Clinical and laboratory diagnostics are particularly important in monitoring the internal homeostasis of the body in high-yielding animals, especially in dairy cows, whose metabolism is under constant pressure to obtain high parameters of milk production and reproduction. Knowledge of laboratory test results and relationships based on significant correlations between various milk and blood parameters may be very useful in veterinary diagnostics and helpful in cattle practice in order to protect animal health and the quality of milk production. The aim of the study was to analyze the correlation between selected hematological biomarkers such as white blood corpuscles (WBC), red blood corpuscles (RBC), hemoglobin concentration (HGB), hematocrit (HCT), platelets (PLT), erythrocyte mean corpuscular volume (MCV), mean corpuscular hemoglobin content (MHC), mean corpuscular hemoglobin concentration (MCHC) and selected quantitative-qualitative parameters of cow’s milk such as current milk production, somatic cells count (SCC), colony of bacteria forming units (CFU), milk fat (MF), milk protein (MP), milk lactose (ML), milk solids (S), solids non-fat in milk (SNF), daily milk production. Samples were collected three times at daily intervals from 11 clinically healthy late-lactation dairy cows obtaining 33 sets of test results. This repeated study of cows allowed for obtaining a homogeneous group in order to determine statistical correlations between selected blood and milk parameters. Many significant correlations were found between the examined parameters. In cows, significant positive correlations were recorded between milk production and HGB, HCT, MCV or MHC. Significant negative correlations were also found between SCC and HGB, SCC and HCT, SNF and MCV, SNF and MHC, and between MF and RBC.

Cardiopulmonary resuscitation (CPR) is a widely practiced lifesaving skill. Conventional CPR is based on manual chest compressions and delivering mouth-to-mouth breaths. There has been advancement in biomedical technology over the last few decades which has led to the introduction of new techniques and devices in CPR as well. In light of these advancements, we propose SMEAR (Standard, Mechanical, ECMO Assisted, Augmented virtual and Remote) classification system to provide structured overview from traditional to novel methods and devices. The standard or Manual CPR, widely practiced by the general public during out-of-hospital cardiac arrests, combines active chest compressions with or without mouth breathing. However, to enhance CPR’s efficacy, various mechanical devices have been developed, encompassing Active Chest Compression, Passive Decompression, and those integrated with Automated External Defibrillators. Feedback sensor-equipped devices, include the Metronome, Accelerometer, Barometer, and Triaxial Field Induction. Mechanical devices, classified by their compression mechanisms, can be isolated – like the Piston-driven, Load-distributing, and Active Compression-Decompression (ACD) – or combined, as in ACD-ITV (Impedance Threshold Device), ACD-IAC (Interposed Abdominal Compression), and ACD-ITV-EECP (Enhanced External Counter Pulsation). Beyond mechanics, Extracorporeal CPR offers veno-arterial Extracorporeal Membrane Oxygenation in refractory cardiac arrest and can improve outcomes. Augmented Virtual Reality usage in training and provision of CPR is at the early stages. It has the potential of expanded usage in training public to provide high-quality CPR. A provider can be remotely guided step by step via telephone or smartphone applications, ensuring continuous support until professional assistance arrives.

The prevalence of patients on buprenorphine therapy presenting for elective surgery has increased. Buprenorphine is a widely used medication for management of patients with chronic pain. It is also used for maintenance therapy for patients with a history of opioid use disorder (OUD). Due to lack of standardized protocol for managing patients on buprenorphine peri-operatively, we performed a retrospective analysis to compare pain score outcomes and post-operative opiate requirements between patients who continued versus discontinued buprenorphine. We identified 35 patients, 11 continued buprenorphine and 24 discontinued buprenorphine. The average Post-Anesthesia Care Unit (PACU) pain score was 7.54 for those who discontinued pre-operative buprenorphine and 5.59 for those who continued (P value 0.0339). The average post-operative Morphine Milligram Equivalent (MME) use was 86.13 for those who continued pre-operative buprenorphine and was 107.70 for those who discontinued buprenorphine (P value 0.6439). The results from our study correlate with several previous studies which showed lower PACU pain scores in patients who continued buprenorphine. There is a benefit of decreased pain post-operatively when pre-operative buprenorphine is continued and having a decrease in relapse in those with a history of OUD.

Nystagmus induced by applying an intense vibratory stimulus to the skull (SVIN) indicates vestibular functional asymmetry. In unilateral vestibular loss, a 100-Hz bone-conducted vibration given to either mastoid immediately causes a primarily horizontal nystagmus. Test is performed in darkness to avoid visual fixation (VF) but there is no data about how much VF affects the often-intense SVIN. The aim is to analyze the amount of reduction of SVIN when VF is allowed during testing. Thus, all patients seen in a tertiary hospital for vertigo or dizziness with positive SVIN were included. SVIN was recorded for 10 seconds for each condition: without VF (aSVINwo) and VF (aSVINw). We obtained an aSVINwo and aSVINw as average slow-phase velocities (SPV) without and with VF. VF index (FISVIN) was calculated as the ratio of SPV. Among the 124 patients included, spontaneous nystagmus (SN) was found in 25% and the mSPV (without VF) of SN was 2.62.4º/s. Mean FISVIN was 0.270.29. FISVIN was 0 in 42 patients and >0 FISVIN <1 in 82 (mean FISVIN 0.390.02). Fixation suppression was found in all patients with SVIN in cases of peripheral vestibulopathy. FISVIN clearly delineates two populations of patients: with or without complete visual reduction of nystagmus.

The Shimensi super-large tungsten polymetallic deposit is located in Late Jurassic- Early Cretaceous Porphyry-Skarn tungsten ore belt in the south Yangtze metallogenic belt. There are 3 types of mineralization: veinlet-disseminated type, thick quartze vein type and hydrothermal crypto-explosive breccia type. Based on geological studies, this paper presents new petrographic, microthermometric, laser Raman spectroscopic and hydrogen and oxygen isotope research of the fluid inclusions from the deposit. The results show that there are five different types of fluid inclusions: liquid-rich inclusions, vapor-rich inclusions, pure liquid inclusions, pure vapor inclusions, and fluid inclusions containing a solid crystal. The homogenization temperatures of the fluid inclusion range from 140℃-270℃, the salinities are 3%-5% NaCleq and the densities of ore-forming fluid range from 0.64 g/cm3 to 0.99 g/cm3. For the analyses of Laser Raman spectroscopic, the ore-forming fluids can be approximated by a Ca2+-Na+-SO42--Cl- fluid system with small amount of CO2, CH4 and N2. Otherwise, the datas of the pressure, pH and Eh show a fluid metallogenic environment of low pressure, weak acid and weak reduction. The values of the homogenization temperature in 3 types of orebodies suggest that the mineralization is characterized by the decrease of the temperature under the condition of the fluid immiscibility. The H-O isotope values are interpreted to indicate that the ore-forming fluids are mainly composed of magmatic water, and also the meteoric water was added with the process of the magma rising.

Measurement of Globe temperature is essential for investigating thermal comfort in street canyon. Globe thermometer is the most common instrument used to measure globe temperature (GT), however its application in scale models is still uncertain and not thoroughly investigated as of today. Therefore, this study is explicitly conducted to investigate globe thermometer measurements and proposed an improvised customization of the globe thermometer size to enhance reliability in scale models. The experiments were carried out outdoors using a typical street canyon model (scale 1:100) with East-West street orientation. The experiment presented a comparison between a low solar reflective street canyon (albedo of 0.4) and a high solar reflective canyon (albedo of 0.6) in terms of surface temperatures, heat flux and globe temperature. Furthermore, this study also investigated the influence of solar orientation on the globe temperature using both experimental using scale models and microclimatic modelling using ENVI-met. It is observed that although the surface temperatures are lower with high solar reflective canyon compared to that with low solar reflective canyon, GT is higher in high reflective canyon during daytime, which could be due to combined effect of direct radiation and shortwave reflection. However, for hours after the sun set, GT becomes lower (up to 1°C) in the case of high reflective canyon compared to low reflective canyon.

This study used Dutch potatoes at the end of dormancy as the material to explore the impact of menthol (0.2 and 0.5 g/kg based on potato mass) treatment on sprouting inhibition and potato quality. The findings revealed that a menthol concentration of 0.5 g/kg effectively inhibited potato tuber sprouting and significantly reduced glucoside alkaloids production. After a storage period of 15 days, the sprouting percentage and glucoside alkaloids content of potatoes treated with 0.5 g/kg menthol were observed to be significantly lower at 4.17% and 68.63 mg/kg, respectively, compared to the control group which exhibited values of 100% and 282.01 mg/kg, respectively (P < 0.05). Throughout the storage period, 0.5 g/kg of menthol promoted respiration, reduced malondialdehyde production in potatoes, inhibited polyphenol oxidase activity, and slowed down tissue browning. Additionally, it mitigated the decline in starch and soluble protein content, inhibiting the accumulation of reducing sugars.

Breast cancer brain metastasis (BCBM) is a challenging condition with limited treatment options and poor prognosis. Understanding the interactions between tumor cells and the blood-brain barrier (BBB) is critical for developing novel therapeutic strategies. One promising target is estrogen receptor β (ERβ), which promotes the expression of key tight junction proteins, sealing the BBB and reducing its permeability. In this study, we investigated the effects of 17β-estradiol (E2) and the selective ERβ agonist diarylpropionitrile (DPN) on endothelial and cancer cells. Western blot analysis revealed the expression patterns of ERs in these cell lines, and estrogen treatment upregulated claudin-5 expression in brain endothelial cells. Using in vitro models of the BBB, we found that DPN treatment significantly increased BBB tightness about suppressed BBB transmigration activity of representative HER2-positive (BT-474) and triple-negative (MDA-MB-231) breast cancer cell lines. However, the efficacy of DPN treatment decreased when cancer cells were pre-differentiated in the presence of E2. Our results support ERβ as a potential target for the prevention and treatment of BCBM and suggest that targeted vector-based approaches may be effective for future preventive and therapeutic implications.

This study focused on evaluating the potential of natural fermentation of pea flour (F) to improve the release of antioxidant compounds. Two fermentation conditions of F were performed: 1: 36.4% w/w, 24 h, 30°C (FF1); 2: 14.3% w/w, 24 h, 37°C (FF2); pH values decreased to 4.4-4.7, with a predominance of lactic acid bacteria. An increment of the proteolysis degree (TNBS method) (greater for FF2), polypeptides aggregation and decrease of solubility, increase of &lt; 2 kDa peptides, and increase in the ORAC potency of PBS-soluble fractions after fermentation was demonstrated. After simulated gastrointestinal digestion (SGID, COST-INFOGEST), FF1D and FF2D showed greater proteolysis degrees (63 and 53%) than F1D and F2D (45%), with differences in the molecular composition of the different digests. ORAC and HORAC potencies increased in all cases. FF2D presented the greater ORAC value, with higher activities for &gt; 4 kDa, some in the range 2 to 0.3 kDa. and &lt; 0.10 kDa fractions. Fermentation also increased the 60 % ethanol extracted phenolic compounds, mainly flavonoids, and the ORAC activity. After SGID, the flavan-3-ols disappeared but some phenolic acids increased respect to F. Fermentation in condition 2 was considered the most appropriate to obtain a functional antioxidant ingredient.

This review article explores the significance and prospects of using diverse T-cell variants in the context of combined therapy for lung cancer treatment. Recently, there has been an increase in research focused on understanding the critical role of tumor-specific T-lymphocytes and the potential benefits of autologous T-cell-based treatments for individuals with lung cancer. One promising approach involves intravenous administration of ex vivo-activated autologous lymphocytes to improve the immune status of patients with cancer. Investigations are also exploring the factors that influence the success of T-cell therapy and the methods used to stimulate them. Achieving a comprehensive understanding of the characteristics of activated lymphocytes and deciphering the mechanisms underlying their activation of innate anti-tumor immunity will pave the way for numerous clinical trials and the development of innovative strategies for cancer therapy.

Gastroesophageal cancers, are among the most prevalent cancers globally and represent the third leading cause of cancer-related mortality worldwide. Surgical resection remains the primary curative approach for localized and locally advanced stages, but its effectiveness is limited for locally advanced diseases, evidenced by a low 5-year survival rate of around 25%. High relapse rates post-surgery, particularly in western populations, necessitate the use of neoadjuvant, adjuvant, or perioperative strategies involving chemotherapy and radiation to improve surgical outcomes. Neoadjuvant chemoradiation therapy has demonstrated a significant improvement in overall survival. Recent advances have identified several target genes and pathways involved in the pathogenesis and progression of these cancers, leading to the development of targeted drugs, including immunotherapy, anti-HER-2 antibodies, and anti-VEGFR antibodies. These targeted therapies are emerging as promising interventions for better patient outcomes and personalized treatment approaches and therefore could eventually evolve into a novel therapeutic regimen for gastroesophageal cancer.

Activating the cytosolic innate immune sensor cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway via natural and synthetic agonists holds great potential for priming robust antitumor immunity. However, the effectiveness of STING agonists is often impeded by the insufficient tumor accumulation, poor cellular entry, and rapid clearance, thus leading to difficulty of their clinic translation. Herein, we apply the human serum albumin as the single-molecule nanoreactor to encapsulate SR-717 (SH-NPs) for enhanced targeting delivery efficiency and biological potency. SH-NPs with rational size distribution exhibited superior serum stability, considerable cellular uptake and abundant tumor accumulation, thus increasing the STING signaling including phosphorylation of STING-associated proteins (TBK1, IRF3), and cytokines secretion inside tumor region. Subsequently, SH-NPs remarkably reshape the immunosuppressive tumor microenvironment into an immunogenic one that boosts antitumor T-cell immunity and improves the therapeutic efficacy of checkpoint blockade against murine tumors. We also validate SH-NPs in freshly isolated human renal tumor tissues to highlight their clinic translation capability. These findings pave the way towards targeted STING agonist delivery for reinvigorated immunotherapy of intractable cancers.

Triple-negative breast cancer (TNBC), lacking specific receptors found in other breast cancer subtypes, poses significant treatment challenges due to limited therapeutic options. Therefore, it is necessary to develop novel treatment approaches for TNBC. In the last few decades, many attempts have been reported for alternative tools for TNBC treatment: immunotherapy, radiotherapy, targeted therapy, combination therapy, and nanotechnology-based therapy. Among them, combination therapy and nanotechnology-based therapy show the most promise for TNBC treatment. This review outlines recent advancements in these areas, highlighting the efficacy of combination therapy (immunotherapy paired with chemotherapy, targeted therapy, or radiotherapy) in both preclinical and clinical stages and nanotechnology-based therapies utilizing various nanoparticles loaded with anticancer agents, nucleic acids, immunotherapeutics, or CRISPRs in preclinical stages for TNBC treatment.

The FAS ligand (FASLG) is expressed on lymphocytes, which employ it to activated death receptors on targets cells. Cancer cells are generally resistant to apoptosis triggered by FASLG. In this work we found a way to circumvent this resistance by treatment with actinomycin D (ActD) and nutlin-3a (Nut3a). We selected this drug combination based on our transcriptomic data showing strong activation of proapoptotic genes, including the ones for receptor mediated apoptosis, in cells exposed to actinomycin D and nutlin-3a. To test our hypothesis, we pre-exposed cancer cell lines to this drug combination for 45h and next we treated them with recombinant FASLG. This almost instantaneously killed most cells. Actinomycin D and nutlin-3a strongly synergized in the sensitization because the effect of the drugs acting solo was not as spectacular as the drug combination, which together with FASLG killed more than 99% of cells. Based on the caspase activation pattern (caspase-8, caspase-9, caspase-10), we conclude that both extrinsic and intrinsic pro-apoptotic pathways were engaged. In engineered p53-deficient cells this pro-apoptotic effect was completely lost. Therefore, the combination of ActD+Nut3a activates p53 in an extraordinary way, which overcomes the resistance of cancer cells to apoptosis triggered by FASLG. Interestingly, other combinations of drugs, e.g., etoposide + nutlin-3a, actinomycin D + RG7112 and actinomycin D + idasanutlin had similar effect. Moreover, normal human fibroblasts are less sensitive to death induced by ActD+Nut3a+FASLG. Our findings create the opportunity to revive the abandoned attempts of cancer immunotherapy employing the recombinant FAS ligand.

Background: Large-cell neuroendocrine carcinoma presents significant treatment challenges owing to its rarity and limited therapeutic options. The LANCE study was designed to explore the survival benefits of incorporating atezolizumab in chemotherapy for metastatic LCNEC. Methods: In this non-randomized study, patients with metastatic LCNEC were treated with ei-ther standard chemotherapy plus atezolizumab or standard chemotherapy alone. The primary outcomes measured were progression-free survival (PFS) and overall survival (OS), with an ex-ploratory analysis of miR375 in plasma as a potential biomarker. Results: Of the 22 screened patients, 17 met the inclusion criteria and were stratified into the atezolizumab and chemotherapy (n=10) or chemotherapy alone(n=7) groups. After a median follow-up of 23.3 months, the 12-month survival rate for the atezolizumab group was 57.1% (95% CI: 32.6%-100%) and 45.7% at 24 months (95% CI: 22.4%-93.2%). In contrast, the chemotherapy group had a 14.3% survival rate at both 12 and 24 months (95% CI: 2.33%-87.7%). The log-rank test for survival showed a statistically significant difference in the atezolizumab-treated group (chi-squared = 4, df = 1, p = 0.04). A non-significant correlation was found between disease pro-gression and elevated levels of miR375. Conclusions: This pilot study suggests that atezolizumab combined with chemotherapy may be effective in treating metastatic LCNEC. The non-significant correlation between plasma miR375 levels and disease progression suggests its biomarker potential, warranting further validation research.

Osteosarcoma (OS) are the most prevalent malignant bone tumors in adolescents and young adults.. OS cells grow in a permissive local microenvironment which modulates their behavior and facilitates all steps in tumor development (e.g., proliferation/quiescence, invasion/migration, drug resistance) and contributes to their intrinsic heterogeneity. The lung parenchyma is the most common metastatic site in OS, and metastatic foci are frequently associated with a poor clinical outcome. Although multiple factors may be responsible for the disease, including genetic mutations (e.g., Rb, p53), the molecular mechanism of development of OS remains unclear and the conventional treatment for OS is still based on a sequential approach that combines chemotherapy and surgery. Also, despite the increase in clinical trials, the survival rates for OS have not improved. Non-specific targeting therapies thus show poor therapeutic effects with side effects at high doses. For these reasons, many efforts have been done to characterize the complex genome of osteosarcoma thanks to the whole exome analysis with the aim to identify predictive biomarkers to give to these patients a better therapeutic option. This review aims to summarize and discuss the main recent advances in OS molecular research for precision medicine.

Tumor infiltrating lymphocytes (TILs) are an emerging biomarker predictive of response to immunotherapy across a spectrum of solid organ malignancies. The characterization of TILs in gastric cancer (GC) treated with contemporary, multiagent neoadjuvant chemotherapy (NAC) is understudied. In this retrospective investigation, we analyzed the degree of infiltration, phenotype, and spatial distribution of TILs via immunohistochemistry within resected GC specimens treated with or without NAC at a Western center. We hypothesized that NAC executes immunostimulatory roles evidenced by an increased number of anti-tumor TILs in the tumor microenvironment. We found significantly elevated levels of conventional and memory CD8+ T cells, and total TILs (CD4+, CD8+, Treg, B cells) within chemotherapy-treated tumors compared to chemotherapy-naïve specimens. We also revealed important associations between survival and pathologic response with enhanced TIL infiltration. Taken together, our findings advocate for an immunostimulatory role of chemotherpy and underscore the potential synergistic effect of combining chemotherapy with immunotherapy in resectable gastric cancer.

Recently, immunotherapy has arisen as a novel treatment approach for patients with colorectal cancer (CRC), but the effectiveness of immunotherapy varies in these patients. We hypothesized that immune checkpoint molecules (ICMs), which are the targets of immunotherapy, are often exhibit concomitantly. Our objective was to investigate the patterns of ICM expression in patients with CRC and the differences in ICM expression based on the microsatellite instability status. Immunohistochemical expression of programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), and lymphocyte-activation gene 3 (LAG-3) in the tumor center and periphery was assessed in patients with non-metastatic colorectal cancer. We enrolled 83 patients with CRC: 40 with microsatellite stable (MSS) and 43 with microsatellite instability-high (MSI-H). PD-L1 was more frequently expressed in the tumor center in patients with MSI-H than that in patients with MSS (18 [41.9 %] vs. 3 [7.5 %], respectively; P &lt; 0.001), and the same trend was observed for TIM-3 expression (30 [69.8 %] vs. 19 [47.5 %], respectively; P = 0.047). Concomitant expression of two or more ICMs was more frequently observed than no expression or expression of a single molecule in both MSS and MSI-H groups; 34 (79.7 %) patients with MSI-H and 23 (57.5 %) with MSS showed ICM expression at the tumor center, whereas 34 (79.7 %) patients with MSI-H and 22 (55 %) with MSS showed expression at the tumor periphery. Patients with the genetic characteristics of MSI-H showed higher expression levels of ICMs than that in patients with MSS, and predominantly, two or more ICMs were concurrently expressed. Our findings highlight the potential efficacy of the dual-blockade approach in immunotherapy, particularly in patients with MSI-H CRC.

Immune checkpoint inhibitors (ICI’s) are in the forefront of advanced Non Small Cell Lung Cancer (NSCLC) treatment. Still, only 27- 46% of patients respond to initial therapy with ICI’s and of those, up to 65% develop resistance within four years. After disease progression (PD), treatment options are limited, with 10% Objective Response Rate (ORR) to second or third-line chemotherapy. In this context, ICI rechallenge is an appealing option for NSCLC. Most data on the efficacy of ICI rechallenge are based on retrospective real-world studies of small, heavily pretreated, and heterogeneous patient groups. Despite these limitations, these studies suggest that ICI monotherapy rechallenge in unselected NSCLC patient populations who discontinued initial ICI due to PD is generally ineffective, with a median Progression-Free Survival (PFS) of 1.6-3.1 months and a Disease Control Rate (DCR) of 21.4%-41.6%. However, there is a subpopulation that benefits from this strategy, and further characterization of this subgroup is essential. Furthermore, immunotherapy rechallenge in patients who discontinued initial immunotherapy following treatment protocol completion and progressed after an immunotherapy-free interval showed promising efficacy, with a DCR of 75-81%, according to post-hoc analyses of several clinical trials. Future research of ICI rechallenge for NSCLC should focus on better patient stratification, to reflect the underlying biology of immunotherapy resistance more accurately.

Background and Objectives: Cancer as the second leading cause of death in the United States poses a huge healthcare burden. Barriers to access to advanced therapies influence the outcome of cancer treatment. In this study, we examined whether insurance types affect the quality of cancer clinical care regarding access to an important monoclonal antibody, ramucirumab. Materials and Methods: Data for 13,340 cancer patients with Purchased or Medicaid insurance from the All of Us Database were collected for this study. The Chi-square test of proportions was employed to determine the significance of patient cohort characteristics and ramucirumab usage between Purchased and Medicaid insurance groups. The independent t-test was utilized to assess the influences of other determinants on insurance types. Results: Cancer patients who are African American, with lower socioeconomic status, or with lower educational attainment are more likely to be insured by Medicaid. Analysis of survey questions demonstrated the relationship between income and education level with insurance type as Medicaid cancer patients were less likely to receive primary care and specialist physician access and more likely to request lower cost medications. In addition, those with Medicaid insurance were identified to have poorer access to expensive therapeutics like ramucirumab compared to those with Purchased insurance.  Conclusions: The inequities of the US healthcare system are observed for cancer patient care; access to physicians and therapeutics are highly varied and dependent on insurance types. Socioeconomic status determines insurance type, which unfortunately generates a significant impact on cancer treatment and disease outcome.

Background Glioblastoma (GBM) is a poor prognosis malignant grade 4 glioma. After surgical resection, standard therapy consists of concurrent radiotherapy (RT) and temozolomide (TMZ) followed by TMZ alone. The DC vaccination increased the amount of intratumoral-activated cytotoxic T lymphocytes and decreased the number of FoxP3-positive regulatory T cells. Based on these da-ta, we have developed a phase II protocol with the DC vaccine concomitant to standard RT-CT in patients undergoing surgery for GBM. Methods This is a single-arm, monocentric, phase II trial evaluating progression-free survival (PFS) and the safety of a DC vaccination integrated with standard therapy in resected GBM patients. The vaccine administration begins at the end of the RT-CT (Induction Phase) and is subsequently al-ternated with TMZ cycles (Maintenance Phase). The primary endpoints are PFS and safety. Among the secondary endpoints, are the in vitro and in vivo Immune response evaluations. Results By December 2022 , nine patients had been enrolled in the first step. Two patients progressed within three months after leukapheresis and none had experienced DC vaccine-related G3-4 tox-icity. Five patients had a positive DTH test against KLH. By June 2023. The median OS from leu-kapheresis was 23.1 months and 24.7 from surgery. Conclusions This combination therapy is well-tolerated, and we have achieved the two endpoints required for the first step. Therefore, the study will proceed to enroll the remaining 19 patients.

Hepatocellular carcinoma (HCC) is characterized by uncontrolled cellular proliferation driven by aberrant signal transduction. Cells respond to potential carcinogenic signals by inducing cellular senescence (CS) as a defense mechanism. However, assessing CS levels in various tumors is challenging due to heterogeneity and the lack of universal CS markers. This study integrates single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data from HCC samples to analyze gene expression profiles. HCC-specific senescence-related pathways are identified, and genes from these pathways distinguish molecular subtypes associated with senescence in HCC. These subtypes exhibit significant variations in biological and clinical attributes. A specific CS risk model is developed, revealing associations between CS scores and prognosis, clinical staging, immune infiltration, immunotherapy response, and drug sensitivity. The key gene G6PD is identified as a potential senescence-related target in liver cancer. Molecular experiments confirm the effective suppression of HepG2 cell proliferation, invasion, and migration upon G6PD knockdown. In summary, this analysis enhances our understanding of HCC-specific senescence molecular features and introduces a novel senescence-related biomarker, offering promising implications for future research.

Allergen immunotherapy (AIT) with aeroallergens is the only disease modifying treatment for patients with different allergic conditions. Despite the effectiveness of AIT has been evidenced in both randomized controlled trials and real word studies, it remains underused in less than 10% of subjects with allergic rhinitis (AR) and/or asthma (A). We aimed to determine the current eligibility for house dust mite (HDM) AIT by means of a Precision Allergy Molecular Diagnosis (PAMD@) model in a selected cohort of youngsters with different allergic phenotypes according to the available evidence. A complex response to both HDM and storage mite allergens was depicted regardless of the subjects´ basal atopic condition. No solely specific IgE binding responses to Der p 1, Der p 2 and/or Der p 23 were found in the studied cohort. Despite patients with A and atopic dermatitis showed significantly higher serum titers to 6 mite allergens than subjects with AR, no specific molecular profile could be regarded as disease specific. Given the increasing complexity of specific IgE responses to the local prevailing aeroallergens, the identification and presence of such molecules are needed in commercially available AIT in the era of precision medicine.

Dermatophagoides pteronyssinus (Der p) subcutaneous immunotherapy (SCIT) has demonstrated efficacy in clinical trials of childhood allergic rhinitis (AR). Currently, there is a lack of some generally accepted biomarkers that may predict the clinical response to SCIT to eventually achieve personalized therapy. In this study, 28 children with AR received Der p SCIT for 26-30 months at baseline, and four efficacy endpoints, serum interleukin (IL)-5, periostin, Der p-specific IgE (sIgE), and Der p sIgG4, were measured by ELSIA. Clinical symptoms and characteristics were assessed by questionnaires, and the associations among periostin, Der p 2 sIgE and clinical efficacy were analyzed. The results showed that SCIT demonstrated a significant reduction in Der p 1 sIgE (P < 0.05) and Der p 2 sIgE (P < 0.01), an increase in Der p sIgG4 (P < 0.001) and an improvement in clinical efficacy at the fourth efficacy endpoint compared with that at baseline. A positive linear correlation was found in serum periostin and Der p sIgE (Pearson correlation=0.8868, P=0.045), Der p sIgG4 (Pearson correlation=-0.9025, P=0.036), and clinical efficacy. Importantly, the concentration of serum Der p 2 sIgE showed a positive linear correlation with clinical efficacy and serum periostin (Pearson correlation=0.9581, P=0.010). These results suggest that SCIT can result in reduced type 2 cytokines and Der p sIgE and has long-term efficacy in children with AR. Der p 2 sIgE has a positive linear correlation with clinical efficiency and serum periostin and may be a useful biomarker for the prediction of SCIT.

The microbiome is pivotal in maintaining health and influencing disease by modulating essential inflammatory and immune responses. Hepatocellular carcinoma (HCC), ranking as the third most common cause of cancer-related fatalities globally, is influenced by the gut microbiome through bidirectional interactions between the gut and liver, as evidenced in both mouse models and human studies. Consequently, biomarkers based on gut microbiota represent promising non-invasive tools for the early detection of HCC. There is a growing body of evidence suggesting that the composition of the gut microbiota may play a role in the efficacy of immunotherapy in different types of cancer, thus it could be used as a predictive biomarker. In this review, we will dissect the gut microbiome's role as a potential predictive and diagnostic marker in HCC and evaluate the latest progress in leveraging the gut microbiome as a novel therapeutic avenue for HCC patients, with a special emphasis on immunotherapy.

EGFR tyrosine kinase inhibitors (TKIs) are the preferred initial treatment for non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. However, remission is transient, and no further effective treatment options are available for EGFR-TKI-advanced EGFR-mutant NSCLCs. Immunotherapy with immune checkpoint inhibitors (ICIs) induces sustained cancer remission in a subset of NSCLCs. However, ICI therapy exhibits limited activity in most EGFR-mutant NSCLCs. Mechanistically, the strong oncogenic EGFR signaling in EGFR-mutant NSCLCs contributes to the non-inflamed tumor immune microenvironment (TIME), characterized by a limited number of CD8+ T cell infiltration, a high number of regulatory CD4+ T cells and a high number of inactivated infiltrated T cells. Besides, EGFR-mutant NSCLC patients are generally non-smokers with low levels of PD-L1 expression and tumor mutation burden. However, current understanding only partially explains why a small population of EGFR-mutant NSCLCs durably respond to ICI therapy, resulting in many researchers actively working in this field. This review reviews the hope seen from pre-clinical studies and clinical trials which may be adopted to improve the outcome of ICI therapy in EGFR-mutant NSCLCs. Besides, the underlying mechanisms leading to the inferior clinical outcome of ICI therapy in EGFR-mutant NSCLCs are discussed.

Skin cancer is a prevalent and heterogenous disease with several subtypes, such as melanoma, basal cell carcinoma, and squamous cell carcinoma. Among them, melanoma is the most aggressive subtype, with a higher propensity to spread compared to most solid tumors. The application of OMICS approaches has revolutionized the field of melanoma research by providing comprehensive insights into the molecular alterations and biological processes underlying melanoma development and progression. This review aims to offer an overview of melanoma biology, covering its transition from primary to malignant melanoma, as well as the key genes and pathways involved in the initiation and progression of this disease. Utilizing online databases, we extensively explored the general expression profile of genes, identified the most frequently altered genes, and gene mutations, and examined genetic alterations responsible for drug resistance. Additionally, we studied the mechanisms responsible for immune checkpoint inhibitors resistance in melanoma.

Hymenoptera allergens are the main triggers for anaphylaxis in susceptible dogs and humans. Hymenoptera venom specific immunotherapy (VIT), the only disease-modifying treatment, has the potential to prevent future life-threatening reactions in human patients. Prospective clinical data on VIT efficacy in dogs are currently lacking. Therefore, the aim of this study was to show that VIT is not only safe but also efficacious in preventing anaphylaxis in dogs allergic to Hymenoptera. This uncontrolled prospective clinical trial included 10 client-owned dogs with a history of anaphylaxis following repeated Hymenoptera stings. The sensitization to bee and wasp allergens was demonstrated by intradermal testing (IDT) and allergen-specific IgE serology. For VIT induction (induction phase), dogs received a shortened rush immunotherapy protocol with aqueous allergens, which was then followed by monthly injections of 100 g of alum-precipitated allergen (maintenance phase). VIT efficacy was determined by observing patients’ clinical reactions to re-stings. No systemic adverse events were seen during the induction and maintenance phase. From the seven re-stung dogs, only one developed a mild angioedema at the site of the sting; the remaining dogs were asymptomatic. These results show that VIT represents a safe and effective treatment option for Hymenoptera-allergic dogs.

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

Gliomas are aggressive, primary central nervous system tumours arising from glial cells. Glioblastomas are the most malignant. They are known for their poor prognosis or median overall survival. Current standard of care is overwhelmed by the heterogeneous, immunosuppressive tumour microenvironment promoting immune evasion and tumour proliferation. The advent of immunotherapy with its various modalities – immune checkpoint inhibitors, cancer vaccines, oncolytic viruses, chimeric antigen receptor T cells and NK cells have shown promise. Clinical trials incorporating combination therapies of the above have overcome the microenvironment resistance and yielded survival and prognostic benefit. Rolling these new therapies out in the real-world scenario in a low cost, high throughput manner is the unmet need of the hour. These will bring practice changing implications to the glioma treatment landscape. In this review article, we focus on describing the hallmarks of the glioma microenvironment and its interplay with the different emerging modalities of immunotherapy.

Tissue programmed death ligand-1 (PD-L1) protein is the recognized predictive immune biomarker of immune checkpoint inhibitor (ICI) treatment benefit in metastatic non-small cell lung cancer (NSCLC). However, tissue PD-L1 protein testing can be limited by tumor heterogeneity and fraught with tissue acquisition difficulties. A plasma PD-L1 assay potentially overcomes these tissue limitations. Patients with metastatic NSCLC treated with first-line ICI-based treatment and available results of plasma cfRNA PD-L1 by real-time polymerase chain reaction (RT-PCR) and tissue PD-L1 protein PD-L1 with the Dako 22C3 monoclonal antibody were retrospectively assessed for median and landmark 3-year overall survival (OS). OS was identical whether positive plasma cfRNA PD-L1 expression or positive tissue PD-L1 protein expression (median OS 15 months; 3-year landmark OS 30%; hazard ratio (HR) 0.97; 95% CI, 0.44-2.10). Positive plasma cfRNA PD-L1 patients also demonstrated a numerically longer median and higher 3-year OS compared to patients lacking PD-L1 expression (median 15 months versus 8 months; 3-year landmark OS 30% versus 15%; HR 0.56; 95% CI, 0.27-1.17). Plasma cfRNA PD-L1 expression by RT-PCR was similarly predictive of ICI-based treatment benefit as tissue PD-L1 protein expression.

The burden of hepatocellular carcinoma (HCC) continues to pose a significant global health problem. Several systemic therapies have recently been shown to improve survival for patients with unresectable disease. However, evidence is limited to support the use of neoadjuvant or adjuvant systemic therapies in patients with resectable disease, despite the high risk of recurrence. Neoadjuvant and adjuvant systemic therapies are being investigated for their potential to reduce recurrence after resection and improve overall survival. Our review identified various early-phase clinical trials showing impressive preliminary signals of pathologic complete response in resectable disease and others suggesting neoadjuvant therapies, particularly when combined with adjuvant strategies, may convert unresectable disease to resectable and cause significant tumor necrosis, potentially decreasing recurrence rates. The role of adjuvant therapies alone may also have a role in the management of these patients, particularly in reducing recurrence rates. Heterogeneity in trial design, therapies used, patient selection, and a scarcity of randomized phase III trials necessitate the cautious implementation of these treatment strategies. Future research is required to identify predictive biomarkers, optimize the timing and type of therapeutic combinations, and minimize treatment-related adverse effects, thereby personalizing and enhancing treatment strategies for patients with resectable and borderline resectable HCC.

Triple negative breast cancer (TNBC) has a negative expression of estrogen receptors (ER), progesterone receptors (PR), or human epidermal growth factor receptors (HER2). The survival rate for TNBC is generally worse than other breast cancer subtypes. TNBC treatment has made significant advances, but certain limitations remain. Treatment for TNBC can be challenging since the disease has various subtypes. Individualized therapy is recommended rather than generalized therapy, given the genetic variations among these TNBC subtypes. A precise and effective treatment for TNBC requires identifying prognostic markers. Depending on the type and stage of TNBC, patients are treated with various therapeutic interventions. A variety of treatment options are available, such as chemotherapy, immunotherapy, radiotherapy, and surgery. Chemotherapy is the most common of these options. TNBC is generally treated with systemic chemotherapy using drugs such as anthracyclines and taxanes in the neoadjuvant or adjuvant settings. Developing resistance to anticancer drugs and off target toxicity are the primary hindrances to chemotherapeutic solutions for cancer. It is imperative that researchers, clinicians, and pharmaceutical companies work together to develop effective treatment options for TNBC. Several studies have suggested nanotechnology as a potential solution to the problem of suboptimal TNBC treatment.

Immune checkpoint inhibitors (ICIs) are a class of drug that produces durable and sustained anti-tumour responses in a wide variety of malignancies. The exponential rise in their use has been mirrored by a rise in immune-related adverse events (irAEs). Knowledge of such toxicities, as well as effective management algorithms for these toxicities, is essential to optimize clinical efficacy and safety. Currently, the guidelines for management of the irAEs are based largely on retrospective studies and case series. In this article, we review the current landscape of clinical trials investigating the management of irAEs with an aim to develop standardized, randomized controlled trial-based management algorithms for ICI-related toxicities.

The tumor microenvironment (TME) plays a critical role in cancer progression and treatment outcomes. Despite advances in cancer research, many therapeutic strategies have failed to provide the desired clinical outcomes. In this integrated review, aimed to explore the role of TME in cancer biology and develop novel therapeutic strategies that target not only cancer cells but also the surrounding microenvironment. Study conducted a comprehensive literature search using PubMed, Embase, and Web of Science databases for articles published between 2016 and 2022. Inclusion of articles that discussed the impact of TME on cancer development and progression, as well as articles that proposed novel therapeutic strategies targeting the TME. The analysis of the literature revealed that the TME plays a crucial role in cancer development and progression by promoting cancer cell survival, angiogenesis, invasion, and metastasis, and by interfering with the efficacy of cancer therapies. The TME is composed of a complex network of non-cancerous cells, extracellular matrix components, and signaling molecules that interact with cancer cells. Several novel therapeutic strategies have been proposed based on the modulation of TME components. One of the most promising approaches is the use of immunotherapy, which aims to enhance the immune system's ability to recognize and attack cancer cells. Immunotherapy drugs such as checkpoint inhibitors, chimeric antigen receptor (CAR) T cells, and immune-stimulatory monoclonal antibodies have been approved for the treatment of different cancer types. These approaches have shown promising results in preclinical studies and clinical trials. The TME plays a critical role in cancer development and progression, and targeting its components represents a promising avenue for cancer therapy. Novel therapeutic strategies such as immunotherapy, extracellular matrix-targeting drugs, and nanoparticle-based therapies have shown promising results in preclinical studies and clinical trials. However, further research is needed to identify the most effective strategies and to overcome the challenges associated with TME targeting.

Abstract: The gut microbiome refers to microorganisms and their genetic material influencing local and systemic inflammation. Inflammation is known to contribute to cancer development, progression, and treatment. Evidence suggests that modulating the gut microbiome may affect responses to various cancer therapies. The gut microbiota has been suggested to have an impact on immunotherapy efficacy, especially the currently widely used immune checkpoint inhibitors in various malignancies. Microbial Interventions like fecal microbiota transplantation, various probiotics, or even antibiotics can increase or de-crease the tumor's sensitivity to immunotherapy. However, not all tumors react in the same manner, highlighting the tumor microenvironment heterogeneity across tumor types and the influence this has on the crosstalk between the microbiome and therapy outcomes. In this study, we intend to review the association between the gut microbiota and immunotherapy response in cancer patients and the factors regulating this interaction.

Cutaneous Melanoma (CM) is the most lethal form of skin cancer if it becomes metastatic, where treatment options and survival chances decrease dramatically. Immunotherapy treatments based on the immunologic checkpoint inhibitors (PD-1 and CTLA4) constituted a main breakthrough in the treatment of metastatic CM, particularly in the long-term benefit. However, several molecular pathways are responsible for the failure of this strategy in about 50-70% of CM patients. Some Long Non-coding RNAs (lncRNAs), and circular RNAs (circRNA) are implicated in triggering pro- and antitumorigenic responses to various cancer treatments. The relationship between lncRNA, circRNA and Immune Checkpoint Blockade (ICB) immunotherapy is not extensively explored in cutaneous metastatic melanoma (CMM). The aim of this study is to evaluate the potential role of both circRNA and lncRNA as a predictive immunotherapy biomarker in CMM. RNA-seq from 12 FFPE samples from the metastatic biopsy of metastatic melanoma patients treated with Nivolumab were analyzed. Our findings indicate that specific lncRNA and circRNA are involved in regulatory networks of the immune response against metastatic melanoma under treatment with nivolumab. Moreover, we have established a risk score that allows the prediction of Overall survival (OS) and Progression-free survival (PFS) of CMM patients with high accuracy. This proof of principle work provides a possible insight on the function of ceRNA, contributing to decipher the complex molecular mechanism of ICB cancer treatment response.

Immune Checkpoint Inhibitors are monoclonal antibodies that are used to treat over one in three cancer patients. While they have changed the natural history of disease, prolonging life and preserving quality of life, they are highly active in less than 40% of patients, even in the most responsive malignancies such as melanoma, and cause significant autoimmune side effects. Licenced biomarkers include tumour Programmed Death Ligand 1 expression by immunohistochemistry, microsatellite instability, and Tumour Mutational Burden, none of which are particularly sensitive or specific. Emerging tumour and immune tissue biomarkers such as novel immunohistochemistry scores, tumour, stromal and immune cell gene expression profiling, and liquid biomarkers such as systemic inflammatory markers, kynurenine/tryptophan ratio, circulating immune cells, cytokines and DNA are discussed in this review. We also examine the influence of the faecal microbiome on treatment outcome and its use as a biomarker of response and toxicity.

The most effective method of treating allergic diseases, aimed not at relieving symptoms, but at eliminating the cause of the disease, is allergen-specific immunotherapy (AIT). To reduce the risk of side effects and improve the delivery of allergens to the mucosa, various delivery systems, such as liposomes, dendrimers, nanoparticles, etc., can be used. To date, there are data on the creation of delivery systems based on glycyrrhizic acid (GA) and its derivatives, but such a delivery system has not been used for allergen-specific therapy until now. At the same time, it is known that GA has an anti-inflammatory effect, shifts the balance towards Th1, and increases the number of Treg cells, which means that in the future it can enhance the anti-allergic effect of AIT and reduce the risk of unwanted side effects. Thus, the study of the immunomodulatory effect of supramolecular complexes (micelles) of GA with extracts of allergens seems to be very promising for the development of new drugs for AIT.

Background: In the last years, many new treatment options have widened the therapeutic scenario of genitourinary malignancies. Immunotherapy has shown efficacy, especially in the urothelial and renal cell carcinomas, with no particular relevance in prostate cancer. However, despite the use of immune checkpoint inhibitors, there is still high morbidity and mortality among these neo-plasms. Cancer vaccines represent another way to activate the immune system. We sought to summarize the most recent advances in vaccine therapy for genitourinary malignancies with this review. Methods: We searched Pubmed, Embase and Cochrane Database for clinical trials conducted in the last ten years, focusing on cancer vaccines in the prostate, urothelial and renal cancer. Results: Various therapeutic vaccines, including DNA-based, RNA-based, peptide-based, dendritic cells, viral vectors, and modified tumor cells, have been demonstrated to induce specific immune responses in a variable percentage of patients. However, these responses rarely corresponded to significant survival improvements. Conclusions: Further pre-clinical and clinical studies will improve the knowledge about cancer vaccines in genitourinary malignancies to optimize dosage, select targets with a driver role for tumor development and growth, and finally overcome resistance mechanisms. Combination strategies represent possibly more effective and long-lasting treatments.

The prevalence of food allergy has increased in recent years, especially in children. Food allergen avoidance and symptomatic drugs in case of an allergic reaction remain the standard of care in food allergy. Nevertheless, increasing attention has been given to the possibility to treat food allergy, through immunotherapy, particularly oral immunotherapy (OIT). Several OIT protocols and clinical trials have been published. Most of them focus on children allergic to milk, egg, or peanuts, although recent studies developed protocols for other foods, such as wheat and different nuts. OIT efficacy in randomized controlled trials is usually evaluated as the possibility for patients to achieve desensitization, while the issue of a possible long-term sustained unresponsiveness has not been completely addressed. Here, we evaluated current OIT knowledge, focusing on the results of clinical trials and current guidelines. Specifically, we wanted to highlight what is known in terms of OIT efficacy and effectiveness, safety, and impact on quality of life. For each aspect, we reported the pros and the cons, inferable from published literature. In conclusion, even though many protocols, reviews and meta-analysis have been published on this topic, OIT remains a controversial therapy and no definitive generalized conclusion may be drawn so far. It should be an option provided by specialized teams, when both patients and their families are prone to adhere to the proposed protocol. Efficacy, long-term effectiveness, possible role of adjuvant therapies, risk of severe reactions including anaphylaxis or eosinophilic esophagitis, and impact on the quality of life of both children and caregivers are all aspects that should be discussed before starting OIT. Future studies are needed to provide firm clinical and scientific evidence, which should also consider patient reported outcomes.

Air pollution has been a major environmental issue worldwide from the last few decades. It is a man-made issue that has a serious harmful impact on the environment and the health of humans. There are different sources of emission, but industrial processes and motor vehicles contribute to a chief part of air pollution. It has acute as well as chronic effects on the health of humans and affects different organs. It is thought the main environmental risk factor in the incidence and progression of several diseases such as lung cancer, asthma, Alzheimer's and Parkinson's diseases. Long-term exposure to air pollution has different toxicological impacts on humans such as respiratory and cardiovascular diseases, neuropsychiatric complications, eye irritation and skin diseases. As per the study by the World Health Organization (WHO), nitrogen oxides (NOx), carbon monoxide (CO), ozone (O₃), sulfur dioxide (SO₂), volatile organic compounds (VOCs) and heavy metals are the major air contaminants. These pollutants are different in their properties, composition and time of disintegration. The aim of this study is to review the different sources, types, impacts, challenges and mitigation of air pollution in detail.

Metabolic syndrome (MetS), first conceptualized in 1923, encompasses a cluster of metabolic abnormalities, including insulin resistance (IR), hyperglycemia, dyslipidemia, hypertension, and central obesity. This syndrome significantly increases the risk for cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Its global prevalence has surged, largely attributed to lifestyle factors such as poor diet and physical inactivity. Recent research highlights the crucial role of caveolae, small cellular structures, in the pathophysiology of MetS, particularly in insulin signaling, lipid metabolism, and vascular function. Managing MetS effectively requires a comprehensive strategy focused on lifestyle modifications and pharmacological treatments. Dietary approaches, environmental factors, regular physical activity and behavioral changes have demonstrated positive impacts on metabolic health. Despite current pharmacological options to individual conditions of MetS, emerging therapies targeting caveolae offer promising new avenues for treatment. While, microbiome modulation and certain natural agents may assist in managing the syndrome. Public health initiatives, including educational campaigns and stress reduction programs, are essential for the prevention and management of MetS. A multifaceted approach combining lifestyle changes, pharmacotherapy, and personalized interventions is vital for effective management. Future strategies may benefit from precision medicine and the integration of emerging biomarkers for targeted therapies.

We propose a universal approach for modeling complex integrated photonic resonators based on the scattering matrix method. By dividing devices into basic elements including directional couplers and connecting waveguides, our approach can be used to model integrated photonic resonators with both unidirectional and bidirectional light propagation, with the simulated spectral response showing good agreement with experimental results. A simplified form of our approach, which divides devices into several independent submodules such as microring resonators and Sagnac interferometers, is also introduced to streamline the calculation of spectral transfer functions. Finally, we discuss the deviations introduced by approximations in our modeling, along with strategies for improving modeling accuracy. Our approach is universal across different integrated platforms, providing a useful tool for designing and optimizing integrated photonic devices with complex configurations.

This study presents the Bayesian-Optimized Attentive Neural Network (BOANN), a novel approach enhancing image classification performance by integrating Bayesian optimization with channel and spatial attention mechanisms. Traditional image classification struggles with the extensive data in today's big data era. Bayesian optimization has been integrated into neural networks in recent years to enhance model generalization, while channel and spatial attention mechanisms improve feature extraction capabilities. This paper introduces a model combining Bayesian optimization with these attention mechanisms to boost image classification performance. Bayesian optimization optimizes hyperparameter selection, accelerating model convergence and accuracy; the attention mechanisms augment feature extraction. Compared to traditional deep learning models, our model utilizes attention mechanisms for initial feature extraction, followed by a Bayesian-optimized neural network. On the CIFAR-100 dataset, our model outperforms classical models in metrics such as accuracy, loss, precision, recall, and F1 score, achieving an accuracy of 77.6%. These technologies have potential for broader application in image classification and other computer vision domains.

Titanium alloys, notably Ti6Al4V, are frequently employed in biomedical applications due to their high mechanical strength and biocompatibility. But improving their surface qualities like biocompatibility and resistance to corrosion remains a crucial topic of study. This study investigates the effects of rhenium-carbon coatings deposited on Ti6Al4V substrates using magnetron sputtering technique with a molybdenum anchoring layer. Despite successful formation of rhenium carbides, elemental rhenium, and rhenium oxides confirmed by EDS and XRD analysis, the coatings exhibited poor adhesion, resulting in significant delamination as observed in SEM images. Corrosion resistance tests revealed that the coatings adversely affected the Ti6Al4V substrate, as indicated by increased corrosion current densities and more negative corrosion potentials in potentiodynamic polarization tests. Biocompatibility assessments using PK15 cells showed a notable reduction in cell viability and metabolic activity, particularly with coatings of higher surface roughness. These findings underscore the need for improved surface preparation and coating processes to enhance adhesion and biocompatibility of rhenium-carbon coatings on Ti6Al4V substrates. Future research should focus on optimizing coating adhesion, investigating cytotoxicity mechanisms related to surface roughness, and expanding biocompatibility evaluations to various cell types and biological environments.

Segregating one space from another is a rudimentary act of architecture and the basic principle of this act is creating differentiation between outside and inside. Thresholds, in their expanded or summed form, also produce spaces. They establish the staging for threshold areas in conjunction with space-defining elements. Threshold spaces are typically complicated spatial formations that serve as transition points. They pose a challenge to the interacting human senses in terms of perception. In this research threshold areas have been studied under a specific typology of architecture i.e the traditional housing in historic cities of India. The traditional dwelling settlements have evolved and grown over multiple layers of history, influenced by the culture, society, economy, climate and topography. The purpose of this research is to examine the characteristics of these transition spaces of the traditional dwelling units in relation to the symbolic reference and social meanings assigned to them that influence the architectural and urban spaces attached to them. It seeks to describe transition space in terms of its nature, character, morphology, and social significance. Transparency and material articulation, as well as hierarchy and enclosure, will be investigated. The importance and quality of the nature of "transition" will be examined from the inside to the outside. The research reveals that the space has great functional and socio-cultural importance. It allows multiple activities, provides protection from sun and rain, defines boundaries, connects people within the neighborhood, enhances security and gives an identity to the owner. The contributions made by this research have the potential to improve design considerations for transition areas between the dwelling units and the street.

In order to explore the effect of Wickerhamomyces on the production of flavor compounds in Xiaoqu Baijiu, this study examined the correlation between the fungal communities in Xiaoqu and ester compounds. It was hypothesized that Wickerhamomyces contributes to the aroma of Xiaoqu. Enhanced fermentation methods were used to validate the role of Wickerhamomyces in Xiaoqu Baijiu brewing. Compared to traditional Xiaoqu, enhanced fermentation significantly increased the acidity of fermented grains and starch utilization rate (P<0.05). The fungal communities in fermented grains were analyzed by high-throughput sequencing technology. The dominant fungi in both control and test groups were Saccharomyces, Cyberlindnera, Rhizopus, and Meyerozyma, with Wickerhamomyces replacing Saccharomymycopsis in the enhanced group. Flavor compounds in the fermentation experiments were analyzed, revealing that ethyl acetate content in Xiaoqu Baijiu increased by 949.94 mg/L in the test group, while isoamyl alcohol decreased by 23.62 mg/L and isobutanol decreased by 34.81 mg/L. Functional prediction analysis using PICRUSt2 confirmed a higher relative abundance of enzymes involved in ethyl acetate metabolism and a lower relative abundance of enzymes involved in higher alcohol metabolism in the test group. These findings demonstrate that Wickerhamomyces enhances ethyl acetate production and reduces higher alcohols during Xiaoqu Baijiu brewing, offering a theoretical foundation for enhancing the quality of Xiaoqu Baijiu.

Background: Symmetry is a special kind of balance. This study aims to systematically explore and apply the role of balanced composition in aesthetic judgments by focusing on balanced composition features and employing research methods from computational aesthetics and Neuroaesthetics. Methods: First, experimental materials were classified by quantifying balanced composition using several indices, including symmetry, center of gravity, and negative space. An EEG experiment was conducted with 18 participants, who were asked to respond dichotomously to the same stimuli under different judgment tasks (balance and aesthetics), with both behavioral and EEG data being recorded and analyzed. Subsequently, participants' data were combined with balanced composition indices to construct and analyze various SVM classification models. Results: Participants largely used balanced composition as a criterion for aesthetic evaluation. ERP data indicated that from 300-500ms post-stimulus, brain activation was more significant in the aesthetic task, with unbeautiful and imbalanced stimuli eliciting larger frontal negative waves and occipital positive waves. From 600-1000ms, beautiful stimuli caused smaller negative waves in the PZ channel. The results of the SVM models indicated that the model incorporating aesthetic subject data (ACC=0.9989) outperforms the model using only balanced composition parameters of the aesthetic object (ACC=0.7074). Conclusions: Balanced composition is a crucial indicator in aesthetics, with similar early processing stages in both balance and aesthetic judgments. Multimodal data models validated the advantage of including human factors in aesthetic evaluation systems. This interdisciplinary approach not only enhances our understanding of the cognitive and emotional processes involved in aesthetic judgments but also enables the construction of more reasonable machine learning models to simulate and predict human aesthetic preferences.

Introduction: Known for its persistent blood-feeding behavior from dawn to dusk, Aedes albopictus is recognized as one of the most dangerous mosquito species due to its role as a vector for diseases such as dengue. Studies have demonstrated that Aedes albopictus thrives in micro-breeding sites predominantly located on private properties, including abandoned containers and manholes used for rainwater and irrigation. This study investigates an innovative methodology, the TombiniNet, to mitigate the proliferation of Aedes albopictus by engaging citizens in the active management of micro-breeding sites on their properties. Materials and Methods: The study was conducted in Alessandria, a city with approximately 100,000 inhabitants, focusing on a sample of 200 houses and a population of about 5,000 people. Researchers conducted a comprehensive survey and analysis of micro-breeding sites for Aedes albopictus on both private and communal properties. The larval control measures were conducted from April to October, aligning with the peak mosquito breeding season. The study's sample included 51% of houses that allowed researchers access, and within these, 81% had Aedes albopictus larvae, often found in diverse water Containers holes of which basically manholes on villa garden floors. For monitoring the adult populations were used ovitraps that were not placed in private homes but in public areas to monitor and control the mosquito population. Results: The study identified that up to 70% of micro-breeding sites for Aedes albopictus in northern Alessandria were located on private properties. Citizen participation was critical to the success of the intervention, with a marked decrease in the number of adult tiger mosquitoes observed in areas where residents actively managed breeding sites using the TombiniNet. The TombiniNet was particularly effective in private areas, as it could be regularly maintained by residents, preventing debris accumulation that could hinder drainage. Discussion: The findings highlight the importance of engaging citizens in mosquito control programs to effectively manage Aedes albopictus populations in urban areas. The TombiniNet intervention demonstrated that a simple, cost-effective solution could significantly reduce mosquito breeding sites on private properties. By addressing both communal and private breeding sites, a comprehensive and sustainable approach to mosquito management can be achieved, thereby reducing the risk of disease transmission. Future studies should focus on long-term monitoring and the development of additional innovative solutions to enhance citizen participation and control measures. The study's success also pointed out the limitations of applying such interventions in public areas where debris could impede the net's effectiveness.

Pesticides are chemical compounds or mixtures of hazardous substances that are used by humans to increase and protect crops from pests and control disease-carrying insects. Because of its wide use, it may be poisonous to helpful and non-targeting plants and animals. Spraying or spreading pesticides over whole fields of crops can cause runoff to transfer the chemicals into aquatic ecosystems, and wind can carry the chemicals to nearby grazing regions, farms, and populated areas, where they can endanger other animals. This review summarises recent studies on pesticide combination toxicity to aquatic biota and approaches used to anticipate toxic effects. When toxicants harm economically significant organisms that humans consume, the negative effects become more severe and can cause stress conditions, vital organ damage, biochemical damage, or even the death of living things in both terrestrial and aquatic environments. Pesticides are highly toxic to aquatic organisms such as snails, fish, etc. Neurological dysfunction in freshwater organisms is also caused by pesticides. By producing excessive ROS, pesticides can cause severe biochemical and histological changes in freshwater organisms. So, it is therefore easy to understand the attention of the public on these substances. Because aquatic organisms play a major part in the food chain. However, through the biomagnification process, the quantity of pesticides increases in the higher organisms through the food chain. Which results play a terrific role in the higher organism’s body. So, It's essential to comprehend the way that insecticides work on aquatic organisms. In this review article, we are focusing on the way that pesticides work, which will help in the system of biomonitoring.

As the global population faces an increasing prevalence of physical disabilities, the challenge of motor rehabilitation has become increasingly urgent. Considering that approximately 15% of the global population lives with some form of disability, with a significant number having motor disa-bilities that greatly impact their quality of life, the integration of robotic technologies into rehabili-tation processes offers an opportunity for significant improvement in functional recovery and pa-tient autonomy. This analysis aims to evaluate the progress and challenges encountered in imple-menting robotic technology for the rehabilitation of patients with physical disabilities, highlighting the potential of emerging technologies such as exoskeletons, assisted training devices, and brain-computer interface systems in facilitating motor recovery. By examining relevant clinical studies, the analysis demonstrates the varied effectiveness of robotic therapies compared to traditional re-habilitation methods, while also highlighting the need for ongoing research to optimize care prac-tices and address challenges related to cost, accessibility, and treatment personalization. In con-clusion, robotic technologies represent a promising direction in motor rehabilitation, with the po-tential to revolutionize the care of patients with physical disabilities, significantly improving quali-ty of life and social integration.

In the main prickly pear (Opuntia ficus-indica) producing region in the State of Mexico, fruit production (tunas) occupies the largest cultivated area with 15,800 ha, while 900 ha are cultivated for fresh consumption (“nopal” or “nopalitos”). Two composite samples consisting of prickly pear cactus cladodes (n=6) and another of nopal vegetable (n=6) showing virus-like symptoms were collected. Both sample sets were subjected to high-throughput sequencing (HTS) to identify the viruses and viroids present. The HTS results were verified using RT-PCR and Sanger sequencing. Subsequently, 86 nopal samples (nopal vegetable, prickly pear cactus, xoconostle and wild) were analyzed via RT-PCR with specific primers for the viruses and viroids previously detected via HTS. Three viruses were discovered [Opuntia virus 2 (OV2), cactus carlavirus 1 (CCV-1), and Opuntia potexvirus A (OPV-A)], along with a previously reported viroid [Opuntia viroid 1 (OPVd-1)]. Additionally, two new viroid species were identified, provisionally named Mexican opuntia viroid (genus Pospiviroid) and Opuntia viroid 2 (OVd-2). Phylogenetic analysis, pairwise identity comparison, and conserved structural elements analysis confirmed the classification of these two viroids as new species within the Pospiviroidae family. This is the first report of a pospiviroid and two apscaviroids infecting prickly pear in the world. Overall, this study enhances our understanding of the virome associated with nopal in Mexico.

In recent years, the treatment of locally-advanced rectal cancer (LARC) has been spotlighted in a number of landmark, practice-changing trials, heralding in the age of so-termed “total neoadjuvant therapy” (TNT). However, the lack of a common control arm, standard inclusion criteria, or, indeed, definition of TNT necessitates further study in this field, particularly using real-world data. We conducted a retrospective analysis of all patients treated for LARC at a single Canadian academic cancer centre between July 1st 2019 and July 14th 2022. This includes the June 2020 incorporation of TNT. 290 patients were included in the final analysis, and 124 variables were collected on each patient, including demographics, treatment type, adverse events, response to treatment, surgery versus watchful waiting and survival. Our findings demonstrate that both TNT and non-TNT regimens are highly toxic, with regards to both overall toxicity and grade 2+ adverse effects. 62 (96.9%) of patients on TNT experienced toxicities, compared to 186 (82.3%) of the non-TNT patients. Grade 2+ toxicities were 46 (71.9%) and 143 (63.3%), respectively. TNT, however, was associated with improved rates of complete response, compared to non-TNT treatment regimens (44% vs 24%). These findings suggest that TNT harbours both benefit and risk in a real-world population, and both of these aspects should be considered when deciding on a treatment approach for an individual patient. More work in the area is needed to determine longer term survival, as well as impact of surgery versus organ preservation approach on patient outcomes.

This study delves into the complex interplay among attachment styles, hypersexuality, and sexual and couple satisfaction in emerging adults within the Mexican population. Despite established correlations between anxious and avoidant attachment styles and emotion dysregulation and hypersexuality, the roles of sexual and couple satisfaction in this context have remained relatively unexplored. This study aims to fill this gap by examining how these variables interact and contribute to psychological distress and sexual risk behaviors. Data analysis on 214 emerging adults, utilizing the Experiences in Close Relationships scale, Couple Satisfaction Index, Sexual Satisfaction Scale, SCL-90, and SAST-R, revealed a significant association between risky sexual behaviors—such as a higher number of sexual partners, drug and alcohol use during sexual activity, and lack of sexual protection—and heightened levels of hypersexuality. Notably, individuals with hypersexual tendencies reported diminished levels of sexual satisfaction but elevated levels of couple satisfaction. Avoidant attachment emerged as the attachment style most strongly correlated with early sexual experiences. Moreover, the abbreviated versions of the Couple Satisfaction Index (CSI-4) and the Experiences in Close Relationships scale (ECR-8) exhibited commendable psychometric properties, enhancing their applicability for research and clinical purposes. This research furnishes valuable insights into the complex dynamics among attachment styles, hypersexuality, and couple and sexual satisfaction, emphasizing the need for targeted interventions to foster healthier sexual and relationship behaviors among emerging adults.

Bacteriocins is a term given to products of the secondary metabolism of many bacterial genera described today with antimicrobial activity. Although there are several biomolecules with such activity, even today it has not been possible to reach a consensus on the method of classification for these biomolecules. In addition, many of them are not authorized for therapeutic use against multi-drug resistant microorganisms due to possible toxic effects. However, recent research has achieved significant progress in their understanding, classification, and elucidation of the mechanisms of action against microorganisms of medical and biotechnological interest. Therefore, in more recent times, protocols are already being carried out for their optimal use and applications to use them on the hopes of solving multiple health and food conservation problems.

Deep underground laboratories offer advantages for conducting high-precision observations of weak geophysical signals, benefitting from a low background noise level. It is both valuable and feasible to enhance strong, noisy ground electromagnetic (EM) field data using synchronously recorded underground EM signals, which typically exhibit a high signal-to-noise ratio. In this study, we propose an EM field reconstruction method employing a Long Short-Term Memory (LSTM) recurrent neural network with referenced deep underground EM observations. Initially, a deep learning model was developed to capture the time-varying features of underground multi-component EM fields using the LSTM recurrent neural network. Subsequently, this model was applied to process synchronously observed strong, noisy data from other conventional observation systems, such as those at surface, to achieve noise suppression through signal reconstructions. Both theoretical analysis and practical observational data suggest that the proposed method effectively suppresses noise and reconstructs clean EM signals. This method is efficient and time-saving, representing an effective approach to fully utilizing the advantages of deep underground observation data. Furthermore, this method could be extended to the processing and analysis of other geophysical data.

In the most cases, invasive ductal carcinoma (IDC) of the breast is identifiable when they present with classic infiltrative growth pattern. However, subset of IDC can occur in a very sneaky way, significantly mimicking the appearance of ductal carcinoma in situ (DCIS). In this condition, it’s much easier to miss the invasive component without pulling ancillary staining when morphologic findings are extremely compatible with DCIS, especially the diagnosis of DCIS was made on the previous biopsy. Here, we reported a 55 year-old female who was noted to have microcalcification at the 11:00 o’clock of the right posterior breast on routine mammographic examination in 09/2023. Biopsy of the calcification area in 10/2023 reported high grade DCIS (ER+ PR-). Histologic examination of subsequent mastectomy specimen showed two separate DCIS-looking areas (Figure 1A-D and Figure 2). Immunohistochemical (IHC) staining showed that myoepithelial markers, smooth muscle myosin heavy chain (SMMHC), p63, CK5/6 and S100, were retained at the periphery of all the expanded acini in one area (Figure 1E-H). Unexpectedly and surprisingly, myoepithelial markers were completely lost at the periphery of part of the DCIS-looking acini in another area (Figure 3A-H), immunohistochemically compatible with the diagnosis of invasive ductal carcinoma admixed with DCIS. Knowing that invasive ductal carcinoma of the breast can present as DCIS-looking morphology, especially given the condition that the diagnosis of DCIS was rendered on the previous biopsy, will enhance awareness of pathologists to recognize DCIS-looking invasive ductal carcinoma. In turn, this will prevent misdiagnosis and under-treatment of patients with invasive ductal carcinoma of the breast.

This research investigates the perceptions of parents belonging to the Sidama ethnic group re-garding the significance of technology in early childhood education. The study aims to elucidate how parents perceive the role of technology, such as digital devices and educational applications, in the education and development of their young children. Through qualitative interviews con-ducted with 30 parents and thematic analysis, the study uncovers diverse perspectives, shedding light on cultural, socioeconomic, and educational factors influencing parental attitudes towards technology in early childhood education among the Sidama people. Findings indicate a spectrum of views ranging from enthusiastic embracement to cautious reservation, revealing nuanced considerations that inform parental decisions regarding technology integration in their children's learning experiences.

This study presents a comprehensive investigation into the spectrum and determinants of child abuse and neglect in Nkpor-Uno, a community in Anambra State, Nigeria. Through a descriptive surveys design, the study explores various forms of abuse and neglect experienced by children, as well as the underlying factors contributing to these phenomena. The population for the study consisted of 1000 parents/ caregivers who are residents of Nkpor-uno. The sample for the study consisted of 100 respondents, purposive sampling techniques was used for the study. The questionnaire was a self-designed structured questionnaire. Data collected were analyzed using frequency, mean and standard deviation. Findings reveal alarming prevalence rates of child maltreatment, including physical, emotional, sexual abuse, and neglect. Socioeconomic factors such as poverty, parental substance abuse, family dynamics, and inadequate sex education emerged as significant contributors to child maltreatment. The study underscores the urgent need for targeted interventions and support systems to address the root causes of abuse and neglect and safeguard the well-being and development of children in Nkpor-Uno. By raising awareness, enhancing access to resources, and promoting positive parenting practices, we can strive towards building a safer and healthier environment for children, ensuring they are protected from harm and given the opportunity to thrive.

Keywords: grape pomace extracts, encapsulation, freeze-drying, bioaccessibility, phenolic compounds

The Yb/Al multilayer films exhibit excellent theoretical reflectivity in the 54-90nm wavelength range. This study attempted to incorporate 1.5% wt.% of Si impurities into Al to suppress the crystallization of Al, reduce interfacial roughness, and enhance the actual reflectivity of the prepared Yb/Al multilayer films. The internal microstructure changes of the film layers before and after Si impurity doping were investigated using GIXRR, AFM, and XRD techniques. The reflectivity of two types of multilayer films, Yb/Al(1.5wt.%Si) and Yb/Al(pure), was tested to evaluate the effect of Si impurity on the film performance.

Enhancing the Efficiency of Natural Gas Liquid (NGL) Extraction and Fractionation Trains: An Integrated Approach of Simulation Analysis, Advanced Modifications, and Technological Advancements. Through comprehensive research, innovative solutions such as the heat pump aided distillation (HPAD) system and self-heat recuperation technology (SHRT) have been developed to significantly reduce the energy consumption associated with conventional distillation systems. To identify a practical system for NGL fractionation trains, this study extensively examined and compared various HPAD and SHRT options to retrofit a single column. The objective was to find the most suitable and efficient solution for the fractionation process of natural gas liquids (NGLs). The retrofit options analyzed in this study encompassed a range of techniques, including vapor compression (VC), mechanical vapor re-compression (MVR), thermal vapor re-compression (TVR), bottom flashing (BF), side heat exchanger (SHE), intermediate heating and cooling (IHC), self-heat recuperative (SHR), and modified self-heat recuperative (MSHR) distillation. These methods were carefully examined to determine their suitability and effectiveness in improving the performance of NGL fractionation trains.In this study, a depropanizer column, typically employed in conventional NGL plants, was selected as a case study. The simulation software Aspen HYSYS V7.3 was employed to model and analyze eight retrofit designs based on predefined criteria. The simulation data was carefully evaluated to identify the most efficient design for minimizing energy consumption. Among the retrofit options, the mechanical vapor re-compression (MVR) technique demonstrated the most significant energy cost reduction, with a remarkable 68.11 percent improvement compared to the base case conventional column. These findings highlight the potential of MVR as an effective solution for lowering energy costs in NGL fractionation trains.Following the MVR retrofit option, the study found that vapor compression (VC) achieved a considerable energy cost reduction of 66.65 percent, closely followed by modified self-heat recuperative (MSHR) at 64.02 percent, bottom flashing (BF) at 62.88 percent, self-heat recuperative (SHR) at 55.85 percent, side heat exchanger (SHE) at 54.23 percent, intermediate heating and cooling (IHC) at 39.54 percent, and thermal vapor re-compression (TVR) also at 39.54 percent. These findings highlight the significant potential for energy savings offered by these retrofit options, with VC being the most popular choice, closely followed by MSHR, BF, SHR, SHE, IHC, and TVR.

Naturally fermented dairy products are an important component of the human diet. They are a valuable source of nutrients as well as vitamins and minerals. Their importance as a source of probiotic bacterial strains should not be overlooked. A number of studies highlights the positive effects of species of the Lactobacillacea on the intestinal microbiota, the overall homeostasis of the body, as well as a complementary treatment for some diseases. However, data on the effects on intestinal epithelial cells of postmetabolites released by bacteria are incomplete. This is likely due to the fact that these effects are species and strain specific. In the present study, we investigated the effects of postmetabolites produced by a pre-selected candidate probiotic strain Limosilactobacillus fermentum on HT-29 intestinal epithelial cells. Our data showed a pronounced proliferative effect, evaluated by flow cytometry, quantification of cell population, and determination of mitotic index. This was accompanied by stabilization of the cell monolayer, measured by increase of TEER (trans epithelial electric resistance) and reorganization of actin filaments. The data obtained are a clear indication of the positive effects, that the products secreted by L. fermentum strain 53 have on the intestinal epithelial cells.

(1) Background: Until December 2021, French Guiana (FG), located in South America, faced four consecutive COVID-19 epidemic waves. This study sought to analyze the mortality trend of severe COVID-19 patients admitted to the referral ICU of FG. (2) Methods: We conducted a prospective, observational, and non-interventional study in ICU at Cayenne Hospital. We included 383 patients older than 18 admitted with SARS-CoV-2-related pneumonia hospitalized from May 2020 to December 2021. The study covers three periods. Period 1 (Waves 1 and 2, original variant), period 2 (Wave 3, gamma variant), and period 3 (Wave 4, delta variant). (3) Results: The median age was 63 years (52-70). Frailty was diagnosed in 36 patients over 70 (32.4%). Only 4.8% of patients were vaccinated. The median ICU LOS was 10 days (6-19). Hospital mortality was 37.3%. It was 30.9% in period 1, 36.6% in period 2 (p=0.329 vs. period 1), and 47.1% in period 3 (0.015 vs. period 1). In multivariate analysis, independent factors associated with hospital mortality were age more than 40 years (]40-60 years] OR=5.2, 95%CI: 1.4-19.5; (]60-70 years] OR=8.5 95%CI: 2.2-32; (]70+ years] OR=17.9, 95%CI: 4.5-70.9), frailty (OR=5.6, 95%CI: 2.2-17.2), immunosuppression (OR=2.6, 95%CI: 1.05-6.7), and MV use (OR=11, 95%CI: 6.1-19.9). This model had an overall sensitivity of 72%, a specificity of 80.4%, a positive predictive value of 68.7%, and a negative predictive value of 82.8%. (4) Conclusions: The mortality of severe COVID-19 patients in French Amazonia was higher during the delta variant wave. This over-death is explained by the virulence of the responsible SARS-CoV-2 variant and the under-vaccination coverage of the studied population.

Culture signifies the customs, language, ceremonies, Indigenous Medical Knowledge (IMK) and other material objects of a tribe. These and many other features are a representation of identity for many Zambian communities. IMK practices are skills inherent by certain individuals in a tribal grouping who are chosen by the spirits (gods) or trained by those who practice. This intrinsic skill is in danger of diminishing as a result of modern medication. This article attempts to understand the role of traditional healers (also known as asing’anga in local language) in preservation of IMK in Chibombo District of Zambia. In so doing, the paper examined methods of preservation used by asing’anga and the challenges faced. Using hermeneutic phenomenology and linear snowball sampling, findings revealed that preservation was done through training. The study found unwillingness, expiration, and spirituality as challenges in the process of preserving IMK. The study recommended that the Lenje Cultural Association consider documenting and disseminating information to the local people by showcasing what is available in the Mukuni Culture Village Museum and Library. This was seen as a way through which many youths would be encouraged to appreciate the indigenous values in their culture.

This study aimed to explore the intricate relationship between mitochondrial dysfunction, infections, and neuroinflammation, focusing specifically on the impact of pathogenic epitopes of Epstein-Barr Virus (EBV) nuclear antigen 1 (EBNA1) in a mouse model of mitochondrial dysfunctions. The investigation included female middle-aged PARK2^-/- and C57BL/6J wild-type mice immunized with EBNA1_386-405 or with active experimental autoimmune encephalomyelitis (EAE) induction by myelin oligodendrocyte glycoprotein (MOG)_35-55 peptide. PARK2^-/- mice developed more severe EAE than wild-type mice. Following immunization with EBNA1_386-405, only PARK2^-/- exhibited symptoms resembling EAE. During the acute phase, PARK2^-/- mice immunized with either MOG_35-55 or EBNA1_386-405 exhibited similar infiltration of T cells and macrophages in the spinal cord and decreased GFAP expression in the brain. However, EBNA1_386-405 -immunized PARK2^-/- mice showed significantly increased frequencies of CD8a+ T cells and CD11c+ B cells, and distinct cytokine profiles in the periphery compared to wild-type controls. These findings highlight the role of EBV in exacerbating inflammation, particularly in the context of mitochondrial deficiencies.

Tourism Geographers in Anglo-American geographical departments migrate to teach and research tourism in applied schools and departments such as business, resource and environment, and even cultural and creative industry. Under national research assessment and funding pressures, tourism geographers are not encouraged to keep on undertaking serious theoretical researches related to their mother discipline and transferred to research applied researches and publish in hybrid journals. Such changes in tourism geographers` research behavior have not been tested and reported in Asian academic contexts, especially Taiwan while frequently being discussed internationally. This research aims to investigate the differences in the research behavior of tourism geographers between those who are staffed in geography departments and those who migrate to applies departments such as tourism and recreation, resource and environment, and others in terms of publishing journals, paradigmatic approaches, research types(qualitative, quantitative, and mixed), research methods and geographical scales conducted based on content analysis of articles published by tourism geographers in geography and tourism and recreation departments. This study revealed that there are significant differences in the research behavior of tourism geographers between different department. Finally, this paper explains the differences in terms of Taiwan changing social and economic conditions, academic traditions and politics of geography and applied departments, research habits and preferences of tourism geographers among departments and other aspects. This study can help international tourism geography academic circles to understand the complexity and diversity of tourism geography academic landscape of the Chinese language.

Detecting IgE sensitizations in the serum of allergic dogs is commonly done using allergen extracts, but these are difficult to standardize. This article details the development and validation of the Pet Allergy Xplorer (PAX; Nextmune, Stockholm, Sweden), the first multiplex macroarray for the detection of IgE sensitization in dogs using allergen extracts and molecular components; the PAX is derived from the Allergy Xplorer (ALEX2; MacroArray Diagnostics, Vienna, Austria). The selection of allergens, cartridge processing, strategy for identifying and blocking IgE directed against cross-reactive carbohydrate determinants (CCD), and the method used for determining the positivity threshold are described. The validation of the PAX included evaluations of the specificity of its anti-IgE monoclonal antibody, specificity of IgE binding to target allergens, assay precision, and internal consistency. Additionally, the influence of possible confounding factors, such as sample type, the influence of hemolysis, lipemia, bilirubinemia, and elevated CCD-IgE, was tested. Finally, the sensitization rates of 23,858 European dogs to 145 environmental and Hymenoptera venom allergens were summarized. The PAX is accurate and reproducible and has a unique CCD-detection and blocking strategy; its molecular allergens offer a unique window on allergen cross-reactivity.

while composting of organic wastes is increasingly adopted in sustainable agriculture, continued interest on biochar application, dark soils, and compost, showed morphological aspects and functionality of biochar as a challenge to solve the CO2 aspects related to climatic change, and carbon stability in sustainable soils, as Black carbon presents long chemical permanency due to incomplete combustion of biomass. The objective of this work was to study the characteristics of soil amendments and to review the state of the art of biochar, showing differences in composition and main microorganisms with relevant presence in the soils. Arbuscular mycorrhizal spores (Scutellospora sp., Glomus like, Funneliformis geosporus, Glomus crenatum, and Acaulospora excavata, obtained from TPI soil samples are shown. New strategies are highlighted such as nutrient supplementation of compost, which can constitute the basis for improved compost-based biofertilizers in the future. Thus, the most important strategies for C sequestration are underlined to diminish substantial organic agro- and municipal wastes, increasingly disposed in the fields, landfills or either released by burning or discarding.

Diffusion magnetic resonance imaging (dMRI) is an imaging technique that provides information on the microstructural organization of biological tissue. dMRI allows for non-invasive visualization and quantitative assessment of white matter architecture in the brain by characterizing restrictions on the random motion of water molecules. Ultra-high field MRI scanners, such as those operating at 7 Tesla (7T) or higher, can boost signal-to-noise ratio (SNR) to improve dMRI compared with what is attainable at conventional field strengths such as 3T or 1.5T. However, at 7T wavelength effects cause lower transmit magnetic field efficiency in the human brain, mainly in the posterior fossa region, manifesting as signal dropouts in this region. Recently, we reported a simple approach of using a wireless radiofrequency (RF) surface array to improve transmit efficiency and signal sensitivity at 7T. Here we demonstrate the feasibility and effectiveness of using this RF enhancer for in-vivo dMRI at 7T. The use of the RF enhancer can effectively recover signal dropouts in the regions with intrinsically lower SNR such as cerebellum, leading to a better depiction of principal fiber orientations and enhanced visualization of extended tracts to the brainstem and pons enabling more comprehensive delineation of the full white matter architecture.

Blueberries are rich in a variety of functional substances and have high nutritional and health values, but they are not resistant to decline during fresh storage. Here, the effects of six Bacillus species on storage quality of, and antioxidant levels in, the southern highbush blueberry ‘O'Neal’ fruit were investigated. Bacillus treatments reduced the fruit decay rate, slowed fruit quality decline, inhibited malondialdehyde accumulation, and increased superoxide dismutase and peroxidase activity levels. Bacillus altitudinis Y-14 had the best effect overall. Further, the effects of 1-methylcyclopropene (1-MCP), B. altitudinis Y-14, and 1-MCP+B. altitudinis Y-14 treatments on the storage quality and antioxidant of rabbiteye blueberry ‘Brightwell’ fruit were investigated, and each treatment effectively reduced the decay rate and weight loss of fruit. When stored for 25 days, the decay rate of the 1-MCP+B. altitudinis Y-14 group was only 8.33%, significantly lower than that of the control. The three treatments delayed the fruit quality decline, inhibited malondialdehyde accumulation, and increased superoxide dismutase and peroxidase activity levels. The 1-MCP+B. altitudinis Y-14 treatment had the best effect. Thus, the combined 1-MCP and B. altitudinis Y-14 treatment may be an effective way to improve the storage quality and extend the storage period of blueberries.

New strategies for enhancing drug delivery to the blood–brain barrier (BBB) represents a major challenge in treating cerebral diseases. Nano-emulsion based nanocarriers represent an ideal candidate to improve drug delivery thanks to their versatility in functionalization and cargo protection. In this work, a paclitaxel loaded nano-emulsion has been firstly functionalized and stabilized with two layers constituted of chitosan and hyaluronic acid, and, secondly, the latter has been conjugated to the CRT peptide. CRT is a bioactive peptide that selectively recognizes bEnd.3 cells, model of the BBB, thanks to its interactions with transferrin (Tf) and its receptor (TfR). Cytotoxic results showed a higher uptake of CRT functionalized nano-emulsion 41.5 % more than the negative control, demonstrating the ability of this novel tool to be accumulated on the brain endothelium tissue. Thanks to these results, our approach can be fully generalizable to the design of multifunctional nanocarriers for delivery of therapeutic agents to the central nervous systems.

Objective To explore the endoscopic anatomical structures of lumbar surgery. Methods A total of 290 patients who underwent lumbar endoscopic surgery due to lumbar intervertebral disc (IVD) herniation from September 2020 to September 2022 were retrospectively reviewed in our hospital,179 patients had complete surgical video recordings, including 108 males and 71 females, aged from 19 to 65 years, with an average age of 41±16 years. The endoscopic structures through the intervertebral foramen and interlaminar space were independently identified by 3 doctors with more than 3 years of related surgery experience. When there were differences of opinions, the three doctors would discuss and come to a consensus. The probability, location, and neighboring structures of each specific structures were statistically analyzed. Results The anatomical structures observed through the lumbar foramen under endoscopy include muscles and ligaments attached to the superior articular process (SAP), main blood vessels inside the intervertebral foramen, blood vessels on the surface of IVD, and blood vessels on the surface of the dural sac and nerve root. The major anatomical structures observed through interlaminar space are multifidus, the conjugated ligament of ligament flavum and capsule ligament (capsule part of flavum ligaments), edges of the lamina, specific vessel bundle to facet with exit nerve root. Conclusion The anatomical structures under spinal endoscopy have certain characteristics, which are grossly different from those under open surgery. Familiarity with these anatomical structures has important clinical significance.

Background: The safety and effectiveness of factor-Xa (FXa) inhibitors for nonvalvular atrial fibrillation (NVAF) remains inconclusive. We investigated the current dosing of rivaroxaban, apixaban and edoxaban by monitoring drug plasma concentration (PC) and coagulation activity. Methods and Results: This multicenter clinical study monitored the drug PC levels and two coagulation biomarkers (fibrinogen: FIB, and fibrin monomer complex: FMC) at peak and trough timing in 268 outpatients receiving rivaroxaban (n = 72), apixaban (n = 71), and edoxaban (n = 125) for NVAF. Doses were adjusted according to the dose adjustment criteria of each drug. Based on our previous study, each peak drug PC remained below the cut-off level for predicting bleeding events except in eight patients (three on rivaroxaban, two on apixaban and three on edoxaban) in whom bleeding events occurred; among them, two (one each on rivaroxaban and edoxaban) had a peak drug PC below the cut-off level. Drug PCs widely varied from peak to trough, whereas FMC levels remained within the normal range (< 6.1 µg/ml) regardless of PC variation. These finding suggested that the anticoagulant effects of these drugs persisted throughout the day regardless of the drug PC levels, dosage, and frequency of dosing. Regarding the change in peak drug PC levels over time, rivaroxaban tended to accumulate more than edoxaban (p

The growing deforestation of tropical forests requires the implementation of restoration actions capable of assisting the recovery of biodiversity and functioning of these ecosystems. This research aimed to identify the environmental factors that influence woody plant recruitment abundance and diversity in an Andean forest restoration project in Medellin (Colombia). Data from all individuals taller than 80 cm was collected in 22 plots of 200 m2. The environmental factors selected were edaphic variables, plantation structure, slope, elevation, prior land use and landscape forest cover. A generalized linear model was adjusted for recruitment density, and linear mixed models were built for recruited species richness, diversity and dominance. Woody plant recruitment attributes in our study area were similar to a typical secondary succession in an Andean forest, but planted trees contributed little to these attributes. While recruitment density was affected by slope, canopy closure and landscape forest cover, recruitment diversity was influenced by physical (bulk density) and chemical (pH, aluminum, CEC) edaphic factors, planted trees diversity (species richness and composition), canopy closure and mortality rate of planted trees. We conclude that a good development of planted trees enhances both recruitment attributes, indicating a synergy between active restoration and passive regeneration processes.

Plastics, once regarded as a revolutionary material shaping modern society, now poses an unprecedented threat to our environment. Household solid waste sorting stations produce several fractions, one of which contains a high concentration of Low-Density Polyethylene (LDPE) film waste (packaging, sunscreen film, etc.). This fraction is difficult to recycle because it contains quite a lot of impurities. Usually, it is sent to the cement factories that burn it together with other fuels. However, with some processing techniques such catalytic pyrolysis this fraction could be valorized. In this paper the experiments which were carried out at a laboratory scale installation, in batches with a processing capacity of 1-3 kg of waste. The pyrolysis reactor is connected to a distillation column giving the possibility to separate the fractions. The gaseous and liquid fractions were characterized by GC-FID-TCD (gases) and GC-MS (liquids) analysis. Natural catalysts such as bentonite or clinoptilolite were studied and used in the melting of plastic mass to simplify the process as much as possible. To test the activity of the catalysts, the pyrolysis of LDPE granules was initially studied. It was found that natural zeolites are much more active than bentonite and that a minimum concentration of 5-10% is needed to have a positive effect on the composition of the fractions (increasing the weight of the light fractions C1-C6, C6-C10 and C11-C13) in relation to the heavy fractions C13-C20 and C20+. Catalytic pyrolysis gives a completely different distribution of light hydrocarbons. The best catalyst selected from LDPE lab experiments, was then tested upon the pyrolysis of plastic film waste obtained by a waste treatment plant. The research objective reported in this paper was to obtain a fraction of combustible gases in the largest possible proportion, which can be much easier exploited by burning in an engine that drives an electric generator.

Academic procrastination, more than merely postponing tasks, represents a significant failure in the self-regulation process of learning. Research on study skills highlights academic time management as one of the crucial elements of learning strategies and sustainable education. These abilities will help achieve the Sustainable Development Goals fourth goal. Therefore, this study aimed to understand how students plan time management in school activities and its influence on study procrastination, analyzing differences between genders and the hours students spend studying. The Time Management Planning Inventory, the Study Procrastination Questionnaire, and a personal and school data sheet were used. A sample of 506 students from elementary schools in northern Portugal was utilized. The results revealed that gender and study hours significantly influence how students plan time management for school tasks in the short and long term. This variable also showed a significant impact on the procrastination of study activities. The practical implications of this study are substantial, as they provide educators and researchers insights into the factors influencing academic procrastination and the role of time management planning and study hours. These insights can be applied to develop effective strategies to reduce academic procrastination and promote sustainable education.

This study investigates anomaly detection of IoT device traffic using Convolutional Neural Networks (CNN) and Variational Autoencoders (VAE) to enhance the detection capability of security threats in IoT environments. A series of hardware configurations, software environments, and hyperparameters were utilized to optimize the training and testing processes of the models. The CNN model demonstrates robust classification performance, achieving an accuracy rate of 95.85% on the test dataset, effectively distinguishing between different types of IoT device traffic. Meanwhile, the VAE model exhibits proficient anomaly detection capabilities by effectively capturing abnormal patterns in the data using reconstruction loss and KL divergence. The combined use of CNN and VAE models offers a comprehensive solution to cybersecurity challenges in IoT environments. Future research directions include exploring diverse IoT traffic data, practical deployment for validation, and further optimization of model structures and parameters to improve performance and applicability.

Introduction: Transportation logistics play a pivotal role in facilitating both individual mobility and supply chain operations on a global scale. However, conventional transportation systems have contributed significantly to urban congestion and environmental degradation. In response to these challenges, there is a growing momentum towards the adoption of intelligent transportation systems (ITS) and sustainable transportation solutions. This research aims to explore the potential of renewable energy sources to power electric vehicles (EVs) and flying automobiles, thereby accelerating the transition towards a low-carbon future. Objectives: The primary objectives of this research are as follows: - Investigate the role of renewable fuels in powering both EVs and flying cars to reduce reliance on fossil fuels and mitigate carbon emissions. - Analyze the dynamic growth and sustainability implications of advancements in battery technology and alternative renewable energy sources, such as Hydrogen Fuel Cells. - Evaluate the challenges and opportunities associated with the integration of flying vehicles into existing transportation infrastructure, focusing on safety, airspace control, and infrastructure development. - Review insights and guidance to stakeholders on promoting sustainable transportation solutions for EVs and flying cars through the utilization of renewable energy sources and the reduction of carbon emissions from the literature. Methodology: This research employs a mixed-method approach, combining literature review, and causal loop diagram analysis. The literature review provides a comprehensive understanding of current trends, challenges, and opportunities in sustainable transportation and renewable energy technologies. A causal loop diagram is utilized to visualize the dynamic interactions between various factors influencing the adoption of EVs and flying cars, including technological advancements, policy interventions, and market dynamics. Results and Discussion: The findings of this research highlight the significant potential of renewable energy sources, such as solar, wind, and hydrogen, in powering both EVs and flying cars. Advances in battery technology and hydrogen fuel cells are identified as key drivers in accelerating the transition towards sustainable transportation systems. However, challenges remain in terms of infrastructure development, safety regulations, and airspace management for flying vehicles. Nevertheless, there is a noticeable advancement in reducing carbon emissions and reliance on fossil fuels with the widespread adoption of EVs. By harnessing renewable energy and implementing effective policy measures, stakeholders might able to promote the widespread adoption of sustainable transportation solutions, thereby contributing to environmental protection and societal well-being. Conclusion: Literally, this research underscores the importance of sustainable transportation solutions in addressing urban congestion, environmental pollution, and energy security concerns. By leveraging renewable energy sources and embracing technological advancements, such as EVs and flying cars, stakeholders pave the way for a more sustainable and resilient transportation system. However, concerted efforts are needed to overcome existing challenges and ensure the successful integration of these technologies into existing infrastructure. Through collaborative partnerships and innovative initiatives, a low-carbon future for transportation logistics can be achieved, benefiting both the environment and society as a whole.

(1) Background: The lateral arm flap has been the very useful choice in the reconstruction of small- to medium-sized defects like hand, extremity, oral head and neck area reconstructions. Its versatile characteristics and surgical feasibility allow this flap to be widely applied, but the reconstructive potential in facial subunit after tumor ablative procedures has never been reported. In this study, we aimed to utilize the advantages of the flap to treat facial temple subunit defect reconstruction. (2) Methods: Between 2020 and 2023, 12 patients underwent temple reconstruction with lateral arm free flaps after malignant tumor wide excision. There were 7 women and 5 men, and the mean patient age was 60.6 years old. Among the patients with cancer, 6 had squamous cell carcinoma, 5 had basal cell carcinoma and 1 had myxofibrosarcoma. All the flaps were elevated under general anesthesia. Aloprostadil(PGE1, Eglandin®) were administered postoperatively. (3) Results: All the flap types were fasciocutaneous type with varied sizes from 3 × 4 to 5 × 7 cm (Average size of flap 22.7cm2) were utilized. The average pedicle length was 6.1cm. The versatility of the lateral arm flap enabled successful coverage of all cases with no specific complications. Good functional outcome and range of motion in the recipient arm were obtained after surgery. (4) Conclusion: The authors successfully verified the advantages of lateral arm flaps in the treatment of medium sized facial subunt temple defect reconstruction.

Background: Self-harm (SH) refers to self-injury or intentional self-poisoning with varying degrees of suicidal intent and is a major public health issue for children and adolescents (C&A) worldwide. Given significant gaps exist in our understanding of the associated psychopathology in C&A, this paper outlines the protocol for a prospective clinical study examining risk factors of SH and additional candidate parameters (not routinely assessed) during an acute SH episode. Methods: The EXPAAND (EXploring Psychiatric and Attentional risk-factors in Adolescents Needing intervention for Deliberate self-harm) is a randomised control trial to assess additional novel candidate risk factors for SH in C&A and to evaluate the effectiveness of SH-targeted brief psychological intervention (Therapeutic Assessment (TA)), within a real-world acute clinical setting, as we include neurodiversity and gender diversity in this study. EXPAAND is conducted in 4 phases: (i) recruitment & randomisation; (ii) extended assessment; (iii) randomised intervention; and (iv) follow-up observational period to ascertain clinical outcomes for comparison. Expected Results: We envisage that by diagnosing and treating attentional disorders when detected will mitigate potential confounding effects of these conditions. We also expect that SH-focused TA will be effective in reducing subsequent SH and in improving engagement in follow-up and subsequent treatments.

This study provides a comprehensive comparison of the Peter Chew Sum method and Newton's Sum in Quadratic Root Function Computations. Both methods offer significant advancements by alleviating the need for memorization of multiple formulas. However, when confronted with higher-order quadratic root functions such as the calculation of power 33. Newton's Sum method proves cumbersome due to its requirement of all previous answers for final computation, leading to increased steps and error risks. In contrast, the Peter Chew Sum method simplifies the computational process by requiring only a few previous answers, resulting in a more straightforward series of operations. We contextualize our analysis within the historical progression of mathematical techniques, highlighting the transformative leap represented by the Peter Chew Sum method in quadratic root function computations. Peter Chew Sum addressing the limitations of Newton's Sum , especially concerning higher-order functions such as the calculation of power 256. Furthermore, study demonstrates that the innovative approach of the Peter Chew Sum method not only simplifies complex computations but also fosters enhanced conceptual understanding among students. In conclusion, study findings underscore the profound impact of the Peter Chew Sum method on quadratic root function computations.

This research follows the publication of recent scoping and systematic reviews of existing literature on vaccine literacy (VL), its relationship to vaccine hesitancy (VH), and associated variables, such as vaccination beliefs, attitudes, and behaviors towards immunization. In this review, 17 articles were selected, published between December 2022 and November 2023, in which VL tools were used, most of which support the notion of a negative association between VL and VH, although not confirmed by others. Moreover, the definitions of the variables under consideration were not homogeneous between studies, some aimed to evaluate the association of VL with vaccine confidence, while others were more focused on outcomes such as willingness to be vaccinated or vaccine uptake. The complexity of the factors underlying VL, and the heterogeneity of the methods applied in the studies, in particular the limitations of cross-sectional surveys, still make it difficult to have a comprehensive understanding of the role of VL. Therefore, it is important to develop future assessment tools that consider not just the measurement of psychological factors connected to the motivational aspect of VL, but also those related to knowledge and competencies. For this purpose, a theoretical framework is proposed, where the positioning of VL at the intersection between antecedents and beliefs/attitudes leading to behaviors explains why and how VL serves as a tool and a critical, direct, or mediating driver of vaccination choices, overcoming VH and increasing vaccination rates, operating at personal, as well as at organizational and community level.

The Yellow-legged Hornet (Vespa velutina nigrithorax) (YLH) is an invasive insect that arrived in Europe in 2004 and is now spread across nine countries. It is a threat to the native entomofauna and harmful to beekeeping and agriculture, as it is a ravenous predator of the European Honey Bee (Apis mellifera) and other pollinating species. Its expansion has been unstoppable and all resources are needed to fight against it, including native vertebrate predators. Among these, the European Bee-eater (Merops apiaster) (EBE) is a potential one, but little is known about its predation on YLH. In a study carried out in Portugal, remains of YHL were detected in EBE nesting sites, which to the best of our knowledge is the first such report. This means that this bird could be one more agent in the biological control of this pest (although research on predation intensity is still needed), in conjunction with other natural predators and other strategies. In the Iberian Peninsula both species are allopatric in vast regions, so the role of EBE may be more limited. However, in the rest of Europe, at a country or continent scale, the scenario may be different and sympatry may occur to a greater extent.

This study uses the social impact theory to analyse consumer behaviour amidst Covid-19. Fear of scarcity has changed consumer buying behaviour in crisis times such as the now abating global health crisis – i.e., Covid-19. The study asserts that the existing five-stage model of consumer purchasing decisions does not fit neatly in turbulent times. It proposes a shortened four-stage process of need recognition, purchase, ownership and satisfaction as a better and more adaptable fit. Cutting out information search and evaluation of alternatives in the old model, and replacing these with ownership, is where the main contribution of the study lies. The study has implications for managing the marketing mix as we know it. It asserts that not all the 4Ps of the marketing mix are important in crisis times.

In recent years, bioengineered and biotechnological products have gained tremendous attention to identify unique biologic features associated with oncology. To overwhelm the complexity of tumor personalized medicines (PM) or vaccines could be a promising way-out to be considered. Cancer is a heterogeneous disease. This characteristic variability of cancer provides itself to the emergent era of PM i.e., precision oncology. The prime objective of PM is merely to deliver the right treatment to the right patient at the right time. For instance, imatinib was effectively targeted chronic myeloid leukemia. To date, attainment in using PM approaches to cancer treatment have been mixed. The next-generation sequencing (NGS), and the use of several biomarkers (e.g., HER2, BRAF, ALK, etc.), to drive precise cancer treatment through a timely and cost-effective manner. In current review, author summarizes the advancement in the field of PM such as CRISPR-Cas9, NGS, pharmacogenomics, and the benefits of machine learning techniques. The precise communication between healthcare professionals, regulatory bodies, and patients is essential to translate advances in PM into immense benefits for patients with cancer globally.

Wheat, a component of the staple diet globally, is a common food allergen in children. The symptoms of wheat allergy (WA) range from skin rash to shortness of breath, significantly impairing quality of life. Following initial clinical suspicion, individuals may undergo wheat allergen-specific skin prick test (SPT), blood test for serum immunoglobulin E (sIgE) levels or oral food challenge. Conventional management of WA lies in wheat avoidance, yet accidental consumption may be inevitable owing to the ubiquity of wheat in various food products. This article aims to provide an overview of the immunologic pathway of WA, followed by its novel diagnostic methods, namely alcohol-soluble SPT extracts, component-resolved diagnosis and basophil activation test (BAT). The mechanisms underlying wheat allergen-specific oral immunotherapy (OIT) as well as a summary of the efficacy, tolerability and safety of related clinical trials will then be discussed.

The treatment of acute myeloid leukemia (AML) with adverse genetics remains unsatisfactory, with very low response rates to standard chemotherapy and shorter durations of remission commonly observed in these patients. The complex biology of AML with adverse genetics is continuously evolving. Herein, we discuss recent advances which have investigated the contribution of cell intrinsic mechanisms as well as of the immune system to myeloid leukemogenesis in this specific subset of AML. We focus on the biological rationales for combining targeted therapy and immunotherapy, which are currently being investigated in ongoing trials, and could hopefully ameliorate the poor outcomes for these patients

Colorectal cancer (CRC) is the second cause of cancer-related death where the CpG-island methylation pathways (CIMP) is associated to KRAS/BRAF mutations, two oncogenes rewiring cell metabolism, worst prognosis and resistance to classical chemotherapies. Despite this, the question of a possible metabolic rewiring in CIMPs has never been asked. Here we asked if metabolic dysregulations were associated to the methylation status of tumours by evaluating the transcriptome of CRC tumours. CIMP-high patients were found to present a hyper-metabolism activating mainly carbohydrates, folates, sphingolipids and arachidonic acid metabolic pathways. A third of these genes had epigenetic targets of Myc in their proximal promoter, activating carboxylic acid, tetrahydrofolate interconversion, nucleobase, and oxoacid metabolisms. Amongst the Myc signature, the expression of GAPDH, TYMS, DHFR, TK1 was enough to predict methylation levels, microsatellite instability (MSI) and mutations in the mismatch repair (MMR) machinery, which are strong indicators of responsiveness to immunotherapies. Finally, we discovered that CIMP patients harboured an increase in genes involved in the one-carbon metabolism, a pathway critical to provide nucleotides for cancer growth and methyl donors for DNA methylation which was associated to worse prognosis. Transcriptomics could hence become a tool to help clinicians stratify their patients better.

Purpose: Pancreatic cancer (PAAD) is one of the most lethal malignancies. Immunotherapy is largely ineffective in PAAD. T-cell exhaustion contributes to the resistance for immunotherapies. We investigated the prognostic potential of T cell exhaustion-related genes (TEXGs). Methods: Single-cell RNA (scRNA) sequencing dataset from TISCH, and bulk sequencing datasets from TCGA and GTEx were applied to screen differently expressed TEXGs. Kaplan-Meier survival, LASSO regression, and Univariate/Multivariate Cox regression analysis were performed to construct TEXGs risk model. This model was used to predict the prognosis, tumor immune microenvironment, and immunotherapy response. PAAD cohorts from ICGC and GSE71729 datasets were used to validate this risk model. Pan-cancer expression of SPOCK2 was performed in TISCH database. Results: A six-gene (SPOCK2, MT1X, LIPH, RARRES3, EMP1, and MEG3) risk model was constructed. Low-risk PAAD patients had longer survival time in both training dataset (TCGA-PAAD, n=178) and validation datasets (ICGC-PACA-CA, ICGC-PAAD-US, and GSE71729, n=412). Multivariate Cox regression analysis demonstrated that the risk score was an independent prognostic variable for PAAD. High-risk patients correlated with cancer-related KEGG pathway enrichment, higher mutation frequency of KRAS and TP53 genes, and immunosuppressive status. Immunohistochemistry staining confirmed the changes of TEXGs in clinical samples. Moreover, pan-cancer scRNA sequencing datasets from TISCH analysis indicated that SPOCK2 might be a novel marker of exhausted CD8+ T cells. Conclusion: In conclusion, we established and validated a T cell exhaustion-related prognostic signature for PAAD patients. Moreover, our study suggests that SPOCK2 may be a novel marker of exhausted CD8+ T cells.

The aberrant glycosylation is a hallmark of cancer progression and chemoresistance. It is also an immune therapeutic target for various cancers. Tunicamycin (TM) is one of the potent nucleo-side antibiotics and an inhibitor of aberrant glycosylation in various cancer cells, including breast cancer, gastric cancer, and pancreatic cancer, parallel with inhibition of cancer cell growth and progression of tumors. Thus, TM can be considered a potent antitumor drug in various cancers and may promote chemosensitivity. Mechanistically, TM impedes the role of the UDP-HexNAc enzyme in the biosynthesis of oligosaccharides, specialized macromolecules instrumental in N-linked glycosylation. Further, like chemotherapies such as doxorubicin (DOX), 5'fluorouracil, etoposide, and Cisplatin, TM induces the unfolded protein response (UPR) by blocking aberrant glycosylation. Despite TM's antitumor effectiveness, its lack of cell-type specific cytotoxicity impedes its anticancer efficacy. Thus, various nanoencapsulation techniques and materials have been considered for use in experiments to reduce TM's cytotoxicity and improve efficacy as a targeted therapy. The current review is a profound audit of the benefits and pitfalls of TM in various cancers, focusing on breast, colon, and pancreatic cancers. Additional progressive studies have also discussed the use of TM in immune checkpoints and other unique pathways. Cytotoxicity and other possibly adverse effects of TM are highlighted based on the data from in vitro and in vivo assays. In addition, the recent advances in nano-based drug delivery systems regarding TM have been emphasized. However, the potential of this nucleoside inhibitor re-quires thorough investigation and research to determine its likeliness as a viable chemotherapeutic.

Acute myeloid leukemia (AML) is a rare subtype of acute leukemia in the pediatric and adolescent population but causes disproportionate morbidity and mortality in this age group. Standard chemotherapeutic regimens for AML have changed very little in the past 3-4 decades, but addition of targeted agents in recent years have led to improved survival in select subsets of patients as well as a better biologic understanding of the disease. One key paradigm of bench-to-bedside practice in the context of adult AML currently is the focus on leukemia stem cell (LSC)-targeted therapies. Here we review current and emerging immunotherapies and other targeted agents that are in clinical use for pediatric AML, through the lens of what is known (and not known) about their LSC-targeting capability. Based on a growing understanding of pediatric LSC biology, we also briefly discuss potential future agents on the horizon.

Renal cell carcinoma (RCC), alternative term for kidney cancer, is becoming more common worldwide each year, and there are many different contributing factors. Among all cancers, RCC is the 14th most prevalent; and it ranks as the 14th and 9th most prevalent cancer overall for women and men respectively. RCC cases increased by more than 430,000 in 2020. While disease burdens are highest in Eastern Europe (Belarus and Russia) and North America (Canada and the United States), Africa, Asia, and Latin America are predicted to report increase in prevalence as these regions embrace change in lifestyle. The majority of RCC cases are accidentally found on imaging, and survival is greatly impacted by the disease stage at diagnosis, with a metastatic cancer having a 5-year survival rate of 12%. As a consequence of early discovery and more improved treatments, RCC mortality has declined. The key epidemiologic variables of RCC include vast regional and geographical heterogeneity in prevalence rates, and the cause is largely unclear. Recognized risk factors include smoking, being overweight, having previous episodes of hypertension, and suffering chronic renal illness. Unexpectedly swift, RCC diagnosis and therapy have advanced. RCC prevalence continues to rise although survival rates have sharply improved. Cancer survival and treatment have improved, and more gains are projected as a result of clinical and translational research. In this review, kidney cancer statistics and recent literatures are examined on a global scale. It covered aspects of kidney cancer, including its epidemiology, causes, risk factors, current immunotherapy, chances for prevention, and future planning.

Immunotherapy with stereotactic body radiotherapy (SBRT), low-dose antiangiogenics, immune adjuvants, nanomedicine, or other combinations will likely play a lead role in managing malignancies soon. Presently, its benefit extends to about 12% to 20% of patients, in the background of possible recurrence eventually and the toxicities, including in non-responders. Stereotactic body radiotherapy (SBRT) not only eliminates the indexed lesions, but recently, the evidence is accumulating about its systemic abscopal effects. It needs to be evolved to a dependable in situ therapeutic vaccine production and to activate short- and long-term memory immune lymphocytes. The in-situ immune cascade happens with the ability of SBRT to generate Tumor-specific neoantigens and neoepitopes, which enhance the activation of antigen-presenting cells, invoke and restore the competence of Tumor-infiltrating lymphocytes, resulting in cancer cell lysis. This cell lysis, in turn, can generate further neoantigens and epitopes, imparting a virtuous cycle that is the hallmark of effective vaccines. Additionally, SBRT can synergistically enhance the other in situ vaccination strategies, concurrent in vitro vaccines or nanomedicines, making it a primary tool for sensitizing even the “cold” tumors for immunotherapy. The present proposed hypotheses, primarily based on a preclinical literature review, focus on the critical aspects of the in-situ vaccination generation capability of SBRT when used in pulsed, cyclical, or intermittent endothelial-sparing single dose schedules along with immunotherapy and other supportive measures. This schedule is categorized as in situ vaccine dose (ISVD) radiotherapy (RT) (distinguishable from the standard therapeutic SBRT schedule) in metastatic cancer settings after standard /first-line therapies.

In the last years, molecularly targeted agents and immune based treatments (ITs) have deeply changed the landscape of anti-cancer therapy. Indeed, ITs proved to be very effective in metastatic solid tumors, where outcomes were extremely poor with standard approaches. Such a scenario has been only partially reproduced in hematologic malignancies. In acute myeloid leukemia (AML), as innovative drugs are eagerly awaited in relapsed/refractory setting, different ITs have been explored, but the results are still unsatisfactory. In this work, we will discuss the most important clinical studies to date adopting ITs in AML, providing the bases to understand how this approach, although still in its infancy, may represent a promising therapeutic tool for the next future treatment of AML patients.

The microenvironment of most tumors is complex, comprising numerous aspects of immunosuppression. Several studies have indicated that the adrenergic system is vital for controlling immunological responses. In the context of tumor microenvironment, Nor-Adrenaline (NA) is poured-in by innervating nerves and tumor tissues itself. The receptors for nor-adrenaline are present on the surface of cancer and immune cells and are often involved in activation of pro-tumoral signaling pathways. β2-adrenergic receptor (β2-AR) is an emerging class of receptors that are capable of modulating the functioning of immune cells. β2-AR is reported to activate the regulatory immune cells and inhibit the effector immune cells. Blocking β2-AR increases activation, proliferation and cytokine release of T lymphocytes. Moreover β2-AR deficiency during metabolic reprograming of T cells increases mitochondrial membrane potential and biogenesis. In the view of available research data, immunosuppressive role of β2-AR in T cells presents it a targetable checkpoint in CAR-T cell therapies. In this review, we have abridged contemporary knowledge about adrenergic stress mediated β2-AR activation on T lymphocytes inside tumor milieu.

Current methodologies for developing patient-derived xenografts (PDX) in humanized mice in preclinical trials to test response to immune-based therapies are limited by graft versus host disease. Here we compared two approaches for establishing PDX tumors in humanized mice: 1) PDX are first established in immune-deficient mice; 2) PDX are initially established in humanized mice, before transplanting established PDX’s to a larger cohort of humanized mice for preclinical trials. With the first approach, there was rapid wasting of PDX-bearing humanized mice with high levels of activated T cells in the circulation and organs, indicating immune-mediated toxicity. In contrast, with the second approach, toxicity was less of an issue and long-term human melanoma tumor growth and maintenance of human chimerism was achieved. Pre-clinical trials from the second approach revealed that rigosertib, but not anti-PD-1, increased CD8/CD4 T cell ratios in spleen and blood and inhibited PDX tumor growth. Resistance to anti-PD-1 was associated with limited infiltration of CD8+ T cell into the tumor. Our findings suggest that it is essential to carefully manage immune editing by first establishing PDX tumors in the presence of human immune cells before expanding PDX tumors into a larger cohort of humanized mice to evaluate therapy response.

Immune cells such as T cells and macrophages express α7 nicotinic acetylcholine receptors (α7 nAChRs), which contribute to the regulation of immune and inflammatory responses. Earlier findings suggest α7 nAChR activation promotes the development of regulatory T cells (Tregs) in mice. Using human CD4+ T cells, we investigated the mRNA expression of the α7 subunit and the human-specific dupα7 nAChR subunit, which functions as a dominant-negative regulator of ion channel function, under resting conditions and T cell receptor (TCR)-activation. We then explored the effects of the selective α7 nAChR agonist GTS-21 on proliferation of TCR-activated T cells and Treg development. Varied levels of mRNA for both the α7 and dupα7 nAChR subunits were detected in resting human CD+ T cells. mRNA expression of the α7 nAChR subunit was profoundly suppressed on days 4 and 7 of TCR-activation as compared to day 1, whereas mRNA expression of the dupα7 nAChR subunit remained nearly constant. GTS-21 did not alter CD4+ T cell proliferation but significantly promoted Treg development. These results suggest the potential ex vivo utility of GTS-21 for preparing Tregs for adoptive immunotherapy, even with high expression of the dupα7 subunit.

Aim: to provide a comprehensive overview of the existing literature concerning the applications of positron emission tomography (PET)-radiomics in lung cancer patients candidates or undergoing immunotherapy. Materials and Methods: A systematic review was conducted on databases and web sources. English-language original articles were considered. The title and abstract were in-dependently reviewed to evaluate study inclusion. Papers duplicate, out-of-topic, review or edi-torials articles and letters to editors were excluded. For each study, the radiomics analysis was assessed based on the relies on radiomics quality score (RQS 2.0). The review was registered on the PROSPERO database with the number CRD42023402302. Results: 15 papers were included, 13 were qualified as conventional radiomics approaches, and two were as Deep Learning radiomics. The content of each study was different, indeed, 7 papers investigated the potential role of radiomics to predict PD-L1 expression and tumor microenvironment before starting immunotherapy. Moreo-ver, 2 were relative to the prediction of response and 4 investigated the utility of radiomics to predict the response to immunotherapy. Finally, 2 papers were relative to the prediction of adverse events due to the immunotherapy. Conclusions: radiomics is promising in the evaluation of TME and for the prediction of response to immunotherapy, but some limitations should be overpassed.