Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST)

Although gastrointestinal stromal tumors (GISTs) harboring activating KIT or platelet-derived growth factor receptor A (PDGFRA) mutations respond to treatment with targeted KIT/PDGFRA inhibitors such as imatinib mesylate, these treatments are rarely curative. Most often, a sizeable tumor cell subpopulation survives and remains quiescent for years, eventually resulting in acquired resistance and treatment failure. Here, we report that imatinib induces autophagy as a survival pathway in quiescent GIST cells. Inhibiting autophagy, using RNAi-mediated silencing of autophagy regulators (ATGs) or antimalarial lysosomotrophic agents, promotes the death of GIST cells both in vitro and in vivo. Thus, combining imatinib with autophagy inhibition represents a potentially valuable strategy to promote GIST cytotoxicity and to diminish both cellular quiescence and acquired resistance in GIST patients.     

<Emphasis Type="Italic">Punica granatum</Emphasis>(Pomegranate) juice provides an HIV-1 entry inhibitor and candidate topical microbicide

Background  

For ≈ 24 years the AIDS pandemic has claimed ≈ 30 million lives, causing ≈ 14,000 new HIV-1 infections daily worldwide in 2003. About 80% of infections occur by heterosexual transmission. In the absence of vaccines, topical microbicides, expected to block virus transmission, offer hope for controlling the pandemic. Antiretroviral chemotherapeutics have decreased AIDS mortality in industrialized countries, but only minimally in developing countries. To prevent an analogous dichotomy, microbicides should be: acceptable; accessible; affordable; and accelerative in transition from development to marketing. Already marketed pharmaceutical excipients or foods, with established safety records and adequate anti-HIV-1 activity, may provide this option.     

Dietary L-leucine improves the anemia in a mouse model for Diamond-Blackfan anemia

Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by a functional haploinsufficiency of genes encoding for ribosomal proteins. Recently, a case study reported a patient who became transfusion-independent in response to treatment with the amino acid L-leucine. Therefore, we have validated the therapeutic effect of L-leucine using our recently generated mouse model for RPS19-deficient DBA. Administration of L-leucine significantly improved the anemia in Rps19-deficient mice (19% improvement in hemoglobin concentration; 18% increase in the number of erythrocytes), increased the bone marrow cellularity, and alleviated stress hematopoiesis. Furthermore, the therapeutic response to L-leucine appeared specific for Rps19-deficient hematopoiesis and was associated with down-regulation of p53 activity. Our study supports the rationale for clinical trials of L-leucine as a therapeutic agent for DBA.     

Discovery of an orally active small-molecule irreversible inhibitor of protein disulfide isomerase for ovarian cancer treatment

Protein disulfide isomerase (PDI), an endoplasmic reticulum chaperone protein, catalyzes disulfide bond breakage, formation, and rearrangement. The effect of PDI inhibition on ovarian cancer progression is not yet clear, and there is a need for potent, selective, and safe small-molecule inhibitors of PDI. Here, we report a class of propynoic acid carbamoyl methyl amides (PACMAs) that are active against a panel of human ovarian cancer cell lines. Using fluorescent derivatives, 2D gel electrophoresis, and MS, we established that PACMA 31, one of the most active analogs, acts as an irreversible small-molecule inhibitor of PDI, forming a covalent bond with the active site cysteines of PDI. We also showed that PDI activity is essential for the survival and proliferation of human ovarian cancer cells. In vivo, PACMA 31 showed tumor targeting ability and significantly suppressed ovarian tumor growth without causing toxicity to normal tissues. These irreversible small-molecule PDI inhibitors represent an important approach for the development of targeted anticancer agents for ovarian cancer therapy, and they can also serve as useful probes for investigating the biology of PDI-implicated pathways.     

Multiple myeloma presenting as acute pancreatitis.

Acute pancreatitis is a very uncommon presenting feature of multiple myeloma. We report an elderly non-alcoholic man presenting with acute abdominal pain and rapidly progressing renal failure. Investigations revealed lytic lesions in the vertebrae and skull, M band on urine electrophoresis, and radiological and biochemical evidence of acute pancreatitis. The patient died despite conservative management of the pancreatitis.     

Silane treatment effects on glass/resin interfacial shear strengths.

OBJECTIVE: Methacrylic resin-based dental composites normally use a bifunctional silane coupling agent with an intermediary carbon connecting segment to provide the interfacial phase that holds together the organic polymer matrix with the reinforcing inorganic phase. In this study, fiber pull-out tests were used to measure the interfacial bond strength at the fiber-matrix interface. METHODS: Glass fibers (approximately 30 microm diameter, 8 x 10 (-2)m length, MoSci) were silanated using various concentrations (1, 5 and 10%) of either 3-methacryloxypropyl-trimethoxysilane (MPS) or glycidoxypropyltrimethoxy-silane (GPS) in acetone (99.8%). Rubber (poly(butadiene/acrylonitrile), amine terminated, M(w) 5500) molecules were also attached to the fiber surface via GPS molecules. The resin was comprised of a 60/40 mixture of Bis-phenol-A bis-(2-hydroxypropyl)-methacrylate (BisGMA) and tri (ethylene glycol) dimethacrylate (TEGDMA). A bead of resin approximately 2-4 x 10(-3)m in embedded length was placed on the treated fibers and light cured. The load required to pull the fiber out of the resin was converted to shear bond strength. RESULTS: Interfacial shear strengths were greater for silanated specimens compared with unsilanated, and for MPS compared with GPS. The same set of samples soaked in 50:50 (v/v) mixtures of ethanol and distilled water for a period of 1 month showed a decrease in properties. SIGNIFICANCE: A positive correlation was found between the amount of silane on the filler surface and the property loss after soaking. Rubber treatment provided improvement in interfacial strength. 5% MPS samples had the highest strength both in soaked as well as unsoaked samples.     

Identification of phenolic constituents and antioxidant activity of Aloe barbadensis flower extracts

Aloe vera (Aloe barbadensis Miller) has been used as topical and oral therapeutic. This research highlights the phenolic constituents’ profile and antioxidant activity of 70% ethanol extracts of Aloe vera flower for the first time. The ethanol-based extracts showed the inhibition for linoleic acid oxidation and free radical-induced DNA damage. Among about 11 phenolic constituents of the extract, identified by using high performance liquid chromatography (HPLC), the content of vanillic acid was highest, corresponding to strong antioxidant activities of the extract. The extracts elevated superoxide dismutase, catalase, and glutathione peroxidase enzymes activities in the liver tissue of hydrogen peroxide-treated BALB/c mice. The radical-scavenging activities of the extracts were well-correlated to the total phenolic content. Therefore, Aloe bardadensis flower might be an effective source of natural antioxidant.     

Therapeutic effects of Ligularia stenocephala against inflammatory bowel disease by regulating antioxidant and inflammatory mediators

In this report, we studied the effect of leaf extracts of Ligularia stenocephala (LS) on inflammatory bowel disease (IBD) by regulating antioxidant and inflammatory mediators. The water extracts (LSW) exhibited more antioxidant activity than that of ethanol extracts (LSE). The extracts suppress the formation of nitric oxide by down-regulating the inducible nitric oxide synthase and pro-inflammatory cytokines (eg tumor necrosis factor alpha, interleukin (IL)-6, IL-10 and IL-1β expression) through the suppression of nuclear factor-?β activation and mitogen-activated protein kinases phosphorylation in lipopolysaccharide-stimulated macrophage cells. Our in vivo study reveals that the extracts could suppress tissue damage significantly in mice colon. The expression regarding immune-related cytokines was also down-regulated by the extracts of LS leaf. Thus, it is concluded that the extracts could be used as a functional food, which could reduce the formation of oxidants, inflammation and IBD effectively.     

A QSAR investigation of the role of hydrophobicity in regulating mutagenicity in the ames test: 1. Mutagenicity of aromatic and heteroaromatic amines in Salmonella typhimurium TA98 and TA100

Quantitative structure-activity relationships (QSAR) have been derived for the mutagenic activity of 88 aromatic and heteroaromatic amines acting on Salmonella typhimurium TA98 + S9 and 67 amines acting on TA100 + S9. Mutagenic activity is linearly dependent on hydrophobicity, the energy of the highest occupied molecular orbital, and the energy of the lowest unoccupied molecular orbital of the amine. The dependence of mutagenic activity on hydrophobicity and electronic effects is nearly identical for TA98 and TA100. Mutagenic activity in TA98 is also found to depend on the size of the aromatic ring system. Different QSARs are derived for the mutagenic activity of hydrophilic amines (log P < 1) acting on either TA98 or TA100. The mechanism of amine activation and reaction with DNA is considered in light of these findings.     

Indications for and technique of first metatarsophalangeal joint arthroscopy

BACKGROUND: Arthroscopy of the great toe metatarsophalangeal joint has been used for a variety of indications, ranging from synovitis to osteochondral defects. The purpose of the present study was to define the indications for arthroscopy, assess its efficacy, and demonstrate the limitations of this procedure. METHODS: Hallux metatarsophalangeal joint arthroscopy was used in 20 patients (25 feet). Indications included degenerative disease with early osteophytosis, chondromalacia, osteochondral defects, loose bodies, arthrofibrosis, synovitis, gouty arthritis, first metatarsophalangeal joint pain with no obvious findings clinically and radiographically in young adults, and intra-articular fracture of the first metatarsophalangeal joint. All patients had a minimal followup of 2 years and were evaluated clinically and radiographically. RESULTS: Arthroscopic surgery resulted in pain free first metatarsophalangeal joints in 95% (19 of 20 patients). Patients with degenerative disease had a pain-free joint for a minimum of 2 years. The patients with gouty arthritis and intra-articular fracture had good functional outcomes. Arthroscopy also helped in identifying the pathology in painful joints with no obvious radiographic features that included conditions such as 'meniscoid' and other impingement lesions. CONCLUSION: Arthroscopy of the first metatarsophalangeal joint is not suitable for patients with extensive degenerative changes and large osteophytes and those that require cheilectomy or arthrodesis. Arthroscopic management of certain painful hallucal metatarsophalangeal joints is a specialized technique, which if performed for the right indications, gives a favorable outcome with minimal complications.