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Objective: To analyze the prevalence and incidence of Human Papillomavirus (HPV) infection and its possible association with type 2 diabetes mellitus. Materials and Methods: A retrospective cohort study was conducted. Exposure was HPV-infection. Results: 13234 females were analyzed [median of age=46], 1215 cases of diabetes (median of age=53) and 12019 cases without diabetes (median of age=45). There were 1495 (11.3%; 95%CI 10.8–11.8) new cases of HPV infection by any genotype, 234 (1.8%; 95%CI 1.5–2.0) by genotype-16, 102 (0.8%; 95%CI 0.8–0.8) by genotype-18, and 1279 (9.7%; 95%CI 9.2–10.1) by high risk (HR) genotypes. The global crude-prevalence by any genotype, and HR-genotypes was significantly lower (p=0.008) in subjects with diabetes compared with their counterparts without diabetes. The mean duration of follow-up was 1.1 years. The global crude-incidence rate of HPV-infection per 1000 person-years by any genotype, and genotypes-16, - 18, and -HR was 99.36, 15.55, 6.78, and 85.01, respectively. The crude hazard ratio of infection by HPV-18 genotype was higher in women with diabetes and age between 20-24y (HR=36.611; 95%CI 4.009-334.303, p=0.001), and 40-44y (HR=3.947; 95%CI 1.124-13.857, p=0.032) compared with their counterparts without diabetes. Conclusion: Type 2 diabetes mellitus increases the risk of infection by HPV-genotype-18 in young adult woman.

PDF file - 315K, Immunostaining of ASS1, TS, and DHFR in representative urothelial carcinomas.

PDF file - 408K, Pyrosequencing data of bladder cancer cell lines and primary bladder cancer samples.

PDF file - 177K, Kaplan-Meier plot and log-rank test for disease-specific and metastasis-free survival.

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PDF file - 198K, Table S1 Correlation between ASS1 expression and various clinicopathological factors. Table S2 Univariate log-rank analysis for disease-specific survival and metastasis-free survival. Table S3 Correlation between ASS1 IHC and pyrosequencing of primary bladder cases. Table S4 Combination index (CI) analysis.

Prostate cancer is significantly more common in Western men than in Asian men, but the basis for this difference remains unknown. Because genomic studies of Asian prostate cancer are very limited, we used a genome-wide approach to reveal the genomic alterations in Chinese prostate cancers. We found a significant reduction in the frequency of certain somatic genomic changes that are commonly found in Western prostate cancers, including the 21q22.2-22.3 deletion, which involves the TMPRSS2:ERG fusion gene, and 10q deletion, which causes PTEN inactivation. Array results were confirmed by PCR-based molecular copy-number counting in selected samples. The different frequencies of these genomic changes were further evaluated by fluorescent in situ hybridization and immunohistochemistry analyses of tissue microarray samples. These alterations might be key genetic changes underlying the regional/ethnic difference in clinical incidence and might be induced by specific environmental and/or genetic risk factors that Western men are exposed to. Our findings suggest that tumors arise in Western and Chinese populations by alternative pathogenetic mechanisms. Cancer Res; 70(13); 5207–12. ©2010 AACR.

PDF file - 802K, Metabolomics of ADI-PEG20 in a corroborative cell line panel (mesothelioma).

Supplementary Figures 1-2, Tables 1-8 from Distinct Genomic Alterations in Prostate Cancers in Chinese and Western Populations Suggest Alternative Pathways of Prostate Carcinogenesis

Mallines are Patagonian wetlands characterized by permanent waterlogging on its soils, sustaining small shallow lakes that hosts a vast biodiversity. In these ecosystems, aquatic plants (i.e. macrophytes) develop different life forms adapted to humid conditions, allowing them to regulate the physical and chemical conditions of the mallin. A distinctive characteristic of Patagonia is the exponential west-east decrease in rainfall, which generates three biozones: forest, ecotone and steppe. These biozones have been typified using landform plants, but whether macrophytes assemblages are related to each biozone or not has not been evaluated yet. The aim of this work is to compare the attributes of the macrophyte and wetlands landform plants community in each biozone. During the 2013-2014 austral Summer, 20 shallow lakes were sampled in the west province of Chubut, assessing macrophyte richness and physical and chemical water variables. Macrophytes were classified according to their life forms, origin, and its diversity was calculated. A total of 62 taxa were determined, most of them corresponding to the Cyperaceae, Poaceae and Ranunculaceae families. The steppe exhibited alkaline pH values, and higher conductivity and soluble reactive phosphorus (SRP) than the ecotone and the forest. High SRP values favored the abundance of macrophytes and macroalgae. However, three sites were eutrophic, exhibiting high chlorophyll a and total phosphorus values. Those sites showed higher abundances of macroalgae and emerging macrophytes. The sampled shallow lakes would act as reservoirs of macrophyte diversity at both local and regional scales. Thus, understanding the relationships among macrophytes and environmental variables could be useful for the mallines biodiversity conservation plans.

In 2016, the World Health Organization classification system of testicular tumors included the new entity prepubertal-type teratoma based on its morphological and molecular profile, and the realization that these tumors may occur in postpubertal men. For treatment and prognostic purposes, it is important to distinguish prepubertal-type teratoma from the usual postpubertal-type teratoma, because the former is benign unlike the latter. The distinction may be challenging. In this study, we investigated clinical, morphological, and molecular criteria for distinguishing prepubertal-type teratoma from postpubertal-type teratoma in a prospective series of pure testicular teratomas. All cases of pure teratoma in postpubertal men assessed at Barts Health NHS Trust or in consultation since the introduction of routine investigation of chromosome 12p status in 2010 were reviewed. Morphological features suggestive of prepubertal-type teratoma were observed in 14 out of 35 cases. All underwent molecular testing and none displayed 12p amplification. Mean tumor size was 16 mm (range 7–28 mm). None had associated germ cell neoplasia in situ or significant atrophy. Four incorporated a well-differentiated neuroendocrine tumor, 1–2 mm in size. Of the ten patients with follow-up information, none have recurred or metastasized. Twenty-one of the 35 cases were diagnosed as postpubertal-type teratoma, mean tumor size 40 mm (range 6–90 mm). One case underwent molecular testing: a tumor of pure skeletal muscle differentiation and possessed 12p amplification. Three cases presented with clinical metastases. Eight cases contained immature areas, ten cases had associated germ cell neoplasia in situ, and 17 cases had severe atrophy of the parenchyma. One case with neither germ cell neoplasia in situ nor atrophy showed necrosis. We conclude that both morphological and molecular features are of help in differentiating prepubertal-type teratoma from postpubertal-type teratoma. In nearly all postpubertal-type teratomas, molecular testing was unnecessary, and merely confirmed the morphological impression in the prepubertal-type teratomas. Our study confirmed the high incidence of well-differentiated neuroendocrine tumors in the prepubertal-type.

Contains fulltext : 286841.pdf (Publisher’s version ) (Closed access) BACKGROUND: Resistant hypertension is associated with increased cardiovascular risk. The endothelin pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically, thereby leaving this relevant pathophysiological pathway unopposed with currently available drugs. The aim of the study was to assess the blood pressure lowering efficacy of the dual endothelin antagonist aprocitentan in patients with resistant hypertension. METHODS: PRECISION was a multicentre, blinded, randomised, parallel-group, phase 3 study, which was done in hospitals or research centres in Europe, North America, Asia, and Australia. Patients were eligible for randomisation if their sitting systolic blood pressure was 140 mm Hg or higher despite taking standardised background therapy consisting of three antihypertensive drugs, including a diuretic. The study consisted of three sequential parts: part 1 was the 4-week double-blind, randomised, and placebo-controlled part, in which patients received aprocitentan 12·5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio; part 2 was a 32-week single (patient)-blind part, in which all patients received aprocitentan 25 mg; and part 3 was a 12-week double-blind, randomised, and placebo-controlled withdrawal part, in which patients were re-randomised to aprocitentan 25 mg or placebo in a 1:1 ratio. The primary and key secondary endpoints were changes in unattended office systolic blood pressure from baseline to week 4 and from withdrawal baseline to week 40, respectively. Secondary endpoints included 24-h ambulatory blood pressure changes. The study is registered on ClinicalTrials.gov, NCT03541174. FINDINGS: The PRECISION study was done from June 18, 2018, to April 25, 2022. 1965 individuals were screened and 730 were randomly assigned. Of these 730 patients, 704 (96%) completed part 1 of the study; of these, 613 (87%) completed part 2 and, of these, 577 (94%) completed part 3 of the study. The least square mean (SE) change in office systolic blood pressure at 4 weeks was -15·3 (SE 0·9) mm Hg for aprocitentan 12·5 mg, -15·2 (0·9) mm Hg for aprocitentan 25 mg, and -11·5 (0·9) mm Hg for placebo, for a difference versus placebo of -3·8 (1·3) mm Hg (97·5% CI -6·8 to -0·8, p=0·0042) and -3·7 (1·3) mm Hg (-6·7 to -0·8; p=0·0046), respectively. The respective difference for 24 h ambulatory systolic blood pressure was -4·2 mm Hg (95% CI -6·2 to -2·1) and -5·9 mm Hg (-7·9 to -3·8). After 4 weeks of withdrawal, office systolic blood pressure significantly increased with placebo versus aprocitentan (5·8 mm Hg, 95% CI 3·7 to 7·9, p

International audience; Standard clinical parameters fail to accurately differentiate indolent from aggressive prostate cancer. Our previous studies showed that immunohistochemical testing for Ki-67 improved prediction of prostate cancer death in a previous cohort of conservatively treated clinically localized prostate cancer. However there is a need for validation of usage with whole biopsy sections rather than tissue micro-arrays for use in routine diagnostics. Prostate cancer biopsy cases were identified in the UK, between 1990 and 2003, treated conservatively. Tumor extent and prostate-specific antigen (PSA) serum measurements were available. Biopsy cases were centrally reviewed by three uropathologists and Gleason conformed to contemporary ISUP 2014 criteria. Follow-up was through cancer registries up until 2012. Deaths were divided into those from prostate cancer and those from other causes. The percentage of Ki-67 in tumor cells was evaluated by immunohistochemistry on whole biopsy sections and was available for 756 patients. This percentage was used in analysis of cancer specific survival using a Cox proportional hazards model. In univariate analysis, the interquartile hazard ratio (HR) (95% confidence intervals) for continuous Ki-67 was 1.68 (1.49, 1.89), χ 1 2 = 47.975, P < 0.001. In grade groups 1 and 2, continuous Ki-67 was a statistically significant predictor of time to death from prostate cancer, HR (95% CI) = 1.97 (1.34, 2.88), χ 1 2 = 9.017, p = 0.003. In multivariate analysis, continuous Ki-67 added significant predictive information to that provided by grade groups, extent of disease and serum PSA, HR (95% CI) = 1.34 (1.16, 1.54), Δχ 1 2 = 13.703, P < 0.001. We now advocate the introduction of Ki-67 as a viable and practicable prognostic biomarker in clinical practice. The association of Ki-67 with mortality was highest in grade groups 1 and 2, showing that Ki-67 can be used as a routine biomarker in patients being considered for active surveillance.

Introduction In mammals, the preBotzinger complex (preBotC) is a bilateral and symmetrical neural network located in the brainstem which is essential for the generation and modulation of respiratory rhythm. Few human studies have addressed the preBotC and its relationship with neurological diseases has not been described. However, the possibility that the preBotC is important in neural control of breathing, and potentially involved in neurological diseases in humans, has been suggested based on pharmacological manipulation and lesion of the preBotC in animal models, both in vivo and in vitro. Method In this review, we describe the effects of certain drugs on the inspiratory activity in vitro in a transverse slice that contains the preBotC, as well as some in vivo experiments. Drugs were classified according to their effects on the main neurotransmitter systems and their importance as stimulators or inhibitors of preBotC activity and therefore for the generation of the respiratory rhythm. Conclusion Clinical neurologists will find this information relevant to understanding how the central nervous system generates the respiratory rhythm and may also relate this information to the findings made in daily practice.

Resumen: Introducción: En los mamíferos, el complejo pre-Bötzinger (preBötC) es una red neuronal bilateral y simétrica localizada en el tallo cerebral, la cual es indispensable para la generación y modulación del ritmo respiratorio. En humanos existen pocos estudios acerca del preBötC y su relación con enfermedades neurológicas no ha sido descrita. Sin embargo, la importancia del preBötC en el control neural del ritmo respiratorio y su posible participación en enfermedades neurológicas en humanos ha sido mostrada gracias a la manipulación farmacológica y de lesiones del preBötC realizadas en modelos animales in vivo e in vitro. Método: En esta revisión describimos los efectos de algunos fármacos sobre la actividad inspiratoria in vitro en el modelo de rebanada transversal del tallo cerebral que contiene el preBötC, y algunos experimentos in vivo. La farmacología fue clasificada de acuerdo con los principales sistemas de neurotransmisión y con la importancia de los fármacos como estimuladores o inhibidores de la actividad del preBötC y, por tanto, de la generación del ritmo respiratorio. Conclusiones: El neurólogo clínico encontrará esta información relevante para entender cómo el sistema nervioso central genera el ritmo respiratorio y, además, podrá relacionarla con las observaciones hechas durante su práctica. Abstract: Introduction: In mammals, the preBötzinger complex (preBötC) is a bilateral and symmetrical neural network located in the brainstem which is essential for the generation and modulation of respiratory rhythm. There are few human studies about the preBötC and, its relationship with neurological diseases has not been described. However, the importance of the preBötC in neural control of breathing and its potential participation in neurological diseases in humans, has been suggested based on pharmacological manipulation and lesion of the preBötC in animal models, both in vivo and in vitro. Method: In this review, we describe the effects of some drugs on the inspiratory activity in vitro in a transverse slice that contains the preBötC, as well as some in vivo experiments. Drugs were classified according to their effects on the main neurotransmitter systems and their importance as stimulators or inhibitors of preBötC activity and therefore for the generation of the respiratory rhythm. Conclusion: Clinical neurologists will find this information relevant to understanding how the central nervous system generates the respiratory rhythm and may also relate this information to the findings made in daily practice. Palabras clave: Generación del ritmo respiratorio, Respiración, Complejo pre-Bötzinger, Control neural de la respiración, NK1R, In vitro, Keywords: Respiratory rhythm generation, Breathing, preBötzinger complex, Neural control of breathing, NK1R, In vitro

AIMS It has been recommended that the percentage of high-grade (HG) Gleason patterns 4 and 5 should be quantified in prostate cancer. However, this has not been assessed in a cohort using prostate cancer death as an outcome, and there is debate as to whether the biopsy with the 'worst' percentage of HG disease or an 'overall' percentage of HG disease should be reported. Such data may assist in active surveillance decisions. METHODS AND RESULTS Men with clinically localised prostate cancer diagnosed by needle biopsy from 1990 to 2003 were included. The endpoint was prostate cancer death. Clinical variables included Gleason score (GS), prostate-specific antigen level, age, clinical stage, and disease extent. Deaths were divided into those from prostate cancer and those from other causes, according to World Health Organization criteria. Nine hundred and eighty-eight biopsy cases were centrally reviewed according to criteria agreed at the Chicago International Society of Urological Pathology conference in 2014. Cores were given individual GSs and Grade Groups (GGs), and a percentage of each grade was given for each core. Both the worst percentage of HG disease seen in a biopsy series and overall percentage of HG disease were calculated. The overall percentage of HG disease was highly significant, with a hazard ratio of 4.45 for the interquartile range (95% confidence interval 3.30-6.01, P

Knowledge of immature habitats is an important focus for investigations of mosquito community ecology, and may improve our understanding of how environmental variables increase risk of mosquito-borne diseases by influencing the distributions and abundances of species. In Patagonia region, where climatic and ecological factors could be only borderline suitable for mosquito development, relatively little is known about larval ecology. The present study focuses on associations of environmental conditions in natural aquatic habitats with abundances of mosquito species that have colonized such habitats in Patagonia. We described the mosquito community composition within 26 natural temporary pools, and assessed the general relationships between environmental variables (pH, water temperature, conductivity, salinity, dissolved oxygen, aquatic plant cover and main nutrients) and larval abundances using redundancy analysis (RDA). Additionally, we compiled monthly climate data and vegetation indices for each larval habitat, and estimated the probability of presence for two of the most abundant species, describing through generalized linear models (GLM) the environmental, climatic and landscape variables-probability of occurrence relationships. Seven species belonging to the genera Culex and Aedes were identified, with Culex apicinus, Cx. acharistus and Aedes albifasciatus being the most abundant. Mean larval densities were low (6.8 ± 2.8 larvae/dip), and the highestspecies richness and larval densities were recorded in northern and central areas. Aedes albifasciatus, a species of sanitary importance, was widely distributed, being the only one collected south of the 45th parallel of S latitude. RDA indicated that aquatic conductivity, pH, water depth, dissolved oxygen, ammonia and soluble reactive phosphorous accounted for the main part of the variation in the species composition. According to GLMs, wind speed was thevariable that best described the presence of Ae. albifasciatus, and the probability of finding this species was positively associated with high wind speed values. On the other hand, the EVI vegetation index was the only variable included in the Cx. apicinus model, whereby there was a great probability of presence in arid areas with lower EVI values. Our results enhance our knowledge of larval habitat ecology under the extreme environmental conditions of Patagonia and will guide future efforts to understand how multiple effects can affect mosquito ecology and public health at higher latitudes. Fil: Grech, Marta Gladys. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Centro de Investigación Esquel de Montaña y Estepa Patagóica. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Esquel. Centro de Investigación Esquel de Montaña y Estepa Patagónica; Argentina Fil: Manzo, Luz Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Centro de Investigación Esquel de Montaña y Estepa Patagóica. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Esquel. Centro de Investigación Esquel de Montaña y Estepa Patagónica; Argentina Fil: Epele, Luis Beltran. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Centro de Investigación Esquel de Montaña y Estepa Patagóica. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Esquel. Centro de Investigación Esquel de Montaña y Estepa Patagónica; Argentina Fil: Laurito, Magdalena. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Centro de Investigaciones Entomológicas de Córdoba; Argentina Fil: Claverie, Alfredo Ñancuche. Universidad Nacional de la Patagonia "San Juan Bosco"; Argentina Fil: Ludueña Almeida, Francisco. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Centro de Investigaciones Entomológicas de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina Fil: Miserendino, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Centro de Investigación Esquel de Montaña y Estepa Patagóica. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Esquel. Centro de Investigación Esquel de Montaña y Estepa Patagónica; Argentina Fil: Almiron, Walter Ricardo. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Centro de Investigaciones Entomológicas de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina

There are few studies into the rate and causes of histopathological false-positive diagnosis of prostate cancer. Only two of these, including a previous one from our group, incorporate survival data. In addition, in none of the previous studies had immunohistochemistry been originally requested on any of the misdiagnosed cases. Diagnostic biopsies (n=1080) and trans-urethral resection of prostate specimens (n=314) from 1394 men with clinically localised prostate cancer diagnosed in the UK but treated conservatively between 1990 and 2003 were reviewed by a panel of 3 genitourinary pathologists. Thirty five cases were excluded for being potentially incomplete. Of the remaining 1359, 30 (2.2%) were re-assigned to a non-malignant category (26 benign and 4 suspicious for malignancy). Immunohistochemistry had been originally performed on 7 of these. The reasons for the errors were recorded on each case: adenosis (19), partial atrophy (3), PIN (2), seminal vesicle epithelium (1) and hyperplasia (1). Follow-up of these men revealed only one prostate cancer related death, possibly due to un-sampled tumour. In conclusion, a relatively small number of prostate cancer mimics were responsible for a large proportion of the false-positive prostate cancer diagnoses and the use of immunohistochemistry did not prevent the overcall of benign entities as cancer in approximately a quarter of these cases. Targeting these mimics at educational events and raising awareness of the pitfalls in the interpretation of immunohistochemistry in prostate cancer diagnosis, emphasising that glands within a suspicious focus should be treated as a whole rather than individually, may be beneficial in lowering the rate of false-positive diagnosis.

Ecological regions are areas of similar nature in terms of environmental features. Examination of the correspondence between organismal assemblage structure and function at different levels of spatial scale is crucial regarding pond conservation, especially in unexplored areas as continental austral Patagonia, where the extensive sheep breeding has been the historical land use. We assessed relationships between invertebrate assemblages and environmental characteristics at local (hydrogeomorphology and genesis) and landscape scale (phytogeographical and biozones) on 20 isolated wetland ponds (Southern Patagonia, Argentina). Additionally, we recognized best environmental predictors of invertebrate community attributes using generalized linear models (GLM). Most ponds displayed low anthropogenic stress since most of them were far from urban and rural settlements. Even though a few sites showed strong oxygen depletion (n = 3), most were well oxygenated (>85%, >11 mg/l). Also, ponds had low ammonia and soluble reactive phosphorus contents (>60%, 25 µg/l). A total of 80 invertebrate taxa were found, with Insecta and Oligochaeta displaying the highest richness. Cyanallagma interruptum (Anisoptera), Parapsectrocladius sp. and Parachironomus sp. (Chironomidae) were the most abundant taxa. Redundancy Analysis (RDA) showed that local environmental factors greatly explained the abundance patterns of invertebrates. In addition, variance partitioning analyses displayed that taxa responded more strongly to pond genesis (7% of variation) than to the other levels of spatial scale analyzed. Structural and functional attributes of communities (metrics) also showed that genesis (local scale) resulted a reliable predictor. Thus, the community composition changed according to fluvial, glacigenic, mass removal or anthropogenic origin of the ponds. Our results suggest that ponds across the austral continental Patagonia area appeared as crucial reservoirs of invertebrate biodiversity sustaining several endemic taxa. However, the expansion of new agricultural and land use practices in surrounding areas could impact negatively on pond integrity. Conservation programs should include major constrains at both, local and landscape scale, in which part of the physical complexity is driving by pond origin. Fil: Manzo, Luz Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Centro de Investigación Esquel de Montaña y Estepa Patagóica. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Esquel. Centro de Investigación Esquel de Montaña y Estepa Patagónica; Argentina Fil: Epele, Luis Beltran. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Centro de Investigación Esquel de Montaña y Estepa Patagóica. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Esquel. Centro de Investigación Esquel de Montaña y Estepa Patagónica; Argentina Fil: Grech, Marta Gladys. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Centro de Investigación Esquel de Montaña y Estepa Patagóica. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Esquel. Centro de Investigación Esquel de Montaña y Estepa Patagónica; Argentina Fil: Kandus, Patricia. Universidad Nacional de San Martín. Instituto de Investigación en Ingeniería Ambiental; Argentina Fil: Miserendino, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Centro de Investigación Esquel de Montaña y Estepa Patagóica. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Esquel. Centro de Investigación Esquel de Montaña y Estepa Patagónica; Argentina

The efficiency of biodiversity assessments and biomonitoring studies is commonly challenged by limitations in taxonomic identification and quantification approaches. In this study, we assessed the effects of different taxonomic and numerical resolutions on a range of community structure metrics in invertebrate compositional data sets from six regions distributed across North and South America. We specifically assessed the degree of similarity in the metrics (richness, equitability, beta diversity, heterogeneity in community composition and congruence) for data sets identified to a coarse resolution (usually family level) and the finest taxonomic resolution practical (usually genus level, sometimes species or morphospecies) and by presence-absence and relative abundance numerical resolutions. Spearman correlations showed highly significant and positive associations between univariate metrics (richness and equitability) calculated for coarse- and finest-resolution datasets. Procrustes analysis detected significant congruence between composition datasets. Higher correlation coefficients were found for datasets with the same numerical resolutions regardless of the taxonomic level (about 90%), while the correlations for comparisons across numerical resolutions were consistently lower. Our findings indicate that family-level resolution can be used as a surrogate of finer taxonomic resolutions to calculate a range of biodiversity metrics commonly used to describe invertebrate community structure patterns in New World freshwater wetlands without significant loss of information. However, conclusions on biodiversity patterns derived from datasets with different numerical resolutions should be critically considered in studies on wetland invertebrates. Fil: Marques Pires, Mateus. Universidad de Vale do Rio dos Sinos; Brasil Fil: Grech, Marta Gladys. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Centro de Investigación Esquel de Montaña y Estepa Patagónica. Universidad Nacional de la Patagonia "San Juan Bosco". Centro de Investigación Esquel de Montaña y Estepa Patagónica; Argentina Fil: Stenert, Cristina. Universidad de Vale do Rio dos Sinos; Brasil Fil: Maltchik, Leonardo. Universidad de Vale do Rio dos Sinos; Brasil Fil: Epele, Luis Beltran. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Centro de Investigación Esquel de Montaña y Estepa Patagónica. Universidad Nacional de la Patagonia "San Juan Bosco". Centro de Investigación Esquel de Montaña y Estepa Patagónica; Argentina Fil: McLean, Kyle I.. United States Geological Survey; Estados Unidos Fil: Kneitel, Jamie M.. California State University; Estados Unidos Fil: Bell, Douglas A.. East Bay Regional Park District; Estados Unidos Fil: Greig, Hamish S.. The University Of Maine (the University Of Maine); Fil: Gagne, Chase R.. The University Of Maine (the University Of Maine); Fil: Batzer, Darold P.. University of Georgia; Estados Unidos

Introduction The growth hormone (GH) has been reported as a crucial neuronal survival factor in the hippocampus against insults of diverse nature. Status epilepticus (SE) is a prolonged seizure that produces extensive neuronal cell death. The goal of this study was to evaluate the effect of intracerebroventricular administration of GH on seizure severity and SE-induced hippocampal neurodegeneration. Methodology Adult male rats were implanted with a guide cannula in the left ventricle and different amounts of GH (70, 120 or 220 ng/3 μl) were microinjected for 5 days; artificial cerebrospinal fluid was used as the vehicle. Seizures were induced by the lithium–pilocarpine model (3 mEq/kg LiCl and 30 mg/kg pilocarpine hydrochloride) one day after the last GH administration. Neuronal injury was assessed by Fluoro-Jade B (F-JB) staining. Results Rats injected with 120 ng of GH did not had SE after 30 mg/kg pilocarpine, they required a higher number of pilocarpine injections to develop SE than the rats pretreated with the vehicle, 70 ng or 220 ng GH. Prefrontal and parietal cortex EEG recordings confirmed that latency to generalized seizures and SE was also significantly higher in the 120 ng group when compared with all the experimental groups. FJ-B positive cells were detected in the hippocampus after SE in all rats, and no significant differences in the number of F-JB cells in the CA1 area and the hilus was observed between experimental groups. Conclusion Our results indicate that, although GH has an anticonvulsive effect in the lithium–pilocarpine model of SE, it does not exert hippocampal neuroprotection after SE.

Fil: Epele, Luis Beltrán. Centro de Investigación Esquel de Montaña y Estepa Patagónica (CONICET-UNPSJB), Esquel, Chubut, Argentina 2Facultad de Ciencias Naturales y Ciencias de la Salud, UNPSJB, Esquel, Chubut, Argentina 3Freshwater Ecology, Hydrology and Management group (FEHM), Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals, Institut de Recerca de la Biodiversitat (IRBio), Universitat de Barcelona, Barcelona, Spain Fil: Dos Santos Daniel Andrés. Instituto de Biodiversidad Neotropical, CONICET –UNT, Cúpulas Universitarias S/N, Cátedra de Biología Animal, Facultad de Ciencias Naturales e IML, UNT, Yerba Buena, Tucumán, Argentina Fil: Sarremejane, Romain. INRAE, UR-RiverLy, Centre de Lyon-Grenoble Auvergne-Rhône- Alpes, Villeurbanne Cedex, France Fil: Grech, Marta Gladys. Centro de Investigación Esquel de Montaña y Estepa Patagónica (CONICET-UNPSJB), Esquel, Chubut, Argentina 2Facultad de Ciencias Naturales y Ciencias de la Salud, UNPSJB, Esquel, Chubut, Argentina Fil: Macchi, Pablo Antonio. Universidad Nacional de Río Negro, Instituto de Investigación en Paleobiología y Geología, Río Negro, Argentina Fil: Manzo, Luz María. Centro de Investigación Esquel de Montaña y Estepa Patagónica (CONICET-UNPSJB), Esquel, Chubut, Argentina Fil: MIserendino, María Laura. Centro de Investigación Esquel de Montaña y Estepa Patagónica (CONICET-UNPSJB), Esquel, Chubut, Argentina 2Facultad de Ciencias Naturales y Ciencias de la Salud, UNPSJB, Esquel, Chubut, Argentina Fil: Bonada, Núria. Freshwater Ecology, Hydrology and Management group (FEHM), Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals, Institut de Recerca de la Biodiversitat (IRBio), Universitat de Barcelona, Barcelona, Spain Fil: Cañedo-Argüelles, Miguel. Serra-Hunter fellow, Freshwater Ecology, Hydrology and Management group (FEHM), Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals, Institut de Recerca de l'Aigua (IdRA), Universitat de Barcelona, Barcelona, Spain Aim: To assess the relative importance of wind intensity and direction in explaining wetland invertebrate metacommunity organization. Location: Seventy-eight wetland ponds in Patagonia (Argentina) covering a study area of 3.5 × 10 5 km 2 . Time period: Ponds were sampled once between 2006 and 2014. Major taxa studied: One hundred and fifty-eight taxa of wetland aquatic invertebrates. Methods: We generated two beta diversity matrices (based on flying and non-flying invertebrates) and six predictor matrices, including three environmental distance matrices, a topographic distance between ponds, and two wind pairwise matrices differing in wind speed. Using Moran spectral randomization of Mantel (MSR-Mantel) tests (which account for spatial autocorrelation), we assessed the relationship between the response and the predictor matrices. We used a network-constrained version of the nestedness metric based on overlap and decreasing fill (NODF), to assess if wind anisotropy (i.e., direction-dependent) affected community nestedness among ponds. Results: Flying dispersers’ dissimilarity was significantly explained by environmental variables, whereas non-flying invertebrates’ dissimilarity was not significantly explained by any of the distances tested. When wind direction was ignored, wind speed had a negligible effect on both types of communities, whereas when it was considered a consistent nested pattern emerged, with the eastern ponds (downwind) communities being subsets of those from the western ponds (upwind). Aim: To assess the relative importance of wind intensity and direction in explaining wetland invertebrate metacommunity organization. Location: Seventy-eight wetland ponds in Patagonia (Argentina) covering a study area of 3.5 × 10 5 km 2 . Time period: Ponds were sampled once between 2006 and 2014. Major taxa studied: One hundred and fifty-eight taxa of wetland aquatic invertebrates. Methods: We generated two beta diversity matrices (based on flying and non-flying invertebrates) and six predictor matrices, including three environmental distance matrices, a topographic distance between ponds, and two wind pairwise matrices differing in wind speed. Using Moran spectral randomization of Mantel (MSR-Mantel) tests (which account for spatial autocorrelation), we assessed the relationship between the response and the predictor matrices. We used a network-constrained version of the nestedness metric based on overlap and decreasing fill (NODF), to assess if wind anisotropy (i.e., direction-dependent) affected community nestedness among ponds. Results: Flying dispersers’ dissimilarity was significantly explained by environmental variables, whereas non-flying invertebrates’ dissimilarity was not significantly explained by any of the distances tested. When wind direction was ignored, wind speed had a negligible effect on both types of communities, whereas when it was considered a consistent nested pattern emerged, with the eastern ponds (downwind) communities being subsets of those from the western ponds (upwind).

Simple Summary There is a tremendous amount of gene expression information available for prostate cancer, but very few tools exist to combine the disparate datasets generated across sample types and technical platforms. We present a method of integrating different types of expression data from different study cohorts to increase analytic power, and improve our understanding of the molecular changes underlying the development and progression of prostate cancer from normal to advanced disease. Using this approach, we identified nine additional disease stage-specific candidate genes with prognostic significance, which were not identified in any one study alone. We have developed a free online tool summarizing our results, and making the complete combined dataset available for further translational research. Abstract Next-generation sequencing of primary tumors is now standard for transcriptomic studies, but microarray-based data still constitute the majority of available information on other clinically valuable samples, including archive material. Using prostate cancer (PC) as a model, we developed a robust analytical framework to integrate data across different technical platforms and disease subtypes to connect distinct disease stages and reveal potentially relevant genes not identifiable from single studies alone. We reconstructed the molecular profile of PC to yield the first comprehensive insight into its development, by tracking changes in mRNA levels from normal prostate to high-grade prostatic intraepithelial neoplasia, and metastatic disease. A total of nine previously unreported stage-specific candidate genes with prognostic significance were also found. Here, we integrate gene expression data from disparate sample types, disease stages and technical platforms into one coherent whole, to give a global view of the expression changes associated with the development and progression of PC from normal tissue through to metastatic disease. Summary and individual data are available online at the Prostate Integrative Expression Database (PIXdb), a user-friendly interface designed for clinicians and laboratory researchers to facilitate translational research.

Autism spectrum disorder is associated with alterations in GABAergic and glutamatergic neurotransmission. Here, we aimed to determine the concentration of GABA, glutamate, glutamine, aspartate, taurine, and glycine in brain tissue and plasma of rats prenatally exposed to valproic acid (VPA), a well-characterized experimental model of autism. Pregnant rats were injected with VPA (600mg/Kg) during the twelfth-embryonic-day. Control rats were injected with saline. On the fourteen-postnatal-day, rats from both groups (males and females) were anesthetized, euthanized by decapitation and their brain dissected out. The frontal cortex, hippocampus, amygdala, brain stem and cerebellum were dissected and homogenized. Homogenates were centrifuged and supernatants were used to quantify amino acid concentrations by HPLC coupled with fluorometric detection. Blood samples were obtained by a cardiac puncture; plasma was separated and deproteinized to quantify amino acid concentration by HPLC. We found that, in VPA rats, glutamate and glutamine concentrations were increased in hippocampus and glycine concentration was increased in cortex. We did not find changes in other regions or in plasma amino acid concentration in the VPA group with respect to control group. Our results suggest that VPA exposure in utero may impair inhibitory and excitatory amino acid transmission in the infant brain.

Pathological risk factors for metastatic disease in patients with testicular non-seminomatous germ cell tumors are debated. The tumor-node-metastasis (TNM) classification eighth edition for testicular cancers includes divergent versions, by the International Union Against Cancer (UICC) and by the American Joint Committee for cancer (AJCC). We investigated pathological predictors of metastatic disease at presentation in 219 non-seminomatous germ cell tumors with reference to both classifications. Age, tumor size, percentage of embryonal carcinoma, lymphovascular invasion, invasion of stromal rete testis, hilar soft tissue, epididymis, spermatic cord, and tunica vaginalis, as well as tumor at spermatic cord margin, were assessed and correlated with clinical stage at presentation. Of the 219 NSGCT cases, 151 (69%) were clinical stage I, 68 (31%) were clinical stage II/III. On univariate analysis, tumor size (P = 0.028), percentage of embryonal carcinoma (P = 0.004), lymphovascular invasion (P = 0.001), stromal rete testis invasion (P = 0.001), hilar soft tissue invasion (P = 0.010), epididymis invasion (P = 0.010), direct spermatic cord invasion (P = 0.001), and tumor at spermatic cord margin ((P = 0.009) were associated with higher clinical stage. On multivariate analysis, lymphovascular invasion (P = 0.003), tumor size (P = 0.005), percentage of embryonal carcinoma (P = 0.005), stromal rete testis invasion (P = 0.008) remained significant. A tumor size of 6 cm and an embryonal carcinoma percentage of 70% were the significant cut-off values. We conclude that in addition to lymphovascular invasion, stromal rete testis invasion, tumor size, and embryonal carcinoma percentage are strong predictors of metastatic disease at presentation and their inclusion should be considered in any future TNM revision. Further, our results support the changes in the AJCC TNM eighth edition as invasion of the epididymis and hilar soft tissue were both univariately significant.

Detection, characterization and classification of patterns within time series from electrophysiological signals have been a challenge for neuroscientists due to their complexity and variability. Here, we aimed to use graph theory to characterize and classify waveforms within biological signals using maxcliques as a feature for a deep learning method. We implemented a compact and easy to visualize algorithm and interface in Python. This software uses time series as input. We applied the maxclique graph operator in order to obtain further graph parameters. We extracted features of the time series by processing all graph parameters through K-means, one of the simplest unsupervised machine learning algorithms. As proof of principle, we analyzed integrated electrical activity of XII nerve to identify waveforms. Our results show that the use of maxcliques allows identification of two distinct types of waveforms that match expert classification. We propose that our method can be a useful tool to characterize and classify other electrophysiological signals in a short time and objectively. Reducing the classification time improves efficiency for further analysis in order to compare between treatments or conditions, e.g., pharmacological trials, injuries, or neurodegenerative diseases.

La Patagonia comprende una vasta región (> 1.000.000 km2) que exhibe una remarcable heterogeneidad espacial, en donde las formas de relieve como montañas, mesetas, y valles están drenadas por sistemas fluviales que desaguan al Atlántico y al Pacífico. Además de lagos y lagunas, son numerosos los “mallines” (área donde se acumula agua) que están presentes en el área. Examinamos las diferentes alternativas de bioindicación utilizadas hasta la fecha a modo de brindar un panorama respecto a la salud de los cuerpos de agua y zonas ribereñas. Describimos resultados en relación a mecanismos que operan a nivel de la membrana celular, invertebrados acuáticos, macrófitas, ecosistemas de ribera, y calidad de hábitat. Si bien es notorio el trabajo realizado en diversas cuencas patagónicas, en donde diferentes instituciones han puesto esfuerzos y recursos, vislumbramos que aún falta mejorar la articulación con los entes de gestión. Fil: Miserendino, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Centro de Investigación Esquel de Montaña y Estepa Patagónica. Universidad Nacional de la Patagonia San Juan Bosco. Centro de Investigación Esquel de Montaña y Estepa Patagónica; Argentina Fil: Epele, Luis Beltran. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Centro de Investigación Esquel de Montaña y Estepa Patagónica. Universidad Nacional de la Patagonia San Juan Bosco. Centro de Investigación Esquel de Montaña y Estepa Patagónica; Argentina Fil: Brand, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Centro de Investigación Esquel de Montaña y Estepa Patagónica. Universidad Nacional de la Patagonia San Juan Bosco. Centro de Investigación Esquel de Montaña y Estepa Patagónica; Argentina Fil: Manzo, Luz Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Centro de Investigación Esquel de Montaña y Estepa Patagónica. Universidad Nacional de la Patagonia San Juan Bosco. Centro de Investigación Esquel de Montaña y Estepa Patagónica; Argentina

The identification of perineural invasion (PNI) and extraprostatic extension (ECE) in prostate cancer (PC) biopsies is time consuming and can be difficult. Although this is required information in many datasets, there is little evidence on their effect on outcome in patients treated conservatively. Cases of PC were identified from three cancer registries in the UK from men with clinically localized prostate cancer diagnosed by needle biopsy from 1990-2003. The endpoint was prostate cancer death (DOD). Patients treated radically within 6 months, those with objective evidence of metastases or who had prior hormone therapy were excluded. Follow-up was through cancer registries up until 2012. Deaths were divided into those from PC and those from other causes, according to WHO criteria. 988 biopsy cases (6522 biopsy cores) were centrally reviewed by three uropathologists and assigned a Gleason score and Grade Group (GG). The presence of both PNI and ECE was recorded. Of 988 patients, PNI was present in 288 (DOD = 75) and ECE in 23 (DOD = 5). On univariable analysis PNI was highly significantly associated with DOD (hazard ratio [HR] 2.28, 95% CI: 1.68, 3.1, log-rank test p-value = 4.8 × 10-8), but ECE was not (log-rank test p-value = 0.334). On multivariable analysis with GG, serum PSA (per 10%), clinical stage and extent of disease (per 10%), PNI lost significance (HR 1.16, 95% CI: 0.83, 1.63, likelihood ratio test p-value = 0.371). The utility of routinely examining prostate biopsies for ECE and PNI is doubtful as it is not independently associated with higher grade, stage or prognosis.

Lalu lintas dan angkutan jalan merupakan hal yang penting dalam meningkatkan mobilitas sosial masyarakat. Lalu Lintas dan Angkutan Jalan merupakan hal yang sangat dekat masyarakat. Setiap waktu masyarakat terus bergulat dengan Angkutan Jalan dengan bermacam-macam kepentingan. Pada tahun 2018 khususnya bulan Juni di Kabupaten Tulungagung telah dilaksanakan Pemilukada Bupati Tulungagung yang di dalamnya terdapat 2 pasangan calon Bupati dan Wakil Bupati. Kecelakaan pada saat kampanye seringkali terjadi karena kurang kesadaran diri berlalu lintas dan berkendara bermotor dari peserta kampanye. Yang mereka pikirkan hanya euforia kampanye semata dan tidak memikirkan keselamatan diri mereka serta orang lain yang menggunakan jalan raya lainnya. Rumusan masalah dalam penelian ini adalah: Bagaimana situasi dan kondisi lalu lintas pada saat masa kampanye Pemilukada Bupati Tulungagung 2018? Bagaimana peran Satuan Lalu Lintas dalam masa kampanye Pemilukada Bupati Tulungagung 2018?Faktor-faktor apa saja yang mempengaruhi tugas Satuan Lalu Lintas dalam pencegahan pelanggaran lalu lintas pada masa kampanye Pemilukada Bupati Tulungagung 2018?Rumusan masalah tersebut dikaji secara mendalam dengan menggunakan metode pendekatan lapangan diskriptif kualitatif. Dengan cara menggali data-data dari informan yang memang menguasai dalam bidangnya, lalu dielaborasikan dengan konsep atau teori dan undang-undang yang berlaku. Adapun kesimpulan dari penelitian ini adalah 75 : Pertama,ditemukan beberapa pendukung pasangan calon yang melakukan pelanggaran lalu lintas ketika masa kampanye seperti melanggar ketentuan UU No 22 Tahun 2009 tentang Lalu Lintas dan Angkutan Jalan Pasal 106 ayat (8) tidak menggunakan penutup kepala (Helmt), Pasal 287 ayat (1) Melanggar Rambu Lalu Lintas, Pasal 285 tidak menggunakan knalpot standart (knalpot brong), dan Pasal 47 ayat (2) Menggunakan mobil bak terbuka untuk mengangkut masa/orang. Meski demikian Polantas Polres Tulungagung tetap menindak baik secara teknis dan administrasi bagi mereka yang melakukan pelanggaran ketika melakukan kampanye.Kedua, peranan yang dilakukan oleh Polantas Porles Tulungagung dalam masa kampanye Pilbub Tulungagung 2018 yaitu: inventarisir dan pemetaan potensi pelanggaran lalu lintas, sosialisasi berkendara yang baik pada saat kampanye, koordinasi dengan pihak-pihak yang terkait seperti KPU, BAWASLU dan DISHUB, penempatan anggota dan patroli berkala dan penindakan secara teknis dan administrasi bagi pelanggar lalu lintas.Ketiga, Faktor-faktor yang mempengaruhi Polantas Polres Tulungagung dalam penjagaan lalu lintas pada masa kampanye yakni faktor internal yang meliputi kurangnya pengawasan dari provos kepada anggota, kurang pahamnya anggota terhadap tahapan dan aturan tentang Pilkada, terdapat indikasi dari anggota Polri yang sedikit tidak netral karena terbawa oleh anggota keluarganya yang menjadi pendukung salah satu pasangan calon. Sementara itu faktor eksternal dipengaruhi adanya pelaksana pemilu yang kurang proaktif ketika diajak komunikasi dan koordinasi dan kurangnya kesadaran masyarakat tentang berkendaran yang baik dan benar sesuai dengan ketentuan yang berlaku.

mTOR pathway inhibitors are important drugs for the treatment of advanced renal cell carcinoma (RCC). However, no valid predictive markers have been identified to guide treatment selection and identify patients who are sensitive to these drugs. Mutations activating the mTOR pathway have been suggested to predict response; however, their predictive value is still unclear. Here, we present the genomic and functional characterization of a patient with metastatic clear cell RCC (ccRCC) who experienced a partial response to temsirolimus after a poor response to 2 previous lines of treatment. At the time of publication, the patient was disease-free 8 years after temsirolimus treatment. Multiregion whole-exome sequencing (WES) on 3 regions of the primary tumor, 1 metastasis, and blood revealed tumor mutations in driver genes in ccRCC: a missense mutation in VHL (p.W88L), a loss-of-function mutation in BAP1 (p.E454Rfs*15), and a novel missense mutation in MTOR (p.Y1974H). The MTOR mutation was present in all tumor regions, with similar allele frequency as the VHL mutation, and in vitro functional assessment of the MTOR variant demonstrated that it increased mTORC1 activity. Consistently, immunohistochemistry in the tumor samples demonstrated increased levels of phospho-S6. In conclusion, multiregion WES identified a novel MTOR mutation acquired early during tumor development as the event leading to a high sensitivity to temsirolimus treatment. This study supports tumor multiregion sequencing to detect truncal mutations in the mTOR pathway to identify patients sensitive to mTOR inhibitors.

Background:\ud \ud Response evaluation criteria in solid tumours (RECIST) is widely used to assess tumour response but is limited by not considering disease site or radiological heterogeneity (RH).\ud Objective:\ud \ud To determine whether RH or disease site has prognostic significance in patients with metastatic clear-cell renal cell carcinoma (ccRCC).\ud Design, setting, and participants:\ud \ud A retrospective analysis was conducted of a second-line phase II study in patients with metastatic ccRCC (NCT00942877), evaluating 138 patients with 458 baseline lesions.\ud Intervention:\ud \ud The phase II trial assessed vascular endothelial growth factor-targeted therapy ± Src inhibition.\ud Outcome measurements and statistical analysis:\ud \ud RH at week 8 was assessed within individual patients with two or more lesions to predict overall survival (OS) using Kaplan-Meier method and Cox regression model. We defined a high heterogeneous response as occurring when one or more lesion underwent a ≥10% reduction and one or more lesion underwent a ≥10% increase in size. Disease progression was defined by RECIST 1.1 criteria.\ud Results and limitations:\ud \ud In patients with a complete/partial response or stable disease by RECIST 1.1 and two or more lesions at week 8, those with a high heterogeneous response had a shorter OS compared to those with a homogeneous response (hazard ratio [HR] 2.01; 95% confidence interval [CI]: 1.39–2.92; p < 0.001). Response by disease site at week 8 did not affect OS. At disease progression, one or more new lesion was associated with worse survival compared with >20% increase in sum of target lesion diameters only (HR 2.12; 95% CI: 1.43–3.14; p < 0.001). Limitations include retrospective study design.\ud Conclusions:\ud \ud RH and the development of new lesions may predict survival in metastatic ccRCC. Further prospective studies are required.\ud Patient summary:\ud \ud We looked at individual metastases in patients with kidney cancer and showed that a variable response to treatment and the appearance of new metastases may be associated with worse survival. Further studies are required to confirm these findings.

BACKGROUND: Gleason scoring (GS) has major deficiencies and a novel system of five grade groups (GS⩽6; 3+4; 4+3; 8; ⩾9) has been recently agreed and included in the WHO 2016 classification. Although verified in radical prostatectomies using PSA relapse for outcome, it has not been validated using prostate cancer death as an outcome in biopsy series. There is debate whether an 'overall' or 'worst' GS in biopsies series should be used.METHODS: Nine hundred and eighty-eight prostate cancer biopsy cases were identified between 1990 and 2003, and treated conservatively. Diagnosis and grade was assigned to each core as well as an overall grade. Follow-up for prostate cancer death was until 31 December 2012. A log-rank test assessed univariable differences between the five grade groups based on overall and worst grade seen, and using univariable and multivariable Cox proportional hazards. Regression was used to quantify differences in outcome.RESULTS: Using both 'worst' and 'overall' GS yielded highly significant results on univariate and multivariate analysis with overall GS slightly but insignificantly outperforming worst GS. There was a strong correlation with the five grade groups and prostate cancer death.CONCLUSIONS: This is the largest conservatively treated prostate cancer cohort with long-term follow-up and contemporary assessment of grade. It validates the formation of five grade groups and suggests that the 'worst' grade is a valid prognostic measure.British Journal of Cancer advance online publication, 21 April 2016; doi:10.1038/bjc.2016.86 www.bjcancer.com.