Biomarkers of Innate Immunity and Immunological Susceptibility to Viral Infection in Patients with Alcoholic Cirrhosis.

BACKGROUND: The harmful effect of alcohol on the immune system may be due to both a direct action of the alcohol or its metabolites on immune cells as an indirect action modifying the different mechanisms of intercellular interaction. The interplay between stimulatory (aKIR) and inhibitory (iKIR) natural killer (NK) cell receptors and their corresponding human leukocyte antigen (HLA) ligands influences the outcome of virus infection. The aim was to analyze the influence of the KIR/HLA pair genetic profile in male alcoholic cirrhosis (AC) patients with and without viral infections to find susceptibility biomarkers that can help establish the risks and prevent viral infections. METHODS: A total of 281 male AC patients were analyzed. The sociodemographic characteristics, viral hepatitis C (HCV), hepatitis B (HBV), and cytomegalovirus (CMV) infections were analyzed. Genomic DNA was extracted, and genetic the KIR/HLA profiles were investigated. A total of 6 KIR genes and their corresponding ligands (HLA-C) were analyzed. Patients were grouped into two groups: with and without associated viral infection. RESULTS: A statistically significant increase in the combination of KIR2DL2+/C1C1 was observed in male AC patients with viral infection compared to those without viral infection (45.9% vs. 24.5%, p = 0.021). The analysis of KIR2DL3+/C1+ showed a high frequency comparing healthy controls and male AC patients without virus infection (85% vs. 76.4%; p = 0.026). The analysis of KIR2DL3+/C2C2 frequency showed a statistically significant increase comparing male AC patients without viral infection and healthy controls (23.6% vs. 15%; p = 0.026). CONCLUSIONS: The genetic KIR2DL2+/C2C2 profiles may play a significant role in determining the vulnerability of male AC patients to viral infections, providing valuable insights for future research and potential therapeutic interventions.

Gemtuzumab Ozogamicin in Acute Myeloid Leukemia: Efficacy, Toxicity, and Resistance Mechanisms-A Systematic Review.

Acute myeloid leukemia (AML) is a diverse group of leukemias characterized by the uncontrolled proliferation of clonal neoplastic hematopoietic precursor cells with chromosomal rearrangements and multiple gene mutations and the impairment of normal hematopoiesis. Current efforts to improve AML outcomes have focused on developing targeted therapies that may allow for improved antileukemic effects while reducing toxicity significantly. Gemtuzumab ozogamicin (GO) is one of the most thoroughly studied molecularly targeted therapies in adults. GO is a monoclonal antibody against CD33 IgG4 linked to the cytotoxic drug calicheamicin DMH. The use of GO as a chemotherapeutic agent is not generalized for all patients who suffer from AML, particularly for those whose health prevents them from using intensive conventional chemotherapy, in which case it can be used on its own, and those who have suffered a first relapse, where its combination with other chemotherapeutic agents is possible. This systematic review aimed to comprehensively evaluate GO, focusing on its molecular structure, mode of action, pharmacokinetics, recommended dosage, resistance mechanisms, and associated toxicities to provide valuable information on the potential benefits and risks associated with its clinical use. A systematic review of eight scientific articles from 2018 to 2023 was conducted using PRISMA analysis. The results showed that GO treatment activates proapoptotic pathways and induces double-strand breaks, initiating DNA repair mechanisms. Cells defective in DNA repair pathways are susceptible to GO cytotoxicity. GO has recommended doses for newly diagnosed CD33+ AML in combination or as a single agent. Depending on the treatment regimen and patient status, GO doses vary for induction, consolidation, and continuation cycles. Multidrug resistance (MDR) involving P-glycoprotein (P-gp) is associated with GO resistance. The overexpression of P-gp reduces GO cytotoxicity; inhibitors of P-gp can restore sensitivity. Mitochondrial pathway activation and survival signaling pathways are linked to GO resistance. Other resistance mechanisms include altered pharmacokinetics, reduced binding ability, and anti-apoptotic mechanisms. GO has limited extramedullary toxicity compared to other AML treatments and may cause hepatic veno-occlusive disease (HVOD). The incidence of hepatic HVOD after GO therapy is higher in patients with high tumor burden. Hematological side effects and hepatotoxicity are prominent, with thrombocytopenia and neutropenia observed. In conclusion, GO's reintroduction in 2017 followed a thorough FDA review considering its altered dose, dosing schedule, and target population. The drug's mechanism involves CD33 targeting and calicheamicin-induced DNA damage, leading to apoptosis and resistance mechanisms, including MDR and survival signaling, which impact treatment outcomes. Despite limited extramedullary toxicity, GO is associated with hematological side effects and hepatotoxicity.

Is the Development of Ascites in Alcoholic Liver Patients Influenced by Specific KIR/HLA Gene Profiles?

Decompensated cirrhosis is the most common cause of ascites due to hemodynamic and renal alteration by continuous fluid leakage from the hepatic sinusoids and splanchnic capillaries into the interstitial space. Then, fluid leakage exceeds lymphatic return, leading to progressive fluid accumulation directly into the peritoneal cavity. Alcohol consumption is one of the main risks of developing alcoholic cirrhosis (AC), but not all AC patients develop ascites. Avoiding the development of ascites is crucial, given that it deteriorates prognosis and increases the patient mortality patient. The innate immune system plays a crucial role in cirrhosis through natural killer cells, which are abundant in the liver. The aim of this study was to analyze the KIR/HLA-C genetic profile in AC patients with and without ascites to understand this pathology and find predictive clinical susceptibility biomarkers that can help to establish risks and prevent the development of ascites in AC patients. A total of 281 AC patients with and without ascites were analyzed and compared with 319 healthy controls. Genomic DNA was extracted from peripheral blood in all groups. A PCR-SSO assay was performed for KIR/HLA genotyping analysis. A total of 16 activating and inhibitor KIR genes and their corresponding known ligands, epitopes of HLA-C, and their genotypes were analyzed. According to our analysis, C1 epitopes were statistically significantly decreased in AC patients with and without ascites. When comparing AC patients with ascites and healthy controls, a significant decrease in C1 epitope frequency was also observed. A statistically significant decrease was also found when comparing the C1C2 genotype in AC patients without ascites with controls. In conclusion, the absence of KIR2DL2 and KIR3DL1 genes may be a predisposing factor for the development of ascites in AC patients. The KIR2DS2/KIR2DL2 may could be involved in grade I ascites development, and the presence of the C1+ epitope and the homozygous C2C2 genotype may be protective genetic factors against ascites development in AC patients.

Hepatitis B viral infection and role of alcohol.

End-stage liver disease is frequently caused by hepatitis B virus (HBV) and alcohol consumption. Notably, the mechanism by which alcohol affects the course of HBV-associated liver disease is unknown, and additional research is needed in this area. A reduced immunological response, oxidative stress, endoplasmic reticulum stress, Golgi apparatus stress, and enhanced HBV replication are a few potential causes.

Alcohol-related diseases and liver metastasis: Role of cell-free network communication.

Alcohol intake is a risk factor for cancer development and metastatic disease progression. Extracellular vesicle (EV)-mediated interorgan communication is assumed to be significant in boosting tumorigenic pathways and disease progression. Recent research indicates that exosomes have a variety of roles in the development of cancer during pathophysiological conditions. The involvement of EV signaling during cancer progression in the alcohol environment is unknown. Therefore, understanding communication networks and the role of EVs as biomarkers can contribute significantly to developing strategies to address the serious public health problems associated with alcohol consumption and cancer.

Suicidal Behavior and Its Relationship with Postmortem Forensic Toxicological Findings.

Suicide affects all sociodemographic levels, age groups, and populations worldwide. The factors that can increase the risk of suicidal tendencies are widely studied. The aim of this study was to analyze the types and combinations of toxics found in fatal suicide victims with different suicide mechanisms. A total of 355 autopsies were retrospectively studied, and 26 toxics were determined and related to mechanisms of suicide. Hanging (55%), drug overdose (22.7%), and jumping from a height (17.8%) were most represented suicide mechanisms with positive toxicology. Hanging was the most represented in men (50.3%; p = 0.019), while jumping from a height was more represented in women (29.7%, p = 0.028). Drugs of abuse were the most frequent toxics found in men (55.5%; p < 0.001), while medicines were the most frequent type found in women (70.3%, p < 0.001). Alcohol, nordiazepam, cocaine, and venlafaxine were the most consumed toxics. Benzodiazepines and venlafaxine were found in suicides involving drug overdose, hanging, and jumping from a height. In conclusion, most suicides were associated with drug abuse in men. Hanging was more represented in men and jumping from a height in women. Alcohol was present in combination with other toxics and medicines. The toxicological analysis is fundamental to understanding consumption patterns and establishing strategies and protocols for detecting and preventing suicide.

Is There a Role for the Microbiome and Sudden Death? A Systematic Review.

BACKGROUND: Sudden unexpected death (SUD) is one of the most important and worthy investigation case profiles in emergency medicine and forensic pathology. Sudden unexpected deaths in adults (SUDA) are frequently caused by cardiac events, while infections usually cause those in infants younger than one year (SUDI), and to a lesser extent, in children older than one year (SUDC). However, in some instances of children under the age of one dying (SIDS), a cause is not discovered despite a thorough investigation that includes a review of clinical history, examination of the death scene, and a complete autopsy. Several studies demonstrate that the microbiome influences host immunity, alters susceptibility to viral respiratory infections, and has a vital role in various health, disease, and death outcomes. The main objective of this systematic review was to compile and offer a complete vision of the main lines of research on microbiome and sudden death that have emerged in recent years and their relationship with forensic sciences, as well as the possible contributions or limitations in the field of forensic sciences. METHODS: Following PRISMA principles, a systematic evaluation of the microbiome and sudden death in forensic science was conducted. In this review, our study classified the sudden deaths as SUDA, SUDI, and SIDS. RESULTS: The role of microbiome research in sudden death is discussed in this review. Various studies have linked the detection of different bacteria or viruses as a probable cause of sudden death. Bacteria analysed differ between studies that used autopsy specimens from deaths classified as SUDA, SUDI, and SIDS, or, except in the case of Staphylococcus aureus and Escherichia coli, which have been analysed in both SUDI and SIDS autopsies. In the case of viruses, only Cytomegalovirus has been analysed in both SIDS and SUDI cases. However, all the viruses studied are respiratory viruses found in samples of nasopharyngeal or lung fluid. CONCLUSIONS: Although the application of the microbiome in sudden death and other fields of forensic science is still in its early stages, a role of the microbiome in sudden deaths cannot be ruled out, but we cannot conclude that it is a significant factor either.