Racial Disparities in Mortality Rates among Patients with Hepatic Steatosis, Non-Alcoholic Fatty Liver Disease, and Non-Alcoholic Steatohepatitis: Insights from NHANES III Data.

Background: Insufficient research has been done on NASH-related cirrhosis mortality and potential racial disparities in mortality rates.

Objective: This study aims to analyze racial differences in mortality rates among patients with non-alcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver (NAFL), and non-alcoholic steatohepatitis (NASH), hypothesizing that hazard ratios for mortality among patients with NAFLD, NAFL, and NASH would be significantly different for Mexican American patients compared to other racial groups.

Methods: Data from NHANES III (1988-1994) representing the U.

A link between baseline neurofilament light chain and primary substrate accumulation in cerebrospinal fluid, and clinical outcomes in patients with MPS II from a phase 2/3 clinical trial and extension study of intrathecal idursulfase.

Mucopolysaccharidosis II (MPS II; Hunter syndrome) is a rare, X-linked, recessive lysosomal storage disorder that impacts approximately 1:162000 live births. It is caused by deficiencies in the lysosomal enzyme iduronate-2-sulfatase (I2S), resulting in harmful accumulation of specific glycosaminoglycans in cells, tissues and organs throughout the body. Clinical manifestations are varied and include airway obstruction, impaired mobility and, in two-thirds of cases, neurocognitive impairment (neuronopathic MPS II).

Trends in the incidence and mutational landscape of advanced uterine cancer.

Objective: The aim of this study was to examine disparities in 20-year incidence trends and mutations in advanced-stage uterine cancer in the United States, given poor survival rates.

Methods: Data were obtained from the United States Cancer Statistics for patients from 2001 to 2019 with International Federation of Gynecology and Obstetrics 2009 stage IVA and IVB uterine cancer. SEER∗Stat 8.

Conformational Flexibility of the C-Terminal Region Influences Distal Active Site Residues Across the Tautomerase Superfamily.

Consisting of more than 11,000 members distributed over five families, the tautomerase superfamily (TSF) is a large collection of proteins with diverse biological functions. While much attention has been given to individual TSF enzymes, a majority remain structurally and functionally uncharacterized. Given its large size, studying a representative member of each family offers a viable approach for extracting mechanistic insights applicable to the entire superfamily.

RKIP localizes to the nucleus through a bipartite nuclear localization signal and interaction with importin α to regulate mitotic progression.

Raf kinase inhibitor protein (RKIP) is a multifunctional modulator of intracellular signal transduction. Although most of its functions have been considered cytosolic, we show here that the localization of RKIP is primarily nuclear in both growing and quiescent Madin-Darby canine kidney epithelial cells and in Cal-51 and BT-20 human breast cancer cells. We have identified a putative bipartite nuclear localization signal (NLS) in RKIP that maps to the surface of the protein surrounding a known regulatory region.

Small Molecule Inhibitors of Nuclear Export and the Amelioration of Lupus by Modulation of Plasma Cell Generation and Survival.

Objective: To investigate the hypothesis that selective inhibitors of nuclear export (SINE compounds), recently approved for treatment of refractory plasma cell (PC) malignancy, may have potential in the treatment of lupus.

Methods: Female NZB/NZW mice were treated with the SINE compound KPT-350 or vehicle control. Tissue specimens were harvested and analyzed by flow cytometry, using standard markers.

Regulation of TET2 gene expression and 5mC oxidation in breast cancer cells by estrogen signaling.

Estrogen signaling plays important roles in diverse physiological and pathophysiological processes. However, the relationship between estrogen signaling and epigenetic regulation is not fully understood. Here, we explored the effect of estrogen signaling on the expression of Ten-Eleven Translocation (TET) family genes and DNA hydroxylmethylation in estrogen receptor alpha positive (ERα+) breast cancer cells.

Tumour suppressor TET2 safeguards enhancers from aberrant DNA methylation and epigenetic reprogramming in ERα-positive breast cancer cells.

Aberrant DNA methylation is an epigenetic hallmark of malignant tumours. The DNA methylation level is regulated by not only DNA methyltransferases (DNMTs) but also Ten-Eleven Translocation (TET) family proteins. However, the exact role of genes in breast cancer remains controversial.

Human Papillomavirus Vaccination Trends and Disparities in the United States: Who Is Getting Left Behind?

Background: United States guidelines recommend human papillomavirus (HPV) vaccination for males and females up to 26, with more recent extended coverage for those 27 to 45 years based on discussion with patients' clinician. This study seeks to assess trends and disparities of vaccination in the United States based on demographic characteristics.

Methods: Data were obtained from the National Health and Nutrition Examination Survey between 2007 and 2016.

Individualized Web-Based Attention Training With Evidence-Based Counseling to Address HIV Treatment Adherence and Psychological Distress: Exploratory Cohort Study.

Background: The prevalence of mood, trauma, and stressor-related disorders is disproportionately higher among people living with HIV than among individuals without the virus. Poor adherence to HIV treatment and heightened psychological distress have been linked to symptoms associated with these disorders.

Objective: The objective of this exploratory pilot study was to develop and implement an intervention that combined individualized web-based attention training with evidence-based counseling to promote HIV treatment adherence and reduce psychological distress among people living with HIV.

Selinexor Sensitizes TRAIL-R2-Positive TNBC Cells to the Activity of TRAIL-R2xCD3 Bispecific Antibody.

Triple-negative breast cancer (TNBC) is an aggressive disease with poor prognosis and limited therapeutic options. Recent advances in the immunotherapy field have enabled the development of new treatment strategies, among which the use of bispecific antibodies (BsAbs), able to redirect T cells against tumors, has shown promising results. In particular, a BsAb that uses TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) as a target was constructed and demonstrated good results in redirecting CD3 T cells to kill TRAIL-R2-expressing TNBC cells.

Venetoclax response is enhanced by selective inhibitor of nuclear export compounds in hematologic malignancies.

The selective inhibitor of nuclear export (SINE) compounds selinexor (KPT-330) and eltanexor (KPT-8602) are from a novel class of small molecules that target exportin-1 (XPO1 [CRM1]), an essential nucleo-cytoplasmic transport protein responsible for the nuclear export of major tumor suppressor proteins and growth regulators such as p53, p21, and p27. XPO1 also affects the translation of messenger RNAs for critical oncogenes, including MYC, BCL2, MCL1, and BCL6, by blocking the export of the translation initiation factor eIF4E. Early trials with venetoclax (ABT-199), a potent, selective inhibitor of BCL2, have revealed responses across a variety of hematologic malignancies.

Epigenetic signatures of methylated DNA cytosine in Alzheimer's disease.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common untreatable form of dementia. Identifying molecular biomarkers that allow early detection remains a key challenge in the diagnosis, treatment, and prognostic evaluation of the disease. Here, we report a novel experimental and analytical model characterizing epigenetic alterations during AD onset and progression.

Down-regulation of AR splice variants through XPO1 suppression contributes to the inhibition of prostate cancer progression.

Emerging studies have shown that the expression of AR splice variants (ARv) lacking ligand-binding domain is associated with castrate-resistant prostate cancer (CRPC) and higher risk of tumor metastasis and recurrence. Nuclear export protein XPO1 regulates the nuclear localization of many proteins including tumor suppressor proteins. Increased XPO1 in prostate cancer is associated with a high Gleason score and bone metastasis.

Selinexor reduces the expression of DNA damage repair proteins and sensitizes cancer cells to DNA damaging agents.

Introduction: The goal of this study was to examine the effects of selinexor, an inhibitor of exportin-1 mediated nuclear export, on DNA damage repair and to evaluate the cytotoxic effects of selinexor in combination with DNA damaging agents (DDAs) in cancer cells.

Results: Selinexor reduced the expression of DNA damage repair (DDR) proteins. This did not induce significant DNA damage in tested cell lines.

Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer.

Diabetes is a complex metabolic syndrome that is characterized by prolonged high blood glucose levels and frequently associated with life-threatening complications. Epidemiological studies have suggested that diabetes is also linked to an increased risk of cancer. High glucose levels may be a prevailing factor that contributes to the link between diabetes and cancer, but little is known about the molecular basis of this link and how the high glucose state may drive genetic and/or epigenetic alterations that result in a cancer phenotype.

Leukemogenic nucleophosmin mutation disrupts the transcription factor hub that regulates granulomonocytic fates.

Nucleophosmin (NPM1) is among the most frequently mutated genes in acute myeloid leukemia (AML). It is not known, however, how the resulting oncoprotein mutant NPM1 is leukemogenic. To reveal the cellular machinery in which NPM1 participates in myeloid cells, we analyzed the endogenous NPM1 protein interactome by mass spectrometry and discovered abundant amounts of the master transcription factor driver of monocyte lineage differentiation PU.

Targeting the XPO1-dependent nuclear export of E2F7 reverses anthracycline resistance in head and neck squamous cell carcinomas.

Patient mortality rates have remained stubbornly high (40%) for the past 35 years in head and neck squamous cell carcinoma (HNSCC) due to inherent or acquired drug resistance. Thus, a critical issue in advanced SCC is to identify and target the mechanisms that contribute to therapy resistance. We report that the transcriptional inhibitor, E2F7, is mislocalized to the cytoplasm in >80% of human HNSCCs, whereas the transcriptional activator, E2F1, retains localization to the nucleus in SCC.

Selinexor synergizes with dexamethasone to repress mTORC1 signaling and induce multiple myeloma cell death.

Multiple myeloma (MM) is a plasma cell neoplasm that results in over 11,000 deaths in the United States annually. The backbone therapy for the treatment of MM patients almost always includes combinations with corticosteroids such as dexamethasone (DEX). We found that DEX in combination with selinexor, an inhibitor of exportin-1 (XPO1) activity, synergistically inhibits the mTOR pathway and subsequently promotes cell death in MM cells.

Pharmacological treatment with inhibitors of nuclear export enhances the antitumor activity of docetaxel in human prostate cancer.

Background And Aims: Docetaxel (DTX) modestly increases patient survival of metastatic castration-resistant prostate cancer (mCRPC) due to insurgence of pharmacological resistance. Deregulation of Chromosome Region Maintenance (CRM-1)/ exportin-1 (XPO-1)-mediated nuclear export may play a crucial role in this phenomenon.

Material And Methods: Here, we evaluated the effects of two Selective Inhibitor of Nuclear Export (SINE) compounds, selinexor (KPT-330) and KPT-251, in association with DTX by using 22rv1, PC3 and DU145 cell lines with their.

FoxO-1 contributes to the efficacy of the combination of the XPO1 inhibitor selinexor and cisplatin in ovarian carcinoma preclinical models.

The XPO1/CRM1 inhibitor selinexor (KPT-330), is currently being evaluated in multiple clinical trials as an anticancer agent. XPO1 participates in the nuclear export of FoxO-1, which we previously found to be decreased in platinum-resistant ovarian carcinoma. The aim of this study was to determine whether enriching FoxO-1 nuclear localization using selinexor would increase ovarian cancer cell sensitivity to cisplatin.

Functional role and therapeutic targeting of p21-activated kinase 4 in multiple myeloma.

Dysregulated oncogenic serine/threonine kinases play a pathological role in diverse forms of malignancies, including multiple myeloma (MM), and thus represent potential therapeutic targets. Here, we evaluated the biological and functional role of p21-activated kinase 4 (PAK4) and its potential as a new target in MM for clinical applications. PAK4 promoted MM cell growth and survival via activation of MM survival signaling pathways, including the MEK-extracellular signal-regulated kinase pathway.

Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-κB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death.

The nuclear export protein, exportin-1 (XPO1/CRM1), is overexpressed in many cancers and correlates with poor prognosis. Selinexor, a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound, binds covalently to XPO1 and blocks its function. Treatment of cancer cells with selinexor results in nuclear retention of major tumor suppressor proteins and cell cycle regulators, leading to growth arrest and apoptosis.