Do proton pump inhibitors affect the effectiveness of cyclin-dependent kinase 4/6 inhibitors in advanced HR positive, HER2 negative breast cancer? A meta-analysis.

Background: The CDK 4/6 inhibitors, including palbociclib and ribociclib, are the standard first-line treatment for hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer. Proton pump inhibitors are one of the most globally prescribed types of medications as part of the treatment for gastroesophageal reflux and heartburn complaints. Medication interactions have been demonstrated, leading to a decrease in the effectiveness of chemotherapy drugs such as capecitabine and pazopanib. However, their role and interaction with targeted therapies such as CDK inhibitors are still poorly understood. Methods: We searched PubMed, Embase and Web of Science databases for studies that investigated the use of PPI with CDK 4/6 inhibitors versus CDK4/6 alone for advanced or metastatic breast cancer. We systematically searched for the currently available CDK inhibitors: palbociclib, ribociclib and abemaciclib. We computed hazard ratios (HRs), with 95% confidence intervals (CIs). We used DerSimonian and Laird random-effect models for all endpoints. Heterogeneity was assessed using I2 statistics. R, version 4.2.3, was used for statistical analyses. Results: A total of 2,737 patients with advanced breast cancer in 9 studies were included, with six studies described the status menopausal as 217 (7.9%) pre-menopause and 1851 (67.6%) post-menopause, for endocrine sensitivity only five studies described1489 (54.4%) patients were endocrine-sensitive and 498 (182%) endocrine-resistent, 910 (33.2%) patients used PPIs. The overall Progression-Free Survival was in favor of the PPI non-users (HR 2.0901; 95% CI 1.410-2.9498; p < 0.001). As well as the subgroup taking palbociclib, revealing statistical relevance for the PPI non-users (HR 2.2539; 95% CI 1.3213-3.8446; p = 0.003) and ribociclib subgroup with a slight decrease in hazard ratio (HR 1.74 95% CI 1.02-2.97; p = 0.04; I2 = 40%). In the multivariate analysis, there was no statistical signifance with ECOG (HR 0.9081; 95% CI 0.4978-16566; p 0.753) and Age (HR 1.2772; 95% CI 0.8790-1.8559; p = 0.199). Either, the univariate analysis did not show statistical significance. Conclusion: Women with HR+ and HER2-advanced metastatic breast undergoing treatment with targeted therapies, specifically CDK 4/6 inhibitors, should be monitored for the use of proton pump inhibitors. Therefore, the use of PPIs should be discussed, weighing the advantages and disadvantages for specific cases. It should be individualized based on the necessity in clinical practice for these cases. Systematic Review Registration: identifier CRD42023484755.

Effect of American genomic ancestry on severe toxicities in children with acute lymphoblastic leukemia in the Amazon region.

BACKGROUND: Acute Lymphoblastic Leukemia (ALL) is a neoplasm of the hematopoietic system characterized by a clonal expansion of abnormal lymphocyte precursor cells. ALL is the most common form of cancer in children, but despite advances in treatment, it can still be fatal. Ethnic differences influence survival rates, and genomic ancestry plays an important role, especially in mixed-race populations such as Latin America. This study aims to analyze the influence of genomic ancestry on toxicity in children with ALL in the Amazon region. METHODS: The study included 171 patients (protocol number 119,649/2012-Ethics Committee) with ALL treated at a pediatric treatment center in Belém do Pará, in the Brazilian Amazon. The patients were submitted to the BFM protocol of induction therapy for ALL. Toxicity was assessed based on laboratory tests and adverse events, classified according to the CTC-NCI guide. Genomic ancestry was determined using autosomal informative markers. RESULTS: The majority of children (94.74%) developed some type of toxicity during treatment, 87.04% of which were severe. Infectious toxicity was the most common, present in 84.8% of cases, 77.24% of which were severe. Amerindian ancestry showed an association with the risk of severe general toxicity and severe infectious toxicity, with a contribution of 35.0% demonstrating a significant increase in risk. In addition, post-induction refractoriness and relapse were also associated with an increased risk of death. CONCLUSION: This study highlights the influence of Amerindian genomic ancestry on response to therapy and toxicity in children with ALL in the Amazon region. Understanding these associations can contribute to personalizing treatment and improving clinical outcomes.

Efficacy and Safety of Anti-CD38 Monoclonal Antibodies in Patients with Relapsed or Refractory Multiple Myeloma: A Meta-Analysis of Randomized Clinical Trials.

The benefit of associating anti-CD38 monoclonal antibodies to proteasome inhibitor (PI)/immunomodulatory agent (IA) and dexamethasone in the treatment of patients with relapsed or refractory multiple myeloma (MM) remains unclear. PubMed, Embase, and Cochrane Library databases were searched for randomized controlled trials that investigated the addition of anti-CD38 monoclonal antibodies to a therapy composed of PI/IA and dexamethasone versus PI/IA and dexamethasone alone for treating relapsed or refractory MM. Hazard ratios (HRs) or risk ratios (RRs) were computed for binary endpoints, with 95% confidence intervals (CIs). Six studies comprising 2191 patients were included. Anti-CD38 monoclonal antibody significantly improved progression-free survival (HR 0.52; 95% CI 0.43-0.61; p < 0.001) and overall survival (HR 0.72; 95% CI 0.63-0.83; p < 0.001). There was a significant increase in hematological adverse events, such as neutropenia (RR 1.41; 95% CI 1.26-1.58; p < 0.01) and thrombocytopenia (RR 1.14; 95% CI 1.02-1.27; p = 0.02), in the group treated with anti-CD38 monoclonal antibody. Also, there was a significant increase in non-hematological adverse events, such as dyspnea (RR 1.72; 95% CI 1.38-2.13; p < 0.01) and pneumonia (RR 1.34; 95% CI 1.13-1.59; p < 0.01), in the group treated with anti-CD38 monoclonal antibody. In conclusion, the incorporation of an anti-CD38 monoclonal antibody demonstrated a promising prospect for reshaping the established MM treatment paradigms.

Efficacy and safety of anti-CD38 monoclonal antibodies in patients with relapsed or refractory multiple myeloma: a meta-analysis of randomized clinical trials

The benefit of associating anti-CD38 monoclonal antibodies to proteasome inhibitor (PI)/immunomodulatory agent (IA) and dexamethasone in the treatment of patients with relapsed or refractory multiple myeloma (MM) remains unclear. PubMed, Embase, and Cochrane Library databases were searched for randomized controlled trials that investigated the addition of anti-CD38 monoclonal antibodies to a therapy composed of PI/IA and dexamethasone versus PI/IA and dexamethasone alone for treating relapsed or refractory MM. Hazard ratios (HRs) or risk ratios (RRs) were computed for binary endpoints, with 95% confidence intervals (CIs). Six studies comprising 2191 patients were included. Anti-CD38 monoclonal antibody significantly improved progressionfree survival (HR 0.52; 95% CI 0.43­0.61; p < 0.001) and overall survival (HR 0.72; 95% CI 0.63­0.83; p < 0.001). There was a significant increase in hematological adverse events, such as neutropenia (RR 1.41; 95% CI 1.26­1.58; p < 0.01) and thrombocytopenia (RR 1.14; 95% CI 1.02­1.27; p = 0.02), in the group treated with anti-CD38 monoclonal antibody. Also, there was a significant increase in non-hematological adverse events, such as dyspnea (RR 1.72; 95% CI 1.38­2.13; p < 0.01) and pneumonia (RR 1.34; 95% CI 1.13­1.59; p < 0.01), in the group treated with anti-CD38 monoclonal antibody. In conclusion, the incorporation of an anti-CD38 monoclonal antibody demonstrated a promising prospect for reshaping the established MM treatment paradigms.

Efficacy and safety of Zolbetuximab plus chemotherapy for advanced CLDN18.2-positive gastric or gastro-oesophageal adenocarcinoma: a meta-analysis of randomized clinical trials.

BACKGROUND: The benefit of adding Zolbetuximab to the treatment in patients with Claudin-18 isoform 2 (CLDN18.2)-positive, human epidermal growth factor receptor 2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GC/GEJ) is not yet fully elucidated. METHODS: We searched PubMed, Embase and Cochrane databases for randomized controlled trials (RCTs) that investigated Zolbetuximab plus chemotherapy versus chemotherapy alone for GC or GEJ adenocarcinoma. We computed hazard-ratios (HRs) or odds-ratios (ORs) for binary endpoints, with 95% confidence intervals (CIs). RESULTS: Three studies and 1,233 patients were included. Comparing with Zolbetuximab plus chemotherapy versus chemotherapy alone, progression-free survival (PFS) rate (HR 0.64; 95% CI 0.49-0.84; p < 0.01) and overall survival (OS) rate (HR 0.72; 95% CI 0.62-0.83; p < 0.01) were significant in favor of the Zolbetuximab group. Regarding effectiveness, the Objective Response Rate (ORR) was (OR 1.15; 95% CI 0.87-1.53; p = 0.34). CONCLUSIONS: In this comprehensive systematic review and meta-analysis of RCTs, the incorporation of Zolbetuximab alongside chemotherapy offers a promising prospect for reshaping the established treatment paradigms for patients diagnosed with advanced CLDN18.2-positive GC/GEJ cancer.

PARP1 Characterization as a Potential Biomarker for BCR::ABL1 p190+ Acute Lymphoblastic Leukemia.

Detection of t(9;22), and consequent BCR::ABL1 fusion, is still a marker of worse prognosis for acute lymphoblastic leukemia (ALL), with resistance to tyrosine-kinase inhibitor therapy being a major obstacle in the clinical practice for this subset of patients. In this study, we investigated the effectiveness of targeting poly-ADP-ribose polymerase (PARP) in a model of BCR::ABL1 p190+ ALL, the most common isoform to afflict ALL patients, and demonstrated the use of experimental PARP inhibitor (PARPi), AZD2461, as a therapeutic option with cytotoxic capabilities similar to that of imatinib, the current gold standard in medical care. We characterized cytostatic profiles, induced cell death, and biomarker expression modulation utilizing cell models, also providing a comprehensive genome-wide analysis through an aCGH of the model used, and further validated PARP1 differential expression in samples of ALL p190+ patients from local healthcare institutions, as well as in larger cohorts of online and readily available datasets. Overall, we demonstrate the effectiveness of PARPi in the treatment of BCR::ABL1 p190+ ALL cell models and that PARP1 is differentially expressed in patient samples. We hope our findings help expand the characterization of molecular profiles in ALL settings and guide future investigations into novel biomarker detection and pharmacological choices in clinical practice.

Epidemiological Profile of Ophir Loyola Cancer Hospital: A Snapshot of the Incidence of Solid Neoplasms in the Eastern Amazon.

BACKGROUND: Solid neoplasms have a heterogeneous incidence worldwide and in Brazil. Thus, the region delimited by the Legal Amazon has a distinct epidemiological profile. In Pará, Ophir Loyola Cancer Hospital(OLCH) accounts for 71.11% of hospital visits in the state. METHODS: This was an ecological, exploratory, and mixed descriptive studythat investigated the epidemiological profile of patients with cancer treated at OLCH from January to December 2020. Sociodemographic data at admission were the primary variables, which were analyzed according to spatial distribution. RESULTS: In this study, the data of 2952 patients were analyzed, with the majority being between the ages of 50 and 79 years (62.47%), female (59.49%), and diagnosed but without previous treatment (87.30%). The most common cancers were breast (16.50%), cervical (13.40%), stomach (8.98%), and prostate (7.72%). Of the 12 integration regions, Guajará had the highest number of referrals (49.86%), followed by Guamá (12.94%) and Caeté River (8.98%). CONCLUSION: The profile of care at OLCH showed a high incidence of solid malignancies compared to that in other regions of Brazil, indicating environmental and sociocultural influences on the carcinogenic profile present in the eastern Amazon.

Transmission dynamics of SARS-CoV-2 variants in the Brazilian state of Pará.

Introduction: After three years since the beginning of the pandemic, the new coronavirus continues to raise several questions regarding its infectious process and host response. Several mutations occurred in different regions of the SARS-CoV-2 genome, such as in the spike gene, causing the emergence of variants of concern and interest (VOCs and VOIs), of which some present higher transmissibility and virulence, especially among patients with previous comorbidities. It is essential to understand its spread dynamics to prevent and control new biological threats that may occur in the future. In this population_based retrospective observational study, we generated data and used public databases to understand SARS-CoV-2 dynamics. Methods: We sequenced 1,003 SARS-CoV-2 genomes from naso-oropharyngeal swabs and saliva samples from Pará from May 2020 to October 2022. To gather epidemiological data from Brazil and the world, we used FIOCRUZ and GISAID databases. Results: Regarding our samples, 496 (49.45%) were derived from female participants and 507 (50.55%) from male participants, and the average age was 43 years old. The Gamma variant presented the highest number of cases, with 290 (28.91%) cases, followed by delta with 53 (5.28%). Moreover, we found seven (0.69%) Omicron cases and 651 (64.9%) non-VOC cases. A significant association was observed between sex and the clinical condition (female, p = 8.65e-08; male, p = 0.008961) and age (p = 3.6e-10). Discussion: Although gamma had been officially identified only in December 2020/January 2021, we identified a gamma case from Belém (capital of Pará State) dated May 2020 and three other cases in October 2020. This indicates that this variant was circulating in the North region of Brazil several months before its formal identification and that Gamma demonstrated its actual transmission capacity only at the end of 2020. Furthermore, the public data analysis showed that SARS-CoV-2 dispersion dynamics differed in Brazil as Gamma played an important role here, while most other countries reported a new infection caused by the Delta variant. The genetic and epidemiological information of this study reinforces the relevance of having a robust genomic surveillance service that allows better management of the pandemic and that provides efficient solutions to possible new disease-causing agents.

Breast Cancer: Clinical-Epidemiological Profile and Toxicities of Women Receiving Treatment with Taxanes in the Amazon Region.

Breast cancer is the most common malignant disease and the leading cause of mortality among women worldwide. Antineoplastic chemotherapy is one of its primary treatments, typically based on the class of drugs known as taxanes. Despite their proven therapeutic efficacy, these drugs can induce severe toxicities, leading to dose limitations or even treatment discontinuation. The objective of this study was to describe the clinical-epidemiological profile, risk factors, and toxicities of taxane-based chemotherapy treatment in women with breast cancer in the Amazon region. This is a cross-sectional, quantitative, and descriptive study conducted with 300 women diagnosed with breast cancer undergoing taxane treatment. Most patients were in the 40-49 age range, of brown ethnicity, and had completed elementary school. The majority of patients had risk factors such as alcoholism and a sedentary lifestyles. Most women had their first pregnancy between the ages of 18 and 21, breastfed their children, had menarche between the ages of 12 and 13, and were pre-menopausal and with a family history of cancer. The most frequent histological type was non-special invasive carcinoma and the Luminal B subtype. Most participants in this study showed taxane toxicity, with neurotoxicity being the most frequent. These findings reveal the importance of early detection, comprehensive risk factors, and effective management of treatment toxicities to improve patient outcomes in breast cancer care in the Amazon region.

Hepatitis C and Human Pegivirus Coinfection in Patients with Chronic Hepatitis C from the Brazilian Amazon Region: Prevalence, Genotypes and Clinical Data.

Coinfection of HPgV-1 with hepatitis C virus (HCV) is common due to shared modes of transmission, with a prevalence of HPgV-1 viremia of approximately 20% among individuals with chronic HCV infection. The aim of the present study was to estimate the prevalence of HPgV-1 RNA and circulating genotypes in patients with hepatitis C from a health service located in the city of Belém, in the state of Pará, Northern Brazil. A total of 147 samples were included in the study from February to December 2019. Among the participants, 72.1% (106/147) were monoinfected with HCV, with detectable HCV viral RNA, and 27.9% (41/147) were coinfected with HCV/HPgV-1. The most frequently found genotypes were HPgV-1 genotypes 1 and 2 (36.6% and 63.4%), respectively. While for HCV there was a predominance of genotypes 1 and 3 (58.5% and 41.5%). No significant differences were found when comparing any risk, sociodemographic, or clinical factors between groups. Also, there was no statistically significant difference when relating the viral genotypes of both agents. This study indicated that the prevalence of infection by HPgV-1 is high in HCV carriers in Belém, Pará, and probably does not change the clinical course of HCV infection, however, further studies are still needed.

Research for Cytomegalovirus Mutations Associated With Resistance to Antivirals in Kidney Transplant Receptors.

Cytomegalovirus (CMV) mutations associated with antiviral resistance have become a major problem related to high mortality in kidney transplant patients. The aim of the study was to investigate mutations in the CMV genes UL97 and UL54 associated with antiviral resistance. A retrospective observational cohort study was carried out at Hospital Ophir Loyola (HOL), a reference in Kidney Transplantation. A total of 81 patients who underwent kidney transplantation were followed up between 2016 and 2018 were monitored for CMV viral load by performing qPCR. Sanger sequencing was performed on 66 patients. All CMV-positive kidney transplant recipients were included. Mutations were observed in 15 samples (22.72%) from patients. Most cases involved UL97 mutations. Mutation in UL54 without mutation in UL97 was detected in only 2 cases. Resistance mutations in UL97 were identified, such as M460V, L595S, H520Q, two co-mutations D465R + Del524 and A594P + D413A and a 3 codon deletion (del598-601). The search for mutations in the CMV genes identified mutations that confer resistance to conventional antivirals, such as ganciclovir and cidofovir, used in the treatment of these patients. Confirmation of the association with increased CMV viral load in transplanted patients, due to mutation in resistance genes, requires phenotypic analysis for confirmation purposes. These were the first findings in patients in northern Brazil that we know of.

Molecular Changes in the Brain of the Wintering Calidris pusilla in the Mangroves of the Amazon River Estuary.

Migrant birds prepare differently to fly north for breeding in the spring and for the flight to lower latitudes during autumn, avoiding the cold and food shortages of the Northern Hemisphere's harsh winter. The molecular events associated with these fundamental stages in the life history of migrants include the differential gene expression in different tissues. Semipalmated sandpipers (Calidris pusilla) are Arctic-breeding shorebirds that migrate to the coast of South America during the non-breeding season. In a previous study, we demonstrated that between the beginning and the end of the wintering period, substantial glial changes and neurogenesis occur in the brain of C. pusilla. These changes follow the epic journey of the autumn migration when a 5-day non-stop transatlantic flight towards the coast of South America and the subsequent preparation for the long-distance flight of the spring migration takes place. Here, we tested the hypothesis that the differential gene expressions observed in the brains of individuals captured in the autumn and spring windows are consistent with the previously described cellular changes. We searched for differential gene expressions in the brain of the semipalmated sandpiper, of recently arrived birds (RA) from the autumnal migration, and that of individuals in the premigratory period (PM) in the spring. All individuals were collected in the tropical coastal of northern Brazil in the mangrove region of the Amazon River estuary. We generated a de novo neurotranscriptome for C. pusilla individuals and compared the gene expressions across libraries. To that end, we mapped an RNA-Seq that reads to the C. pusilla neurotranscriptome in four brain samples of each group and found that the differential gene expressions in newly arrived and premigratory birds were related with neurogenesis, metabolic pathways (ketone body biosynthetic and the catabolic and lipid biosynthetic processes), and glial changes (astrocyte-dopaminergic neuron signaling, astrocyte differentiation, astrocyte cell migration, and astrocyte activation involved in immune response), as well as genes related to the immune response to virus infections (Type I Interferons), inflammatory cytokines (IL-6, IL-1ß, TNF, and NF-κB), NLRP3 inflammasome, anti-inflammatory cytokines (IL-10), and cell death pathways (pyroptosis- and caspase-related changes).

The altered metabolic pathways of diffuse large B-cell lymphoma not otherwise specified.

Altered metabolic fingerprints of Diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS) may offer novel opportunities to identify new biomarkers and improve the understanding of its pathogenesis. This study aimed to investigate the modified metabolic pathways in extranodal, germinal center B-cell (GCB) and non-GCB DLBCL NOS from the head and neck. Formalin-fixed paraffin-embedded (FFPE) tissues from eleven DLBCL NOS classified according to Hans' algorithm using immunohistochemistry, and five normal lymphoid tissues (LT) were analyzed by high-performance liquid chromatography-mass spectrometry-based untargeted metabolomics. Partial Least Squares Discriminant Analysis showed that GCB and non-GCB DLBCL NOS have a distinct metabolomics profile, being the former more similar to normal lymphoid tissues. Metabolite pathway enrichment analysis indicated the following altered pathways: arachidonic acid, tyrosine, xenobiotics, vitamin E metabolism, and vitamin A. Our findings support that GCB and non-GCB DLBCL NOS has a distinct metabolomic profile, in which GCB possibly shares more metabolic similarities with LT than non-GCB DLBCL NOS.

One binge-type cycle of alcohol plus ketamine exposure induces emotional-like disorders associated with oxidative damage in adolescent female rats.

Drug abuse is a global public health problem among adolescents, with alcohol often used in association with other psychotropic drugs, such as ketamine. Considering the scarcity of evidence, this study aimed to investigate emotional behavioral effects induced by ethanol plus ketamine co-abuse, as well as oxidative biochemistry, and neurotrophic mediator in the prefrontal cortex and hippocampus in the early withdrawal of adolescent female rats. Animals were divided into control, ethanol, ketamine, and ethanol plus ketamine groups. The protocol administration was performed for 3 consecutive days (binge-like pattern). Behavioral assays of open field, elevated plus maze, and forced swim test were performed. After that, the prefrontal cortex and hippocampus were collected to evaluate oxidative biochemistry (reactive oxygen species-ROS; Antioxidant capacity against peroxyl radicals-ACAP; and lipid peroxidation). We found that isolated or combined ethanol and ketamine exposure displayed anxiety- and depressive-like profile, in a non-synergistically manner during early withdrawal. However, oxidative damage was aggravated in the co-administered animals than in isolated exposed subjects. We concluded that ethanol plus ketamine co-abuse may intensify oxidative damage in the hippocampus and prefrontal cortex in the early withdrawal of adolescent female rats, which was not reflected in the emotional behavioral phenotype. DATA AVAILABILITY STATEMENT: The datasets used and/or analyzed during the current investigation are available upon reasonable request from the corresponding author.

Influence of Genetic Variations in miRNA and Genes Encoding Proteins in the miRNA Synthesis Complex on Toxicity of the Treatment of Pediatric B-Cell ALL in the Brazilian Amazon.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer in the world. Single nucleotide variants (SNVs) in miRNA and genes encoding proteins of the miRNA synthesis complex (SC) may affect the processing of drugs used in the treatment of ALL, resulting in treatment-related toxicities (TRTs). We investigated the role of 25 SNVs in microRNA genes and genes encoding proteins of the miRNA SC, in 77 patients treated for ALL-B from the Brazilian Amazon. The 25 SNVs were investigated using the TaqMan® OpenArray™ Genotyping System. SNVs rs2292832 (MIR149), rs2043556 (MIR605), and rs10505168 (MIR2053) were associated with an increased risk of developing Neurological Toxicity, while rs2505901 (MIR938) was associated with protection from this toxicity. MIR2053 (rs10505168) and MIR323B (rs56103835) were associated with protection from gastrointestinal toxicity, while DROSHA (rs639174) increased the risk of development. The rs2043556 (MIR605) variant was related to protection from infectious toxicity. SNVs rs12904 (MIR200C), rs3746444 (MIR499A), and rs10739971 (MIRLET7A1) were associated with a lower risk for severe hematologic toxicity during ALL treatment. These findings reveal the potential for the use of these genetic variants to understand the development of toxicities related to the treatment of ALL in patients from the Brazilian Amazon region.

Study of Genotoxicity, Activities on Caspase 8 and on the Stabilization of the Topoisomerase Complex of Isoeleutherin and Analogues.

This study evaluated the genotoxicity of Ethanol Extract (EEEp), Dichloromethane Fraction (FDCMEp) and isoeleutherin isolated from Eleutherine plicata, using the micronucleus test and the impact of structural alterations on toxicity and molecular docking (topoisomerase II and DNA complex). The extract was obtained by maceration and fractionation in a chromatography column. The genotoxicity was evaluated by the micronucleus test in human hepatoma cells (HepG2). Isoeleutherin was the starting molecule in the search for analogues by structural similarity, using the ZINC and e-Molecules databases. Isoeleutherin and analogues were subjected to in silico toxicity prediction, and compounds free of toxicological risks (CP13, CP14, CP17 and isoeleutherin) were selected for molecular docking in Topoisomerase II (PDB: 1ZXM). In the micronucleus test, isoeleutherin was less genotoxic. Among the 22 isoeleutherin analogues there were variations in the toxicity profile. Molecular docking studies showed that the compounds have good complementarity in the active site with important hydrogens bonds. Therefore, the structural changes of isoeleutherin led to the obtaining of a molecule with a lower mutagenic potential, and the CP13 can be considered a prototype compound for the development of new molecules with pharmacological potential.

Association between the rs820218 Variant within the SAP30BP Gene and Rotator Cuff Rupture in an Amazonian Population.

BACKGROUND: Rotator cuff disease is one of the leading causes of musculoskeletal pain and disability, and its etiology is most likely multifactorial but remains incompletely understood. Therefore, the objective of this research was to investigate the relationship of the single-nucleotide rs820218 polymorphism of the SAP30-binding protein (SAP30BP) gene with rotator cuff tears in the Amazonian population. METHODS: The case group consisted of patients who were operated on due to rotator cuff tears in a hospital in the Amazon region between 2010 and 2021, and the control group was composed of individuals who were selected after negative physical examinations for rotator cuff tears. Genomic DNA was obtained from saliva samples. For the genotyping and allelic discrimination of the selected single nucleotide polymorphism (rs820218) in the SAP30BP gene, real-time PCR was performed. RESULTS: The frequency of the A allele in the control group was four times as high as that in the case group (AA homozygotes); an association of the genetic variant rs820218 of the SAP30BP gene with rotator cuff tears was not established (p = 0.28 and 0.20), as the A allelic frequency is ordinarily low in the general population. CONCLUSIONS: The presence of the A allele indicates protection against rotator cuff tears.

Impact of pri-let-7a-1 rs10739971 for Gastric Cancer Predisposition in an Amazon Region.

Gastric cancer (GC) is the fifth most common type of cancer and the fourth leading cause of cancer death. In Brazil, GC has a high incidence and mortality rates, and it is highly variable by region. The Amazon region has significant rising rates among all Brazil regions. Only very few studies have evaluated the association between genetic variants and the risk of gastric cancer in the Brazilian Amazon population. Therefore, this study aimed to investigate associations between single nucleotide polymorphisms of miRNA processing genes and the risk for GC in this population. Potentially functional single nucleotide polymorphisms from miRNA processing genes were genotyped in 159 cases and 193 healthy controls by QuantStudio Real Time PCR. According to our findings, the genotype GG of the variant rs10739971 presents a lower risk to the development of GC in comparison to the remaining genotypes (p = 0.000016; OR = 0.055; 95% CI = 0.015-0.206). This is the first study to report the association of pri-let-7a-1 rs10739971 with GC in the Brazilian Amazon population, which is a highly mixed population with a unique genetic constitution that is different from other populations that are studied in the vast majority of scientific research.

Oral follicular lymphoma: a clinicopathologic and molecular study.

Follicular lymphoma is a hematolymphoid neoplasm that originates from germinal center B cells. It is made up of a combination of small cleaved centrocytes and a varying quantity of larger non-cleaved centroblasts to describe the clinical, microscopic, immunohistochemical, and molecular features of oral follicular lymphomas. Follicular lymphomas affecting the oral cavity were retrieved from pathology files. Immunohistochemistry was performed to confirm the diagnosis, and fluorescence in situ hybridization (FISH) was employed to detect rearrangements in BCL2, BCL6, and MYC genes. Clinical and follow-up data were obtained from the patient's medical and pathology files. Twenty cases were obtained. There was an equal sex distribution (10 males: 10 females) and a mean age of 60.9 years (range: 10-83 years-old). Lesions presented as asymptomatic swellings, usually in the palate (10 cases) and the buccal mucosa (7 cases). Five patients presented with concomitant nodal involvement. Microscopic evaluation depicted the follicular growth pattern with diffuse areas in six cases. Grades 1 and 2 follicular lymphomas represented 12 cases, while grade 3A neoplasms accounted for other 8 cases. Two cases showed rearrangements in MYC, BCL2, and BCL6 genes, while single BCL2 translocation was found in eight cases. Two cases had no translocation. Three patients deceased and the 2-year overall survival achieved 88%. Follicular lymphoma affecting the oral cavity is uncommon, usually affects the palate as a non-ulcerated swelling and the presence of a systemic disease most always be ruled out.

Incidence of Hereditary Gastric Cancer May Be Much Higher than Reported.

Hereditary gastric cancers (HGCs) are supposed to be rare and difficult to identify. Nonetheless, many cases of young patients with gastric cancer (GC) fulfill the clinical criteria for considering this diagnosis but do not present the defined pathogenic mutations necessary to meet a formal diagnosis of HGC. Moreover, GC in young people is a challenging medical situation due to the usual aggressiveness of such cases and the potential risk for their relatives when related to a germline variant. Aiming to identify additional germline alterations that might contribute to the early onset of GC, a complete exome sequence of blood samples from 95 GC patients under 50 and 94 blood samples from non-cancer patients was performed and compared in this study. The number of identified germline mutations in GC patients was found to be much higher than that from individuals without a cancer diagnosis. Specifically, the number of high functional impact mutations, including those affecting genes involved in medical diseases, cancer hallmark genes, and DNA replication and repair processes, was much higher, strengthening the hypothesis of the potential causal role of such mutations in hereditary cancers. Conversely, classically related HGC mutations were not found and the number of mutations in genes in the CDH1 pathway was not found to be relevant among the young GC patients, reinforcing the hypothesis that existing alternative germline contributions favor the early onset of GC. The LILRB1 gene variants, absent in the world's cancer datasets but present in high frequencies among the studied GC patients, may represent essential cancer variants specific to the Amerindian ancestry's contributions. Identifying non-reported GC variants, potentially originating from under-studied populations, may pave the way for additional discoveries and translations to clinical interventions for GC management. The newly proposed approaches may reduce the discrepancy between clinically suspected and molecularly proven hereditary GC and shed light on similar inconsistencies among other cancer types. Additionally, the results of this study may support the development of new blood tests for evaluating cancer risk that can be used in clinical practice, helping physicians make decisions about strategies for surveillance and risk-reduction interventions.