Gene Expression Analysis for Uterine Cervix and Corpus Cancer Characterization.

The analysis of gene expression quantification data is a powerful and widely used approach in cancer research. This work provides new insights into the transcriptomic changes that occur in healthy uterine tissue compared to those in cancerous tissues and explores the differences associated with uterine cancer localizations and histological subtypes. To achieve this, RNA-Seq data from the TCGA database were preprocessed and analyzed using the KnowSeq package. Firstly, a kNN model was applied to classify uterine cervix cancer, uterine corpus cancer, and healthy uterine samples. Through variable selection, a three-gene signature was identified (VWCE, CLDN15, ADCYAP1R1), achieving consistent 100% test accuracy across 20 repetitions of a 5-fold cross-validation. A supplementary similar analysis using miRNA-Seq data from the same samples identified an optimal two-gene miRNA-coding signature potentially regulating the three-gene signature previously mentioned, which attained optimal classification performance with an 82% F1-macro score. Subsequently, a kNN model was implemented for the classification of cervical cancer samples into their two main histological subtypes (adenocarcinoma and squamous cell carcinoma). A uni-gene signature (ICA1L) was identified, achieving 100% test accuracy through 20 repetitions of a 5-fold cross-validation and externally validated through the CGCI program. Finally, an examination of six cervical adenosquamous carcinoma (mixed) samples revealed a pattern where the gene expression value in the mixed class aligned closer to the histological subtype with lower expression, prompting a reconsideration of the diagnosis for these mixed samples. In summary, this study provides valuable insights into the molecular mechanisms of uterine cervix and corpus cancers. The newly identified gene signatures demonstrate robust predictive capabilities, guiding future research in cancer diagnosis and treatment methodologies.

PTCH1 Gene Variants, mRNA Expression, and Bioinformatics Insights in Mexican Cutaneous Squamous Cell Carcinoma Patients.

BACKGROUND: Skin cancer is one of the most frequent types of cancer, and cutaneous squamous cell carcinoma (cSCC) constitutes 20% of non-melanoma skin cancer (NMSC) cases. PTCH1, a tumor suppressor gene involved in the Sonic hedgehog signaling pathway, plays a crucial role in neoplastic processes. METHODS: An analytical cross-sectional study, encompassing 211 cSCC patients and 290 individuals in a control group (CG), was performed. A subgroup of samples was considered for the relative expression analysis, and the results were obtained using quantitative real-time PCR (qPCR) with TaqMan® probes. The functional, splicing, and disease-causing effects of the proposed variants were explored via bioinformatics. RESULTS: cSCC was predominant in men, especially in sun-exposed areas such as the head and neck. No statistically significant differences were found regarding the rs357564, rs2236405, rs2297086, and rs41313327 variants of PTCH1, or in the risk of cSCC, nor in the mRNA expression between the cSCC group and CG. A functional effect of rs357564 and a disease-causing relation to rs41313327 was identified. CONCLUSION: The proposed variants were not associated with cSCC risk in this Mexican population, but we recognize the need for analyzing larger population groups to elucidate the disease-causing role of rare variants.

Downregulation of Serotonergic System Components in an Experimentally Induced Cryptorchidism in Rabbits.

Cryptorchidism (CO) or undescended testes is defined as the failure of one or both testes to be positioned inside the scrotum. Typically, cryptorchidism is detected at birth or shortly thereafter, and in humans, it is considered to be part of the testicular dysgenesis syndrome (TDS), a complex pathology regarding the male reproductive system that apparently involves the interaction of both genetic and environmental harmful factors, mainly during embryonic development. Serotonin (5-HT) is an ancient molecule that participates in a broad range of body functions, and in recent years, its importance in reproduction has started to be elucidated. In male pathologies such as infertility, varicocele, erectile dysfunction, and primary carcinoid tumors, an increase in 5-HT concentration or its metabolites in the blood, semen, and urine has been directly related; nevertheless, the role of 5-HT in CO remains unknown. In the present work, our goal was to answer two important questions: (1) whether some serotonergic system components are present in adult male Oryctolagus cuniculus (chinchilla rabbit) and (2) if there are changes in their expression in an experimental model of CO. Using histological, molecular, and biochemical approaches, we found the presence of some serotonergic system components in the adult chinchilla rabbit, and we demonstrated that its expression is downregulated after CO was pharmacologically induced. Although we did not test the role of 5-HT in the etiology of CO, our results suggest that this indoleamine could be important for the regulation of steroidogenesis and spermatogenesis processes in the chinchilla rabbit during adulthood. Finally, in parallel experimental series, we found downregulation of kynurenine concentration in COI rabbits when compared to control ones, suggesting that CO could be affecting the kynurenine pathway and probably testicular immune privilege which in turn could lead to infertility/sterility conditions in this disorder.

Surface Modification of Nerve Guide Conduits with ECM Coatings and Investigating Their Impact on Schwann Cell Response.

In this study, layer-by-layer coatings composed of heparin and collagen are proposed as an extracellular mimetic environment on nerve guide conduits (NGC) to modulate the behavior of Schwann cells (hSCs). The authors evaluated the stability, degradation over time, and bioactivity of six bilayers of heparin/collagen layer-by-layer coatings, denoted as (HEP/COL)6 . The stability study reveals that (HEP/COL)6 is stable after incubating the coatings in cell media for up to 21 days. The impact of (HEP/COL)6 on hSCs viability, protein expression, and migration is evaluated. These assays show that hSCs cultured in (HEP/COL)6 have enhanced protein expression and migration. This condition increases the expression of neurotrophic and immunomodulatory factors up to 1.5-fold compared to controls, and hSCs migrated 1.34 times faster than in the uncoated surfaces. Finally, (HEP/COL)6 is also applied to a commercial collagen-based NGC, NeuraGen, and hSC viability and adhesion are studied after 6 days of culture. The morphology of NeuraGen is not altered by the presence of (HEP/COL)6 and a nearly 170% increase of the cell viability is observed in the condition where NeuraGen is used with (HEP/COL)6 . Additionally, cell adhesion on the coated samples is successfully demonstrated. This work demonstrates the reparative enhancing potential of extracellular mimetic coatings.

Long-Term Outcomes of Pharmacoinvasive Strategy Versus Primary Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction: A Study from Mexico City.

Although primary percutaneous coronary intervention (pPCI) is the treatment of choice in ST-elevation myocardial infarction (STEMI), challenges may arise in accessing this intervention for certain geodemographic groups. Pharmacoinvasive strategy (PIs) has demonstrated comparable outcomes when delays in pPCI are anticipated, but real-world data on long-term outcomes are limited. The aim of the present study was to compare long-term outcomes among real-world patients with STEMI who underwent either PIs or pPCI. This was a prospective registry including patients with STEMI who received reperfusion during the first 12 hours from symptom onset. The primary objective was cardiovascular mortality at 12 months according to the reperfusion strategy (pPCI vs PIs) and major cardiovascular events (cardiogenic shock, recurrent myocardial infarction, and congestive heart failure), and Bleeding Academic Research Consortium type 3 to 5 bleeding events were also evaluated. A total of 799 patients with STEMI were included; 49.1% underwent pPCI and 50.9% received PIs. Patients in the PIs group presented with more heart failure on admission (Killip-Kimbal >I 48.1 vs 39.7, p = 0.02) and had a lower proportion of pre-existing heart failure (0.2% vs 1.8%, p = 0.02) and atrial fibrillation (0.25% vs 1.2%, p = 0.02). No statistically significant difference was observed in cardiovascular mortality at the 12-month follow-up (hazard ratio for PIs 0.74, 95% confidence interval 0.42 to 1.30, log-rank p = 0.30) according to the reperfusion strategy used. The composite of major cardiovascular events (hazard ratio for PIs 0.98, 95% confidence interval 0.75 to 1.29, p = 0.92) and Bleeding Academic Research Consortium type 3 to 5 bleeding rates were also comparable. A low socioeconomic status, Killip-Kimball >2, age >60 years, and admission creatinine >2.0 mg/100 ml were predictors of the composite end point after multivariate analysis. In conclusion, this prospective real-world registry provides additional support that long-term major cardiovascular outcomes and bleeding are not different between patients who underwent PIs versus primary PCI.

AXL/WRNIP1 Mediates Replication Stress Response and Promotes Therapy Resistance and Metachronous Metastasis in HER2+ Breast Cancer.

Therapy resistance and metastatic progression are primary causes of cancer-related mortality. Disseminated tumor cells possess adaptive traits that enable them to reprogram their metabolism, maintain stemness, and resist cell death, facilitating their persistence to drive recurrence. The survival of disseminated tumor cells also depends on their ability to modulate replication stress in response to therapy while colonizing inhospitable microenvironments. In this study, we discovered that the nuclear translocation of AXL, a TAM receptor tyrosine kinase, and its interaction with WRNIP1, a DNA replication stress response factor, promotes the survival of HER2+ breast cancer cells that are resistant to HER2-targeted therapy and metastasize to the brain. In preclinical models, knocking down or pharmacologically inhibiting AXL or WRNIP1 attenuated protection of stalled replication forks. Furthermore, deficiency or inhibition of AXL and WRNIP1 also prolonged metastatic latency and delayed relapse. Together, these findings suggest that targeting the replication stress response, which is a shared adaptive mechanism in therapy-resistant and metastasis-initiating cells, could reduce metachronous metastasis and enhance the response to standard-of-care therapies. SIGNIFICANCE: Nuclear AXL and WRNIP1 interact and mediate replication stress response, promote therapy resistance, and support metastatic progression, indicating that targeting the AXL/WRNIP1 axis is a potentially viable therapeutic strategy for breast cancer.

Role of SLC5A8 as a Tumor Suppressor in Cervical Cancer.

BACKGROUND: The SLC5A8 gene is silenced in various types of cancer, including cervical cancer; we recently demonstrated that the SLC5A8 gene is also silenced in cervical cancer by hypermethylation of the CpG island in the gene promoter. This study aims to analyze whether SLC5A8 could be a tumor suppressor in cervical cancer. METHODS: After ectopic expressing SLC5A8 in the HeLa cell line, we evaluated its effects on cell behavior both in vitro and in vivo by Confocal immunofluorescence, cell proliferation, migration assays, and xenograft transplants. RESULTS: Overexpression of SLC5A8 in the HeLa cell line decreased its proliferation by arresting cancer cells in the G1 phase and inhibiting cellular migration. Furthermore, we observed that pyruvate increased the SLC5A8 effect, inducing S-phase arrest and inhibiting the entry into mitosis. SLC5A8 decreased tumor growth in xenograft transplants, significantly reducing the volume and tumor weight at 35 days of analysis. CONCLUSIONS: In summary, our results indicate that SLC5A8 has a role as a tumor suppressor in cervical cancer.

Chroma-dependence of CIEDE2000 acceptability thresholds for dentistry.

OBJECTIVES: Determine visual 50:50% color difference acceptability thresholds (AT) for regions of the dental color space with varying chromaticity. METHODS: A 40-observer panel belonging to two different groups (dentists and laypersons) evaluated 144 dental resin composites pairs (divided in three different sets of 48 pairs according to chroma value: Low Chroma (LC), Medium Chroma (MC) and High Chroma (HC) placed 40 cm away and inside of a viewing cabinet (D65 Standard light source; diffuse/0° geometry). A Takagi-Sugeno-Kang (TSK) fuzzy approximation was used for fitting the data points and calculate the 50:50% acceptability thresholds in CIEDE2000. A paired t-test was used to evaluate the statistical significance between thresholds differences and Bonferroni correction was applied. RESULTS: The CIEDE2000 50:50% AT were ∆E00 = 2.84, ∆E00 = 2.31 and ∆E00 = 1.80 for LC, MC and HC sets of sample pairs, respectively. The 50:50% AT values were statistically significant between the different sets of sample pairs, as well as the 50:50% AT values obtained for different observer groups. CONCLUSIONS: 50:50% CIEDE2000 acceptability thresholds for dentistry are significantly different depending on the chromaticity of the samples. Observers show higher acceptability for more achromatic samples (low chroma value) than for more chromatic samples. CLINICAL SIGNIFICANCE: The difference in the AT for distinct regions of the dental color space can assist professionals as a quality control tool to assess clinical performance and interpret visual and instrumental findings in clinical dentistry, dental research, and subsequent standardization processes.

Novel methodology for detecting and localizing cancer area in histopathological images based on overlapping patches.

Cancer disease is one of the most important pathologies in the world, as it causes the death of millions of people, and the cure of this disease is limited in most cases. Rapid spread is one of the most important features of this disease, so many efforts are focused on its early-stage detection and localization. Medicine has made numerous advances in the recent decades with the help of artificial intelligence (AI), reducing costs and saving time. In this paper, deep learning models (DL) are used to present a novel method for detecting and localizing cancerous zones in WSI images, using tissue patch overlay to improve performance results. A novel overlapping methodology is proposed and discussed, together with different alternatives to evaluate the labels of the patches overlapping in the same zone to improve detection performance. The goal is to strengthen the labeling of different areas of an image with multiple overlapping patch testing. The results show that the proposed method improves the traditional framework and provides a different approach to cancer detection. The proposed method, based on applying 3x3 step 2 average pooling filters on overlapping patch labels, provides a better result with a 12.9% correction percentage for misclassified patches on the HUP dataset and 15.8% on the CINIJ dataset. In addition, a filter is implemented to correct isolated patches that were also misclassified. Finally, a CNN decision threshold study is performed to analyze the impact of the threshold value on the accuracy of the model. The alteration of the threshold decision along with the filter for isolated patches and the proposed method for overlapping patches, corrects about 20% of the patches that are mislabeled in the traditional method. As a whole, the proposed method achieves an accuracy rate of 94.6%. The code is available at https://github.com/sergioortiz26/Cancer_overlapping_filter_WSI_images.

GproteinDb in 2024: new G protein-GPCR couplings, AlphaFold2-multimer models and interface interactions.

G proteins are the major signal proteins of ∼800 receptors for medicines, hormones, neurotransmitters, tastants and odorants. GproteinDb offers integrated genomic, structural, and pharmacological data and tools for analysis, visualization and experiment design. Here, we present the first major update of GproteinDb greatly expanding its coupling data and structural templates, adding AlphaFold2 structure models of GPCR-G protein complexes and advancing the interactive analysis tools for their interfaces underlying coupling selectivity. We present insights on coupling agreement across datasets and parameters, including constitutive activity, agonist-induced activity and kinetics. GproteinDb is accessible at https://gproteindb.org.

Efficacy and safety of hydroxychloroquine for treatment of mild SARS-CoV-2 infection and prevention of COVID-19 severity in pregnant and postpartum women: A randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Pregnant women have an increased risk of severe COVID-19. Evaluation of drugs with a safety reproductive toxicity profile is a priority. At the beginning of the pandemic, hydroxychloroquine (HCQ) was recommended for COVID-19 treatment. MATERIAL AND METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted in eight teaching hospitals in Spain to evaluate the safety and efficacy of HCQ in reducing viral shedding and preventing COVID-19 progression. Pregnant and postpartum women with a positive SARS-CoV-2 PCR (with or without mild COVID-19 signs/symptoms) and a normal electrocardiogram were randomized to receive either HCQ orally (400 mg/day for 3 days and 200 mg/day for 11 days) or placebo. PCR and electrocardiogram were repeated at day 21 after treatment start. Enrollment was stopped before reaching the target sample due to low recruitment rate. Trial registration EudraCT #: 2020-001587-29, on April 2, 2020. CLINICAL TRIALS: gov # NCT04410562, registered on June 1, 2020. RESULTS: A total of 116 women (75 pregnant and 41 post-partum) were enrolled from May 2020 to June 2021. The proportion of women with a positive SARS-CoV-2 PCR at day 21 was lower in the HCQ group (21.8%, 12/55) than in the placebo group (31.6%, 18/57), although the difference was not statistically significant (P = 0.499). No differences were observed in COVID-19 progression, adverse events, median change in QTc, hospital admissions, preeclampsia or poor pregnancy and perinatal outcomes between groups. CONCLUSIONS: HCQ was found to be safe in pregnant and postpartum women with asymptomatic or mild SARS-CoV-2 infection. Although the prevalence of infection was decreased in the HCQ group, the statistical power was insufficient to confirm the potential beneficial effect of HCQ for COVID-19 treatment.

Genome-wide association study for reproduction traits in Colombian Creole Blanco Orejinegro cattle.

The profitability of the beef cattle production system relies heavily on reproductive traits. Unfortunately, certain traits, such as age at first calving (AFC), calving interval (CI), and gestation length (GL), can pose challenges in traditional breeding programs because of their low heritability (0.01-0.12) and sex-limited characteristics. Another important aspect is the conservation of the genetic resources of animals adapted to the Colombian regions, which implies the preservation and rational use of the creole breeds in the country market. Therefore, this study aimed to identify genomic regions in the creole cattle breed Blanco Orejinegro (BON) that influence the reproductive traits in females. The dataset comprised 439 animals and 118,116 single-nucleotide polymorphisms' (SNPs) markers. The GS3 program was used to identify the SNP effects employing the BAYES Cπ methodology. The number of SNPs with effect for AFC was 25, 1527 for CI, and 23 for GL. Some of the genes found associated with reproductive and growth traits as well as immune response and environmental adaptation ECE1, EPH, EPHB2, SMARCAL1, IGFBP5, IGFBP2, FCGRT, EGFR, MUL1, PINK1, STPG1, CNGB1, TGFB1, OXTR, IL22RA1, MYOM3, OXTR, CNR2, HIVEP3, CTPS1, CXCL8, FCGRT, MREG, TMEM169, PECR, and MC1R. Our results evidenced a high contribution of the genetic architecture of the Colombian creole cattle breed Blanco Orejinegro that may impact should be included in implementing genetic improvement and conservation programs.

Phylogenetic analysis of the partial sequences of the env and tax BLV genes reveals the presence of genotypes 1 and 3 in dairy herds of Antioquia, Colombia.

Bovine leukemia virus (BLV) is a retrovirus that primarily infects dairy cows. Although few studies have also used the tax gene, phylogenetic studies of BLV use mostly the env gene. The aim of this work was to establish the circulating genotypes of BLV in specialized dairy cattle from Antioquia, Colombia. Twenty blood samples from Holstein Friesian cows were collected, and their DNA was isolated. A PCR was performed for a partial region of the env and tax genes. A phylogenetic analysis was carried out using the maximum likelihood and Bayesian methods for both genes. Nineteen sequences were identified as genotype 1 by env and tax genes. Only one sequence was clustered with genotype 3 and had the highest proportion of different nucleotide sites compared to other strains. Four amino acid substitutions in the 134 amino acid residue fragment of the Env protein were identified in the Colombian sequences, and three new amino acid substitutions were reported in the 296 amino acid residue fragment of the Tax protein. R43K (Z finger), A185T (Activation domain), and L105F changes were identified in the genotype 3 sample. This genotype has been reported in the United States, Japan, Korea, and Mexico, but so far, not in Colombia. The country has a high rate of imported live animals, semen, and embryos, especially from the United States. Although it is necessary to evaluate samples from other regions of the country, the current results indicate the presence of two BLV genotypes in specialized dairy herds.

[North-south syndrome, a complication of circulatory assistance with Veno-Arterial ECMO. A case report.] / El síndrome de norte-sur, una complicación de la asistencia circulatoria con ECMO Venoarterial. Reporte de caso.

We present the case of a 34-year-old male patient with a history of Marfan syndrome who was admitted to the emergency room for acute aortic regurgitation secondary to aneurysmal dilation of the ascending thoracic aorta. In the postoperative period, post-cardiotomy cardiogenic shock was documented, so circulatory support was initiated with peripheral Veno-Arterial ECMO, which developed hypoxemia due to bacterial pneumonia and data compatible with North-South syndrome. We present a review, non-conventional cannulation strategies and a diagnostic alternative for this entity.

Elucidating Structural Stability, Bandgap, and Photocatalytic Hydrogen Evolution of (H2 O/DMF)@HKUST-1 Host-guest Systems.

The H2 O@HKUST-1 and DMF@HKUST-1 systems were experimental and computationally assessed, employing XRD/TGA/FT-IR/DFT-calculations, evidencing that H2 O or DMF coordinated to Cu, modulating HKUST-1 photocatalytic properties. DMF@HKUST-1 has narrower bandgap promoting higher-crystallinity and light-harvesting. H2 O@HKUST-1 showed smaller particle sizing and sharp morphology. Theoretical models, (H2 O)1 @HKUST-1 and (DMF)1 @HKUST-1, containing one coordinated molecule, elucidated bandgap modulation associated with infiltration. H2 O@HKUST-1/DMF@HKUST-1 presented bandgaps [eV] of 3.6/3.4, by Tauc plots, and 3.55/3.26, by theoretical calculations, narrowing bandgap, compared with non-solvated HKUST-1(HKUST-1NS ). Both composites raised the valence band (VB) and lowered the conduction band (CB), but DMF@HKUST-1 most raised VB. Topological analysis revealed that guests i) with higher electronic density, raised VB, and ii) induced π-backbonding, lowering CB. DMF@HKUST-1 presented a higher photocatalytic hydrogen evolution (µmol), 26.45, in the first 30 min of the reaction, nevertheless, H2 O@HKUST-1 presented a competitive activity, of 17.32. In large periods, H2 O@HKUST-1/DMF@HKUST-1 showed practically the same hydrogen evolution, 45.50/49.03.

Understanding Sociodemographic Factors among Hispanics Through a Population-Based Study on Testicular Cancer in Mexico.

Testicular cancer (TCa) is a rare malignancy affecting young men worldwide. Sociodemographic factors, especially socioeconomic level (SEL) and healthcare access, seem to impact TCa incidence and outcomes, particularly among Hispanic populations. However, limited research has explored these variables in Hispanic groups. This study aimed to investigate sociodemographic and clinical factors in Mexico and their role in health disparities among Hispanic TCa patients. We retrospectively analyzed 244 Mexican TCa cases between 2007 and 2020 of a representative cohort with diverse social backgrounds from a national reference cancer center. Logistic regression identified risk factors for fatality: non-seminoma histology, advanced stage, and lower education levels. Age showed a significant trend as a risk factor. Patient delay and healthcare distance lacked significant associations. Inadequate treatment response and chemotherapy resistance were more likely in advanced stages, while higher education positively impacted treatment response. Cox regression highlighted non-seminoma histology, below-median SEL, higher education, and advanced-stage survival rates. Survival disparities emerged based on tumor histology and patient SEL. This research underscores the importance of comprehensive approaches that integrate sociodemographic, biological, and environmental factors to address health disparities improving outcomes through personalized interventions in Hispanic individuals with TCa.

Novel Strategy to Enhance Human Mesenchymal Stromal Cell Immunosuppression: Harnessing Interferon-Gamma Presentation in Metal-Organic Frameworks Embedded on Heparin/Collagen Multilayers.

The immunomodulatory potential of human mesenchymal stromal cells (hMSCs) can be boosted when exposed to interferon-gamma (IFN-γ). While pretreating hMSCs with IFN-γ is a common practice to enhance their immunomodulatory effects, the challenge lies in maintaining a continuous IFN-γ presence within cellular environments. Therefore, in this research, we investigate the sustainable presence of IFN-γ in the cell culture medium by immobilizing it in water-stable metal-organic frameworks (MOFs) [PCN-333(Fe)]. The immobilized IFN-γ in MOFs was coated on top of multilayers composed of combinations of heparin (HEP) and collagen (COL) that were used as a bioactive surface. Multilayers were created by using a layer-by-layer assembly technique, with the final layer alternating between collagen (COL) and heparin (HEP). We evaluated the viability, differentiation, and immunomodulatory activity of hMSCs cultured on (HEP/COL) coated with immobilized IFN-γ in MOFs after 3 and 6 days of culture. Cell viability, compared to tissue culture plastic, was not affected by immobilized IFN-γ in MOFs when they were coated on (HEP/COL) multilayers. We also verified that the osteogenic and adipogenic differentiation of the hMSCs remained unchanged. The immunomodulatory activity of hMSCs was evaluated by examining the expression of indoleamine 2,3-dioxygenase (IDO) and 11 essential immunomodulatory markers. After 6 days of culture, IDO expression and the expression of 11 immunomodulatory markers were higher in (HEP/COL) coated with immobilized IFN-γ in MOFs. Overall, (HEP/COL) multilayers coated with immobilized IFN-γ in MOFs provide a sustained presentation of cytokines to potentiate the hMSC immunomodulatory activity.

Analysis of immortal-time effect in post-infarction ventricular septal defect.

Introduction: Time-fixed analyses have traditionally been utilized to examine outcomes in post-infarction ventricular septal defect (VSD). The aims of this study were to: (1) analyze the relationship between VSD closure/non-closure and mortality; (2) assess the presence of immortal-time bias. Material and methods: In this retrospective cohort study, patients with ST-elevation myocardial infarction (STEMI) complicated by VSD. Time-fixed and time-dependent Cox regression methodologies were employed. Results: The study included 80 patients: surgical closure (n = 26), transcatheter closure (n = 20), or conservative management alone (n = 34). At presentation, patients without VSD closure exhibited high-risk clinical characteristics, had the shortest median time intervals from STEMI onset to VSD development (4.0, 4.0, and 2.0 days, respectively; P = 0.03) and from STEMI symptom onset to hospital arrival (6.0, 5.0, and 0.8 days, respectively; P < 0.0001). The median time from STEMI onset to closure was 22.0 days (P = 0.14). In-hospital mortality rate was higher among patients who did not undergo defect closure (50%, 35%, and 88.2%, respectively; P < 0.0001). Closure of the defect using a fixed-time method was associated with lower in-hospital mortality (HR = 0.13, 95% CI 0.05-0.31, P < 0.0001, and HR 0.13, 95% CI 0.04-0.36, P < 0.0001, for surgery and transcatheter closure, respectively). However, when employing a time-varying method, this association was not observed (HR = 0.95, 95% CI 0.45-1.98, P = 0.90, and HR 0.88, 95% CI 0.41-1.87, P = 0.74, for surgery and transcatheter closure, respectively). These findings suggest the presence of an immortal-time bias. Conclusions: This study highlights that using a fixed-time analytic approach in post-infarction VSD can result in immortal-time bias. Researchers should consider employing time-dependent methodologies.

Molecular mechanisms of resveratrol as chemo and radiosensitizer in cancer.

One of the primary diseases that cause death worldwide is cancer. Cancer cells can be intrinsically resistant or acquire resistance to therapies and drugs used for cancer treatment through multiple mechanisms of action that favor cell survival and proliferation, becoming one of the leading causes of treatment failure against cancer. A promising strategy to overcome chemoresistance and radioresistance is the co-administration of anticancer agents and natural compounds with anticancer properties, such as the polyphenolic compound resveratrol (RSV). RSV has been reported to be able to sensitize cancer cells to chemotherapeutic agents and radiotherapy, promoting cancer cell death. This review describes the reported molecular mechanisms by which RSV sensitizes tumor cells to radiotherapy and chemotherapy treatment.