MELLODDY: Cross-pharma Federated Learning at Unprecedented Scale Unlocks Benefits in QSAR without Compromising Proprietary Information.

Federated multipartner machine learning has been touted as an appealing and efficient method to increase the effective training data volume and thereby the predictivity of models, particularly when the generation of training data is resource-intensive. In the landmark MELLODDY project, indeed, each of ten pharmaceutical companies realized aggregated improvements on its own classification or regression models through federated learning. To this end, they leveraged a novel implementation extending multitask learning across partners, on a platform audited for privacy and security. The experiments involved an unprecedented cross-pharma data set of 2.6+ billion confidential experimental activity data points, documenting 21+ million physical small molecules and 40+ thousand assays in on-target and secondary pharmacodynamics and pharmacokinetics. Appropriate complementary metrics were developed to evaluate the predictive performance in the federated setting. In addition to predictive performance increases in labeled space, the results point toward an extended applicability domain in federated learning. Increases in collective training data volume, including by means of auxiliary data resulting from single concentration high-throughput and imaging assays, continued to boost predictive performance, albeit with a saturating return. Markedly higher improvements were observed for the pharmacokinetics and safety panel assay-based task subsets.

Day-case catheterless and drainless minimal-access pyeloplasty in adults: A single-center experience of 13 years.

OBJECTIVES: To analyze our practice of drainless and catheterless day-case minimal-access pyeloplasty with regard to feasibility, safety and long-term outcomes. METHODS: Patients undergoing minimal-access pyeloplasty (laparoscopic, with or without robotic assistance) in a single center between 2007 and 2020 were included in this retrospective observational study. Patient demographics and the success rate of day-case discharge along with postoperative outcomes were analyzed. RESULTS: A total of 129 patients underwent minimal-access pyeloplasty in this time period, of whom 116 met the inclusion criteria. The mean patient age was 48 years. A total of 65% of the patients (n = 75) were discharged on the same day and 88% (n = 101) were discharged within 23 h of surgery. Of the 14 patients with a hospital stay of >24 h, pain was the most common reason (60%) for delayed discharge. The overall subjective (pain-free status) and objective (unobstructed drainage) success rates were 91% and 86%, respectively. CONCLUSION: This study demonstrates that routine drains or urethral catheters are not necessary in minimal-access pyeloplasty, and their omission could facilitate early recovery and day-case discharge without compromising long-term surgical outcomes. Large randomized controlled studies are required to prospectively evaluate outcomes.

Integrating in Silico and in Vitro Approaches To Predict Drug Accessibility to the Central Nervous System.

Estimation of uptake across the blood-brain barrier (BBB) is key to designing central nervous system (CNS) therapeutics. In silico approaches ranging from physicochemical rules to quantitative structure-activity relationship (QSAR) models are utilized to predict potential for CNS penetration of new chemical entities. However, there are still gaps in our knowledge of (1) the relationship between marketed human drug derived CNS-accessible chemical space and preclinical neuropharmacokinetic (neuroPK) data, (2) interpretability of the selected physicochemical descriptors, and (3) correlation of the in vitro human P-glycoprotein (P-gp) efflux ratio (ER) and in vivo rodent unbound brain-to-blood ratio (Kp,uu), as these are assays routinely used to predict clinical CNS exposure, during drug discovery. To close these gaps, we explored the CNS druglike property boundaries of 920 market oral drugs (315 CNS and 605 non-CNS) and 846 compounds (54 CNS drugs and 792 proprietary GlaxoSmithKline compounds) with available rat Kp,uu data. The exact permeability coefficient (Pexact) and P-gp ER were determined for 176 compounds from the rat Kp,uu data set. Receiver operating characteristic curves were performed to evaluate the predictive power of human P-gp ER for rat Kp,uu. Our data demonstrates that simple physicochemical rules (most acidic pKa ≥ 9.5 and TPSA < 100) in combination with P-gp ER < 1.5 provide mechanistic insights for filtering BBB permeable compounds. For comparison, six classification modeling methods were investigated using multiple sets of in silico molecular descriptors. We present a random forest model with excellent predictive power (∼0.75 overall accuracy) using the rat neuroPK data set. We also observed good concordance between the structural interpretation results and physicochemical descriptor importance from the Kp,uu classification QSAR model. In summary, we propose a novel, hybrid in silico/in vitro approach and an in silico screening model for the effective development of chemical series with the potential to achieve optimal CNS exposure.

QSAR workbench: automating QSAR modeling to drive compound design.

We describe the QSAR Workbench, a system for the building and analysis of QSAR models. The system is built around the Pipeline Pilot workflow tool and provides access to a variety of model building algorithms for both continuous and categorical data. Traditionally models are built on a one by one basis and fully exploring the model space of algorithms and descriptor subsets is a time consuming basis. The QSAR Workbench provides a framework to allow for multiple models to be built over a number of modeling algorithms, descriptor combinations and data splits (training and test sets). Methods to analyze and compare models are provided, enabling the user to select the most appropriate model. The Workbench provides a consistent set of routines for data preparation and chemistry normalization that are also applied for predictions. The Workbench provides a large degree of automation with the ability to publish preconfigured model building workflows for a variety of problem domains, whilst providing experienced users full access to the underlying parameterization if required. Methods are provided to allow for publication of selected models as web services, thus providing integration with the chemistry desktop. We describe the design and implementation of the QSAR Workbench and demonstrate its utility through application to two public domain datasets.

Arterio-Ureteral Fistula: A Rare Elusive Cause of Significant Hematuria.

Arterioureteral fistula (AUF) is a direct communication between the ureter and an artery and is a rare cause of catastrophic, life-threatening haematuria. Fistulation may occur between the ureter and the abdominal aorta, common iliac, external and internal iliac, and inferior mesenteric arteries, and is typically observed in patients with a prior history of pelvic radiotherapy, oncological pelvic surgeries, aortoiliac vascular procedures, and pelvic exenteration. There is also an increased frequency of cases amongst patients who have undergone urological diversion surgeries and in those with chronic indwelling ureteric stents requiring repeated exchange. As AUF is so rarely encountered in clinical practice, the urologist may fail to appreciate its presence until late in the patient's presentation; such diagnostic delay is associated with high mortality and thus rapid clinical suspicion and investigative action are necessary. There are sporadic cases of this rare entity mentioned in literature. In this report, we present two cases as well as a review of the literature. A 73-year-old female presented with repeated episodic haematuria for a week in whom the cause of symptoms remained persistently elusive despite repeated imaging and operative approaches. An eventual diagnosis of a secondary right internal iliac-ureteral fistula was ascertained on a subsequent digital subtraction angiography of the renal tract. The fistula was embolised using an endovascular approach. The patient remained stable post emobilisation and was successfully discharged shortly after the procedure. In the second case, a 51-year-old female, presented with hematuria from her ileal conduit for a few days. Initially, the cause of symptoms was thought to be due to ureteric stents. During a change in her stents, brisk bleeding led to further investigation including an iliac angiogram confirming bleeding from the left common iliac artery. She had a covered common iliac artery stent, which successfully controlled her bleeding This report emphasizes the diagnostic difficulty of AUF, outlines the management principles of this rare disease, and aims to increase awareness of this rare yet potentially lethal phenomenon among practitioners of urology and interventional radiology.

Initial treatment costs of organ-confined prostate cancer: a general perspective.

With the increasing prevalence of prostate cancer and evolving methods for the definitive treatment of OCPCa, health economic analyses will be critically important, albeit difficult to carry out. Preliminary studies point to RPP as the most cost-effective treatment for OCPCa. The quickest postoperative recovery, in experienced hands, occurs in RARP and RPP, with ORPP having a slightly, but statistically in significant, shorter hospital stay. It should be stressed that initial treatment costs are not the only important factor in healthcare costs. Readmission for early and late complications and the loss of productivity resulting from variation in time to return to work, need also to be considered. Loss of productivity may also vary in cost between different institutions and countries depending upon the proportion of patients employed. Further large-scale multicentre studies are necessary to assess this.

Lead optimization using matched molecular pairs: inclusion of contextual information for enhanced prediction of HERG inhibition, solubility, and lipophilicity.

Previous studies of the analysis of molecular matched pairs (MMPs) have often assumed that the effect of a substructural transformation on a molecular property is independent of the context (i.e., the local structural environment in which that transformation occurs). Experiments with large sets of hERG, solubility, and lipophilicity data demonstrate that the inclusion of contextual information can enhance the predictive power of MMP analyses, with significant trends (both positive and negative) being identified that are not apparent when using conventional, context-independent approaches.

Using Physicochemical Measurements to Influence Better Compound Design.

During the past decade, the physicochemical quality of molecules under investigation at all stages of the drug discovery process has come under particular scrutiny. The issues associated with excessive lipophilicity and poor solubility in particular are many and varied, ranging from poor outcomes in screening campaigns to promiscuity, limited and/or poorly predictable pharmacokinetic exposure, and, ultimately, greater chances of clinical failure. In this review, contemporary methods to secure key measurements are described along with their relevance to understanding the behavior of molecules in environments pertinent to pharmacological activity. Together, the various measurements contribute to predictive models of both the physicochemical properties themselves and the outcomes they influence.

Nephron-sparing surgery: a call for greater application of established techniques.

OBJECTIVES: To examine the results of open partial nephrectomy (OPN) over a 15-year period in a large UK teaching hospital and to compare results with other series including minimally invasive techniques, as nephron-sparing techniques are still under-utilized in the surgical treatment of renal carcinoma. A standardized technique is described that we think minimizes the risk of postoperative urinoma. PATIENTS AND METHODS: We retrospectively reviewed a series of 141 patients who underwent OPN performed over a 15-year period in one centre by the senior author (D.M.A.W.). A notable feature of this series compared with others is the high proportion of patients undergoing other major synchronous surgery. RESULTS: In all, 141 patients underwent 147 OPNs, with six undergoing bilateral procedures, of which 82 were for imperative indications (single kidney, bilateral synchronous tumours, or pre-existing renal impairment). There were three perioperative deaths, two in patients undergoing other synchronous major surgery. In all, 38 patients had postoperative complications: 28 patients required blood transfusion (four required intervention for their bleeding), five required acute dialysis and three late dialysis. There was a 90% cancer-specific survival rate at a median follow-up of 2 years. CONCLUSIONS: This series confirms the trend towards improved outcomes and decreased complications in OPN at a time when its place is challenged by minimally invasive techniques.

HumanMethylation450K Array-Identified Biomarkers Predict Tumour Recurrence/Progression at Initial Diagnosis of High-risk Non-muscle Invasive Bladder Cancer.

BACKGROUND: High-risk non-muscle invasive bladder cancer (HR-NMIBC) is a clinically unpredictable disease. Despite clinical risk estimation tools, many patients are undertreated with intra-vesical therapies alone, whereas others may be over-treated with early radical surgery. Molecular biomarkers, particularly DNA methylation, have been reported as predictive of tumour/patient outcomes in numerous solid organ and haematologic malignancies; however, there are few reports in HR-NMIBC and none using genome-wide array assessment. We therefore sought to identify novel DNA methylation markers of HR-NMIBC clinical outcomes that might predict tumour behaviour at initial diagnosis and help guide patient management. PATIENTS AND METHODS: A total of 21 primary initial diagnosis HR-NMIBC tumours were analysed by Illumina HumanMethylation450 BeadChip arrays and subsequently bisulphite Pyrosequencing. In all, 7 had not recurred at 1 year after resection and 14 had recurred and/or progressed despite intra-vesical BCG. A further independent cohort of 32 HR-NMIBC tumours (17 no recurrence and 15 recurrence and/or progression despite BCG) were also assessed by bisulphite Pyrosequencing. RESULTS: Array analyses identified 206 CpG loci that segregated non-recurrent HR-NMIBC tumours from clinically more aggressive recurrence/progression tumours. Hypermethylation of CpG cg11850659 and hypomethylation of CpG cg01149192 in combination predicted HR-NMIBC recurrence and/or progression within 1 year of diagnosis with 83% sensitivity, 79% specificity, and 83% positive and 79% negative predictive values. CONCLUSIONS: This is the first genome-wide DNA methylation analysis of a unique HR-NMIBC tumour cohort encompassing known 1-year clinical outcomes. Our analyses identified potential novel epigenetic markers that could help guide individual patient management in this clinically unpredictable disease.

Prostate cancer susceptibility is mediated by interactions between exposure to ultraviolet radiation and polymorphisms in the 5' haplotype block of the vitamin D receptor gene.

Vitamin D receptor (VDR) polymorphisms are prostate cancer risk candidates. We determined if SNPs in haplotype block sub-regions C2 (SNPs C2-1, G/C(3436), C2-2, A/G(3944)) or C1 (C1-1, C/T(20965), C1-2, C/T(30056)) are associated with risk in an ultraviolet radiation (UVR)-dependent manner. In men with very low exposure, SNPs in both sub-regions were associated with risk. Various haplotypes in haplotype block C including G(3436)-A(3944)-C(20965)-C(30056), (G or C)-A-C-C and G-A-(C or T)-C were significantly associated with increased risk (odds ratios between 1.95 and 2.37). These findings suggest various block C SNPs are associated with prostate cancer risk via a mechanism involving exposure to sunlight.

Evolution of a Novel, Orally Bioavailable Series of PI3Kδ Inhibitors from an Inhaled Lead for the Treatment of Respiratory Disease.

A four-step process of high-quality modeling of existing data, deconstruction, identification of replacement cores, and an innovative synthetic regrowth strategy led to the rapid discovery of a novel oral series of PI3Kδ inhibitors with promising selectivity and excellent in vivo characteristics.

Quantitative genome-wide methylation analysis of high-grade non-muscle invasive bladder cancer.

High-grade non-muscle invasive bladder cancer (HG-NMIBC) is a clinically unpredictable disease with greater risks of recurrence and progression relative to their low-intermediate-grade counterparts. The molecular events, including those affecting the epigenome, that characterize this disease entity in the context of tumor development, recurrence, and progression, are incompletely understood. We therefore interrogated genome-wide DNA methylation using HumanMethylation450 BeadChip arrays in 21 primary HG-NMIBC tumors relative to normal bladder controls. Using strict inclusion-exclusion criteria we identified 1,057 hypermethylated CpGs within gene promoter-associated CpG islands, representing 256 genes. We validated the array data by bisulphite pyrosequencing and examined 25 array-identified candidate genes in an independent cohort of 30 HG-NMIBC and 18 low-intermediate-grade NMIBC. These analyses revealed significantly higher methylation frequencies in high-grade tumors relative to low-intermediate-grade tumors for the ATP5G2, IRX1 and VAX2 genes (P<0.05), and similarly significant increases in mean levels of methylation in high-grade tumors for the ATP5G2, VAX2, INSRR, PRDM14, VSX1, TFAP2b, PRRX1, and HIST1H4F genes (P<0.05). Although inappropriate promoter methylation was not invariantly associated with reduced transcript expression, a significant association was apparent for the ARHGEF4, PON3, STAT5a, and VAX2 gene transcripts (P<0.05). Herein, we present the first genome-wide DNA methylation analysis in a unique HG-NMIBC cohort, showing extensive and discrete methylation changes relative to normal bladder and low-intermediate-grade tumors. The genes we identified hold significant potential as targets for novel therapeutic intervention either alone, or in combination, with more conventional therapeutic options in the treatment of this clinically unpredictable disease.

Methylation of HOXA9 and ISL1 Predicts Patient Outcome in High-Grade Non-Invasive Bladder Cancer.

INTRODUCTION: Inappropriate DNA methylation is frequently associated with human tumour development, and in specific cases, is associated with clinical outcomes. Previous reports of DNA methylation in low/intermediate grade non-muscle invasive bladder cancer (NMIBC) have suggested that specific patterns of DNA methylation may have a role as diagnostic or prognostic biomarkers. In view of the aggressive and clinically unpredictable nature of high-grade (HG) NMIBC, and the current shortage of the preferred treatment option (Bacillus:Calmette-Guerin), novel methylation analyses may similarly reveal biomarkers of disease outcome that could risk-stratify patients and guide clinical management at initial diagnosis. METHODS: Promoter-associated CpG island methylation was determined in primary tumour tissue of 36 initial presentation high-grade NMIBCs, 12 low/intermediate-grade NMIBCs and 3 normal bladder controls. The genes HOXA9, ISL1, NKX6-2, SPAG6, ZIC1 and ZNF154 were selected for investigation on the basis of previous reports and/or prognostic utility in low/intermediate-grade NMIBC. Methylation was determined by Pyrosequencing of sodium-bisulphite converted DNA, and then correlated with gene expression using RT-qPCR. Methylation was additionally correlated with tumour behaviour, including tumour recurrence and progression to muscle invasive bladder cancer or metastases. RESULTS: The ISL1 genes' promoter-associated island was more frequently methylated in recurrent and progressive high-grade tumours than their non-recurrent counterparts (60.0% vs. 18.2%, p = 0.008). ISL1 and HOXA9 showed significantly higher mean methylation in recurrent and progressive tumours compared to non-recurrent tumours (43.3% vs. 20.9%, p = 0.016 and 34.5% vs 17.6%, p = 0.017, respectively). Concurrent ISL1/HOXA9 methylation in HG-NMIBC reliably predicted tumour recurrence and progression within one year (Positive Predictive Value 91.7%), and was associated with disease-specific mortality (DSM). CONCLUSIONS: In this study we report methylation differences and similarities between clinical sub-types of high-grade NMIBC. We report the potential ability of methylation biomarkers, at initial diagnosis, to predict tumour recurrence and progression within one year of diagnosis. We found that specific biomarkers reliably predict disease outcome and therefore may help guide patient treatment despite the unpredictable clinical course and heterogeneity of high-grade NMIBC. Further investigation is required, including validation in a larger patient cohort, to confirm the clinical utility of methylation biomarkers in high-grade NMIBC.

Prostate cancer risk and exposure to ultraviolet radiation: further support for the protective effect of sunlight.

Recent studies have suggested that exposure to ultraviolet (UV) radiation may be protective to some internal cancers including that in the prostate. We describe a confirmatory study in 212 prostatic adenocarcinoma and 135 benign prostatic hypertrophy patients designed to determine whether previous findings showing a protective effect for UV exposure could be reproduced. We used a validated questionnaire to obtain data on aspects of lifetime exposure to UV. The data confirmed that higher levels of cumulative exposure, adult sunbathing, childhood sunburning and regular holidays in hot climates were each independently and significantly associated with a reduced risk of this cancer.

Associations between prostate cancer susceptibility and parameters of exposure to ultraviolet radiation.

Low sunlight exposure confers increased prostate cancer risk. In a study conducted in northern England, we investigated how combinations of exposure measures affect this risk. Recursive partitioning was used to identify combinations of exposure parameters that distinguished 453 prostate cancers from 312 benign hypertrophy patients. Sunbathing score most significantly defined cancer patients; 78.7% men with low scores (8.0) had cancer. These subgroups were stratified by childhood sunburning, holidays in a hot climate and skin type such that subgroups with a 13.0-fold increased risk of cancer were identified.

Polymorphisms in the vitamin D receptor gene, ultraviolet radiation, and susceptibility to prostate cancer.

Ultraviolet radiation (UVR) exposure may protect against prostate cancer development via a mechanism involving vitamin D. The vitamin D receptor (VDR) gene is therefore a candidate susceptibility factor for prostate cancer. This possibility has been previously investigated with conflicting results. We examined the association of VDR genotypes (variants at the CDX-2, Fok1, and Taq1 sites), haplotypes, and genotype combinations with risk by studying 368 prostate cancer and 243 benign prostatic hypertrophy (BPH) patients. CDX-2, Fok1, and Taq1 genotype and haplotype frequencies were not significantly different in cancer and BPH patients. As the impact of VDR polymorphisms may depend on UVR exposure, we studied associations of variants with risk in men stratified into low (below median) and high (above median) cumulative exposure/year groups. In men with UVR exposure above the median (1,100 hr/year), CDX-2 GA and AA (odds ratios [OR] = 2.11 and 2.02, respectively) and Fok1 ff (OR = 2.91) were associated with increased prostate cancer risk. No associations were observed for Taq1 genotypes. Of the genotype combinations, relative to all other CDX-2 and Taq1 and combinations, GGTT (P = 0.022, OR = 0.30), and relative to all other Fok1 and Taq1 combinations, FFTT (P = 0.026, OR = 0.35) were associated with reduced prostate cancer risk in the presence of the main effects. None of the other two- or three-genotype combinations was associated with risk. These data indicate that VDR variants influence prostate cancer risk and that this association is dependent on the extent of UVR exposure.

On the mechanism of human intestinal absorption.

In order to investigate whether the main step in intestinal absorption in humans is dominated by partition or by diffusion, we have transformed % human intestinal absorption into a first-order rate constant, and have regressed the latter, as logk, against our solvation parameters. The obtained regression coefficients are compared with those for diffusion and partition processes. The coefficients in the logk equation are completely different to those for water/solvent partitions, but are very similar to those for processes (not involving transport through membranes) in which diffusion is the major step. It is suggested that the main step in the absorption process is diffusion through a stagnant mucus layer, together with transfer across the mucusmid R:membrane interface. It is further shown that for strong Bronsted acids and bases, the rate constant for absorption of ionic species is close to that for absorption of the corresponding neutral species, so that to a first approximation the % intestinal absorption can be calculated from properties of the neutral species.

A unique presentation, and management, of acute urinary retention in a young boy with underlying vesicoureteral reflux.

Vesicoureteral reflux (VUR) affects ∼1% of children. We present an unusual case of urinary retention secondary to an obstructing urethral stone, underlying reflux, and its management. A 7-year-old boy presenting with acute urinary retention had a palpable penile shaft swelling and patent urethral meatus on examination. Cysto-urethroscopy with a 6.6Fr ureteroscope, due to unavailability of paediatric instruments, revealed an obstructing calculus impacted in the navicular fossa. This was laser fragmented and extracted. Cystoscopy revealed multiple bladder calculi with a patulous right ureteric orifice. Post-operative investigations revealed a small, scarred right kidney (ultrasound), bilateral ureteric reflux (micturating-cystourethrogram), 4 cm by 0.8 cm right ureteric calculus (CT-KUB) and 4% right split renal function (DMSA). Right laparoscopic nephroureterectomy was subsequently performed. Our case highlights the variety with which VUR can present and the effectiveness of a ureteroscope in an emergency setting as an alternative to a paediatric cystoscope to visualize the urethra and the bladder.