Cutaneous melanoma susceptibility and progression genes

This review aims to provide an up-to-date view on our understanding of the molecular genetics of melanoma development. It gives an overview of genes (and loci) currently known to be substantially involved in melanoma predisposition and progression. Broadly, the review falls into 3 sections: genes/loci involved in melanoma susceptibility through germline mutation, tumor suppressor genes somatically mutated or deleted in melanoma, and oncogenes mutated somatically in melanoma. The main cellular pathways in which these genes are involved are summarized and discussed. From this it is evident that abberations of cell cycle regulation, DNA repair and receptor-mediated signal transduction are important for melanocytic neoplasia.     

Assessment of quality of life among HIV-infected persons in Pune,India

Objective: To study dimensions of Quality of Life (QOL) amongst HIV infected persons, their relationship with socio-demographic characteristics and disease progression.Design: Cross-sectional study with one time assessment of QOL.Methods: Modified Medical Outcome Study (MOS) core instrument [The Medical Outcome Study 116 core set of Measures of functioning and well being, Appendix A, core survey instrument (internet)] was interview -administered to 100 HIV infected individuals.Results: The instrument showed significant positive inter-domain correlations and desired linear association between QOL scores and the CD4 counts. The scale had a Cronbach α value of 0.75. QOL was markedly affected in the domains of physical health, work and earnings, routine activities and appetite and food intake. Women had significantly lower QOL scores than men despite having less advanced disease. The QOL scores were significantly lower among persons with lower CD4 counts mainly in different domains of physical health.Conclusions: The modified MOS scale had the desired reliability and validity for evaluation of QOL in the HIV-infected persons in India. Low scores in the domains of physical health compared to other domains suggest a strategy to focus on medical intervention. A need for psychosocial intervention for women was perceived. Longitudinal studies must be done to assess the impact of anti-retroviral therapy being rolled out through the national programme on QOL.Source of Funding: National AIDS Research Institute, Intra-mural funds Indian Council Of Medical Research, New Delhi, India.     

Somatic and renal effects of growth hormone in rats with chronic renal failure

Recombinant human growth hormone (rhGH) has been widely used to improve growth in children with chronic renal failure (CRF). However, there has been great concern that GH may aggravate renal disease and hasten the progression to end-stage renal failure. We therefore investigated the effect of prolonged administration of rhGH at various doses on somatic growth and renal function and structure in rats with CRF, divided into four groups based on rhGH dose (vehicle, 0.4, 2.0, and 10.0 IU/day). rhGH was administered subcutaneously daily for 8 weeks. The mean growth was significantly greater in rats treated with high-dose rhGH (10.0 IU) than those treated with low-dose rhGH (P = 0.0089) or vehicle (P = 0.0011). Body weight gain increased in parallel with body length (Creatinine clearance at the end of the experiment was significantly lower in rats on high or medium-dose rhGH than those on low-dose rhGH and controls (P <0.05). The glomerular sclerosing index was greater in rats treated with higher doses of rhGH. There were significant differences between rats treated with high-dose rhGH and controls (P = 0.0144) and also between rats on medium-dose rhGH and controls (P = 0.0065). Although there was no significant difference, rats treated with higher doses of rhGH tended to excrete more protein. Renal insulin-like growth factor-I (IGF-I) content and circulating IGF-I and IGF-II levels did not significantly differ among groups. We conclude that: (1) GH improves somatic growth failure in rats with CRF, but prolonged administration of GH dose-dependently induces deterioration in renal function and structure and (2) this effect was induced neither via circulating IGF-I and IGF-II nor by local production of IGF-I, but seems to be direct. Received June 7, 1996; received in revised form and accepted November 19, 1996     

康肾冲剂延缓早期慢性肾功能衰竭的临床研究

目的 观察中药康肾冲剂延缓早期慢性肾功能衰竭（CRF）的临床疗效作用。方法 采用前瞻性、随机的临床研究方法，将158例CRF氮质血症期患者随机分为治疗组与对照组，对照组予福辛普利及低蛋白饮食治疗，治疗组在上述治疗同时予以中药康肾冲剂，平均随访时间（20．3±6．9）月，对比研究2组主要临床指标以及营养状况的差异，计算血清肌酐倒数与时间的直线回归斜率以评估CRF的进展速度，利用Kaplan-Maier生存分析评估康肾冲剂对肾存活率的影响。结果 2组治疗后，主要临床症状与实验室指标均获得改善，但治疗组在血肌酐水平降低、内生肌酐清除率升高、生活质量改善等方面优于对照组；②血清肌酐倒数与时间的直线回归斜率治疗组、对照组分别为（-0．0224±0．0072）、（-0．0121±0．0038），2组比较差异有统计学意义（P〈0．05）；③治疗组与对照组分别有7例和14例患者随访终点，组间差异有统计学意义（P=0．038）。Kaplan．Maier生存分析显示加用中药康肾冲剂治疗能够显著提高患者肾存活率，延缓CRF的进展（P=0．044）。结论 康肾冲剂能够延缓CRF患者肾功能的进展，具有良好的临床应用价值。     

European Association of Urology (EAU) Prognostic Factor Risk Groups for Non–muscle-invasive Bladder Cancer (NMIBC) Incorporating the WHO 2004/2016 and WHO 1973 Classification Systems for Grade: An Update from the EAU NMIBC Guidelines Panel

BackgroundThe European Association of Urology (EAU) prognostic factor risk groups for non–muscle-invasive bladder cancer (NMIBC) are used to provide recommendations for patient treatment after transurethral resection of bladder tumor (TURBT). They do not, however, take into account the widely used World Health Organization (WHO) 2004/2016 grading classification and are based on patients treated in the 1980s.ObjectiveTo update EAU prognostic factor risk groups using the WHO 1973 and 2004/2016 grading classifications and identify patients with the lowest and highest probabilities of progression.Design, setting, and participantsIndividual patient data for primary NMIBC patients were collected from the institutions of the members of the EAU NMIBC guidelines panel.InterventionPatients underwent TURBT followed by intravesical instillations at the physician’s discretion.Outcome measurements and statistical analysisMultivariable Cox proportional-hazards regression models were fitted to the primary endpoint, the time to progression to muscle-invasive disease or distant metastases. Patients were divided into four risk groups: low-, intermediate-, high-, and a new, very high-risk group. The probabilities of progression were estimated using Kaplan-Meier curves.Results and limitationsA total of 3401 patients treated with TURBT ± intravesical chemotherapy were included. From the multivariable analyses, tumor stage, WHO 1973/2004–2016 grade, concomitant carcinoma in situ, number of tumors, tumor size, and age were used to form four risk groups for which the probability of progression at 5 yr varied from <1% to >40%. Limitations include the retrospective collection of data and the lack of central pathology review.ConclusionsThis study provides updated EAU prognostic factor risk groups that can be used to inform patient treatment and follow-up. Incorporating the WHO 2004/2016 and 1973 grading classifications, a new, very high-risk group has been identified for which urologists should be prompt to assess and adapt their therapeutic strategy when necessary.Patient summaryThe newly updated European Association of Urology prognostic factor risk groups for non–muscle-invasive bladder cancer provide an improved basis for recommending a patient’s treatment and follow-up schedule.     

P16<Superscript>INK4a</Superscript> expression and progression risk of low-grade intraepithelial neoplasia of the cervix uteri

The aim of the study was to evaluate the immunohistochemical expression of p16^INK4a as a marker of progression risk in low-grade dysplastic lesions of the cervix uteri. p16^INK4a immunohistochemistry was performed on 32 CIN1 with proven spontaneous regression of the lesion in the follow-up (group A), 31 (group B) with progression to CIN3 and 33 (group C) that were randomly chosen irrespective of the natural history of the lesion. p16^INK4a staining pattern was scored as negative (less than 5% cells in the lower third of dysplastic epithelium stained), as focally positive (25%) and as diffuse positive (>25%). A diffuse staining pattern was detected in 43.8% of CIN1 of group A, 74.2% of group B and 56.3% of group C. No p16^INK4a staining was detected in 31.3% and 12.9% CIN1 lesions of groups A and B, respectively. Overall, 71.4% and 37.8% of p16^INK4a-negative and diffusely positive CIN1 had regressed at follow-up, whereas 28.6% and 62.2% negative and diffusely positive CIN1 were progressed to CIN3, respectively (P<0.05). All CIN3 lesions analyzed during follow-up of group B were diffusely stained for p16^INK4a. Although p16^INK4a may be expressed in low-grade squamous lesions that undergo spontaneous regression, in this study, CIN1 cases with diffuse p16^INK4a staining had a significantly higher tendency to progress to a high-grade lesion than p16^INK4a-negative cases. p16^INK4a may have the potential to support the interpretation of low-grade dysplastic lesions of the cervix uteri.     

Stage-specific gene expression during hepatocarcinogenesis in the rat

The alteration of genetic expression ubiquitously seen in both preneoplastic and neoplastic tissues has been investigated for many years in the hope that the critical molecular changes resulting in cancer can be elucidated. The alteration of the expression of specific genes has already been employed in diagnostic and even screening procedures for this disease. In the past many observations of such alterations have led to a variety of theories but not definitive generalizations. Studies of the alteration of genetic expression may now be viewed in the light of our understanding of the multistage nature of neoplastic development. This brief review describes a number of genes the expressions of which are altered during the stages of initiation and promotion, in contrast to the alteration of expression of genes during the stage of progression. The promotion stage is concerned primarily with the chronic interaction of promoting agents in the environment with the genetic apparatus of the cell, played out on the altered genetic background resulting from the stage of initiation. In contrast, the progression stage is characterized primarily by an evolving karyotypic instability resulting in continual genetic changes during this stage. On the basis of these distinctions it is possible to identify genes the altered expression of which is unique to the stage of progression. The identification of these genes and an understanding of mechanisms resulting in their altered expression will allow not only a better molecular characterization of the progression stage but also the quantitative analysis of neoplastic development in several model animal systems as well as eventually in the human.Abbreviations GSTP glutathioneS-transferase placental form - GTT -glutamyltranspeptidase - TGF transforming growth factor Dedicated to the Cancer Institute on the occasion of its 60th anniversary and to Dr. Haruo Sugano on the occasion of his 70th birthday. This work was supported in part by grants from the National Cancer Institute (CA-07175, CA-22484 and CA-45700)     

Factors associated with progression to macroalbuminuria in microalbuminuric Type 1 diabetic patients: the EURODIAB Prospective Complications Study

Aims/hypothesis Type 1 diabetic patients who develop microalbuminuria are clearly disadvantaged in terms of their risk of morbidity and mortality from renal and cardiovascular diseases. It is therefore important to identify potential factors that can predict progression to macroalbuminuria.Methods This is a 7-year follow-up study of 352 microalbuminuric Type 1 diabetic patients from 31 European centres. Risk factors at baseline were compared in patients who progressed to macroalbuminuria and in patients who remained microalbuminuric or reverted to normoalbuminuria. Risk factors and albumin excretion rate (AER) were measured centrally.Results Over 7.3 years, 13.9% of the microalbuminuric patients progressed to macroalbuminuria, 35.5% remained microalbuminuric and 50.6% reverted to normoalbuminuria. Independent baseline risk factors for progression to macroalbuminuria were HbA₁c (7.9% vs 6.8%, p=0.004), AER (64.4 vs 44.9 µg/min, p=0.0001) and—after adjusting for diabetes duration, HbA₁c and AER—body weight (72 vs 67 kg, p=0.05). Independent factors associated with regression to normoalbuminuria were diabetes duration (15 vs 18 years, p=0.004), AER (37.2 vs 44.9 µg/min, p=0.0001) and—after adjusting for diabetes duration, HbA₁c and AER—waist-to-hip ratio (0.83 vs 0.86, p=0.05) and incidence of peripheral neuropathy at baseline (24% vs 38%, p=0.001). Blood pressure and smoking did not emerge as risk factors at baseline for the outcome of microalbuminuria.Conclusions/interpretation A significant fraction of microalbuminuric Type 1 diabetic patients will progress to overt proteinuria. Patients with higher AER values, sub-optimal metabolic control, excess body fat and peripheral neuropathy may carry a particularly high risk of clinical nephropathy requiring aggressive therapeutic intervention.Abbreviations AER albumin excretion rate - CVD cardiovascular disease - Gamma GT gamma-glutamyltransferase - OR odds ratio - PCS Prospective Complications Study - RR relative risk - SERR standardised estimates of relative risk - SREs standardised regression effects - vWF von Willebrand Factor     

Glycated Hemoglobin and Subclinical Atherosclerosis in People Without Diabetes

BackgroundThe metabolic injury caused by protein glycation, monitored as the level of glycated hemoglobin (HbA1c), is not represented in most risk scores (i.e., Systematic Coronary Risk Estimation or atherosclerotic cardiovascular disease risk scale).ObjectivesThe purpose of this study was to assess the association between HbA1c and the extent of subclinical atherosclerosis (SA) and to better identify individuals at higher risk of extensive SA using HbA1c on top of key cardiovascular risk factors (CVRFs).MethodsA cohort of 3,973 middle-aged individuals from the PESA (Progression of Early Subclinical Atherosclerosis) study, with no history of cardiovascular disease and with HbA1c in the nondiabetic range, were assessed for the presence and extent of SA by 2-dimensional vascular ultrasound and noncontrast cardiac computed tomography.ResultsAfter adjusting for established CVRFs, HbA1c showed an association with the multiterritorial extent of SA (odds ratio: 1.05, 1.27, 1.27, 1.36, 1.80, 1.87, and 2.47 for HbA1c 4.9% to 5.0%, 5.1% to 5.2%, 5.3% to 5.4%, 5.5% to 5.6%, 5.7% to 5.8%, 5.9% to 6.0%, and 6.1% to 6.4%, respectively; reference HbA1c ≤4.8%; p < 0.001). The association was significant in all pre-diabetes groups and even below the pre-diabetes cut-off (HbA1c 5.5% to 5.6% odds ratio: 1.36 [95% confidence interval: 1.03 to 1.80]; p = 0.033). High HbA1c was associated with an increased risk of SA in low-risk individuals (p < 0.001), but not in moderate-risk individuals (p = 0.335). Relative risk estimations using Systematic Coronary Risk Estimation or atherosclerotic cardiovascular disease predictors confirmed that inclusion of HbA1c modified the risk of multiterritorial SA in most risk categories.ConclusionsRoutine use of HbA1c can identify asymptomatic individuals at higher risk of SA on top of traditional CVRFs. Lifestyle interventions and novel antidiabetic medications might be considered to reduce both HbA1c levels and SA in individuals without diabetes.