Programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors have shown activity in metastatic clear cell renal cell carcinoma (ccRCC). Data on the activity of these agents in patients with non-clear ...cell RCC (nccRCC) or patients with sarcomatoid/rhabdoid differentiation are limited. In this multicenter analysis, we explored the efficacy of PD-1/PD-L1 inhibitors in patients with nccRCC or sarcomatoid/rhabdoid differentiation. Baseline and follow-up demographic, clinical, treatment, and radiographic data were collected. The primary endpoint was objective response rate. Secondary endpoints include time-to-treatment failure (TTF), overall survival (OS), and biomarker correlates. Forty-three patients were included: papillary (
= 14; 33%), chromophobe (
= 10; 23%), unclassified (
= 9; 21%), translocation (
= 3; 7%), and ccRCC with sarcomatoid differentiation (
= 7, 16%). Of those 43 patients, 11 patients (26%) had sarcomatoid and/or rhabdoid differentiation (
= 7 with ccRCC;
= 4 nccRCC). Overall, 8 patients (19%) objectively responded, including 4 patients (13%) who received PD-1/PD-L1 monotherapy. Responses were observed in patients with ccRCC with sarcomatoid and/or rhabdoid differentiation (
= 3/7, 43%), translocation RCC (
= 1/3, 33%), and papillary RCC (
= 4/14, 29%). The median TTF was 4.0 months 95% confidence interval (CI), 2.8-5.5 and median OS was 12.9 months (95% CI, 7.4-not reached). No specific genomic alteration was associated with clinical benefit. Modest antitumor activity for PD-1/PD-L1-blocking agents was observed in some patients with nccRCC. Further prospective studies are warranted to investigate the efficacy of PD-1/PD-L1 blockade in this heterogeneous patient population.
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This paper describes outcomes of the 2019 Cryo-EM Model Challenge. The goals were to (1) assess the quality of models that can be produced from cryogenic electron microscopy (cryo-EM) maps using ...current modeling software, (2) evaluate reproducibility of modeling results from different software developers and users and (3) compare performance of current metrics used for model evaluation, particularly Fit-to-Map metrics, with focus on near-atomic resolution. Our findings demonstrate the relatively high accuracy and reproducibility of cryo-EM models derived by 13 participating teams from four benchmark maps, including three forming a resolution series (1.8 to 3.1 Å). The results permit specific recommendations to be made about validating near-atomic cryo-EM structures both in the context of individual experiments and structure data archives such as the Protein Data Bank. We recommend the adoption of multiple scoring parameters to provide full and objective annotation and assessment of the model, reflective of the observed cryo-EM map density.
New X‐ray crystallography and cryo‐electron microscopy (cryo‐EM) approaches yield vast amounts of structural data from dynamic proteins and their complexes. Modeling the full conformational ensemble ...can provide important biological insights, but identifying and modeling an internally consistent set of alternate conformations remains a formidable challenge. qFit efficiently automates this process by generating a parsimonious multiconformer model. We refactored qFit from a distributed application into software that runs efficiently on a small server, desktop, or laptop. We describe the new qFit 3 software and provide some examples. qFit 3 is open‐source under the MIT license, and is available at https://github.com/ExcitedStates/qfit-3.0.
Despite advances and social progress, the exclusion of diverse groups in academia, especially science, technology, engineering, and mathematics (STEM) fields, across the US and Europe persists, ...resulting in the underrepresentation of diverse people in higher education. There is extensive literature about theory, observation, and evidence-based practices that can help create a more equitable, inclusive, and diverse learning environment. In this article, we propose the implementation of a Diversity, Equity, Inclusion, and Justice (DEIJ) journal club as a strategic initiative to foster education and promote action towards making academia a more equitable institution. By creating a space for people to engage with DEIJ theories* and strategize ways to improve their learning environment, we hope to normalize the practice and importance of analyzing academia through an equity lens. Guided by restorative justice principles, we offer 10 recommendations for fostering community cohesion through education and mutual understanding. This approach underscores the importance of appropriate action and self-education in the journey toward a more diverse, equitable, inclusive, and just academic environment.
Metastatic urothelial carcinoma (mUC) is a genomically diverse disease with known alterations in the mTOR pathway and tyrosine kinases including FGFR. We investigated the efficacy and safety of ...combination treatment with everolimus and pazopanib (E/P) in genomically profiled patients with mUC.
mUC patients enrolled on a Phase I dose escalation study and an expansion cohort treated with E/P were included. The primary end point was objective response rate (ORR); secondary end points were safety, duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Patients were assessed for mutations and copy number alterations in 300 relevant cancer-associated genes using next-generation sequencing and findings were correlated with outcomes. Time-to-event data were estimated with Kaplan-Meier methods.
Of the 23 patients enrolled overall, 19 had mUC. ORR was 21% (one complete response (CR), three partial responses (PR), eight with stable disease (SD). DOR, PFS and OS were 6.5, 3.6, and 9.1 months, respectively. Four patients with clinical benefit (one CR, two PR, one SD) had mutations in TSC1/TSC2 or mTOR and a 5th patient with PR had a FGFR3-TACC3 fusion.
Combination therapy with E/P is safe in mUC and select patients with alterations in mTOR or FGFR pathways derive significant clinical benefit.
High-risk localized prostate cancer (HRLPC) is associated with a substantial risk of recurrence and disease mortality. Recent clinical trials have shown that intensifying anti-androgen therapies ...administered before prostatectomy can induce pathologic complete responses or minimal residual disease, called exceptional response, although the molecular determinants of these clinical outcomes are largely unknown. Here, we perform whole-exome and transcriptome sequencing on pre-treatment multi-regional tumor biopsies from exceptional responders (ERs) and non-responders (NRs, pathologic T3 or lymph node-positive disease) to intensive neoadjuvant anti-androgen therapies. Clonal SPOP mutation and SPOPL copy-number loss are exclusively observed in ERs, while clonal TP53 mutation and PTEN copy-number loss are exclusively observed in NRs. Transcriptional programs involving androgen signaling and TGF-β signaling are enriched in ERs and NRs, respectively. These findings may guide prospective validation studies of these molecular features in large HRLPC clinical cohorts treated with neoadjuvant anti-androgens to improve patient stratification.
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•SPOP mutation and SPOPL copy-number loss are exclusive to exceptional responders•Androgen signaling expression programs are enriched in exceptional responders•Non-responders harbor TP53 mutation, PTEN loss, and TGF-β transcriptional programs•Phylogenetic analysis reveals that key response mediators are truncal in nature
Leveraging pretreatment multi-regional biopsies from patients with high-risk localized prostate cancer, Tewari et al. identify whole-exome and transcriptional features associated with exceptional response and non-response to neoadjuvant androgen pathway inhibition. These results may have major stratification and treatment implications for this large patient population.
The genomic landscape of primary clear cell renal cell carcinoma (ccRCC) has been well described. However, little is known about cohort genomic alterations (GA) landscape in ccRCC metastases, or how ...it compares to primary tumours in aggregate. The genomic landscape of metastases may have biological, clinical, and therapeutic implications.
We collected targeted next-generation sequencing mutation calls from two independent cohorts and described the metastases GA landscape and descriptively compared it to the GA landscape in primary tumours.
The cohort 1 (n = 578) consisted of 349 primary tumours and 229 metastases. Overall, the most common mutations in the metastases were VHL (66.8%), PBRM1 (41.87%), and SETD2 (24.7%). TP53 was more frequently mutated in metastases compared to primary tumours (14.85% versus 8.9%; p = 0.031). No other gene had significant difference in the cohort frequency of mutations between the metastases and primary tumours. Mutation burden was not significantly different between the metastases and primary tumours or between metastatic sites. The second cohort (n = 257) consisted of 177 primary tumours and 80 metastases. No differences in frequency of mutations or mutational burden were observed between primaries and metastases.
These data support the theory that ccRCC primary tumours and metastases encompass a uniform distribution of common genomic alterations tested by next-generation sequencing targeted panels. This study does not address variability between matched primary tumours and metastases or the change in genomic alterations over time and after sequential systemic therapies.
•Quality of care was lower for Black patients in most care measures.•Notably, utilization of neoadjuvant chemotherapy for advanced disease stages was more common in black patients.•Black race was ...associated with inferior overall survival.•The survival disparity varied by facility type and geographical region.•Compared to previous studies, the survival disparity has narrowed.
To examine the impact of race on quality of care and overall survival (OS) among patients with muscle invasive bladder cancer (MIBC) treated with radical cystectomy (RC) in the U.S.
Our cohort consisted of 12,652 patients receiving RC for MIBC within the National Cancer Database from 2004 to 2012. Patients were stratified by race (Black non-Hispanic vs. White non-Hispanic) and imbalances in patient characteristics mitigated using propensity score weighting. Logistic and Cox regressions examined the impact of race on quality of care metrics (receipt of pelvic lymph node dissection (PLND), lymph node count, hospital volume, length of stay, delay of treatment) and on OS. The difference in OS was expressed as Delta, and stratified by facility-type, hospital volume, and region.
Blacks were less likely to receive PLND (odds ratio OR 0.70, 95% confidence interval CI: 0.55–0.91), or to have a greater number of lymph nodes removed (OR 0.76, 95%CI: 0.64–0.90). They exhibited greater length of stay (OR 1.34, 95%CI: 1.13–1.59), and delay of RC among recipients of neoadjuvant chemotherapy (OR 2.59, 95%CI: 1.77–3.85) (all P ≤ 0.001). Notably, utilization of neoadjuvant chemotherapy in advanced disease stages was more common in blacks (OR 2.82, 95%CI: 1.93–4.13, P < 0.001). Additionally, Black race was associated with inferior OS (Hazard ratio 0.87, 95%CI: 0.79–0.97, P < 0.014). Disparities in OS varied based on facility type and geographical region, but not hospital volume. Specifically, Blacks had worse OS when treated in a community cancer program (Delta 0.42, 95%CI: 0.28–0.57,P < 0.001), or within New England/Middle Atlantic region (Delta 0.16, 95% CI: 0.07–0.24,P < 0.001).
Black race is an independent predictor of inferior quality of care and OS in patients undergoing RC for MIBC. Survival disparities vary based on geographical region and facility type. Notably, the OS disparity appears to have narrowed in comparison to previous studies.
A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million ...people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption
. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein-protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
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