The pleiotropic approach to coronavirus disease-19 pathogenesis: The impact of liver diseases associated host genetic variants.

Coronavirus disease-2019 (COVID-19) is a novel multisystemic viral disease caused pandemic. The disease impact involves liver and associated systems. Undoubtedly, host genetic background influences the predisposition and prediction of infection. Variants among human populations might increase susceptibility or protect against severe outcomes. In this manner, rs738409 variant of patatin-like phospholipase domain-containing protein 3 gene appears to be protective in some populations in spite of its aggravating effect on non-alcoholic fatty liver diseases (NAFLDs) and steatohepatitis. DRB1*15:01 allele of human leukocyte antigen is associated with protective effect in European and Japanese populations. DRB1*03:01 contrarily increases the susceptibility of severe COVID-19 infection in European populations. rs1260326 in glucokinase regulatory protein gene, rs112875651 in tribbles homolog 1 gene, rs429358 in apolipoprotein 1, and rs58542926 in transmembrane 6 superfamily 2 alleles are found related with NAFLD and obesity; thus, hypercoagulability and severe COVID-19 outcomes. In chronic or acute liver diseases, comorbid syndromes are the key factors to explain increased severity. There might not be a direct association between the variant and severe COVID-19 infection. As it is concluded, there are genes and variants known and unknown yet to be studied to reveal the association with disease severity.

The effect of sarcopenia and sarcopenic obesity on survival in gastric cancer.

BACKGROUND: Sarcopenic obesity arises from increased muscle catabolism triggered by inflammation and inactivity. Its significance lies in its role in contributing to morbidity and mortality in gastric cancer. This study aims to explore the potential correlation between sarcopenia, sarcopenic obesity, and gastric cancer, as well as their effect on survival. MATERIALS AND METHODS: This retrospective study included 162 patients aged ≥ 18 years who were diagnosed with stomach cancer. Patient age, gender, diagnostic laboratory results, and cancer characteristics were documented. Sarcopenia was assessed using the skeletal muscle index (SMI) (cm2/m2), calculated by measuring muscle mass area from a cross-sectional image at the L3 vertebra level of computed tomography (CT). RESULTS: Among the 162 patients, 52.5% exhibited sarcopenia (with cut-off limits of 52.4 cm2/m2 for males and 38.5 cm2/m2 for females), and 4.9% showed sarcopenic obesity. Average skeletal muscle area (SMA) was 146.8 cm2; SMI was 50.6 cm2/m2 in men and 96.9 cm2 and 40.6 cm2/m2 in women, respectively. Sarcopenia significantly reduced mean survival (p = 0.033). There was no association between sarcopenic obesity and mortality (p > 0.05), but mortality was higher in sarcopenic obesity patients (p = 0.041). Patient weight acted as a protective factor against mortality, supporting the obesity paradox. Tumor characteristics, metabolic parameters, and concurrent comorbidities did not significantly impact sarcopenia or mortality. CONCLUSION: Sarcopenia is more prevalent in the elderly population and is linked to increased mortality in gastric cancer patients. Paradoxically, higher body mass index (BMI) was associated with improved survival. Computed tomography offers a practical and reliable method for measuring muscle mass and distinguishing these distinctions. TRIAL REGISTRATION: This study was approved by Istanbul Training and Research Hospital Clinical Research Ethics Committee of the University of Health Sciences (29.05.2020/2383).

Effect of testicular morphology on embryo development to the blastocyst stage after round spermatid injection.

If spermatozoa cannot be found after testiculer sperm extraction (TESE) in patients followed up due to nonobstructive azospermia (NOA) and the patients do not want donor spermatozoa, performance of round spermatid injection (ROSI) with the current technology seems to be the last resort. This retrospective study was conducted to evaluate the effect of testicular morphology on the development of embryos to the blastocyst stage obtained from ROSI. Between September 2019 and March 2020, after TESE and biopsy 29 patients who had only spermatid were taken to study. Tubular appearance, basal membrane appearance, Johnson score, peritubular fibrosis, interstitial fibrosis, and Leydig cell proliferation were pathologically examined. Following egg collection, ROSI was applied to the oocytes using the piezoelectric method. The embryos were monitored until the blastocyst stage. The mean age of the 29 patients was 36.3±5.01 years. Also, 7 patients had not previously undergone TESE, 20 had previously undergone once, and 2 had previously undergone twice. It was observed that having a history of TESE and a high Johnson score increased the likelihood of the embryo remaining in the blastocyst stage (P=0.021 and 0.014, respectively). However, other parameters do not affect the likelihood of blastocyst formation (P>0.05). Low TESE history and high Johnson score were associated with embryo development to the blastocyst stage. If spermatozoa are not found in patients with nonobstructive azoospermia, ROSI performed during initial TESE increases the likelihood of blastocyst formation.

A Novel Function for KLF4 in Modulating the De-differentiation of EpCAM-/CD133- nonStem Cells into EpCAM+/CD133+ Liver Cancer Stem Cells in HCC Cell Line HuH7.

The complex and heterogeneous nature of hepatocellular carcinoma (HCC) hampers the identification of effective therapeutic strategies. Cancer stem cells (CSCs) represent a fraction of cells within tumors with the ability to self-renew and differentiate, and thus significantly contribute to the formation and maintenance of heterogeneous tumor mass. Increasing evidence indicates high plasticity in tumor cells, suggesting that non-CSCs could acquire stem cell properties through de-differentiation or reprogramming processes. In this paper, we reveal KLF4 as a transcription factor that can induce a CSC-like phenotype in non-CSCs through upregulating the EpCAM and E-CAD expression. Our studies indicated that KLF4 could directly bind to the promoter of EpCAM and increase the number of EpCAM+/CD133+ liver cancer stem cells (LCSCs) in the HuH7 HCC cell line. When KLF4 was overexpressed in EpCAM-/CD133- non-stem cells, the expressions of hepatic stem/progenitor cell genes such as CK19, EpCAM and LGR5 were significantly increased. KLF4 overexpressing non-stem cells exhibited greater cell viability upon sorafenib treatment, while the cell migration and invasion capabilities of these cells were suppressed. Importantly, we detected an increased membranous expression and colocalization of ß-CAT, E-CAD and EpCAM in the KLF4-overexpressing EpCAM-/CD133- non-stem cells, suggesting that this complex might be required for the cancer stem cell phenotype. Moreover, our in vivo xenograft studies demonstrated that with a KLF4 overexpression, EpCAM-/CD133- non-stem cells attained an in vivo tumor forming ability comparable to EpCAM+/CD133+ LCSCs, and the tumor specimens from KLF4-overexpressing xenografts had increased levels of both the KLF4 and EpCAM proteins. Additionally, we identified a correlation between the KLF4 and EpCAM protein expressions in human HCC tissues independent of the tumor stage and differentiation status. Collectively, our data suggest a novel function for KLF4 in modulating the de-differentiation of tumor cells and the induction of EpCAM+/CD133+ LCSCs in HuH7 HCC cells.

Comparison of Different Sources of Mesenchymal Stem Cells: Palatal versus Lipoaspirated Adipose Tissue.

OBJECTIVES: The purpose of this study was to compare the proliferation and differentiation potential of mesenchymal stem cells (MSCs) derived from palatal adipose tissue (PAT) and lipoaspirated adipose tissue (LAT). MATERIALS AND METHODS: PATs were obtained from 2 healthy female patients undergoing surgery for gingival recession, and LATs were obtained from 2 healthy female patients undergoing plastic surgery. LAT- and PAT-derived MSCs were confirmed by flow cytometry using MSC-specific surface markers. The multilineage differentiation capacity of the MSCs was analyzed. The expression of immunophenotyping, embryonic, and differentiation markers was compared between both MSC lines. The proliferation of PAT- and LAT-MSCs was evaluated using a real-time cell analyzer, and telomerase activity was determined using an ELISA-based TRAP assay. Stem cells isolated from PAT and LAT were analyzed by real-time PCR and whole genome array analysis. RESULTS: The cells isolated from PAT had MSC characteristics. In addition, PAT-MSCs had significantly higher alkaline phosphatase activity and osteogenic potential than LAT-MSCs. Although the proliferation and telomerase activities of LAT-MSCs were higher than those of PAT-MSCs, the difference was not statistically significant. The level of embryonic stem cell markers (Oct4 and Nanog) was higher in LAT-MSCs than in PAT-MSCs. The whole genome array analysis demonstrated that 255 gene sequences were differentially expressed, with more than a twofold change in expression. CONCLUSIONS: This is the first comparative analysis of the isolation and characterization of MSCs from PAT and LAT. PAT is an accessible source of MSCs, which could be used in periodontal and craniofacial tissue engineering.

Role of Albumin in Growth Inhibition in Hepatocellular Carcinoma.

OBJECTIVE: Levels of serum albumin have recently emerged, together with C-reactive protein, as an important prognostic indicator for hepatocellular carcinoma (HCC). It has recently been reported that larger HCCs are associated with lower albumin levels. However, the albumin-mediated growth decrease has yet to be determined. METHODS: We examined a large HCC cohort and then by direct exposure of HCC cells in vitro, the relationship of albumin levels to HCC growth. RESULTS: We found that patients with lower albumin levels had significantly larger maximum tumor diameters, more portal vein thrombosis, more tumor multifocality, higher α-fetoprotein levels, and a lower survival than patients with higher albumin levels. Direct addition of exogenous albumin at physiological concentrations resulted in decreased growth in several HCC cell lines in vitro. We found a decrease in MAP kinase levels and in levels of Cdk2 and Cdk4, cyclinE, as well as in α-fetoprotein. CONCLUSION: These results indicate that in addition to its role as a monitor of systemic inflammation, albumin may have a direct role in HCC growth inhibition, either through modulation of α-fetoprotein or through its actions on growth-controlling kinases.

Effect of adipocyte-secreted factors on EpCAM+/CD133+ hepatic stem cell population.

Recent epidemiological studies have associated obesity with a variety of cancer types including HCC. However, the tumor initiating role of obesity in hepatocarcinogenesis is still unknown. The objective of this paper is to investigate the effect of adipocyte-secreted factors on EpCAM+/CD133+ cancer stem cells and to identify which factors play a role in modulating hepatic cancer stem cell behavior. Our results demonstrated that adipocyte-secreted factors affect motility and drug resistance of EpCAM+/CD133+ cells. When incubated with adipocyte conditioned media, EpCAM+/CD133+ cells exhibited augmented motility and reduced sorafenib-induced apoptosis. Using array-based system, we identified secretion of several cytokines such as IL6, IL8 and MCP1 by cultured adipocytes and activation of c-Met, STAT3 and ERK1/2 signaling pathways in EpCAM+/CD133+ cells incubated with adipocyte conditioned media. Treating EpCAM+/CD133+ cancer stem cells with IL6 receptor blocking antibody or c-Met inhibitor SU11274 both reduced the increase in motility; however SU11274 had greater effect on relieving protection from sorafenib-induced apoptosis. These results indicate that adipocyte-secreted factors might regulate cancer stem cell behavior through several signaling molecules including c-Met, STAT3 and ERK1/2 and inhibition of these signaling pathways offer novel strategies in targeting the effect of adipose-derived cytokines in cancer.