Investigation of and gene polymorphisms and their association with susceptibility to colorectal cancer.

Background: This study investigates the association of single nucleotide polymorphism in glutathione S transferase P1 (rs1695 and rs1138272) and phosphatase and TENsin homolog (rs701848 and rs2735343) with the risk of colorectal cancer (CRC).

Patients And Methods: In this case-control study, 250 healthy controls and 200 CRC patients were enrolled. All subjects were divided into 3 groups: healthy control, patients, and overall (control + patients).

Engineered Age-Mimetic Breast Cancer Models Reveal Differential Drug Responses in Young and Aged Microenvironments.

Aging is one of the most significant risk factors for breast cancer. With the growing interests in the alterations of the aging breast tissue microenvironment, it has been identified that aging is related to tumorigenesis, invasion, and drug resistance. However, current pre-clinical disease models often neglect the impact of aging and sometimes result in worse clinical outcomes.

Differential glycosylation in mutant vitamin D-binding protein decimates the binding stability of vitamin D.

Vitamin D (VD) is produced by the skin upon exposure to sunlight or is obtained from dietary sources. Several risk factors are associated with VD deficiency including mutations and post-translational modifications in its transport protein known as vitamin D binding protein (VDBP) or GC-globulin. The two common single nucleotide polymorphisms rs7041 and rs4588 create three major isoforms of VDBP, including GC-1F also called wild type, GC1S, and GC-2.

The junior doctor contract 2 years on: one trust's experience of exception reporting.

The new junior doctor contract allows trainees to exception report when they breach safe working hours. After a full year of foundation year 1 rotations, analysis from a large NHS trust in London showed that exception reporting works to highlight rota and working issues. It is unsurprising that trainees are busy but simple things such as competent infrastructure and senior support could go a long way to improving working conditions.

Fibulin-7, a heparin binding matricellular protein, promotes renal tubular calcification in mice.

Ectopic calcification occurs during development of chronic kidney disease and has a negative impact on long-term prognosis. The precise molecular mechanism and prevention strategies, however, are not established. Fibulin-7 (Fbln7) is a matricellular protein structurally similar to elastogenic short fibulins, shown to bind dental mesenchymal cells and heparin.

Adipocyte Xbp1s overexpression drives uridine production and reduces obesity.

Objective: The spliced transcription factor Xbp1 (Xbp1s), a transducer of the unfolded protein response (UPR), regulates lipolysis. Lipolysis is stimulated by fasting when uridine synthesis is also activated in adipocytes.

Methods: Here we have examined the regulatory role Xbp1s in stimulation of uridine biosynthesis in adipocytes and triglyceride mobilization using inducible mouse models.

Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism.

Three-prime repair exonuclease 1 knockout (Trex1) mice suffer from systemic inflammation caused largely by chronic activation of the cyclic GMP-AMP synthase-stimulator of interferon genes-TANK-binding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) signaling pathway. We showed previously that Trex1-deficient cells have reduced mammalian target of rapamycin complex 1 (mTORC1) activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1 mice and cells that revealed both cellular and systemic metabolic defects, including reduced mitochondrial respiration and increased glycolysis, energy expenditure, and fat metabolism.

Targeting glutamine metabolism sensitizes pancreatic cancer to PARP-driven metabolic catastrophe induced by ß-lapachone.

Background: Pancreatic ductal adenocarcinomas (PDA) activate a glutamine-dependent pathway of cytosolic nicotinamide adenine dinucleotide phosphate (NADPH) production to maintain redox homeostasis and support proliferation. Enzymes involved in this pathway (GLS1 (mitochondrial glutaminase 1), GOT1 (cytoplasmic glutamate oxaloacetate transaminase 1), and GOT2 (mitochondrial glutamate oxaloacetate transaminase 2)) are highly upregulated in PDA, and among these, inhibitors of GLS1 were recently deployed in clinical trials to target anabolic glutamine metabolism. However, single-agent inhibition of this pathway is cytostatic and unlikely to provide durable benefit in controlling advanced disease.

Distinct regulatory mechanisms governing embryonic versus adult adipocyte maturation.

Pathological expansion of adipose tissue contributes to the metabolic syndrome. Distinct depots develop at various times under different physiological conditions. The transcriptional cascade mediating adipogenesis is established in vitro, and centres around a core program involving PPARγ and C/EBPα.

The estrogen-related receptor α inverse agonist XCT 790 is a nanomolar mitochondrial uncoupler.

XCT 790 is widely used to inhibit estrogen-related receptor α (ERRα) activity as an inverse agonist. Here, we report that XCT 790 potently activates AMP kinase (AMPK) in a dose-dependent and ERRα-independent manner, with active concentrations more than 25-fold below those typically used to perturb ERRα. AMPK activation is secondary to inhibition of energy production as XCT 790 rapidly depletes the pool of cellular ATP.

Mutation of mouse Samd4 causes leanness, myopathy, uncoupled mitochondrial respiration, and dysregulated mTORC1 signaling.

Sterile alpha motif domain containing protein 4 (Samd4) is an RNA binding protein that mediates translational repression. We identified a Samd4 missense mutation, designated supermodel, that caused leanness and kyphosis associated with myopathy and adipocyte defects in C57BL/6J mice. The supermodel mutation protected homozygous mice from high fat diet-induced obesity, likely by promoting enhanced energy expenditure through uncoupled mitochondrial respiration.

Pin1 null mice exhibit low bone mass and attenuation of BMP signaling.

Bone is constantly formed and resorbed throughout life by coordinated actions of osteoblasts and osteoclasts. However, the molecular mechanisms involved in osteoblast function remain incompletely understood. Here we show, for the first time, that the peptidyl-prolyl isomerase PIN1 controls the osteogenic activity of osteoblasts.

SNS-032 prevents hypoxia-mediated glioblastoma cell invasion by inhibiting hypoxia inducible factor-1alpha expression.

Hypoxia and hypoxia inducible factor-1alpha (HIF-1alpha) play a critical role in glioblastoma (GBM) which is characterized by highly aggressive and widespread cell invasion into adjacent normal brain tissue. The purpose of this study was to investigate the effect of the novel aminothiazole com-pound SNS-032 in glioblastoma cell invasion under hypoxic condition. SNS-032 is a potent and selective inhibitor of cyclin-dependent kinases 2, 7 and 9 and inhibits both cell cycle and transcription.

The death domain-containing kinase RIP1 regulates p27(Kip1) levels through the PI3K-Akt-forkhead pathway.

Elucidating the cross-talk between inflammatory and cell proliferation pathways might provide important insights into the pathogenesis of inflammation-induced cancer. Here, we show that the receptor-interacting protein 1 (RIP1)-an essential mediator of inflammation-induced nuclear factor-kappaB (NF-kappaB) activation-regulates p27(Kip1) levels and cell-cycle progression. RIP1 regulates p27(Kip1) levels by an NF-kappaB-independent signal that involves activation of the phosphatidylinositol 3-kinase (PI3K)-Akt-forkhead pathway.

SNS-032 prevents tumor cell-induced angiogenesis by inhibiting vascular endothelial growth factor.

Cell proliferation, migration, and capillary network formation of endothelial cells are the fundamental steps for angiogenesis, which involves the formation of new blood vessels. The purpose of this study is to investigate the effect of a novel aminothiazole SNS-032 on these critical steps for in vitro angiogenesis using a coculture system consisting of human umbilical vein endothelial cells (HUVECs) and human glioblastoma cells (U87MG). SNS-032 is a potent selective inhibitor of cyclin-dependent kinases 2, 7, and 9, and inhibits both transcription and cell cycle.

Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion.

Hypoxia and hypoxia-inducible factor-1 (HIF-1) play a critical role in glioblastoma multiforme (GBMs). CXCR4 is involved in angiogenesis and is upregulated by HIF-1alpha. CXCR4 is a chemokine receptor for stromal cell-derived factor-1 (SDF-1)alpha, also known as CXCL12.

Correlation of HER1/EGFR expression and degree of radiosensitizing effect of the HER1/EGFR-tyrosine kinase inhibitor erlotinib.

Epidermal growth factor receptor (HER1/EGFR)-mediated signal transduction pathways are important in cellular response to ionizing radiation. High HER1/EGFR expression on cancer cells may contribute to radioresistance. In this pre-clinical study, we evaluated the radiosensitizing effect of erlotinib, a small molecule HER1/EGFR inhibitor in three human cancer cell lines with different HER1/EGFR expression--A431 (very high expression), H157 (moderate expression) and H460 (low expression).

Noscapine inhibits hypoxia-mediated HIF-1alpha expression andangiogenesis in vitro: a novel function for an old drug.

Overexpression of hypoxia-inducible factor-1 (HIF-1) is a common feature in solid malignancies related to oxygen deficiency. Since increased HIF-1 expression correlates with advanced disease stage, increased angiogenesis and poor prognosis, HIF-1 and its signaling pathway have become targets for cancer chemotherapy. In this study, we identified noscapine to be a novel small molecule inhibitor of the HIF-1 pathway based on its structure-function relation-ships with HIF-1 pathway inhibitors belonging to the benzylisoquinoline class of plant metabolites and/or to microtubule binding agents.

The cyclin-dependent kinase 2 inhibitor down-regulates interleukin-1beta-mediated induction of cyclooxygenase-2 expression in human lung carcinoma cells.

Overexpression of cyclooxygenase-2 (COX-2) is frequently observed in several human cancers, including lung, colon, and head and neck. Malignancies are also associated with the dysregulation of cell cycle events and concomitant elevated activity of cyclin-dependent kinases (CDK). CDK2 is a key cell cycle regulatory protein that controls the transition of cells from G(1) to S phase.

Flavopiridol downregulates hypoxia-mediated hypoxia-inducible factor-1alpha expression in human glioma cells by a proteasome-independent pathway: implications for in vivo therapy.

Angiogenesis is a critical step required for sustained tumor growth and tumor progression. The stimulation of endothelial cells by cytokines secreted by tumor cells such as vascular endothelial growth factor (VEGF) induces their proliferation and migration. This is a prominent feature of high-grade gliomas.

Stromal cell-derived factor-1alpha and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor.

The genetic hallmark of hemangioblastomas and clear cell-renal cell carcinomas (CC-RCCs) is loss-of-function of the von Hippel-Lindau (VHL) tumor suppressor protein. VHL is required for oxygen-dependent degradation of hypoxia-inducible factor-1alpha (HIF-1alpha). In hemangioblastomas and CC-RCCs, HIF-1alpha is constitutively overexpressed leading to increased transcription of HIF-1-regulated genes, including vascular endothelial growth factor (VEGF).

Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain.

Invasion into surrounding brain tissue is a fundamental feature of gliomas and the major reason for treatment failure. The process of brain invasion in gliomas is not well understood. Differences in gene expression and/or gene products between invading and noninvading glioma cells may identify potential targets for new therapies.

Reliability of serum iron, ferritin, nitrite, and association with risk of renal cancer in women.

Reliability of serum levels of iron, ferritin and nitrite (NO(2)(-)) over a 2-year period were evaluated in 40 healthy women (20 pre-menopausal and 20 post-menopausal), ages 39-65 years, from the New York University Women's Health Study (NYUWHS). Three blood samples per woman collected at yearly intervals were analyzed. Reliability coefficients (RCs) of serum iron, ferritin, and nitrite were 0.

Calcein as a fluorescent iron chemosensor for the determination of low molecular weight iron in biological fluids.

The fluorescence quenching of calcein (CA) is not iron specific and results in a negative calibration curve. In the present study, deferoxamine (DFO), a strong iron chelator, was used to regenerate the fluorescence quenched by iron. Therefore, the differences in fluorescence reading of the same sample with or without addition of DFO are positively and specifically proportional to the amounts of iron.

Roles of bioavailable iron and calcium in coal dust-induced oxidative stress: possible implications in coal workers' lung disease.

Marked regional differences in prevalence of pneumoconiosis are apparent in the US despite comparable dust exposure. In the present study, we examined the ability of 28 coal samples to release bioavailable iron (BAI) and calcium, as well as other metals such as Cr, Ni, Cu, and Co, from three coal mine regions in Utah (UT), West Virginia (WV), and Pennsylvania (PA), respectively. BAI is defined as iron (both Fe2+ and Fe3+) released by the coals in 10 mM phosphate solution, pH 4.