Microbiota dynamics preceding bariatric surgery as obesity treatment: a comprehensive review.

The review present data on the intricate relationship between bariatric surgery, gut microbiota, and metabolic health in obesity treatment. Bariatric surgery, is recognized as an effective intervention for managing morbid obesity, including various techniques with distinct mechanisms of action, efficacy, and safety profiles including Roux-en-Y Gastric Bypass (RYGB), Sleeve Gastrectomy (SG), Laparoscopic Adjustable Gastric Banding (LAGB), and Biliopancreatic Diversion (BPD). RYGB and SG are the most prevalent procedures globally, inducing gut microbiota changes that influence microbial diversity and abundance. Post-surgery, alterations in bacterial communities occur, such as the increased of Escherichia coli inversely correlated with fat mass and leptin levels. During digestion, microbiota produce physiologically active compounds like bile acids (Bas) and short-chain fatty acids (SCFAs). SCFAs, derived by microbial fermentation, influence appetite, energy metabolism, and obesity-related pathways. Bas, altered by surgery, modulate glucose metabolism and insulin sensitivity. Furthermore, SG and RYGB enhance incretin secretion, particularly glucagon-like peptide 1 (GLP-1). Therefore, understanding microbiota changes after bariatric surgery could be crucial for predicting metabolic outcomes and developing targeted interventions for obesity management.

Thyroid cancer in Ecuador: A genetic variants review and a cross-sectional population-based analysis before and after COVID-19 pandemic.

Objectives: The purpose of this study is to describe the genetic variants present in the Ecuadorian population and the incidence and mortality patterns of thyroid cancer in Ecuador from 2016 to 2021. Methods: The present research constitutes a nationwide cross-sectional study encompassing all reported cases of thyroid cancer (C-73) in Ecuador from 2016 to 2021. Incidence rates were calculated based on the annual population at risk, considering factors such as ethnicity, sex, age group, and the geographic location of the incidence. All data was collected from the Hospital Discharge Statistics and the Statistical Registry of General Deaths Databases. Results: Between 2016 and 2021, a total of 20,297 hospital admissions and 921 deaths attributed to thyroid cancer were reported in Ecuador. The incidence of thyroid cancer remained relatively stable from 2016 to 2019. However, there was a notable decrease in 2020, followed by an increase in 2021. Notably, thyroid cancer prevalence rates were found to be higher in highlands regions. Moreover, two genetic variants, the BRAFV600E and KITL678F, have been identified in the Ecuadorian population. It is noteworthy that women exhibited a higher susceptibility to thyroid cancer, being five times more likely than men to develop this condition. Conclusion: Ecuador exhibits one of the highest global incidences of thyroid cancer. Consequently, describing the genetic variants and epidemiological characteristics of thyroid cancer is imperative for enhancing healthcare access and formulating evidence-based public health policies. This research contributes towards a comprehensive understanding of thyroid cancer in the Ecuadorian context, aiming to improve targeted interventions and health outcomes.

Population-Specific Distribution of TPMT Deficiency Variants and Ancestry Proportions in Ecuadorian Ethnic Groups: Towards Personalized Medicine.

Purpose: Thiopurine S-methyltransferase (TPMT) is an enzyme that metabolizes purine analogs, agents used in the treatment of acute lymphoblastic leukemia. Improper drug metabolism leads to toxicity in chemotherapy patients and reduces treatment effectiveness. TPMT variants associated with reduced enzymatic activity vary across populations. Therefore, studying these variants in heterogeneous populations, such as Ecuadorians, can help identify molecular causes of deficiency for this enzyme. Methods: We sequenced the entire TPMT coding region in 550 Ecuadorian individuals from Afro-Ecuadorian, Indigenous, Mestizo, and Montubio ethnicities. Moreover, we conducted an ancestry analysis using 46 informative ancestry markers. Results: We identified 8 single nucleotide variants in the coding region of TPMT. The most prevalent alleles were TPMT*3A, TPMT*3B, and TPMT*3C, with frequencies of 0.055, 0.012, and 0.015, respectively. Additionally, we found rare alleles TPMT*4 and TPMT*8 with frequencies of 0.005 and 0.003. Correlating the ancestry proportions with TPMT-deficient genotypes, we observed that the Native American ancestry proportion influenced the distribution of the TPMT*1/TPMT*3A genotype (OR = 5.977, p = 0.002), while the contribution of African ancestral populations was associated with the TPMT*1/TPMT*3C genotype (OR = 9.769, p = 0.003). The rates of TPMT-deficient genotypes observed in Mestizo (f = 0.121) and Indigenous (f = 0.273) groups provide evidence for the influence of Native American ancestry and the prevalence of the TPMT*3A allele. In contrast, although Afro-Ecuadorian groups demonstrate similar deficiency rates (f = 0.160), the genetic factors involved are associated with contributions from African ancestral populations, specifically the prevalent TPMT*3C allele. Conclusion: The distribution of TPMT-deficient variants offers valuable insights into the populations under study, underscoring the necessity for genetic screening strategies to prevent thiopurine toxicity events among Latin American minority groups.

Associations of MYPN, TTN, SCN5A, MYO6 and ELN Mutations With Arrhythmias and Subsequent Sudden Cardiac Death: A Case Report of an Ecuadorian Individual.

Cardiac pathologies are among the most frequent causes of death worldwide. Regarding cardiovascular deaths, it is estimated that 5 million cases are caused by sudden cardiac death (SCD) annually. The primary cause of SCD is ventricular arrhythmias. Genomic studies have provided pathogenic, likely pathogenic, and variants of uncertain significance that may predispose individuals to cardiac causes of sudden death. In this study, we describe the case of a 43-year-old individual who experienced an episode of aborted SCD. An implantable cardioverter defibrillator was placed to prevent further SCD episodes. The diagnosis was ventricular fibrillation. Genomic analysis revealed some variants in the MYPN (pathogenic), GCKR (likely pathogenic), TTN (variant of uncertain significance), SCN5A (variant of uncertain significance), MYO6 (variant of uncertain significance), and ELN (variant of uncertain significance) genes, which could be associated with SCD episodes. In addition, a protein-protein interaction network was obtained, with proteins related to ventricular arrhythmia and the biological processes involved. Therefore, this study identified genetic variants that may be associated with and trigger SCD in the individual. Moreover, genetic variants of uncertain significance, which have not been reported, could contribute to the genetic basis of the disease.

Genetic diet interactions of ACE: the increased hypertension predisposition in the Latin American population.

Hypertension is one of the primary risk factors associated with cardiovascular diseases (CVDs). It is a condition that affects people worldwide, and its prevalence is increasing due to several factors, such as lack of physical activity, population aging, and unhealthy diets. Notably, this increase has primarily occurred in low and middle-income countries (LMICs). In Latin America, approximately 40% of adults have been diagnosed with hypertension. Moreover, reports have shown that the Latin American genetic composition is highly diverse, and this genetic background can influence various biological processes, including disease predisposition and treatment effectiveness. Research has shown that Western dietary patterns, which include increased consumption of red meat, refined grains, sugar, and ultra-processed food, have spread across the globe, including Latin America, due to globalization processes. Furthermore, a higher than recommended sodium consumption, which has been associated with hypertension, has been identified across different regions, including Asia, Europe, America, Oceania, and Africa. In conclusion, hypertension is a multifactorial disease involving environmental and genetic factors. In Latin America, hypertension prevalence is increasing due to various factors, including age, the adoption of a "Westernized" diet, and potential genetic predisposition factors involving the ACE gene. Furthermore, identifying the genetic and molecular mechanisms of the disease, its association with diet, and how they interact is essential for the development of personalized treatments to increase its efficacy and reduce side effects.

The Autosomal Short Tandem Repeat Polymorphisms Are Potentially Associated with Cardiovascular Disease Predisposition in the Latin American Population: A Mini Review.

According to the World Health Organization, cardiovascular diseases (CVDs) are the leading cause of death worldwide across nearly all ethnic groups. Inherited cardiac conditions comprise a wide spectrum of diseases that affect the heart, including abnormal structural features and functional impairments. In Latin America, CVDs are the leading cause of death within the region. Factors such as population aging, unhealthy diet, obesity, smoking, and a sedentary lifestyle have increased the risk of CVD. The Latin American population is characterized by its diverse ethnic composition with varying percentages of each ancestral component (African, European, and Native American ancestry). Short tandem repeats (STRs) are DNA sequences with 2-6 base pair repetitions and constitute ~3% of the human genome. Importantly, significant allele frequency variations exist between different populations. While studies have described that STRs are in noncoding regions of the DNA, increasing evidence suggests that simple sequence repeat variations may be critical for proper gene activity and regulation. Furthermore, several STRs have been identified as potential disease predisposition markers. The present review is aimed at comparing and describing the frequencies of autosomal STR polymorphisms potentially associated with cardiovascular disease predisposition in Latin America compared with other populations.

Molecular pathways and nutrigenomic review of insulin resistance development in gestational diabetes mellitus.

Gestational diabetes mellitus is a condition marked by raised blood sugar levels and insulin resistance that usually occurs during the second or third trimester of pregnancy. According to the World Health Organization, hyperglycemia affects 16.9% of pregnancies worldwide. Dietary changes are the primarily alternative treatment for gestational diabetes mellitus. This paper aims to perform an exhaustive overview of the interaction between diet, gene expression, and the metabolic pathways related to insulin resistance. The intake of foods rich in carbohydrates can influence the gene expression of glycolysis, as well as foods rich in fat, can disrupt the beta-oxidation and ketogenesis pathways. Furthermore, vitamins and minerals are related to inflammatory processes regulated by the TLR4/NF-κB and one carbon metabolic pathways. We indicate that diet regulated gene expression of PPARα, NOS, CREB3L3, IRS, and CPT I, altering cellular physiological mechanisms and thus increasing or decreasing the risk of gestational diabetes. The alteration of gene expression can cause inflammation, inhibition of fatty acid transport, or on the contrary help in the modulation of ketogenesis, improve insulin sensitivity, attenuate the effects of glucotoxicity, and others. Therefore, it is critical to comprehend the metabolic changes of pregnant women with gestational diabetes mellitus, to determine nutrients that help in the prevention and treatment of insulin resistance and its long-term consequences.

Role of the gut microbiota in hematologic cancer.

Hematologic neoplasms represent 6.5% of all cancers worldwide. They are characterized by the uncontrolled growth of hematopoietic and lymphoid cells and a decreased immune system efficacy. Pathological conditions in hematologic cancer could disrupt the balance of the gut microbiota, potentially promoting the proliferation of opportunistic pathogens. In this review, we highlight studies that analyzed and described the role of gut microbiota in different types of hematologic diseases. For instance, myeloma is often associated with Pseudomonas aeruginosa and Clostridium leptum, while in leukemias, Streptococcus is the most common genus, and Lachnospiraceae and Ruminococcaceae are less prevalent. Lymphoma exhibits a moderate reduction in microbiota diversity. Moreover, certain factors such as delivery mode, diet, and other environmental factors can alter the diversity of the microbiota, leading to dysbiosis. This dysbiosis may inhibit the immune response and increase susceptibility to cancer. A comprehensive analysis of microbiota-cancer interactions may be useful for disease management and provide valuable information on host-microbiota dynamics, as well as the possible use of microbiota as a distinguishable marker for cancer progression.

The Molecular Mechanisms of the Relationship between Insulin Resistance and Parkinson's Disease Pathogenesis.

Parkinson's disease (PD) is a degenerative condition resulting from the loss of dopaminergic neurons. This neuronal loss leads to motor and non-motor neurological symptoms. Most PD cases are idiopathic, and no cure is available. Recently, it has been proposed that insulin resistance (IR) could be a central factor in PD development. IR has been associated with PD neuropathological features like α-synuclein aggregation, dopaminergic neuronal loss, neuroinflammation, mitochondrial dysfunction, and autophagy. These features are related to impaired neurological metabolism, neuronal death, and the aggravation of PD symptoms. Moreover, pharmacological options that involve insulin signaling improvement and dopaminergic and non-dopaminergic strategies have been under development. These drugs could prevent the metabolic pathways involved in neuronal damage. All these approaches could improve PD outcomes. Also, new biomarker identification may allow for an earlier PD diagnosis in high-risk individuals. This review describes the main pathways implicated in PD development involving IR. Also, it presents several therapeutic options that are directed at insulin signaling improvement and could be used in PD treatment. The understanding of IR molecular mechanisms involved in neurodegenerative development could enhance PD therapeutic options and diagnosis.

The Impact of a Very-Low-Calorie Ketogenic Diet in the Gut Microbiota Composition in Obesity.

The very-low-calorie KD (VLCKD) is characterized by a caloric intake of under 800 kcal/day divided into less than 50 g/day of carbohydrate (13%) and 1 to 1.5 g of protein/kg of body weight (44%) and 43% of fat. This low carbohydrate intake changes the energy source from glucose to ketone bodies. Moreover, clinical trials have consistently shown a beneficial effect of VLCKD in several diseases, such as heart failure, schizophrenia, multiple sclerosis, Parkinson's, and obesity, among others. The gut microbiota has been associated with the metabolic conditions of a person and is regulated by diet interactions; furthermore, it has been shown that the microbiota has a role in body weight homeostasis by regulating metabolism, appetite, and energy. Currently, there is increasing evidence of an association between gut microbiota dysbiosis and the pathophysiology of obesity. In addition, the molecular pathways, the role of metabolites, and how microbiota modulation could be beneficial remain unclear, and more research is needed. The objective of the present article is to contribute with an overview of the impact that VLCKD has on the intestinal microbiota composition of individuals with obesity through a literature review describing the latest research regarding the topic and highlighting which bacteria phyla are associated with obesity and VLCKD.

Identification of mutations on the EMD and EYA4 genes associated with Emery-Dreifuss muscular dystrophy and deafness: a case report.

Introduction: Hearing loss is the most common sensory disability, and it is estimated that 50% of cases are caused by genetic factors. One of the genes associated with deafness is the eyes absent homolog 4 (EYA4) gene, a transcription factor related to the development and function of the inner ear. Emery-Dreifuss muscular dystrophy is a rare inherited disease characterized by atrophy and weakness of the humeroperoneal muscles, multi-joint contractures, and cardiac manifestations. It is inherited in an autosomal-dominant, X-linked, or less frequently autosomal recessive manner; one of the genes associated with EDMD is the emerin (EMD) gene. Case description: A total of two Ecuadorian siblings aged 57 (Subject A) and 55 (Subject B) were diagnosed with deafness and an unspecified type of muscular dystrophy based on family history and clinical findings. Next-generation sequencing (NGS) using the TruSight Cardio and Inherited Disease kits at the Centro de Investigación Genética y Genómica CIGG, Universidad UTE, was performed. The genetic analyses showed two mutations: a stop mutation in exon 11/20 (NM_004100.4:c.940G>T) of the EYA4 gene and a missense mutation in exon 6 (NM_000117.2:c.548C>G) of the EMD gene. Discussion and conclusion: The in silico predictions described the EYA4 variant as likely pathogenic and the EMD variant as a variant of uncertain significance (VUS). Moreover, an ancestry analysis was performed using 46 Ancestry Informative Insertion/Deletion Markers (AIM-InDels), and the ancestral composition of subject A was 46% African, 26.1% European, and 27.9% American Indian ancestry, whereas the ancestral composition of subject B was 41.3% African, 38.2% European, and 20.5% American Indian ancestry. The present case report describes two Ecuadorian siblings with a mainly African ancestral component, muscular dystrophy, and deafness phenotypes. Moreover, using next-generation sequencing (NGS), a mutation in the EMD and a novel mutation in EYA4 genes possibly associated with the subjects' phenotype were identified and discussed.

Genomic analysis of a novel pathogenic variant in the gene LMNA associated with cardiac laminopathies found in Ecuadorian siblings: A case report.

Introduction: Cardiac laminopathies are caused by mutations in the LMNA gene and include a wide range of clinical manifestations involving electrical and mechanical changes in cardiomyocytes. In Ecuador, cardiovascular diseases were the primary cause of death in 2019, accounting for 26.5% of total deaths. Cardiac laminopathy-associated mutations involve genes coding for structural proteins with functions related to heart development and physiology. Family description: Two Ecuadorian siblings, self-identified as mestizos, were diagnosed with cardiac laminopathies and suffered embolic strokes. Moreover, by performing Next-Generation Sequencing, a pathogenic variant (NM_170707.3:c.1526del) was found in the gene LMNA. Discussion and conclusion: Currently, genetic tests are an essential step for disease genetic counseling, including cardiovascular disease diagnosis. Identification of a genetic cause that may explain the risk of cardiac laminopathies in a family can help the post-test counseling and recommendations from the cardiologist. In the present report, a pathogenic variant ((NM_170707.3:c.1526del) has been identified in two Ecuadorian siblings with cardiac laminopathies. The LMNA gene codes for A-type laminar proteins that are associated with gene transcription regulation. Mutations in the LMNA gene cause laminopathies, disorders with diverse phenotypic manifestations. Moreover, understanding the molecular biology of the disease-causing mutations is essential in deciding the correct type of treatment.

Differential microRNA expression for diagnosis and prognosis of papillary thyroid cancer.

Papillary thyroid cancer accounts for 85% of thyroid cancer. The diagnosis is based on ultrasound methods and tumor biopsies (FNA). In recent years, research has revealed the importance of miRNAs, non-coding RNA molecules that regulate gene expression and are involved in many diseases. The present mini review describes upregulated and downregulated miRNAs expression in papillary thyroid cancer patient samples (tissue, serum, plasma) and the genes regulated by these non-coding molecules. In addition, a bibliographic search was performed to identify the expression of miRNAs that are common in tumor tissue and blood. The miRNAs miR-146b, miR-221-3p, miRNA 222, miR-21, miR-296-5p, and miR-145 are common in both tissue and bloodstream of PTC patient samples. Furthermore, these miRNAs regulate genes involved in biological processes such as cell differentiation, proliferation, migration, invasion, and apoptosis. In conclusion, miRNAs could potentially become valuable biomarkers, which could help in the early diagnosis and prognosis of papillary thyroid cancer.

Avian Influenza: Strategies to Manage an Outbreak.

Avian influenza (AI) is a contagious disease among the poultry population with high avian mortality, which generates significant economic losses and elevated costs for disease control and outbreak eradication. AI is caused by an RNA virus part of the Orthomyxoviridae family; however, only Influenzavirus A is capable of infecting birds. AI pathogenicity is based on the lethality, signs, and molecular characteristics of the virus. Low pathogenic avian influenza (LPAI) virus has a low mortality rate and ability to infect, whereas the highly pathogenic avian influenza (HPAI) virus can cross respiratory and intestinal barriers, diffuse to the blood, damage all tissues of the bird, and has a high mortality rate. Nowadays, avian influenza is a global public health concern due to its zoonotic potential. Wild waterfowl is the natural reservoir of AI viruses, and the oral-fecal path is the main transmission route between birds. Similarly, transmission to other species generally occurs after virus circulation in densely populated infected avian species, indicating that AI viruses can adapt to promote the spread. Moreover, HPAI is a notifiable animal disease; therefore, all countries must report infections to the health authorities. Regarding laboratory diagnoses, the presence of influenza virus type A can be identified by agar gel immunodiffusion (AGID), enzyme immunoassay (EIA), immunofluorescence assays, and enzyme-linked immunoadsorption assay (ELISAs). Furthermore, reverse transcription polymerase chain reaction is used for viral RNA detection and is considered the gold standard for the management of suspect and confirmed cases of AI. If there is suspicion of a case, epidemiological surveillance protocols must be initiated until a definitive diagnosis is obtained. Moreover, if there is a confirmed case, containment actions should be prompt and strict precautions must be taken when handling infected poultry cases or infected materials. The containment measures for confirmed cases include the sanitary slaughter of infected poultry using methods such as environment saturation with CO2, carbon dioxide foam, and cervical dislocation. For disposal, burial, and incineration, protocols should be followed. Lastly, disinfection of affected poultry farms must be carried out. The present review aims to provide an overview of the avian influenza virus, strategies for its management, the challenges an outbreak can generate, and recommendations for informed decision making.

Human virome: Implications in cancer.

In recent years, the human virome has gained importance, especially after the SARS-CoV-2 pandemic, due to its possible involvement in autoimmune, inflammatory diseases, and cancer. Characterization of the human virome can be carried out by shotgun next-generation sequencing (metagenomics), which allows the identification of all viral communities in an environmental sample and the discovery of new viral families not previously described. Variations in viral quantity and diversity have been associated with disease development, mainly due to their effect on gut bacterial microbiota. Phages can regulate bacterial flora through lysogeny; this is associated with increased susceptibility to infections, chronic inflammation, or cancer. The virome characterization in different human body ecological niches could help elucidate these particles' role in disease. Hence, it is important to understand the virome's influence on human health and disease. The present review highlights the significance of the human virome and how it is associated with disease, focusing on virome composition, characterization, and its association with cancer.

Genetics, genomics, and diet interactions in obesity in the Latin American environment.

Obesity is a chronic disease characterized by abnormal or excessive fat accumulation that could impact an individual's health; moreover, the World Health Organization (WHO) has declared obesity a global epidemic since 1997. In Latin America, in 2016, reports indicated that 24.2% of the adult population was obese. The environmental factor or specific behaviors like dietary intake or physical activity have a vital role in the development of a condition like obesity, but the interaction of genes could contribute to that predisposition. Hence, it is vital to understand the relationship between genes and disease. Indeed, genetics in nutrition studies the genetic variations and their effect on dietary response; while genomics in nutrition studies the role of nutrients in gene expression. The present review represents a compendium of the dietary behaviors in the Latin American environment and the interactions of genes with their single nucleotide polymorphisms (SNPs) associated with obesity, including the risk allele frequencies in the Latin American population. Additionally, a bibliographical selection of several studies has been included; these studies examined the impact that dietary patterns in Latin American environments have on the expression of numerous genes involved in obesity-associated metabolic pathways.

Case report: Genomic screening for inherited cardiac conditions in Ecuadorian mestizo relatives: Improving familial diagnose.

Introduction: Genomic screening is an informative and helpful tool for the clinical management of inherited conditions such as cardiac diseases. Cardiac-inherited diseases are a group of disorders affecting the heart, its system, function, and vasculature. Among the cardiac inherited abnormalities, one of the most common is Wolff-Parkinson-White syndrome. Similarly, hypertrophic cardiomyopathy is another common autosomal dominant inherited cardiac disease. Hypertrophic cardiomyopathy is associated with an increased incidence of Wolff-Parkinson-White syndrome; reports have suggested that it could be caused by a mutation in the protein-coding gene PRKAG2, which encodes a subunit of the AMP-activated protein kinase. Case presentation: A 37-year-old Ecuadorian male (Subject A) with familiar history of bradycardia, cardiac pacemaker implantation, and undiagnosed cardiac conditions began with episodes of tachycardia, dizziness, shortness of breath, and a feeling of fainting. He was diagnosed with hypertrophic myocardiopathy and Wolff Parkinson White preexcitation syndrome. Furthermore, his cousin's son, an 18-year-old Ecuadorian male (Subject B), started suffering from migraine and tachycardia at any time of the day. He was diagnosed with hypertrophic myocardiopathy; his electrocardiogram showed a systolic overload. Next-generation sequencing and ancestry analyses were performed. A c.905G>A p.(Arg302Gln) mutation in the gene PRKAG2 and a mainly European composition were identified in both subjects. Conclusion: Genetic testing is a valuable tool as it can provide important information regarding a disease, including its cause and consequences, not only for single individuals but to identify at-risk relatives. Furthermore, NGS results could guide the physician into targeted therapy. In the present case report, a missense pathogenic Arg302Gln mutation in the PRKAG2 gene has been identified in two related Ecuadorian Subjects diagnosed with hypertrophic myocardiopathy and Wolff-Parkinson-White. The variant has not been reported in Latin America; hence, this is the first report of the Arg302Gln mutation in the PRKAG2 gene in mestizo Ecuadorian subjects with mainly European ancestry components.

Clinical, cytogenetic, and genomic analyses of an Ecuadorian subject with Klinefelter syndrome, recessive hemophilia A, and 1;19 chromosomal translocation: a case report.

BACKGROUND: Hemophilia A is considered one of the most common severe hereditary disorders. It is an X-linked recessive disease caused by a deficiency or lack of function of the blood clotting factor VIII. Klinefelter syndrome is a genetic disorder that affects male individuals due to one or more extra X chromosomes, present in all cells or with mosaicism. The aneuploidy is due to either mitotic or meiotic chromosome non-disjunction. Chromosomal translocations are a group of genome abnormalities in which a region or regions of a chromosome break and are transferred to a nonhomologous chromosome or a new location in the same chromosome. CASE PRESENTATION: Our subject was born in Ecuador at 36 weeks of gestation by vaginal delivery. At 3 months old, the Factor VIII activity measure showed a 23.7% activity indicating a diagnosis of mild hemophilia A. At 1 year old, the karyotype showed an extra X chromosome, consistent with a diagnosis of Klinefelter syndrome, and a translocation between the long arms of chromosomes 1 and 19, at positions q25 and q13, respectively. CONCLUSIONS: Klinefelter syndrome and hemophilia are a rare combination. In the present case report, the subject presents both, meaning that he has inherited one X chromosome from the father and one X chromosome from the mother. Since the father has severe hemophilia A; and the subject presents a below 40% Factor VIII activity, a skewed X inactivation is suggested. Additionally, the proband presents a translocation with the karyotype 47,XXY,t(1;19)(q25;q13). No similar report with phenotypic consequences of the translocation was found. The present report highlights the importance of a correct diagnosis, based not only on the clinical manifestations of a disease but also on its genetic aspects, identifying the value of integrated diagnostics. The subject presents three different genetic alterations, Klinefelter syndrome, hemophilia A, and a 1;19 chromosomal translocation.

The close interaction between hypoxia-related proteins and metastasis in pancarcinomas.

Many primary-tumor subregions exhibit low levels of molecular oxygen and restricted access to nutrients due to poor vascularization in the tissue, phenomenon known as hypoxia. Hypoxic tumors are able to regulate the expression of certain genes and signaling molecules in the microenvironment that shift it towards a more aggressive phenotype. The transcriptional landscape of the tumor favors malignant transformation of neighboring cells and their migration to distant sites. Herein, we focused on identifying key proteins that participate in the signaling crossroads between hypoxic environment and metastasis progression that remain poorly defined. To shed light on these mechanisms, we performed an integrated multi-omics analysis encompassing genomic/transcriptomic alterations of hypoxia-related genes and Buffa hypoxia scores across 17 pancarcinomas taken from the PanCancer Atlas project from The Cancer Genome Atlas consortium, protein-protein interactome network, shortest paths from hypoxia-related proteins to metastatic and angiogenic phenotypes, and drugs involved in current clinical trials to treat the metastatic disease. As results, we identified 30 hypoxia-related proteins highly involved in metastasis and angiogenesis. This set of proteins, validated with the MSK-MET Project, could represent key targets for developing therapies. The upregulation of mRNA was the most prevalent alteration in all cancer types. The highest frequencies of genomic/transcriptomic alterations and hypoxia score belonged to tumor stage 4 and positive metastatic status in all pancarcinomas. The most significantly associated signaling pathways were HIF-1, PI3K-Akt, thyroid hormone, ErbB, FoxO, mTOR, insulin, MAPK, Ras, AMPK, and VEGF. The interactome network revealed high-confidence interactions among hypoxic and metastatic proteins. The analysis of shortest paths revealed several ways to spread metastasis and angiogenesis from hypoxic proteins. Lastly, we identified 23 drugs enrolled in clinical trials focused on metastatic disease treatment. Six of them were involved in advanced-stage clinical trials: aflibercept, bevacizumab, cetuximab, erlotinib, ipatasertib, and panitumumab.