In vivo reduction of RAD51-mediated homologous recombination triggers aging but impairs oncogenesis.

Homologous recombination (HR) is a prominent DNA repair pathway maintaining genome integrity. Mutations in many HR genes lead to cancer predisposition. Paradoxically, the implication of the pivotal HR factor RAD51 on cancer development remains puzzling. Particularly, no RAD51 mouse models are available to address the role of RAD51 in aging and carcinogenesis in vivo. We engineered a mouse model with an inducible dominant-negative form of RAD51 (SMRad51) that suppresses RAD51-mediated HR without stimulating alternative mutagenic repair pathways. We found that in vivo expression of SMRad51 led to replicative stress, systemic inflammation, progenitor exhaustion, premature aging and reduced lifespan, but did not trigger tumorigenesis. Expressing SMRAD51 in a breast cancer predisposition mouse model (PyMT) decreased the number and the size of tumors, revealing an anti-tumor activity of SMRAD51. We propose that these in vivo phenotypes result from chronic endogenous replication stress caused by HR decrease, which preferentially targets progenitors and tumor cells. Our work underlines the importance of RAD51 activity for progenitor cell homeostasis, preventing aging and more generally for the balance between cancer and aging.

Impacts of fire and prospects for recovery in a tropical peat forest ecosystem.

Uncontrolled fires place considerable burdens on forest ecosystems, compromising our ability to meet conservation and restoration goals. A poor understanding of the impacts of fire on ecosystems and their biodiversity exacerbates this challenge, particularly in tropical regions where few studies have applied consistent analytical techniques to examine a broad range of ecological impacts over multiyear time frames. We compiled 16 y of data on ecosystem properties (17 variables) and biodiversity (21 variables) from a tropical peatland in Indonesia to assess fire impacts and infer the potential for recovery. Burned forest experienced altered structural and microclimatic conditions, resulting in a proliferation of nonforest vegetation and erosion of forest ecosystem properties and biodiversity. Compared to unburned forest, habitat structure, tree density, and canopy cover deteriorated by 58 to 98%, while declines in species diversity and abundance were most pronounced for trees, damselflies, and butterflies, particularly for forest specialist species. Tracking ecosystem property and biodiversity datasets over time revealed most to be sensitive to recurrent high-intensity fires within the wider landscape. These megafires immediately compromised water quality and tree reproductive phenology, crashing commercially valuable fish populations within 3 mo and driving a gradual decline in threatened vertebrates over 9 mo. Burned forest remained structurally compromised long after a burn event, but vegetation showed some signs of recovery over a 12-y period. Our findings demonstrate that, if left uncontrolled, fire may be a pervasive threat to the ecological functioning of tropical forests, underscoring the importance of fire prevention and long-term restoration efforts, as exemplified in Indonesia.

Evaluation of maize varieties via multivariate analysis: Roles of ionome, antioxidants, and autophagy in salt tolerance.

Salt stress presents a major obstacle to maize (Zea mays L.) production globally, impeding its growth and development. In this study, we aimed to identify salt-tolerant maize varieties through evaluation using multivariate analysis and shed light on the role of ionome, antioxidant capacity, and autophagy in salt tolerance. We investigated multiple growth indices, including shoot fresh weight, shoot dry weight, plant height, chlorophyll content, electrolyte leakage, potassium and sodium contents, and potassium-to-sodium ratio in 20 maize varieties at the V3 stage under salt stress (200 mM NaCl). The results showed significant differences in the growth indices, accompanied by a wide range in their coefficient of variation, suggesting their suitability for screening salt tolerance. Based on D values, clustering analysis categorized the 20 varieties into four distinct groups. TG88, KN20, and LR888 (group I) emerged as the most salt-tolerant varieties, while YD9, XD903, and LH151 (group IV) were identified as the most sensitive. TG88 showcased nutrient preservation and redistribution under salt stress, surpassing YD9. It maintained nitrogen and iron levels in roots while YD9 experienced decreases. TG88 redistributed more nitrogen, zinc, and potassium to its leaves, outperforming YD9. TG88 preserved sulfur levels in both roots and leaves, unlike YD9. Additionally, TG88 demonstrated higher enzymatic antioxidant capacity (SOD, POD, APX, and GR) both at the enzyme and gene expression levels, upregulation of autophagy-related (ATG) genes (ZmATG6, ZmATG8a, and ZmATG10), and increased autophagic activity. Overall, this study offers insights into accurate maize varieties evaluation methods and the physiological mechanisms underlying salt tolerance and identifies promising materials for further research.

Phylodynamic signatures in the emergence of community-associated MRSA.

Community-associated, methicillin-resistant Staphylococcus aureus (MRSA) lineages have emerged in many geographically distinct regions around the world during the past 30 y. Here, we apply consistent phylodynamic methods across multiple community-associated MRSA lineages to describe and contrast their patterns of emergence and dissemination. We generated whole-genome sequencing data for the Australian sequence type (ST) ST93-MRSA-IV from remote communities in Far North Queensland and Papua New Guinea, and the Bengal Bay ST772-MRSA-V clone from metropolitan communities in Pakistan. Increases in the effective reproduction number (Re) and sustained transmission (Re > 1) coincided with spread of progenitor methicillin-susceptible S. aureus (MSSA) in remote northern Australian populations, dissemination of the ST93-MRSA-IV genotype into population centers on the Australian East Coast, and subsequent importation into the highlands of Papua New Guinea and Far North Queensland. Applying the same phylodynamic methods to existing lineage datasets, we identified common signatures of epidemic growth in the emergence and epidemiological trajectory of community-associated S. aureus lineages from America, Asia, Australasia, and Europe. Surges in Re were observed at the divergence of antibiotic-resistant strains, coinciding with their establishment in regional population centers. Epidemic growth was also observed among drug-resistant MSSA clades in Africa and northern Australia. Our data suggest that the emergence of community-associated MRSA in the late 20th century was driven by a combination of antibiotic-resistant genotypes and host epidemiology, leading to abrupt changes in lineage-wide transmission dynamics and sustained transmission in regional population centers.

Development of depression in patients using androgen deprivation therapy: A systemic review and meta-analysis.

BACKGROUND: Androgen deprivation therapy (ADT) is an effective treatment for advanced prostate cancer (PCa). Multiple studies have highlighted serious consequences this therapy poses to mental health, particularly depression. We aimed to review the incidence and association between ADT in men with PCa and the risk of depression. METHODS: We systematically searched multiple databases, including MEDLINE, Scopus till August 2023 for studies that compared ADT versus control for treating PCa reporting depression as outcome. Meta-analysis was performed using random-effects models and results presented as odds ratios (ORs) with 95% confidence interval (CI). Quality assessment of the included studies was conducted using Joanna Briggs Institute critical appraisal checklists. RESULTS: A total of 38 studies (17 retrospective studies, 16 prospective studies, two cross-sectional studies and two randomized trials) with 360,650 subjects met the inclusion criteria and were included in this meta-analysis. The estimated pooled incidence of depression among ADT patients is 209.5 (95% CI = 122.3; 312.2) per 1000 patients. There is statistically significant relationship between ADT treatment and depression (OR = 1.46, 95% CI = 1.28, 1.67; p = 0, I2 = 86.4%). The results remained consistent across various subgroups. No risk of publication bias was detected by funnel plot and Eggers's test (p > 0.05). CONCLUSION: There is a higher risk of depression for men receiving ADT. Further studies evaluating optimal treatments for depression in men on ADT are warranted.

Potential application of artificial intelligence in cancer therapy.

PURPOSE OF REVIEW: This review underscores the critical role and challenges associated with the widespread adoption of artificial intelligence in cancer care to enhance disease management, streamline clinical processes, optimize data retrieval of health information, and generate and synthesize evidence. RECENT FINDINGS: Advancements in artificial intelligence models and the development of digital biomarkers and diagnostics are applicable across the cancer continuum from early detection to survivorship care. Additionally, generative artificial intelligence has promised to streamline clinical documentation and patient communications, generate structured data for clinical trial matching, automate cancer registries, and facilitate advanced clinical decision support. Widespread adoption of artificial intelligence has been slow because of concerns about data diversity and data shift, model reliability and algorithm bias, legal oversight, and high information technology and infrastructure costs. SUMMARY: Artificial intelligence models have significant potential to transform cancer care. Efforts are underway to deploy artificial intelligence models in the cancer practice, evaluate their clinical impact, and enhance their fairness and explainability. Standardized guidelines for the ethical integration of artificial intelligence models in cancer care pathways and clinical operations are needed. Clear governance and oversight will be necessary to gain trust in artificial intelligence-assisted cancer care by clinicians, scientists, and patients.

A Deep Dive into Cu2 ZnSnS4 (CZTS) Solar Cells: A Review of Exploring Roadblocks, Breakthroughs, and Shaping the Future.

Renewable energy is crucial for sustainable future, and Cu2 ZnSnS4 (CZTS) based solar cells shine as a beacon of hope. CZTS, composed of abundant, low-cost, and non-toxic elements, shares similarities with Cu(In,Ga)Se2 (CIGS). However, despite its promise and appealing properties for solar cells, CZTS-based solar cells faces performance challenges owing to inherent issues with CZTS material, and conventional substrate structure complexities. This review critically examines these roadblocks, explores ongoing efforts and breakthroughs, providing insight into the evolving landscape of CZTS-based solar cells research. Furthermore, as an optimistic turn in the field, the review first highlights the crucial need to transition to a superstrate structure for CZTS-based single junction devices, and summarizes the substantial progress made in this direction. Subsequently, dive into the discussion about the fascinating realm of CZTS-based tandem devices, providing an overview of the existing literature as well as outlining the possible potential strategies for enhancing the efficiency of such devices. Finally, the review provides a useful outlook that outlines the priorities for future research and suggesting where efforts should concentrate to shape the future of CZTS-based solar cells.

Use of physician-modified inverted limb in conjunction with Zenith fenestrated stent graft to rescue failed previous endovascular and open repair.

OBJECTIVE: To evaluate outcomes and performance of inverted limbs (ILs) when used in conjunction with Zenith fenestrated stent grafts (Zfens) to treat patients with short distance between the lowest renal artery (RA) and aortic or graft bifurcation (A/GB). METHODS: This study was a multicenter, retrospective review of prospectively maintained database of patients with complex aortic aneurysms, failed endovascular aneurysm repair (EVAR), or open surgical repair (OSR) with short distance between LRA and A/GB treated using a combination of Zfen and an IL between 2013 and 2023. Endpoints included technical success, aneurysm sac regression, long-term device integrity, and target vessel patency. We defined technical success as implantation of the device with no endoleak, conversion to an aorto-uni-iliac or OSR. RESULTS: During this time, 52 patients underwent endovascular rescue of failed repair. Twenty (38.5%) of them required relining of the failed repairs using IL due to lowest RA to A/GB length restrictions. Two patients had undergone rescue with a fenestrated cuff alone but developed type III endoleaks. One patient with no previous implant had a short distance between the lowest RA and aortic bifurcation to accommodate the bifurcated distal device, and two patients had failed OSR or anastomotic pseudoaneurysms. The majority (94%) were men with a mean age of 76.8 ± 6.1 years. The mean aortic neck diameter and aneurysm size were 32 ± 4 cm and 7.2 ± 1.3 cm, respectively. The median time laps between initial repair and failure was 36 months (interquartile range [IQR], 24-54 months). Sixteen patients (80%) were classified as American Society of Anesthesiologists class III, whereas four were class IV. Seventy-eight vessels were targeted and successfully incorporated. Technical success was 100%, and median estimated blood loss was 100 mL (IQR, 100-200 mL). Mean fluoroscopy time and dose were 61 ± 18 minutes and 2754 ± 1062 mGy, respectively. Average hospital length of stay was 2.75 ± 2.15 days. Postoperative complication occurred in one patient who required lower extremity fasciotomy for compartment syndrome. At a median follow-up of 50 months (IQR, 18-58 months), there were no device migration, components separation, aneurysmal related mortality, and type I or type III endoleak. Aneurysm sac regression (95%) or stabilization (5%) was observed in all patients, including in four patients (25%) with type II endoleak. CONCLUSIONS: The use of IL in conjunction with Zfen to treat patients with short distance between the lowest RA and A/GB is safe, effective, and has excellent long-term results. The technique expands the indication of Zfen, especially in patients with failed previous EVAR.

Comparative analysis of Streptococcus agalactiae serotypes Ia and II isolates from China and Pakistan in a murine model: A focus on pathogenesis and immune response.

Bovine mastitis, caused by Streptococcus agalactiae (Group B Streptococcus; GBS), poses significant economic challenges to the global dairy industry. Mouse models serves as valuable tools for assessing GBS-induced infections as an alternative to large animals. This study aimed to investigate the LD50 dose, organ bacterial load, and quantification of peritoneal leukocyte populations for GBS serotypes Ia and II isolates from China and Pakistan. Additionally, we measured indicators such as lactoferrin, albumin, and myeloperoxidase (MPO) activity. Pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6, and IL-2) and anti-inflammatory cytokines (IL-10 and TGF-ß) in serum and tissue samples were evaluated using ELISA and qPCR, respectively. BALB/c mice (4 mice per group) received individual intraperitoneal injections of 100 µl containing specific bacterial inoculum concentrations (ranging from 105 to 109 CFU per mouse) of Chinese and Pakistani GBS isolates (serotypes Ia and II). Control groups received 100 µL of sterile PBS. Results revealed that the LD50 bacterial dose causing 50 % mortality in mice was 107 CFU. The highest bacterial load in all experimental groups was quantified in the peritoneum, followed by blood, mammary gland, liver, spleen, lungs, and brain. The most significant bacterial dissemination was observed in mice inoculated with Pakistani serotype Ia at 24 h, with a subsequent notable decline in bacterial counts at day 3. Notably, infection with Pakistani serotype Ia showed a trend of increased total leukocyte counts, significantly higher than Pakistani serotype II, Chinese Serotype Ia, and Chinese serotype II. A substantial influx of neutrophils and lymphocytes was observed in response to all tested serotypes, with Pakistani serotype Ia inducing a significantly higher influx compared to other groups (Pakistani serotype II, Chinese serotype Ia, and Chinese serotype II). Furthermore, TNF-α, IL-1ß, IL-2, and IL-6 expressions were significantly increased in mice one day after infection with the Pakistani serotype Ia. Compared to mice infected with the Pakistani serotype II, Chinese Serotype Ia, and Chinese serotype II, those infected with the Pakistani serotype Ia isolate exhibited the highest production of IL-10 and TGF-ß, along with significantly increased concentrations of lactoferrin, albumin, and MPO. These findings suggest that the persistence and severity of infection caused by the Pakistani serotype Ia may be linked to its ability to spread to deeper tissues. This study enhances our understanding of the clinical characteristics of bovine mastitis caused by S. agalactiae in China and Pakistan.

Population assessment of health system performance in 16 countries.

Objective: To demonstrate how the new internationally comparable instrument, the People's Voice Survey, can be used to contribute the perspective of the population in assessing health system performance in countries of all levels of income. Methods: We surveyed representative samples of populations in 16 low-, middle- and high-income countries on health-care utilization, experience and confidence during 2022-2023. We summarized and visualized data corresponding to the key domains of the World Health Organization universal health coverage framework for health system performance assessment. We examined correlation with per capita health spending by calculating Pearson coefficients, and within-country income-based inequities using the slope index of inequality. Findings: In the domain of care effectiveness, we found major gaps in health screenings and endorsement of public primary care. Only one in three respondents reported very good user experience during health visits, with lower proportions in low-income countries. Access to health care was rated highest of all domains; however, only half of the populations felt secure that they could access and afford high-quality care if they became ill. Populations rated the quality of private health systems higher than that of public health systems in most countries. Only half of respondents felt involved in decision-making (less in high-income countries). Within countries, we found statistically significant pro-rich inequalities across many indicators. Conclusion: Populations can provide vital information about the real-world function of health systems, complementing other system performance metrics. Population-wide surveys such as the People's Voice Survey should become part of regular health system performance assessments.

Inequalities in the management of diabetic kidney disease in UK primary care: A cross-sectional analysis of a large primary care database.

AIMS: To determine differences in the management of diabetic kidney disease (DKD) relevant to patient sex, ethnicity and socio-economic group in UK primary care. METHODS: A cross-sectional analysis as of January 1, 2019 was undertaken using the IQVIA Medical Research Data dataset, to determine the proportion of people with DKD managed in accordance with national guidelines, stratified by demographics. Robust Poisson regression models were used to calculate adjusted risk ratios (aRR) adjusting for age, sex, ethnicity and social deprivation. RESULTS: Of the 2.3 million participants, 161,278 had type 1 or 2 diabetes, of which 32,905 had DKD. Of people with DKD, 60% had albumin creatinine ratio (ACR) measured, 64% achieved blood pressure (BP, <140/90 mmHg) target, 58% achieved glycosylated haemoglobin (HbA1c, <58 mmol/mol) target, 68% prescribed renin-angiotensin-aldosterone system (RAAS) inhibitor in the previous year. Compared to men, women were less likely to have creatinine: aRR 0.99 (95% CI 0.98-0.99), ACR: aRR 0.94 (0.92-0.96), BP: aRR 0.98 (0.97-0.99), HbA1c : aRR 0.99 (0.98-0.99) and serum cholesterol: aRR 0.97 (0.96-0.98) measured; achieve BP: aRR 0.95 (0.94-0.98) or total cholesterol (<5 mmol/L) targets: aRR 0.86 (0.84-0.87); or be prescribed RAAS inhibitors: aRR 0.92 (0.90-0.94) or statins: aRR 0.94 (0.92-0.95). Compared to the least deprived areas, people from the most deprived areas were less likely to have BP measurements: aRR 0.98 (0.96-0.99); achieve BP: aRR 0.91 (0.8-0.95) or HbA1c : aRR 0.88 (0.85-0.92) targets, or be prescribed RAAS inhibitors: aRR 0.91 (0.87-0.95). Compared to people of white ethnicity; those of black ethnicity were less likely to be prescribed statins aRR 0.91 (0.85-0.97). CONCLUSIONS: There are unmet needs and inequalities in the management of DKD in the UK. Addressing these could reduce the increasing human and societal cost of managing DKD.

Phosphate-Solubilizing Bacillus sp. Modulate Soil Exoenzyme Activities and Improve Wheat Growth.

Phosphorus (P) is a vital mineral nutrient in agriculture and its deficiency results in reduced growth, yield, and grain quality in cereals. Much of the applied P in agriculture becomes fixed in soils, limiting its accessibility to plants. Thus, investigating sustainable strategies to release fixed P resources and enhance plant uptake is crucial. This study explored how plant-associated bacteria employ phosphate solubilizing mechanisms to improve P availability. The growth patterns of four bacterial strains, namely Bacillus subtilis ZE15 and ZR3, along with Bacillus megaterium ZE32 and ZR19, were examined in Pikovskaya's broth culture with and without the addition of insoluble phosphorus (P). In the absence of P amendment, most strains reached a stationary growth phase by the fourth day. However, their responses diverged when exposed to P-amended media. Particularly, ZE15 demonstrated the highest P solubilization capability, achieving up to 130 µg mL-1 solubilization in vitro. All strains produced organic acids in Pikovskaya's broth culture. A comparison of the influence of Ca3(PO4)2 revealed significantly greater organic acid quantities in the presence of insoluble P. Notably, strain ZE15 exhibited the highest phosphate esterase activity (3.65 nmol g-1 dry matter), while strain ZE32 showed the highest ß-D glucosidase activity (2.81 nmol g-1 dry matter) in the presence of insoluble P. The ability of Bacillus species to solubilize P in combination with increased exoenzyme activity in the rhizosphere could be used in future studies to support P uptake through enhanced solubilization and mineralization.

An SNP based genotyping assay for genes associated with drought tolerance in bread wheat.

BACKGROUND: SnRK2 plays vital role in responding to adverse abiotic stimuli. The applicability of TaSnRK2.4 and TaSnRK2.9 was investigated to leverage the potential of these genes in indigenous wheat breeding programs. METHODS: Genetic diversity was assessed using pre-existing markers for TaSnRK2.4 and TaSnRK2.9. Furthermore, new markers were also developed to enhance their broader applicability. KASP markers were designed for TaSnRK2.4, while CAPS-based markers were tailored for TaSnRK2.9. RESULTS: Analysis revealed lack of polymorphism in TaSnRK2.4 among Pakistani wheat germplasm under study. To validate this finding, available gel-based markers for TaSnRK2.4 were employed, producing consistent results and offering limited potential for application in marker-assisted wheat breeding with Pakistani wheat material. For TaSnRK2.9-5A, CAPS2.9-5A-1 and CAPS2.9-5A-2 markers were designed to target SNP positions at 308 nt and 1700 nt revealing four distinct haplotypes. Association analysis highlighted the significance of Hap-5A-1 of TaSnRK2.9-5A, which exhibited association with an increased number of productive tillers (NPT), grains per spike (GPS), and reduced plant height (PH) under well-watered (WW) conditions. Moreover, it showed positive influence on NPT under WW conditions, GPS under water-limited (WL) conditions, and PH under both WW and WL conditions. High selection intensity observed for Hap-5A-1 underscores the valuable role it has played in Pakistani wheat breeding programs. Gene expression studies of TaSnRK2.9-5A revealed the involvement of this gene in response to PEG, NaCl, low temperature and ABA treatments. CONCLUSION: These findings propose that TaSnRK2.9 can be effectively employed for improving wheat through marker-assisted selection in wheat breeding efforts.

Exposure to urban particulate matter alters responses of olfactory mucosal cells to SARS-CoV-2 infection.

Respiratory viruses have a significant impact on health, as highlighted by the COVID-19 pandemic. Exposure to air pollution can contribute to viral susceptibility and be associated with severe outcomes, as suggested by recent epidemiological studies. Furthermore, exposure to particulate matter (PM), an important constituent of air pollution, is linked to adverse effects on the brain, including cognitive decline and Alzheimer's disease (AD). The olfactory mucosa (OM), a tissue located at the rooftop of the nasal cavity, is directly exposed to inhaled air and in direct contact with the brain. Increasing evidence of OM dysfunction related to neuropathogenesis and viral infection demonstrates the importance of elucidating the interplay between viruses and air pollutants at the OM. This study examined the effects of subacute exposure to urban PM 0.2 and PM 10-2.5 on SARS-CoV-2 infection using primary human OM cells obtained from cognitively healthy individuals and individuals diagnosed with AD. OM cells were exposed to PM and subsequently infected with the SARS-CoV-2 virus in the presence of pollutants. SARS-CoV-2 entry receptors and replication, toxicological endpoints, cytokine release, oxidative stress markers, and amyloid beta levels were measured. Exposure to PM did not enhance the expression of viral entry receptors or cellular viral load in human OM cells. However, PM-exposed and SARS-CoV-2-infected cells showed alterations in cellular and immune responses when compared to cells infected only with the virus or pollutants. These changes are highly pronounced in AD OM cells. These results suggest that exposure of human OM cells to PM does not increase susceptibility to SARS-CoV-2 infection in vitro, but it can alter cellular immune responses to the virus, particularly in AD. Understanding the interplay of air pollutants and COVID-19 can provide important insight for the development of public health policies and interventions to reduce the negative influences of air pollution exposure.

Comparative Efficacy and Safety of Different Stent Types for Pancreatic Fluid Collections: A Systematic Review and Network Meta-Analysis.

BACKGROUND AND AIMS: Drainage of pancreatic fluid collections (PFCs) is required in select cases including infected or symptomatic collections. In this network meta-analysis, we have compared lumen-apposing metal stents (LAMS), fully covered self-expandable metal stents (FCSEMS), and double-pigtail stents (DPS) to identify the most useful stent type in the management of PFCs. METHODS: We reviewed several databases to identify studies that compared DPS or FCSEMS with LAMS and the ones which compared DPS with FCSEMS for the treatment of PFCs. Our outcomes of interest were clinical success, adverse events, technical success, recurrence of PFCs, and procedure duration. Random effects model and frequentist approach were used for statistical analysis. RESULTS: We included 28 studies with 2974 patients. Rate of clinical success was significantly lower with DPS compared to LAMS, OR (95% CI): 0.43 (0.32, 0.59). Rate of recurrence was higher with DPS compared to LAMS, OR (95% CI): 2.06 (1.19, 3.57). We found no significant difference in rate of adverse events between groups. Rate of technical success was higher for FCSEMS compared to LAMS. Procedure duration was significantly shorter for LAMS compared to DPS and FCSEMS. Based on frequentist approach, LAMS was found to be superior to DPS and FCSEMS in achieving higher clinical success, lower rate of adverse events and recurrence, and shorter procedure time. CONCLUSIONS: This network meta-analysis demonstrates the superiority of LAMS over DPS and FCSEMS in the management of PFCs in achieving a higher clinical success, shorter procedure time, and lower rate of recurrence. Some of the analyses are not adequately powered to make firm conclusions, and future large multicenter RCTs are required to further evaluate this issue.

Glycoprotein nonmetastatic melanoma protein B impacts the malignant potential of bladder cancer cells through its hem-immunoreceptor tyrosine-based activation motif.

Bladder cancer is one of the most common cancers among men worldwide. Although multiple genomic mutations and epigenetic alterations have been identified, an efficacious molecularly targeted therapy has yet to be established. Therefore, a novel approach is anticipated. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane glycoprotein that is highly expressed in various cancers. In this study, we evaluated bladder cancer patient samples and found that GPNMB protein abundance is associated with high-grade tumors, and both univariate and multivariate analyses showed that GPNMB is a prognostic factor. Furthermore, the prognosis of patients with high GPNMB levels was significantly poorer in those with nonmuscle invasive bladder cancer (NMIBC) than in those with muscle invasive bladder cancer (MIBC). We then demonstrated that knockdown of GPNMB in MIBC cell lines with high GPNMB inhibits cellular migration and invasion, whereas overexpression of GPNMB further enhances cellular migration and invasion in MIBC cell lines with originally low GPNMB. Therefore, we propose that GPNMB is one of multiple driver molecules in the acquisition of cellular migratory and invasive potential in bladder cancers. Moreover, we revealed that the tyrosine residue in the hemi-immunoreceptor tyrosine-based activation motif (hemITAM) is required for GPNMB-induced cellular motility.

Dual role of mesenchymal stem/stromal cells and their cell-free extracellular vesicles in colorectal cancer.

Colorectal cancer (CRC) is one of the main causes of cancer-related deaths. However, the surgical control of the CRC progression is difficult, and in most cases, the metastasis leads to cancer-related mortality. Mesenchymal stem/stromal cells (MSCs) with potential translational applications in regenerative medicine have been widely researched for several years. MSCs could affect tumor development through secreting exosomes. The beneficial properties of stem cells are attributed to their cell-cell interactions as well as the secretion of paracrine factors in the tissue microenvironment. For several years, exosomes have been used as a cell-free therapy to regulate the fate of tumor cells in a tumor microenvironment. This review discusses the recent advances and current understanding of assessing MSC-derived exosomes for possible cell-free therapy in CRC.

RAD51 protects against nonconservative DNA double-strand break repair through a nonenzymatic function.

Selection of the appropriate DNA double-strand break (DSB) repair pathway is decisive for genetic stability. It is proposed to act according to two steps: 1-canonical nonhomologous end-joining (C-NHEJ) versus resection that generates single-stranded DNA (ssDNA) stretches; 2-on ssDNA, gene conversion (GC) versus nonconservative single-strand annealing (SSA) or alternative end-joining (A-EJ). Here, we addressed the mechanisms by which RAD51 regulates this second step, preventing nonconservative repair in human cells. Silencing RAD51 or BRCA2 stimulated both SSA and A-EJ, but not C-NHEJ, validating the two-step model. Three different RAD51 dominant-negative forms (DN-RAD51s) repressed GC and stimulated SSA/A-EJ. However, a fourth DN-RAD51 repressed SSA/A-EJ, although it efficiently represses GC. In living cells, the three DN-RAD51s that stimulate SSA/A-EJ failed to load efficiently onto damaged chromatin and inhibited the binding of endogenous RAD51, while the fourth DN-RAD51, which inhibits SSA/A-EJ, efficiently loads on damaged chromatin. Therefore, the binding of RAD51 to DNA, rather than its ability to promote GC, is required for SSA/A-EJ inhibition by RAD51. We showed that RAD51 did not limit resection of endonuclease-induced DSBs, but prevented spontaneous and RAD52-induced annealing of complementary ssDNA in vitro. Therefore, RAD51 controls the selection of the DSB repair pathway, protecting genome integrity from nonconservative DSB repair through ssDNA occupancy, independently of the promotion of CG.

PACSIN1 promotes immunosuppression in gastric cancer by degrading MHC-I.

Gastric cancer (GC) is a common gastrointestinal system malignancy. PACSIN1 functions as an oncogene in various cancers. This study aims to investigate the potential of PACSIN1 as a target in GC treatment. Gene expression is determined by RT-qPCR, immunofluorescence staining, and immunohistochemistry assay. FISH is performed to determine the colocalization of PACSIN1 and the major histocompatibility complex (MHC-I). Cytokine release and cell functions are analyzed by flow cytometry. In vivo assays are also conducted. Histological analysis is performed using H&E staining. The results show that PACSIN1 is overexpressed in GC patients, especially in those with immunologically-cold tumors. A high level of PACSIN1 is associated with poor prognosis. PACSIN1 deficiency inhibits autophagy but increases antigen presentation in GC cells. Moreover, PACSIN1 deficiency inhibits the lysosomal fusion and selective autophagy of MHC-I, increases CD8 + T-cell infiltration, and suppresses tumor growth and liver metastasis in vivo. Additionally, PACSIN1 knockout enhances the chemosensitivity of cells to immune checkpoint blockade. In summary, PACSIN1 mediates lysosomal fusion and selective autophagy of MHC-I and suppresses antigen presentation and CD8 + T-cell infiltration, thus inhibiting antitumor immunity in GC.

Artificial intelligence-enhanced electrocardiography for accurate diagnosis and management of cardiovascular diseases.

Electrocardiography (ECG), improved by artificial intelligence (AI), has become a potential technique for the precise diagnosis and treatment of cardiovascular disorders. The conventional ECG is a frequently used, inexpensive, and easily accessible test that offers important information about the physiological and anatomical state of the heart. However, the ECG can be interpreted differently by humans depending on the interpreter's level of training and experience, which could make diagnosis more difficult. Using AI, especially deep learning convolutional neural networks (CNNs), to look at single, continuous, and intermittent ECG leads that has led to fully automated AI models that can interpret the ECG like a human, possibly more accurately and consistently. These AI algorithms are effective non-invasive biomarkers for cardiovascular illnesses because they can identify subtle patterns and signals in the ECG that may not be readily apparent to human interpreters. The use of AI in ECG analysis has several benefits, including the quick and precise detection of problems like arrhythmias, silent cardiac illnesses, and left ventricular failure. It has the potential to help doctors with interpretation, diagnosis, risk assessment, and illness management. Aside from that, AI-enhanced ECGs have been demonstrated to boost the identification of heart failure and other cardiovascular disorders, particularly in emergency department settings, allowing for quicker and more precise treatment options. The use of AI in cardiology, however, has several limitations and obstacles, despite its potential. The effective implementation of AI-powered ECG analysis is limited by issues such as systematic bias. Biases based on age, gender, and race result from unbalanced datasets. A model's performance is impacted when diverse demographics are inadequately represented. Potentially disregarded age-related ECG variations may result from skewed age data in training sets. ECG patterns are affected by physiological differences between the sexes; a dataset that is inclined toward one sex may compromise the accuracy of the others. Genetic variations influence ECG readings, so racial diversity in datasets is significant. Furthermore, issues such as inadequate generalization, regulatory barriers, and interpretability concerns contribute to deployment difficulties. The lack of robustness in models when applied to disparate populations frequently hinders their practical applicability. The exhaustive validation required by regulatory requirements causes a delay in deployment. Difficult models that are not interpretable erode the confidence of clinicians. Diverse dataset curation, bias mitigation strategies, continuous validation across populations, and collaborative efforts for regulatory approval are essential for the successful deployment of AI ECG in clinical settings and must be undertaken to address these issues. To guarantee a safe and successful deployment in clinical practice, the use of AI in cardiology must be done with a thorough understanding of the algorithms and their limits. In summary, AI-enhanced electrocardiography has enormous potential to improve the management of cardiovascular illness by delivering precise and timely diagnostic insights, aiding clinicians, and enhancing patient outcomes. Further study and development are required to fully realize AI's promise for improving cardiology practices and patient care as technology continues to advance.