Interview analyses offered further explanations (see the explanations in parenthesis) why MUW found the intervention messages acceptable (encourages proactive behavior), feasible (simple and easy to understand), and appropriate (helpful and informative). Barriers including lack of trust and fear of results were identified. The findings suggest that an intervention that combines the 3R model and self-sampling may increase CCS among MUW.

In comparison to the general population, lung cancer patients are more likely to suffer from severe Coronavirus disease (COVID-19) and mortality associated with it. Considering this increased risk, and in order to prevent symptoms and severe disease, patients with lung cancer have been prioritized for COVID-19 vaccinations, primary and booster doses. Despite this, the pivotal clinical trials did not include these patients, which leaves open questions regarding vaccine efficacy and humoral immune response. This review outlines the findings of recent investigations into the humoral responses of lung cancer patients to COVID-19 vaccination, particularly the primary doses and first boost.

Background: Pathologic complete response (pCR) of breast cancer after neoadjuvant chemotherapy (NAC) is highly related to molecular subtypes. Patients who achieved tumor pCR after NAC have a better prognosis. However, despite of better prognosis, pCR patients have a potential for recurrence. There is little evidence of risk factors of recurrence in patients with pCR. We aim to analyze factors associated with tumor recurrence in patients who achieved pCR. Methods: This study retrospectively reviewed the data of patients diagnosed with breast cancer who achieved pCR after receiving NAC between January 2009 and December 2018 in Samsung Medical Center. pCR was defined as no residual invasive cancer in the breast and axillary nodes even if there is residual ductal carcinoma in situ (ypT0 or ypTis with ypN0). Breast cancers are classified into 4 subtypes based on hormone receptors (HR) and human epithelial growth factor receptor 2 (HER2) status. Patients who had bilateral breast cancer, inflammatory breast cancer, distant metastasis, unknown subtype, and histologically unique case were excluded from the study. Results: In total 483 patients were included in this study except for patients who corresponded to the exclusion criteria. The median follow-up duration was 59.0 months (range, 0.5-153.3 months). Breast cancer recurred in 4.1% of patients (20 of 483). There was a significant difference in clinical T (p = .004) and clinical N (p = .034) stage in the Kaplan-Meier curve for disease-free survival. Molecular subtypes (p = .573), Ki67 (p = 1.000), and breast surgery type (p = .574) were not associated with tumor recurrence in patients who achieved pCR after NAC. In the clinical T stage and clinical N stage, there was a significant difference between recurrence and no-recurrence groups (clinical T stage; p = .045, clinical N stage; p = .002). Univariable Cox regression revealed statistical significance in the clinical T stage (p = .049) and clinical N stage (p = .010), while multivariable Cox regression demonstrated non-significance in the clinical T stage (p = .320) and clinical N stage (p = .073). Conclusion: Results in this study showed that clinical T, clinical N stage, and molecular subtypes were not statistically significant predictors of recurrence in patients who achieved pCR after NAC. It is hypothesized that a multicenter-based study would lead to the identification of factors as predictors of recurrence after achieving pCR.

Accurate retroperitoneal lymph node metastasis (LNM) prediction in early-stage testicular germ cell tumours (TGCT) harbours the potential to significantly reduce over- or undertreatment and treatment-related morbidity in this group of young patients as an important survivorship imperative. We investigated the role of computed tomography (CT) radiomics models integrating clinical predictors for the individualized prediction of LNM in early-stage TGCT. Ninety-one patients with surgically proven testicular germ cell tumours and contrast-enhanced CT were included in this retrospective study. Dedicated radiomics software was used to segment 273 retroperitoneal lymph nodes and extract features. After feature selection, radiomics-based machine learning models were developed to predict LN metastasis. The robustness of the procedure was controlled by 10-fold cross-validation. Using multivariable logistic regression modelling, we developed three prediction models: A radiomics-only model, a clinical-only model and a combined radiomics-clinical model. The models' performance was evaluated using the area under the receiver operating characteristic curve (AUC). Finally, decision curve analysis was performed to estimate the clinical usefulness of the predictive model. The radiomics-only model for predicting lymph node metastasis reached a greater discrimination power than the clinical-only model, with an AUC of 0.84 (± 0.17; 95% CI ) vs 0.60 (± 0.22; 95% CI) in our study cohort. The combined model integrating clinical risk factors and selected radiomics features outperformed the clinical-only and the radiomics-only prediction models and showed good discrimination with an area under the curve of 0.94 ( ± 0.10; 95% CI). The decision curve analysis demonstrated the clinical usefulness of our proposed combined model. The presented combined CT-based radiomics-clinical model represents an exciting non-invasive prediction tool for individualized prediction of LN metastasis in testicular germ cell tumours. Multi-centre validation is required to generate high-quality evidence for its clinical application.

Polyacetylene phytochemicals are emerging as potentially responsible for the chemoprotective effects of consuming apiaceous vegetables. There is some evidence suggesting that polyacetylenes impact carcinogenesis by influencing a wide variety of signalling pathways, which are important in regulating inflammation, apoptosis, cell cycle regulation, etc. Studies have shown a correlation between human dietary intake of polyacetylene-rich vegetables with reduced risk of inflammation and cancer. Polyacetylene supplementation can influence cell growth, gene expression, and immunological responses, and reduce tumour number in rat and mouse models. Cancer chemoprevention by dietary polyacetylenes involves several mechanisms, including effects on inflammatory cytokines, the NF-κB pathway, antioxidant response elements, UPR pathway, growth factor signalling, cell cycle progression, and apoptosis. This review summarises the published research on falcarinol-type polyacetylene compounds and their mechanisms of action regarding cancer chemoprevention and treatment, and also identifies some gaps in our current understanding of the health benefits of these polyacetylenes.

Pancreatic cancer is projected to be the second leading cause of cancer-related death by 2030 in the US. The benefits of the most common systemic therapy for various pancreatic cancer have been masked by high drug toxicities, adverse reactions, and resistance. Using nanocarriers like liposomes to overcome these unwanted effects has become very popular. This study aimed to formulate 1,3-bis tetrahydrofuran-2yl-5FU (MFU)-loaded liposomal nanoparticles (Zhubech) and evaluate the stability, MFU release kinetics, in vitro and in vivo anticancer activities, and biodistribution. Particle size and zeta potential were determined using a particle size analyzer, while cellular uptake of rhodamine-entrapped liposomal nanoparticle (Rh0-LnP) was determined by confocal microscopy. Gadolinium hexanoate (Gd-Hex) was synthesized and entrapped into the liposomal nanoparticle (LnP) (Gd-Hex-LnP) as a model contrast agent, to evaluate gadolinium biodistribution and accumulation by LnP in vivo using inductively coupled plasma mass spec-trometry (ICP-MS). The mean hydrodynamic diameters of the blank LnP and Zhubech were 90.0 ± 0.65 nm and 124.9 ± 3.2 nm, respectively. The hydrodynamic diameter of Zhubech was found to be highly stable at 4o C and 25oC for 30 days in solution. In vitro drug release of MFU from Zhubech formulation exhibited the Higuchi model (R2 value = 0.95). Both Miapaca-2 and Panc-1 treated with Zhubech showed reduced viability, two- or four-fold lower than that of MFU-treated cells in 3D spheroids (IC50Zhubech = 3.4 ± 1.0μM vs IC50MFU = 6.8 ± 1.1μM) and organoids (IC50Zhubech = 9.8 ± 1.4μM vs IC50MFU = 42.3 ± 1.0μM) culture models. Confocal imaging confirmed high uptake of rhodamine-entrapped LnP by Panc-1 cells in a time-dependent manner. Tumor efficacy studies in PDX bearing mouse model revealed more than 9-fold decrease in mean tumor volumes in Zhu-bech treated (108 ± 13.5 mm3) compared to 5-FU treated (1,107 ± 116.2 mm3) animals respectively. This study demonstrates that Zhubech may be a potential candidate for delivering drugs for pancreatic cancer treatment.

Cervical cancer is mostly diagnosed cancer of women worldwide and the second most common cancer among middle-aged women in Bangladesh. Knowledge and perception of women are considered one of the major components of prevention strategy. We carried out this survey to assess the existing knowledge level of students and their perception to the role of vaccination in preventing cervical cancer. The participants were female undergraduate students studying Public Health in a university in Chattogram city of Bangladesh. A total of 275 female students were interviewed through prescribed questionnaire possessing questions on basic information of cervical cancer, its causal agent, risk factors, prevention methods, and vaccination. We marked the responses of participants with zero for wrong answer and one for every correct answer and ranked the knowledge level of students. The mean age of study participants was 20.68 years. In total, 69.1% students possessed poor knowledge whereas, 30.9% had good knowledge. The country of students has significant association with their level of knowledge. Most of the students got information on cervical cancer from traditional media (49.8%) and doctor (30.9%) and the effect of these two sources was statistically significant on the knowledge level of students. Students mostly identified vaccination (21.1%) and Gynecological examination (14.39%) as preventing methods. However, 65.5% of them acknowledge that vaccines cannot prevent this cancer and 33.4% believe in different risks of vaccine. Although students have heard of cervical cancer the overall knowledge was insufficient and perceived negative concepts about cancer vaccine. Therefore, we recommend the initiation of educational programs on basic reproductive health and health seeking behaviour targeting young women to successfully control and prevention of this life-threatening health problem.

Assessment of stigma among cancer patients is of utmost importance as stigma may lead to various psychological sequelae and lower quality of life. This study aimed to translate the English version of the Shame and Stigma Scale (SSS) into Malay and validate the Malay version of the SSS (SSS-M) among cancer patients in Malaysia. Initially, concurrent translation and back translation of the SSS-M was performed, and face and content validity were assessed. Then, the SSS-M was administered to a total of 234 patients of mixed types of cancer to assess its reliability (internal consistency and test-retest reliability), construct validity (convergent and discriminant validity), exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). The SSS-M total score registered good internal consistency (Cronbach’s α of 0.886) and test-retest reliability (intraclass correlation coefficient of 0.846, p < 0.001). EFA and CFA confirmed that the SSS-M consisted of 20 items in 5 domains. Its convergent and discriminant validity were achieved. Hence, the SSS-M demonstrated good psychometric properties and is available for use to assess stigma among cancer patients in Malaysia.

Therapeutic vaccine studies should be designed to elicit durable, high magnitude, and efficacious T cell responses, all of which can be impacted by the choice of vaccination schedule. Here, we compare different prime-boost intervals (PBI) in a human papillomavirus (HPV) model using HPV16E6E7 Venezuelan equine encephalitis virus replicon particle (VRP) vaccination to address the optimal boosting schedule, quality of immune response, and overall in vivo efficacy. Six different vaccine regimens were tested with each group receiving booster vaccinations at different time intervals. Analysis of T-cell responses demonstrated a significant HPV16 E7 specific CD8+T cell response with minimally a one-week PBI between antigen re-exposure. Significant E7-specific in vivo cytotoxicity was also observed with longer PBIs. Additionally, longer PBIs led to an enhanced memory recall response to tumor challenge, which correlated with differential expansion of T cell memory subsets. Our findings imply that when using alphavirus vector platforms as a vaccination strategy, a one-week PBI is sufficient to induce high magnitude effector T cells with potent anti-tumor activity. However, longer PBIs lead to enhanced long-term protective anti-tumor immunity. These findings have implications for therapeutic vaccine clinical trials in which shorter intervals of prime-boost regimens may lead to suboptimal durable immune responses.

Background: We aimed to identify overexpressed genes or related pathways associated with good responses to anti-HER2 therapy and to suggest a model for predicting drug response in neoadjuvant therapy with trastuzumab in HER2-positive breast cancer patients. Methods: We recruited 64 women with breast cancer and categorized them into three groups according to anti-HER2 therapy response. RNA from twenty core needle biopsy paraffin-embedded tissues and four cultured cell was extracted, reverse transcribed, and subjected to microarray. The obtained data were analyzed using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and database for annotation, visualization, and integrated discovery. Results: In total, 6,656 genes differentially expressed between trastuzumab-susceptible and trastuzumab-resistant cell lines (3,224 upregulated and 3,432 downregulated). Expression changes in 34 genes in several pathways were found to be related to the response to trastuzumab-containing treatment, interfering with adhesion to other cells or tissues (focal adhesion) and regulating extracellular matrix interactions and phagosome action. Thus, decreased tumor invasiveness and enhanced drug effects might be the mechanisms explaining the better drug response in complete response group. Conclusions: This multigene assay-based study provides insights into breast cancer signal transduction and the possible prediction of treatment response to targeted therapies such as trastuzumab.

Background: Risk of metastatic recurrence of breast cancer after initial diagnosis and treatment depends on the presence of a number of risk factors. Although most univariate risk factors have been identified using classical methods, machine-learning methods are also being conducted to tease out non-obvious contributors to a patient’s individual risk of developing late distant metastasis. Bayesian-network algorithms may predict not only risk factors but also interactions among these risks, which consequently lead to metastatic breast cancer. We proposed to apply a previously developed machine-learning method to predict risk factors of 5-, 10- and 15-year metastasis. Methods: We applied a previously validated algorithm named the Markov Blanket and Interactive risk factor Learner (MBIL) on the electronic health record (EHR)-based Lynn Sage database (LSDB) from the Lynn Sage Comprehensive Breast Cancer at Northwestern Memorial Hospital. This algorithm provided an output of both single and interactive risk factors of 5-, 10-, and 15-year metastasis from LSDB. We individually examined and interpreted the clinical relevance of these interactions based on years to metastasis and the reliance on interactivity between risk factors. Results: We found that with lower alpha values (low interactivity score), the prevalence of variables with an independent influence on long term metastasis was higher (i.e., HER2, TNEG). As the value of alpha increased to 480, stronger interactions were needed to define clusters of factors that increased the risk of metastasis (i.e., ER, smoking, race, alcohol usage). Conclusion: MBIL identified single and interacting risk factors of metastatic breast cancer, many of which were supported by clinical evidence. These results strongly recommend the development of further large data studies with different databases to validate the degree to which some of these variables impact metastatic breast cancer in the long term.

β-apopicropodophyllin (APP), a derivative of podophyllotoxin (PPT), has been identified as a potential anti-cancer drug. This study tested whether APP acts as an an-ti-cancer drug and can sensitize colorectal cancer (CRC) cells to radiation treatment. APP had an anti-cancer effect against the CRC cell lines HCT116, and DLD-1, SW480 and COLO320DM with IC50 values of 7.88 nM, and 8.22 nM, 9.84 nM and 7.757 nM, respec-tively induction of DNA damage. Colonogenic and cell counting assays indicated that the combined treatment of APP and γ-ionizing radiation (IR) showed greater retardation of cell growth than either alone, suggesting that APP sensitizes CRC cells to IR. Annexin V-propidium iodide (PI) assays and immunoblot analysis showed that the combined treatment of APP and IR increased apoptosis in CRC cells compared with either APP or IR alone. Results obtained from the xenograft experiments also indicated that the combination of APP and IR enhanced apoptosis in in vivo animal model. Apoptosis induction by the combined treatment of APP and IR resulted from reactive oxygen species (ROS). Inhibition of ROS by N-acetylcysteine (NAC) restored cell viability and decreased the induction of apoptosis by APP and IR in CRC cells. Taken together, these results indicate that a combined treatment of APP and IR might promote apoptosis by inducing ROS in CRC cells.

The most important predictors for outcomes after ischemic stroke, that is, for health deterioration and death, are chronological age and stroke severity; gender, genetics and lifestyle / environmental factors also play a role. Of all these, only the latter can be influenced after the event, even though recurrent stroke may be prevented by antiaggregant/anticoagulant therapy, angioplasty of high-grade stenoses, and treatment of cardiovascular risk factors. Moreover, blood cell composition and protein biomarkers such as C-reactive protein or interleukins in serum are frequently considered as biomarkers of outcome. We surveyed protein biomarkers that were reported to be predictive for outcome after ischemic stroke, specifically considering biomarkers that predict long-term outcome (≥3 months) and that are measured over the first days following the event. We classified the protein biomarkers as immune‑inflammatory, coagulation-related, and adhesion-related biomarkers. Some of these biomarkers are closely related to cellular senescence and, in particular, to the inflammatory processes that can be triggered by senescent cells. Moreover, the processes that underlie inflammation, hypercoagulation and cellular senescence connect stroke to cancer, and biomarkers of cancer-associated thromboembolism, as well as of sarcopenia, overlap strongly with the biomarkers discussed here. Finally, we demonstrate that most of the outcome-predicting protein biomarkers form a close-meshed functional interaction network, suggesting that the outcome after stroke is partially determined by an interplay of molecular processes relating to inflammation, coagulation, cell adhesion and cellular senescence.

Cancer is a prevalent disease worldwide and treatments such as radiotherapy and chemotherapy sometimes lead to adverse events. Oral mucositis is one of the most disabling and clinical guidelines do not take into account nutritional interventions. The primary endpoint was to gather the evidence about the efficacy of nutritional interventions in the prevention and/or treatment of antineoplastic induced oral mucositis in oncological patients. It was carried out a bibliographic review in PubMed data base by combining MesH terms with boolean operators. Articles were selected based on inclusion and exclusion criteria; 50 final articles were found. Although further evidence is needed, glutamine, honey and vitamins appear to be a good therapeutic option. The rest of the compounds presented controversial or insufficient results to draw conclusions over their utilization as prevention or treatment options. Low evidence is reported about oral mucositis nutritional interventions in spite of being attainable and affordable compounds. Scarce evidence is shown in paediatric patients compared to adults. Developing higher quality studies and combinations with the compounds researched is necessary to create stronger evidence.

We report the development of in vitro propagation protocols through adventitious shoot induction pathway for a rare and medicinal Scutellaria havanensis. In vitro propagation studies using nodal explants showed MS medium supplemented with 10µM 6-Benzylaminopurine induced highest number of adventitious shoots in a time dependent manner. A ten - day incubation was optimum for shoot bud induction as longer exposures resulted in hyperhydricity of the explants and shoots induced. We also report preliminary evidence of Agrobacterium tumefaciens EHA105 - mediated gene transfer transiently expressing of green fluorescent protein in this species. Transformation studies exhibited amenability of various explant tissues, internode being the most receptive. As the plant has medicinal value, research was carried out to evaluate its potential antioxidant capacity and the efficacy of methanolic leaf extracts in curbing the viability of human colorectal cancer cell line HCT116. Comparative total polyphenol, and flavonoid content measurement of fresh and air dried leaf extract revealed that the fresh leaf extracts contain higher total polyphenol and flavonoid content. The HCT 116 cell viability assessed by colorimetric assay using a 3-(4, 5-dimethyl-thiazol-2-yl)-2, 5-diphenyltetrazolium bromide, showed a steady growth inhibition after 24 hours of incubation. Scanning Electron Microscopy of leaf surface revealed high density of glandular and non-glandular trichomes. This research provides basis for the conservation of this rare plant and future phytochemical screening and clinical research.

Background: About 10% of Wilms Tumor (WT) patients have a malformation or cancer predisposition syndrome (CPS) with causative germline genetic or epigenetic variants. Knowledge on CPS is essential for genetic counselling. Methods: This retrospective analysis focused on 2927 consecutive patients with WTs registered between 1989 and 2017 in the SIOP/GPOH studies. Results: (GU, N=66, 2,3%), Beckwith-Wiedemann spectrum (BWS, N=32, 1,1%), isolated hemihypertrophy (IHH, N=29, 1,0%), Denys-Drash syndrome (DDS, N=24, 0,8%) and WAGR syndrome (N=20, 0,7%) were reported most frequently. Compared to others, these patients were younger at WT diagnosis (median age 24,5 months vs. 39,0 months), had smaller tumors (334,8mL vs. 496,9mL), less often metastasis (8,2% vs. 18%), but more often nephroblastomatosis (12,9% vs. 1,9%). WT with IHH was associated with blastemal WT and DDS with stromal subtype. Bilateral WTs were common in WAGR (30%), DDS (29%) and BWS (31%). Chemotherapy induced reduction in tumor volume was poor in DDS (7,7% increase) and favorable in BWS (84,6% reduction). The event-free survival (EFS) of patients with BWS was significantly (p=0,002) worse than in others. Conclusions: CPS should be considered in WTs with specific clinical features resulting in referral to a geneticist. Their outcome was not always favorable.

Background: Ovarian cancer (OC) represents the eighth most common cancer and the fifth leading cause of cancer-related deaths among the female population. In the advanced setting, chemotherapy represents the first-choice treatment, despite a high recurrence rate. In the last ten years, immunotherapy based on immune checkpoint inhibitors (ICIs) has profoundly modified the therapeutic scenario of many solid tumors. We sought to summarize the main findings regarding the clinical use of ICIs in the OC. Methods: We searched the PubMed, Embase, and Cochrane Databases, and conference abstracts from international congresses (such as ASCO, ESMO, SGO) for clinical trials, focusing on ICIs both as monotherapy and as combinations in the advanced OC. Results: 20 studies were selected, of which 16 were phase I or II and 4 phase III trials. ICIs targeting PD1 (nivolumab, pembrolizumab), PD-L1 (avelumab, atezolizumab, durvalumab), and CTLA4 (ipilimumab, tremelimumab) were employed. No significant survival improvement was achieved; conversely, early terminations due to futility or toxicity were recorded. Combinations with chemotherapy, anti-VEGF, and, overall, PARP-inhibitors seem feasible and enhance the response rate and survival, notwithstanding a worse safety profile. Conclusions: The identification of biomarkers with a predictive role for ICIs’ efficacy is mandatory. Moreover, genomic and immune profiling of the OC might lead to an improved treatments selection and design of tailored trials.

Most oral squamous cell carcinomas (OSCCs) arise from oral epithelial dysplasia; however, there is no useful marker for early OSCC detection, likely owing to the inability to continuously observe the carcinoma sequence. We aimed to establish an experimental model to observe changes in the sequential expression pattern of mRNA and protein in the same rat using liquid-based cytology techniques. Cytology specimens were collected from a 4-nitroquinoline 1-oxide-induced rat tongue cancer model at 2, 5, 8, 11, 14, 17, and 21 weeks. We examined candidate biomarker expression using immunocytochemistry and quantitative real-time PCR. The percentage of positively stained nuclei was calculated as the labeling index (LI). All rats had OSCC of the tongue at 21 weeks. Brd4 (Brd4), Myc (c-Myc), and Tp53 (p53) mRNA levels were upregulated during progression from negative for intraepithelial lesion or malignancy to SCC. Brd4- and c-Myc-LI were increased in low- and high-grade squamous intraepithelial lesions and SCC specimens. p53-LI was significantly increased in SCC specimens. Our experimental model allowed the observation of sequential morphological changes and mRNA and protein expression patterns in the same rat during carcinogenesis. By reducing the false negative rate, BRD4 and c-Myc can be useful markers for the early detection of OSCC.

Circular RNAs (circRNAs), which are a class of non-coding RNA with covalently closed loops, play important roles in epigenetics regulation of gene expression at both the transcriptional and post-transcriptional level. Accumulating evidence demonstrated that numerous circRNAs were abnormally expressed in tumors and their dysregulation was involved in the tumorigenesis and metastasis of cancer. Although the functional mechanisms of many circRNAs have been revealed, why circRNAs are dysregulated in cancer remains elusive. CircRNAs are generated by a “backsplicing” process, which is regulated by different cis-regulatory elements and trans-acting proteins. Therefore, how these cis- and trans-elements change during tumorigenesis and how they regulate the biogenesis of circRNAs in cancer are two questions that interest us. In this review, we summarized the pathways for the biogenesis of circRNAs; and then illustrated why circRNAs dysregulated in cancer by discussing the changes of cis-regulatory elements and trans-acting proteins that related to circRNA splicing and maturation in cancer.

PIK3CA is a gene usually mutated in breast cancer and has an important role in tumor progression and treatment. Therefore, there is required a technique to detect low-rate PIK3CA mutations improving the clinical conduct. This study aimed to compare chip-based dPCR and Sanger sequencing to detect PIK3CA mutations in breast cancer patients. Fifty-seven tumor samples from breast cancer patients were collected and analyzed by Sanger sequencing and dPCR for PIK3CA mutations (E545K, H1047R, and H1047L). Digital PCR sensitivity, specificity, and overall performance were estimated by contingency tables, receptor operator characteristic (ROC), and area under the curve (AUC). Sanger sequencing identified PIK3CA mutations in six patients (10.5%), two with H1047R, and four with E545K. Digital PCR confirmed those mutations and identified 19 additional patients with at least one mutation. Comparison between dPCR and Sanger sequencing showed a sensitivity of 100% (95% CI 53-100%), and a specificity of 84.2% (95% CI 83 - 84.2%). Besides, H1047R mutation showed a significant association with breast cancer phenotype (p =0.019) and lymphatic node infiltration (p =0.046). Digital PCR showed a high sensitivity to detect mutations in tumor samples and it might be capable to detect low-rate mutations and tumor subpopulations not detected by Sanger sequencing.

Aims: To assess the occurrence of Chemotherapy-induced nausea and vomiting (CINV) after standard antiemetic therapy in the acute (24 h post-chemotherapy) and delayed (2–5 days post-chemotherapy) phases, as well as to identify risk factors for CINV in the acute and delayed phases. Methods: This prospective longitudinal and observational study analyzed the data of 400 breast cancer patients scheduled for chemotherapy over two cycles in two hospitals. The self-report survey was developed to assess the occurrence of CINV and their associated factors. CINV was evaluated with a Multinational Association of Supportive Care in Cancer Antiemetic Tool (MAT) on days 2 and 6 of chemotherapy. The incidence of acute and delayed CINV were presented by frequency and percentage. Generalized equation estimates (GEE) was used to identify risk factors of acute and delayed CINV. Results: There were 400 evaluable patients with complete Round 1 data, 334 for Round 2 data. Among 400 patients, 29.8% and 23.5% experienced acute and delayed CINV, respectively. Risk factors associated with for acute CINV were pain/insomnia, history of CINV, history of motion sickness (MS), and highly emetogenic chemotherapy regimen, while history of MS, CINV history, number of completed chemotherapy cycle number < 3, and the incidence of acute CINV were risk factors of delayed CINV (all p < 0.05). Conclusions: The findings may help nurses working for Chinese population in identifying patients at risk for CINV and in planning effective program to reduce the occurrence of CINV.

Objective: To investigate the protein expression levels of cyclin‑dependent kinase subunit 2 (CKS2) and cluster of differentiation (CD) 47 in gastric cancer (GC) and their clinical significances. Methods: A total of 126 GC patients who underwent radical resection were selected as study subjects. Additionally, 32 patients with benign gastric tumor, 42 patients with low-grade intraepithelial neoplasia (LGIEN), and 49 patients with high-grade intraepithelial neoplasia (HGIEN) who underwent surgery were selected as the control groups. Immunohistochemistry was used to detect the expression of CKS2 and CD47 in surgical specimens. We statistically analyzed the clinical significance of the expression of the two factors. Results: (1) The positivity rates for CKS2 in benign gastric tumor tissue, LGIEN tissue, HGIEN tissue, and GC tissue gradually increased, i.e., 6.3% (2/32), 30.9% (13/42), 38.8% (19/49), and 60.3% (76/126), respectively, and the positivity rates for CD47 were 18.8% (6/32), 38.1% (16/42), 46.9% (23/49), and 65.9% (83/126), respectively. (2) High expression of CKS2 and CD47 were associated with tumor diameter, Lauren classification, number of lymph node metastases, and TNM stage. In addition, the immunohistochemical scores for CKS2 and CD47 were positively correlated (r=0.625, P=0.000). (3) The median follow-up time of 126 patients was 46.5 months, and the overall survival rate was 40.5% (51/126). Survival analysis showed that compared with that in the CKS2 (-) group, the overall survival rate for patients in the CKS2 (+) group was significantly worse (25.0% vs 64.0%, 2=15.67, P=0.000) and that compared with the CD47 (-) group, the CD47 (+) group had significantly worse overall survival (30.1% vs 60.5%, 2=15.67, P=0.000). (4) The overall survival rates of CKS2(+)CD47(+) group, CKS2(+)CD47(-) group, CKS2(-)CD47(+) group, and CKS2 (-)CD47 (-) group were 20.0%(13/65), 58.3%(7/12), 57.1%(8/14), 65.7% (23/35), respectively, the prognosis of patients in CKS2(+)CD47(+) group was significantly poor. Conclusion: High expression levels of CKS2 and CD47 were closely related to the occurrence of GC and can be used as independent risk factors to assess the prognosis of patients.

The aim of this study was to determine whether a rowing training program improved the quantity and quality of physical activity and quality of life in female breast cancer survivors (stage I - 4.35%; II - 30.43%; III - 52.17%; and IV - 8.7%) diagnosed 6.57 ± 5.02 years previously, who had undergone a subsequent intervention (preservation 53.52%; total mastectomy 39.13% and double mastectomy 4.35%) and had a current mean age of 53.70 ± 7.88 years. The participants (N = 30) engaged in a 12-week training program, each week comprising three sessions and each session lasting 60-90 minutes. An anthropometric evaluation was performed before and after the program. The short form of the International Physical Activity Questionnaire (IPAQ-SF) and the Short Form 36 Health Survey (SF-36) were also administered. The results showed statistically significant improvements in levels of physical activity and in the dimensions of quality of life. We can conclude that a 12-week rowing training program tailored to women who have had breast cancer increases physical activity levels, leading to improved health status and quality of life.

Triple negative breast cancer (TNBC) is the most aggressive breast cancer accounting for around 15% of identified breast cancer cases. TNBC, by lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), is unresponsive to current targeted therapies. Existing treatment relies on chemotherapeutic treatment but, despite an initial response to chemotherapy, the inception of resistance and relapse is unfortunately common. Dasatinib is an approved second-generation inhibitor of multiple tyrosine kinases and literature data strongly support its use in the management of TNBC. However, dasatinib binds to plasma proteins and undergoes extensive metabolism through oxidation and conjugation. To protect dasatinib from fast pharmacokinetic degradation and to prolong its activity, it was encapsulated on poly(styrene-co-maleic acid) (SMA) micelles. The obtained SMA-dasatinib nanoparticles (NPs) were evaluated for their physicochemical properties, in vitro antiproliferative activity in different TNBC cell lines, and in vivo anticancer activity in a syngeneic model of breast cancer. Obtained results showed that SMA-dasatinib is more potent against 4T1 TNBC tumor growth in vivo compared to free drug. This enhanced effect was ascribed to the encapsulation of the drug protecting it from a rapid metabolism. Our finding highlights the often-overlooked value of nanoformulations in protecting its cargo from degradation. Overall, results may provide an alternative therapeutic strategy for TNBC management.

High-throughput screening technologies continues to produce large amounts of multiomics data from different populations and cell types for various diseases, such as cancer. However, analysis of such data encounters difficulties due to cancer heterogeneity, further exacerbated by human biological complexity and genomic variability. There is a need to redefine the drug discovery development pipeline, bringing an Artificial Intelligence (AI)-powered informational view that integrates relevant biological information and explores new ways to develop effective anticancer approaches. Here, we show SynPred, an interdisciplinary approach that leverages specifically designed ensembles of AI-algorithms, links omics and biophysical traits to predict synergistic anticancer drug synergy. SynPred exhibits state-of-the-art performance metrics: accuracy – 0.85, precision – 0.77, recall – 0.75, AUROC – 0.82, and F1-score - 0.76 in an independent test set. Moreover, data interpretability was achieved by deploying the most current and robust feature importance approaches. A simple web-based application available online at http://www.moreiralab.com/resources/synpred/ was constructed to predict synergistic anticancer drug combinations requiring only the upload of the two drug SMILES to be tested, allowing easy access by non-expert researchers.

Cancer patients and their family caregivers experience various losses when patients become terminally ill, yet little is known about the grief experienced by patients and caregivers and factors that influence grief as patients approach death. Additionally, few, if any, studies have explored associations between advance care planning (ACP) and grief resolution among cancer patients and caregivers. To fill this knowledge gap, the current study examined changes in grief over time in patients and their family caregivers and whether changes in patient grief are associated with changes in caregiver grief. We also sought to determine how grief changed following completion of advance directives. The sample included advanced cancer patients and caregivers (n=98 dyads) from Coping with Cancer III, a federally funded, multi-site prospective longitudinal study of end-stage cancer care. Participants were interviewed at baseline and at follow-up roughly 2 months later. Results suggest synchrony, whereby changes in patient grief were associated with changes in caregiver grief. We also found that patients who completed a living will (LW) experienced increases in grief, while caregivers of patients who completed a do-not-resuscitate (DNR) order experienced reductions in grief, suggesting that ACP may prompt “grief work” in patients while promoting grief resolution in caregivers.

Colorectal cancer is a major threat to the society causing the death through metastasis to several patients with stage IV. Computational tools provide a relatively quick procedure in order to evaluate several molecules for their drug activity. Prenylated flavonoids are well known for their anticancer properties even in colon cancer. Here, we provided altered structures of chalcones, based on theoretical studies that are showing better binding affinities to several colon cancer related proteins. Using molecular docking and dynamics, alongside with density function theory and ADMET studies we are representing two new derivatives of Xanthohumol prenylated flavonoids having promising results against this disease.

The aim of this study was to determine whether a rowing training program improved the quantity and quality of physical activity and quality of life in female breast cancer survivors (stage I - 4.35%; II - 30.43%; III - 52.17%; and IV - 8.7%) diagnosed 6.57 ± 5.02 years previously, who had undergone a subsequent intervention (preservation 53.52%; total mastectomy 39.13% and double mastectomy 4.35%) and had a current mean age of 53.70 ± 7.88 years. The participants (N = 30) engaged in a 12-week training program, each week comprising three sessions and each session lasting 60-90 minutes. An anthropometric evaluation was performed before and after the program. The short form of the International Physical Activity Questionnaire (IPAQ-SF) and the Short Form 36 Health Survey (SF-36) were also administered. The results showed statistically significant improvements in levels of physical activity and in the dimensions of quality of life. We can conclude that a 12-week rowing training program tailored to women who have had breast cancer increases physical activity levels, leading to improved health status and quality of life.

Prostate cancer (Pca) is a highly heterogeneous disease and the second more common tumor in males. Molecular and genetic profiles have been used to identify subtypes and guide therapeutic intervention. However, roughly 26% of primary Pca are driven by unknown molecular lesions. We use Principal Component Analysis (PCA) and custom RNAseq-data normalization to identify a gene expression signature which segregates primary PRAD from normal tissues. This Core-Expression Signature (PRAD-CES) includes 33 genes and accounts for 39% of data complexity along the PC1-cancer axis. The PRAD-CES is populated by protein-coding (AMACR, TP63, HPN) and RNA-genes (PCA3, ARLN1) sparsely found in previous studies, validated/predicted biomarkers (HOXC6, TDRD1, DLX1), and/or cancer drivers (PCA3, ARLN1, PCAT-14). Of note, the PRAD-CES also comprises six over-expressed LncRNAs without previous Pca association, four of them potentially modulating driver’s genes TMPRSS2, PRUNE2 and AMACR. Overall, our PCA capture 57% of data complexity within PC1-3. GO enrichment and correlation analysis involving major clinical features (i.e., Gleason Score, AR Score, TMPRSS2-ERG fusion and Tumor Cellularity) suggest that PC2 and PC3 gene signatures might describe more aggressive and inflammation-prone transitional forms of PRAD. Of note, surfaced genes may entail novel prognostic biomarkers and molecular alterations to intervene. Particularly, our work uncovered RNA genes with appealing implications on Pca biology and progression.

Chemotherapy-related deaths, the result of treatment with faulty medications, account for nearly 10% of all breast cancer deaths (Rashbass, 2016). Patient-specific, personalized medicine is evidently required to administer optimized therapeutics and prevent treatment-related mortality. In order to develop a predictive model for breast cancer therapy, the following study analyzed the mRNA data of 4,704 genes derived from 20 breast cancer patients before and after doxorubicin treatment for 16 weeks (O’brien et al., 2006; Perou et al., 2000). The genomic data of each patient was first stratified into 9 groups (corresponding to the 9 Mechanisms defined in Figure 4) based on mRNA expression in response to the tumor and to the doxorubicin treatment. The study then employed the Planckian Distribution Equation (PDE) discovered at Rutgers University to model the stratified samples by transforming each mechanism into a single long-tailed histogram fitted by the PDE. Our PDE model is based on 3 parameters - A, B, and C - of which 2 were extracted from each model to generate the plots seen in figures 5e and 5f. The drug-induced slopes of the A vs C plots were then determined for all 9 mechanisms of each patient. The study observed an increase in post-treatment mRNA levels for longer surviving patients in 6 mechanisms. Further analysis displayed how the drug treatment uniquely altered each of the mechanisms based on the length of patient survival. These results indicate that the PDE-based procedures described herein may provide a novel tool for discovering potential anti-breast cancer pharmaceuticals.

The consumption of sweet beverages, including sugar-sweetened beverages (SSB), artificially sweetened beverages (ASB) and fruit juices (FJ) is associated with the risk of different cardiometabolic diseases and probably with some tumors as well. We carried out a systematic review and meta-analysis of observational studies aimed at evaluating the association between sweet beverage intake and different types of cancer risk. Suitable papers published up to June 2020 were searched through PubMed, Web of Science and SCOPUS databases, using relevant keywords. Overall, 64 studies were identified for the systematic review, of which 27 were selected for the meta-analysis. This was performed by analyzing the multivariable-adjusted OR, RR or HR of the highest compared with the lowest sweet beverage intake categories. Random effects showed significant positive association between SSBs intake and breast (RR: 1.14, 95% CI: 1.01 – 1.30) and prostate cancer risk (RR: 1.18, 95% CI: 1.10 – 1.27), also between FJs and prostate cancer risk (RR: 1.03, 95% CI: 1.01 – 1.05). Associations between SSBs and colorectal and pancreatic cancer risk, FJs and breast, colorectal and pancreatic cancer risk, ASBs and pancreatic cancer risk tended to be positive but did not reach the statistically significant threshold. This study supports the recommendation to limit the consumption of SSBs and FJs for cancer prevention and proposes to further investigate the potential harmful role of ASBs intake in cancer risk.

Epidemiological studies have shown a strong association between high body mass index (BMI) and papillary thyroid cancer (PTC). We assessed the clinical and histopathological features of PTC in patients with a higher BMI and compared them to analogous parameters in PTC patients with a normal BMI. We retrospectively analyzed 5,021 medical records of patients admitted and surgically treated for thyroid tumors in one center between 2008 and 2018. Finally, we extracted data from 523 adult patients with PTC and stratified patients into two groups according to BMI: Group 1 with BMI < 25 kg/m² and Group 2 with BMI ≥25 kg/m². Data stratification was performed to estimate the association of overweight and obesity with clinical and histopathological features of PTC in both univariate and multivariate binary logistic regression analyses. Overall, compared to patients with a normal BMI, overweight and obese patients had a greater risk of minimal extrathyroidal extension (minimal ETE), multifocality and bilaterality of PTC (p<0.001 for all). Analysis did not show that BMI was significantly associated with more advanced tumor-node-metastasis (TNM) stage (p=0.894). Obesity and overweight were significantly associated with higher aggressiveness of PTC. When considering various management options for PTC patients, these findings regarding overweight and obesity should be taken into consideration during the decision-making process.

Translational medicine requires facile experimental systems to replicate the dynamic biological systems of diseases. Drug approval continues to lag, partly due to incongruencies in the research pipeline that traditionally involve 2D models, which could be improved with 3D models. The bone marrow (BM) poses challenges to harvest as an intact organ making it difficult to study disease processes such as breast cancer (BC) survival in BM, and to effective evaluation of drug response in BM. Furthermore, it is a challenge to develop 3D BM structures due to its weak physical properties, and complex hierarchical structure and cellular landscape. To address this, we leveraged 3D bioprinting to create a BM structure with varied methylcellulose (M):alginate (A) ratios. We selected hydrogels containing 4% (w/v) M and 2% (w/v) A, which recapitulates rheological and ultrastructural features of the BM while maintaining stability in culture. This hydrogel sustained the culture of two key primary BM microenvironmental cells found at the perivascular region, mesenchymal stem cells and endothelial cells. More importantly, the scaffold showed evidence of cell autonomous dedifferentiation of BC cells to cancer stem cell properties. This scaffold could be the platform to create BM models for various disease and also for drug screening.

Iron (Fe) is a trace element that plays essential roles in various biological processes such as DNA synthesis and repair, as well as cellular energy production, or oxygen transport, and it is currently widely recognized that iron homeostasis is dysregulated in many cancers. Indeed, several iron homeostasis proteins may be responsible for malignant tumor initiation, proliferation, and for metastatic spread of tumors. A large number of studies demonstrated the potential clinical value of turning these deregulated proteins as prognostic and/or predictive biomarkers of malignancy and /or response to anticancer treatments. Additionally, the iron addiction of cancer cells and the importance of iron in ferroptosis cell death signaling pathways prompted the development of therapeutic strategies against advanced stage or resistant cancers. In this review, we selected relevant and promising studies in the field of iron metabolism in cancer research and clinical oncology. Besides, we discuss some co-existing discrepant findings. We will also present and discuss the latest lines of research related to targeting iron, or its regulatory pathways, as potential promising anti-cancer strategies for human therapy. Iron chelators, such as deferoxamine or iron-oxide based nanoparticles, which are already tested in clinical trials, alone or in combination with chemotherapy will also be reported.

Over the last two months, as oncology specialists, we have frequently been contacted for estimating prognosis for cancer patients affected by COVID-19 infection. Until now, there have been no clear markers to guide decision making regarding the appropriateness of invasive ventilation in cancer patients affected by COVID-19 infection. Therefore, we developed a practical tool encompassing a prognostic score. We aimed at identifying a subgroup of patients likely to have a better outcome and therefore may be potential candidates for invasive ventilation, "The Milano Policlinico ONCOVID-ICU score". The score is composed by three groups of variables: patient’s characteristics such as sex, age, BMI and comorbidities; oncological variables (treatment intent, life expectancy, on or off-treatment status) and clinical parameters in association with laboratory values (SOFA score and D-dimer). The SOFA score includes six different clinical parameters and during the first few days of ICU admissions has an important prognostic role. The oncological history should never represent, per se, a contraindication to intensive care and must be considered together with other variables, such as laboratory values, clinical parameters and patient characteristics, in order to make the hardest but best possible choice. The Milano Policlinico ONCOVID-ICU score, to our knowledge, is the first prognostic score proposed in this setting of patients and may be a useful tool to assess the prognosis of cancer patients being in this critical condition.

Colorectal cancer (CRC) is the third most common cancer, with rising incidence due to lifestyle and diet. 40% of CRC cases are found to have KRAS mutations. In this study, we investigate the survival outcome of metastatic Colorectal cancer mCRC) patients in Brunei Darussalam restrospectively. Chi-squared test was used to compare the survival outcomes of mCRC patients, and Mann-Whitney U test was used to compare the median ages of both groups. Kaplan-Meier survival curves were drawn and logrank test was used to compare the survival outcome between two groups. There was a total of 105 patients with stage IV CRC being treated during the study period. 81.6% (n=62) of mCRC patients were found to have the primary tumours on the left side of the colon. 19 of these 26 (73.1%) mutant KRAS mCRC patients died, while 23 of 50 (46.0%) wild-type KRAS mCRC patients died at the end of the study period, contributing to death rates of 45.2% and 54.8%, correspondingly. 30.3% (n=23) of the study population had a single metastatic site detected (either liver, or lung or any other organs), while 69.7% (n=53) of the 76 mCRC patients had two (double) or more metastatic sites. 69.2% (n=18) and 30.8% (n=8) of the mutant KRAS mCRC patients had mutations within codons 12 and 13, respectively. To our knowledge, this is the first study in Brunei Darussalam to analyse both the survival outcomes of metastatic CRC patients and those of mutant KRAS mCRC patients. Chi-squared analysis showed a significant difference between the survival outcomes of wild-type KRAS and mutant KRAS mCRC patients (p-value = 0.024). There was a significant difference in the survival outcome between the mutant KRAS mCRC patients with RCC and mutant KRAS mCRC with LCC patients. There was no significant difference between the survival outcomes of mutant KRAS patients with mutations in either codon 12 or 13 of the KRAS gene (Table 3). However, there is a significant difference in the median survival periods between the mutant KRAS mCRC patients with mutations in codon 12 and those with mutation in codon 13 of the KRAS gene (p-value = 0.003). In conclusion, we found that mutant KRAS mCRC patients had a significantly poorer OS, which was shown to be worse when the primary tumours were found at the left side of the colon. Mutant KRAS mCRC patients with mutations in codon 12 were found to have shorter survival median periods than those with mutations within codon 13.

Background: ethical issues that arise during the care of a pregnant woman with cancer are challenging to physicians, policymakers, lawyers, and the bioethics community. This article is restricted to a discussion of ethical dilemmas and controversial case reports, mainly focused before the third trimester of pregnancy, when a conflict could exist between cancer and pregnancy outcomes.Methods: published literature was retrieved through searches in PubMed or Medline, CINAHL, the Cochrane and Google Academic in April 2020, using appropriate controlled keywords (cancer, neoplasm, pregnancy, ethics). Results were restricted to review articles, ethical perspectives, clinical practice guidelines and case-based teaching guides.Discussion: when a conflict arises in the maternal-foetus dyad, like the one related with cancer treatment and the risk of foetal demise, a range of ethical frameworks might be useful to consider in the decision-making process. Pragmatic theoretical approaches include case-based analysis, ethics of care, feminist theory, and traditional ethical principlism using the framework of autonomy, beneficence, non-maleficence, and justice. Also, societal and practitioner values could add value and an ethics consultation may be helpful to mediate conflict resolution. The physician must balance autonomy and beneficence-based obligations to the pregnant woman with cancer, along with beneficence-based obligations to the foetus.Conclusions: ethical challenges have received less attention in the literature, particularly before the third trimester of pregnancy. Best, unbiased and balanced information must be granted both to the patient and to the family, regarding the benefits and harms for the woman herself as well as for the foetal outcome.

Objective: Application of ERA methods to investigate the atmospheric pollution and built environment factors influencing lung cancer incidence rate in Chinese women. Methods: Lung cancer incidence rate among Chinese women at 339 cancer registries were obtained from the China Cancer Registry Annual Report 2017, air quality and built environment data were obtained from the Greenpeace and China Construction Yearbook. After multiple covariates variables were eliminated, an exploratory regression analysis was performed using the world standardized population incidence rate as the dependent variable. Air quality and built environment factors as the independent variable. Results: Shandong Peninsula, Hebei and Liaoning are high incidence rate areas of female lung cancer in China, with significant regional aggregation. In addition to air quality factors such as industrial smoke emission data, the association between built environmental factors such as urbanization rate, development LUI, population density and greening coverage of built-up areas and female lung cancer incidence rate is statistically significant. Conclusion: In addition to air quality factors, urban spatial factors can also significantly affect respiratory health. The LUI is positively while urbanization rates and population density are negatively correlated with the incidence rate of lung cancer. The role of green space for respiratory health has not been proven. In addition, there is little relationship between income and health, and similar findings are found for indicators such as the public transportation and roads network.

The standard care for metastatic breast cancer (MBC) is systemic therapies with imbrication of focal treatment for symptoms. Recently, thanks to implementation of radiological and metabolic exams and development of new target therapies, oligometastatic and oligoprogressive settings are even more common, paving the way to a paradigm change of focal treatments role. In fact, according to immunophenotype, radiotherapy can be considered with radical intent in these settings of patients. The aim of this literature review is to analyse available clinical data on prognosis of bone metastases from breast cancer and benefits of available treatments for developing a practical guide for clinicians.

Antibiotics (ABs) are common medications used for treating infections. In cancer patients treated with immune checkpoint inhibitors (ICIs), concomitant exposure to ABs may impair the efficacy of ICIs and lead to a poorer outcome compared to AB non-users. We report here the results of a meta-analysis evaluating the effects of ABs on the outcome of patients with solid tumors treated with ICIs. PubMed, the Cochrane Library, and Embase were searched from inception until September 2019 for observational or prospective studies reporting prognosis of adult patients with cancer treated with ICIs and with or without ABs. Overall survival (OS) was the primary endpoint, and progression-free survival (PFS) was the secondary endpoint. The effect size was reported as hazard ratios (HRs) with a 95% confidence interval (CI), and an HR > 1 associated with a worse outcome in ABs users compared to no-ABs users. Fifteen publications were retrieved for a total of 2363 patients. In the main analysis (n = 15 studies reporting data), OS was reduced in patients exposed to ABs before or during treatment with ICIs (HR = 2.07, 95%CI 1.51–2.84; P<.01). Similarly, PFS was inferior in ABs users in n = 13 studies with data available (HR = 1.53, 95%CI 1.22–1.93; p<.01). In cancer patients treated with ICIs, AB use significantly reduces OS and PFS. Short duration/course of ABs may be considered in clinical situations in which they are strictly needed.

Background: Lung cancer is one of the leading causes of morbidity and mortality worldwide with 25% of deaths due to lung cancer occurring in Europe. This study therefore sought to assess the burden of lung cancer by country and to evaluate the magnitude of fine Particulate Matter (PM2.5) and cigarette smoking by country in Europe. Methods: An ecological study nested on the World Health Organization air pollution database 2016 was conducted. We sampled 30 European Countries, with a total of 1625 mean annual samples of Particulate Matter (PM2.5) collected from 1625 designated sites (n = 1625). We further used the ‘World Health Disease Rankings’ database to extract Lung Cancer Morbidity and Mortality Rate by country. We used SAS version 9.4 to indicate the distribution of PM2.5 and Lung Cancer Mortality Rate. Results: Lung cancer Relative Risk (RR) was 1.0 in all never- smokers. RR for Ex-smokers for Adeno carcinoma was 3.5 in males and 1.1 in females, small cell carcinoma was 16.2 in males and 3.8 in females. RR for current smokers for Adeno carcinoma was 8.0 in males and 4.1 in females, small cell carcinoma was 57.9 in males and 18.2 in females. Mean annual PM2.5 by country ranged from 6.01 to 37.28µg/m3 whereas lung cancer mortality rate by country ranged from 19.67 to 54.26 deaths per 100,000 population. Conclusion: Cigarette smoking and exposure to both second hand smoke and high concentration of PM2.5 resulted into increased burden of lung cancer in Europe. Countries should re-strategize to reduce the burden of lung cancer in Europe.

Background: Pancreatic invasive ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality in Japan. The early diagnosis of pancreatic cancer, which will increase the number of patients with resectable tumors, is urgently needed. The purpose of the present study was to examine the earliest signs of pancreatic abnormalities on CT in order to facilitate the diagnosis and treatment of PDAC. Methods: Forty-one patients with pancreatic cancer and their 154 CTs were selected for the present study. We used the images that were acquired prior to the diagnosis and examined the pancreas in these images to observe serial changes in the morphology of the pancreas after selecting CT images in which PDAC was suspected. We also confirmed whether the main pancreatic duct was observed around that area of the pancreas. Four thousand two hundred seventy-seven patients without pancreato-biliary disease with 4630 CTs were selected for the control group. Results: Two pancreas shapes were detected: localized constriction of the pancreatic parenchyma referred to as the K-shaped sign, and localized fatty changes. Twenty-four (58.5%) of 41 patients showed the K-shaped sign. The main pancreatic duct without dilatation was noted around the K-shaped sign in 9 of the 24 patients. Eight of 41 patients (19.5%) showed localized fatty changes. Nine of 41 patients (21.9%) showed no abnormality. In the control group, only seven of 4277 patients (0.16%) showed the K-shaped sign. Conclusions: The K-shaped sign including localized fatty changes is the earliest CT sign that presents with pancreatic abnormalities. The K-shaped sign does not indicate PDAC itself but may predict its future development.

Risk of cardiovascular disease (CVD), common in childhood cancer survivors (CCSs), may be affected by diet. We assessed sodium (Na) and potassium (K) intake, estimated from food frequency questionnaires (FFQs) and morning urine spots, and its associations with cardiovascular risk in CCSs. We stratified CCS into three risk profiles based on A) personal history (CVD, CVD risk factors, or CVD risk free), B) body mass index (obese, overweight, or normal/underweight), and C) cardiotoxic treatment (anthracyclines and/or chest irradiation, or neither). We obtained a FFQ from 802, and sent a spot urine sample collection kit to 212, of which 111 (52%) returned. We estimated Na intake 2.9 g/day based on spot urine and 2.8 g/day based on FFQ; estimated K intake was 1.6 g/day (spot urine) and 2.7 g/day (FFQ). CCSs with CVD risk factors had a slightly higher Na intake (3.3 g/day), than CCSs risk free (2.9 g/day) or with CVD (2.7 g/day, p = 0.017), and obese participants had higher Na intake (4.2 g/day) than normal/underweight CCSs (2.7 g/day, p<0.001). Daily Na intake was above, and daily K intake below national recommended levels. Adult survivors of childhood cancer need dietary assistance to reduce Na and increase K intake.

Lung cancer remains the leading cancer killer worldwide. Early diagnosis can effectively increase the patient cure rate but existing diagnostic methods limit early lung cancer diagnosis. Therefore, development of a simple but efficient lung cancer screening method is important to improvement of both the diagnosis rate and the survival rate of lung cancer patients. In this study, ten photosensitive materials with high sensitivity and high specificity were screened accurately to construct a microarray sensor that can rapidly identify six types of lung cancer biomarkers in exhaled breath. Results from hierarchical cluster analysis (HCA), principal component analysis (PCA) and difference maps showed that the classification of the analytes agreed with structure similarity laws. The detection results from parallel experiments and structurally similar analytes, in turn, cluster into a group; the fingerprints of the different analytes have specific response regions. The well-screened sensor chip fabrication workload and cost were both reduced by approximately two thirds, while the microfluidic device sensitivity and stability increased by approximately 1.3 times their corresponding values before optimization. The dual-channel device also offers real-time contrast detection and synchronous parallel detection functions and has potential application prospects for use in extensive screening of high-risk populations for lung cancer.

The dynamic and never exactly repeatable tumor transcriptomic profile of people affected by the same form of cancer requires a personalized and time-sensitive approach of the gene therapy. The Gene Master Regulators (GMRs) were defined as genes whose highly controlled expression by the homeostatic mechanisms commands the cell phenotype by modulating major functional pathways through expression correlation with their genes. The Gene Commanding Height (GCH), a measure that combines the expression control and expression correlation with all other genes, is used to establish the gene hierarchy in each cell phenotype. We developed the experimental protocol, the mathematical algorithm and the computer software to identify the GMRs from transcriptomic data in surgically removed tumors, biopsies or blood from cancer patients. The GMR approach is illustrated with applications to our microarray data on human kidney, thyroid and prostate cancer samples, and on thyroid, prostate and blood cancer cell lines. We proved experimentally that each patient has his/her own GMRs, that cancer nuclei and surrounding normal tissue are governed by different GMRs, and that manipulating the expression has larger consequences for genes with higher GCH. Therefore, we launch the hypothesis that silencing the GMR may selectively kill the cancer cells from a tissue.

Background and objectives: Colorectal cancer (CRC) is the second most common cause of cancer-related death in the world, but early diagnosis ameliorates the survival of CRC. This report directed to identify molecular biomarker signatures in CRC. Materials and Methods: We analyzed two microarray datasets (GSE35279 and GSE21815) from Gene Expression Omnibus (GEO) to identify mutual differentially expressed genes (DEGs). We integrated DEGs with protein-protein interaction and transcriptional/post-transcriptional regulatory networks to identify reporter signaling and regulatory molecules; utilized functional overrepresentation and pathway enrichment analyses to elucidate their roles in biological processes and molecular pathways; performed survival analyses to evaluate their prognostic performance; and applied drug repositioning analyses through Connectivity map (CMap) and geneXpharma tools to hypothesize possible drug candidates targeting reporter molecules. Results: A total of 727 up-regulated and 99 down-regulated DEGs were detected. The PI3K-Akt signaling, Wnt signaling, ECM-interaction, and cell cycle were identified as significantly enriched pathways. Ten hub proteins (ADNP, CCND1, CD44, CDK4, CEBPB, CENPA, CENPH, CENPN, MYC, and RFC2), 10 transcription factors (ETS1, ESR1, GATA1, GATA2, GATA3, AR, YBX1, FOXP3, E2F4, and PRDM14) and 2 miRNAs (miR-193b-3p and miR-615-3p) were detected as reporter molecules. The survival analyses through Kaplan Meier curves indicated remarkable performance of reporter molecules in estimation of survival probability in CRC patients. In addition, several drug candidates including anti-neoplastic and immunomodulating agents were repositioned. Conclusions: This study presents biomarker signatures at protein and RNA levels with prognostic capability in CRC. We think that the molecular signatures and candidate drugs presented in this study might be useful in future studies indenting development of accurate diagnostic and/or prognostic biomarker screens and efficient therapeutic strategies in CRC.

As a result of the cancer immunotherapy revolution hundreds of clinical trials of the newly approved immunotherapies are now under way to improve responses. Not unexpectedly, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their development of cancer therapy by blockade of co-inhibitory signals. While success stories of terminal cancer patients achieving complete remissions are accumulating, not enough research has been done into the risks of the new therapies. Since the use of immunotherapy is becoming more common, and is expected to develop into first- and second-line treatments, immunotoxicity and autoimmunity are emerging as the nemesis of immunotherapy. Immune-related adverse events (IrAEs) could affect any tissue, their incidence may reach up to 90% of patients and toxicity is dose-dependent. While the combination of two immune checkpoint inhibitors (ICIs) increased efficacy, the incidence of severe adverse events was also increased. Apparently, ICIs cannot be restricted to the targeted anti-tumor T cell population. The long lasting objective of cancer regression can only be achieved by paying a price: tolerance to healthy self tissues is compromised. In the face of an ipilimumab induced pan-lymphocytic activation, a therapeutic paradigm shift is required. The task is not desperately trying to put the genie back in the bottle by immune suppressive treatments, but instead harnessing the autoimmune forces by an off label low-dose combined anti-CTLA-4 and anti-PD1 antibody blockade, which is supplemented with conventional interleukin-2 stimulation and hyperthermia. The proof-of-principle of the low-dose-combination therapy was demonstrated in a heavily pre-treated triple negative breast cancer (TNBC) patient with far advanced pulmonary metastases and severe shortness of breath, who had exhausted all conventional treatment. Her pulmonary metastases went into complete remission with transient WHO I-II diarrhea and skin rash. She lived for 27 months after starting the low-dose-combination therapy. She had recurrence as a sternal mass and pleural metastases up to 3 cm. Since the low-dose-combination protocol consists only of approved drugs and treatments, this exceptional response should instigate further research efforts.

EZH2 overexpression is associated with tumor proliferation, metastasis, and poor prognosis. Targeting and inhibiting EZH2 may be an effective therapeutic strategy for head and neck squamous cell carcinoma (HNSCC). We previously analyzed EZH2 mRNA expression in a well-characterized dataset of 230 (110 original and 120 validation cohorts) human head and neck cancer samples. This study aimed to investigate the effects of inhibiting EZH2, either via RNA interference or via pharmacotherapy, on HNSCC growth. EZH2 upregulation was significantly correlated with recurrence (P < 0.001) and the methylation index of tumor suppressor genes (P < 0.05). DNMT3A was significantly upregulated upon EZH2 upregulation (P = 0.043). Univariate analysis revealed that EZH2 upregulation was associated with poor disease-free survival (log-rank test, P < 0.001). In multivariate analysis, EZH2 upregulation was evaluated as a significant independent prognostic factor of disease-free survival (hazard ratio: 2.085, 95% confidence interval: 1.390–3.127; P < 0.001). Cells treated with RNA interference and DZNep, an EZH2 inhibitor, showed the most dramatic changes in expression, accompanied with a reduction in the growth and survival of FaDu cells. These findings suggest that EZH2 upregulation is correlated with tumor aggressiveness and adverse patient outcomes in HNSCC. Evaluation of EZH2 expression might help predict the prognosis of HNSCC patients.

Chemoradiation-based bladder preservation therapy (BPT) is currently a curative option for non-metastatic muscle-invasive bladder cancer (MIBC) patients at favorable risk or an alternative to radical cystectomy (RC) for those who are unfit for RC. In BPT, only patients who achieve complete response (CR) after chemoradiation have favorable prognosis and quality of life with preserved functional bladder. Thus, predicting CR and favorable prognosis is important for optimal patient selection for BPT. We reviewed biomarkers for predicting clinical outcomes of chemoradiation-based BPT. Biomarkers studied were categorized into those related to apoptosis, cell proliferation, receptor tyrosine kinases, DNA damage response genes, hypoxia, molecular subtype, and others. Among these biomarkers, Ki-67 labeling index (Ki-67 LI) and meiotic recombination 11 may be used for selecting BPT or RC. Ki-67 LI and erythroblastic leukemia viral oncogene homolog 2 (erbB2) may be used for predicting both chemoradiation response and prognosis of patients on BPT. Concurrent use of trastuzumab and a combination of carbogen and nicotinamide can overcome chemoradiation resistance conferred by erbB2 overexpression and tumor hypoxia. Further studies are needed to confirm the practical utility of these biomarkers for progress on biomarker-directed personalized management of MIBC patients.

Pseudopterosin, produced by the sea whip of the genus Antillogorgia, possesses a variety of promising biological activities including potent anti-inflammatory effects. However, few studies examined pseudopterosin in the treatment of cancer cells and, to our knowledge, the ability to inhibit triple negative breast cancer (TNBC) proliferation or invasion has not been explored. Thus, we evaluated the as yet unknown mechanism of action of pseudopterosin: Pseudopterosin was able to inhibit proliferation of TNBC. Interestingly, analyzing breast cancer cell proliferation after knocking down glucocorticoid receptor α (GRα) revealed that anti-proliferative effects of pseudopterosin were significantly inhibited when GRα expression was reduced. Furthermore, pseudopterosin inhibited invasion of MDA-MB-231 3D tumor spheroids embedded in an extracellular-like matrix. Remarkably, the knockdown of GRα in 3D tumor spheroids revealed increased ability of cells to invade the surrounding matrix. In a co-culture, encompassing peripheral blood mononuclear cells (PBMC) and MDA-MB-231 cells, production of interleukin 6 (IL-6) and interleukin 8 (IL-8) significantly increased compared to monoculture. Notably, pseudopterosin proved to block cytokine elevation, representing key players in tumor progression, in the co-culture. Thus, our results reveal pseudopterosin treatment as a potential novel approach in TNBC therapy.

Introduction: We investigated the potential effect of smoking on pathological staging in clinically low-risk patients. Material-Methods: Data of 59 patients who were diagnosed with a bladder tumor for the first time and had a single lesion radiologically and endoscopically smaller than 3 cm were investigated, retrospectively. A total of 33 patients who currently smoke or smoked were classified as ever smokers group and 26 patients who did not ever smoke were classified as never smokers group. Pathological diagnoses of the patients in both groups were compared. Results: A total of 9 patients (27.3%) in ever smokers group and 18 patients (69.2%) in never smokers group had Ta disease (p<0.05). Morover, 19 patients (57.6%) in ever smokers group and 5 patients (19.2%) in never smokers group had T1 disease (p<0.05). The number of patients with low grade (LG) tumor were 8 (24.2%) and 19 (73.1%) in ever smoking and never smoking groups, respectively (p<0.05). The number of patients with high grade (HG) tumor were 25 (75.8%) and 7 (26.9%) in ever smoking and never smoking groups, respectively (p<0.05). Ta HG was detected in 9 (27.3%) patients in ever smoking group. In contrast, no patients in never smoking group had Ta HG disease (p<0.05). The number of patients with T1 HG was 17 (51.5%) in ever smoking group and 2 (7.69%) in never smoking group (p<0.05). Conclusion:Smoking seems to associate with pathologically worse stage and grade in patients with primary, single, < 3cm bladder cancer.

We report on the development of chemical vapour deposition (CVD) based graphene field effect transistor (GFET) immunosensors for the sensitive detection of Human Chorionic Gonadotropin (hCG), a glycoprotein risk biomarker of certain cancers. The GFET sensors were fabricated on Si/SiO₂ substrate using photolithography with evaporated chromium and sputtered gold contacts. GFET channels were functionalized with a linker molecule to immobile anti-hCG antibody on the surface of graphene. Binding reaction of the antibody with varying concentration levels of hCG antigen demonstrated the limit of detection of the GFET sensors to be below 1 pg/mL using four-probe electrical measurements. We also show annealing can significantly improve the carrier transport properties of GFETs and shift the Dirac point (Fermi level) with reduced p-doping in back-gated measurements. The developed GFET biosensors are generic and could find applications in a broad range of medical diagnostics in addition to cancer, such as neurodegenerative (Alzheimer’s, Parkinson’s and Lewy body) and cardiovascular disorders.

In most industrialized countries, screening programs for cervical cancer have shifted from cytology (Pap smear or ThinPrep) alone on clinician-obtained samples to the addition of screening for human papillomavirus (HPV), its main causative agent. For HPV testing, self-sampling instead of clinician-sampling has proven to be equally accurate, in particular for assays that use nucleic acid amplification techniques. In addition, HPV testing of self-collected samples in combination with a follow-up Pap smear in case of a positive result is more effective in detecting precancerous lesions than a Pap smear alone. Self-sampling for HPV testing has already been adopted by some countries, while others have started trials to evaluate its incorporation into national cervical cancer screening programs. Self-sampling may result in more individuals willing to participate in cervical cancer screening, because it removes many of the barriers that prevent women, especially those in low socioeconomic and minority populations, from participating in regular screening programs. Several studies have shown that the majority of women who have been underscreened but who tested HPV-positive in a self-obtained sample, will visit a clinic for follow-up diagnosis and management. Additionally, a self-collected sample can also be used for vaginal microbiome analysis, which can provide additional information about HPV infection persistence as well as vaginal health in general.

We evaluated oleanolic acid (OA)-induced anti-cancer activity, apoptotic mechanism, cell cycle status, and MAPK kinase signaling in DU145 (prostate cancer), MCF-7 (breast cancer), and U87 (human glioblastoma) cells. The IC50 values for OA-induced cytotoxicity were 112.57 in DU145, 132.29 in MCF-7, and 163.60 in U87 cells, respectively. OA (at 100 µg/mL) increased the number of apoptotic cells to 27.0% in DU145, 27.0% in MCF-7, and 15.7% in U87 cells, when compared to control cells. This enhanced apoptosis was due to increases in p53, cytochrome c, and Bax expression. OA-treated DU145 cells were arrested in G2 because of the activation of p-ERK and p21, and the decrease in cyclin B1 and cyclin E expression. Furthermore, OA-treated MCF-7 cells were arrested in G1 owing to the activation of p-JNK, p-ERK, p21, and p27, and the decrease in p-AKT, cyclin E, and CDK2. U87 cells also exhibited G1 phase arrest caused by the increase in p-ERK, p-JNK, p21, and p27, and the decrease in CDK2. Thus, OA arrests the cell cycle in different phases, and increases apoptosis in cancer cells. These results suggest that OA may alter the expression of cell cycle regulatory proteins in a cancer type-dependent manner.

Circulating tumor cells (CTC) have shown to be prognostic in advanced colorectal cancer (advCRC), but their value for predicting response to treatment or as a source of molecular data is debated. We compared CellSearch® (Janssen Diagnostics, LLC) and IsoFlux^TM (Fluxion Biosciences Inc, South San Francisco, CA) systems for the enumeration of CTC in patients with newly diagnosed advCRC (group 1; n=34). Using castPCR^TM we studied KRAS status in CTC isolated with IsoFlux^TM and compared it with that of the primary tumor in patients from group 1 and in KRAS wild-type (KRAS^WT) patients with progressive disease (group 2; n=22). Median number of CTC detected with CellSearch® (groups 1 and 2) was 1 (range: 0-78) and with IsoFlux^TM (group 1) was 8 (range: 0-419), showing a modest correlation (r=0.345, P=0.036), which improved if lung metastases (r=0.805, P=0.016) or if lung and liver metastases were present (r=0.812, P=0.05). A Bland-Altman plot showed that the higher the number of CTC detected the larger the difference between both methods in favor of IsoFlux^TM. After a median follow-up since CTC collection of 16 months (range: 1-30) CellSearch® ≥ 3 CTC (HR 2.77, 95% CI 0.77-9.95) and IsoFlux^TM ≥ 11 CTC (HR 4.14, 95% CI 1.05-16.19) were established as the best cutoff points for predicting survival. Using castPCR^TM we found KRAS mutations in CTC in 4 out of 8 patients from group 1 and in 2 out of 3 patients from group 2. None of these mutations were found in the primary tumor using standard methods, possibly reflecting intratumor heterogeneity or treatment selection pressure. We conclude that IsoFlux^TM is more efficient than CellSearch® in the isolation of CTC in patients with advCRC, achieving, in a majority of cases, the established minimum of CTC for castPCR^TM-based genetic analyses.