Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

The mitochondrial LYR protein SDHAF1 is required for succinate dehydrogenase activity in Arabidopsis.

Succinate dehydrogenase (SDH, complex II), which plays an essential role in mitochondrial respiration and tricarboxylic acid metabolism, requires the assembly of eight nuclear-encoded subunits and the insertion of various cofactors. Here, we report on the characterization of an Arabidopsis thaliana leucine-tyrosine-arginine (LYR) protein family member SDHAF1, (At2g39725) is a factor required for SDH activity. SDHAF1 is located in mitochondria and can fully complement the yeast SDHAF1 deletion strain. Knockdown of SDHAF1 using RNA interference resulted in a decrease in seedling hypocotyl elongation and reduced SDH activity. Proteomic analyses revealed a decreased abundance of various SDH subunits and assembly factors. Protein interaction assays revealed that SDHAF1 can interact exclusively with the Fe-S cluster-containing subunit SDH2 and HSCB, a cochaperone involved in Fe-S cluster complex recruitment. Therefore, we propose that in Arabidopsis, SDHAF1 plays a role in the biogenesis of SDH2 to form the functional complex II, which is essential for mitochondrial respiration and metabolism.

Interfacial Adsorption Kinetics of Methane in Microporous Kerogen.

Rapid declines in unconventional shale production arise from the poorly understood interplay between gas transport and adsorption processes in microporous organic rock. Here, we use high-fidelity molecular dynamics (MD) simulations to resolve the time-varying adsorption of methane gas in realistic organic rock samples, known as kerogen. The kerogen samples derive from various geological shale fields with porosities ranging between 20% and 50%. We propose a kinetics sorption model based on a generalized solution of diffusive transport inside a nanopore to describe the adsorption kinetics in kerogen, which gives excellent fits with all our MD results, and we demonstrate it scales with the square of the length of kerogen. The MD adsorption time constants for all samples are compared with a simplified theoretical model, which we derive from the Langmuir isotherm for adsorption capacitance and the free-volume theory for steady, highly confined bulk transport. While the agreement with the MD results is qualitatively very good, it reveals that, in the limit of low porosity, the diffusive transport term dominates the characteristic time scale of adsorption, while the adsorption capacitance becomes important for higher pressures. This work provides the first data set for adsorption kinetics of methane in kerogen, a validated model to accurately describe this process, and a qualitative model that links adsorption capacitance and transport with the adsorption kinetics. Furthermore, this work paves the way to upscale interfacial adsorption processes to the next scale of gas transport simulations in mesopores and macropores of shale reservoirs.

Pyrolysis of Mixed Date Stones and Pistachio Shells: Identification of Bio-Oil and Utilization of Bio-Char as Activated Carbon Precursor.

Thermal pyrolysis of mixed date stones and pistachio shells in a semi-batch reactor was addressed in this study. The highest yield of liquids (51.20 %) was produced at 500 °C, 90 min, 20 °C/min heating rate, and 50 mesh particle size. Under these conditions, yield of liquid from date stones and pistachio shells separately was 49.12 % and 47.67 %, respectively. The FT-IR results confirmed the presence of multiple oxygen-containing compounds in the bio-oil. Results from GC-MS declared that it was predominately composed of acids (57.57 %), esters (21.35 %), phenols (4.63 5), and alcohols (3.49 5). The obtained biochar was transformed into activated carbon (AC) by the optimized ZnCl2 activation method. The ideal AC was synthesized at 600 °C for 60 min using a 2 : 1 ZnCl2 : biochar impregnation ratio. FESEM and XRD measurements showed that the AC was amorphous. The prepared AC was effective in eliminating dibenzothiophene (DBT) from model fuel (200 ppm DBT/hexane) with a maximum performance 95.26 % at 40 °C for 1h using 0.35 g of the AC. The exhausted AC was regenerated and reutilized 4 times, and removal efficiency reached 88.23 % in the 4th cycle under ideal working conditions.

A Zintl Cluster for Transition Metal-Free Catalysis: C═O Bond Reductions.

The first fully characterized boron-functionalized heptaphosphide Zintl cluster, [(BBN)P7]2- ([1]2-), is synthesized by dehydrocoupling [HP7]2-. Dehydrocoupling is a previously unprecedented reaction pathway to functionalize Zintl clusters. [Na(18-c-6)]2[1] was employed as a transition metal-free catalyst for the hydroboration of aldehydes and ketones. Moreover, the greenhouse gas carbon dioxide (CO2) was efficiently and selectively reduced to methoxyborane. This work represents the first examples of Zintl catalysis where the transformation is transition metal-free and where the cluster is noninnocent.

Management of patients with a persistently elevated PSA after radical prostatectomy: a narrative review.

INTRODUCTION: The management of the postoperative biological relapse of prostate cancer is most often based on salvage radiotherapy (SRT) with or without the addition of a variable duration of hormone therapy (HT). The indications for SRT +/- HT are established in the setting of a rising PSA level after a period where an undetectable PSA was achieved. However, in case of detectable PSA immediately after radical prostatectomy, the treatment options and prognosis are still unclear. MATERIALS AND METHODS: We conducted a narrative review based on an analysis of the literature focusing on articles targeting the population of patients with postoperative persistently detectable PSA level. Case reports, original articles, clinical trials, and published reviews were studied for this purpose. CONCLUSION: This article will describe current management of patients with detectable PSA immediately after radical prostatectomy, notably the contribution of modern imaging and new treatment options involving the combination of RT and HT.

Impact of Surface Roughness on Flow Physics and Entropy Generation in Jet Impingement Applications.

In this paper, a numerical investigation was performed of an air jet incident that normally occurs on a horizontal heated plane. Analysis of flow physics and entropy generation due to heat and friction is included using a simple easy-to-manufacture, surface roughening element: a circular rib concentric with the air jet. This study shows how varying the locations and dimensions of the rib can deliver a favorable trade-off between entropy generation and flow parameters, such as vortex generation and heat transfer. The performance of the roughness element was tested at three different radii; R/D = 1, 1.5 and 2, where D was the jet hydraulic diameter and R was the radial distance from the geometric center. At each location, the normalized rib height (e/D) was increased from 0.019 to 0.074 based on an increment of (e/D) = 0.019. The jet-to-target distance was H/D = 6 and the jet Reynolds number (Re) ranged from 10,000 to 50,000 Re, which was obtained from the jet hydraulic diameter (D), and the jet exit velocity (U). All results are presented in the form of entropy generation due to friction and heat exchange, as well as the total entropy generated. A detailed comparison of flow physics is presented for all ribs and compared with the baseline case of a smooth surface. The results show that at higher Reynolds numbers, adding a rib of a suitable height reduced the total entropy (St) by 31% compared to the no rib case. In addition, with ribs of heights 0.019, 0.037 and 0.054, respectively, the entropy generated by friction (Sf) was greater than that due to heat exchange (Sh) by about 42%, 26% and 4%, respectively. The rib of height e/D = 0.074 produced the minimum St at R/D = 1. As for varying R/D, varying rib location and Re values had a noticeable impact on Sh, Sf and (St). Placing the rib at R/D = 1 gave the highest total entropy generation (St) followed by R/D = 1.5 for all Re. Finally, the Bejan number increased as both rib height and rib location increased.

Testosterone treatment is associated with reduced adipose tissue dysfunction and nonalcoholic fatty liver disease in obese hypogonadal men.

PURPOSE: In both preclinical and clinical settings, testosterone treatment (TTh) of hypogonadism has shown beneficial effects on insulin sensitivity and visceral and liver fat accumulation. This prospective, observational study was aimed at assessing the change in markers of fat and liver functioning in obese men scheduled for bariatric surgery. METHODS: Hypogonadal patients with consistent symptoms (n = 15) undergoing 27.63 ± 3.64 weeks of TTh were compared to untreated eugonadal (n = 17) or asymptomatic hypogonadal (n = 46) men. A cross-sectional analysis among the different groups was also performed, especially for data derived from liver and fat biopsies. Preadipocytes isolated from adipose tissue biopsies were used to evaluate insulin sensitivity, adipogenic potential and mitochondrial function. NAFLD was evaluated by triglyceride assay and by calculating NAFLD activity score in liver biopsies. RESULTS: In TTh-hypogonadal men, histopathological NAFLD activity and steatosis scores, as well as liver triglyceride content were lower than in untreated-hypogonadal men and comparable to eugonadal ones. TTh was also associated with a favorable hepatic expression of lipid handling-related genes. In visceral adipose tissue and preadipocytes, TTh was associated with an increased expression of lipid catabolism and mitochondrial bio-functionality markers. Preadipocytes from TTh men also exhibited a healthier morpho-functional phenotype of mitochondria and higher insulin-sensitivity compared to untreated-hypogonadal ones. CONCLUSIONS: The present data suggest that TTh in severely obese, hypogonadal individuals induces metabolically healthier preadipocytes, improving insulin sensitivity, mitochondrial functioning and lipid handling. A potentially protective role for testosterone on the progression of NAFLD, improving hepatic steatosis and reducing intrahepatic triglyceride content, was also envisaged. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02248467, September 25th 2014.

The need of a system phantom for quantitative hybrid nuclear imaging of PET/CT: A systematic review.

INTRODUCTION: There has already been a rising demand in utilising phantom for hybrid Positron Emission Tomography/ Computed Tomography (PET/CT) scanner of nuclear imaging. This review further clarifies this topic and investigates how the previous research phantoms operated with the need for quantitative hybrid nuclear imaging of PET/CT while providing a relatively high image quality when it was performed. In this article, the necessity of previous and current phantom studies in hybrid nuclear imaging of PET/CT scanners is reviewed. METHODS: PubMed and Google Scholar were systematically searched for the relevant studies by following the PRISMA 2009 checklist. A past decade literature search was conducted from 2010 until November 2020 to secure the relevance of the phantom study. Databases were recruited using keywords such as phantom, quantification, standardisation, harmonisation, image quality, standardised uptake value and multicentre study. However, all keywords were related to PET/CT. All abstracts and eligible full-text articles were screened independently, and finally, the quality assessments of this review were performed. RESULTS: From the 200 retrieved articles, 80 were rejected after the screening of the abstracts and 35 after reading the full-text. The 20 accepted articles addressed the distribution of phantom types used in selected articles studies which were NEMA (67%), ACR (8%) and others (25%). The articles showed the various experimental studies, either phantom studies (35%) or phantom plus clinical studies (65%). For clinical studies (n = 829), the distribution of prospective studies was (n = 674) and retrospective studies was (n =155). The distribution of phantom pathway application showed the studies focused on 40% of reconstruction protocol studies, 30% of the multicentre and standardisation of accreditation program studies, and 30% of the quantification of uptake values studies. CONCLUSIONS: According to this review, the phantom study have a pivotal role in hybrid nuclear imaging of PET/CT either in technical aspects of the scanners (such as data acquisition and reconstruction protocol) or clinical characteristics of patients. In addition to this, the necessity to identify the suitable system phantoms to use within PET/CT scans by considering the continuous development of new phantom studies are needed. Researchers are encouraged to adopt efforts on phantom quantitative validation, including verification with clinical data of patients.

A randomised phase II trial of three dosing regimens of radium-223 in patients with bone metastatic castration-resistant prostate cancer.

BACKGROUND: Radium-223 prolongs overall survival and delays symptomatic skeletal events (SSEs) in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. The approved radium-223 regimen is 55 kBq/kg every 4 weeks (q4w) for six cycles (standard dose). We investigated different radium-223 regimens in patients with mCRPC. PATIENTS AND METHODS: Patients were randomised 1 : 1 : 1 to radium-223 standard-dose, high-dose (88 kBq/kg q4w for six cycles) or extended-schedule arms (55 kBq/kg q4w for 12 cycles). The primary end point, SSE-free survival (SSE-FS), was compared in patients treated with a high- versus standard-dose regimen, or with a standard dose in an extended (>6 to 12 cycles) versus standard schedule (six cycles). RESULTS: A total of 391 patients were randomised; baseline characteristics were balanced between arms. On-treatment SSEs developed in 37/130 (28%), 42/130 (32%) and 48/131 (37%) patients in the standard-dose, high-dose and extended-schedule arms, respectively. There was no statistically significant difference in SSE-FS in the high- versus standard-dose arms [median 12.9 months versus 12.3 months; hazard ratio (HR) 1.06, 80% confidence interval (CI) 0.88-1.27, P = 0.70], and in the extended- versus standard-schedule arms (median 10.8 months versus 13.2 months; HR 1.26, 80% CI 0.94-1.69, P = 0.31). Overall survival in the three treatment arms was similar. As many as 370 (95%) patients received treatment (median of six cycles) in each arm. Grade ≥3 treatment-emergent adverse events (TEAEs) affected 34% of patients in the standard-dose, 48% in the high-dose and 53% in the extended-schedule arm, causing permanent discontinuation in 9%, 16% and 17% of patients, respectively. CONCLUSION: Radium-223 high-dose or extended-schedule regimens resulted in no change in SSE-FS or other efficacy end points and were associated with more grade ≥3 TEAEs. The extended-schedule regimen (beyond six doses) could not be implemented in a large proportion of patients due to disease progression. Therefore, the standard-dose schedule remains one of the standard therapies for patients with symptomatic mCRPC. TRIAL REGISTRATION: ClinicalTrials.govNCT02023697.

Differential effects of 11 years of long-term injectable testosterone undecanoate therapy on anthropometric and metabolic parameters in hypogonadal men with normal weight, overweight and obesity in comparison with untreated controls: real-world data from a controlled registry study.

BACKGROUND AND SIGNIFICANCE: Obesity is a chronic disease, warranting long-term medical intervention. We evaluated effects of testosterone (T) therapy (Th) in men with T deficiency with normal weight, overweight and obesity on anthropometric and metabolic parameters, compared with untreated men. METHODS: Hypogonadal men (n = 823) with total T ≤ 12.1 nmol/L (age: 60.6 ± 7.0 years) participated in an ongoing registry study. Among these men 474 (57.6%) were obese, 286 (34.8%) overweight and 63 (7.7%) had normal weight. T undecanoate injections were administered to 428 men and 395 remained untreated. Anthropometric and metabolic parameters were measured at least twice a year and changes adjusted for confounding factors to account for baseline differences between groups. RESULTS: Long-term TTh in hypogonadal men, irrespective of weight at baseline, produced improvements in body weight, waist circumference (WC) and body mass index (BMI). Furthermore, TTh decreased fasting blood glucose and HbA1c and improved lipid profiles. Gradual decreases in blood pressure (systolic and diastolic) and pulse pressure occurred in men treated with T in each group. Marked reductions in mortality and major cardiovascular events were recorded in men receiving TTh. CONCLUSIONS: Our findings demonstrate that TTh produces reductions in weight, WC, and BMI. There were 77 (19.5%) deaths in the untreated groups and 23 (5.4%) in the T-groups. Based on these findings we suggest that long-term TTh in overweight and obese hypogonadal men produces progressive and sustained clinically meaningful weight loss and that TTh may contribute to reductions in mortality and incident major adverse cardiovascular events.

Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer.

BACKGROUND: In the SPARTAN study, compared with placebo, apalutamide added to ongoing androgen deprivation therapy significantly prolonged metastasis-free survival (MFS) and time to symptomatic progression in patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC). Overall survival (OS) results at the first interim analysis (IA1) were immature, with 104 of 427 (24%) events required for planned final OS analysis. Here, we report the results of a second pre-specified interim analysis (IA2). METHODS: One thousand two hundred and seven patients with nmCRPC were randomized 2 : 1 to apalutamide (240 mg daily) or placebo. The primary end point of the study was MFS. Subsequent therapy for metastatic CRPC was permitted. When the primary end point was met, the study was unblinded. Patients receiving placebo who had not yet developed metastases were offered open-label apalutamide. At IA2, pre-specified analysis of OS was undertaken, using a group-sequential testing procedure with O'Brien-Fleming-type alpha spending function. Safety and second progression-free survival (PFS2) were assessed. RESULTS: Median follow-up was 41 months. With 285 (67% of required) OS events, apalutamide was associated with an improved OS compared with placebo (HR 0.75; 95% CI 0.59-0.96; P = 0.0197), although the P-value did not cross the pre-specified O'Brien-Fleming boundary of 0.0121. Apalutamide improved PFS2 (HR 0.55; 95% CI 0.45-0.68). At IA2, 69% of placebo-treated and 40% of apalutamide-treated patients had received subsequent life-prolonging therapy for metastatic CRPC. No new safety signals were observed. CONCLUSION: In patients with nmCRPC, apalutamide was associated with a 25% reduction in risk of death compared with placebo. This OS benefit was observed despite crossover of placebo-treated patients and higher rates of subsequent life-prolonging therapy for the placebo group.

Oral Candidal carriage and associated risk indicators among adults in Sakaka, Saudi Arabia.

BACKGROUND: Candida is a ubiquitous organism in nature which inhabits the oral cavity as part of the normal microbial flora. The oral carriage of Candida is perpetuated by several predisposing factors. METHODS: This cross-sectional study was designed to investigate the carriage rate of Candida among 104 voluntary adults at the college of medicine - Jouf University. The concentrated oral rinse technique using Sabouraud Dextrose agar medium supplemented with 0.05% Chloramphenicol was used to isolate Candida. The relative factors affecting the colonization of Candida and the concentration of each type were also determined. RESULTS: Candida species were isolated from the oral cavity of 45 (43.4%) subjects. Of these 55.6% were identifies as C. albicans as determined by the Vitek 2 compact system. Other Candida species were represented by C. glabrata (11.1%), C. krusei (11.1%), C. dubliniensis (8.9%), C. parapsilosis (6.7%), C. tropicalis (4.4%), and C. famata (2.2%). Subjects with very poor plaque status, severe gingivitis and diabetes had significantly (P = 0.001) high concentration of Candida spp. CONCLUSION: Plague, severe gingivitis, and diabetes were found to be significantly associated with higher Candida colonization.

Effects of long-term treatment with testosterone on weight and waist size in 411 hypogonadal men with obesity classes I-III: observational data from two registry studies.

BACKGROUND/OBJECTIVES: Long-term testosterone replacement therapy (TRT) up to 5 years has been shown to produce progressive and sustainable weight loss (WL) in hypogonadal men. This study investigated effects of long-term TRT up to 8 years in hypogonadal men with different obesity classes. SUBJECTS/METHODS: From two independent observational registries we identified a total of 411 obese, hypogonadal men receiving TRT in urological clinics. The effects of TRT on anthropometric as well as metabolic parameters were studied for a maximum duration of 8 years, mean follow-up: 6 years. All men received long-acting injections of testosterone undecanoate in 3-monthly intervals. RESULTS: In all three classes of obesity, T therapy produced significant WL, decrease in waist circumference (WC) and body mass index (BMI). In patients with class I obesity, mean weight decreased from 102.6±6.4 to 84.1±4.9 kg, change from baseline: -17.4±0.5 kg and -16.8±0.4%. WC in this group of patients decreased from 106.8±7.4 to 95.1±5.3 cm, change from baseline: -10.6±0.3 cm. BMI decreased from 32.69±1.4 to 27.07±1.57, change from baseline: -5.52±0.15 kg m(-2). In patients with class II obesity, weight decreased from 116.8±6.9 to 91.3±6.3 kg, change from baseline: -25.3±0.5 kg and -21.5±0.4%. WC decreased from 113.5±7.5 to 100.0±5.4 cm, change from baseline: -13.9±0.4 cm. BMI decreased from 37.32±1.45 to 29.49±1.71, change from baseline: -8.15±0.17 kg m(-2). In patients with class III obesity, weight decreased from 129.0±5.6 to 98.9±4.8 kg, change from baseline: -30.5±0.7 kg and -23.6±0.5%. WC decreased from 118.5±5.6 to 103.8±4.9 cm, change from baseline: -14.3±0.4 cm. BMI decreased from 41.93±1.48 to 32.46±1.59, change from baseline -9.96±0.29 kg m(-2). CONCLUSIONS: Testosterone therapy appears to be an effective approach to achieve sustained WL in obese hypogonadal men irrespective of severity of obesity. Based on these findings we suggest that T therapy offers safe and effective treatment strategy of obesity in hypogonadal men.

Testosterone supplementation and body composition: results from a meta-analysis of observational studies.

PURPOSE: The concept of testosterone (T) supplementation (TS) as a new anti-obesity medication in men with testosterone deficiency syndrome (TDS) is emerging. Data from placebo-controlled trials are more conflicting. The aim of this study is to systematically review and meta-analyze available observational and register studies reporting data on body composition in studies on TS in TDS. METHODS: An extensive MEDLINE, Embase, and Cochrane search was performed including the following words: "testosterone" and "body composition." All observational studies comparing the effect of TS on body weight and other body composition and metabolic endpoints were considered. RESULTS: Out of 824 retrieved articles, 32 were included in the study enrolling 4513 patients (mean age 51.7 ± 6.1 years). TS was associated with a time-dependent reduction in body weight and waist circumference (WC). The estimated weight loss and WC reduction at 24 months were -3.50 [-5.21; -1.80] kg and -6.23 [-7.94; -4.76] cm, respectively. TS was also associated with a significant reduction in fat and with an increase in lean mass as well as with a reduction in fasting glycemia and insulin resistance. In addition, an improvement of lipid profile (reduction in total cholesterol as well as of triglyceride levels and an improvement in HDL cholesterol levels) and in both systolic and diastolic blood pressure was observed. CONCLUSIONS: Present data support the view of a positive effect of TS on body composition and on glucose and lipid metabolism. In addition, a significant effect on body weight loss was observed, which should be confirmed by a specifically designed RCT.

Hypogonadal men with psoriasis benefit from long-term testosterone replacement therapy - a series of 15 case reports.

Psoriasis is increasingly recognised as a skin disease with far-reaching systemic effects, associated with a high prevalence of comorbid disease such as cardiometabolic dysfunction, shifting the focus from a single organ disease confined to the skin to a systemic inflammatory condition. Chronic and systemic inflammation plays a major role in the development of these diseases, and there are striking similarities between the molecular and inflammatory pathways in psoriasis and atherosclerosis. In a single-centre, cumulative, prospective registry study of 347 hypogonadal men (total testosterone ≤12.1 nmol l(-1) ), fifteen men with psoriasis could be studied. Upon testosterone administration, the skin disease improved considerably. Scores on the Psoriasis Area and Severity Index and Physician Global Assessment for Psoriasis showed significant improvement for the first 24 months. Thereafter, these improvements were sustained. Upon testosterone treatment, C-reactive protein declined significantly. There were significant improvements of obesity and of lipid profiles. Adipose tissue is now regarded as a source of inflammatory factors. These preliminary results deserve to be studied in a specifically designed study to investigate the effects of testosterone on psoriasis and its associated immunopathology.

Effects of continuous long-term testosterone therapy (TTh) on anthropometric, endocrine and metabolic parameters for up to 10 years in 115 hypogonadal elderly men: real-life experience from an observational registry study.

Subnormal levels of testosterone are associated with significant negative health consequences, with higher risks of all-cause and cardiovascular mortality. The numbers of studies reporting on the benefits of normalisation of testosterone is increasing but longer-term data on (elderly) men receiving testosterone treatment are almost nonexistent. In this single-centre, cumulative, prospective, registry study, 115 hypogonadal men (mean age 59.05 years) received injections with testosterone undecanoate in 12-week intervals for up to 10 years. Waist circumference, body weight and mean BMI dropped progressively with statistical significance versus previous year for 7 years and, respectively, 8 years for weight and body mass index. Similarly, fasting glucose displayed a significant decrease after the first year continuing to decrease thereafter. A decline in HbA1c , from 6.4% to 5.6% (mean <6%), was observed from year 2 on, together with a decrease in the ratio of triglycerides:high-density lipoprotein (HDL), a surrogate marker of insulin resistance, with an increase in HDL levels. The total cholesterol:HDL ratio and non-HDL cholesterol declined significantly. A decrease was also observed in systolic and diastolic blood pressure, with a decrease in levels of the inflammation marker C-reactive protein. No major adverse cardiovascular events were observed throughout the study.

Treatment of mCRPC in the AR-axis-targeted therapy-resistant state.

BACKGROUND: The increased use of the androgen receptor axis-targeted (ARAT) agents abiraterone and enzalutamide in first- and second-line treatment of metastatic castration-resistant prostate cancer (mCRPC) has improved patient outcomes, but resistance to these agents is inevitable. Early identification of patients with primary or secondary resistance to ARAT therapy is of increasing clinical concern. DESIGN: PubMed and conference proceedings were searched for studies of agents used after progression on abiraterone or enzalutamide. The key search terms (or aliases) used a combination of mCRPC and abiraterone or enzalutamide, and results were limited to clinical trials and comparative or validation studies. RESULTS AND CONCLUSION: This systematic review assembles current evidence and provides an approach to treatment using available clinical factors. Issues of patient selection, use of laboratory and clinical biomarkers to identify patients at risk of poor outcomes, and the timing and sequencing of available treatment options are addressed. Our findings reveal a lack of high-level evidence regarding predictive factors and treatment of patients with resistance to ARAT therapy, and a need for further research in this area. In the meantime, we suggest practical strategies to guide management of ARAT treatment-resistant patients based on available data.

Capturing needles in haystacks: a comparison of B-cell receptor sequencing methods.

BACKGROUND: Deep-sequencing methods are rapidly developing in the field of B-cell receptor (BCR) and T-cell receptor (TCR) diversity. These promise to revolutionise our understanding of adaptive immune dynamics, identify novel antibodies, and allow monitoring of minimal residual disease. However, different methods for BCR and TCR enrichment and amplification have been proposed. Here we perform the first systematic comparison between different methods of enrichment, amplification and sequencing for generating BCR and TCR repertoires using large sample numbers. RESULTS: Resampling from the same RNA or cDNA pool results in highly correlated and reproducible repertoires, but resampling low frequency clones leads to stochastic variance. Repertoires generated by different sequencing methods (454 Roche and Illumina MiSeq) and amplification methods (multiplex PCR, 5' Rapid amplification of cDNA ends (5'RACE), and RNA-capture) are highly correlated, and resulting IgHV gene frequencies between the different methods were not significantly different. Read length has an impact on captured repertoire structure, and ultimately full-length BCR sequences are most informative for repertoire analysis as diversity outside of the CDR is very useful for phylogenetic analysis. Additionally, we show RNA-based BCR repertoires are more informative than using DNA. CONCLUSIONS: Repertoires generated by different sequencing and amplification methods are consistent, but we show that read lengths, depths and error profiles should be considered in experimental design, and multiple sampling approaches could be employed to minimise stochastic sampling variation. This detailed investigation of immune repertoire sequencing methods is essential for informing basic and clinical research.