Breast cancer mortality rates vary across ethnic groups in Israel, where protective factors such as high fertility and breastfeeding rates may be moderated by socioeconomic factors and mammography rates. We aim to investigate disparities in breast cancer mortality between Jewish and Muslim Arab women in Israel and examine how sociodemographic variables and number of children are associated with mortality. Our retrospective follow-up study uses data from the Israeli Central Bureau of Statistics and multivariable Cox regression models, adjusting for age, number of children, country of origin, locality size, and socioeconomic status. Compared to Jewish women, Muslim Arab women exhibited lower breast cancer mortality rates. However, after adjusting for multiple sociodemographic variables, no significant differences persisted between Jewish and Muslim Arab women. Having more than three children was associated with lower mortality among Muslim Arab women, but not among Jewish women. European/American origin, larger localities, and medium socioeconomic status were associated with higher mortality. Sociodemographic factors may therefore explain the disparities in breast cancer mortality between Jewish and Muslim Arab women in Israel. Targeted intervention programs considering unique characteristics and risk factors of different ethnic groups are needed to reduce disparities and improve outcomes.

In this study, we utilized the UniProt database to extract breast cancer genes Total 2658 genes in Homo sapiens are obtain. Then 166 genes are taken and after delating duplicates 158 genes were remains. These genes were then analyzed for their biological pathways using Gene Ontology enrichment analysis through the Genecodis platform, resulting in the identification of 12 unique genes involved in disease pathways. Protein-protein interaction (PPI) network analysis was conducted using the STRING database and Cytoscape software, identifying ANLN,TREM1,LZTFL1,OXSM,PLA2G3,TAS2R13,ABCB10,ECT2,TRPC,BCAS3,PLA2G3,ZDHHC7 and ERBB2 as potential gene targets for breast cancer.

Maternal diet plays a significant role in the fatty acid composition of breast milk. Natural trans fatty acids (TFAs) are generated through the biohydrogenation of unsaturated fatty acids (FAs) in the rumen of animals by bacterial isomerases and are consequently found in milk, dairy products, and meat from ruminant animals. Dietary products such as milk and meat are the primary sources of natural TFAs for humans, derived from rumen fermentations. These peculiar fatty acids hold nutritional significance as they not only lack the detrimental effects on endothelium characteristic of industrially produced trans fat, but also exhibit anti-inflammatory properties. The relationship between the presence in breast milk of eight fatty acids (including natural TFAs trans-vaccenic and conjugated linoleic acid) and maternal diet has been explored, and their abundance has been compared to that of infant formulas. Two cohorts of lactating women participated in this study, originating from a Spanish region adhered to the Southern European Atlantic Diet or Atlantic Diet. While the consumption of conventional meat or dairy products does not seem to increase the abundance of trans fatty acids in breast milk, trans-vaccenic and oleic acid are among the most distinctive features of breast milk fat in mothers consuming naturally improved dairy products, with an improved fatty acid profile. The most significant differences between natural breastfeeding and formula feeding lie in natural trans fatty acids, since formula are notably deficient, while overfortified in alpha-linolenic acid in comparison to breast milk.

The development of multiple drug resistant (MDR) cancer all too often signals the need for alternative toxic therapy or palliative care. Our recent in vivo and in vitro studies using canine MDR lymphoma cancer cells demonstrated that the Anaphase Promoting Complex (APC) is impaired in MDR cells compared to normal canine control and drug sensitive cancer cells. Here, we sought to establish whether this phenomena is a generalizable mechanism independent of species, malignancy type or chemotherapy regime. To test the association of blunted APC activity with MDR cancer behavior, we used matched parental and MDR MCF7 human breast cancer cells, and a patient derived xenograft (PDX) model of human breast cancer. We show that APC activating mechanisms, such as APC subunit 1 (APC1) phosphorylation and CDC27/CDC20 protein associations, are reduced in MCF7 MDR cells when compared to chemosensitive matched cell lines. Consistent with impaired APC function in MDR cells, APC substrate proteins failed to be effectively degraded. Similar to our previous observations in canine MDR lymphoma cells, chemical activation of the APC using Mad2 Inhibitor-1 (M2I-1) in MCF7 MDR cells enhanced APC substrate degradation and resensitized MDR cells in vitro to the cytotoxic effects of the alkylating chemotherapeutic agent, Doxorubicin (DOX). Using cell cycle arrest/release experiments we show that chemo-sensitive and -resistant MCF7 cells progress through the cell cycle at similar rates, but mitosis is delayed in MDR cells with elevated substrate levels. When treated with M2I-1, MDR cells progress through mitosis at a faster rate that coincides with reduced levels of APC substrates. In our PDX model, mice growing a clinically-MDR human breast cancer tumor show significantly reduced tumor growth when treated with M2I-1, with evidence of increased DNA damage and apoptosis. Thus, our results strongly support the hypothesis that APC impairment is a driver of aggressive tumor development and that targeting the APC for activation has the potential for meaningful clinical benefits in treating recurrent cases of MDR malignancy.

The APIS Breast Cancer Subtyping Kit is an mRNA-based assessment of the three biomarkers routinely assessed in all newly diagnosed breast cancers (BC), estrogen receptor (ER), progesterone receptor (PR), and HER2 as well as an additional four genes that create a novel proliferation signature, MKI67, PCNA, CCNA2, KIF23. Taken together the data is used to produce a molecular sub-type for every sample. The kit was evaluated against the current standard protocol of immunohistochemistry (IHC) and/or in situ hybridization (ISH) in breast cancer patients. The data was presented at the weekly breast Multidisciplinary Team (MDT) meeting. 98 consecutive cases of pre-operative breast cancer core biopsies and two core biopsy of nodal metastases yielding 100 cases were assessed. IHC and APIS Results were available for 100 and 99 cases. ER was concordant in 97% cases, PR in 89% and HER2 results were concordant with IHC/ISH in 100% of the cases. Ki-67 IHC was discordant in 3% cases when compared with MK167 alone but discordant in 24% when compared with the four gene proliferation signature. In conclusion, our study, indicates that the APIS Breast Cancer Subtyping Kit is highly concordant when compared to the results produced for ER/PR/HER2 by IHC and/or ISH. The assay could play a role in the routine assessment of newly diagnoses Breast Cancer (BC) specimens.

The aim of the study was to compare the standard baseline imaging, with extended radiological staging. To assess our hypothesis, we performed a prospective, single-centre study which included 132 participants recruited between October 2015 and March 2020. Descriptive statistics, the Friedman and chi-squared tests were performed and p < 0.05 was considered significant. Patients were grouped into two cohorts, CT scan cohort (n=87) and PET-CT cohort (n=43). In the first group the originally determined disease stage changed in 36.8 % of cases, in second group in 51.2 %. The consistency between assessment of axillary lymph nodes by imaging (cN) and the postoperative pathology report (pN) was evaluated. In most cases, clinical and pathological evaluation of involved nodes was consistent, for CT scan the result was χ2(1) = 18.98; p < 0.001, for PET-CT the result was χ2(1) = 6.41; p = 0.03. Highly customized radiation therapy defined as dose boost within the involved lymph nodes, not covered by surgeon, was applied in nine patients.

This comprehensive review elucidates the profound relationship between the human microbiome and breast cancer managrement. Recent findings highlight the significance of microbial alterations in tissues, such as the gut and the breast, and their role in influencing breast cancer risk, development, progression, and treatment outcomes. We delve into how the gut microbiome can modulate systemic inflammatory responses and estrogen levels, thereby impacting cancer initiation and therapeutic drug efficacy. Furthermore, we explore the unique microbial diversity within breast tissue, indicating potential imbalances brought about by cancer and highlighting specific microbes as promising therapeutic targets. Emphasizing a holistic One Health approach, this review underscores the importance of integrating insights from human, animal, and environmental health to gain a deeper understanding of the complex microbe-cancer interplay. As the field advances, strategic manipulation of the microbiome and its metabolites presents innovative prospects for enhancing cancer diagnostics and therapeutics. However, rigorous clinical trials remain essential to confirm the potential of microbiota-based interventions in breast cancer management.

Background. Currently, most of the research in breast cancer has been carried out in conventional two-dimensional (2D) cell culture due to its practical benefits, however, the three-dimensional (3D) cell culture is becoming the model of choice in cancer research because it allows cell-cell and cell-extracellular matrix (ECM) interactions, mimicking the native microenvironment of tumors in vivo. Methods. in this work, we evaluated the effect of 3D cell organization on the expression pattern of miRNAs (by Small-RNAseq) and mRNAs (by microarrays) in the breast cancer SKBR3 cell line and analyzed the biological processes and signaling pathways regulated by the differ-entially expressed protein-coding genes (DE-mRNAs) and miRNAs (DE-microRNAs) found in the organoids. Results. We obtained well-defined cell-aggregated organoids with a grape cluster-like morphology with a size up to 9.2×105 μm3. The transcriptomic assays showed that cell growth in organoids significantly affected (all p < 0.01) the gene expression patterns of both, miRNAs and mRNAs, finding 20 upregulated and 19 downregulated DE-microRNAs, as well as 49 upregulated and 123 downregulated DE-mRNAs. In silico analysis showed that a subset of 11 upregulated DE-microRNAs target 70 downregulated DE-mRNAs. These genes are involved in 150 gene on-tology (GO) biological processes such as regulation of cell morphogenesis, regulation of cell shape, regulation of canonical Wnt signaling pathway, morphogenesis of epithelium, regulation of cy-toskeleton organization, as well as in the MAPK and AGE-RAGE signaling KEGG-pathways. In-terestingly, hsa-mir-122-5p (Fold Change (FC)=15.4), hsa-mir-369-3p (FC=11.4), and hsa-mir-10b-5p (FC=20.1) regulated up to the 81 % of the 70 downregulated DE-mRNAs. Conclu-sion, the organotypic 3D cell-organization architecture of breast cancer SKBR3 cells impacts the expression pattern of miRNAs-mRNAs network mainly through overexpression of hsa-mir-122-5p, hsa-mir-369-3p, and hsa-mir-10b-5p. All these findings suggest that the interaction between cell-cell and cell-ECM as well as the change in the culture architecture impacts gene ex-pression, and therefore, support the pertinence of migrating breast cancer research from conven-tional cultures to 3D models.

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.

The DNA methylation profile of breast cancer differs from that in healthy tissue and can be used as a diagnostic and prognostic biomarker. Aim of the study: to compare gene methylation in small malignant breast tumors less than 2 cm and in healthy tissue and fibroadenoma. Methylation of the following 15 genes was studied: MAST1, PRDM14, ZNF177, DNM2, SSH1, AP2M1, CACNA1E, CPEB4, DLGAP2, CCDC181, GCM2, ITPRIPL1, POM121L2, KCNQ1, TIMP3. Methods: analysis was made by our modified MS-HRM method followed confirmation of the results by pyrosequencing. The genes were selected from publications that studied DNA methylation in breast cancer with high genome coverage. The study group included 48 samples of breast cancer, the control group included 24 samples of fibroadenoma and 24 samples of healthy tissue. Results: significant differences were found in methylation of 8 genes: CCDC181, GSM2, ITPRIPL1, ZNF177, CACNA1E, DLGAP2, TIMP3 (all р<0.001), and PRDM14 (р=0.002). The most accurate diagnostic value, based on logistic regression, was shown with the compound of two genes – CCDC181 and ZNF177 (AUC=0.99) in pyrosequencing analysis. Conclusion: small breast cancer tumors have a specific DNA methylation profile that distinguishes them from healthy tissue and benign proliferative lesions.

Endophytic fungi are a diverse group of microorganisms that colonize the inter- or intracellular spaces of plants for mutual benefits. The interactions with a host plant and other microbiomes are multidimensional and play a crucial role in the production of secondary metabolites. We screened bioactive compounds present in the extracts of Aspergillus flavus, an endophytic fungus isolated from the roots of the medicinal grass Cynodon dactylon, for its anticancer potential. Ethyl acetate extract from isolated A. flavus showed significant cytostatic effects (IC50: 16.25 μg mL−1) against breast cancer cells (MCF-7). Morphology of cells and DAPI stained nuclei along with the results of flow cytometry annexin V/PI assay suggested apoptosis to be the main process leading to cells’ death. While investigating the mechanism that triggers apoptosis, we found that the extract of A. flavus increased ROS generation and caused loss of mitochondrial membrane potential of MCF-7 cells. To identify the metabolites that might be responsible for the anticancer effect, the extract was examined using gas chromatography-mass spectrometry (GC-MS). Interestingly, nine phytochemicals were found to have potential inhibitory effects of anti-apoptotic protein (Bcl-2) in the breast cancer cells. In the in silico molecular docking and molecular dynamics simulation studies revealed that two compounds: 2,4,7-Trinitrofluorenone and 3alpha, 5alpha-Cyclo-ergosta-7,9(11),22t-triene-6beta-ol exhibited significant binding affinities (-9.20, and -9.50 Kcal mol-1, respectively) against Bcl-2 along with binding stability and intermolecular interactions of its ligand-Bcl-2 complexes. Overall, the study found that the endophytic A. flavus from C. dactylon contains plant-like bioactive compounds that have a promising effect in breast cancer.

Up to 25% of early human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients will relapse despite the improvement achieved by the introduction of HER2-targeted therapy. Beyond trastuzumab, other agents approved for early HER2+ BC include the monoclonal antibody pertuzumab, the antibody-drug conjugate (ADC) trastuzumab-emtansine (T-DM1) and the reversible HER2 inhibitor lapatinib. New agents, such as trastuzumab-deruxtecan or tucatinib in combination with capecitabine and trastuzumab, have also shown an improvement in the metastatic setting. Other therapeutic strategies to overcome treatment resistance have been explored in HER2+ BC, mainly in HER2+ that also overexpress estrogen receptors (ER+). One strategy has been to target the cyclin-dependent kinases 4/6 (CDK4/6) as they are downstream of HER2 and many of the cellular pathways associated with resistance to HER2-targeted therapies play a key role in cell cycle and proliferation. Different trials have explored these strategies with encouraging results, but definitive results are needed. In addition, HER2+ BC is known to be more immunogenic than other BC subgroups, with high variability between tumors. Different immunotherapeutic agents have been investigated in this setting, with promising but controversial results obtained to date.

Immune checkpoint blockade (ICB)-based therapy is revolutionizing cancer treatment by fostering successful immune surveillance and effector cell responses against various types of cancers. However, patients with HER2+ cancers are yet to benefit from this therapeutic strategy. Precisely, several questions regarding the right combination of drugs, drug modality, and effective dose recommendations pertaining to the use of ICB-based therapy for HER2+ patients remain unanswered. In this study, we use a mathematical modeling-based approach to quantify the growth inhibition of HER2+ breast cancer (BC) cell colonies (ZR75) when treated with anti-HER2; trastuzumab (TZ) and anti-PD-1/PD-L1 (BMS-202) agents. Our data show that a combination therapy of TZ and BMS-202 can significantly reduce the viability of ZR75 cells and trigger several morphological changes. The combination decreased the cell’s invasiveness along with altering several key pathways, such as Akt/mTor and ErbB2 compared to monotherapy. In addition, BMS-202 causes dose-dependent growth inhibition of HER2+ BC cell colonies alone, while this effect is significantly improved when used in combination with TZ. Based on the in-vitro monoculture experiments conducted, we argue that BMS-202 can cause tumor growth suppression not only by mediating immune response but also by interfering with the growth signaling pathways of HER2+ BC. Nevertheless, further studies are imperative to substantiate this argument and to uncover the potential crosstalk between PD-1/PD-L1 inhibitors and HER2 growth signaling pathways in breast cancer.

Background: transcriptome data provide a valuable resource for the study of cancer molecular mechanisms, but technical biases, samples’ heterogeneity and small sample sizes result in poorly reproducible lists of regulated genes. Additionally, the presence of multiple cellular components contributing to cancer development complicate the interpretation of bulk transcriptomic profiles. Methods: we collected 48 microarray datasets of laser capture microdissected breast tumors, and performed a meta-analysis to identify robust lists of genes differentially expressed in these tumors. We created a database with carefully harmonized metadata to be used as a resource for the research community. Results: combining the results of multiple datasets improved the statistical power, and the analysis of stroma and epithelium separately allows identifying genes with different contribution in each compartment. Conclusions: our database can profitably help biomarkers’ discovery and is readily accessible through a user-friendly web interface (https://aurorasavino.shinyapps.io/metalcm/).

Breast cancer is the most widespread malignancy in women from corner to corner of the world. Nanostructured lipid carrier (NLC) proved its efficacy in the treatment of cancer. NLC loaded with Imatinib (IMA) (NANIMA) was prepared and evaluated for in vitro efficacy in MCF-7 breast cancer cells. Hot homogenization method was used for the preparation of NANIMAs. Aqueous solution of surfactants (hot) was mixed with molten mixture of stearic acid and sesame oil (hot) under homogenization. The prepared NANIMAs were characterized and evaluated for size, polydispersity index, zeta potential, encapsulation efficiency, release studies, stability studies and MTT assay (cytotoxicity studies). The optimized NANIMA revealed particle size of 104.63 ± 9.55 d.nm, PdI of 0.227 ± 0.06 and EE of 99.79 ± 0.03. All NANIMAs revealed slow and sustained release behaviour. The surfactants used in the preparation of NANIMAs exhibited their effects on particle size, zeta potential, encapsulation efficiency, stability studies and release studies. The cytotoxicity studies unveiled 8.75 times increase in cytotoxicity for optimized NANIMA (IC50 = 6 µM) when compared with IMA alone (IC50 = 52.5 µM) on MCF-7 breast cancer cells. After this, NLC containing IMA possibly will be employed for the cure of breast cancer. A lesser amount of IMA loaded NLC will be sufficient than IMA alone for the treatment of breast cancer. Moreover, the patient will exhibit not as much of adverse effects as in case of IMA alone. Consequently, NANIMA could prove to be useful for effective therapeutic outcome in breast cancer treatment.

Cancers overexpressing the ERBB2 oncogene are aggressive and associated with a poor prognosis. Trastuzumab is a ERBB2 specific recombinant antibody employed for the treatment of these diseases since it blocks ERBB2 signaling causing growth arrest and survival inhibition. While the effects of Trastuzumab on ERBB2 cancer cells are well known, those on the extracellular vesicles released from these cells are scarce. This study focused on ERBB2+ breast cancer cells and aimed to establish what type of EVs they release and whether Trastuzumab affects their morphology and molecular composition. To these aims, we performed immunoelectron microscopy, immunoblot, and high-resolution mass spectrometry analyses on EVs purified by differential centrifugation of culture supernatant. Here we show that EVs released from ERBB2+ breast cancer cells are polymorphic in size and appearance, and that ERBB2 is preferentially associated with large (120 nm) EVs. Moreover, we report that Tz induces the expression of a specific glycosylated 50 kDa isoform of the CD63 tetraspanin and modulates the expression of 51 EVs proteins, including TOP1. As these proteins are functionally associated with organelle organization, cytokinesis, and response to lipids, we suggest that Tz may influence these cellular processes in target cells at distant sites via modified EVs.

Background. This study aims to estimate the rate of death by cancer, according to Radio Base Stations (RBS) radiofrequency exposure, especially for the types of breast, cervix, lung and esophagus cancer. Methods. We collected information about the number of deaths by cancer, gender, age group, Gross Domestic Product per capita, death year and the amount of exposure over the lifetime. We investigated all cancer types and some specific types (breast, cervix, lung and esophagus cancers). Results. In capitals where RBS radiofrequency exposure was higher than 2,000/antennas-year, the average mortality rate was 112/100,000 for all cancers. The adjusted analysis showed that the higher the exposure to RBS radiofrequency, the higher cancer mortality. The highest adjusted risk was observed for cervix cancer (Rate Ratio = 2.18). The spatial analysis showed that the highest RBS radiofrequency exposure was observed in a city in southern Brazil, which also showed the highest mortality rate for all types of cancer and specifically for lung and breast cancer. Conclusion. The balance of our results indicates that the exposure to radiofrequency electromagnetic fields from RBS increases the rate of death by all types of cancer.

Epithelial-mesenchymal transition (EMT) is a cellular biological process involved in migration of primary cancer cells to secondary sites facilitating metastasis. Besides, EMT also confers properties such as stemness, drug resistance and immune evasion which can aid a successful colonization at the distant site. EMT is not a binary process; recent evidence suggests that cells in partial EMT or hybrid E/M phenotype(s) can have enhanced stemness and drug resistance as compared to those undergoing a complete EMT. Moreover, partial EMT enables collective migration of cells as clusters of circulating tumor cells or emboli, further endorsing that cells in hybrid E/M phenotypes may be the ‘fittest’ for metastasis. Here, we review mechanisms and implications of hybrid E/M phenotypes, including their reported association with hypoxia. Hypoxia-driven activation of HIF-1α can drive EMT. In addition, cyclic hypoxia, as compared to acute or chronic hypoxia, shows the highest levels of active HIF-1α and can augment cancer aggressiveness to a greater extent, including enriching for a partial EMT phenotype. We also discuss how metastasis is influenced by hypoxia, partial EMT and collective cell migration, and call for a better understanding of interconnections among these mechanisms. We discuss the known regulators of hypoxia, hybrid EMT and collective cell migration and highlight the gaps which needs to be filled for connecting these three axes which will increase our understanding of dynamics of metastasis and help control it more effectively.

Breast cancer (BC) is among the leading causes of mortality from cancer in women. Many of the available anticancer drugs have various side effects. Therefore, researchers are seeking novel anticancer agents particularly from natural compounds and in this regard, snake venom is still one of the main sources of drug discovery. Previous studies showed potential anticancer effects of Cytotoxin II (CTII) from Naja naja oxiana against the different types of cancers. In this study, a pET-SUMO-CTII vector was transformed into SHuffle® T7 Express, an Escherichia coli strain, for recombinant protein expression (rCTII) and the cytotoxic effects of this protein was assessed in MCF-7 cells. The flow cytometry assay was applied to measure the apoptosis and cell cycle. Also, mRNA levels of the Bax, Bcl2, P53, caspase-3, caspase-8, caspase-9, caspase-10, matrix metalloproteinases (MMP)-3, and MMP-9 were analyzed by quantitative real-time PCR to determine the underlying cellular pathways affected by rCTII. The results of this study showed that treatment with 4 µg mL-1 of rCTII enhanced apoptosis through the intrinsic and extrinsic pathways. Also, the increase of the cells' proportion in the sub-G1 phase as well as a reduction in S phase was observed. In addition, the expression of MMP-3 and MMP-9 was decreased in the treated group in comparison to the control group that may contribute to the reduced migratory ability of tumor cells. These experimental results indicate that rCTII has anti-proliferative potential, and so this protein could be a potential drug for BC therapy in combination with other drugs.

Doxorubicin (DOX) is a frequently used chemotherapeutic drug for breast cancer, but its site specificity and local internalization into tumor cells is rather low. In this paper we conjugated magnetic nanoparticles (MNPs) with DOX and/or a pseudopeptide NucAnt (N6L) as modality to enhance DOX-induced antitumor effects in breast cancer cells (BT474). In this context, we determined cellular uptake of MNP formulations, analyzed cell viability and expression of apoptotic and cell cycle proteins after magnetic hyperthermia (43°C, 1 h) in vivo and in vitro. We have shown that i) the presence of N6L on the surface of DOX-functionalized MNPs increases their internalization into a target cells and potentiates the cytotoxic potential of the anticancer drug, ii) in combination with hyperthermia, DOX functionalized MNPs influence the expression of apoptotic and cell cycle proteins, and also favors tumor regression in vivo. Our data show that intratumoral application of DOX coupled MNPs is able to overcome biological barriers to chemotherapeutic drugs, enabling them to penetrate into the target cells. Combined with hyperthermia these MNPs can be an effective method in enhancing the localised delivery and penetration of DOX into breast cancer cells.

With advances in next-generation sequencing(NGS) technologies, large number of multiple types of high-throughput genomics data are available. A great challenge in exploring cancer mechanism is to identify the driver genes from the mutation genes by analyzing and integrating multi-types genomics data. Breast cancer is known as a heterogeneous disease. The identification of subtype-specific driver genes is critical to guide the diagnosis, assessment of prognosis and treatment of breast cancer. We developed an integrated frame based on gene expression profilings and copy number variation(CNV) data to identify breast cancer subtype-specific driver genes. In this frame, we employed statistical machine-learning method to select gene subsets and utilized an module-network analysis method to identify potential candidate driver genes. The final subtype-specific driver genes were acquired by paired-wise comparison in subtypes. To validate specificity of the driver genes, the gene expression data of these genes were applied to classify the patient samples with 10-fold cross validation and the enrichment analysis were also conducted on the identified driver genes. The experimental results show that the proposed integrative method can identify the potential driver genes and the classifier with these genes acquired better performance than with genes identified by other methods.

Heterosis of growth traits in economic fish has benefited the production of aquaculture for many years, yet its genetic and molecular basis has been remained obscure. Nowadays, a new germplasm of hybrid Jinhu grouper (Epinephelus fuscoguttatus♀ × E. tukula♂), exhibiting paternal-biased growth heterosis, has provided an excellent model for investigating the potential regulatory mechanisms of heterosis. We integrated transcriptome and methylome to unravel the changes of gene expression, epigenetic modification, and subgenome dominance in Jinhu grouper compared with maternal E. fuscoguttatus. Integration analyses showed that the heterotic hybrids showed lower genomic DNA methylation levels than the purebred parent, and the up-regulated genes were mostly DNA hypomethylation. Furthermore, allele-specific expression (ASE) detected paternal subgenome dominance regulated paternal-biased heterosis, and paternal bias differentially expressed genes (DEGs) were wholly up-regulated in the muscle. Muti-omics results highlighted the role of lipid metabolism, particularly “Fatty acid synthesis”, “EPA biosynthesis”, and “Signaling lipids”, in Jinhu grouper heterosis formation. Coherently, our studies have proved that the eicosapentaenoic acid (EPA) of Jinhu grouper was greater than that of maternal E. fuscoguttatus (8.46% vs 7.46%). Finally, we constructed a potential regulatory network for control of the heterosis formation in Jinhu grouper. Among them, fasn, pparg, dgat1, igf1, pomca, fgf8a, and fgfr4, were identified as key genes. Our results provide new and valuable clues for understanding paternal-biased growth heterosis in Jinhu grouper, taking a significant step towards the molecular basis of heterosis.

Many anti-tumor effects of group-specific component-derived macrophage-activating factors (GcMAFs) have been reported; however, the specific mechanisms remain unclear. Controlling tumor-associated macrophages (TAMs) in the tumor microenvironment is essential for cancer treatment. This study assessed the role of GcMAF in macrophage activation, elucidated the mechanisms by which it exerts its anti-tumor effects, and determined its effects on TAMs in the tumor microenvironment. GcMAF-stimulated RAW264.7 macrophages and EMT6 breast tumor cells were co-cultured in a 0.4-µm pore cell culture insert, and gene and protein expression and cell viability were evaluated. DNA microarray analysis of GcMAF-stimulated RAW264.7 cells was conducted. The induction of M2 RAW264.7 cells by interleukin (IL)-4 and IL-13 was analyzed. GcMAF stimulation increased the tumor necrosis factor-α and inducible nitric oxide synthase mRNA and protein levels in RAW264.7 cells but decreased the viability of co-cultured EMT6 cells. These results were confirmed in the M2 RAW264M2.7 cells, suggesting that GcMAF exerts anti-tumor effects by inducing the differentiation of macrophages into the M1 type and reprogramming M2 macrophages to the M1 type. The anti-tumor activity of GcMAF via M2-to-M1 macrophage reprogramming could aid in developing novel cancer immunotherapies.

Developing sustainability competences is an important endeavor for education, as competence development can be complex and requires appropriate approaches. In the case of preparing future educators, this becomes even more important, because of their multiplier role. The current study presents how a project, based on living-lab methodology, helped preservice preschool teachers, attending a course on sustainability issues, develop sustainability-specific professional action competence. Students collaborated with an organization and a school and were trained to deliver to 6-year-old pupils, activities concerning the protection of sea turtles. The process included reflection, based on a given template. After the intervention, the preservice preschool teachers reflected upon their role and professional performance and discussed how they, benefited from this project. They further analyzed through a group interview, how the Living Lab methodology raised their professional confidence and self-efficacy, and helped them develop content knowledge, pedagogical content knowledge, and a sense of purpose and motivation for teaching about sustainability. Outcomes indicate that participants felt confident and efficacious to teach about sustainability, and developed their content knowledge, pedagogy content knowledge, motivation, and volition due to a strong sense of purpose and responsibility. The overall process facilitated the development of critical thinking, systemic thinking, reflection, and collaboration..

Through the use of Smart Sensor Networks (SSN), Marine Observatories (MO) provide continuous ocean monitoring. Deployed sensors may not perform as intended due to the heterogeneity of SSN devices’ hardware and software when combined with the Internet. Hence, SSN are regarded as complex distributed systems. As such, SSN designers will encounter challenges throughout the design phase related to time, complexity, sharing diverse domain experiences (viewpoints), and ensuring optimal performance for the deployed SSN. To this end, we describe in this article how we extended our previously proposed ArchiMO meta-model and design tool by extending an Enterprise Architecture Framework based on the ArchiMate Modeling Language. This extension proposes the incorporation of new Underwater Environmental Constraints (UEC) for SSN in ArchiMO which is coupled with the fusion of sensors with Artificial Intelligence. This serves as the basis for generating a new version of our ArchiMO design tool, which incorporates the new added constraints and invokes the AI created Database. To illustrate our proposal, we use the newly generated ArchiMO to create a model in the MO domain. Furthermore, we use our self-developed domain-specific model compiler to produce the relevant simulation code. Throughout the design phase, our approach contributes to handle and control the uncertainties and variances of the provided quality of service that may occur during the performance of the SSN, hence reducing the design activity’s complexity and time. It provides a way to share the different viewpoints of the designers in the domain of SSN.

Fluorescent bioprobes are invaluable tools for visualizing live cells and deciphering complex biological processes by targeting intracellular biomarkers without disrupting cellular functions. In addition to protein-binding concepts, fluorescent probes utilize various mechanisms, including membrane, metabolism, and gating-oriented strategies. This study introduces a novel fluorescent mechanism distinct from existing ways. Here, we developed a B-cell selective probe, CDrB, with unique transport mechanisms. Through SLC-CRISPRa screening, we identified two transporters, SLCO1B3 and SLC25A41, by sorting out populations exhibiting higher and lower fluorescence intensities, respectively, demonstrating contrasting activities. We confirmed that SLCO1B3, with comparable expression levels in T and B cells, facilitates the transport of CDrB into cells, while SLC25A41, overexpressed in T lymphocytes, actively exports CDrB. The observation suggests that SLC25A41 plays a crucial role in discriminating between T and B lymphocytes. Furthermore, it reveals the potential for reversible localization of SLC25A41 to demonstrate its distinct activity. This study is the first report to unveil a novel strategy of SLC by exporting the probe. We anticipate that this research will open up new avenues for developing fluorescent probes.

The structural transitions RNAs undergo during trafficking are not well-understood. Here, we used the well-developed yeast Ty1 retrotransposon to provide the first structural model of genome (g) RNA in the nucleus from a retrovirus-like transposon. Through a detailed comparison of nuclear Ty1 gRNA structure with those established in the cytoplasm, virus-like particles (VLPs), and synthesized in vitro, we detected Ty1 gRNA structural alternations that occur during retrotransposition. Full-length Ty1 gRNA serves as the mRNA for Gag and Gag-Pol proteins and as the genome that is reverse transcribed within VLPs. We show that about 60% of base pairs predicted for the nuclear Ty1 gRNA appear in the cytoplasm, and active translation does not account for such structural differences. Most of the shared base pairs are represented by short-range interactions, while the long-distance pairings seem unique for each compartment. Highly structured motifs tend to be preserved after nuclear export of Ty1 gRNA. In addition, our study highlights the important role of Ty1 Gag in mediating critical RNA:RNA interactions required for retrotransposition.

Plant-parasitic nematodes cause expressive annual yield losses to worldwide agricultural production. Most cultivated plants have no known resistance against nematodes and the few bearing a resistance gene can be overcome by certain species. The chemical methods that have been deployed to control nematodes were largely banned from use due to their poor specificity and high toxicity. Hence, there is an urgent need for the development of cleaner and more specific control methods. Recent advances in nematode genomics, including in phytoparasitic species, provide an unprecedented opportunity to identify genes and functions specific to these pests. Using phylogenomics, we compared 61 nematode genomes, including 16 for plant-parasitic species and identified more than 24,000 protein families specific to these parasites. In the genome of Meloidogyne incognita, one of the most devastating plant parasites, we found ca. 10,000 proteins with orthologs restricted only to phytoparasitic species and no further homology in protein databases. Among these phytoparasites-specific proteins, ca. 1,000 shared the same properties as known secreted effectors involved in essential parasitic functions. Of those, 68 were novel and showed strong expression during the endophytic phase of the nematode life cycle, based on both RNA-seq and RT-qPCR analyses. Besides effector candidates, transcription-related and neuro-perception functions were enriched in phytoparasites-specific proteins, revealing interesting targets for nematode control methods. This phylogenomics analysis, constitutes an unprecedented resource for the further understanding of the genetic basis of nematode adaptation to phytoparasitism and for the development of more efficient control methods.

African locust bean (Parkia biglobosa (Jacq.) is a multi-purpose economic tree with genetic potentials in sub-Saharan Africa. Its cultivation and production is declining with increased aging and genetically threatened throughout its natural ranges. Research efforts are needed to change the present scenario to sustainable cultivation and utilization, hence this present study. This study was aimed at evaluating genetic diversity and geographical spread relationships of twenty landraces collected from different ecological zones of Nigeria using simple sequence repeat (SSR) markers. Ten SSR markers were screened and five primers (PbL02, PbL03, PbL04, PbL05 and PbL09) were selected based on clear amplification products and reproducible scorable bands. The SSR primers detected a total of 55 alleles ranged from 10 to 14 alleles with a mean of 11. The percentage polymorphisms were high and ranged from 68.75 % in PbL04 to 84.21 % in PbL05 with a mean of 74.16 %. The polymorphic information content (PIC) was in the range of 0.31 in PbL02 to 0.37 in PbL09. The genetic diversity and heterozygosity values ranged from 0.39 to 0.50 and 0.00 to 0.68 while the average genetic distance for all pair wise comparisons was 0.31.The first five Principal Component (PC) accounted for 70.20 % of the total variation out of which PC1 (31.50%) and PC2 (19.20%) extracted 49.70% molecular similarity. The dendrogram resulted in separation of the 19 landraces into three major clusters based on unweighted pair group method with arithmetic average. Cluster I comprised of five landraces: ABNo130 and BENo023; OYNo11, KANo125 and NiNo262 while cluster II had only one (BANo116). Cluster III was diverse comprising 13 landraces: ZANo188, KNNo162, KENo220, GMNo076 and EbNo260, ADNo64, EdNo164, KANo137, KENo217, KwNo270, NiNo241, OsNo206 and PLNo120. The homogeneity of alleles among the studied landraces suggested suspicion of loss of genetic intra-specific variation among the landraces of P. biglobosa which calls for concerted efforts toward better cultivation, conservation, management, utilization and genetic improvement of the species in Nigeria.

A variety of techniques have been utilized in metal additive manufacturing (AM) for melt pool size management, including modeling and feed-forward approaches. In a few cases, closed-loop control has been demonstrated. In this research, closed-loop melt pool size control for large-scale, laser-wire based Directed Energy Deposition is demonstrated with a novel modification: site-specific changes to the controller set-point were commanded at trigger points, the locations of which were generated by the projection of a secondary geometry onto the primary 3D-printed component geometry. The present work shows that, through this technique, it is possible to print a specific geometry that occurs beyond the actual toolpath of the print head. This is denoted as an extra-toolpath geometry and is fundamentally different from other methods of generating component features in metal AM. A proof-of-principle experiment is presented in which a complex oak leaf geometry was embossed on an otherwise ordinary double-bead wall made from Ti-6Al-4V. The process is introduced and characterized primarily from a controls perspective with reports on the performance of the control system, the melt pool size response, and the resulting geometry. The implications of this capability, which extend beyond localized control of bead geometry to the potential mitigations of defects and functional grading of component properties, are discussed.

The application of thermoelectric generators (TEG) on the nozzle of an aviation jet engine was studied by finite element TEG-simulations. Against the background of system-level requirements of the reference aircraft this work reports the resulting requirements on the TEG design with respect to applied thermoelectric (TE) element lengths and fill factors (F) within the TE modules in order to maintain a positive effect on the specific fuel consumption. Assuming a virtual optimized TE material and varying the convective heat transfer coefficients at the nozzle surfaces this work reports the achievable power output. System-level requirement on the gravimetric power density (> 100 Wkg-1) can only be met for F ≤ 21%. Extrapolating TEG coverage to the full nozzle surface, the power output reaches 1.65 kW per engine. Assessment of further potential is demonstrated by a parametric study on the fill factor, convective heat transfer coefficients, and materials performance. This study confirms a feasible design range for TEG installation on the aircraft nozzle with a positive impact on the fuel consumption. This application translates into a reduction of operational costs, allowing for an economically efficient installation of TEG in consideration of the cost-specific power output of modern thermoelectric materials.

Abstract: Breast cancer is one of the leading causes of death in the female population due to the re-sistance of cancer cells to many anticancer drugs used. Curcumin has cytotoxic activities against breast cancer cells, although it has limited use due to its poor bioavailability and rapid metabolic elimination. The synthesis of metal complexes of curcumin and curcuminoids is a relevant topic in the search for more active and selective derivatives of these molecular scaffolds. However, solubil-ity and bioavailability are concomitant disadvantages of these types of molecules. To overcome such drawbacks, the preparation of inclusion complexes offers a chemical and pharmacologically safe option for improving the aqueous solubility of organic molecules. Herein, we describe the preparation of the inclusion complex of dimethoxy curcumin magnesium complex with cyclodex-trin (DiMeOC-Mg-BCD, 5) in the stoichiometric relationship 1:1. This new inclusion complex's solubility in aqueous media (PBS) was improved by a factor of 6x over the free metal complex (DiMeOC-Mg). Furthermore, 5 affects cell metabolic rate, cell morphology, cell migration, induced apoptosis, and downregulation of the MMP-2 and MMP-9, IL-6, and STAT3 expression levels on MDA MB 231 cell lines. Results of an antitumor assay in an in-ovo model showed up to 30% inhi-bition of tumour growth for breast cancer (MDA-MB-231) when using 5 (0.650 mg/Kg dose), and 17.29 % inhibition with the free homoleptic metal complex (1.5 mg/Kg dose, DiMeOC-Mg). While the formulation of inclusion complexes from metal complexes of curcuminoids demonstrates its usefulness in improving the solubility and bioavailability of these metallodrugs, the new DiMeOC-Mg-BCD exhibits excellent potential for use as a therapeutic agent in the battle against breast cancer.

Background: Circulating rare cells participate in breast cancer evolution as systemic components of the disease and thus, are a source of theranostic information. Exploration of cancer-associated rare cells is in its infancy. We determined the validity of a rare-cell detection platform and demonstrated the usefulness of a certain rare cell subset as a novel approach to characterize the breast cancer system. Methods: Linearity of the Rarmax® platform was established using a spike-in approach. The platform includes red blood cell lysis, leukocyte depletion and high-resolution fluorescence image recording. Rare cell analysis was conducted on 28 samples (before and after surgery) from 14 patients with breast cancer, 20 healthy volunteers and 9 non-cancer control volunteers. In-depth identification of rare cells, including circulating tumor cells, endothelial-like cells, erythroblasts and inflammation-associated cells, was performed using a phenotype and morphology-based classification system. Results: The platform performed linearly over a range of 5-950 spiked cells, with an average recovery of 84.6%. Circulating epithelial and endothelial-like cell subsets have been demonstrated to be associated with or independent of cancer with tumor presence. Furthermore, certain cell patterns may be associated with treatment-related adverse effects. The sensitivity in detecting tumor-presence and cancer-associated abnormality before surgery was 50% and 85.7%, respectively and the specificity was 100% and 96.6%, respectively. Conclusion: The present study supports the idea of a cancer-associated rare cell abnormality to represent tumor entities as well as systemic cancer. The latter is independent of the apparent clinical cancer.

This study delves into the realm of potential therapeutics for breast cancer by conducting a comprehensive docking simulation and virtual screening analysis using Autodock Vina Algorithm. The focus based on the human epidermal growth factor receptor 2 (HER2), a key protein associated with various cancers, particularly in the context of breast cancer.The results reveal compelling insights into the binding interactions of several natural compounds and drugs with HER2. Notably, Acebilustat, Bemcentinib, and Amentoflavone exhibit outstanding binding energies, averaging around -10 kcal/mol, suggesting strong and favorable interactions with the HER2 target.These encouraging findings not only emphasize the potential biological significance of these compounds but also hint at their potential usefulness in fighting breast cancer.Their promising binding affinities with HER2 position them as potential candidates for further investigation and development as therapeutic agents against breast cancer.

As breast cancer continues to take a devasting public health toll, most primary prevention approaches are targeted at individual actions. We have proposed, instead, developing systemic, population approaches to preventing the disease. We used a combined qualitative-quantitative methodology, Group Concept Mapping (GCM), to identify Importance and Feasibility ratings of systemic interventions across a wide spectrum of approaches and stakeholders. Participants (n=351) from across the state of California sorted 84 potential interventions into topical piles, and then rated each intervention on perceived Importance and Feasibility. Multidimensional scaling and cluster analysis identified eleven clusters or themes of interventions. Participants rated interventions on Importance and Feasibility differently depending on the region of the state in which they lived. The results of this study underscore the importance of sharing health information with and seeking public health solutions from community partners in general and from beyond the urban areas usually studied.

Obesity is one of the most prevalent chronic diseases and has become a global epidemic. Obesity leads to a greater risk of breast cancer (BC), metastases, recurrence, and decreased survival. For sustained weight loss, bariatric surgery is effective as a long-term solution. Bariatric surgery is associated with improved outcomes of several cancers including BC, although the mechanisms mediating this protection are unknown. We hypothesized that elevated bile acid pools detected after bariatric surgery may be factors that contribute to improved BC outcomes. Indeed, patients with greater expression of the bile acid receptor FXR displayed improved survival in specific BC subtypes. Patients with tumors that are estrogen receptor negative (ER-) displayed significantly elevated survival with higher FXR (NR1H4) expression compared to lower expression. FXR is a nuclear hormone receptor activated by bile acids. Therefore, we posited that activating FXR using an established FDA-approved agonist would display anticancer effects. Indeed, FXR agonism by the bile acid mimetic known commercially as OCALIVA (“OCA”), or Obeticholic acid (INT-747), significantly reduced BC progression and overall tumor burden in a pre-clinical model. In human and murine BC analyses in vitro, agonism of FXR significantly and dose-dependently inhibited proliferation, migration, and viability. In contrast, synthetic agonism of another common bile acid receptor, the G protein-coupled bile acid receptor (GPBAR1, TGR5) which is mainly activated by secondary bile acids, failed to significantly alter cancer cell dynamics. In conclusion, agonism of FXR by primary bile acid memetic OCA yields potent anti-tumor effects potentially through inhibition of proliferation and migration and reduced cell viability. Findings suggest that FXR is a tumor suppressor gene with high potential for personalized therapeutic strategies for individuals with BC.

Protein-drug interactions are crucial for understanding drug delivery and cell functions. Jacalin is a suitable molecule for such targeting, as it specifically recognizes the tu-mor-associated Thomsen-Friedenreich antigen that is expressed on the glycosylated proteins in cancer cells. The present paper describes the interaction of curcumin and jacalin, a possible carrier molecule for the delivery of antitumor drugs due to its ability to recognize tumor cells. Our results have shown that both steady state fluorescence and fluorescent label-ling of jacalin are two reliable methods to determine jacalin-curcumin interactions. The affinity of jacalin for curcumin is consistently within the micromolar range (using flu-orescence and microscale thermophoresis) showing high-affinity binding of the com-plex. In vitro experiments on the triple negative breast cancer MDA-MB-231 cells indi-cated inhibition of cell growth after treating with the jacalin-curcumin complex for 48 h. The cell survival fraction was significantly reduced to 50% after combined treatment. In this paper, we report for the first time about the jacalin-curcumin interaction. We quantified this unique biomolecular interaction and gathered additional information on the binding event. We observed that the jacalin-curcumin complex inhibits the proliferation of the triple negative breast cancer MDA-MB-231 cells.

Mucinous breast carcinoma is a rare subtype of mammary neoplasm encountered in medical practice. It represents approximately 1-6% of all breast cancers and is more common in postmenopausal women. There are two subtypes of mucinous breast carcinoma: pure and mixed. We report the case of a 73-year-old Caucasian woman diagnosed with mucinous pancreatic cystadenoma in 2007. She underwent a surgical procedure involving pancreatectomy of the body and tail, along with multiple known cardiovascular and metabolic comorbidities. In November 2019, during a clinical-biological evaluation for associated diseases, a mucinous carcinoma of the right breast was accidentally detected and later confirmed through further investigations. For treatment, a surgical procedure was performed involving lower right quadrantectomy with right axillary lymph node dissection. The postoperative clinical course was favorable. In conclusion, we present the case of a patient diagnosed with mixed mucinous breast carcinoma, without axillary lymph node invasion. Postmenopausal women with diabetes, overweight, and obesity have an increased susceptibility to breast cancer, with our patient having all these risk factors. To date, no study has demonstrated the genetic or radiation implication in the occurrence of mucinous carcinomas, nor the possible development of mucinous carcinomas in series in the same patient. Current data are insufficient to provide recommendations for the screening of malignant mucinous tumors in subjects with significant cardiometabolic risk factors.

Two monoclonal antibodies (mAbs) against human epidermal growth factor receptor 2 (HER2), trastuzumab and pertuzumab, were clinically approved. We previously developed a highly sensitive and specific anti-HER2 mAb, H2Mab-139 (mouse IgG1, kappa). In this study, we produced a defucosylated IgG2a version of anti‑HER2 mAb (H2Mab-139-mG2a-f) to enhance ADCC-mediated antitumor activity. H2Mab-139-mG2a-f exhibits a high binding affinity in flow cytometry with the dissociation constant (KD) determined to be 3.9 × 10‑9 M and 7.7 × 10‑9 M against HER2‑overexpressed Chinese hamster ovary (CHO)-K1 (CHO/HER2) and HER2-positive BT-474 cells, respectively. Moreover, we showed that H2Mab-139-mG2a-f exerted ADCC and complement-dependent cytotoxicity against CHO/HER2 and BT-474 cells in vitro and exhibited potent antitumor activities in the xenograft models. These results indicated that H2Mab-139-mG2a-f exerts antitumor effects against HER2-positive human breast cancers and could be useful for an antibody treatment regimen for HER2-positive human cancers.

Background The purpose of this study was to clarify the relationship structure of quality of life (QOL) in survivors of breast cancer, including difficulty in daily life and negative experience as health-related indicators. Methods Participants were survivors of breast cancer for more than 2 years after primary breast cancer surgery and belonged to self-help groups. The assessment used FACT-B (QOL), HADS (anxiety and depression), SOC (sense of coherence), WHODAS 2.0 (difficulties in daily life), and CAOD (negative experiences). Bayesian structural equation modeling (BSEM) was performed to analyze the hypothesized model. If the causal model was significant, multiplication of the path coefficient from anxiety and depression to QOL, and from SOC to anxiety and depression, was considered a direct effect on QOL, and from SOC to difficulty in daily life, from difficulty in daily life to negative experiences, and from negative experiences to anxiety and depression were considered indirect effects on QOL. Results Goodness of fit of the model in the BSEM was satisfactory. The direct effect was 0.274, and indirect effect was 0.163. Conclusions These direct and indirect approaches to difficulties in daily life are very significant because they can provide a basis for development of support strategies to increase QOL.

Aim: This study aimed to investigate whether baseline 18F-FDG PET-derived semiquantitative parameters could predict disease-free survival in patients with grade III breast cancer of different molecular subtypes undergoing neoadjuvant chemotherapy (NAC). Materials and Methods: Patients were retrospectively retrieved from the databases of two Italian hospitals (University of Padua and University Hospital of Ferrara). Inclusion criteria were: 1) histologically proven diagnosis of grade III breast cancer; 2) history of NAC; 3) execution of a baseline 18F-FDG PET/CT scan before the start of NAC; 4) adequate follow-up time to compute the 3Y-DFS. For each 18F-FDG-PET/CT scan, the following parameters were calculated in the primary tumor (SUVmax, SUVmean, MTV, TLG) and whole-body (WB_SUVmax, WB_MTV, and WB_TLG). Receiver operating characteristic (ROC) analysis was used for each parameter to assess the prediction capability for 3Y-DFS. DFS differences between groups were assessed using Kaplan-Meier curves and compared by log-rank test. Results: Ninety-five grade III breast cancer patients with different molecular types were retrieved (luminal A: 5; luminal B: 34; luminal B-HER2: 22; HER2-enriched: 7; triple-negative: 27). In the whole group of patients, WB_SUVmax was the best predictor of recurrence (AUC: 0.66; best cut-off: WB_SUVmax>9.43; SS: 96%; SP: 38.1%; p<0.008). Patients with luminal A and Her-2-enriched breast cancer types were excluded from the molecular subgroup analysis due to the small study samples (5 and 7, respectively). In luminal B patients (n=34), WB_MTV (AUC: 0.75; best cut-off: WB_MTV>195.33; SS: 55.56%, SP: 100%; p=0.002) and WB_TLG (AUC: 0.73; best cut-off: WB_TLG>1066.21; SS: 55.56%, SP: 100%; p=0.05) were the best predictors of 3Y-DFS. Patients had a higher probability of DFS in case of a WB_MTV≤195.33 (3429±210 vs. 446±144 days; p<0.001) or WB_TLG≤ 1066.33 (937.35±19 vs. 496±131 days; p<0.001). In luminal B-HER2 patients (n=22), WB_SUVmax was the only predictor of 3Y-DFS (AUC: 0.857; best cut-off: WB_SUVmax>13.12; SS: 100%; SP: 71.43%; p<0.001); patients with WB_SUVmax≤13.12 had a significantly longer DFS (3857 days) than patients with a WB_SUVmax >13.12 (1693±430 days; p<0.004). No parameter resulted significant in the prediction of 3Y-DFS in patients with grade III triple-negative cancer. Conclusion: Volume-based parameters, extracted from baseline 18F-FDG PET, seem to be promising tools in the prediction of recurrence within 3 years in patients with grade III luminal B and luminal B- HER2 breast cancer undergoing NAC. Larger study samples are needed to confirm these preliminary findings.

TomoBreast hypothesized that hypofractionated 15 fractions/3 weeks image-guided radiation therapy (H-IGRT) can reduce lung-heart toxicity, as compared with normofractionated 25-33 fractions/5-7 weeks conventional radiation therapy (CRT). 123 women with stage I-II operated breast cancer were randomized to receive CRT (N=64) or H-IGRT (N=59). The primary endpoint used a four-items measure of the time to 10% alteration in any of patient self-reported measure, physician clinical evaluation, echocardiography or lung function tests, analyzed by intention-to-treat without exclusion. Results found comparable survivals, but H-IGRT significantly reduced the toxicity measured by lung diffusion capacity and alveolar volume as compared with CRT, G1 in 53% (31/59) versus 72% (44/61) patients, P=0.006; G2, 29% versus 48%, P=0.020. H-IGRT significantly reduced the risk of composite cardio-pulmonary alteration at 5 years, 10.2% versus 26.7%, P=0.024. In conclusion, TomoBreast is a proof-of-concept that image-guided radiation-therapy can improve the overall balance of lung-heart outcomes in breast cancer adjuvant therapy. Furthermore, the significance of the findings supports the efficacy of a small trial size design, which can be critical when clinical research resources are limited.

Deep convolutional neural networks (CNNs) have been widely used in various medical imaging tasks. However, due to the intrinsic locality of convolution operation, CNNs generally cannot model long-range dependencies well, which are important for accurately identifying breast cancer from unregistered multi-view mammograms. This motivates us to leverage the architecture of Vision Transformers to capture long-range relationships of multiple mammograms from the same patient. For this purpose, we employ local Transformer blocks to separately learn patch relationships within a specific view (CC/MLO) of one side (right/left) of mammogram. The outputs from different views and sides are concatenated and fed into global Transformer blocks, to jointly learn patch relationships between two different views of the left and right breasts. To evaluate the proposed model, we retrospectively assembled a dataset involving 949 sets of CC and MLO view mammograms, which include 470 malignant cases and 479 normal or benign cases. We trained and evaluated the model using a five-fold cross-validation method. Without any arduous preprocessing steps (e.g., optimal window cropping, chest wall or pectoral muscle removal, two-view image registration, etc.), our two-view Transformer-based model achieves lesion classification accuracy of 77.0% and area under ROC curve (AUC = 0.814), outperforming state-of-the-art multi-view CNNs by 3.1% and 3%, respectively. Meanwhile, the new two-view model improves mammographic case classification accuracies of two single-view models by 7.4% (CC) and 4.5% (MLO), respectively. The promising results unveil the great potential of using Transformers to develop high-performing computer-aided diagnosis (CADx) schemes of mammography.

The resistance of cancer cell subpopulations, including cancer stem cell (CSC) populations, to apoptosis-inducing chemotherapeutic agents is a key barrier to improved outcomes for cancer patients. The cationic amphiphilic drug hexamethylene amiloride (HMA) has been previously demonstrated to efficiently kill bulk breast cancer cells independent of tumor subtype or species, but acts poorly toward non-transformed cells derived from multiple tissues. Here we demonstrate that HMA is similarly cytotoxic toward breast CSC-related subpopulations that are resistant to conventional chemotherapeutic agents, but poorly cytotoxic toward normal mammary stem cells. HMA inhibits the sphere-forming capacity of FACS-sorted human and mouse mammary CSC-related cells in vitro, specifically kills tumor but not normal mammary organoids ex vivo, and inhibits metastatic outgrowth in vivo, consistent with CSC suppression. Moreover, HMA inhibits viability and sphere formation by lung, colon, pancreatic, brain, liver, prostate and bladder tumor cell lines, suggesting that its effects may be applicable to multiple malignancies. Mechanistically, HMA elicits the permeabilization of the limiting lysosomal membrane, a hallmark feature of the lysosome-dependent cell death pathway. Our observations expose a key vulnerability intrinsic to cancer stem cells, and point to novel strategies for the exploitation of cationic amphiphilic drugs in cancer treatment.

This document summarizes the evidence currently available about the effects of the anesthetic agents and techniques used in primary cancer surgery and long-term oncologic outcomes, and the biomolecular mechanisms involved in their interaction..

Formation of new blood (angiogenesis) and lymphatic (lymphangiogenesis) vessels are major events associated with most epithelial malignancies, including breast cancer. Angiogenesis is essential for cancer cell survival. Lymphangiogenesis is critical in maintaining tumoral interstitial fluid balance and importing tumor-facilitatory immune cells. Both vascular routes also serve as conduits for cancer metastasis. Intratumoral hypoxia promotes both events by stimulating multiple angiogenic/lymphangiogenic growth factors. Studies on tumor-associated lymphangiogenesis and its exploitation for therapy have received less attention from the research community than those on angiogenesis. Inflammation is a key mediator of both processes, hijacked by many cancers by aberrant expression of the inflammation-associated enzyme cyclo-oxygenase (COX)-2. In this review, we focus on breast cancer and show that COX-2 is a major promoter of both events, primarily resulting from the activation of Prostaglandin (PG) E receptor EP4 on tumor cells, tumor-infiltrating immune cells, and endothelial cells; and induction of oncogenic microRNAs. COX-2/EP4 pathway also promotes additional events in breast cancer progression, such as cancer cell migration, invasion, and stimulation of stem–like cells. Based on a combination of studies using multiple breast cancer models, we show that EP4 antagonists hold a major promise in breast cancer therapy in combination with other modalities including immune check-point inhibitors

To gain new insights into the potential of mother-to-child transmission of Zika virus (ZIKV) through breast milk or breastfeeding practices, we systematically searched regional and international databases and screened 1,658 non-duplicate records describing women with suspected or confirmed ZIKV infection, intending to breastfeed or give breast milk to an infant. Fourteen studies met our inclusion criteria and inform this analysis. These studies reported on 97 mother-children pairs who provided breast milk for ZIKV assessment. Seventeen breast milk samples from different women were found positive for ZIKV via RT-PCR, and ZIKV replication was found in cell cultures from five out of seven breast milk samples from different women. Only three out of six infants who had ZIKV infection were breastfed, no evidence of clinical complications were found to be associated with ZIKV RNA in breast milk. This review updates our previous report by synthesizing the evidence from 12 new articles and we find no evidence of mother-to-child transmission through breast milk intake or breastfeeding. As the certainty of the present evidence is low, additional studies are still warranted to completely understand any potential of transmission of ZIKV through breastfeeding.

Breast Cancer (BC) is the second most common type of cancer worldwide and displays the highest cancer-related mortality among women worldwide. Targeted therapies have revolutionized the way BC has been treated in the last decades improving life expectancies of millions of women. Among the different molecular pathways that have been of interest for the development of targeted therapies are the Cyclin-Dependent Kinases (CDK). CDK inhibitors are a class of molecules that already exist in nature and those belonging to the INK4 protein family specifically inhibit the CDK4/6 proteins. CDK4/6 inhibitors specifically block the transition from the G1 to the S phase of the cell cycle by dephosphorylation of the retinoblastoma tumor suppressor protein. In the past four years CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib received their first FDA approval for the treatment of Hormone Receptor (HR)-positive and Human Epidermal growth factor Receptor 2 (HER2)-negative breast cancer after showing significant improvements in progression-free survival in the PALOMA-1, MONALEESA-2 and the MONARCH-2 randomized clinical trials, respectively. After the encouraging results from these clinical trials, CDK4/6 inhibitors have also been investigated in the other BC subtypes. In HER2-positive BC, combination of CDK4/6 inhibitors with HER2-targeted therapies showed promise in preclinical studies and their clinical evaluation is ongoing. Moreover, in triple-negative BC, CDK4/6 inhibitors efficacy has been investigated in combination with other targeted therapies or immunotherapies. This review summarizes the molecular background and clinical efficacy of CDK4/6 inhibitors as single agents or in combination with other targeted therapies for the treatment of BC. Future directions of ongoing clinical trials and predictive biomarkers will be further debated.

Circulating tumor cells (CTCs) in the peripheral blood are the precursors to distant metastasis but the underlying mechanisms are poorly understood. This study aims at understanding the molecular features within CTCs in relation to their metastatic potential. Using in vitro CTC models, in which breast cancer cell lines are cultured in non-adherent conditions simulating the microenvironment in the blood stream, we found that suspension culture resulted in resistance to TNF-related apoptosis inducing ligand (TRAIL)-mediated cell death. Such a resistance was directly correlated with a reduction in surface and total levels of DR5 protein. In the non-adherent state, cells underwent rapid autophagic flux characterized by an accumulation of autophagosome organelles. Notably, DR5 was translocated to autophagosomes and underwent lysosomal degradation. Our data suggest that CTCs may evade TNF cytokine mediated immune surveillance through downregulation of DR expression. The data warrants further studies in cancer patients to find the status of DRs and other molecular features within primary CTCs in relation to disease progression or chemoresistance.

Introduction The authors reviewed the published evidence on the presence of oligosaccharides in human milk (HMO) and their benefits in in vitro and in vivo studies, as well as to evaluate published data on the addition of some of HMOs to infant formula. Method PubMed was searched from inception to April 2018 Results The presence of HMOs is a dynamic process, determined by many factors such as duration of lactation, environmental and genetic factors. HMOs may support immune function development and provide protection against infectious diseases directly through the interaction of the gut epithelial cells or indirectly through the modulation of the gut microbiota, including the stimulation of the bifidobacteria. Only a few of the many HMOs can be made industrially, and are added to infant formula. They have been shown to be safe and well tolerated, including normal growth and a trend towards health benefit. Conclusions HMOs are one of the major differences between cow’s milk and human milk , and evidence indicates that these components do have a health promoting benefit. The addition of one or two of these components to infant formula is safe, and brings infant formula closer to human milk.

Formalin-Fixed Paraffin Embedded (FFPE) tissues are a valuable resource in studying different markers and mechanistic molecules (protein, DNA and RNA) in order to understand the etiology of different cancers as well as many other diseases. Degradation and modification of RNA is the major challenge in utilizing FFPE tissue samples in medical research. Recently, non-protein coding transcripts long non-coding RNAs (lncRNAs), have gained significant attention due to their important biological actions and potential involvement in cancer. There is no validated method except qRTPCR or RNAseq to evaluate and study lncRNA expression. We have standardized and are reporting a sensitive Z probe based in situ hybridization method to identify, localize and quantitate lncRNA in FFPE tissues. This assay is sensitive to single transcript and localizes lncRNA in individual cells within tumor. We have characterized a tumor suppressor lncRNA-NRON (non coding repressor of NFAT), which is scarcely expressed, a moderately expressed oncogeneic lncRNA UCA1 (urothelial cancer associated 1), and a highly studied and expressed lncRNA MALAT1 (metastasis associated lung adenocarcinoma transcript1) in different cancers. High MALAT1 staining was found in colorectal, breast and pancreatic cancer. MALAT1 expression increased with the progression of the stage in colorectal cancer and invasiveness in breast cancer.

1) Background: Studies indicate that caffeic acid (CA), caffeic acid phenethyl ester (CAPE) are compounds with potent chemopreventive effects. Breast cancer is a common cancer among women worldwide. The study shows comparison of caffeic acid and its ester activity in the cells of breast cancer line MDA-MB-231; 2) Methods: The cells of MDA-MB-231 were treated by CA and CAPE with doses from 10 to 100 µM in time 24 h and 48 h. Cytotoxicity MTT test, apoptosis by Annexin V and cell cycle with Dead Cell Assay were performed; 3) Results: The cytotoxic activity was greater for CAPE comparing to CA, in both incubation time (same dosage). IC50 values for CAPE were 27.84 (24h) and 15.83 (48h) and >10000 (24h) and >1000 (48h) for CA. Polyphenols induced apoptosis, higher apoptotic effect observed for CAPE (dose dependent). CAPE induced cell cycle arrest in S phase (time and dose dependent). Dose dependent decline G0/G1 phase (48h) and elimination of phase G2/M (100 µM of CAPE). For CA, only after 48 hours, small effect of cell cycle at phase S (however dose dependent), and slight decline of phase G0/G1 and G2/M only for highest doses (50 and 100 µM); 4) Conclusions: Comparing CA and CAPE activity, on the MDA-MB-231, we clearly see better activity of CAPE, with the same dosage and experiment time.

We conducted a retrospective evaluation of the clinical outcomes and prognostic factors in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) treated with first-line androgen receptor signaling inhibitors (ARSI) in real-world clinical practice in Japan. Between 2012 and 2023, a total of 127 consecutive patients with nmCRPC received ARSI treatment. Overall survival (OS), metastatic-free survival (MFS), and prostate-specific antigen progression–free survival (PSA-PFS) from ARSI initiation were assessed using Kaplan–Meier methodology. Clinical factors associated with OS in nmCRPC were analyzed using the Cox proportional hazards model. Among the patients, 72, 26, 12, and 17 received enzalutamide (ENZ), abiraterone (ABI), apalutamide (APA), and darolutamide (DARO) as first-line therapy. The median OS and MFS for all patients were 79.0 and 42.0 months, respectively. Median PSA-PFS was 27.0, 20.0, 10.0, and 14.0 months for patients treated with ENZ, ABI, APA, and DARO, respectively (p = 0.33). Multivariate analysis revealed that a baseline PSA level ≥3.67 ng/ml at ARSI initiation was significantly associated with poorer OS (p = 0.002). ARSI demonstrated favorable efficacy in nmCRPC patients. There were no significant differences in clinical outcomes among different types of ARSI therapy for nmCRP. Elevated baseline PSA at ARSI initiation was significantly associated with poorer OS.

The assessment of Health-Related Quality of Life (HRQoL) in Thalassemia offers a holistic approach to the disease and facilitates better communication between physicians and patients. This study aimed to evaluate the HRQoL of Transfusion-Dependent Thalassemia (TDT) patients in Greece. This was a multicentre, cross-sectional study conducted in 2017, involving 283 adult TDT patients. All participants completed a set of two QoL questionnaires, the generic SF-36v2 and the disease-specific TranQol. Demographic and clinical characteristics were used to predefine patient subgroups. Significant factors identified in univariate analysis were entered into a multivariate analysis to assess their effect on HRQoL. The SF-36 scores of TDT patients were consistently lower, compared to the general population in Greece. The mean summary score of TranQol was relatively high (71±14%), exceeding levels observed in national surveys in other countries. Employment emerged as the most significant independent factor associated with better HRQoL, whereas age had the most significant negative effect. This study represents the first comprehensive QoL assessment in a representative sample of the TDT population in Greece. The implementation of TranQol allowed for the quantification of HRQoL in Greece, establishing a baseline for future follow-up, and identifying more vulnerable patient subgroups.

A calibrated mathematical model of antiviral immune response to SARS-CoV-2 infection is developed. The model considers the innate and antigen-specific responses to SARS-CoV-2 infection. Recently published data sets from human challenge studies with SARS-CoV-2 were used for parameter estimation. Understanding the regulation of multiple intertwined reaction components of the immune system is necessary for linking the clinical phenotypes of COVID-19 with the kinetics of immune responses. Consideration of multiple immune reaction components in a single calibrated mathematical model allowed us to address some fundamental issues related to pathogenesis of COVID-19, i.e. sensitivity of the peak viral load to parameters characterizing the specific response components, the kinetic coordination of the individual responses, and the factors favoring a prolonged viral persistence. The model provides a tool for predicting the infectivity of patients, i.e. the amount of virus which is transmitted via droplets from the person infected with SARS-CoV-2, depending on the time of infection. The thresholds in the relative unbalance between innate and adaptive response parameters which lead to a prolonged persistence of SARS-CoV-2 due to the loss of a kinetic response synchrony/coordination were identified.

Modules composed of a resistance gene flanked by Xer site-specific recombination sites, the vast majority of which were found in Acinetobacter baumannii, are thought to behave as elements that facilitate horizontal dissemination. The A. baumannii xerC and xerD genes were cloned, and the recombinant clones used to complement the cognate Escherichia coli mutants. The complemented strains supported resolution of plasmid dimers, and, as is the case with E. coli and Klebsiella pneumoniae plasmids, the activity was enhanced when cells were growing in low osmolarity growth medium. Binding experiments showed that partially purified A. baumannii XerC and XerD proteins (XerC_Ab and XerD_Ab) bound synthetic Xer site-specific recombination sites, some of them with a nucleotide sequence deduced from existing A. baumannii plasmids. Incubation with suicide substrates resulted in covalent attachment of DNA to a recombinase, probably XerC_Ab, indicating that the first step in the recombination reaction took place. The results described show that XerC_Ab and XerD_Ab are functional proteins and support the hypothesis that they participate in horizontal dissemination of resistant genes among bacteria.

Increased nutrient withdrawal by rapidly expanding intensive cropping systems, in combination with imbalanced fertilization, is leading to potassium (K) depletion from agricultural soils in Asia. There is an urgent need to better understand the soil K-supplying capacity and K-use efficiency of crops to address this issue. Maize is increasingly being grown in rice-based systems in South Asia, particularly in Bangladesh and North East India. The high nutrient extraction, especially K, however, causes concerns for the sustainability of maize production systems in the region. The present study was designed to estimate, through a plant-based method, the magnitude, and variation in K-supplying capacity of a range of soils from the maize-growing areas and the K-use efficiency of maize in Bangladesh. Eighteen diverse soils were collected from several upazillas (or sub-districts) under 11 agro-ecological zones to examine their K-supplying capacity from the soil reserves and from K fertilization (@ 100 mg K kg-1 soil) for successive seven maize crops grown up to V10-V12 in pots inside a net house. A validation field experiment was conducted with five levels of K (0, 40, 80, 120 and 160 kg ha-1) and two fertilizer recommendations based on “Nutrient Expert for Maize-NEM” and “Maize Crop Manager-MCM” decision support tools (DSSs) in 12 farmers’ fields in Rangpur, Rajshahi and Comilla districts in Bangladesh. Grain yield and yield attributes of maize responded significantly (P < 0.001) to K fertilizer, with grain yield increase from 18 to 79% over control in all locations. Total K uptake by plants not receiving K fertilizer, considered as potential K-supplying capacity of the soil in the pot experiment, followed the order: Modhukhali >Mithapukur >Rangpur Sadar >Dinajpur Sadar >Jhinaidah Sadar >Gangachara >Binerpota >Tarash >Gopalpur >Daudkandi >Paba >Modhupur >Nawabganj Sadar >Shibganj >Birganj >Godagari >Barura >Durgapur. Likewise in the validation field experiment, the K-supplying capacity of soils was 83.5, 60.5 and 57.2 kg ha-1 in Rangpur, Rajshahi, and Comilla, respectively. Further, the order of K-supplying capacity for three sites was similar to the results from pot study confirming the applicability of results to other soils and maize-growing areas in Bangladesh and similar soils and areas across South Asia. Based on the results from pot and field experiments, we conclude that the site-specific K management using the fertilizer DSSs can be the better and more efficient K management strategy for maize.

Postoperative RT is recommended after breast conserving surgery and mastectomy (with risk factors). Consideration of pros and cons including potential side effects demands for optimization of adjuvant RT and a risk-adapted approach. There is clear de-escalation in fractionation - hypofractionation should be considered standard. For selected low risk situations PBI only or even the omission of RT might be appropriate. In contrast, tendencies in escalating RT are obvious. Preoperative RT seems attractive for patients in whom breast reconstruction is planned or for defining the tumor location more precisely with the potential of giving ablative doses. Dose escalation by a (simultaneous integrated) boost or the combination with new compounds/systemic treatments may increase antitumor efficacy but also toxicity. Despite low evidence, RT for oligometastatic disease is becoming increasingly popular. The omission of axillary dissection in node-positive disease led to an escalation of regional RT. Studies are ongoing to test if any axillary treatment can be omitted and which oligometastatic patients do really benefit from RT. Besides technical improvements the incorporation of molecular risk profiles but also the response to neoadjuvant systemic therapy have the potential to optimize the decision-making if and how local and/or regional RT should be administered.

Dolichandrone spathacea is a rare and endangered semi-mangrove plant species with an extremely small population, naturally distributed only in Zhanjiang City and the east coast of Hainan Island, China. Regrettably, the present situation of the D. spathacea population in China has not yet been carefully investigated. In this study, we aim to evaluate the current resource status and population dynamic characteristics of D. spathacea on Hainan Island, China, in order to propose sustainable conservation and management strategies for future ecological restoration of its natural population. Our results show that D. spathacea on Hainan Island can be divided into four populations. All the D. spathacea populations present a state of overall dispersion, local concentration, and occasionally sporadic existence, and they exist in geographical isolation. The young, middle, and old D. spathacea plants account for 20.42%, 66.20%, and 13.38%, respectively, indicating that the overall age class of the D. spathacea population on Hainan Island belongs to a declining type. Furthermore, instead of temporal structure, we chose diameter at breast height (DBH) to establish a static life table, draw a population survival curve, and quantify the future development trend through population dynamic analysis and time-series prediction. These results directly point out that the D. spathacea population on Hainan Island is sensitive to external disturbances and possesses two main increases in mortality rate—namely, in its juvenile and mature stages—due to weak vitality, competition, and anthropogenic interferences, which are the most important reasons for its endangered status. Depending on the current conditions of the D. spathacea population, we should conserve and expand mature trees in situ, preserve their germplasm resources, rehabilitate their habitats to promote provenance restoration, and conduct artificial cultivation and spreading planting in order to realize the sustainable conservation and management of D. spathacea.

Background: Extracellular Vesicles are pivotal mediators in intercellular communication, facilitating the exchange of biological information among healthy, pathological and tumor cells. Between the diverse subtypes of extracellular vesicles, exosomes have unique properties, clinical and therapeutical applications, even towards cancer. Breast cancer ranks as one of the most prevalent malignancies across the globe. Both the tumor core and its surrounding microenvironment engage in a complex, orchestrated interaction that facilitates the cancer’s growth and spread. Methods: The most valuable and significant PubMed Literature about extracellular vesicles and adipose–derived stem cells exosomes was selected and analyzed in order to report their biological properties and potential applications, in particular on the Triple–Negative Breast Cancer. Results: Adipose–derived stem cells exosomes represent a potential tool to target the tumor core of the Triple–Negative Breast Cancer, its microenvironment and surrounding tissues including metastasis. The authors are developing a supportive Triple–Adipose–derived stem cells Exosomes [T.A.E.] Technology against breast cancer in order to perform a selective preconditioning of the cancer before or while the traditional oncological treatments are running. Conclusion: The possibility to exploit the impact of Adipose–derived stem cells exosomes within the T.A.E. Technology against the Triple–Negative breast cancer is real, highlighting a new era for supportive measures against breast cancer.Keywords: Extracellular vesicles; Exosomes; Adipose–derived stem cells, Tumor microenvironment, Triple–Negative Breast Cancer, T.A.E. Technology.

The Hippo pathway plays crucial roles in governing various biological processes during tumorigenesis and metastasis. Within this pathway, upstream signaling stimuli activate a core kinase cascade, involving MST1/2 and LATS1/2, which subsequently phosphorylates and inhibits the transcriptional co-activators YAP and its paralog TAZ. This inhibition modulates the transcriptional regulation of downstream target genes, impacting cell proliferation, migration, and death. Despite the acknowledged significance of protein kinases in the Hippo pathway, the regulatory influence of protein phosphatases remains largely unexplored. In this study, we conducted the first gain-of-functional screen for protein tyrosine phosphatases (PTPs) regulating the Hippo pathway. Utilizing a LATS kinase biosensor (LATS-BS), a YAP/TAZ activity reporter (STBS-Luc), and a comprehensive PTP library, we identified numerous novel PTPs that play regulatory roles in the Hippo pathway. Subsequent experiments validated PTPN12, a master regulator of oncogenic receptor tyrosine kinases (RTKs), as a previously unrecognized negative regulator of the Hippo pathway effectors, oncogenic YAP/TAZ, influencing breast cancer cell proliferation and migration. In summary, our findings offer valuable insights into the roles of PTPs in the Hippo signaling pathway, significantly contributing to our understanding of breast cancer bi-ology and potential therapeutic strategies.

Breast cancer (BC) is the most common malignancy among women worldwide. In recent years, significant progress has been made in BC therapy. However, serious side effects resulting from the use of standard chemotherapeutic drugs, as well as the phenomenon of multidrug resistance (MDR), limit the effectiveness of approved therapies. Advanced research in the BC area is necessary to create more effective and safer forms of therapy to improve the outlook for individuals diagnosed with this aggressive neoplasm. For decades, plants and natural products with anti-cancer properties have been successfully utilized in treating various medical conditions. Anthracene derivatives are tricyclic secondary metabolites of natural origin that have been identified in plants, lichens, and fungi. They represent a few botanical families, e.g., Rhamnaceae, Rubia-ceae, Fabaceae, Polygonaceae, and others. The review comprehensively covers and analyzes the most recent advances in the anticancer activity of anthracene derivatives (emodin, aloe-emodin, hypericin, chrysophanol, rhein, and physcion) applied both individually, or in combination with other chemotherapeutic agents in in vitro and in vivo BC models.

(1) Background: This case presents a rare and challenging clinical scenario involving a 50-year-old female patient diagnosed with Inflammatory Carcinoma, a particularly aggressive and rapidly growing form of breast cancer. The disease is characterized by heat, redness, swelling and noticeable changes in the breast's skin texture, resembling the skin of an orange (peau d'orange). This case is important because it contributes to the limited clinical literature on such aggressive forms of breast cancer.; (2) Methods: The multidisciplinary approach was employed. Diagnostic procedures such as imaging tests, biopsy, and histopathological examination were performed to confirm the diagnosis of Inflammatory Carcinoma and assess the extent of the disease. The presence of the HER2 protein on the tumor cells supported the selection of a combination therapy involving systemic chemotherapy and targeted biological therapy.; (3) Results: The patient responded positively to the combination therapy consisting of systemic chemotherapy and targeted biological therapy. The aggressive nature of Inflammatory Carcinoma, characterized by rapid growth and distinct skin changes, was effectively addressed. The presence of the HER2 protein on the tumor cells indicated the potential efficacy of the combination therapy in aggressive forms of breast cancer.; (4) Conclusions: This case highlights the critical importance of a multidisciplinary approach in managing complex cases of breast cancer, especially rare and aggressive subtypes like Inflammatory Carcinoma. The positive response of the patient to the combination therapy involving systemic chemotherapy and targeted biological therapy demonstrates the potential for favorable outcomes in aggressive disease presentations.

(1) Background: This case report focuses on a 46-year-old female patient diagnosed with a rare and aggressive form of breast cancer known as rapidly growing, ulcerated breast cancer. The patient exhibited rapid progression of the disease, experiencing discomfort and noticeable changes in the size and texture of the affected breast over a short period of time; (2) Methods: An intensive neoadjuvant chemotherapy regimen was employed as the primary treatment approach. The patient's response to this treatment was closely monitored and assessed. Various diagnostic tests and imaging techniques were utilized to evaluate the extent of the disease and track its response to the chemotherapy; (3) Results: The patient's response to the neoadjuvant chemotherapy regimen was remarkable, resulting in a complete pathologic response. This outcome, although unusual in rapidly growing, ulcerated breast cancers, highlights the effectiveness of neoadjuvant chemotherapy in managing large, locally advanced breast cancers; (4) Conclusions: The multidisciplinary approach employed in managing this complex breast cancer case proved to be crucial to the patient's favorable outcome. Despite the aggressive nature of the disease and the challenges posed by the rapid growth and ulceration, the patient achieved a positive result. This case contributes to the limited clinical literature on such unusual and aggressive breast cancer cases, providing valuable insights for future clinical practice.8

The botanical species Ceratonia siliqua L., commonly referred to as the Carob tree, and locally as “L’Kharrûb”, holds significance as an agro-sylvo-pastoral species, and is traditionally utilized in Morocco for treating a variety of ailments. This current investigation aims to ascertain the antioxidant, antimicrobial, and cytotoxic properties of the ethanolic extract of C. siliqua leaves (CSEE). Initially, we analyzed the chemical composition of CSEE through high-performance liquid chromatography with Diode-Array Detection (HPLC-DAD). Subsequently, we conducted various assessments, including DPPH scavenging capacity, β-carotene bleaching assay, ABTS scavenging, and total antioxidant capacity assays, to evaluate the antioxidant activity of the extract. In this study, we investigated the antimicrobial properties of CSEE against five bacterial strains (two gram-positive, Staphylococcus aureus, and Enterococcus faecalis; and three gram-negative bacteria, Escherichia coli, Escherichia vekanda, and Pseudomonas aeruginosa) and two fungi (Candida albicans, and Geotrichum candidum). Additionally, we evaluated the cytotoxicity of CSEE on three human breast cancer cell lines (MCF-7, MDA-MB-231, and MDA-MB-436) and assessed the potential genotoxicity of the extract using the comet assay. Through HPLC-DAD analysis, we determined that phenolic acids and flavonoids were the primary constituents of the CSEE extract. The results of the DPPH test indicated a potent scavenging capacity of the extract with an IC50 of 302.78 ± 7.55 µg/mL, which was comparable to that of ascorbic acid with an IC50 of 260.24 ± 6.45 µg/mL. Similarly, the β-carotene test demonstrated an IC50 of 352.06 ± 12.16 µg/mL, signifying the extract's potential to inhibit oxidative damage. The ABTS assay revealed IC50 values of 48.13 ± 3.66 TE µmol/mL, indicating a strong ability of CSEE to scavenge ABTS radicals, and the TAC assay demonstrated an IC50 value of 165 ± 7.66 µg AAE/mg. The results suggest that the CSEE extract had potent antioxidant activity. Regarding its antimicrobial activity, the CSEE extract was effective against all five tested bacterial strains, indicating its broad-spectrum antibacterial properties. However, it only showed moderate activity against the two tested fungal strains, suggesting it may not be as effective against fungi. The CSEE exhibited a noteworthy dose-dependent inhibitory activity against all the tested tumor cell lines in vitro. The extract did not induce DNA damage at the concentrations of 6.25, 12.5, 25, and 50 µg/ml, as assessed by the comet assay. However, the 100 µg/ml concentration of CSEE resulted in a significant genotoxic effect compared to the negative control. A computational analysis was conducted to determine the physicochemical and pharmacokinetic characteristics of the constituent molecules present in the extract. The Prediction of Activity Spectra of Substances (PASS) test was employed to forecast the potential biological activities of these molecules. Additionally, the toxicity of the molecules was evaluated using the Protox II webserver.

Despite the recognized benefits of fecal occult blood test (FOBT) and mammography screenings, participation in breast (BC) and colorectal cancer (CRC) screening programs is still suboptimal. This study investigates municipal characteristics associated with their BC/CRC screening uptake profiles among women aged 55–69 years. Using data from 308 municipalities of Flanders from 2014 to 2017, a profile for each municipality based on its BC/CRC screening uptake compared with the median screening uptake was created. Logistic regression with generalized estimating equations was used to assess the associations between municipal characteristics and BC/CRC screening uptake profiles. The overall median uptake of cancer screening was higher for CRC (57.4%) than for BC (54.6%). The following municipal characteristics were associated with worse performance in terms of only CRC, only BC, or both CRC and BC screening uptake, respectively: foreign nationality, self-employment rate, (early) retirement rate, diabetes, disabilities; (early) retirement rate; age group 65–69, foreign nationality, self-employment rate, (early) retirement rate, wage-earners, diabetes. The following municipal characteristics were associated with better performance in terms of only CRC, only BC, or both CRC and BC screening uptake respectively: residential stability, having a partner, having children, jobseeker rate, GP visits, preventive dental visits; having children, GP visits; age group 55–59, residential stability, having a partner, having children, jobseeker rate, higher education, GP visits, preventive dental visits. This study’s results regarding the interrelation between the BC and CRC screening could be used to tailor interventions to improve the participation of the target population in both programs.

Fibroepithelial lesions (FL) of the breast, in particular Phyllodes tumors (PT) and fibroadenomas, pose a significant diagnostic challenge. There are no generally accepted criteria that distinguish benign, borderline, malignant PT, and FA. Combined genome-wide DNA methylation and copy number variant (CNV) profiling is an emerging strategy to classify tumors. We compiled a series of patient-derived archival biopsy specimens reflecting the FL spectrum and histological mimickers including clinical follow-up data. DNA methylation and CNVs were determined by well-established microarrays. Comparison of the patterns with a pan-cancer dataset assembled from public resources including "The Cancer Genome Atlas" (TCGA) and "Gene Expression Omnibus" (GEO) suggests that FLs form a methylation class distinct from both control breast tissue as well as common breast cancers. Complex CNVs were enriched in clinically aggressive FLs. Subsequent fluorescence in situ hybridization (FISH) analysis detected respective aberrations in the neoplastic mesenchymal component of FLs only, confirming that the epithelial component is non-neoplastic. Of note, our approach could lead to the elimination of the diagnostically problematic category of borderline PT and allow for optimized prognostic patient stratification. Furthermore, the identified recurrent genomic aberrations such as 1q gains (including MDM4), CDKN2a/b deletions and EGFR amplifications may inform therapeutic decision-making.

Telehealth is the delivery of many health care services and technologies to individuals at different geographical areas and is categorized as asynchronously or synchronously. The coronavirus disease 2019 (COVID-19) pandemic has caused major disruptions in health care delivery to breast cancer (BCa) patients and there is increasing demand for telehealth services. Globally, telehealth has become an essential means of communication between patient and health care provider. The application of telehealth to the treatment of BCa patients is evolving and increasingly research has demonstrated its feasibility and effectiveness in improving clinical, psychological and social outcomes. Two areas of telehealth that have significantly grown in the past decade and particularly since the beginning of the COVID-19 pandemic are telerehabilitation and teleoncology. There two technological systems provides opportunities at every stage of the cancer care continuum for BCa patients. We conducted a systematic literature review that examined the use of telehealth services via its various modes of delivery among BCa patients particularly in areas of screening, diagnosis, treatment modalities, as well as satisfaction among patients and health care professionals. The advantages of telehealth models of service and delivery challenges in delivery to patients in remote arears are discussed.

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the chief concern of the international community in almost no time. As of May 9th, 2021, more than 150 million cases and 3.2 million deaths have been recorded. Considering the early struggle in treating COVID-19 patients, the researchers and clinicians have decided to try the previously available drugs according to their mechanisms of action. Hence, many antivirals, antibiotics, antiparasitics, and antipyretics have been proposed. Pregnant women, fetuses, and infants are known high-risk populations that are threatened during disease outbreaks. Therefore, this article reviews the safety of potential drugs for COVID-19 patients during pregnancy and breastfeeding.

Genome-wide association studies have revealed a locus at 8p12 that is associated with breast cancer risk. Fine-mapping of this locus identified 16 candidate causal variants (CCVs). However, as these variants are intergenic, their function is unclear. To map chromatin looping from this risk locus to a previously identified candidate target gene, DUSP4, we performed chromatin conformation capture analyses in normal and tumoral breast cell lines. We identified putative regulatory elements, containing CCVs, that loop to the DUSP4 promoter region. Using reporter gene assays, we found that the risk allele of CCV rs7461885 reduced the activity of a DUSP4 enhancer element, consistent with the function of DUSP4 as a tumor suppressor gene. Furthermore, the risk allele of CCV rs12155535, located in another DUSP4 enhancer element, was negatively correlated with looping of this element to the DUSP4 promoter region, suggesting that this allele would be associated with reduced expression. These findings provide the first evidence that CCV risk alleles downregulate DUSP4 expression, suggesting that this gene is a regulatory target of the 8p12 breast cancer risk locus.

Human milk composition is dynamic and substitute formulae are intended to mimic its protein content. The purpose of this study was to investigate the potentiality of matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) followed by multivariate data analyses as a tool to analyze peptide profiling of mammalian, human and formula milks. Breast milk samples from women at different lactation stages (2 (n = 5), 30 (n = 6), 60 (n = 5), and 90 (n = 4) days postpartum), and milk from donkeys (n = 4), cows (n = 4), buffaloes (n = 7), goats (n = 4), ewes (n = 5), and camels (n = 2) were collected. Different brands (n = 4) of infant formulae were also analyzed. Protein content (<30 kDa) was analyzed by MS and data were exported for statistical elaborations. Mass spectra for each milk closely clustered together, whereas different milk samples resulted well separated. Human samples formed a cluster in which colostrum constituted a well-defined subcluster. None of the milk formulae correlated with animal or human milk, although specifically characterized and well correlated each other. These findings propose MALDI-TOF MS milk profiling as an analytical tool to discriminate, in a blinded way, different milk types. As each formula has a distinct specificity, shifting a baby from one to another formula implies a specific proteomic exposure. These profiles may assist in milk proteomics for easiness of use and low cost consuming, suggesting that the MALDI-TOF MS pipelines may result useful for milk adulteration assessment but also for the characterization of banked milk specimens in paediatric clinical settings.

Sympatric mountain ungulates experience population fluctuations due to intra and inter-specific competition and climate variations. In this comprehensive three-year study (2012-2015), we investigated the population dynamics, spatial distribution, and habitat use of Tibetan Antelope (Chiru) (Panthalops hodgsonii) in relation to four other sympatric ungulates (Argali Ovis ammon, Wild Yak Bos mutus, Tibetan Wild Ass Equus kiang, and Greater Bharal Pseudois nayaur) in the cold arid Changchenmo Valley of Ladakh, India. We conducted 162 intensive surveys covering 918.60 km, we recorded 215 animal sightings, encompassing 1670 Chiru individuals, exclusively males. Chiru exhibited encounter rate of 1.19±1.17 S.D individuals/km walked and 1.53±1.37 S.D. individuals/hr and a typical group sizes of 13.69. Our findings suggest spatio-temporal resource partitioning through habitat selection which favour species coexistence under harsh climatic conditions. While resource sharing occurred during summer, competition was observed during peak winters and springs. Noteworthy in our study was the coexistence of Chiru and Tibetan Wild Ass in shared habitats, indicating facilitation rather than interspecific competition. However, significant habitat segregation was observed between Chiru and other ungulates, highlighting distinct ecological preferences. The study reports a stable Chiru population and reveals a novel phenomenon of some individuals remaining in the area during winters, a behavior not previously documented. The overlap of all species in limited winter habitats poses a potential threat to Chiru survival. Additional threats include climate change, infrastructure development, armed conflict, and livestock competition. Special management efforts, including awareness programs for armed forces and stringent development regulations, are crucial. Our findings provide critical insights into complex species interactions and habitat preferences, forming an essential foundation for the conservation and management of Chiru and other Tibetan ungulates in the Trans-Himalayan landscapes affected by climate change.

Enzymes reliant on pyridoxal 5'-phosphate (PLP), the metabolically active form of vitamin B6, hold significant importance in both biology and medicine. They facilitate various biochemical reactions, particularly in amino acid and neurotransmitter metabolisms. Vitamin B6 is absorbed by organisms in its non-phosphorylated form and phosphorylated within cells by pyridoxal kinase (PLK) and pyridox-(am)-ine 5'-phosphate oxidase (PNPOx). The flavin mononucleotide dependent PNPOx enzyme converts pyridoxine 5'-phosphate and pyridoxamine 5'-phosphate into PLP. PNPOx is vital for both biosynthesis and salvage pathways in organisms producing B6 vitamers. However, for those depending on vitamin B6 as nutrient, PNPOx participates only in the salvage pathway. Transferring PLP produced by PNPOx to client apo-enzymes is indispensable for their catalytic function, proper folding and targeting to specific organelles. PNPOx activity deficiencies due to inborn errors lead to severe neurological pathologies, particularly neonatal epileptic encephalopathy. PNPOx enzymes from different organisms maintain PLP homeostasis through highly regulated mechanisms, including structural alterations throughout the catalytic cycle and allosteric PLP binding influencing substrate transformation at the active site. Despite shared features, species-specific regulations are evident among PNPOx enzymes.

This work presents noble composites of AAILs@MCM-48 by functionalizing ordered mesopo-rous silicon MCM-48 with two amino acid-based ionic liquids (AAILs) ([Emim][Gly] and [Em-im][Ala]) to improve carbon capture and selectivity of CO2 over nitrogen. Thermogravimetric and XRD analyses of the composites show that the MCM-48 support's thermal and structural in-tegrity was preserved after the AAILs were encapsulated. An N2 adsorption-desorption study at 77 K also confirms AAIL encapsulation in the porous support. Under post-combustion flue gas conditions, both [Emim][Gly]@MCM-48 and [Emim][Ala]@MCM-48 demonstrated improved CO2 adsorption in comparison to unmodified MCM-48, with a CO2 partial pressure of around 0.15 bar. In terms of maximal CO₂ uptake, the 40wt%-[Emim][Gly] composite outperformed the others at 303K, with values of 0.74 and 0.82 mmol g-1, respectively, at 0.1 and 0.2 bar. These numbers show a 10x and 5x increase, respectively, as compared to the pure MCM-48 under iden-tical conditions. In addition, the selectivity of the composites was improved significantly, at 0.1 bar, the selectivity of composites containing 40wt% [Emim][Ala] increased to 17, compared to 2 for pristine MCM-48.

This article describes a novel electrochemical on-chip biosensor that utilizes anti-PSA antibody (Ab) and silver nanoparticles (AgNPs) to enhance the sensing and detection capability of prostate specific antigen (PSA) in the blood. The AgNPs are prepared, characterized, and applied onto a silicon photonic on-chip biosensing receptor platform designed to enhance the accurate detection of PSA. The AgNPs were synthesized by a chemical reduction method using silver nitrate (AgNO₃) as the precursor. Transmission electron microscopy (TEM), selected area electron diffraction (SAED), energy dispersion X-ray spectroscopy (EDS), small angle X-ray scattering (SAXS), X-ray diffraction (XRD), and light microscopy were among the methods used in the characterization and analysis of the AgNPs. Each stage of the immunosensor fabrication was characterized using cyclic voltammetry. The proposed immunosensor was applied in the detection of PSA, a prostate cancer biomarker, with a high sensitivity and a limit of detection of 0.17 ng/mL over a linear concentration range of 2.5 to 11.0 ng/mL. The immunosensor displayed good stability and was selective in the presence of interfering species like immunoglobulin (Ig) in human serum, ascorbic acid (AA), and diclofenac (Dic). The detectivity and sensitivity are significantly higher than previous reports on similar or related technologies.

This study presents the encapsulation of two amino acid-based ionic liquids (AAILs), 1-Ethyl-3-methylimidazolium glycine [Emim][Gly] and 1-Ethyl-3-methylimidazolium alanine [Emim][Ala], in a highly porous metal organic framework (MOF-177), to generate state-of-the-art composites for post-combustion CO2 capture. The thermogravimetric analysis (TGA) demonstrated a successful encapsulation of the AAILs, consequently dramatically reducing the composites' surface area and pore volume. Both [Emim] [Gly]@MOF-177 and [Emim][Ala]@MOF-177 had close to 3 times the CO2 uptake of MOF-177 at 20 wt.% loading, 0.2 bar, and 303 K. Additionally, 20-[Emim][Gly]@MOF-177 and 20-[Emim] [Ala]@MOF-177 enhanced their CO2/N2 selectivity from 5 (pristine MOF-177) to 13 and 11, respectively.

Optical networks offer a wide range of benefits to the telecommunication sector world- wide with its provision of higher bandwidth which leads to faster data speed, longer transmission distance, and improved latency. Currently, the complexity associated with advancements in optical networks poses problems to network flexibility, reliability, and quality of service. Over the years, many reviews and proposals have been implemented by several literatures to provide solutions for optical networks using software-defined networks and network service orchestrators. This paper reviews the significant challenges in current optical network applications, the various solutions rendered by software-defined networks as well as network service orchestration, the impediments, and gaps in these software – defined networks. This paper will go a step further to look into the various improvements and implementations of software-defined networks tailored to solve specific optical network problems. This paper further proposes a flexible orchestration architecture for software-defined networks for solving flexibility and scalability problems in optical networks. This proposal uses Open Network System (ONOS) SDN controller, leveraging on dockerisation as well as kubernetes clusterisation and orchestration. This solution presents a more flexible, reliable, customable, and higher quality of service which is an improvement upon current solutions in literature.

Pure orbital blowout fractures occur within the confines of the internal orbital wall. Restoration of orbital form and volume is paramount to prevent functional and esthetic impairment. The anatomical peculiarity of the orbit has encouraged surgeons to develop implants with customized features to restore its architecture. This has resulted in worldwide clinical demand for patient-specific implants (PSIs) designed to fit precisely in the patient's unique anatomy. Fused filament fabrication (FFF) three-dimensional (3D) printing technology has enabled the fabrication of implant-grade polymers such as Polyetheretherketone (PEEK), paving the way for a more sophisticated generation of biomaterials. This study evaluates the FFF 3D printed PEEK orbital mesh customized implants with a metric considering the relevant design, biomechanical, and morphological parameters. The performance of the implants is studied as a function of varying thicknesses and porous design constructs through a finite element (FE) based computational model and a decision matrix based statistical approach. The maximum stress values achieved in our results predict the high durability of the implants, and the maximum deformation values were under one-tenth of a millimeter (mm) domain in all the implant profile configurations. The circular patterned implant (0.9 mm) had the best performance score. The study demonstrates that compounding multi-design computational analysis with 3D printing can be beneficial for the optimal restoration of the orbital floor.

Despite the remarkable success of Carnot’s heat engine cycle in founding the discipline of thermodynamics two centuries ago, false viewpoints of his use of the caloric theory in the cycle still linger, limiting his legacy. An action revision of the Carnot cycle can correct this, showing that the heat flow powering external mechanical work is compensated internally with configurational changes in the thermodynamic or Gibbs potential of the working fluid, differing in each stage of the cycle quantified by Carnot as caloric. Action (@) is a property of state having the same physical dimensions as angular momentum (mrv=mr2ω). However, this property is scalar rather than vectorial, including a dimensionless phase angle (@=mr2ωδφ). We have recently confirmed with atmospheric gases that their entropy is a logarithmic function of the relative vibrational, rotational and translational action ratios with Planck’s quantum of action ħ. The Carnot principle shows that the maximum rate of work (puissance motrice) possible from the reversible cycle is controlled by the difference in temperature of the hot source and the cold sink, the colder the better. This temperature difference between the source and the sink also controls the isothermal variations of the Gibbs potential of the working fluid, that Carnot identified as reversible temperature-dependent but unequal exchanges in caloric. Importantly, the engine’s inertia ensures that heat from work performed adiabatically in the expansion phase is all restored to the working fluid during the adiabatic recompression, less the net work performed. This allows both the energy and the thermodynamic potential to return to the same values at the beginning of each cycle, a point strongly emphasized by Carnot. Our action revision equates Carnot’s calorique, or the non-sensible heat later described by Clausius as ‘work-heat’ exclusively to negative Gibbs energy (-G) or quantum field energy. This action field complements the sensible energy or vis-viva heat as molecular kinetic motion and its recognition should have significance for designing more efficient heat engines or better understanding of the heat engine powering the Earth’s climates.

The move to a low carbon economy is very important for enhancing international competitiveness. The eco-innovation is the critical factor of the green paradigm. This study is designed to investigate deeply the determinants of eco-innovation of manufacturing firms in Korea by suggesting anticipated regulations, self-regulations, and industry-specific characteristics as external factors and open information sources as internal factors. The data used in the analysis is 1946 sample firms from Korean Innovation Survey 2010 based on the Oslo Manual. Using the multi-variate probit analysis and the zero-inflated negative binomial (ZINB) regression analysis, we have found out that the anticipated regulations and self-regulations have significant influences both on eco-process innovation and eco-product innovation, while industrial characteristics have no effects. The empirical results also show that the breadth of information sources has a positive effect on businesses in implementing eco-innovations. Our findings show that the Korean government should provide a good platform where firms can better understand the future trends of environmental policies, particularly policies on anticipated and self-regulations. At the same time, Korean firms should establish a voluntary system to control environmental activities so that they can improve eco-innovations through integrating external information.

Fibroblast growth factor 14 (FGF14) is a member of the intracellular FGFs, a group of proteins with roles in neuronal ion channel regulation and synaptic transmission. We have previously demonstrated that a male Fgf14-/- mouse model recapitulates salient endophenotypes of synaptic dysfunction and behaviors associated with schizophrenia (SZ). As the underlying etiology of SZ and its sex-specific onset remain elusive, the Fgf14-/- model provides a valuable tool to interrogate pathways that might be related to the disease mechanism. Here, we performed label free quantitative proteomics and bioinformatics to identify enriched pathways at the proteome level in the male and female hippocampi from Fgf14+/+ and Fgf14-/- mice. We discovered that many differentially expressed proteins in Fgf14-/- animals are associated with SZ. In addition, measured changes in the proteome and signaling pathways were predominantly sex-specific with the male Fgf14-/- being distinctly enriched for pathways associated with neuropsychiatric disorders and addiction and the female exhibiting modest changes. In the male Fgf14-/- mouse the major protein changes that could in part explain the previously described neurotransmission and behavioral phenotype of this model were loss of ALDH1A1 and PRKAR2B. ALDH1A1 has been shown to mediate an alternative pathway for GABA synthesis, while PRKAR2B is essential for dopamine 2 receptor signaling, which is the basis of current antipsychotics. Collectively, our results provide new insights in the role of FGF14 and support the use of the Fgf14-/- mouse as a useful preclinical model of SZ for generating hypothesis on the disease mechanism, sex-specific manifestation and therapy.

During the last few decades, the main focus of numerus studies has been on the human breast milk microbiota and its influence on the infant intestinal microbiota and overall health. The presence of lactic acid bacteria in breast milk affects both the quantitative and qualitative composition of the infant gut microbiota. The aim of this study was to assess the dominant cultivable rod-shaped lactic acid bacteria, specific for breast milk of healthy Bulgarian women and fecal samples of their infants over the first month of life, in 14 mother-infant tandem pairs. Additionally, we evaluated strain diversity among the dominant newly isolated species. 68 gram-positive and catalase negative strains were subjected to identification by using MALDI-TOF technique. Predominant culturable populations belonging to the rod-shaped lactic acid bacteria have been identified as Lacticaseibacillus rhamnosus, Limosilactobacillus fermentum, Lacticaseibacillus paracasei and Limosilactobacillus reuteri. Also, we confirmed the presence of Lactiplantibacillus plantarum and Lactobacillus gasseri. 27 isolates were selected as representatives and analyzed by 16S rDNA sequencing for strain identity confirmation and a phylogenetic tree based on 16S rDNA gene sequence was constructed. Comparative analysis by four RAPD primers revealed genetic differences between newly isolated L. rhamnosus strains. This pilot study provides data for the current first report concerning investigation on characteristic microbiota of human breast milk and infant feces in Bulgaria.

BReast CAncer gene 1 (BRCA1) and BReast CAncer gene 2 (BRCA2) encode for tumor suppressor proteins which are critical regulators of the homologous recombination (HR) pathway, the most precise and important DNA damage response mechanism. Dysfunctional HR proteins cannot repair double-stranded DNA breaks in mammalian cells, a situation called HR deficiency. Since their identification, pathogenic variants and other alterations of BRCA1 and BRCA2 genes have been associated with an increased risk of developing mainly breast and ovarian cancer. Interestingly, HR deficiency is also detected in tumors not carrying BRCA1/2 mutations, a condition termed “BRCAness”. One of the main mechanisms causing the BRCAness phenotype is the methylation of the BRCA1/2 promoters and this epigenetic modification is associated with carcinogenesis and poor prognosis mainly among patients with breast and ovarian cancer. BRCA1 promoter methylation has been suggested as an emerging biomarker of great predictive significance, especially concerning Poly (ADP-ribose) Polymerase inhibitors (PARP inhibitor-PARPi) responsiveness, along with or beyond BRCA1/2 mutations. However, as its clinical exploitation is still insufficient, the impact of BRCA1/2 promoter methylation status needs to be further evaluated. The current review aims to gather the latest findings about the mechanisms that underline BRCA1/2 function as well as the molecular characteristics of tumors associated with BRCA1/2 defects, by focusing on DNA methylation. Furthermore, we critically analyze their translational meaning and the validity of BRCA methylation biomarkers in predicting treatment response and we suggest a diagnostic pipeline that could be implemented in liquid biopsy to aid precision pharmacotherapy in BRCA-associated tumors.

Simple Summary: Breast cancer is the most common invasive cancer among women. Triple-negative breast cancer (TNBC) accounts for 15–20% of newly diagnosed breast cancers and has the worst prognosis. However, TNBC patients are not a homogeneous group, and there are differences in the course of the disease as well as in response to treatment. For this reason, differentiation of subtypes of this tumor is important for optimal therapeutic decision and risk prediction. The presented study focuses on the expression of the androgen receptor (AR) and the infiltration of T-lymphocytes in the tumor stroma (TILs) of TNBC patients. Correlation of these tested biomarkers with standard prognostic factors. Defining new prognostic factors for 3-year overall survival (OS). Abstract: Background: Analysis of the practical benefit of testing the expression of AR and the TILs in patients with TNBC and their correlation with standard prognostic factors. Methods: The study group consisted of 86 female patients treated for TNBC. T-lymphocyte infiltration was examined in H+E staining. AR expression, CD8 and CD4 T-lymphocytes were evaluated in immunohistochemistry. Results: Significantly negative correlation was found between AR expression and the CD8 T-lymphocyte infiltration levels. A significant negative correlation was found between the AR expression and G and Ki 67, and a positive correlation between the TILs levels and G and Ki 67. Patients with AR expression and low TILs levels had the highest percentage of diagnosed distant metastases and 3-years OS. Patients with high TILs no distant metastases or deaths were diagnosed. The level of TILs turned out to be a significant independent prognostic factor. Conclusions: Based on the assessment of AR expression and TILs infiltration, the group of highest and lowest risk was determined. The prognostic factor of known parameters such as TNM and a new factor - TILs was confirmed. On the other hand, parameters such as G and Ki 67 and the tested factor - AR had no effect on the prognosis.

Obesity and environmental toxins are risk factors for breast cancer, however there is limited knowledge on how these risk factors interact to promote breast cancer. Acrylamide, a probable carcinogen and obesogen, is a biproduct in foods prevalent in the obesity-inducing Western diet. Acrylamide is metabolized by cytochrome P450 2E1 (CYP2E1) to the genotoxic epoxide, glycidamide, and is associated with increased risk for breast cancer. To investigate how acrylamide and obesity interact to increase breast cancer risk, female mice were fed a low-fat (LFD) or high-fat diet (HFD) and 0.7mM acrylamide-supplemented water or control water. While HFD significantly enhanced weight gain in mice, the addition of acrylamide did not significantly alter body weights compared to respective controls. Mammary epithelial cells from obese, acrylamide-treated mice had increased DNA strand breaks and oxidative DNA damage compared to all other groups. In vitro, glycidamide-treated COMMA-D cells showed significantly increased DNA strand breaks while acrylamide-treated cells demonstrated significantly higher levels of intracellular reactive oxygen species. Knockdown of CYP2E1 rescued the acrylamide-induced oxidative stress. These studies suggest that long-term acrylamide exposure through foods common in the Western diet may enhance DNA damage and CYP2E1-induced generation of oxidative stress in mammary epithelial cells, potentially enhancing obesity-induced breast cancer risk.

The microbiome is capable of modulating the bioavailability of chemotherapy drugs mainly due to metabolizing these agents. Multiple cytostatic bacterial metabolites were recently identified that have cytostatic properties on cancer cells. In this study we addressed the question whether the cytostatic bacterial metabolites (cadaverine, indolepropionic acid, indoxylsulfate) can interfere with the cytostatic effects of the chemotherapy agents used in the management of breast cancer (doxorubicin, gemcitabine, irinotecan, methotrexate, rucaparib, 5-fluorouracil, paclitaxel). The chemotherapy drugs were applied in a wide concentration range to which a bacterial metabolite was added in a concentration within its serum reference range and the effects on cell proliferation were assessed. There was no interference between doxorubicin, gemcitabine, irinotecan, methotrexate, rucaparib and the bacterial metabolites. Nevertheless, cadaverine increased the Hill coefficient of the inhibitory curve of 5-fluorouracil and indolepropionic acid increased the IC50 value of 5-fluorouracil that are either disadvantageous effects or effects of unknown significance. Nevertheless, indolepropionic acid decreased the IC50 value of paclitaxel that is a potentially advantageous combination.

Background: The circadian system, a vital temporal regulator influencing physiological processes, has implications for cancer development and treatment response. Our study assesses circadian timing's impact on whole-brain radiotherapy outcomes in brain metastases for personalized cancer therapy insights. Aim: Evaluate circadian influence on radiation treatment timing and its correlation with clinical outcomes. Identify patient populations benefiting from interventions synchronizing circadian rhythms, considering subgroup differences and potential disparities related to social determinants of health (SDoH). Design: IRB-approved retrospective analysis of 237 patients undergoing whole-brain radiotherapy for brain metastases (2017–2021), receiving over 80% of treatments in the morning or afternoon. Survival analyses utilized Kaplan–Meier curves. Setting/Participants: Single-institution study involving patients receiving whole-brain radiotherapy. Collected demographic, disease, and socioeconomic parameters from electronic medical records. Results: Morning treatment (n=158) showed a trend towards improved overall survival vs. afternoon (n=79), median survival 158 vs. 79 days (p=0.20, HR=0.84, CI95% 0.84–0.91). Subgroup benefits for morning treatment in females (p=0.04) and trends in controlled primary disease (p=0.11) and breast cancer metastases (p=0.08). SDoH-based disparities observed, with Black and lower-income patients exhibiting diminished circadian influence. Conclusions: Emphasizes chronobiological factors' relevance in brain metastases radiation therapy. Morning treatment correlates with improved survival, particularly in specific subgroups. Identifies potential circadian influence disparities based on SDoH, laying a foundation for personalized cancer therapy and interventions synchronizing circadian rhythms for enhanced treatment efficacy.

Lipofilling is an option for breast reconstruction after tumor resection to avoid the complications of an implant-based reconstruction. Although some concerns exist regarding the oncological safety of a tissue rich in mesenchymal stem cells with their proangiogenic and proliferation-supportive properties, there are also reports that adipose tissue-derived stem cells can exhibit antitumoral properties. We isolated primary adipose tissue-derived stem cells. Both conditioned medium and exosomes were harvested from the cell culture and used to treat the breast cancer cell line MCF-7. Cell viability, cytotoxicity, and gene expression of MCF-7 cells in response to the indirect co-culture were evaluated. MCF-7 cells incubated with exosomes from adipose tissue-derived stem cells show reduced cell viability in comparison to MCF-7 cells incubated with adipose-tissue derived stem cell-conditioned medium. Expression of proapoptotic genes was upregulated, expression of antiapoptotic genes was downregulated. The debate about the oncological safety of autologous fat grafting after tumor resection continues. Here, we show that exosomes from adipose tissue-derived stem cells exhibit some antitumoral properties on breast cancer cell line MCF-7.

The main aim of this study is to predict whether the type of breast cancer is “benign” or “malignant” by classical generalized linear model (GLM) approach and an extended family of GLM called generalized linear mixed model (GLMM) approach for binomially distributed response variable with binary link functions. In this study, an advanced statistical modeling approach based on the GLMM to the traditional statistical modeling approach based on the GLM for binomially distributed response variable with various binary link functions is proposed to investigate the relationships between the “malignant or benign diagnosis of the BC in patients” and “nine attributes” of 699 BC diagnosed patients. This study also focuses on the statistical significance of the accurate classification of the BC diagnosed patients in cancer studies in medicine in “benign” or “malignant” type based on the WBC dataset. In this study, the superiority of the GLMM approach over the GLM approach for the binary response variable especially belonging to the WBC dataset is emphasized in the field of cancer diagnosis in medicine. Also the importance and the power of the IC and performance metrics as the goodness-of-fit test statistics are strongly emphasized for accurate statistical inferences from the “best” fitted model. In this study, from the main findings, the best fitted model among the GLM and GLMM approaches for the binary response variable is determined as the GLMM under “logit” link function with “id” random effect with the most statistically significant odds of the occurance of the BC being “malignant” as 7.9104, 5.6888, 5.6643, 4.9842, 4.1212, 2.0679, 1.8755, and 1.3970 times more than being “benign” for every one-unit increase in the quantities of “clump thickness”, “bland chromatin”, “mitoses”, “bare nuclei”, “cell shape”, “marginal adhesion”, “epithelial cell size”, and “cell size”, respectively.

The influence of diet and nutritional status of milk donors on the nutritional composition of donor human milk (DHM) is unknown. The present study aimed to determine the nutritional profile of DHM and the associations of donors’ dietary intake and nutritional status with micronutrient and lipid composition in DHM. For this purpose, 113 donors completed a food frequency questionnaire, provided a 5-day weighed dietary record, and collected milk for 5 consecutive days. Nutrient determinations in donors’ erythrocytes, plasma, urine, and milk were performed. Multiple linear regressions were conducted for the evaluation of the associations. We highlight the following results: DHM docosahexaenoic acid (DHA) was positively associated with donors’ plasma DHA content and donors’ DHA intake (R2 0.45, p < 0.001). For every 1 g/day of DHA intake, the percentage of DHA in DHM increased by 0.38% (% of total fat) and the percentage of total omega-3 in DHM increased by 0.78% (R2 0.29, p < 0.001). DHM saturated fatty acids were positively associated with erythrocyte dimethyl acetals, plasma stearic acid, trans fatty acids intake, and breastfeeding duration, and negatively associated with erythrocyte margaroleic acid (R2 0.34, p < 0.01). DHM cholecalciferol was associated with plasma cholecalciferol levels and dairy intake (R2 0.57, p < 0.01). Other weaker associations were found for free thiamine, free riboflavin, pyridoxal, dehydroascorbic acid, and lipid profile in DHM. In conclusion, the diet and nutritional status of donors influences the fatty acid profile and micronutrient content of DHM.

The prompt and accurate diagnosis of breast lesions, including the distinction between cancer, non-cancer, and suspicious cancer, plays a crucial role in the prognosis of breast cancer. In this paper, we introduce a novel method based on feature extraction and reduction for detection of breast cancer in mammography images. First, we extract features from multiple pre-trained convolutional neural network (CNN) models, and then concatenate them. The most informative features are selected based on their mutual information with the target variable. Subsequently, the selected features can be classified using a machine learning algorithm. We evaluate our approach using four different machine learning algorithms, and our results demonstrate that the neural network-based classifier yields an accuracy as high as 92% for the RSNA dataset which is a new dataset that provides two views and additional features such as age. We compare our proposed algorithm with state-of-the-art methods and demonstrate its superiority, particularly in terms of accuracy and sensitivity. For the MIAS dataset, we achieve an accuracy as high as 94.5%, and for the DDSM dataset, an accuracy of 96% is attained. These results highlight the effectiveness of our method in accurately diagnosing breast lesions and surpassing existing approaches.

Next Generation Sequencing based cancer risk screening with multigene panels has become the most successful method for programming cancer prevention strategies. ATM germ-line heterozygosity has been described as able to increase tumor susceptibility. In particular, families that carry heterozygous germ-line variants of ATM gene show a 5- to 9-fold risk of developing breast cancer. Recent studies identified ATM as the second most mutated gene after CHEK2 in BRCA-negative patients. Nowadays, more than 170 potential missense variants and several truncating mutations have been identified in ATM gene. Here we present the molecular characterization a new ATM deletion, identified thanks to the CNV algorithm implemented in the NGS analysis pipeline. An automated workflow implementing the SOPHiA Genetics’ Hereditary Cancer Solution (HCS) protocol was used to generate NGS libraries that were sequenced on Illumina MiSeq Platform. NGS data analysis allowed to identify a new inactivating deletion of exons 19-27 of ATM gene. DNA breakpoint was characterized both at DNA and RNA level

Noninvasive and portable diagnoses via angle-resolved coherent spectral data are presented. ACTIRS (Angle- resolved coherent tomographic IR spectroscopy) through angle-coherent return spectra from photonic quantum ring laser of whispering gallery modes, which is not photocurrent-converted after the cortical, vascular or muscular diffuse paths, can be a new method for brain/heart studies. Also it will be eligible for frequent do-it-yourself diagnoses of breast cancer before hospital visits. The unique angle-coherent multi-spectra will eventually lead to study ionic or protein contents of cranial, arterial or lactiferous ducts that have been obtained only from uncomfortable biopsy, NMR, CT or mammography. The spectral data can be spatially or temporally improved and correlated for extracting more meaningful diagnostic conclusions

Ketogenic diet (KD) is getting in the focus as auxiliary cancer therapy, since it provides sufficient energy supply for healthy cells, while impairing energy production in tumor cells underlying the Warburg effect. Thereby, it can assist in inhibiting tumor growth and simultaneously counteract cachexia, which is frequently observed in cancer patients under chemotherapy. In order to provide molecular evidence for the proposed synergistic inhibition of tumor growth, we applied untargeted quantitative metabolome analysis on a breast cancer xenograft mouse model. Healthy mice and such bearing breast cancer xenografts and receiving chemotherapy were compared after treatment with control diet and KD. Metabolomic profiling was performed on plasma samples, applying high-performance liquid chromatography coupled to tandem mass spectrometry. Statistical analysis revealed metabolic fingerprints comprising numerous significantly regulated features in the group of mice bearing breast cancer. This fingerprint disappeared after treatment with KD, resulting in recovery to the metabolic status observed in healthy mice receiving control diet. Moreover, amino acid metabolism as well as fatty acid transport were found to be affected by both, the tumor and the applied KD. Our results provide clear evidence of a significant molecular effect of KD in the context of tumor growth inhibition.

Lipid-based drugs are emerging as an interesting class of novel anticancer drugs with the potential to target specific cancer cell metabolic pathway linked to their proliferation and invasiveness. In particular, ω−3 polyunsaturated fatty acids (PUFA) derivatives such as epoxides and their bioisosteres have demonstrated the potential to suppress growth and promote apoptosis in triple-negative human breast cancer cells MDA-MB-231. In this study 16-(4’-chloro-3’-trifluorophenyl)carbamoylamino]hexadecanoic acid (ClFPh-CHA), an anticancer lipid derived from ω−3,17,18-epoxyeicosanoic acid, was formulated as a stable nanoemulsion with size around 150 nm and narrow droplet size distribution (PDI<0.200) through phase-inversion emulsification process followed by high pressure homogenization in view of an oral administration. The ClFPh-CHA-loaded nanoemulsions were able to significantly decrease the relative tumor volume in mice bearing an intramammary tumor xenograft at all doses tested (2.5, 10 and 40 mg/kg) after 32 days of daily oral administration. Furthermore, absolute tumor weight was decreased to 50% of untreated control at 10 and 40 mg/kg, while intraperitoneal administration could achieve a significant reduction only at the highest dose of 40 mg/kg. Results suggest that oral administration of ClFPh-CHA formulated as a nanoemulsion has a sufficient bioavailability to provide an anticancer effect in mice and that the activity is at least equal if not superior to that obtained by a conventional parenteral administration of equivalent doses of the same drug.

This study investigates the properties of solution processed hybrid pol-yimide, PI nanocomposites containing a variety of nanofillers, including polyaniline copolymer modified clay, PNEA, nanographene sheets, NGS, and carbon nanotube sheet, CNT-PVDF, respectively. Through a series of experiments, the flow behavior of poly(amic acid), PAA solution and PAA suspension containing polyaniline copolymer modified clay, PNEA was determined as a function of the shear rate, processing temperature and polymerization time. It is shown that the neat PAA solution exhibited a complex rheological behavior ranging from shear thickening to New-tonian behavior with increasing shear rate and testing temperature. The presence of modified clay in PAA solution significantly reduced the viscosity of PAA. Differential Scanning Calorimetry (DSC) analysis show that polyimide-nanographene sheets, PI NGS nanocomposites processed at high spindle speed (100 rpm) had lower total heat of decomposition which is indicative of improved fire retardancy. The effect of processing temperature on the specific capacitance of polyimide-CNT-PVDF composites containing electrodeposited polypyrrole fillers was determined by using cyclic voltammetry, CV. It was shown that the hybrid composite working electrode material processed at 90˚C produced a remarkably higher overall stored charge when compared to the composite electrode material processed at 250˚C. Consequently, the specific capacitance ob-tained at a scan rate of 5 mV/s for the hybrid nanocomposite processed at 90°C was about 858 F/g after 1 cycle, which is about 6.3 times higher than the specific capacitance of 136 F/g produced by the hybrid nanocomposite processed at 250°C. These findings show that the properties of the hybrid nanocomposites are remarkably influenced by the processing conditions and highlights the need for process optimization.

The mixing of terrestrial groundwater and seawater creates dynamic reaction zones in intertidal areas, where land-derived Fe(II) is oxidized to Fe(III) and then precipitates as Fe hydroxides at groundwater-seawater interface. These hydrogeochemical processes contribute to the formation of iron curtains beneath soil surface, which in turn influences the evolution of coastal aquifers. This paper provides a comprehensive review of physical and geochemical processes at field scale in coastal areas, explores the impact of mineral precipitation on pore structure at pore scale, and synthesizes reactive transport modeling (RTM) approaches for illustrating continuum-scale soil physio-chemical parameters during the evolution of porous media. Upon this review, knowledge gaps and research needs are identified. Additionally, challenges and opportunities are presented. Therefore, the incorporation of observational data into a comprehensive physico-mathematical model becomes imperative for capturing the pore-scale processes in porous media and their influence on groundwater flow and solute transport at large scales. Furthermore, a synergistic approach integrating pore-scale modeling and non-invasive imaging can provide detailed insights into intricate fluid-pore-solid interactions for future studies, as well as facilitate the development of regional engineering-scale models and physio-chemical coupled models with diverse applications in submarine science and engineering.

This study introduces a specialized Automatic Speech Recognition (ASR) system, leveraging the Whisper Large-v2 model, specifically adapted for radiological applications in French language. Our methodology focused on adapting the model to accurately transcribe medical terminology and diverse accents within the French language context, achieving a notable Word Error Rate (WER) of 17.121%. The research involved extensive data collection and preprocessing, utilizing a wide range of French medical audio content. The results demonstrate the system's effectiveness in transcribing complex radiological data, underscoring its potential to enhance medical documentation efficiency in French-speaking clinical settings. The discussion extends to the broader implications of this technology in healthcare, including its potential integration with Electronic Health Records (EHRs) and its utility in medical education. The study also explores future research directions, such as tailoring ASR systems to specific medical specialties and languages. Overall, this research contributes significantly to the field of medical ASR systems, presenting a robust tool for radiological transcription in the French language and paving the way for advanced technology-enhanced healthcare solutions.

LC-SPIK is a liver cancer-specific isoform of Serine Protease Inhibitor Kazal and has been proposed as a new biomarker for the detection of HCC given its unique 3-D structure which differs from normal pancreatic SPIK. An ELISA technology based on its unique structure was developed to use LC-SPIK as an effective biomarker for the clinical diagnosis of HCC. AFP, the most widely used biomarker for HCC surveillance currently, suffers from poor clinical performance, especially in the detection of early-stage HCC. In one case-control study, which included 164 HCC patients and 324 controls, LC-SPIK had an AUC of 0.87 compared to only 0.70 for AFP in distinguishing HCC from liver disease controls (cirrhosis, HBV/HCV). LC-SPIK also performed significantly better than AFP for the 81 patients with early-stage HCC (BCLC stage 0 and A), with an AUC of 0.85 compared to only 0.61 for AFP. Cirrhosis is the major risk factor for HCC, about 80% of patients with newly diagnosed HCC have preexisting cirrhosis. LC-SPIK’s clinical performance was also studied in HCC patients with viral and non-viral cirrhosis including cirrhosis caused by nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). In a total of 163 viral cirrhosis patients with 93 HCC patients (50 early-stage), LC-SPIK had an AUC of 0.85, while AFP had an AUC of 0.70. For patients with early-stage HCC, LC-SPIK had a similar AUC of 0.83, while AFP had an AUC of only 0.60. For 120 patients with nonviral cirrhosis, including 62 HCC (23 early-stage) patients, LC-SPIK had an AUC of 0.84 while AFP had an AUC of only 0.72. For the 23 patients with early-stage HCC, LC-SPIK had a similar AUC of 0.83, while the AUC for AFP decreased to 0.65. All these results suggest that LC-SPIK has significantly better performance in the detection of HCC than AFP in all etiologies of liver diseases. In addition, LC-SPIK accurately detected the presence of HCC in 71%-91% of HCC patients with false-negative AFP test results in viral associated HCC and non-viral associated HCC.

To better understand how immunity develops against SARS-CoV-2 during the pandemic period of 2020 to 2022, we analyzed the immune response of a small group of university staff and students who were either infected or vaccinated. We investigated the levels of receptor-binding domain (RBD)-specific and nucleocapsid (N)-specific IgG and IgA antibodies in serum and saliva samples taken early (around 10 days after infection or vaccination) and later (around 1 month later), as well as N-specific T-cell responses. One patient who had been infected in 2020 developed serum RBD and N-specific IgG antibodies, but declined 8 months later, then mRNA vaccination in 2021 produced a higher level of anti-RBD IgG than natural infection. In the vaccination of naïve individuals, vaccines induced anti-RBD IgG, but it declined after 6 months. A third vaccination boosted the IgG level again, albeit to a lower level than after the second. In 2022, when the Omicron variant became dominant, familial transmission occurred even among vaccinated people. In infected individuals, the levels of serum anti-RBD IgG antibodies increased later, while anti-N IgG peaked earlier. The N-specific activated T cells expressing IFN- or CD107a were detected early. In saliva, SARS-CoV-2-specific IgG but not IgA was detected. Interestingly, two individuals showed a temporary peak in RBD- and N-specific IgA antibodies in their saliva on the second day after infection. Thus, SARS-CoV-2 infection triggers typical immune responses in humans against acute viral infections, but mucosal immune responses, which are temporarily induced early during infection, may be more important for protection than current intramuscular vaccines.