tbuckley/cabot-search huggingface dataset:
Characterizing Pneumocystis jirovecii Pneumonia in patients with Primary Immunodeficiency Disorders, Data from the US Immunodeficiency Network (USIDNET) Registry
Authors: Elisa Ochfeld, Nina Srdanovic, Elizabeth Garabedian, Kathleen Sullivan, Rebecca Marsh, Jennifer Puck, Amer Khojah
Journal: Journal of Allergy and Clinical Immunology (2020)
FIDES-02, a phase Ib/II study of derazantinib (DZB) as monotherapy and combination therapy with atezolizumab (A) in patients with surgically unresectable or metastaticurothelial cancer (UC) and FGFR genetic aberrations.
Authors: Arvind Chaudhry, Cora N. Sternberg, Maria De Santis, Joaquim Bellmunt, Andrea Necchi, Thomas Powles, Frederique Cantero, Michalina Marszewska, Michal Grzyb, Paul McSheehy, Stephan Braun, Arlene O. Siefker-Radtke
Journal: Journal of Clinical Oncology (2020)

TPS590 Background: Deregulation of the FGFR signaling pathway is implicated in various cancers. In UC, FGFR genetic aberrations include FGFR1/2/3 mutations (M) and, less commonly, fusions (F), while the role of amplifications warrants further research. Prognosis of UC patients is overall poor and treatment options are limited. DZB is an oral small-molecule FGFR1/2/3 and CSF1R kinase inhibitor, which demonstrated promising antitumor activity in preclinical studies, including FGFR-driven patient-derived xenograft models. Preclinical data show that DZB reduced CSF1-stimulated CSF1R phosphorylation in macrophages, with a maximal effect similar to the CSF1R inhibitor BLZ945, suggesting DZB could have an effect on tumor-associated macrophage regulation. Thus, DZB+A (PD-L1 immune-checkpoint blockade [ICB]) is a rationale combination for immunogenic tumors like UC. FIDES-02 is a multicenter, multicohort open-label Phase 1b/2 study evaluating the effect of DZB as monotherapy and DZB+A combination. Methods: The study evaluates 300 mg DZB p.o. daily or DZB+A (1200 mg i.v.) in UC patients with FGFR1-3 M/F per liquid or tissue biopsy-based NGS. Cohort 1 (C1) enrolls pts after one or more standard chemotherapy ± ICB regimens (Phase 2; treatment: DZB); C2 enrolls patients with any advanced solid tumor, any FGFR status, any prior treatment (Phase 1b; for RP2D of DZB+A); C3 enrolls first-line patients with cisplatin-ineligible, PD-L1-low UC (Phase 2; DZB v DZB+A); C4 enrolls UC patients resistant to FGFR inhibitor treatment (Phase 2; DZB v DZB+A). Treatment will continue until disease progression, intolerance, withdrawal of informed consent, or death. Using Simon’s two-stage designs, objective response rate (per RECIST 1.1 central review) is the primary endpoint to assess the antitumor activity of DZB or DZB+A in Ph2. Main secondary objectives include evaluation of median PFS, duration of response, safety profile, HR-QoL (incl., QLQ C30, FACT-Bl, EQ-5D), and symptom response from baseline. The study was initiated in July 2019 and C1 (N=71) and C2 (N=24) are currently open for enrollment. Clinical trial information: NCT04045613.
Pain response and health-related quality of life (HRQL) analysis in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving cabazitaxel (CBZ) versus abiraterone or enzalutamide in the CARD study.
Authors: Karim Fizazi, Gero Kramer, Jean-Christophe Eymard, Johann S. De Bono, Cora N. Sternberg, Bertrand F. TOMBAL, Daniel Castellano, Christian Wülfing, Michail Liontos, Joan Carles, Roberto Iacovelli, Bohuslav Melichar, Asgerour Sverrisdottir, Christine Theodore, Susan Feyerabend, Carole Helissey, Pascaline Picard, Ayse Ozatilgan, Christine Geffriaud-Ricouard, Ronald De Wit
Journal: Journal of Clinical Oncology (2020)

16 Background: The CARD NCT02485691 study reported superior rPFS and OS with CBZ vs abiraterone or enzalutamide in patients with mCRPC who progressed on docetaxel and within 12 months on a previous alternative androgen-signaling-targeted inhibitor (ARTA). This analysis evaluated changes in pain and HRQL associated with CBZ and ARTA during the CARD study. Methods: Pain response was defined as a decrease &gt; 30% from baseline in BPI-SF pain intensity score with no increased analgesic use. HRQL was assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. Patients were evaluable if they had received at least one dose of CBZ or ARTA and had a baseline FACT-P score plus at least one subsequent FACT-P measurement. A clinically meaningful improvement or deterioration of total FACT-P score was defined as a difference of ± 10 points from baseline. Clinically meaningful changes in HRQL and pain response were confirmed at two consecutive evaluations ≥ 3 weeks apart during the on-treatment period. Survival curves were generated by Kaplan–Meier estimates. Results: Of the 255 patients randomized, 172 (67.5%) had moderate to severe pain at randomization. Pain response and HRQL were evaluable for 111 (86.0%) and 108 (83.7%) for CBZ and 109 (86.5%) and 114 (90.5%) for ARTA. Pain response was 45.9% vs 19.3% for CBZ vs ARTA (p &lt; 0.0001). The probability of not having pain progression after 12 months was 66.2% vs 45.3% CBZ vs ARTA (HR 0.55; 95% CI 0.32–0.97; p = 0.0348). An improvement in total FACT-P score from baseline was reported by 27 (25.0%) patients vs 26 (22.8%) for CBZ vs ARTA. FACT-P score was maintained or improved for 81 (75.0%) patients with CBZ and 86 (75.4%) patients with ARTA. A deterioration in FACT-P from baseline was reported by 22.2% with CBZ vs 24.6% with ARTA. Median time to FACT-P deterioration was 14.8 months for CBZ vs 8.9 months for ARTA (HR 0.72; 95% CI 0.44–1.20; p = 0.2072). Conclusions: CBZ was associated with a greater pain response and delayed pain progression vs ARTA. CBZ and ARTA were associated with similar trends in HRQL but time to FACT-P deterioration was longer with CBZ vs ARTA. Clinical trial information: NCT02485691.
MiR-27a-3p: An AR-modulatory microRNA with a distinct role in prostate cancer progression and therapy.
Authors: Foteini Kalofonou, Ailsa Sita-Lumsden, Damien Leach, Claire Fletcher, Jonathan Waxman, Charlotte L. Bevan
Journal: Journal of Clinical Oncology (2020)

193 Background: Prostate cancer (PCa) is an androgen dependent malignancy. PCa patients initially respond to androgen ablation but eventually the disease becomes castrate resistant. MicroRNAs (miRs) are considered to be master regulators of gene expression and could be potential biomarkers and therapeutic targets for PCa. We previously showed miR-27a-3p to be an androgen receptor (AR)-modulatory oncomiR, with a role in PCa progression. Methods: RNA sequencing was carried out on xenograft tumours treated with an inhibitory antisense oligonucleotide for miR-27a (ASO-27a), or control. Differentially expressed genes were cross-referenced with publicly available patient tissue datasets. ASO-27a was transfected in a panel of PCa cell lines mirroring disease progression, to verify changes in transcriptional and translational levels. Immunohistochemical analysis of encoded proteins was undertaken in a cohort of 46 PCa patients with Gleason 3+4 or 4+3 disease and compared with normal tissue-control. Results: Putative target genes tested included the tumour suppressor HIP2, the oncogenes SRC3, YAP, and PAX3, which can act both as oncogene and tumour suppressor. MRNA or protein levels of the majority of those genes tested were upregulated after ASO-27a treatment of PCa cell lines. In 22Rv1 cells, HIPK2 mRNA levels were significantly upregulated with ASO-27a (p = 0.0137), while protein levels were downregulated . PAX3 mRNA levels were significantly reduced by ASO-27a in 22Rv1 cells (p = 0.0364), while protein levels were significantly increased (p = 0.0112). Immunohistochemically, PAX3 protein was lower in Gleason 7 tumours than in normal tissue, while YAP expression was higher in patients with Gleason 4+3, relative to those with 3+4. SRC3 immunostaining was slightly, but not significantly, higher in patients with 3+4 compared to 4+3. Conclusions: MiR-27a-3p is an AR-modulatory oncomiR in PCa, with potential as a therapeutic target. MiR-27a interaction with its target genes and especially HIPK2, YAP, SRC3 and PAX3 could provide the basis for therapeutic advance in screening and in the treatment of castrate resistant disease, through ASO-27a inhibition.
Minimising the environmental impact of inhaled therapies: problems with policy on low carbon inhalers
Authors: Duncan Keeley, Jane E. Scullion, Omar S. Usmani
Journal: European Respiratory Journal (2020)

<b>The greenest inhaler is an appropriately prescribed device, that the patient has been properly taught and assessed how to use, is happy with and most important of all, gives them clinical benefit</b>https://bit.ly/2VKicQW
Outcomes of advanced plasmacytoid urothelial carcinoma receiving systemic therapy.
Authors: Erik Andrews, Catherine Curran, Petros Grivas, Leonidas Nikolaos Diamantopoulos, Alexandra Drakaki, Rohit K. Jain, Ankita Tandon, Neeraj Agarwal, Abhishek Tripathi, Victor Sacristan Santos, Syed A. Hussain, Guru Sonpavde
Journal: Journal of Clinical Oncology (2020)

580 Background: Plasmacytoid urothelial carcinoma (pUC) is an aggressive variant with poor outcomes reported in small retrospective studies. Patients (pts) with plasmacytoid-predominant tumor histology have generally been excluded from clinical trials. Given the lack of systematic data regarding outcomes in metastatic pUC, we conducted a retrospective multicenter study to broadly examine outcomes. Methods: Pts who underwent any systemic therapy for metastatic pUC were eligible from collaborating institutions. Data were collected for demographics, clinical and pathological variables. Descriptive statistics were reported to examine tumor regression, time to treatment discontinuation or failure (TTF), and overall survival (OS). Results: 52 pts with metastatic pUC were evaluable from 7 institutions. The ECOG-PS ranged from 0-3 (median 1), median age was 65 (range 46 – 85), and 14 pmts (26.9%) were female. The histology consisted of predominant urothelial, predominant plasmacytoid, and pure plasmacytoid carcinoma in 35 (67.3%), 14 (26.9%) and 3 (5.8%) pts, respectively. The median OS for evaluable pts according to histology were 234 (n=21), 203 (n=11), and 12 (n=1) days (d), respectively. The sites of metastasis (mets) were liver +/- other, non-liver visceral +/- soft tissue/lymph node (ST/LN), and ST/LN only in 5 (9.6%), 36 (69.2%), and 11 (21.2%) pts, respectively. Cisplatin-based chemotherapy (cis-chemo), PD1/L1 inhibitor (i), or other non-cis-chemo was administered in 20 (41.7%), 13 (27.1%), and 15 (31.3%) pts, respectively (therapy unknown in 4 pts). Overall best response PR, CR, SD, and PD were seen in 3 (7%), 3 (7%), 7 (16.3%), and 30 (69.8%) pts, respectively. The overall median TTF and median OS were 91 and 232 d, respectively. The median TTF for cisplatin-based chemo, non-cisplatin based chemo and PD1/L1 inhibitors was 96.5, 122.5 and 73.5 d, respectively and the median OS was 236 (n=12), 221 (n=12) and 161 (n=8) d, respectively. Conclusions: The clinical outcomes of pts with metastatic pUC are dismal and appear worse than conventional UC without plasmacytoid component. Further progress will be possible only with better understanding of tumor biology and rational drug development.
The efficacy of two cycles of neoadjuvant chemotherapy for upper tract urothelial carcinoma patients.
Authors: Kenji Zennami, Kiyoshi Takahara, Kosuke Fukaya, Manabu Ichino, Naohiko Fukami, Hitomi Sasaki, Makoto Sumitomo, Mamoru Kusaka, Ryoichi Shiroki
Journal: Journal of Clinical Oncology (2020)

505 Background: Upper tract urothelial carcinoma (UTUC) is frequently upstaged after surgery and is associated with poor prognosis. However, the efficacy of neoadjuvant chemotherapy (NAC) and optimal No. of NAC cycles for UTUC have been poorly defined. In this study, we evaluated if two cycles of NAC improves survival of UTUC patients in our institute. Methods: A total of 167 patients who underwent radical nephroureterectomy at Fujita Health University between November 2005 and December 2018 were retrospectively analyzed. The study group comprised 114 patients with UTUC who received NAC followed by surgery. The control group consisted of 53 patients who underwent initial surgery without NAC. We compared two groups in overall survival (OS), cancer specific survival (CSS), recurrence free survival (RFS, urinary tract, visceral) and independent prognostic factors. Kaplan-Meier methods, log-rank test and cox proportional-hazards models were used for statistical analysis. Results: Median follow up was 1108 days, and there were no significant differences in preoperative patient characteristics between NAC group and initial surgery (IS) group. NAC had significantly improved 5-year OS (75% vs 55%, p=0.004) and 5-year CSS (84% vs 65%, p=0.024). That is more significant in the analysis with cT3 patients (p=0.0002). NAC also significantly improved visceral RFS (p=0.001). However, NAC does not affect urinary tract RFS (p=0.96) when compared to IS. pDS were observed in 55 out of 114 (48%) in NAC group, and 12 out of 53 (22%) in IS group. Comparison of OS between with pDS and without pDS demonstrated significantly better OS in with pDS group (p=0.0001). Multivariate cox proportional-hazards models identified NAC, pDS, resection margin, pN and cT3 as independent prognostic factors for OS. Conclusions: Two cycles of NAC induced pDS and improved survival of UTUC patients. Reduced number of NAC cycles may offer clinical benefits of low chemo-associated toxicity, appropriate surgery without delay in chemo-resistant case and sufficient cancer regression with pDS.
Sixty seconds on . . . the war on sugar
Authors: Gareth Iacobucci
Journal: BMJ (2020)

It’s quite different, not least because this war might actually be winnable. New research1 has shown that in Chile—a nation beset by obesity—sales of sugary drinks dropped by nearly a quarter in two years after the country introduced a “uniquely comprehensive” set of tough new obesity prevention policies in 2016.

It banned schools from selling all foods and drinks containing …
The Need to Improve the Clinical Utility of Direct-to-Consumer Genetic Tests
Authors: Madison K. Kilbride, Angela R. Bradbury
Journal: JAMA (2020)

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Mohammad Fahim Siddiqui
Authors: Nasima Siddiqui
Journal: BMJ (2020)

On 22 December 2019, Mohammad Fahim Siddiqui finally laid down his scalpel. He was born on 14 December 1941 in Bareilly, British India, but the family emigrated to Pakistan after partition. With his mother, Rafique Fatima; his brothers, Nasim, Khalique, and Atique; two sisters, Sabra and Meena; he settled in Old Sukkar in 1950. His father, Sheikh Yakoob Siddiqui, eventually managed to join them, and the family were reunited several years later.

Fahim was a determined hardworking student, the top floor room of the family’s house was reserved purely for him, a study which no one was allowed to enter to ensure that he could concentrate. When he wasn’t studying, Fahim loved kite flying from the walled rooftop of their Old Sukkar home together with his brothers.

His conscientiousness paid off and having finished his matriculation one year early and gaining a government scholarship, he moved to Hyderabad, aged 17, to study for his bachelor of medicine and surgery at Liaquat Medical College. After graduating, with house officer and demonstrator in anatomy roles under his belt, he emigrated a second time—to the UK, in 1968.

He worked for …
Gut microbiota generation of protein-bound uremic toxins and related metabolites is not altered at different stages of chronic kidney disease
Authors: Tessa Gryp, Kim De Paepe, Raymond Vanholder, Frederiek-Maarten Kerckhof, Wim Van Biesen, Tom Van de Wiele, Francis Verbeke, Marijn Speeckaert, Marie Joossens, Marie Madeleine Couttenye, Mario Vaneechoutte, Griet Glorieux
Journal: Kidney International (2020)

Chronic kidney disease (CKD) is characterized by accumulation of protein-bound uremic toxins such as p-cresyl sulfate, p-cresyl glucuronide, indoxyl sulfate and indole-3-acetic acid, which originate in the gut. Intestinal bacteria metabolize aromatic amino acids into p-cresol and indole, (further conjugated in the colon mucosa and liver) and indole-3-acetic acid. Here we measured fecal, plasma and urine metabolite concentrations; the contribution of gut bacterial generation to plasma protein-bound uremic toxins accumulation; and influx into the gut of circulating protein-bound uremic toxins at different stages of CKD. Feces, blood and urine were collected from 14 control individuals and 141 patients with CKD. Solutes were quantified by ultra-high performance liquid chromatography. To assess the rate of bacterial generation of p-cresol, indole and indole-3-acetic acid, fecal samples were cultured ex vivo. With CKD progression, an increase in protein-bound uremic toxins levels was observed in plasma, whereas the levels of these toxins and their precursors remained the same in feces and urine. Anaerobic culture of fecal samples showed no difference in ex vivo p-cresol, indole and indole-3-acetic acid generation. Therefore, differences in plasma protein-bound uremic toxins levels between different CKD stages cannot be explained by differences in bacterial generation rates in the gut, suggesting retention due to impaired kidney function as the main contributor to their increased plasma levels. Thus, as fractional clearance decreased with the progression of CKD, tubular clearance appeared to be more affected than the glomerular filtration rate, and there was no net increase in protein-bound uremic toxins influx into the gut lumen with increased plasma levels.
SOX9 regulates EGFR/ERBB signaling in pancreatic cancer
Authors: Andreia V Pinho, Adrien Grimont, Mark J Cowley, Cecile Augereau, Amanda Mawson, Marc Giry-Laterriere, Geraldine Van den Steen, Nicola Waddell, Marina Pajic, Christine Sempoux, Jianmin Wu, Sean M Grimmond, Andrew V Biankin, Frederic P Lemaigre, Patrick Jacquemin, Ilse Rooman
Journal: Cancer Research (2014)
Distinctive landscape of genetic mutation in patients with intraductal carcinoma of the prostate (IDC-P).
Authors: Jinge Zhao, Guangxi Sun, Sha Zhu, Jindong Dai, Mengni Zhang, Junru Chen, Xingming Zhang, Xudong Zhu, Haoran Zhang, Zhipeng Wang, Yuchao Ni, Xiaochen Zhao, Pengfei Shen, Ni Chen, Hao Zeng
Journal: Journal of Clinical Oncology (2020)

192 Background: Intraductal carcinoma of the prostate (IDC-P) is an independent predictor associated with poor prognosis in men with prostate cancer (PCa) of different stages. Yet, little is known concerning the characteristics of IDC-P at genetic level. The object of this study is to determine the mutation characteristics of patients with IDC-P, aiming at identifying new therapeutic targets for the treatment of IDC-P. Methods: Totally, data of 104 and 35 patients histopathological documented with prostatic adenocarcinoma concomitant with and without IDC-P were included into the current study, respectively. cfDNA was extracted from blood samples for the PCa-related mutation testing through a 90-gene NGS panel. The mutation frequency of different genes was compared between IDC-P positive and negative cases. Results: Almost all the pathogenetic germline mutations were detected from patients with IDC-P [15/104 (14.4%) vs. 1/35 (2.9%), p=0.064]. Pathogenetic germline BRCA2 mutations were all found in IDC-P positive patients [10/104 (9.6%) vs.0/35 (0.0%), p=0.057]. Besides, in terms of somatic mutations, men with IDC-P had significantly higher proportion of mutations in EGFR [30/104 (28.9%) vs. 2/35 (5.7%), p=0.005], KMT2C [20/104 (19.2%) vs. 1/35 (2.9%), p=0.019] and NCOR2 [19/104 (18.3%) vs. 0/35 (0.0%), p=0.006]. Three high frequently mutated sites of EGFR were identified in men with IDC-P, i.e. p.L861Q (12/104, 11.5%), p.L858R (11/104, 10.6%) and p.G719A/C (12/104, 11.5%). These mutated sites have been proved to be associated with therapeutic response from EGFR tyrosine kinase inhibitors (TKIs) in the treatment of lung carcinoma. Conclusions: Patients with IDC-P are candidates for germline and somatic mutations testing for the high frequency of mutations. Germline DDRs and somatic EGFR mutations were frequently occurred in IDC-P positive patients. Though further verification is needed, these mutations had great potential to be used as therapeutic targets in treating patients with IDC-P.
USP22 controls iNKT immunity through MED1 suppression of histone H2A monoubiquitination
Authors: Yana Zhang, Yajun Wang, Beixue Gao, Yueqi Sun, Liang Cao, Samantha M. Genardi, Chyung-Ru Wang, HuaBin Li, Zhaolin Sun, Yanjie Yang, Deyu Fang
Journal: The Journal of Experimental Medicine (2020)

The ubiquitin pathway has been shown to regulate iNKT cell immunity, but the deubiquitinase involved in this process has not been identified. Herein we found that ubiquitin-specific peptidase 22 (USP22) is highly expressed in iNKT cells during their early developmental stage 1. USP22 deficiency blocked the transition from stage 1 to 2 during iNKT cell development in a cell-intrinsic manner. USP22 suppression also diminishes iNKT17 and iNKT1 differentiation but favors iNKT2 polarization without altering conventional T cell activation and differentiation. USP22 interacts with the Mediator complex subunit 1 (MED1), a transcription coactivator involved in iNKT cell development. Interestingly, while interacting with MED1, USP22 does not function as a deubiquitinase to suppress MED1 ubiquitination for its stabilization. Instead, USP22 enhances MED1 functions for IL-2Rβ and T-bet gene expression through deubiquitinating histone H2A but not H2B monoubiquitination. Therefore, our study revealed USP22-mediated histone H2A deubiquitination fine-tunes MED1 transcriptional activation as a previously unappreciated molecular mechanism to control iNKT development and functions.
Effect of extrusion process on the mechanical and in vitro degradation performance of a biomedical Mg-Zn-Y-Nd alloy
Authors: Beining Du, Ziyang Hu, Jiali Wang, Liyuan Sheng, Hui Zhao, Yufeng Zheng, Tingfei Xi
Journal: Bioactive Materials (2020)

A new type of biomedical Mg–Zn–Y-Nd alloy was developed and thermal extruded by different processes to investigate the effect of extrusion ratio and extrusion pass on its microstructure, mechanical property and degradation performance. The results show that the increase of extrusion ratio could promote the dynamic recrystallization (DRX) process and led to the coarsening of DRXed grains. While the increase of extrusion pass also contributes to the DRX process but refines the DRXed grains. The simultaneous increasing of extrusion ratio and extrusion pass refines the secondary phases obviously. The increase of extrusion ratio has reduced the tensile strength but improved the elongation of the alloy significantly. However, the increase of extrusion pass could enhance the tensile strength and elongation simultaneously, especially the strength. The degradation performance has been optimized effectively through increasing the extrusion ratio and extrusion pass.