Anti-neoplastic sulfonamides alter the metabolic homeostasis and disrupt the suppressor activity of regulatory T cells.

Regulatory T cells (Tregs) are essential to maintain self-tolerance and immune homeostasis but, as components of the tumor microenvironment (TME), are also a major barrier to effective cancer immunosurveillance and immunotherapy. FH535 and its derivative Y3 are two N-aryl-benzene-sulfonamides (NABs) that inhibit HCC cell proliferation and tumor progression. However, the impact of NABs on the immune cells in the TME is not yet known.

Mitochondrial uncoupling and the disruption of the metabolic network in hepatocellular carcinoma.

Background: Hepatocellular Carcinoma (HCC) is the third most common cause of cancer related death worldwide. Adequate treatment options for patients with advanced HCC are currently limited.

Materials And Methods: We studied the anti-HCC effect of FH535 and a novel derivative Y3, on proliferation, mitochondrial function and cellular metabolism focusing on the three key substrates, glutamine, glucose, and fatty acids.

Autophagic flux modulation by Wnt/β-catenin pathway inhibition in hepatocellular carcinoma.

Autophagy targets cellular components for lysosomal-dependent degradation in which the products of degradation may be recycled for protein synthesis and utilized for energy production. Autophagy also plays a critical role in cell homeostasis and the regulation of many physiological and pathological processes and prompts this investigation of new agents to effect abnormal autophagy in hepatocellular carcinoma (HCC). 2,5-Dichloro-N-(2-methyl-4-nitrophenyl) benzenesulfonamide (FH535) is a synthetic inhibitor of the Wnt/β-catenin pathway that exhibits anti-proliferative and anti-angiogenic effects on different types of cancer cells.

Outcomes in patients with portal hypertension undergoing gastrointestinal surgery: A propensity score matched analysis from the NSQIP dataset.

Background/aim: We aim to study the impact of PH in patients undergoing gastrointestinal surgery (GI).

Methods: We queried the ACS-NSQIP database from 2005 through 2010 for patients undergoing GI surgery with PH. Esophageal varices (EV) diagnosis was used as a surrogate of PH.

Effect of critical care complications on perioperative mortality and hospital length of stay after hepatectomy: A multicenter analysis of 21,443 patients.

Objective: To determine predictors of critical care complications (CCC) in patients undergoing hepatectomy.

Methods: All hepatectomy patients in NSQIP from 2012 to 2016 were analyzed. CCC included prolonged ventilation (>48 h), sepsis/septic shock, renal failure/insufficiency, cardiac arrest/AMI and pulmonary embolism.

mTOR Inhibitor Everolimus in Regulatory T Cell Expansion for Clinical Application in Transplantation.

Background: Experimental and preclinical evidence suggest that adoptive transfer of regulatory T (Treg) cells could be an appropriate therapeutic strategy to induce tolerance and improve graft survival in transplanted patients. The University of Kentucky Transplant Service Line is developing a novel phase I/II clinical trial with ex vivo expanded autologous Treg cells as an adoptive cellular therapy in renal transplant recipients who are using everolimus (EVR)-based immunosuppressive regimen.

Methods: The aim of this study was to determine the mechanisms of action and efficacy of EVR for the development of functionally competent Treg cell-based adoptive immunotherapy in transplantation to integrate a common EVR-based regimen in vivo (in the patient) and ex vivo (in the expansion of autologous Treg cells).

Novel biomarkers in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths and the fifth most common cancer worldwide. Most of these patients are seen with advanced disease at the time of presentation. In spite of its high prevalence, there are not many therapeutic options available for patients with advanced-stage HCC.

Evidence of the immunomodulatory role of dual PI3K/mTOR inhibitors in transplantation: an experimental study in mice.

The PI3K/mTOR signaling cascade is fundamental in T-cell activation and fate decisions. We showed the distinct regulation of PI3K/mTOR in regulatory and effector T-cells and proposed the potential therapeutic benefit of targeting this pathway to control the balance between effector and regulatory T-cell activities. Substantial adverse effects in long-term clinical usage of rapamycin suggest the use of alternative treatments in restraining effector T-cell function in transplant patients.

Sorafenib and FH535 in combination act synergistically on hepatocellular carcinoma by targeting cell bioenergetics and mitochondrial function.

Treatment of advanced hepatocellular carcinoma (HCC) remains a challenge due to the high tumor heterogeneity. In the present study, we aim to evaluate the impact of the β-catenin inhibitor, FH535, alone or in combination with the Ras/Raf/MAPK inhibitor Sorafenib, on the bioenergetics profiles of the HCC cell lines Huh7 and PLC/PRF/5. Single low-dose treatments with FH535 or Sorafenib promoted different effects on mitochondrial respiration and glycolysis in a cell type specific manner.

Hexavalent chromium induces malignant transformation of human lung bronchial epithelial cells via ROS-dependent activation of miR-21-PDCD4 signaling.

Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with an increased risk of lung cancer. However, the mechanisms underlying Cr(VI)-induced carcinogenesis remain unclear. MicroRNA-21 (miR-21) is a key regulator of oncogenic processes.

Quercetin inhibits Cr(VI)-induced malignant cell transformation by targeting miR-21-PDCD4 signaling pathway.

Hexavalent chromium [Cr(VI)] is an important human carcinogen associated with pulmonary diseases and lung cancer. Inhibition of Cr(VI)-induced carcinogenesis by a dietary antioxidant is a novel approach. Quercetin is one of the most abundant dietary flavonoids widely present in many fruits and vegetables, possesses potent antioxidant and anticancer properties.

Cancer stem cell marker expression alone and in combination with microvascular invasion predicts poor prognosis in patients undergoing transplantation for hepatocellular carcinoma.

Background: The cancer stem cell hypothesis provides an explanation for hepatocellular carcinoma (HCC) heterogeneity. We investigated the expression of CD44 and CD133 alone and in combination with microvascular invasion (MVI) as predictors of prognosis in patients undergoing liver transplantation for HCC.

Methods: Explanted livers from 95 patients transplanted for HCC were analyzed.

Targeting Wnt/β-catenin pathway in hepatocellular carcinoma treatment.

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Liver cancer is generally related to hepatitis B or C infection and cirrhosis. Usually, patients with HCC are asymptomatic and are diagnosed at late stages when surgical treatment is no longer suitable.

N-Aryl benzenesulfonamide inhibitors of [3H]-thymidine incorporation and β-catenin signaling in human hepatocyte-derived Huh-7 carcinoma cells.

Structure-activity relationships (SAR) in 2,5-dichloro-N-(2-methyl-4-nitrophenyl)benzenesulfonamide (FH535) were examined as part of a program to identify agents that inhibit the Wnt/β-catenin signaling pathway that is frequently upregulated in hepatocellular carcinoma (HCC). FH535 was reported as an inhibitor of both β-catenin in the Wnt signaling pathway and the peroxisome proliferator-activated receptor (PPAR). A β-catenin/T-cell factor (TCF)/Lymphoid-enhancer factor (LEF)-dependent assay (i.

Characterization of IS6110 insertions in the dnaA-dnaN intergenic region of Mycobacterium tuberculosis clinical isolates.

Mycobacterium tuberculosis isolates with identical IS6110 restriction fragment length polymorphism (RFLP) patterns are considered to be clonally related. The presence of IS6110 in the dnaA-dnaN intergenic region, one preferential locus for the integration of IS6110, was evaluated in 125 M. tuberculosis isolates.

IS6110 in oriC affects the morphology and growth of Mycobacterium tuberculosis and attenuates virulence in mice.

The IS6110 element is widely used in studies of molecular epidemiology of tuberculosis and it is considered the gold standard for genotyping Mycobacterium tuberculosis strains. Because of its high frequency of transposition, IS6110 is probably a major contributor to the evolution of M. tuberculosis.

The role of MAPKs in B cell receptor-induced down-regulation of Egr-1 in immature B lymphoma cells.

Cross-linking of the B cell receptor (BCR) on the immature B lymphoma cell line BKS-2 induces growth inhibition and apoptosis accompanied by rapid down-regulation of the immediate-early gene egr-1. In these lymphoma cells, egr-1 is expressed constitutively and has a prosurvival role, as Egr-1-specific antisense oligonucleotides or expression of a dominant-negative inhibitor of Egr-1 also prevented the growth of BKS-2 cells. Moreover, enhancement of Egr-1 protein with phorbol 12-myristate 13-acetate or an egr-1 expression vector rescued BKS-2 cells from BCR signal-induced growth inhibition.

Transcription analysis of the dnaA gene and oriC region of the chromosome of Mycobacterium smegmatis and Mycobacterium bovis BCG, and its regulation by the DnaA protein.

The regions flanking the Mycobacterium dnaA gene have extensive sequence conservation, and comprise various DnaA boxes. Comparative analysis of the dnaA promoter and oriC region from several mycobacterial species revealed that the localization, spacing and orientation of the DnaA boxes are conserved. Detailed transcriptional analysis in M.