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1.
J Cyst Fibros ; 20(6): 937-940, 2021 11.
Article in English | MEDLINE | ID: mdl-32952083

ABSTRACT

BACKGROUND: Infant pulmonary function testing using the raised volume rapid thoracoabdominal compression (RVRTC) technique requires sedation and is time consuming. Many cystic fibrosis (CF) centers do not have access to equipment and the utility of routine testing remains to be determined. We aimed to assess whether RVRTC tests performed during infancy predict spirometry at early school age. METHODS: The RVRTC-based forced expiratory flow measures in infants were compared to the first adequately performed spirometry at school age. All tests were carried out during routine clinic visits and expressed as age related z-scores; only test occasions where patients were considered stable were included in the analysis. RESULTS: 47 patients had useable infant RVRTC as well as matching school age spirometry data. There was weak correlation between infant FEV0.5 and early school age FEV1 (R = 0.29, p = 0.05). Four infants had significantly low zFEV0.5 (zFEV0.5 < -1.96), of which one of those remained under that limit at childhood. Changes in spirometry between infancy and early childhood were negatively correlated to baseline FEV0.5 (R = 0.61 p<0.001) reflecting that the change was driven by where individuals started off with. There was no difference in clinical characteristics between those improving, those with stable or deteriorating in lung function. CONCLUSION: Infant RVRTC measures were not predictive of pulmonary function in early school age, likely due to the high proportion of measures of forced expiratory flows within the normal range at both time points.


Subject(s)
Cystic Fibrosis/physiopathology , Spirometry , Female , Forced Expiratory Volume , Humans , Infant , Infant, Newborn , Male , Predictive Value of Tests
2.
J Phys Condens Matter ; 30(10): 105602, 2018 03 14.
Article in English | MEDLINE | ID: mdl-29393067

ABSTRACT

Properties of electrons in non-crystalline (alias disordered) systems has been a very active research topic for over half a century, since Anderson's ground breaking paper on localization. In strongly disordered systems electrons become Anderson and Mott localized. Interactions become important because screening by localized electrons is ineffective. Dynamical theories for such systems have long been controversial. Nevertheless one theory came to prominence in the literature and is often invoked and/or used. It is shown here that that theory is unsatisfactory in several aspects. It is based on the one-particle density of states, which turns out to be irrelevant to the problem it addresses. Another shortcoming is an implicit conjecture that interacting electrons move independently of each other. The theory is also in questionable agreement with experiment. It is shown that two other theories are free of those problems. They are useful for different types of studies, are compatible with each other and in agreement with experiment.

3.
Prostate Cancer Prostatic Dis ; 20(4): 418-423, 2017 12.
Article in English | MEDLINE | ID: mdl-28653675

ABSTRACT

BACKGROUND: Obesity, a cause of subclinical inflammation, is associated with increased risk of high-grade prostate cancer (PC) and poor outcomes. Whether inflammation occurs in periprostatic white adipose tissue (WAT), and contributes to the negative impact of obesity on PC aggressiveness, is unknown. METHODS: In a single-center, cross-sectional design, men with newly diagnosed PC undergoing radical prostatectomy were eligible for study participation. The primary objective was to examine the prevalence of periprostatic WAT inflammation defined by the presence of crown-like structures (CLS-P) as detected by CD68 immunohistochemistry. Secondary objectives were to explore the clinical and systemic correlates of periprostatic WAT inflammation. Tumor characteristics and host factors including BMI, adipocyte diameter, and circulating levels of lipids, adipokines, and other metabolic factors were measured. Wilcoxon rank-sum, Chi-square, or Fisher's exact tests, and generalized linear regression were used to examine the association between WAT inflammation and tumor and host characteristics. RESULTS: Periprostatic fat was collected from 169 men (median age 62 years; median BMI 28.3). Periprostatic WAT inflammation was identified in 49.7% of patients and associated with higher BMI (P=0.02), larger adipocyte size (P=0.004) and Gleason grade groups IV/V tumors (P=0.02). The relationship between WAT inflammation and high Gleason grade remained significant after adjusting for BMI (P=0.04). WAT inflammation correlated with higher circulating levels of insulin, triglycerides, and leptin/adiponectin ratio, and lower high density lipoprotein cholesterol, compared to those without WAT inflammation (P's <0.05). CONCLUSION: Periprostatic WAT inflammation is common in this cohort of men with PC and is associated with high-grade PC.


Subject(s)
Adipose Tissue, White/pathology , Inflammation/pathology , Obesity/pathology , Prostatic Neoplasms/pathology , Adipose Tissue, White/metabolism , Aged , Body Mass Index , Humans , Inflammation/complications , Inflammation/metabolism , Inflammation/surgery , Male , Middle Aged , Neoplasm Grading , Obesity/complications , Obesity/metabolism , Obesity/surgery , Prostate/metabolism , Prostate/pathology , Prostate/surgery , Prostatectomy , Prostatic Neoplasms/complications , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/surgery
4.
Ann Oncol ; 28(7): 1560-1568, 2017 Jul 01.
Article in English | MEDLINE | ID: mdl-28379421

ABSTRACT

BACKGROUND: We hypothesized that increased baseline BMI and BMI change would negatively impact clinical outcomes with adjuvant breast cancer systemic therapy. METHODS: Data from chemotherapy trials MA.5 and MA.21; endocrine therapy MA.12, MA.14 and MA.27; and trastuzumab HERA/MA.24 were analyzed. The primary objective was to examine the effect of BMI change on breast cancer-free interval (BCFI) landmarked at 5 years; secondary objectives included BMI changes at 1 and 3 years; BMI changes on disease-specific survival (DSS) and overall survival (OS); and effects of baseline BMI. Stratified analyses included trial therapy and composite trial stratification factors. RESULTS: In pre-/peri-/early post-menopausal chemotherapy trials (N = 2793), baseline BMI did not impact any endpoint and increased BMI from baseline did not significantly affect BCFI (P = 0.85) after 5 years although it was associated with worse BCFI (P = 0.03) and DSS (P = 0.07) after 1 year. BMI increase by 3 and 5 years was associated with better DSS (P = 0.01; 0.01) and OS (P = 0.003; 0.05). In pre-menopausal endocrine therapy trial MA.12 (N = 672), patients with higher baseline BMI had worse BCFI (P = 0.02) after 1 year, worse DSS (P = 0.05; 0.004) after 1 and 5 years and worse OS (P = 0.01) after 5 years. Increased BMI did not impact BCFI (P = 0.90) after 5 years, although it was associated with worse BCFI (P = 0.01) after 1 year. In post-menopausal endocrine therapy trials MA.14 and MA.27 (N = 8236), baseline BMI did not significantly impact outcome for any endpoint. BMI change did not impact BCFI or DSS after 1 or 3 years, although a mean increased BMI of 0.3 was associated with better OS (P = 0.02) after 1 year. With the administration of trastuzumab (N = 1395) baseline BMI and BMI change did not significantly impact outcomes. CONCLUSIONS: Higher baseline BMI and BMI increases negatively affected outcomes only in pre-/peri-/early post-menopausal trial patients. Otherwise, BMI increases similar to those expected in healthy women either did not impact outcome or were associated with better outcomes. CLINICAL TRIALS NUMBERS: CAN-NCIC-MA5; National Cancer Institute (NCI)-V90-0027; MA.12-NCT00002542; MA.14-NCT00002864; MA.21-NCT00014222; HERA, NCT00045032;CAN-NCIC-MA24; MA-27-NCT00066573.


Subject(s)
Antineoplastic Agents/administration & dosage , Body Mass Index , Breast Neoplasms/drug therapy , Neoadjuvant Therapy , Weight Gain , Antineoplastic Agents/adverse effects , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Chemotherapy, Adjuvant , Disease Progression , Disease-Free Survival , Female , Humans , Middle Aged , Perimenopause , Postmenopause , Premenopause , Randomized Controlled Trials as Topic , Risk Factors , Time Factors , Treatment Outcome
5.
Eur J Endocrinol ; 174(2): P1-9, 2016 02.
Article in English | MEDLINE | ID: mdl-26563978

ABSTRACT

Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that 'for approved indications, GH is safe'; however, the statement highlighted a number of areas for on-going surveillance of long-term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk, and the need for long-term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement.


Subject(s)
Consensus , Human Growth Hormone/adverse effects , Patient Safety/standards , Societies, Medical/standards , Adult , Child , Education , Endocrinology/standards , Europe , Humans , Pediatrics/standards , Recombinant Proteins
6.
Rhinology ; 53(4): 371-8, 2015 12.
Article in English | MEDLINE | ID: mdl-26275583

ABSTRACT

BACKGROUND: The application of intranasal insulin in healthy humans has been linked to improved memory function, reduced food intake, and increased olfactory thresholds. There has also been some correlation between the morbidities associated with central nervous system (CNS) insulin resistance, such as type II diabetes mellitus, Alzheimer's disease, obesity, and impaired odour recognition. Given that impaired odour recognition is an important component of olfactory performance, mechanisms that govern these effects may account for impaired olfactory functions in anosmic patients. METHODOLOGY: Ten patients with post-infectious olfactory loss received intranasal administration of 40 IU insulin or a placebo solution, as well as olfactory performance tests before and after administration. RESULTS: When administered insulin, patients exhibited an immediate performance improvement with regard to olfactory sensitivity and olfactory intensity ratings. In addition, more odours were correctly identified. Furthermore, an improvement in the odour identification task was detected in patients with higher body mass index. CONCLUSION: Results of this pilot study shed light on the link between cerebral insulin level and an impaired sense of smell. This research line might provide a better understanding of olfactory loss in relation to eating and dietary behavior, and could offer opportunities to develop faster therapeutic intervention for patients with olfactory dysfunction.


Subject(s)
Hypoglycemic Agents/administration & dosage , Insulin/administration & dosage , Olfaction Disorders/drug therapy , Administration, Intranasal , Adult , Body Mass Index , Female , Humans , Male , Middle Aged , Pilot Projects , Young Adult
7.
Am J Physiol Cell Physiol ; 309(5): C332-47, 2015 Sep 01.
Article in English | MEDLINE | ID: mdl-26108665

ABSTRACT

The potent trypanolytic properties of human apolipoprotein L1 (APOL1) can be neutralized by the trypanosome variant surface antigen gene product known as serum resistance-associated protein. However, two common APOL1 haplotypes present uniquely in individuals of West African ancestry each encode APOL1 variants resistant to serum resistance-associated protein, and each confers substantial resistance to human African sleeping sickness. In contrast to the dominantly inherited anti-trypanosomal activity of APOL1, recessive inheritance of these two trypanoprotective APOL1 alleles predisposes to kidney disease. Proposed mechanisms of APOL1 toxicity have included BH3 domain-dependent autophagy and/or ion channel activity. We probed these potential mechanisms by expressing APOL1 in Xenopus laevis oocytes. APOL1 expression in oocytes increased ion permeability and caused profound morphological deterioration (toxicity). Coexpression of BCL2 family members rescued APOL1-associated oocyte toxicity in the order MCL1 ∼ BCLW > BCLXL ∼ BCL2A1 ≫ BCL2. Deletion of nine nominal core BH3 domain residues abolished APOL1-associated toxicity, but missense substitution of the same residues abolished neither oocyte toxicity nor its rescue by coexpressed MCL1. The APOL1 BH3 domain was similarly dispensable for the ability of APOL1 to rescue intact mice from lethal trypanosome challenge. Replacement of most extracellular Na(+) by K(+) also reduced APOL1-associated oocyte toxicity, allowing demonstration of APOL1-associated increases in Ca(2+) and Cl(-) fluxes and oocyte ion currents, which were similarly reduced by MCL1 coexpression. Thus APOL1 toxicity in Xenopus oocytes is BH3-independent, but can nonetheless be rescued by some BCL2 family proteins.


Subject(s)
Apolipoproteins/biosynthesis , Apolipoproteins/toxicity , Lipoproteins, HDL/biosynthesis , Lipoproteins, HDL/toxicity , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Amino Acid Sequence , Animals , Apolipoprotein L1 , Apolipoproteins/genetics , Female , Humans , Lipoproteins, HDL/genetics , Mice , Molecular Sequence Data , Protein Structure, Tertiary/physiology , Proto-Oncogene Proteins c-bcl-2/genetics , Xenopus laevis
8.
Prostate Cancer Prostatic Dis ; 18(2): 167-72, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25753371

ABSTRACT

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. The primary objective of this study was to define the relationship between mutations in OCT1, MATE1 and progression-free survival (PFS) at 12 weeks absolute PFS and PSA response in consenting patients of SAKK 08/09. The secondary objective of this study was to analyze the association between mutations in OCT1, MATE1, metformin-related toxicity, PSA response at 12 weeks and overall survival. RESULTS: Thirty-six patients were evaluable for pharmacogenetic analysis. Homozygous carriers of the polymorphic OCT1 C-allele had no metformin-related toxicity as compared with 41.9% for any metformin-related toxicity in carriers of at least one wild-type A-allele (P=0.07). Disease progression according to RECIST (Response Evaluation Criteria In Solid Tumors) was significantly more frequent in homozygous carriers of the polymorphic OCT1 C-allele (80%) as compared with carriers of at least one wild-type A-allele (28.6%) (P=0.002). Disease progression according to RECIST was also more frequent in carriers of at least one polymorphic MATE1 A-allele (44%) as compared with homozygous carriers of the wild-type G-allele (12.5%) (P=0.07). OCT1 and MATE1 were not associated with PFS. CONCLUSIONS: The polymorphic OCT1 C-allele has been shown to be associated with less metformin-related toxicity and a higher risk of tumor progression in patients with CRPC receiving metformin as an anticancer treatment. Polymorphisms in metformin drug transporters are attractive molecular markers to serve as potential predictors of efficacy in future clinical studies.


Subject(s)
Metformin/adverse effects , Organic Cation Transport Proteins/genetics , Organic Cation Transporter 1/genetics , Prostatic Neoplasms, Castration-Resistant/genetics , Aged , Aged, 80 and over , Alleles , Disease-Free Survival , Genetic Association Studies , Genotype , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Prostate-Specific Antigen/blood , Prostatic Neoplasms, Castration-Resistant/blood , Prostatic Neoplasms, Castration-Resistant/drug therapy
9.
Prostate Cancer Prostatic Dis ; 17(3): 252-8, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24861559

ABSTRACT

BACKGROUND: Metformin is an inhibitor of complex 1 in the respiratory chain, and is widely used to reduce insulin resistance. It has also been described to have pleotropic effects including via AMPK on inhibiting the mTOR kinase. Pre-clinical and epidemiological studies suggest an ability to modulate disease evolution in prostate cancer. In this study, we aimed to (i) demonstrate safety and tolerability of neoadjuvant metformin administration and (ii) document changes in proliferative (Ki67) and AMPK-related signalling indices between matching biopsies and prostatectomies METHODS: Men were treated in a single-arm 'window of opportunity' study between their decision to undergo radical prostatectomy and the operation itself. Forty patients were planned but only 24 patients were enrolled owing to slow accrual. Twenty-one patients were evaluable for pathological outcomes and 22 for serum metabolic indices. Metformin was given at doses to 500 mg t.i.d. Ki67 index was calculated using the Aperio-positive pixel count algorithm, whereas immunohistochemical measurements were by consensus H-Score. Comparative statistics were analysed by students t-tests and/or Wilcoxon matched pairs signed rank test. RESULTS: Baseline characteristics included median PSA 6 ng ml(-1) (3.22-36.11 ng ml(-1)). Median duration of drug treatment was 41 days (18-81). Treatment was well tolerated with only three patients developing G3/4 toxicities. In a per patient and per tumour analyses, metformin reduced the Ki67 index by relative amounts of 29.5 and 28.6 % (P=0.0064 and P=0.0042) respectively. There was also a significant decrease in P-4EBP1 staining (P<0.001) but no change in P-AMPK or P-ACC. There were no correlations between any metabolic, morphometric or cancer-related serum indices. There was a trend towards PSA reduction (P=0.08). The study is limited by small patient numbers and tumour heterogeneity. CONCLUSIONS: Neoadjuvant metformin is well tolerated prior to radical prostatectomy. Data to date indicate promising effects on metabolic and tissue proliferation and signalling parameters.


Subject(s)
Antineoplastic Agents/therapeutic use , Metformin/therapeutic use , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Biomarkers, Tumor/blood , Biopsy , Humans , Male , Metformin/administration & dosage , Metformin/adverse effects , Middle Aged , Neoadjuvant Therapy , Neoplasm Grading , Neoplasm Staging , Pilot Projects , Prostatic Neoplasms/surgery
10.
Prostate Cancer Prostatic Dis ; 16(3): 239-47, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23689346

ABSTRACT

BACKGROUND: Elevated insulin-like growth factor-I (IGF-I) serum levels and phosphatase and tensin homolog (PTEN) loss are prostate cancer (PCa) risk factors that enhance androgen-responsive and castration-resistant PCa xenografts growth. METHODS: The impact of suppressed growth hormone (GH)/IGF-I levels on neoplastic initiation of PTEN-deficient prostate epithelia was assessed histologically and by epithelial-to-mesenchymal marker expression in Ghrhr D60G homozygous (lit/lit) and heterozygous (lit/+) pbARR2-Cre, PTEN(fl/fl) (PTEN-/-) mice. How suppressed GH/IGF-I levels impacted growth of PTEN-/- mouse-derived prostate cells (MPPK) was examined by growth and survival signaling of cells cultured in lit/+ or lit/lit serum. RESULTS: Body weight, prostate weight and serum GH and IGF-I levels were reduced in lit/lit relative to lit/+ PTEN-/- littermates. While the anterior lobes of lit/+ PTEN-/- prostates consistently presented swollen, indicative of ductal blockage, the degree of prostatic dysplasia in 15- and 20-week-old lit/lit and lit/+ PTEN-/- mice was indistinguishable as measured by normalized prostatic weight, tissue histology, or probasin, PSP94, E-cadherin, N-cadherin and vimentin expression. However, growth and AKT activation of MPPK cells was decreased when cultured in lit/lit serum as compared with lit/+ serum and restored in lit/lit serum supplemented with IGF-I and, to a lesser extent, GH. CONCLUSIONS: These results suggest that initiation of prostate carcinogenesis by loss of PTEN is not influenced by germline variation of genes encoding signaling molecules in the GH/IGF-I axis, but suggests that these factors may affect the progression of dysplastic phenotype and supports previous studies, indicating that the GH/IGF milieu does impact the growth of PTEN-deficient dysplastic prostatic cells once transformed.


Subject(s)
Arrestins/genetics , Arrestins/metabolism , Growth Hormone/deficiency , Insulin-Like Growth Factor I/deficiency , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Prostatic Hyperplasia/metabolism , Androgen-Binding Protein/genetics , Androgen-Binding Protein/metabolism , Animals , Body Weight/genetics , Cadherins/genetics , Cadherins/metabolism , Epithelial-Mesenchymal Transition/genetics , Growth Hormone/genetics , Growth Hormone/metabolism , Growth Hormone-Releasing Hormone/genetics , Growth Hormone-Releasing Hormone/metabolism , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , PTEN Phosphohydrolase/deficiency , Prostatic Hyperplasia/genetics , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Prostatic Secretory Proteins/genetics , Prostatic Secretory Proteins/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Tumor Cells, Cultured , Vimentin/genetics , Vimentin/metabolism , beta-Arrestins
11.
Eur J Clin Nutr ; 66(10): 1146-52, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22892437

ABSTRACT

BACKGROUND/OBJECTIVES: The effect of a low glycemic load (GL) diet on insulin-like growth factor-1 (IGF-1) concentration is still unknown but may contribute to lower chronic disease risk. We aimed to assess the impact of GL on concentrations of IGF-1 and IGF-binding protein-3 (IGFBP-3). SUBJECTS/METHODS: We conducted a randomized, controlled crossover feeding trial in 84 overweight obese and normal weight healthy individuals using two 28-day weight-maintaining high- and low-GL diets. Measures were fasting and post-prandial concentrations of insulin, glucose, IGF-1 and IGFBP-3. In all 80 participants completed the study and 20 participants completed post-prandial testing by consuming a test breakfast at the end of each feeding period. We used paired t-tests for diet component and linear mixed models for biomarker analyses. RESULTS: The 28-day low-GL diet led to 4% lower fasting concentrations of IGF-1 (10.6 ng/ml, P=0.04) and a 4% lower ratio of IGF-1/IGFBP-3 (0.24, P=0.01) compared with the high-GL diet. The low-GL test breakfast led to 43% and 27% lower mean post-prandial glucose and insulin responses, respectively; mean incremental areas under the curve for glucose and insulin, respectively, were 64.3±21.8 (mmol/l/240 min; P<0.01) and 2253±539 (µU/ml/240 min; P<0.01) lower following the low- compared with the high-GL test meal. There was no effect of GL on mean homeostasis model assessment for insulin resistance or on mean integrated post-prandial concentrations of glucose-adjusted insulin, IGF-1 or IGFBP-3. We did not observe modification of the dietary effect by adiposity. CONCLUSIONS: Low-GL diets resulted in 43% and 27% lower post-prandial responses of glucose and insulin, respectively, and modestly lower fasting IGF-1 concentrations. Further intervention studies are needed to weigh the impact of dietary GL on risk for chronic disease.


Subject(s)
Glycemic Index , Hyperglycemia/prevention & control , Hyperinsulinism/prevention & control , Insulin-Like Growth Factor Binding Protein 3/blood , Insulin-Like Growth Factor I/analysis , Obesity/metabolism , Overweight/metabolism , Adult , Algorithms , Biomarkers/blood , Blood Glucose/analysis , Body Mass Index , Cross-Over Studies , Dietary Carbohydrates/adverse effects , Dietary Carbohydrates/metabolism , Female , Humans , Hyperglycemia/etiology , Hyperinsulinism/etiology , Insulin/blood , Insulin Resistance , Male , Obesity/blood , Obesity/diet therapy , Overweight/blood , Overweight/diet therapy , Young Adult
12.
Prostate Cancer Prostatic Dis ; 15(4): 346-52, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22614062

ABSTRACT

BACKGROUND: Prostate cancer incidence and mortality vary dramatically by geographical location. Both are higher in developed countries. Some attribute this to westernized lifestyles of high-energy diets and limited physical activity with consequent obesity. Obesity and obesity-related diseases like diabetes cause hyperinsulinaemia, which upregulates pro-survival cell signalling. Previous work revealed diet-induced hyperinsulinaemia enhances prostate cancer xenograft growth in vivo. Metformin, an antidiabetic medication, reduces hyperinsulinaemia and also exhibits antineoplastic properties. Herein, we assess the potential additive benefit of combining bicalutamide antiandrogen therapy with metformin, in vitro and in vivo. METHODS: Using clonogenic assays, we assessed the effect of bicalutamide and/or metformin on clonogenicity in prostate cancer cell lines. Western blot and cell cycle analyses were used to elucidate mechanisms of interaction between the drugs in androgen receptor (AR)-positive (LNCaP) and AR-negative (PC3) cell lines. The combination treatment regimen was assessed in vivo using an LNCaP murine xenograft model. RESULTS: Micromolar bicalutamide or millimolar metformin caused a significant dose-dependent reduction in clonogenicity (P<0.001). Combination treatment further significantly reduced clonogenicity (P<0.005) with greater effects in AR-positive cells. Western blot and cell cycle analyses suggested differing mechanisms of interaction in AR-positive and -negative cell lines. Following combination treatment, LNCaP cells exhibited an altered cell proliferation (decreased phospho mammalian target of rapamycin expression) and perturbed cell cycle kinetics (G1/S cell cycle arrest). PC3 cells showed evidence of enhanced apoptosis (increased Bcl-2-associated X protein and decreased total caspase 3 expression). Markedly diminished tumour growth occurred following combination treatment in vivo (P<0.001). CONCLUSIONS: Combining bicalutamide and metformin significantly reduces prostate cancer cell growth further than either monotherapy. In AR-positive cells, this effect appeared to be mediated by reducing proliferation rates, whereas in AR-negative cells the combination treatment appeared to promote apoptosis. This combination drug regimen may improve prostate-cancer-specific survival by the direct antineoplastic properties outlined.


Subject(s)
Anilides/administration & dosage , Drug Synergism , Metformin/administration & dosage , Nitriles/administration & dosage , Prostatic Neoplasms , Tosyl Compounds/administration & dosage , Androgen Antagonists/administration & dosage , Animals , Apoptosis/drug effects , Cell Survival/drug effects , Cytoprotection/drug effects , Humans , Hypoglycemic Agents/administration & dosage , Male , Mice , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology
13.
Am J Transplant ; 12(7): 1924-8, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22487534

ABSTRACT

Apolipoprotein L-1 (APOL1) gene variants are associated with end-stage renal disease in African Americans (AAs). Here we investigate the impact of recipient APOL1 gene distributions on kidney allograft outcomes. We conducted a retrospective analysis of 119 AA kidney transplant recipients, and found that 58 (48.7%) carried two APOL1 kidney disease risk variants. Contrary to the association seen in native kidney disease, there is no difference in allograft survival at 5-year posttransplant for recipients with high-risk APOL1 genotypes. Thus, we were able to conclude that APOL1 genotypes do not increase risk of allograft loss after kidney transplantations, and carrying 2 APOL1 risk alleles should not be an impediment to transplantation.


Subject(s)
Apolipoproteins/genetics , Black People/genetics , Graft Survival/genetics , Kidney Transplantation , Lipoproteins, HDL/genetics , Adult , Apolipoprotein L1 , Genotype , Humans , Middle Aged
14.
Br J Cancer ; 106(7): 1335-41, 2012 Mar 27.
Article in English | MEDLINE | ID: mdl-22415230

ABSTRACT

BACKGROUND: Laboratory studies suggest a possible role of magnesium intake in colorectal carcinogenesis but epidemiological evidence is inconclusive. METHOD: We tested magnesium-colorectal cancer hypothesis in the Nurses' Health Study, in which 85 924 women free of cancer in 1980 were followed until June 2008. Cox proportional hazards regression models were used to estimate multivariable relative risks (MV RRs, 95% confidence intervals). RESULTS: In the age-adjusted model, magnesium intake was significantly inversely associated with colorectal cancer risk; the RRs from lowest to highest decile of total magnesium intake were 1.0 (ref), 0.93, 0.81, 0.72, 0.74, 0.77, 0.72, 0.75, 0.80, and 0.67 (P(trend)<0.001). However, in the MV model adjusted for known dietary and non-dietary risk factors for colorectal cancer, the association was significantly attenuated; the MV RRs were 1.0 (ref), 0.96, 0.85, 0.78, 0.82, 0.86, 0.84, 0.91, 1.02, and 0.93 (P(trend)=0.77). Similarly, magnesium intakes were significantly inversely associated with concentrations of plasma C-peptide in age-adjusted model (P(trend)=0.002) but not in multivariate-adjusted model (P(trend)=0.61). Results did not differ by subsite or modified by calcium intakes or body mass index. CONCLUSION: These prospective results do not support an independent association of magnesium intake with either colorectal cancer risk or plasma C-peptide levels in women.


Subject(s)
C-Peptide/blood , Colorectal Neoplasms/epidemiology , Diet , Magnesium , Body Mass Index , Calcium , Female , Follow-Up Studies , Humans , Incidence , Insulin/metabolism , Insulin Secretion , Middle Aged , Prospective Studies , Risk Factors , United States/epidemiology
15.
Oncogene ; 31(10): 1334-40, 2012 Mar 08.
Article in English | MEDLINE | ID: mdl-21804605

ABSTRACT

ETV6-NTRK3 (EN), a chimeric tyrosine kinase generated by t(12;15) translocations, is a dominantly acting oncoprotein in diverse tumor types. We previously showed that insulin-like growth factor 1 receptor (IGF1R) is essential for EN-mediated oncogenesis and that insulin receptor substrate 1 (IRS1) is constitutively tyrosine phosphorylated and bound by EN in transformed cells. Given that IRS1 is also an adapter for IGF1R, we hypothesized that IRS1 might localize EN to IGF1R at the membrane to activate phosphatidylinositol 3-kinase (PI3K)-Akt, which is critical for EN oncogenesis. In this study, we examined EN/IRS1/IGF1R complexes in detail. We find that both IRS1 and kinase active IGF1R are required for EN transformation, that tyrosine phosphorylated IRS1 is present in high molecular weight complexes with EN and IGF1R, and that EN colocalizes with IGF1R at the plasma membrane. Both IGF1R kinase activity and an intact cytoplasmic Y950 residue, the IRS1-docking site of IGF1R, are required, confirming the importance of the IGF1R/IRS1 interaction for EN oncogenesis. The dual specificity IGF1R and insulin receptor (INSR) inhibitor, BMS-536924, blocks EN transformation activity, cell survival and its interaction with IRS proteins, and induces a striking shift of EN proteins to smaller sized molecular complexes. We conclude that a tripartite complex of EN, IRS1 and IGF1R localizes EN to the membrane and that this is essential for EN-mediated transformation. These findings provide an explanation for the observed IGF1R dependency of EN transformation. Blocking IGF1R kinase activity may, therefore, provide a tractable therapeutic strategy for the many tumor types driven by the EN oncoprotein.


Subject(s)
Cell Membrane/metabolism , Cell Transformation, Neoplastic , Insulin Receptor Substrate Proteins/physiology , Oncogene Proteins, Fusion/physiology , Receptor, IGF Type 1/physiology , Animals , Interleukin-3/pharmacology , Mice , Phosphorylation
17.
Diabetologia ; 54(9): 2254-62, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21614572

ABSTRACT

AIMS/HYPOTHESIS: There have been growing concerns regarding the long-term effects of insulin glargine (A21Gly,B31Arg,B32Arg human insulin) on the risk of breast cancer. METHODS: We used the UK's General Practice Research Database (GPRD) to identify a cohort of women aged 40 years or over with type 2 diabetes, treated with insulin during 2002-2006 and followed until the first breast cancer diagnosis or 31 December 2009. After the users of insulin glargine had been matched with users of other insulins on age, calendar time and duration of prior insulin use, the HR of breast cancer associated with insulin glargine use was estimated using a Cox proportional hazards model, adjusted for known risk factors for breast cancer. RESULTS: The cohort comprised 15,227 women, including 4,579 glargine users and 10,648 users of other insulins, of which 246 developed breast cancer during up to 8 years follow-up (incidence rate 4.1 per 1,000 per year). Insulin glargine use was not associated with an increased risk of breast cancer during the first 5 years of use (HR 0.9; 95% CI 0.7-1.3). The risk tended to increase after 5 years (HR 1.8; 95% CI 0.8-4.0), and significantly so for the women who had been on insulin before starting glargine (HR 2.7; 95% CI 1.1-6.5). CONCLUSIONS/INTERPRETATION: The risk of breast cancer in women with type 2 diabetes is not increased during the first 5 years of insulin glargine use. However, longer-term use may increase this risk, particularly in women with longstanding use of insulin before starting insulin glargine.


Subject(s)
Breast Neoplasms/epidemiology , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/therapeutic use , Insulin, Long-Acting/adverse effects , Insulin, Long-Acting/therapeutic use , Aged , Cohort Studies , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Humans , Incidence , Insulin Glargine , Middle Aged , Proportional Hazards Models , Retrospective Studies , Risk Factors , Time , United Kingdom
18.
Clin Nephrol ; 75(4): 362-8, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21426891

ABSTRACT

The majority of patients with non-HIV-related collapsing focal segmental glomerular sclerosis (FSGS) have idiopathic disease. Only a few genetic forms associated with rare syndromes have been described in families. Here we report two families with multiple members who have collapsing FSGS with no clear associated secondary etiology. Genetic analysis revealed a defect in the TRPC6 gene in one family, but excluded all known common inherited podocyte defects in the other family. The course and response to treatment differed dramatically among members of the same family.


Subject(s)
Glomerulosclerosis, Focal Segmental/genetics , Adult , Biopsy , Disease Progression , Female , Glomerulosclerosis, Focal Segmental/diagnosis , Glomerulosclerosis, Focal Segmental/drug therapy , Humans , Male , Pedigree
19.
Oncogene ; 30(10): 1174-82, 2011 Mar 10.
Article in English | MEDLINE | ID: mdl-21102522

ABSTRACT

Hypothesis-generating epidemiological research has suggested that cancer burden is reduced in diabetics treated with metformin and experimental work has raised questions regarding the role of direct adenosine monophosphate-activated protein kinase (AMPK)-mediated anti-neoplastic effects of metformin as compared with indirect effects attributable to reductions in circulating insulin levels in the host. We treated both tumor LKB1 expression and host diet as variables, and observed that metformin inhibited tumor growth and reduced insulin receptor activation in tumors of mice with diet-induced hyperinsulinemia, independent of tumor LKB1 expression. In the absence of hyperinsulinemia, metformin inhibited only the growth of tumors transfected with short hairpin RNA against LKB1, a finding attributable neither to an effect on host insulin level nor to activation of AMPK within the tumor. Further investigation in vitro showed that cells with reduced LKB1 expression are more sensitive to metformin-induced adenosine triphosphate depletion owing to impaired ability to activate LKB1-AMPK-dependent energy-conservation mechanisms. Thus, loss of function of LKB1 can accelerate proliferation in contexts where it functions as a tumor suppressor, but can also sensitize cells to metformin. These findings predict that any clinical utility of metformin or similar compounds in oncology will be restricted to subpopulations defined by host insulin levels and/or loss of function of LKB1.


Subject(s)
Antineoplastic Agents/pharmacology , Diet , Metformin/pharmacology , Neoplasms, Experimental/drug therapy , Protein Serine-Threonine Kinases/metabolism , AMP-Activated Protein Kinases , Animals , Blotting, Western , Carcinoma, Lewis Lung , Drug Resistance, Neoplasm/genetics , Genes, Tumor Suppressor , Hyperinsulinism/drug therapy , Hypoglycemic Agents/pharmacology , Male , Mice , Mice, Inbred C57BL , Neoplasms, Experimental/metabolism , Protein Serine-Threonine Kinases/genetics , Signal Transduction/drug effects , Transfection
20.
Br J Cancer ; 104(1): 68-74, 2011 Jan 04.
Article in English | MEDLINE | ID: mdl-21102589

ABSTRACT

BACKGROUND: Phase III trials of the anti-insulin-like growth factor type 1 receptor (IGF-IR) antibody figitumumab (F) in unselected non-small-cell lung cancer (NSCLC) patients were recently discontinued owing to futility. Here, we investigated a role of free IGF-1 (fIGF-1) as a potential predictive biomarker of clinical benefit from F treatment. MATERIALS AND METHOD: Pre-treatment circulating levels of fIGF-1 were tested in 110 advanced NSCLC patients enrolled in a phase II study of paclitaxel and carboplatin given alone (PC) or in combination with F at doses of 10 or 20 mg kg(-1) (PCF10, PCF20). RESULTS: Cox proportional hazards model interactions were between 2.5 and 3.5 for fIGF-1 criteria in the 0.5-0.9 ng ml(-1) range. Patients above each criterion had a substantial improvement in progression-free survival on PCF20 related to PC alone. Free IGF-1 correlated inversely with IGF binding protein 1 (IGFBP-1, ρ=-0.295, P=0.005), and the pre-treatment ratio of insulin to IGFBP-1 was also predictive of F clinical benefit. In addition, fIGF-1 levels correlated with tumour vimentin expression (ρ=0.594, P=0.021) and inversely with E-cadherin (ρ=-0.389, P=0.152), suggesting a role for fIGF-1 in tumour de-differentiation. CONCLUSION: Free IGF-1 may contribute to the identification of a subset of NSCLC patients who benefit from F therapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/drug therapy , Insulin-Like Growth Factor I/metabolism , Lung Neoplasms/blood , Lung Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/administration & dosage , Biomarkers, Tumor/blood , Cadherins/blood , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/pathology , Clinical Trials, Phase II as Topic , Enzyme-Linked Immunosorbent Assay , Female , Follow-Up Studies , Humans , Immunoglobulins, Intravenous , Insulin/blood , Insulin-Like Growth Factor Binding Protein 1/blood , Lung Neoplasms/pathology , Male , Middle Aged , Multicenter Studies as Topic , Neoplasm Staging , Paclitaxel/administration & dosage , Randomized Controlled Trials as Topic , Survival Rate , Treatment Outcome
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