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The diagnosis and management of renal cell carcinoma have changed remarkably rapidly. Although the incidence of renal cell carcinoma has been increasing, survival has improved substantially. As incidental diagnosis of small indolent cancers has become more frequent, active surveillance, robot-assisted nephron-sparing surgical techniques, and minimally invasive procedures, such as thermal ablation, have gained popularity. Despite progression in cancer control and survival, locally advanced disease and distant metastases are still diagnosed in a notable proportion of patients. An integrated management strategy that includes surgical debulking and systemic treatment with well established targeted biological drugs has improved the care of patients. Nevertheless, uncertainties, controversies, and research questions remain. Further advances are expected from translational and clinical studies.

Advanced glycation end-products (AGEs) are an assorted group of molecules formed through covalent bonds between a reduced sugar and a free amino group of proteins, lipids, and nucleic acids. Glycation alters their structure and function, leading to impaired cell function. They can be originated by physiological processes, when not counterbalanced by detoxification mechanisms, or derive from exogenous sources such as food, cigarette smoke, and air pollution. Their accumulation increases inflammation and oxidative stress through the activation of various mechanisms mainly triggered by binding to their receptors (RAGE). So far, the pathogenic role of AGEs has been evidenced in inflammatory and chronic diseases such as chronic kidney disease, cardiovascular disease, and diabetic nephropathy. This review focuses on the AGE-induced kidney damage, by describing the molecular players involved and investigating its link to the excess of body weight and visceral fat, hallmarks of obesity. Research regarding interventions to reduce AGE accumulation has been of great interest and a nutraceutical approach that would help fighting chronic diseases could be a very useful tool for patients’ everyday lives.

ObjectivesTo evaluate the agreement among readers with different expertise in detecting suspicious lesions at prostate multiparametric MRI using Prostate Imaging Reporting and Data System (PI-RADS) version 2.1.MethodsWe evaluated 200 consecutive biopsy-naïve or previously negative biopsy men who underwent MRI for clinically suspected prostate cancer (PCa) between May and September 2017. Of them, 132 patients underwent prostate biopsy. Seven radiologists (four dedicated uro-radiologists and three non-dedicated abdominal radiologists) reviewed and scored all MRI examinations according to PI-RADS v2.1. Agreement on index lesion detection was evaluated with Conger’s k coefficient, agreement coefficient 1 (AC1), percentage of agreement (PA), and indexes of specific positive and negative agreement. Clinical and radiological features that may influence variability were evaluated.ResultsAgreement in index lesion detection among all readers was substantial (AC1 0.738; 95% CI 0.695–0.782); dedicated radiologists showed higher agreement compared with non-dedicated readers. Clinical and radiological parameters that positively influenced agreement were PSA density ≥ 0.15 ng/mL/cc, pre-MRI high risk for PCa, positivity threshold of PI-RADS score 4 + 5, PZ lesions, homogeneous signal intensity of the PZ, and subjectively easy interpretation of MRI. Positive specific agreement was significantly higher among dedicated readers, up to 93.4% (95% CI 90.7–95.4) in patients harboring csPCa. Agreement on absence of lesions was excellent for both dedicated and non-dedicated readers (respectively 85.1% [95% CI 78.4–92.3] and 82.0% [95% CI 77.2–90.1]).ConclusionsAgreement on index lesion detection among radiologists of various experiences is substantial to excellent using PI-RADS v2.1. Concordance on absence of lesions is excellent across readers’ experience.Key Points• Agreement on index lesion detection among radiologists of various experiences is substantial to excellent using PI-RADS v2.1.• Concordance between experienced readers is higher than between less-experienced readers.• Concordance on absence of lesions is excellent across readers’ experience.

Molecular mechanisms associated with human germ cell aplasia in infertile men remain undefined. Here we perform single-cell transcriptome profiling to highlight differentially expressed genes and pathways in each somatic cell type in testes of men with idiopathic germ cell aplasia. We identify immaturity of Leydig cells, chronic tissue inflammation, fibrosis, and senescence phenotype of the somatic cells, as well markers of chronic inflammation in the blood. We find that deregulated expression of parentally imprinted genes in myoid and immature Leydig cells, with relevant changes in the ratio of Lamin A/C transcripts and an active DNA damage response in Leydig and peritubular myoid cells are also indicative of senescence of the testicular niche. This study offers molecular insights into the pathogenesis of idiopathic germ cell aplasia. Molecular mechanisms associated with human germ cell aplasia in infertile men remain undefined. Here the authors perform single-cell transcriptome profiling to highlight differentially expressed genes and pathways in each somatic cell type in testes of men with idiopathic germ cell aplasia.

Dutasteride, an inhibitor of 5α-reductase in the prostate, was tested in a large, randomized trial to determine its ability to prevent prostate cancer. Over the 4 years of the trial, dutasteride, as compared with placebo, reduced the relative risk of biopsy-detected prostate cancer by 23%. The reduction was limited mainly to tumors with Gleason scores of 5 or 6; by year 4, there were 12 tumors with Gleason scores of 8 to 10 in the dutasteride group but only 1 in the placebo group. Dutasteride, an inhibitor of 5α-reductase in the prostate, reduced the relative risk of biopsy-detected prostate cancer by 23%; however, the reduction was limited mainly to tumors with Gleason scores of 5 or 6. The 5α-reductase inhibitors that are used to treat benign prostatic hyperplasia block the conversion of testosterone to dihydrotestosterone and may reduce the risk of prostate cancer. 1 The results of the Prostate Cancer Prevention Trial showed that finasteride, as compared with placebo, reduced the risk of prostate cancer by 25%, but among the tumors that were detected, there was a 27% increase in the number of those that had Gleason scores of 7 to 10. 2 (The Gleason score is the sum of the two most common histologic patterns or grades in a prostate tumor, each of which is graded on a . . .

The aim of this study was to assess time on treatment with abiraterone and enzalutamide, two androgen receptor targeted (ART) drugs, the impact on time on treatment of time interval without drug supply between prescription fillings, and adherence to treatment. By use of data from The National Prostate Cancer Register, The Prescribed Drug Registry and the Patient Registry, time on treatment with the abiraterone and enzalutamide was analyzed in all men with castration resistant prostate cancer (CRPC) in Sweden 2015-2019. Three time intervals between consecutive fillings, i.e. time without drug supply, were assessed. Adherence to the treatment was evaluated by use of the Medication Possession Ratio. Kaplan Meier analysis and multivariable Cox regression model were used to assess factors affecting time on treatment. Between January 2015 and October 2019, 1803 men filled a prescription for abiraterone and 4 534 men filled a prescription for enzalutamide. With a time interval of 30 days or less between two fillings, median time on treatment was 4.9 months (IQR 2.6-11.7) for abiraterone and 8.0 months (IQR 3.6-16.4) for enzalutamide. In sensitivity analyses, allowing for no more than 14 days without drug supply between fillings, median time on treatment was 3.9 months (IQR 2.1-9.0) for abiraterone and 5.9 months (IQR 2.8-12.1) for enzalutamide. Allowing for any time period without drug between fillings, median time on treatment was 5.7 months (IQR 2.7-14.0) for abiraterone and 9.8 months (IQR 4.4-21.0) for enzalutamide. Adherence to treatment was above 90% for both drugs. Time on treatment with abiraterone and enzalutamide was shorter in clinical practice than in randomized controlled trials and varied almost two-fold with time interval without drug. Adherence to treatment was high. The main limitation of our study was the lack of data on use of chemotherapy.

Checkpoint immunotherapy (CPI) has increased survival for some patients with advanced-stage bladder cancer (BCa). However, most patients do not respond. Here, we characterized the tumor and immune microenvironment in pre- and post-treatment tumors from the PURE01 neoadjuvant pembrolizumab immunotherapy trial, using a consolidative approach that combined transcriptional and genetic profiling with digital spatial profiling. We identify five distinctive genetic and transcriptomic programs and validate these in an independent neoadjuvant CPI trial to identify the features of response or resistance to CPI. By modeling the regulatory network, we identify the histone demethylase KDM5B as a repressor of tumor immune signaling pathways in one resistant subtype (S1, Luminal-excluded) and demonstrate that inhibition of KDM5B enhances immunogenicity in FGFR3-mutated BCa cells. Our study identifies signatures associated with response to CPI that can be used to molecularly stratify patients and suggests therapeutic alternatives for subtypes with poor response to neoadjuvant immunotherapy. The response to checkpoint immunotherapy within bladder cancer patients is highly variable. Here, the authors use RNA-seq, ATAC-seq and digital spatial profiling of pre- and post-treatment samples from the PURE01 trial to identify subtypes associated with treatment response.

To assess the prevalence of isolated teratozoospermia (iTZS) in a cohort of infertile and fertile men; explore the relationship between iTZS, inflammatory parameters and sperm DNA fragmentation index (SDF) in the same cohort. 1824 infertile men and 103 fertile controls. Semen analysis, the neutrophil-to-lymphocyte ratio (NLR) and serum hormones were investigated. DFI was tested in infertile men only. According to 2010 WHO semen analysis, patients were categorized in 3 sub-groups of isolated sperm defects: isolated oligozoospermia (iOZS), isolated asthenozoospermia (iAZS) and iTZS. Descriptive statistics and linear regression models tested the association between clinical variables and inflammatory markers. Among infertile men, iAZS, iTZS, and iOZS were found in 13.9%, 11.9% and 4.1% participants, respectively. iTZS was found in 37 (35.9%) fertile men. Infertile men with iTZS had higher NLR values than those with iOZS, iAZS and men with normal semen parameters (all p<0.001). FSH and LH were higher and inhibin B lower in iOZS infertile men compared to all other groups (p[less than or equal to]0.001). Hormonal characteristics were similar between iTZS infertile and fertile men. Similarly, iTZS infertile men had higher SDF than all other groups (all p<0.001). Infertile men with iTZS had higher NLR values than fertile men with iTZS (p<0.01). Linear regression analysis showed that, in infertile men, iTZS was associated with SDF and NLR (all p[less than or equal to]0.01). iTZS was found in 11.9% of infertile men but it was even more prevalent in fertile controls. Infertile men with iTZS had higher NLR than fertile controls and increased SDF values than infertile participant with iAZS, iOZS, or normal semen parameters. No differences in hormonal characteristics were found between infertile and fertile men with iTZS.

To examine the overall and stage-specific age-adjusted incidence, 5-year survival and mortality rates of bladder cancer (BCa) in the United States, between 1973 and 2009. A total of 148,315 BCa patients were identified in the Surveillance, Epidemiology and End Results database, between years 1973 and 2009. Incidence, mortality, and 5-year cancer-specific survival rates were calculated. Temporal trends were quantified using the estimated annual percentage change (EAPC) and linear regression models. All analyses were stratified according to disease stage, and further examined according to sex, race, and age groups. Incidence rate of BCa increased from 21.0 to 25.5/100,000 person-years between 1973 and 2009. Stage-specific analyses revealed an increase incidence for localized stage: 15.4–20.2 (EAPC: +0.5%, p<0.001) and distant stage: 0.5–0.8 (EAPC: +0.7%, p=0.001). Stage-specific 5-year survival rates increased for all stages, except for distant disease. No significant changes in mortality were recorded among localized (EAPC: −0.2%, p=0.1) and regional stage (EAPC: −0.1%, p=0.5). An increase in mortality rates was observed among distant stage (EAPC: +1.0%, p=0.005). Significant variations in incidence and mortality were recorded when estimates were stratified according to sex, race, and age groups. Albeit statistically significant, virtually all changes in incidence and mortality were minor, and hardly of any clinical importance. Little or no change in BCa cancer control outcomes has been achieved during the study period.

Excitation energy transfer (EET) is a key photoinduced process in biological chromophoric assemblies. Here we investigate the factors which can drive EET into efficient ultrafast sub-ps regimes. We demonstrate how a coherent transport of electronic population could facilitate this in water solvated NADH coenzyme and uncover the role of an intermediate dark charge-transfer state. High temporal resolution ultrafast optical spectroscopy gives a 54±11 fs time constant for the EET process. Nonadiabatic quantum dynamical simulations computed through the time-evolution of multidimensional wavepackets suggest that the population transfer is mediated by photoexcited molecular vibrations due to strong coupling between the electronic states. The polar aqueous solvent environment leads to the active participation of a dark charge transfer state, accelerating the vibronically coherent EET process in favorably stacked conformers and solvent cavities. Our work demonstrates how the interplay of structural and environmental factors leads to diverse pathways for the EET process in flexible heterodimers and provides general insights relevant for coherent EET processes in stacked multichromophoric aggregates like DNA strands. Excitation energy transfer is important for many photoinduced biological processes in systems with multiple chromophores. Here, the authors elucidate this process for the coenzyme NADH using ultrafast spectroscopy and quantum dynamics.