Discovery of potent SARS-CoV-2 nsp3 macrodomain inhibitors uncovers lack of translation to cellular antiviral response.

A strategy for pandemic preparedness is the development of antivirals against a wide set of viral targets with complementary mechanisms of action. SARS-CoV-2 nsp3-mac1 is a viral macrodomain with ADP-ribosylhydrolase activity, which counteracts host immune response. Targeting the virus' immunomodulatory functionality offers a differentiated strategy to inhibit SARS-CoV-2 compared to approved therapeutics, which target viral replication directly.

Discovery of SARS-CoV-2 papain-like protease (PL) inhibitors with efficacy in a murine infection model.

Vaccines and first-generation antiviral therapeutics have provided important protection against COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy and protection against potential viral resistance. The SARS-CoV-2 papain-like protease (PL) is one of the two essential cysteine proteases involved in viral replication.

Missing in Action: Reports of Interdisciplinary Integration in Canadian Palliative Care.

Palliative care has an interdisciplinary tradition and Canada is a leader in its research and practice. Yet even in Canada, a full interdisciplinary complement is often lacking, with psychosocial presence ranging from 0-67.4% depending on the discipline and region.

Reflecting on Palliative Care Integration in Canada: A Qualitative Report.

Studies have identified integrated interdisciplinary care as a hallmark of effective palliative care. Although models attempt to show how integration may function, there is little literature available that practically explores how integration is fostered and maintained. In this study we asked palliative care clinicians across Canada to comment on how services are integrated across the healthcare system.

Protein structure, amino acid composition and sequence determine proteome vulnerability to oxidation-induced damage.

Oxidative stress alters cell viability, from microorganism irradiation sensitivity to human aging and neurodegeneration. Deleterious effects of protein carbonylation by reactive oxygen species (ROS) make understanding molecular properties determining ROS susceptibility essential. The radiation-resistant bacterium Deinococcus radiodurans accumulates less carbonylation than sensitive organisms, making it a key model for deciphering properties governing oxidative stress resistance.

Impact of Chemist-In-The-Loop Molecular Representations on Machine Learning Outcomes.

The development of molecular descriptors is a central challenge in cheminformatics. Most approaches use algorithms that extract atomic environments or end-to-end machine learning. However, a looming question is that how do these approaches compare with the critical eye of trained chemists.

Validating the validation: reanalyzing a large-scale comparison of deep learning and machine learning models for bioactivity prediction.

Machine learning methods may have the potential to significantly accelerate drug discovery. However, the increasing rate of new methodological approaches being published in the literature raises the fundamental question of how models should be benchmarked and validated. We reanalyze the data generated by a recently published large-scale comparison of machine learning models for bioactivity prediction and arrive at a somewhat different conclusion.

Development and Testing of the OPLS-AA/M Force Field for RNA.

Significant improvements have been made to the OPLS-AA force field for modeling RNA. New torsional potentials were optimized based on density functional theory (DFT) scans at the ωB97X-D/6-311++G(d,p) level for potential energy surfaces of the backbone α and γ dihedral angles. In combination with previously reported improvements for the sugar puckering and glycosidic torsion terms, the new force field was validated through diverse molecular dynamics simulations for RNAs in aqueous solution.

Contemporary accuracy of death certificates for coding prostate cancer as a cause of death: Is reliance on death certification good enough? A comparison with blinded review by an independent cause of death evaluation committee.

Background: Accurate cause of death assignment is crucial for prostate cancer epidemiology and trials reporting prostate cancer-specific mortality outcomes.

Methods: We compared death certificate information with independent cause of death evaluation by an expert committee within a prostate cancer trial (2002-2015).

Results: Of 1236 deaths assessed, expert committee evaluation attributed 523 (42%) to prostate cancer, agreeing with death certificate cause of death in 1134 cases (92%, 95% CI: 90%, 93%).

Genetic Background, Maternal Age, and Interaction Effects Mediate Rates of Crossing Over in Drosophila melanogaster Females.

Meiotic recombination is a genetic process that is critical for proper chromosome segregation in many organisms. Despite being fundamental for organismal fitness, rates of crossing over vary greatly between taxa. Both genetic and environmental factors contribute to phenotypic variation in crossover frequency, as do genotype-environment interactions.

Predicting high-grade cancer at ten-core prostate biopsy using four kallikrein markers measured in blood in the ProtecT study.

Background: Many men with elevated prostate-specific antigen (PSA) levels in serum do not have aggressive prostate cancer and undergo unnecessary biopsy. Retrospective studies using cryopreserved serum suggest that four kallikrein markers can predict biopsy outcome.

Methods: Free, intact and total PSA, and kallikrein-related peptidase 2 were measured in cryopreserved blood from 6129 men with elevated PSA (≥3.

Gleason drift in the NIHR ProtecT study.

Aims: There is increasing evidence of Gleason score (GS) drift in prostatic core biopsies during the last two decades. The ProtecT study is a randomized controlled study and provides an excellent cohort to study the effect of time, prostate-specific antigen (PSA) level, perineural invasion, tumour length and age on GS.

Methods And Results: The ProtecT study recruited men in the United Kingdom between 1999 and 2010.

Population genomic analysis reveals no evidence for GC-biased gene conversion in Drosophila melanogaster.

Gene conversion is the nonreciprocal exchange of genetic material between homologous chromosomes. Multiple lines of evidence from a variety of taxa strongly suggest that gene conversion events are biased toward GC-bearing alleles. However, in Drosophila, the data have largely been indirect and unclear, with some studies supporting the predictions of a GC-biased gene conversion model and other data showing contradictory findings.

Systematic review and economic modelling of the relative clinical benefit and cost-effectiveness of laparoscopic surgery and robotic surgery for removal of the prostate in men with localised prostate cancer.

Background: Complete surgical removal of the prostate, radical prostatectomy, is the most frequently used treatment option for men with localised prostate cancer. The use of laparoscopic (keyhole) and robot-assisted surgery has improved operative safety but the comparative effectiveness and cost-effectiveness of these options remains uncertain.

Objective: This study aimed to determine the relative clinical effectiveness and cost-effectiveness of robotic radical prostatectomy compared with laparoscopic radical prostatectomy in the treatment of localised prostate cancer within the UK NHS.

Suitability of PSA-detected localised prostate cancers for focal therapy: experience from the ProtecT study.

Background: Contemporary screening for prostate cancer frequently identifies small volume, low-grade lesions. Some clinicians have advocated focal prostatic ablation as an alternative to more aggressive interventions to manage these lesions. To identify which patients might benefit from focal ablative techniques, we analysed the surgical specimens of a large sample of population-detected men undergoing radical prostatectomy as part of a randomised clinical trial.

Structural characteristics of impaction allografting for revision total hip arthroplasty.

Background: The impaction allografting procedure for treatment of failed hip reconstructions has shown promising but variable results. The objective of this study was to compare the structural characteristics of revision total hip arthroplasty constructs with impaction allografting (cement+morsellized bone) with all-cement and all-morsellized bone constructs.

Methods: Uniaxial cyclic compression was applied to a simplified uniaxial, parallel, aluminum tube model to simulate normal gait.

Alteration in urinary matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 ratio predicts recurrence in nonmuscle-invasive bladder cancer.

Purpose: The purpose is to assess the prognostic significance of matrix metalloproteinase (MMP)-9 in patients with bladder cancer using a combination of ELISA (to measure MMP-9 in voided urine) and immunohistochemistry (to study MMP-9 in bladder tumors). The relationship between MMP-9 and its principal inhibitor, tissue inhibitor of metalloproteinase (TIMP)-1 (in voided urine samples) was also studied.

Experimental Design: A total of 134 patients with bladder tumors (7 cis, 76 T(a), 27 T(1), 24 T(2)-T(4); 40 G1, 43 G2, and 44 G3), 33 patients with benign urological conditions, and 36 healthy volunteers was studied.

FGF8 isoform b expression in human prostate cancer.

Overexpression of fibroblast growth factor 8 (FGF8) mRNA has been previously described in prostate cancer. Of its four isoforms, FGF8b is thought to be the most important in carcinogenesis. We hypothesised that immunodetection of FGF8b in archival prostate cancer specimens is of potential prognostic value.

Combined p21WAF1/CIP1 and p53 overexpression predict improved survival in muscle-invasive bladder cancer treated by radical radiotherapy.

Purpose: The prognostic value of p21 and p53 expression was evaluated for patients with muscle-invasive bladder cancer treated by radical radiotherapy.

Methods And Materials: Sixty-eight paraffin-embedded sections from surgically resected tumors taken prior to irradiation were immunostained for p21 and p53.

Results: Nuclear staining for p21 and p53 was demonstrated in 32/68 (47%) and 46/68 (68%) tumors, respectively.

Caveolin-1 expression is associated with high-grade bladder cancer.

Objectives: To assess the levels of caveolin-1 in a series of bladder tumor specimens of varying stage and grade and to identify possible links between caveolin-1 status and clinical behavior. Caveolae have emerged as sites of important regulatory events at the cell membrane in many different cell types. Caveolins are the main structural components of caveolae and belong to a family of highly conserved integral membrane proteins.

aFGF immunoreactivity in prostate cancer and its co-localization with bFGF and FGF8.

Fibroblast growth factors (FGFs) have been implicated in the development of numerous malignancies including prostate cancer. In a pilot study it has been shown that FGF8 mRNA is up-regulated in prostate cancer. The aim of the present study was to determine whether aFGF and bFGF were co-expressed with FGF8 in human prostate cancer.

TP53 accumulation predicts improved survival in patients resistant to systemic cisplatin-based chemotherapy for muscle-invasive bladder cancer.

To examine retrospectively the prognostic significance of TP53 immunoreactivity for both tumor response and patient survival in 83 patients with nonmetastatic muscle-invasive bladder cancer treated with a single transurethral resection (TUR) of tumor and combined cisplatin-based systemic chemotherapy followed by repeat TUR, paraffin-embedded sections of a bladder tumor obtained at TUR before chemotherapy (1 T2, 52 T3, and 30 T4) were immunostained for TP53 using monoclonal PAb1801 and DO-7 antibodies. For the entire cohort, TP53 immunopositivity (PAb1801 or DO-7) did not predict complete response (CR), complete or partial response (PR), progressive disease, or time to death from bladder cancer. There was a highly significant correlation between PAb1801 and DO-7 nuclear immunoreactivity (r = 0.