Gemcitabine resistance of pancreatic cancer cells is mediated by IGF1R dependent upregulation of CD44 expression and isoform switching.

Chemoresistance in pancreatic cancer cells may be caused by the expansion of inherently resistant cancer cells or by the adaptive plasticity of initially sensitive cancer cells. We investigated how CD44 isoforms switching contributed to gemcitabine resistance. Treating CD44 null/low single-cell clones with increasing amounts of gemcitabine caused an increase in expression of CD44 and development of gemcitabine resistant (GR) cells.

Safety and Long-Term Survival Outcome in Patients With Unresectable Barcelona Clinic Liver Cancer (BCLC) Stages C and D Advanced Hepatocellular Carcinoma Treated With 40 μm Drug-Eluting Bead Transcatheter Arterial Chemoembolization.

Background To evaluate the safety, treatment response, and overall survival (OS) following drug-eluting bead transarterial chemoembolization (DEB-TACE) using doxorubicin-loaded 40 μm microspheres in patients with advanced hepatocellular carcinoma (HCC). Methods This was a single-center retrospective evaluation of patients with unresectable HCC without extrahepatic spread and Barcelona Clinic Liver Cancer (BCLC) stages C and D disease who underwent DEB-TACE between August 2015 and January 2018. Pre-treatment data included demographics, medical history, cancer staging, tumor size, laboratory results, and prior treatments for HCC.

The biology and role of CD44 in cancer progression: therapeutic implications.

CD44, a non-kinase transmembrane glycoprotein, is overexpressed in several cell types including cancer stem cells and frequently shows alternative spliced variants that are thought to play a role in cancer development and progression. Hyaluronan, the main ligand for CD44, binds to and activates CD44 resulting in activation of cell signaling pathways that induces cell proliferation, increases cell survival, modulates cytoskeletal changes, and enhances cellular motility. The different functional roles of CD44 standard (CD44s) and specific CD44 variant (CD44v) isoforms are not fully understood.

CD44 Expression Level and Isoform Contributes to Pancreatic Cancer Cell Plasticity, Invasiveness, and Response to Therapy.

Purpose: A subpopulation of pancreatic ductal adenocarcinoma (PDAC) cells is thought to be inherently resistant to chemotherapy or to give rise to tumor cells that become resistant during treatment. Here we determined the role of CD44 expression and its isoforms as a marker and potential target for tumor cells that give rise to invasive and gemcitabine-resistant tumors.

Experimental Design: RT-PCR, Western blotting, and DNA sequencing was used to determine CD44 isoform and expression levels.

Roles of c-Met and RON kinases in tumor progression and their potential as therapeutic targets.

c-Met and receptor originated from nantes (RON) are structurally related transmembrane phosphotyrosine kinase receptors. c-Met and RON show increased expression or activity in a variety of tumors leading to tumor progression and may play a role in acquired resistance to therapy. Although often co-expressed, the distinct functional roles of c-Met and RON are not fully understood.

A miRNA signature of chemoresistant mesenchymal phenotype identifies novel molecular targets associated with advanced pancreatic cancer.

In this study a microRNA (miRNA) signature was identified in a gemcitabine resistant pancreatic ductal adenocarcinoma (PDAC) cell line model (BxPC3-GZR) and this signature was further examined in advanced PDAC tumor specimens from The Cancer Genome Atlas (TCGA) database. BxPC3-GZR showed a mesenchymal phenotype, expressed high levels of CD44 and showed a highly significant deregulation of 17 miRNAs. Based on relevance to cancer, a seven-miRNA signature (miR-100, miR-125b, miR-155, miR-21, miR-205, miR-27b and miR-455-3p) was selected for further studies.

Functional consequences of ferroportin 1 mutations.

The cellular iron exporter ferroportin 1 is expressed in both the duodenum and in cells of the mononuclear phagocyte system. Expression of ferroportin 1 protein on the cell surface is regulated by the interaction of ferroportin 1 with hepcidin. Hepcidin treatment of cells results in internalization and lysosomal degradation of cell surface ferroportin 1.

Regulation of hepcidin and ferroportin expression by lipopolysaccharide in splenic macrophages.

Acute and chronic inflammatory states are associated with many changes in intracellular iron metabolism including sequestration of iron in the mononuclear-phagocyte system (MPS) and a decline in serum iron. Previous work in rodent models of acute inflammation has demonstrated inflammation-induced downregulation of intestinal and MPS iron exporter, ferroportin 1, mRNA and protein. In addition, these models have also demonstrated hepatic induction of mRNA of the small 25 amino acid peptide hepcidin.

Vascular dementia. Advances in nosology, diagnosis, treatment and prevention.

Ischemic or hemorrhagic cerebrovascular disease (CVD) produces injury of brain regions important for executive function, behavior, and memory leading to decline in cognitive functions and vascular dementia (VaD). Cardiovascular disease may cause VaD from hypoperfusion of susceptible brain areas. CVD may worsen degenerative dementias such as Alzheimer disease (AD).

Cholinergic dysfunction in vascular dementia.

Vascular dementia (VaD) is the second most common type of dementia in the elderly after Alzheimer's disease (AD). Evidence is presented indicating the occurrence of cholinergic dysfunction in VaD, independent from AD. Controlled clinical trials of cholinesterase inhibitors (ChEIs) in VaD and in patients with AD plus cerebrovascular disease are reviewed.

Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment and vascular dementia.

Vascular cognitive impairment (VCI) was proposed as an umbrella term to include subjects affected with any degree of cognitive impairment resulting from cerebrovascular disease (CVD), ranging from mild cognitive impairment (MCI) to vascular dementia. VCI may or may not exclude the host of "focal" circumscribed impairments of specialized functions such as language (aphasia), intentional gesture (apraxia), or categorical recognition (agnosia), among others, that may result from a stroke. Therefore, there are no universally accepted diagnostic criteria for VCI.

Facts, myths, and controversies in vascular dementia.

Significant progress in the field of VaD resulted from publication of the NINIDS-AIREN Diagnostic Criteria for VaD (G.C. Roman, T.

A combined analysis of two studies assessing the ocular comfort of antiallergy ophthalmic agents.

Background: Many topical agents with similar efficacies are available for the treatment of ocular allergies. In addition to efficacy, comfort is an important criterion because it affects overall patient satisfaction, compliance, and in turn efficacy.

Objective: The goal of this study was to compare the comfort profiles of permirolast, ketorolac, cromolyn, and nedocromil ophthalmic solutions using combined results from 2 separate clinical trials.

Two mast cell stabilizers, pemirolast potassium 0.1% and nedocromil sodium 2%, in the treatment of seasonal allergic conjunctivitis: a comparative study.

This randomized, double-masked, active-control, parallel-group trial compared the mast cell stabilizers pemirolast potassium 0.1% and nedocromil sodium 2% in the treatment of seasonal allergic conjunctivitis. Pemirolast is currently indicated for four-times-daily administration, nedocromil, for twice-daily dosing.

Biology of osteoclast activation in cancer.

Bone is a frequent site of cancer metastasis. Bone metastases can result in bone destruction or new bone formation. Bone destruction is mediated by factors produced or induced by tumor cells that stimulate formation and activation of osteoclasts, the normal bone-resorbing cells.

Efficacy of the triazole SCH 56592 against Leishmania amazonensis and Leishmania donovani in experimental murine cutaneous and visceral leishmaniases.

Current therapy for leishmaniasis is unsatisfactory. Efficacious and safe oral therapy would be ideal. We examined the efficacy of SCH 56592, an investigational triazole antifungal agent, against cutaneous infection with Leishmania amazonensis and visceral infection with Leishmania donovani in BALB/c mice.

Rabeprazole: pharmacokinetics in patients with stable, compensated cirrhosis.

This single-center, open-label study was undertaken to compare the tolerability and pharmacokinetic profiles of rabeprazole, a new proton-pump inhibitor (PPI), in healthy volunteers and in subjects with chronic cirrhosis. Thirteen healthy men and 10 men with stable, compensated cirrhosis documented by biopsy or liver/spleen scan received a single 20-mg rabeprazole dose. Blood samples were drawn before and up to 24 hours after drug administration for the determination of plasma rabeprazole concentrations using high-performance liquid chromatography.

Annexin II increases osteoclast formation by stimulating the proliferation of osteoclast precursors in human marrow cultures.

Annexin II (AXII), a calcium-dependent phospholipid-binding protein, has been recently found to be an osteoclast (OCL) stimulatory factor that is also secreted by OCLs. In vitro studies showed that AXII induced OCL formation and bone resorption. However, the mechanism of action by which AXII acts as a soluble extracellular protein to induce OCL formation is unknown.

Mechanisms of bone lesions in multiple myeloma and lymphoma.

Background: Bone lesions and hypercalcemia occur rarely in patients with hematologic malignancies, except those patients with multiple myeloma and adult T-cell leukemia/lymphoma (ATL) associated with the human T-cell leukemia/lymphoma virus-1 (HTLV-1) virus. The primary mechanism for bone destruction in patients with myeloma and lymphoma is increased osteoclastic bone resorption. In patients with multiple myeloma, new bone formation is also inhibited.

Angiotensin-converting enzyme inhibitors in left ventricular dysfunction.

Angiotensin-converting enzyme (ACE) inhibitors have been used for more than a decade in the treatment of chronic congestive heart failure. In recent years these agents have been used in patients who survived a myocardial infarction. However, primary care providers are often confused as to which patients would benefit the most, and as a result, these life-prolonging drugs are underutilized.

Effects of parathyroid hormone (PTH)-related protein and PTH on osteoclasts and osteoclast precursors in vivo.

Increased production of PTH-related protein (PTHrP) and PTH is frequently responsible for hypercalcemia and its associated morbidity. However, it is unclear whether these peptides produce identical effects on cells in the osteoclast lineage in vivo. To examine the effects of continuous in vivo exposure to these factors on both the osteoclast precursors and mature osteoclasts, we inoculated Chinese hamster ovarian cells expressing PTH-(1-84), PTHrP-(1-141), or nontransfected Chinese hamster ovarian cells into nude mice.

Characterization of the 5'-flanking region of the human tartrate-resistant acid phosphatase (TRAP) gene.

Tartrate-resistant acid phosphatase (TRAP) is expressed at high levels in osteoclasts and may play an important role in the bone resorptive process. However, factors regulating human TRAP gene expression have not been clearly defined. Therefore, we isolated a genomic clone (CL-9) for TRAP containing a 14-kb insert.

Fluconazole, D0870, and flucytosine treatment of disseminated Candida tropicalis infections in mice.

D0870 is a recently developed triazole with characteristics of a broad spectrum of activity and slow clearance by nonrenal mechanisms. Herein we have evaluated the efficacy of D0870, alone and combined with flucytosine, in a murine model of disseminated Candida tropicalis infection. Four isolates of C.