Pancreatic Cancer: Genetic Conditions and Epigenetic Alterations.

BACKGROUND: Pancreatic cancer is a lethal proliferative disease driven by multiple genetic and epigenetic alterations. Microarrays and omics-based sequencing techniques are potent tools that have facilitated a broader understanding of the complex biological processes that drive pancreatic ductal adenocarcinoma (PDAC). In turn, these tools have resulted in the identification of novel disease markers, prognostic factors, and therapeutic targets. Herein, we provide a review of the genetic and epigenetic drivers of PDAC relative to recent discoveries that impact patient management. METHODS: A review of PubMed, Medline, Clinical Key, and Index Medicus was conducted to identify literature from January 1995 to July 2022 that is related to PDAC genetics and epigenetics. Articles in Spanish and English were considered during selection. RESULTS: Molecular, genetic, and epigenetic diagnostic tools, novel biomarkers, and promising therapeutic targets have emerged in the treatment of pancreatic cancer. The implementation of microarray technology and application of large omics-based data repositories have facilitated recent discoveries in PDAC. Multiple molecular analyses based on RNA interference have been instrumental in the identification of novel therapeutic targets for patients with PDAC. Moreover, microarrays and next-generation omics-based discoveries have been instrumental in the characterization of subtypes of pancreatic cancer, thereby improving prognostication and refining patient selection for available targeted therapies. CONCLUSION: Advances in molecular biology, genetics, and epigenetics have ushered in a new era of discovery in the pathobiology of PDAC. Current efforts are underway to translate these findings into clinical tools and therapies to improve outcomes in patients with PDAC.

Metabolic-associated Fatty Liver Disease Regulation through Nutri Epigenetic Methylation.

Metabolically associated fatty liver disease, formerly called nonalcoholic fatty liver disease, is the most common liver disease globally, representing the third cause of liver transplantation. Metabolically associated fatty liver disease is defined as having more than 5% lipid droplets in hepatocytes without other concomitant liver diseases. Various stimuli such as the secretion of inflammatory cytokines, mitochondrial and endoplasmic reticulum dysfunction due to oxidative stress, alteration of the intestine-liver axis, bacterial dysbiosis, as well as genetic and epigenetic factors can modify the progression of metabolically associated fatty liver disease to fibrosis, cirrhosis, and may reach hepatocellular carcinoma. Epigenetics is responsible for a highly sophisticated regulatory system that controls many cellular processes in response to multiple environmental factors as an adaptive mechanism unrelated to alterations in the primary deoxyribonucleic acid sequence, including gene expression, microRNAs, DNA methylation, modifications in histones, and DNA-protein interactions. Several studies have shown that epigenetic changes are associated with various diseases, including metabolically associated fatty liver disease. Nutri epigenomics is the interaction between nutrition and components at the transcriptional or post-transcriptional level. Methylation processes involve micronutrients that regulate epigenetic states in a physiological and pathological context. Micronutrients such as methionine, folate, and choline are the main components of one-carbon metabolism, functioning as methyl group donors, and their deficiency predisposes to various pathologies such as metabolically associated fatty liver disease. Understanding of epigenetic modifiers leads us to develop new therapeutic therapies for patients with metabolically associated fatty liver disease.

Hepatic steatosis and respiratory diseases: a new panorama.

Non-alcoholic fatty liver disease is defined as hepatic fat accumulation in more than 5% of hepatocytes, without other liver steatosis causes. It comprises a broad spectrum that can range from benign steatosis and progress to non-alcoholic steatohepatitis, fibrosis, and ultimately hepatocellular carcinoma. Non-alcoholic fatty liver is considered a multisystemic disease since it is related to multiple disorders, such as type 2 diabetes mellitus, polycystic ovary syndrome, chronic kidney disease, psoriasis, osteoporosis, hypothyroidism, cardiovascular diseases, and obstructive sleep apnea syndrome; it is becoming increasingly clear that it is also a risk factor for developing certain respiratory diseases. This article aims to understand the liver and chronic obstructive pulmonary disease mechanisms, obstructive sleep apnea syndrome, asthma, and lung cancer. Given that non-alcoholic fatty liver disease has a considerable impact on the patient's well-being and life quality, as well as on the costs they generate for the country's health services, it is essential to continue research, especially in areas such as the respiratory tract, as there is much misinformation about it.

Non-alcoholic fatty liver disease and microRNAs expression, how it affects the development and progression of the disease.

The obesity pandemic that affects the global population generates one of the most unfavorable microenvironmental conditions in the hepatocyte, which triggers the metabolic hepatopathy known as non-alcoholic fatty liver; its annual rates increase in its prevalence and does not seem to improve in the future. The international consortia, LITMUS by the European Union and NIMBLE by the United States of America, have started a race for the development of hepatic steatosis and steatohepatitis reliable biomarkers to have an adequate diagnosis. MicroRNAs have been proposed as diagnostic and prognostic biomarkers involved in adaptation to changes in the liver microenvironment, which could improve clinical intervention strategies in patients with hepatic steatosis.

Cerebral hemodynamics in the non-alcoholic fatty liver.

INTRODUCTION AND OBJECTIVES: The association between non-alcoholic fatty liver disease and cerebral hemodynamics arises from cardiovascular damage mechanisms such as endothelial dysfunction, arterial wall increased stiffness, high thickness of the intimate index of the internal carotid artery, left ventricular hypertrophy, left diastolic dysfunction, calcification coronary arteries and increased epicardial fat. The multidirectional relationship between systemic inflammation and lipid metabolism constitutes a common and simultaneous mechanism that causes vascular damage. This study aims to provide insight into the relationship between non-alcoholic fatty liver disease and the function of systemic circulation and cerebral circulation using Doppler ultrasound. PATIENTS AND METHODS: Is an observational, cross-sectional, prospective, comparative study conducted at Medica Sur Hospital. Thirty-five patients were selected consecutively. The patients consulted neurological service for various symptoms without severity criteria, such as vertigo, primary headache and balance disturbances. RESULTS: There is a difference in the variables mean of the right MCA PI (p = 0.023), left MCA PI" (p = 0.004), and left VA PI (p = 0.036) between the control and NAFLD groups. The correlation analysis between these variables and the CAP showed a positive correlation of the three variables with the CAP, "right MCA PI" (r = 0.384), left MCA PI "(r = 0.509) and" left VA PI " (r = 0.551). CONCLUSIONS: This study demonstrates a subclinical process of the middle cerebral artery in subjects with NAFLD, which suggests it may be involved in the disease development and points the need to make decisions for this liver manifestation prevention and treatment.

Vitamin D deficiency in Mexicans have a high prevalence: a cross-sectional analysis of the patients from the Centro Médico Nacional 20 de Noviembre.

Disorders of vitamin D concentration (deficiency or insufficiency) are a global health problem, which are associated with various chronic diseases. In Latin America, alterations in vitamin D prevalence are different from those shown in previous studies and may be due to differences in geographic location, skin color, and diet type. PURPOSE: To know the prevalence of vitamin D insufficiency (21-29 ng/mL) and deficiency (< 20 ng/mL) in Mexican patients; although it is a risk factor for developing multiple complex diseases, its prevalence in the population is still unknown. METHODS: Cross-sectional study carried out at the endocrinology service of the highly specialized national center November 20. Data on cardiovascular risk factors were obtained and 25-hydroxy vitamin D was measured by chemiluminescence. Prevalence was calculated, and the results were analyzed to categorize the patients according to 25-hydroxy vitamin D deficient or insufficient levels. RESULTS: The mean value of the serum vitamin D concentration was 18.37 ng/mL. Of the 117 patients, 93.2% (n = 109) have decreased vitamin D values; 62.4% (n = 73) of the patients had vitamin D deficiency and 30.8% (n = 36) vitamin D insufficiency. The prevalence of vitamin D deficiency was 62.4% and 30.8% for vitamin D insufficiency. The total prevalence of alterations in vitamin D levels in this population was 93.2%. CONCLUSIONS: This study reports a prevalence of vitamin D deficiency and insufficiency much higher than those described by previous studies, which is of utmost importance for the population due to the morbidities associated with these alterations.

Polycystic ovary syndrome with feasible equivalence to overweight as a risk factor for non-alcoholic fatty liver disease development and severity in Mexican population.

INTRODUCTION AND OBJECTIVES: Polycystic ovary syndrome (PCOS) is the most common endocrinology disorder in women of reproductive age; these patients have a higher risk of suffering from non-alcoholic fatty liver disease (NAFLD). We determine the frequency of NAFLD in Mexican patients with PCOS and matched-controls. PATIENTS AND METHODS: Cross-sectional study, with 98 women of 18-44 years old. Rotterdam 2003 criteria integrated PCOS diagnosis. Those with significant alcohol consumption, chronic liver disease, use of steatogenic drugs, and pharmacological PCOS treatment or fertility protocol were excluded. Controls were matched in a 1:1 ratio by age and body mass index (BMI). The presence of NAFLD was determined by transient elastography performed by a single experienced operator. RESULTS: A total of 98 female volunteers at reproductive age were recruited. NAFLD denoted markedly higher in patients with than without PCOS at 69.3% vs. 34.6%, respectively. Compared to controls, PCOS patients had a significantly higher risk of NAFLD (OR=4.26, 95% CI 1.83-9.93). Severe steatosis was the most frequent NAFLD stage between women with PCOS and NAFLD. Patients with hyperandrogenism have a significantly higher mean CAP 277.83dB/m than controls without hyperandrogenism 191.57dB/m. NAFLD prevalence was 84.3% in PCOS patients with phenotype A, while in another phenotype, it was 41.1%. CONCLUSIONS: PCOS is an independent risk factor for NAFLD development. NAFLD screening needs to be considered in all PCOS patients independently of BMI, except in PCOS patients without hyperandrogenism and BMI<25.

The fibrogenic process and the unleashing of acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a life-threatening condition characterized by a rapid deterioration of previously well-compensated chronic liver diseases. One of the main obstacles in ACLF is the lack of knowledge of the pathogenesis and specific broad-spectrum treatments. An excessive systemic inflammatory response has been proposed to explain the pathogenesis of ACLF; this hypothesis involves stellate cells, which are implicated in many liver homeostatic functions that include vitamin A storage, regulation of sinusoidal blood flow, local inflammation, maintenance of the hepatocyte phenotype and extracellular matrix remodeling. However, when there is damage to the liver, these cells are the main target of the inflammatory stimulus, as a result, the secretion of the extracellular matrix is altered. Activated hepatic stellate cells raise the survival of neutrophils by the stimulation of granulocytes colonies and macrophages, which exacerbates liver inflammation and promotes damage to hepatocytes. Elevation of pathogen-associated molecular patterns is related to liver damage by different pathophysiological mechanisms of decompensation, showing ballooning degeneration and cell death with a predominance of cholestatic infection. Moreover, patients with ACLF present a marked elevation of C-reactive protein together with an elevation of the leukocyte count. Chronic liver disease is a complex pathological state with a heterogeneous pathophysiology in which genetic factors of the host and external triggers interact and culminate in hepatic insufficiency. The better understanding of such interactions should lead to a better comprehension of the disease and to the discovery of new treatment targets that will make acute decompensations preventable and even decrease mortality.