Genetics, Pathophysiology, and Current Challenges in Von Hippel-Lindau Disease Therapeutics.

This review article focuses on von Hippel-Lindau (VHL) disease, a rare genetic disorder characterized by the development of tumors and cysts throughout the body. It discusses the following aspects of the disease. GENETICS: VHL disease is caused by mutations in the VHL tumor suppressor gene located on chromosome 3. These mutations can be inherited or occur spontaneously. This article details the different types of mutations and their associated clinical features. PATHOPHYSIOLOGY: The underlying cause of VHL disease is the loss of function of the VHL protein (pVHL). This protein normally regulates hypoxia-inducible factors (HIFs), which are involved in cell growth and survival. When pVHL is dysfunctional, HIF levels become elevated, leading to uncontrolled cell growth and tumor formation. CLINICAL MANIFESTATIONS: VHL disease can affect various organs, including the brain, spinal cord, retina, kidneys, pancreas, and adrenal glands. Symptoms depend on the location and size of the tumors. DIAGNOSIS: Diagnosis of VHL disease involves a combination of clinical criteria, imaging studies, and genetic testing. TREATMENT: Treatment options for VHL disease depend on the type and location of the tumors. Surgery is the mainstay of treatment, but other options like radiation therapy may also be used. CHALLENGES: This article highlights the challenges in VHL disease management, including the lack of effective therapies for some tumor types and the need for better methods to monitor disease progression. In conclusion, we emphasize the importance of ongoing research to develop new and improved treatments for VHL disease.

Clinical effect of hepatic artery interventional embolization and chemotherapy and its influence on P16 protein expression in patients with liver cancer.

OBJECTIVE: To investigate clinical effects of hepatic artery interventional embolization chemotherapy (TACE) for primary hepatocellular carcinoma (PHC). METHODS: 73 patients with PHC in our hospital from January 2017 to January 2018 were selected and divided into 37 cases in study group and 36 cases in control group by random number table method. The control group received only ultrasound-guided microwave ablation treatment, and the study group received TACE treatment again before surgery based on control group. The expression levels of cancer antigen 125 (CA125), alpha-fetoprotein (AFP), multiple tumor suppressors 1 (P16) proteins, and cancer antigen 19-9 (CA19-9) were compared between the two groups at different time periods after treatment, and the remission rate (ORR), control rate (DCR), complication rate at 3 months after treatment and survival rate at 3 years after treatment were compared. RESULTS: After 1 year of treatment, ORR, DCR, and P16 protein levels in the study group were higher than those in the control group (P < 0.05), and differences were statistically significant; CA125, CA19-9, and AFP levels in study group were lower than those in the control group (P < 0.05), and differences were statistically significant. The regression equation showed that long-term survival rate of both groups showed decreasing trend over time, while long-term survival rate of study group was always higher than that of the control group. CONCLUSION: Comprehensive intervention for hepatic artery interventional chemoembolization in patients with primary hepatocellular carcinoma is more effective, which can effectively reduce incidence of complications and adverse effects in patients and help shorten treatment time of hepatic artery interventional chemoembolization in patients.

Comparative Assessment of miR-185-5p and miR-191-5p Expression: From Normal Endometrium to High-Grade Endometrial Cancer.

Endometrial cancer (EC) is a significant cause of cancer-related deaths in women. MicroRNAs (miRs) play a role in cancer development, acting as oncogenes or tumor suppressors. This study evaluated the diagnostic potential of hsa-miR-185-5p and hsa-miR-191-5p in EC and their correlation with clinical and histopathological features. A cross-sectional study analyzed formalin-fixed, paraffin-embedded tissue samples from 59 patients: 18 with EC, 21 with endometrial hyperplasia (EH), 17 with normal endometrium (NE), and 3 with endometrial polyps (EPs). Quantitative reverse transcription-polymerase chain reaction and TaqMan probes were used for miR expression analysis. The Shapiro-Wilk test was used to analyze the normal distribution of the data. Subsequently, parametric or non-parametric tests were used to evaluate the associations between the expression levels of each miR and clinical parameters. Both miRs were underexpressed in some precursor and malignant lesions compared to certain NE subtypes and benign lesions. Specifically, hsa-miR-185-5p showed underexpression in grade 3 EC compared to some NE and EH subtypes (FC: -57.9 to -8.5, p < 0.05), and hsa-miR-191-5p was underexpressed in EH and EC compared to secretory endometrium and EPs (FC: -4.2 to -32.8, p < 0.05). SETD1B, TJP1, and MSI1 were common predicted target genes. In conclusion, hsa-miR-185-5p and hsa-miR-191-5p are underexpressed in EC tissues, correlating with histopathological grades, highlighting their potential as diagnostic biomarkers and their role as tumor suppressors in EC.

Baseline surveillance in Li Fraumeni syndrome using whole-body MRI: a systematic review and updated meta-analysis.

OBJECTIVES: Li-Fraumeni syndrome (LFS) is a cancer syndrome associated with early-onset neoplasias. The use of whole-body magnetic resonance imaging (WBMRI) is recommended for regular cancer screening, however, evidence supporting the benefits in asymptomatic LFS patients is limited. This study aims to assess the clinical utility of WBMRI in germline TP53 mutation carriers at baseline and follow-up. MATERIALS AND METHODS: We systematically searched PubMed, Cochrane, and Embase databases for studies evaluating WBMRI as an early detection method for tumor screening in patients with LFS. We pooled the prevalence of the included variables along with their corresponding 95% confidence intervals (CIs). Statistical analyses were performed using R software, version 4.3.1. RESULTS: From 1687 results, 11 comprising 703 patients (359 females (51%); with a median age of 32 years (IQR 1-74)) were included. An estimated detection rate of 31% (95% CI: 0.28, 0.34) for any suspicious lesions was found in asymptomatic TP53 carriers who underwent baseline WBMRI. A total of 277 lesions requiring clinical follow-up were identified in 215 patients. Cancer was confirmed in 46 lesions across 39 individuals. The estimated cancer diagnosis rate among suspicious lesions was 18% (95% CI: 0.13, 0.25). WBMRI detected 41 of the 46 cancers at an early-disease stage, with an overall detection rate of 6% (95% CI: 0.05, 0.08). The incidence rate was 2% per patient round of WBMRI (95% CI: 0.01, 0.04), including baseline and follow-up. CONCLUSION: This meta-analysis provides evidence that surveillance with WBMRI is effective in detecting cancers in asymptomatic patients with LFS. CLINICAL RELEVANCE STATEMENT: Our study demonstrates that whole-body MRI is an effective tool for early cancer detection in asymptomatic Li-Fraumeni Syndrome patients, highlighting its importance in surveillance protocols to improve diagnosis and treatment outcomes. KEY POINTS: Current evidence for whole-body MRI screening of asymptomatic Li-Fraumeni Syndrome (LFS) patients remains scarce. Whole-body MRI identified 41 out of 46 cancers at an early stage, achieving an overall detection rate of 6%. Whole-body MRI surveillance is a valuable method for detecting cancers in asymptomatic LFS patients.

HOXA1 3'UTR Methylation Is a Potential Prognostic Biomarker in Oral Squamous cell Carcinoma.

BACKGROUND: HOXA1 is a prognostic marker and a potential predictive biomarker for radioresistance in head and neck tumors. Its overexpression has been associated with promoter methylation and a worse prognosis in oral squamous cell carcinoma (OSCC) patients. However, opposite outcomes are also described. The effect of the methylation of this gene on different gene regions, other than the promoter, remains uncertain. We investigated the methylation profile at different genomic regions of HOXA1 in OSCC and correlated differentially methylated CpG sites with clinicopathological data. METHODS: The HOXA1 DNA methylation status was evaluated by analyzing data from The Cancer Genome Atlas and three Gene Expression Omnibus datasets. Significant differentially methylated CpG sites were considered with a |∆ß| ≥ 0.10 and a Bonferroni-corrected p-value < 0.01. Differentially methylated CpGs were validated by pyrosequencing using two independent cohorts of 15 and 47 OSCC patients, respectively. RESULTS: Compared to normal tissues, we found significantly higher DNA methylation levels in the 3'UTR region of HOXA1 in OSCC. Higher methylation levels in tumor samples were positively correlated with smoking habits and patients' overall survival. CONCLUSIONS: Our findings suggest that HOXA1 gene body methylation is a promising prognostic biomarker for OSCC with potential clinical applications in patient monitoring.

Cavin1 activates the Wnt/ß-catenin pathway to influence the proliferation and migration of hepatocellular carcinoma.

INTRODUCTION AND OBJECTIVES: Cavin1 is a cell membrane caveolin, with controversial function in different tumors. Meanwhile, the role of Cavin1 in hepatocellular carcinoma (HCC) progression remains unclear. In this study, we attempted to elucidate the significance of Cavin1 in HCC occurrence and progression. MATERIALS AND METHODS: Cavin1 content was examined in HCC tissues and paired adjacent normal liver tissues by qRT-PCR and IHC among 81 HCC patients. The Cavin1-mediated regulation of HCC proliferation and metastasis was assessed through in vitro and in vivo experiments. Finally, using GSEA, we found out Cavin1 could be a potential regulator of the Wnt pathway. The alterations of the Wnt pathway-related proteins were identified by Western Blot analysis. RESULTS: Cavin1 was lower expressed in HCC, which implied poor survival outcomes in HCC patients. Phenotypic experiments revealed that Cavin1 strongly suppressed HCC proliferation and migration in vitro and in vivo. Besides, altered epithelial-mesenchymal transition (EMT)-related protein expressions were detected. Based on our GSEA analysis, Cavin1 activated the Wnt pathway, and Western Blot analysis revealed diminished ß-catenin, c-Myc, and MMP9 contents upon Cavin1 overexpression. CONCLUSIONS: Cavin1 suppresses HCC progression by modulating HCC proliferation and migration via inhibiting the Wnt/ß-catenin axis activation.

Factor inducible por hipoxia en cáncer

El oxígeno y dióxido de carbono son vitales en la respiración, sus variaciones fuera del rango fisiológico son una amenaza para la supervivencia de las células. La hipoxia es una condición común en la mayoría de los tumores malignos, la cual promueve angiogénesis y vascularización disfuncional, mayor proliferación celular y la adquisición de un fenotipo de transición epitelial a mesenquimatoso, que contribuye con la metástasis; asimismo, altera el metabolismo de las células cancerosas y genera resistencia a la terapia, ya que induce a la inactividad celular. Por tanto, la hipoxia es un factor negativo, asociado a resultados adversos en la mayoría de los tratamientos de los distintos tipos de cáncer. El factor inducible por hipoxia (HIF) es el factor de transcripción relacionado con la hipoxia en cáncer, que produce la activación de más de una centena de genes reguladores de la actividad celular, que generan funciones cruciales para el desarrollo del cáncer. El objetivo principal de la presente revisión es puntualizar la importancia de la hipoxia en la génesis del cáncer, conocer las principales moléculas que interactúan en la expresión del HIF, explicar los mecanismos moleculares de las vías involucradas en la inducción del HIF, las consecuencias celulares por su alteración y las potenciales terapias dirigidas contra este factor. Se consultaron PubMed, Scopus y SciELO, del año 1990 hasta el año 2022, y se buscaron las referencias bibliográficas en relación con las palabras clave asociadas al factor inducible por hipoxia y cáncer. En conclusión, la sobreexpresión de HIF-1α en biopsias tumorales se asocia con una mayor mortalidad de pacientes en cánceres humanos. Los posibles genes diana regulados por HIF-1α que pueden desempeñar un papel en la progresión tumoral están empezando a descubrirse. A pesar de que se han estudiado cientos de compuestos en relación con el HIF en cáncer, en la actualidad existen pocos inhibidores del HIF aprobados en el mercado mundial; asimismo, muchos estudios clínicos, en sus distintas fases en desarrollo, no muestran resultados alentadores. Probablemente, en el futuro, cuando se tenga una mejor comprensión de la estructura, funcionamiento molecular y biológico de este factor, se desarrollarán fármacos más específicos para la inhibición del HIF.

Oxygen and carbon dioxide are essential for breathing; variations in these gases outside of the normal range are a threat to cell survival. Hypoxia is a common condition that occurs in most malignant tumors, increases angiogenesis and defective vascularization, promotes cell proliferation and acquires an epithelial-mesenchymal transition phenotype, which causes metastasis. It also affects cancer cell metabolism and makes patients resistant to treatment by causing cell quiescence. As a result, hypoxia is a detrimental component that is linked to unfavorable outcomes in most cancer treatments. Through the activation of more than a hundred genes that control cell activity, which produce key functions for cancer development, the transcription factor known as hypoxia-inducible factor (HIF) is linked to hypoxia in cancer. This review's main goals are to highlight the role of hypoxia in the development of cancer, identify the key molecules that interact to promote HIF expression, explain the molecular mechanisms of the pathways that lead to HIF induction, describe the cellular effects of HIF alteration, and discuss potential HIF-targeted therapies. Articles from 1990 to 2022 were reviewed in PubMed, Scopus and SciELO databases. Keywords related to cancer and HIF were searched in bibliographical references. In conclusion, HIF-1α overexpression in tumor biopsies is associated with increased patient mortality in human cancers. Potential HIF-1α-regulated target genes that may play a role in tumor progression are starting to be identified. Although hundreds of chemicals have been studied in relation to HIF in cancer, there are currently few approved HIF inhibitors available on the global market; moreover, many clinical trials, in their various stages of development, do not show encouraging results. It is likely that in the future, when there is a better understanding of the structure, molecular and biological functioning of this factor, more specific drugs for HIF inhibition will be developed.

Antecedente de grado de expresividad de p53 en carcinomas basocelulares como predictor de recurrencia / Background of p53 expressivity grade in basal cell carcinomas as a predictor of recurrence

INTRODUCCIÓN. El gen Tp53 proporciona instrucciones para producir proteína tumoral 53. El Tp53 es un gen supresor tumoral que protege el ciclo celular, reparando el ADN o activando la apoptosis. Es clave en la carcinogénesis del carcinoma basocelular, patología que cobra relevancia en Ecuador, debido a su latitud y altitud, factores que determinan un mayor daño por exposición a radiación ultravioleta y por ende para carcinoma basocelular. Estudios sugieren que la inmunoexpresión de la proteína tumoral 53 podría ser un predictor de recurrencia en esta neoplasia. OBJETIVO. Determinar si el grado de expresividad de especies mutadas de proteína tumoral 53 en pacientes con carcinoma basocelular es una variable que tiene relación con la recurrencia y agresividad en los diferentes subtipos histológicos. MATERIALES Y MÉTODOS. Estudio de revisión bibliográfica de diferentes artículos científicos publicados en revistas indexadas y bases de datos durante los últimos diez años: ElSevier, Medigraphic, PubMed, Redalyc, ResearchGate, ScienceDirect, SpringerLink, Cochrane Database of Systematic Reviews. RESULTADOS. Se obtuvieron 104 resultados de los cuales se seleccionaron 50 artículos científicos que incluyeron revisiones sistemáticas, meta-análisis, artículos originales y reportes de casos en idiomas español e inglés. CONCLUSIÓN. Tp53 se encuentra mutado en más del 50% de carcinomas basocelulares y tiene un rol clave en su carcinogénesis. La inmunoexpresión aberrante de proteína tumoral 53 es un marcador de riesgo de recurrencia y agresividad en carcinoma basocelular, como lo indican los artículos revisados. Sin embargo, se requiere estudios locales que establezcan el verdadero valor de proteína tumoral 53 como marcador de recurrencia y/o agresividad en la población ecuatoriana.

INTRODUCTION. The Tp53 gene provides instructions to produce tumor protein 53. Tp53 is a tumor suppressor gene that protects the cell cycle, repairing DNA or activating apoptosis. It is key in the carcinogenesis of basal cell carcinoma, a pathology that is relevant in Ecuador, due to its latitude and altitude, factors that determine greater damage by exposure to ultraviolet radiation and therefore for basal cell carcinoma. Studies suggest that the immunoexpression of tumor protein 53 could be a predictor of recurrence in this neoplasm. OBJECTIVE. To determine whether the degree of expression of mutated species of tumor protein 53 in patients with basal cell carcinoma is a variable related to recurrence and aggressiveness in the different histologic subtypes. MATERIALS AND METHODS. Bibliographic review study of different scientific articles published in indexed journals and databases during the last ten years: El-Sevier, Medigraphic, PubMed, Redalyc, ResearchGate, ScienceDirect, SpringerLink, Cochrane Database of Systematic Reviews. RESULTS. A total of 104 results were obtained from which 50 scientific articles were selected, including systematic reviews, meta-analyses, original articles and case reports in Spanish and English. CONCLUSIONS. Tp53 is mutated in more than 50% of basal cell carcinomas and plays a key role in their carcinogenesis. Aberrant immunoexpression of tumor protein 53 is a risk marker for recurrence and aggressiveness in basal cell carcinoma, as indicated by the reviewed articles. However, local studies are required to establish the true value of tumor protein 53 as a marker of recurrence and/or aggressiveness in the Ecuadorian population.

MicroRNA-92b targets tumor suppressor gene FBXW7 in glioblastoma.

Introduction: Glioblastoma (GBM) is a highly aggressive and lethal primary brain tumor. Despite limited treatment options, the overall survival of GBM patients has shown minimal improvement over the past two decades. Factors such as delayed cancer diagnosis, tumor heterogeneity, cancer stem cell survival, infiltrative nature of GBM cells, metabolic reprogramming, and development of therapy resistance contribute to treatment failure. To address these challenges, multitargeted therapies are urgently needed for improved GBM treatment outcomes. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression. Dysregulated miRNAs have been identified in GBM, playing roles in tumor initiation, progression, and maintenance. Among these miRNAs, miR-92b (miRNA-92b-3p) has been found to be overexpressed in various cancers, including GBM. However, the specific target genes of miR-92b and its therapeutic potential in GBM remain poorly explored. Methods: Samples encompassed T98G, U87, and A172 human GBM cell lines, GBM tumors from Puerto Rican patients, and murine tumors. In-situ hybridization (ISH) assessed miR-92b expression in patient tumors. Transient and stable transfections modified miR-92b levels in GBM cell lines. Real-time PCR gauged gene expressions. Caspase 3 and Trypan Blue assays evaluated apoptosis and viability. Bioinformatics tools (TargetScanHuman 8.0, miRDB, Diana tools, miRWalk) predicted targets. Luciferase assays and Western Blots validated miRNA-target interactions. A subcutaneous GBM Xenograft mouse model received intraperitoneal NC-OMIs or miR92b-OMIs encapsulated in liposomes, three-times per week for two weeks. Analysis utilized GraphPad Prism 8; statistical significance was assessed using 2-tailed, unpaired Student's t-test and two-way ANOVA as required. Results: This study investigated the expression of miR-92b in GBM tumors compared to normal brain tissue samples, revealing a significant upregulation. Inhibition of miR-92b using oligonucleotide microRNA inhibitors (OMIs) suppressed GBM cell growth, migration, and induced apoptosis, while ectopic expression of miR-92b yielded opposite effects. Systemic administration of liposomal-miR92b-OMIs in GBM xenograft mice resulted in reductions in tumor volume and weight. Subsequent experiments identified F-Box and WD Repeat Domain Containing 7 (FBXW7) as a direct target gene of miR-92b in GBM cells. Discussion: FBXW7 acts as a tumor suppressor gene in various cancer types, and analysis of patient data demonstrated that GBM patients with higher FBXW7 mRNA levels had significantly better overall survival compared to those with lower levels. Taken together, our findings suggest that the dysregulated expression of miR-92b in GBM contributes to tumor progression by targeting FBXW7. These results highlight the potential of miR-92b as a therapeutic target for GBM. Further exploration and development of miR-92b-targeted therapies may offer a novel approach to improve treatment outcomes in GBM patients.

Microbiota composition and its impact on DNA methylation in colorectal cancer.

Colorectal cancer is a complex disease resulting from the interaction of genetics, epigenetics, and environmental factors. DNA methylation is frequently found in tumor suppressor genes to promote cancer development. Several factors are associated with changes in the DNA methylation pattern, and recently, the gastrointestinal microbiota could be associated with this epigenetic change. The predominant phyla in gut microbiota are Firmicutes and Bacteroidetes; however, an enrichment of Bacteroides fragilis, Fusobacterium nucleatum, and Streptococcus bovis, among others, has been reported in colorectal cancer, although the composition could be influenced by several factors, including diet, age, sex, and cancer stage. Fusobacterium nucleatum, a gram-negative anaerobic bacillus, is mainly associated with colorectal cancer patients positive for the CpG island methylator phenotype, although hypermethylation in genes such as MLH1, CDKN2A, MTSS1, RBM38, PKD1, PTPRT, and EYA4 has also been described. Moreover, Hungatella hathewayi, a gram-positive, rod-shaped bacterium, is related to hypermethylation in SOX11, THBD, SFRP2, GATA5, ESR1, EYA4, CDX2, and APC genes. The underlying epigenetic mechanism is unclear, although it could be implicated in the regulation of DNA methyltransferases, enzymes that catalyze the transfer of a methyl group on cytosine of CpG sites. Since DNA methylation is a reversible event, changes in gut microbiota could modulate the gene expression through DNA methylation and improve the colorectal cancer prognosis.

Asparanin A exerts cytotoxicity on human endometrial cancer Ishikawa cells via regulating miR-6236-p5_4 expression.

miRNAs are emerging as a novel proto-oncogene or tumor suppressor in the initiation and progression of cancer. Several plants naturally contain asparanin A (AA), which has potent anticancer properties. Previously, we discovered that AA exposure increased the expression of miR-6236-p5_4 and caused cytotoxicity in endometrial carcinoma (EC) Ishikawa cells. Herein, the regulation mechanism of miR-6236-p5_4 in the anticancer activity of AA in EC was investigated. Our results showed that the overexpressed miR-6236-p5_4 contributed to modulating cell viability and cell cycle arrest, triggering cell apoptosis, and suppressing migration. Conversely, down-regulation of miR-6236-p5_4 attenuated the anti-cancer effect of AA. Additionally, the PI3K-Akt, p53, Ras, and Rap1 signaling pathways were demonstrated to be the key pathways, whereas CDK6, PIK3CB, and KRAS were found to be directly functional target genes. Our findings imply that miRNA-6236-p5_4 can act as both a molecular diagnostic for the clinical identification and prognosis of EC and a tumor suppressor in AA against EC.

Autopsy findings of acute erythroid leukemia.

Acute erythroid leukemia (AEL) is an exceedingly uncommon but distinct hematological malignancy that shows neoplastic proliferation of erythroid precursors with maturation arrest and no significant myeloblasts. We describe an autopsy case of this rare entity in a 62-year-old man with co-morbidities. He underwent a bone marrow (BM) examination for pancytopenia during the first outpatient department visit, which revealed an increased number of erythroid precursors with dysmegakaryopoiesis suggesting the possibility of Myelodysplastic syndromes (MDS). Thereafter, his cytopenia got worsened, warranting blood and platelet transfusions. Four weeks later on the second BM examination, AEL was diagnosed based on morphology and immunophenotyping. Targeted resequencing for myeloid mutations revealed TP53 and DNMT3A mutations. He was initially managed along febrile neutropenia with the stepwise escalation of antibiotics. He developed hypoxia attributed to anemic heart failure. Subsequently, he had hypotension and respiratory fatigue pre-terminally and succumbed to his Illness. A complete autopsy showed infiltration of various organs by AEL and leukostasis. Besides, there was extramedullary hematopoiesis, arterionephrosclerosis, diabetic nephropathy (ISN-RPS class II), mixed dust pneumoconiosis, and pulmonary arteriopathy. The histomorphology of AEL was challenging, and the differential diagnoses were many. Thus, this case highlights the autopsy pathology of AEL, an uncommon entity with a strict definition, and its relevant differentials.

Transcriptomic profiles-based approach to decode the role of miR-122 in triple negative breast cancer.

miR-122 has been considered both as tumor suppressor miRNA and oncomiR in breast tumor phenotypes. However, the role of miR-122 in triple-negative breast cancer (TNBC) is still unknown. In this study, the clinical value of miR-122 was used to describe the transcriptomic landscape of TNBC tumors obtained from The Cancer Genome Atlas database. Low expression levels of miR-122 were associated with poor overall survival (OS) of TNBC patients than those with higher expression levels of miR-122. We identified gene expression profiles in TNBC tumors expressed lower or higher miR-122. Gene coexpression networks analysis revealed gene modules and hub genes specific to TNBC tumors with low or high miR-122 levels. Gene ontology and KEGG pathways analysis revealed that gene modules in TNBC with gain of miR-122 were related to cell cycle and DNA repair, while in TNBC with loss of miR-122 were enriched in cell cycle, proliferation, apoptosis and activation of cell migration and invasion. The expression of hub genes distinguished TNBC tumors with gain or loss of miR-122 from normal breast tissues. Furthermore, high levels of hub genes were associated with better OS in TNBC patients. Interestingly, the gene coexpression network related to loss of miR-122 were enriched with target genes of miR-122, but this did not observed in those with gain of miR-122. Target genes of miR-122 are oncogenes mainly associated with cell differentiation-related processes. Finally, 75 genes were identified exclusively associated to loss of miR-122, which are also implicated in cell differentiation. In conclusion, miR-122 could act as tumor suppressor by controlling oncogenes in TNBC.

Profiles of Expression of SAV1 in Normoxia or Hypoxia Microenviroment are Associated with Breast Cancer Prognosis.

BACKGROUND: In breast cancer (BC), hypoxia is associated with poor prognosis. Protein Salvador homolog 1 (SAV1) acts as a tumor suppressor and is downregulated in the cancer cells. However, there is limited data on the expression profile of SAV1 and its importance in BC. It has not been studied to evaluate this phenomenon in a hypoxic microenvironment yet. AIM: This study aimed to investigate SAV1 expression profiles under normoxia and hypoxia, and the potential of SAV1 in BC prognosis. METHODS: Gene and protein expression analyses were performed using Real-Time quantitative PCR (RT-qPCR) and immunocytochemistry (ICC), respectively, and in silico analyses were performed using The Cancer Genome Atlas (TCGA). The survival curves were constructed using KMplotter. RESULTS: SAV1 expression was lower in BC samples and tumor cell lines than in normal samples. The SAV1 mRNA levels were reduced in hypoxic estrogen receptor positive (ER+) tumors, which were associated with a lower survival probability as compared to normoxic ER+ tumors. Furthermore, lower levels of SAV1 were found in advanced cancer stage samples, which are associated with worse survival curves and can be a risk factor for BC. CONCLUSIONS: These data suggest a potential prognostic role of SAV1 in BC, with lower expressions associated with worse prognosis.

The hsa-miR-516a-5p and hsa-miR-516b-5p microRNAs reduce the migration and invasion on T98G glioblastoma cell line.

microRNAs (miRNAs) are involved in numerous functions and processes in the brain and other organs through the regulation of gene and protein expression. miRNA dysregulation is associated with the development of several diseases, including the brain and Central Nervous System cancer (CNS). The hsa-miR-516a-5p and hsa-miR-516b-5p are involved in proliferation, migration, and invasion in different tumor models, but their antitumor effect has not been evaluated in cancer of CNS. Therefore, we aimed to assess the effect of the miRNAs hsa-miR-516a-5p and miRNA hsa-miR-516b-5p on the Glioblastoma cell line (T98G). We used synthetic miRNA mimics to induce the overexpression of both miRNAs in the cell line, which was corroborated by RT-qPCR. Next, we evaluated the effect on proliferation, migration, and invasion using the CyQuant direct kit, ThinCert ™ inserts and invasion BioCoat ™ Matrigel® Invasion Chambers. We found upregulation of these miRNAs induced significant changes on the migration and invasion processes of T98G cells, but not affected the proliferation rate. These results suggest that both microRNAs could be playing an important role in the control of tumor progression towards metastasis. The bioinformatics analysis showed that target genes for these miRNAs are involved in different biological processes such as in cell adhesion molecule binding and cell junction disassembly, which are important for cancer progression. Further studies and experimental validation are needed to identify the genes regulated by microRNAs.

Autopsy findings of acute erythroid leukemia

ABSTRACT Acute erythroid leukemia (AEL) is an exceedingly uncommon but distinct hematological malignancy that shows neoplastic proliferation of erythroid precursors with maturation arrest and no significant myeloblasts. We describe an autopsy case of this rare entity in a 62-year-old man with co-morbidities. He underwent a bone marrow (BM) examination for pancytopenia during the first outpatient department visit, which revealed an increased number of erythroid precursors with dysmegakaryopoiesis suggesting the possibility of Myelodysplastic syndromes (MDS). Thereafter, his cytopenia got worsened, warranting blood and platelet transfusions. Four weeks later on the second BM examination, AEL was diagnosed based on morphology and immunophenotyping. Targeted resequencing for myeloid mutations revealed TP53 and DNMT3A mutations. He was initially managed along febrile neutropenia with the stepwise escalation of antibiotics. He developed hypoxia attributed to anemic heart failure. Subsequently, he had hypotension and respiratory fatigue pre-terminally and succumbed to his Illness. A complete autopsy showed infiltration of various organs by AEL and leukostasis. Besides, there was extramedullary hematopoiesis, arterionephrosclerosis, diabetic nephropathy (ISN-RPS class II), mixed dust pneumoconiosis, and pulmonary arteriopathy. The histomorphology of AEL was challenging, and the differential diagnoses were many. Thus, this case highlights the autopsy pathology of AEL, an uncommon entity with a strict definition, and its relevant differentials.

A novel mutation in the TSC2 gene protects against colorectal cancer in the Mexican population.

INTRODUCTION: Colorectal cancer (CRC) is a complex disease due to the large number of factors that influence its development, including variants in tumor suppressor genes. OBJECTIVE: To estimate allelic and genotypic frequencies of c.3915G>A and c.5371G>A variants of the TSC2 gene in a Mexican population with CRC, as well as to analyze their association with the development of CRC. METHODS: 126 peripheral blood samples from patients diagnosed with sporadic CRC and 134 from healthy individuals, regarded as the control group, were included. Identification of genotypes was carried out using traditional PCR and enzymatic digestion. All individuals signed an informed consent letter. RESULTS: The A allele of the c.3915G>A variant (OR = 0.31, 95% CI = 0.15-0.69, p = 0.004), as well as A/G haplotype of the c.3915G>A and c.5371G>A variants (OR = 0.28, 95% CI = 0.12-0.68, p = 0.005) showed a possible protective effect against sporadic CRC. In silico analysis indicated that both variants generate modifications in the splicing process. CONCLUSION: The presence of TSC2 gene c.3915G>A variant suggests a possible protective effect against sporadic CRC in the Mexican population; however, no association was observed with the c.5371G>A variant.

INTRODUCCIÓN: El cáncer colorrectal (CCR) es una enfermedad compleja debido al gran número de factores que influyen en su desarrollo, incluyendo variantes en genes supresores de tumores. OBJETIVO: Estimar las frecuencias alélicas y genotípicas de las variantes c.3915G>A y c.5371G>A del gen TSC2 en una población mexicana con CCR, así como analizar la asociación con el desarrollo de CCR. MÉTODOS: Se incluyeron 126 muestras de sangre periférica de pacientes con diagnóstico de CCR esporádico y 134 de individuos sanos, considerados como grupo de control. La identificación de los genotipos se llevó a cabo mediante PCR tradicional y digestión enzimática. Todos los individuos firmaron una carta de consentimiento informado. RESULTADOS: El alelo A de la variante c.3915G>A (RM = 0.31, IC 95 % = 0.15-0.69, p = 0.004), así como el haplotipo A/G de las variantes c.3915G>A y c.5371G>A (RM = 0.28, IC 95 % = 0.12-0.68, p = 0.005) mostraron un posible efecto protector contra CCR esporádico. El análisis in silico indicó que ambas variantes generan modificaciones en el proceso de corte y empalme. CONCLUSIÓN: La presencia de la variante c.3915G>A del gen TSC2 sugiere un posible efecto protector contra CCR esporádico en población mexicana; sin embargo, no se observó esta asociación con la variante c.5371G>A.

The chameleonic behavior of p53 in health and disease: the transition from a client to an aberrant condensate scaffold in cancer.

In 1972, the Weber statement, "The multiplicity of interactions and the variety of effects that follow from them show that multimer proteins are unlikely to be limited to a minimal number of allowed conformations," first addressed the dynamic nature of proteins. This idea serves as a foundation for understanding why several macromolecules, such as p53, exhibit the properties of a molecular chameleon. Functionally competent states comprise a myriad of p53 three-dimensional arrangements depending on the stimuli. For instance, the interaction of p53 with nuclear components could induce liquid-liquid phase separation (LLPS) and the formation of membraneless organelles. The functional or deleterious role of p53 in liquid droplets is still unclear. Functional aspects display p53 interconverting between droplets and tetramer with its functional abilities maintained. In contrast, the aberrant phase separation is likely to fuel the aggregation path, usually associated with the onset and progression of age-related neurodegenerative diseases and cancer. Here, we gathered the most relevant aspects that lead p53 to phase separation and the resulting structural effects, attempting to understand p53's functional and disease-relevant processes. Aberrant phase separation and aggregation of mutant p53 have become important therapeutic targets against cancer.

Nueva mutación en el gen TSC2 protege contra el cáncer colorrectal en población mexicana / A novel mutation in the TSC2 gene protects against colorectal cancer in the Mexican population

Resumen Introducción: El cáncer colorrectal (CCR) es una enfermedad compleja debido al gran número de factores que influyen en su desarrollo, incluyendo variantes en genes supresores de tumores. Objetivo: Estimar las frecuencias alélicas y genotípicas de las variantes c.3915G>A y c.5371G>A del gen TSC2 en una población mexicana con CCR, así como analizar la asociación con el desarrollo de CCR. Métodos: Se incluyeron 126 muestras de sangre periférica de pacientes con diagnóstico de CCR esporádico y 134 de individuos sanos, considerados como grupo de control. La identificación de los genotipos se llevó a cabo mediante PCR tradicional y digestión enzimática. Todos los individuos firmaron una carta de consentimiento informado. Resultados: El alelo A de la variante c.3915G>A (RM = 0.31, IC 95 % = 0.15-0.69, p = 0.004), así como el haplotipo A/G de las variantes c.3915G>A y c.5371G>A (RM = 0.28, IC 95 % = 0.12-0.68, p = 0.005) mostraron un posible efecto protector contra CCR esporádico. El análisis in silico indicó que ambas variantes generan modificaciones en el proceso de corte y empalme. Conclusión: La presencia de la variante c.3915G>A del gen TSC2 sugiere un posible efecto protector contra CCR esporádico en población mexicana; sin embargo, no se observó esta asociación con la variante c.5371G>A.

Abstract Introduction: Colorectal cancer (CRC) is a complex disease due to the large number of factors that influence its development, including variants in tumor suppressor genes. Objective: To estimate allelic and genotypic frequencies of c.3915G>A and c.5371G>A variants of the TSC2 gene in a Mexican population with CRC, as well as to analyze their association with the development of CRC. Methods: 126 peripheral blood samples from patients diagnosed with sporadic CRC and 134 from healthy individuals, regarded as the control group, were included. Identification of genotypes was carried out using traditional PCR and enzymatic digestion. All individuals signed an informed consent letter. Results: The A allele of the c.3915G>A variant (OR = 0.31, 95% CI = 0.15-0.69, p = 0.004), as well as A/G haplotype of the c.3915G>A and c.5371G>A variants (OR = 0.28, 95% CI = 0.12-0.68, p = 0.005) showed a possible protective effect against sporadic CRC. In silico analysis indicated that both variants generate modifications in the splicing process. Conclusion: The presence of TSC2 gene c.3915G>A variant suggests a possible protective effect against sporadic CRC in the Mexican population; however, no association was observed with the c.5371G>A variant.