Evaluation of Cellular Fibronectin Plasma Levels as a Useful Staging Tool in Different Stages of Transitional Cell Carcinoma of the Bladder and Renal Cell Carcinoma

Reliable markers for both renal cell carcinoma (RCC) and transitional cell carcinoma of the bladder (TCC) are lacking

Lipoprotein lipase (LPL) gene variation and progression of carotid artery plaque

Background and Purpose - Coding single nucleotide polymorphisms (cSNPs) in the lipoprotein lipase (LPL) gene have been associated with lipoprotein phenotypes and vascular disease risk. We studied the association between LPL cSNPs and a novel noninvasive measure of disease, namely, cross-sectional carotid plaque area (CPA) on B-mode ultrasound. Methods - Four hundred fifty-two patients from an atherosclerosis prevention clinic had determinations of baseline and total CPA. Traditional atherosclerosis risk factors were recorded, and the LPL D9N, N291S, and S447X cSNPs were genotyped. Multiple regression analysis was used to identify determinants of CPA. Results - Minor allele frequencies for LPL D9N, N291S, and S447X were 2.8%, 0.9%, and 4.4%, respectively. There were no significant between-genotype differences in treated fasting lipids. The LPL D9N genotype was a significant predictor of both baseline CPA (P=0.008) and plaque progression from baseline to 1 year later (P=0.001). Heterozygotes for the N9 allele had higher mean baseline CPA and plaque progression than did LPL D9/D9 homozygotes. Conclusions - LPL D9N genotype may be a determinant of atherosclerosis as estimated by static baseline CPA and by progression of CPA

NPC1L1 haplotype is associated with inter-individual variation in plasma low-density lipoprotein response to ezetimibe

BACKGROUND: NPC1L1 encodes a putative intestinal sterol transporter which is the likely target for ezetimibe, a new type of lipid-lowering medication. We previously reported rare non-synonymous mutations in NPC1L1 in an individual who had no plasma lipoprotein response to ezetimibe. We next hypothesized that common variants in NPC1L1 would underlie less extreme inter-individual variations in the plasma LDL cholesterol response to ezetimibe. RESULTS: In 101 dyslipidemic subjects, we found that NPC1L1 haplotype was significantly associated with inter-individual variation in the response of plasma LDL cholesterol to treatment with ezetimibe for 12 weeks. Specifically, about one subject in eight lacked the common NPC1L1 haplotype 1735C-25342A-27677T and these subjects had a significantly greater reduction in plasma LDL cholesterol with ezetimibe than subjects with at least one copy of this haplotype (-35.9+4.0 versus -23.6+1.6 percent reduction, P = 0.0054). This was paralleled by a similar non-significant trend of between-haplotype difference in reduction of total cholesterol. CONCLUSION: These preliminary pharmacogenetic results suggest that NPC1L1 variation is associated with inter-individual variation in response to ezetimibe treatment

Clinical impact of MDR1-expression in testicular germ cell cancer

Aim: The multidrug resistance protein 1 (MDR1, P-gp, p-170) is a membrane glycoprotein that acts as an energy-dependent drug efflux pump. In various malignancies its expression is associated with resistance to diverse cytostatic drugs, and therefore predicts resistance to systemic treatment. The aim of this study was to investigate the prognostic value of MDR1 expression in primary tumor tissue to predict necrosis or viable cancer in residual tumor masses after systemic chemotherapy for advanced testicular germ cell cancer. Materials and Methods: Out of 77 patients, histopathological characteristics of primary testicular cancer specimens and retroperitoneal lymph node dissection (RPLND) samples following chemotherapy were available from 72 and all 77 patients, respectively. Moreover, MDR1 expression was determined by immunohistochemistry in 47 primary tumors and corresponding 73 RPLND sections. Results: After chemotherapy and subsequent RPLND, the examination of residual tumor masses revealed that mature teratoma and active viable tumor were predominantly found in patients with non-seminoma (NSGCT; p = 0.048), especially in those with containing mature teratoma (p = 0.001). Moreover, using univariate analysis the expression of MDR1 in the primary testicular tumor predicted viable tumor/teratoma residues in RPLND sections (p = 0.003). However, in multivariate analysis including the tumors’ histological subtype, MDR1 expression alone failed to reach statistical significance as an independent prognostic marker for residual vital tumor (p ≥ 0.16). Conclusions: With the limited number of patients given, the correlation between MDR1 expression in primary testis cancer and active residual retroperitoneal disease after chemotherapy failed to reach statistical significance as in independent marker. Therefore, up to now routine MDR1 staining of testicular germ cell cancer samples should not be performed in clinical practice. However, as there was a clear trend, a larger number of patients suffering from metastatic non-seminomas should be studied, as MDR1 expression might have significant prognostic value in this particular subgroup of patients.Белок 1 множественной лекарств енной устойчив ости (MDR1, P-gp, p-170) – это мембранный гликопротеин, функционирующий как энергозависимый насос. При разл ичных фо рмах опухолей его экспр е ссия связана с устойчив о стью опухоли к различным цитостатикам, что может быть использовано для выбора типа терапии. Цель работы — исследование прогности- ческой значимости экспрессии MDR1 в ткани пе рвичной опухоли для оценки возмо жности раз вития некроза или сохран е ния живых клеток в остаточной ткани опухоли после применения системной химиотерапии на поздних стадиях герминативных опухолей яичка. Материалы и методы: про анализиро ваны гисто патоло гические характ е ристики пе рвично й те стикулярной опухоли и образцов, полученных при иссечении ретроперитонеальных лимфатических узлов (RPLND) после хими отерапии 72 и 77 бол ьных соотве тственно. Экспр ессию MDR1 определяли иммун огист охимич еским методом в 47 образцах первичн ой опухоли и соответствующих 73 ср RPLND. Результаты: после хими отерапии и последующей RPLNDисследовани е оста- точных опухолевых тканей показало, чтозрелая тератома и жизнеспособные опух олевые клетки выяв ляют преимущественно у больных, у которых не была обнаружена семинома (NSGCT; p = 0,048), особенно у так овых , у которых была тератома (p = 0,001). Более того, д анные одно факторного анализа показали, что экспр е ссия MDR1 в ткани пе рвично й те стику лярной опу- холи может служить прогностич еским факт ором сохран ения живых опух олевых клеток срезах RPLND (p = 0,003). О нак о применение мультифакторного анализа, в том числе с учетом гистологического подтипа опухоли, показало, что экспр е ссия MDR1 не имеет самостоятельной прогностической значимости для выявления живых остаточных опух олевых клеток (p 0,16). Выводы: ввиду небольшо йвыборкибольных не выяв лено статистически значимойкорреляции между экспр ессией MDR1 в первичной опухоли яичка и наличием активных резидуальных очагов поражения в ретроперитонеальном пространстве. В т о же время, учитывая выявленную тенденцию, экспрессию MDR1, в качестве возможного прогностич еского марк ера, имеет смысл исследовать именно у больных с метастатическими опухолями, не являющимися семиномой

Genetic determinants of statin intolerance

BACKGROUND: Statin-related skeletal muscle disorders range from benign myalgias – such as non-specific muscle aches or joint pains without elevated serum creatinine kinase (CK) concentration – to true myositis with >10-fold elevation of serum CK, to rhabdomyolysis and myoglobinuria. The genetic basis of statin-related muscle disorders is largely unknown. Because mutations in the COQ2 gene are associated with severe inherited myopathy, we hypothesized that common, mild genetic variation in COQ2 would be associated with inter-individual variation in statin intolerance. We studied 133 subjects who developed myopathy on statin monotherapy and 158 matched controls who tolerated statins without incident or complaint. RESULTS: COQ2 genotypes, based on two single nucleotide polymorphisms (SNP1 and SNP2) and a 2-SNP haplotype, all showed significant associations with statin intolerance. Specifically, the odds ratios (with 95% confidence intervals) for increased risk of statin intolerance among homozygotes for the rare alleles were 2.42 (0.99 to 5.89), 2.33 (1.13 to 4.81) and 2.58 (1.26 to 5.28) for SNP1 and SNP2 genotypes, and the 2-SNP haplotype, respectively. CONCLUSION: These preliminary pharmacogenetic results, if confirmed, are consistent with the idea that statin intolerance which is manifested primarily through muscle symptoms is associated with genomic variation in COQ2 and thus perhaps with the CoQ10 pathway

A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia

Numerous single nucleotide polymorphisms (SNPs) have been found in recent genome wide association studies (GWAS) to be associated with subtle plasma triglyceride (TG) variation in normolipidemic subjects. However, since these GWAS did not specifically evaluate patients with rare disorders of lipoprotein metabolism—‘hyperlipoproteinemia’ (HLP)—it remains largely unresolved whether any of these SNP determinants of modest physiological changes in TG are necessarily also determinants of most HLP phenotypes. To address this question, we evaluated 28 TG-associated SNPs from GWAS in 386 unrelated adult patients with one of five Fredrickson phenotypes (HLP types 2A, 2B, 3, 4 and 5) and 242 matched normolipidemic controls. We found that several SNPs associated with TG in normolipidemic samples, including APOA5 p.S19W and -1131T>C, TRIB1 rs17321515, TBL2 rs17145738, GCKR rs780094, GALNT2 rs4846914 and ANGPTL3 rs12130333, were significantly associated with HLP types 2B, 3, 4 and 5. The findings indicate that: (i) the TG-associated Fredrickson HLP types 2B, 3, 4 and 5 are polygenic traits; (ii) these Fredrickson HLP types share numerous genetic determinants among themselves; and (iii) genetic determinants of modest TG variation in normolipidemic population samples also underlie—to an apparently even greater degree—susceptibility to these rare HLP phenotypes. Thus, the TG-associated Fredrickson HLP types 2B, 3, 4 and 5, although historically considered to be distinct are actually complex traits sharing among them several common genetic determinants seen in GWAS of normolipidemic population samples

Evaluation of adipose tissue volume quantification with IDEAL fat-water separation

Purpose: To validate iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) for adipose tissue volume quantification. IDEAL allows MRI images to be produced only from adipose-containing tissues; hence, quantifying adipose tissue should be simpler and more accurate than with current methods. Materials and Methods: Ten healthy controls were imaged with 1.5 Tesla (T) Spin Echo (SE), 3.0T T1-weighted spoiled gradient echo (SPGR), and 3.0T IDEAL-SPGR. Images were acquired from the abdomen, pelvis, mid-thigh, and mid-calf. Mean subcutaneous and visceral adipose tissue volumes were compared between the three acquisitions for each subject. Results: There were no significant differences (P \u3e 0.05) between the three acquisitions for subcutaneous adipose tissue volumes. However, there was a significant difference (P = 0.0002) for visceral adipose tissue volumes in the abdomen. Post hoc analysis showed significantly lower visceral adipose tissue volumes measured by IDEAL versus 1.5T (P \u3c 0.0001) and 3.0T SPGR (P \u3c 0.002). The lower volumes given by IDEAL are due to its ability to differentiate true visceral adipose tissue from other bright structures like blood vessels and bowel content that are mistaken for adipose tissue in non-fat suppressed images. Conclusion: IDEAL measurements of adipose tissue are equivalent to established 1.5T measurement techniques for subcutaneous depots and have improved accuracy for visceral depots, which are more metabolically relevant. © 2011 Wiley-Liss, Inc

Vinflunine in the treatment of relapsed metastatic urothelial cancer: A systematic review and meta-analysis of real-world series

Background. Vinflunine (VFL) is approved in Europe as second-line treatment of metastatic urothelial cancer after failure of platinum-containing therapy. We performed a systematic review and meta-analysis of real-world data (RWD) to assess utilization, efficacy and safety of VFL. Methods. We performed a MEDLINE search for the period of 1/1/2000-31/8/2017. Full-length articles providing post-marketing RWD on VFL in patients failing previous chemotherapy were eligible. Interventional clinical trials were excluded. Results: Ten studies with 797 patients were identified. According to pooled REs analysis, overall response rate was 19%, most frequent, all-grade toxicities were fatigue (41%), constipation (39%), nausea/vomiting (25%), and most prevalent Grade 3–4 toxicities were neutropenia (13%), anaemia (9%), fatigue (8%). Median OS was comparable to results reported in recent randomized studies. Conclusion. Our findings confirm the efficacy and safety of VFL in an unselected population and support the use of VFL in the changing treatment paradigm of relapsed mUC

Statin safety in chinese: A population-based study of older adults

Background Compared to Caucasians, Chinese achieve a higher blood concentration of statin for a given dose. It remains unknown whether this translates to increased risk of serious statinassociated adverse events amongst Chinese patients. Methods We conducted a population-based retrospective cohort study of older adults (mean age, 74 years) newly prescribed a statin in Ontario, Canada between 2002 and 2013, where 19,033 Chinese (assessed through a validated surname algorithm) were matched (1:3) by propensity score to 57,099 non-Chinese. This study used linked healthcare databases. Findings The follow-up observation period (mean 1.1, maximum 10.8 years) was similar between groups, as were the reasons for censoring the observation period (end of follow-up, death, or statin discontinuation). Forty-seven percent (47%) of Chinese were initiated on a higher than recommended statin dose. Compared to non-Chinese, Chinese ethnicity did not associate with any of the four serious statin-associated adverse events assessed in this study [rhabdomyolysis hazard ratio (HR) 0.61 (95% CI 0.28 to 1.34), incident diabetes HR 1.02 (95% CI 0.80 to 1.30), acute kidney injury HR 0.90 (95% CI 0.72 to 1.13), or all-cause mortality HR 0.88 (95% CI 0.74 to 1.05)]. Similar results were observed in subgroups defined by statin type and dose. Conclusions We observed no higher risk of serious statin toxicity in Chinese than matched non-Chinese older adults with similar indicators of baseline health. Regulatory agencies should review available data, including findings from our study, to decide if a change in their statin dosing recommendations for people of Chinese ethnicity is warranted

Ambroxol as a novel disease-modifying treatment for Parkinson\u27s disease dementia: Protocol for a single-centre, randomized, double-blind, placebo-controlled trial

© 2019 The Author(s). Background: Currently there are no disease-modifying treatments for Parkinson\u27s disease dementia (PDD), a condition linked to aggregation of the protein α-synuclein in subcortical and cortical brain areas. One of the leading genetic risk factors for Parkinson\u27s disease is being a carrier in the gene for β-Glucocerebrosidase (GCase; gene name GBA1). Studies in cell culture and animal models have shown that raising the levels of GCase can decrease levels of α-synuclein. Ambroxol is a pharmacological chaperone for GCase and is able to raise the levels of GCase and could therefore be a disease-modifying treatment for PDD. The aims of this trial are to determine if Ambroxol is safe and well-tolerated by individuals with PDD and if Ambroxol affects cognitive, biochemical, and neuroimaging measures. Methods: This is a phase II, single-centre, double-blind, randomized placebo-controlled trial involving 75 individuals with mild to moderate PDD. Participants will be randomized into Ambroxol high-dose (1050 mg/day), low-dose (525 mg/day), or placebo treatment arms. Assessments will be undertaken at baseline, 6-months, and 12-months follow up times. Primary outcome measures will be the Alzheimer\u27s disease Assessment Scale-cognitive subscale (ADAS-Cog) and the ADCS Clinician\u27s Global Impression of Change (CGIC). Secondary measures will include the Parkinson\u27s disease Cognitive Rating Scale, Clinical Dementia Rating, Trail Making Test, Stroop Test, Unified Parkinson\u27s disease Rating Scale, Purdue Pegboard, Timed Up and Go, and gait kinematics. Markers of neurodegeneration will include MRI and CSF measures. Pharmacokinetics and pharmacodynamics of Ambroxol will be examined through plasma levels during dose titration phase and evaluation of GCase activity in lymphocytes. Discussion: If found effective and safe, Ambroxol will be one of the first disease-modifying treatments for PDD. Trial registration: ClinicalTrials.gov NCT02914366, 26 Sep 2016/retrospectively registered