Similarity of Serum and Plasma Insulin-like Growth Factor Concentrations.

Background: Insulin-like growth factors (IGFs) are implicated in many normal physiological processes and pathological states, including cancer. For large consortia projects, it may be necessary to make comparisons among studies with different specimens that were not collected specifically to optimize the measurement of IGFs.

Objective: This study aimed to compare IGFs in matched serum and plasma samples.

Human Kidney Disease-causing INF2 Mutations Perturb Rho/Dia Signaling in the Glomerulus.

Mutations in Inverted Formin 2 (INF2), a diaphanous formin family protein that regulates actin cytoskeleton dynamics, cause focal segmental glomerulosclerosis (FSGS) and Charcot-Marie-Tooth Disease (CMT) in humans. In addition to directly remodeling actin filaments in vitro, we have shown that INF2 regulates intracellular actin dynamics and actin dependent cellular behavior by opposing Rhoa/Dia signaling. As a step towards a better understanding of the human kidney disease, we wanted to explore the relevance of these findings to the in vivo situation.

Circulating Leptin and Risk of Pancreatic Cancer: A Pooled Analysis From 3 Cohorts.

Adiposity is associated with pancreatic cancer; however, the underlying mechanism(s) is uncertain. Leptin is an adipokine involved in metabolic regulation, and obese individuals have higher concentrations. We conducted a pooled, nested case-control study of cohort participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, and the Cancer Prevention Study II Nutrition Cohort to investigate whether prediagnostic serum leptin was associated with pancreatic cancer.

Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial.

Background: In preclinical work and retrospective population studies, the anti-diabetic drug metformin has been associated with antineoplastic activity and decreased burden of many cancers, including pancreatic cancer. There is therefore interest in the hypothesis that this drug might be repurposed for indications in oncology. We aimed to assess the efficacy of the addition of metformin to a standard systemic therapy in patients with advanced pancreatic cancer, and provide the first report of a clinical trial with a survival endpoint of metformin for an oncological indication.

Copy Number Variation at the APOL1 Locus.

Two coding variants in the APOL1 gene (G1 and G2) explain most of the high rate of kidney disease in African Americans. APOL1-associated kidney disease risk inheritance follows an autosomal recessive pattern: The relative risk of kidney disease associated with inheritance of two high-risk variants is 7-30 fold, depending on the specific kidney phenotype. We wished to determine if the variability in phenotype might in part reflect structural differences in APOL1 gene.

Alpha-actinin binding kinetics modulate cellular dynamics and force generation.

The actin cytoskeleton is a key element of cell structure and movement whose properties are determined by a host of accessory proteins. Actin cross-linking proteins create a connected network from individual actin filaments, and though the mechanical effects of cross-linker binding affinity on actin networks have been investigated in reconstituted systems, their impact on cellular forces is unknown. Here we show that the binding affinity of the actin cross-linker α-actinin 4 (ACTN4) in cells modulates cytoplasmic mobility, cellular movement, and traction forces.

Idiopathic pediatric chronic kidney disease: can genomic technology crack the case?

In children, chronic kidney disease (CKD) that results from structural abnormalities and glomerular injury is readily diagnosed; however, most cases of pediatric CKD are of unknown etiology. In this issue of the JCI, Verbitsky and colleagues used chromosomal microarrays to evaluate genomic variation in children with CKD. Compared with control individuals, a substantial proportion of children with idiopathic CKD had clearly identifiable genomic imbalances.

Multidrug and toxin extrusion 1 and human organic cation transporter 1 polymorphisms in patients with castration-resistant prostate cancer receiving metformin (SAKK 08/09).

Background: This study was initiated to explore the impact of organic cation transporter 1 (OCT1) and multidrug and toxin extrusion transporter 1 (MATE1) genetic polymorphisms on toxicity, and clinical activity of metformin in patients with castration-resistant prostate cancer (CRPC).

Methods: The SAKK 08/09 trial included 44 patients with CRPC to receive single-agent metformin 1000 mg two times a day until disease progression or unwanted toxicity. Drug pathway-associated gene polymorphisms of OCT1 (rs622342) and MATE1 (rs2289669) were assessed.

Germ line knockout of IGFBP-3 reveals influences of the gene on mammary gland neoplasia.

Insulin-like growth factor binding protein-3 (IGFBP-3) is an important carrier protein for insulin-like growth factors (IGFs) in the circulation. IGFBP-3 antagonizes the growth-promoting and anti-apoptotic activities of IGFs in experimental systems, but in certain contexts can increase IGF bioactivity, probably by increasing its half-life. The goal of this study was to investigate the role of IGFBP-3 in breast carcinogenesis and breast cancer metastasis.

mTOR coordinates protein synthesis, mitochondrial activity and proliferation.

Protein synthesis is one of the most energy consuming processes in the cell. The mammalian/mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that integrates a multitude of extracellular signals and intracellular cues to drive growth and proliferation. mTOR activity is altered in numerous pathological conditions, including metabolic syndrome and cancer.

Metformin and Rapamycin Reduce Pancreatic Cancer Growth in Obese Prediabetic Mice by Distinct MicroRNA-Regulated Mechanisms.

Metformin treatment is associated with a decreased risk and better prognosis of pancreatic cancer (PC) in patients with type 2 diabetes, but the mechanism of metformin's PC growth inhibition in the context of a prediabetic state is unknown. We used a Panc02 pancreatic tumor cell transplant model in diet-induced obese (DIO) C57BL/6 mice to compare the effects of metformin and the direct mammalian target of rapamycin (mTOR) inhibitor rapamycin on PC growth, glucose regulation, mTOR pathway signaling, and candidate microRNA (miR) expression. In DIO/prediabetic mice, metformin and rapamycin significantly reduced pancreatic tumor growth and mTOR-related signaling.

Clinical Features and Histology of Apolipoprotein L1-Associated Nephropathy in the FSGS Clinical Trial.

Genetic variants in apolipoprotein L1 (APOL1) confer risk for kidney disease. We sought to better define the phenotype of APOL1-associated nephropathy. The FSGS Clinical Trial involved 138 children and young adults who were randomized to cyclosporin or mycophenolate mofetil plus pulse oral dexamethasone with a primary outcome of proteinuria remission.

Recovery of olfactory function induces neuroplasticity effects in patients with smell loss.

The plasticity of brain function, especially reorganization after stroke or sensory loss, has been investigated extensively. Based upon its special characteristics, the olfactory system allows the investigation of functional networks in patients with smell loss, as it holds the unique ability to be activated by the sensorimotor act of sniffing, without the presentation of an odor. In the present study, subjects with chronic peripheral smell loss and healthy controls were investigated using functional magnetic resonance imaging (fMRI) to compare functional networks in one of the major olfactory areas before and after an olfactory training program.

Competing risks of death in younger and older postmenopausal breast cancer patients.

Aim: To show a new paradigm of simultaneously testing whether breast cancer therapies impact other causes of death.

Methods: MA.14 allocated 667 postmenopausal women to 5 years of tamoxifen 20 mg/daily ± 2 years of octreotide 90 mg, given by depot intramuscular injections monthly.

The use of aspirin and the risk of mortality in patients with prostate cancer.

Purpose: The association between the use of aspirin and mortality in patients with prostate cancer remains uncertain. We determine whether the use of aspirin in patients with prostate cancer is associated with a decreased risk of prostate cancer mortality and all cause mortality.

Materials And Methods: Using the United Kingdom National Cancer Data Repository, Clinical Practice Research Datalink and associated databases, we identified a cohort of men with nonmetastatic prostate cancer between 1998 and 2009, followed until 2012.

Metformin: from mechanisms of action to therapies.

Metformin is currently the first-line drug treatment for type 2 diabetes. Besides its glucose-lowering effect, there is interest in actions of the drug of potential relevance to cardiovascular diseases and cancer. However, the underlying mechanisms of action remain elusive.

Serine deprivation enhances antineoplastic activity of biguanides.

Metformin, a biguanide widely used in the treatment of type II diabetes, clearly exhibits antineoplastic activity in experimental models and has been reported to reduce cancer incidence in diabetics. There are ongoing clinical trials to evaluate its antitumor properties, which may relate to its fundamental activity as an inhibitor of oxidative phosphorylation. Here, we show that serine withdrawal increases the antineoplastic effects of phenformin (a potent biguanide structurally related to metformin).

Prediagnostic plasma IGFBP-1, IGF-1 and risk of prostate cancer.

Insulin-like growth factor (IGF)-1 is associated with a higher risk of prostate cancer. IGF-binding protein (IGFBP)-1, a marker for insulin activity, also binds IGF-1 and inhibits its action. Data on IGFBP-1 and prostate cancer risk are sparse and whether the IGF and insulin axes interact to affect prostate cancer carcinogenesis is unknown.

Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development.

Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months. PDAC has been linked with obesity and glucose intolerance, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from individuals with pancreatic cancer (cases) and matched controls from four prospective cohort studies.

Differential effects of metformin on breast cancer proliferation according to markers of insulin resistance and tumor subtype in a randomized presurgical trial.

Treatment of diabetics with metformin is associated with decreased breast cancer risk in observational studies, but it remains unclear if this drug has clinical antineoplastic activity. In a recent presurgical trial, we found a heterogeneous effect of metformin on breast cancer proliferation (ki-67) depending upon insulin resistance (HOMA index). Here, we determined the associations of additional serum biomarkers of insulin resistance, tumor subtype, and drug concentration with ki-67 response to metformin.

Associations between time spent sitting and cancer-related biomarkers in postmenopausal women: an exploration of effect modifiers.

Purpose: Despite evidence that prolonged periods of sitting may influence biological mediators of cancer development, few studies have considered these relationships in a cancer-specific context.

Methods: This cross-sectional study included 755 postmenopausal women enrolled in an ancillary study of the Women's Health Initiative. Plasma levels of Insulin-like growth factor-I (IGF-I), IGF-binding protein-3, leptin, insulin, C-peptide, C-reactive protein (CRP), and Interleukin (IL)-6 were measured.

Post-diagnostic use of beta-blockers and the risk of death in patients with prostate cancer.

Background: Recent observational studies have produced conflicting results with respect to beta-blocker use after prostate cancer diagnosis and mortality outcomes.

Objective: To determine whether post-diagnostic use of beta-blockers is associated with prostate cancer mortality and all-cause mortality.

Patients And Methods: A cohort of 6270 men newly-diagnosed with non-metastatic prostate cancer between 1st April 1998, and 31st December 2009, followed until 1st October 2012, was identified using large population-based electronic databases from the United Kingdom.

Metformin directly acts on mitochondria to alter cellular bioenergetics.

Background: Metformin is widely used in the treatment of diabetes, and there is interest in 'repurposing' the drug for cancer prevention or treatment. However, the mechanism underlying the metabolic effects of metformin remains poorly understood.

Methods: We performed respirometry and stable isotope tracer analyses on cells and isolated mitochondria to investigate the impact of metformin on mitochondrial functions.

Familial FSGS.

Focal segmental glomerulosclerosis (FSGS) and nephrotic syndrome can be caused by rare highly penetrant mutations in number of genes. FSGS can follow both recessive and dominant inheritance patterns. In general, recessive forms present early, whereas the autosomal dominant forms present in adolescence or adulthood.