tbuckley/cabot-search huggingface dataset:
Evaluation of Proclarix, a prostate cancer risk score, used together with magnetic resonance imaging for the diagnosis of clinically significant prostate cancer.
Authors: Hayley Pye, Hashim Ahmed, Susan Heavey, Urszula Stopka-Farooqui, Edward Johnston, Ralph Schiess, Silke Gillessen, Shonit Punwani, Mark Emberton, Hayley Whitaker
Journal: Journal of Clinical Oncology (2020)

278 Background: The use of multi-parametric magnetic resonance imaging (mpMRI) has been a significant advance in the diagnosis of prostate cancer (PCa) recommended in a number of guidelines. There are considerable resource implications in scanning all men at risk of PCa. Furthermore, a significant number of mpMRIs are reported as indeterminate, leading to unnecessary biopsies. Proclarix is a CE-marked test based on two novel biomarkers, thrombospondin 1 (THBS1) and cathepsin D (CTSD), combined with PSA and age. A software algorithm returns a risk score that can be used as an aid in the identification of clinically significant PCa (any Grade Group 2 or greater). We aimed to assess the potential of Proclarix to identify those men who could safely avoid an upfront mpMRI or those men who could avoid biopsy when the mpMRI was indeterminate. Methods: Proclarix was correlated retrospectively with diagnostic data from 282 men recruited in the INNOVATE study (NCT02689271). INNOVATE involved men undergoing mpMRI followed by targeted and systematic biopsies in those with a suspicious mpMRI. Results: Median age and PSA were 66 (IQR 59-70) and 5.4 (3.8-7.8) ng/mL. 182 (65%) men underwent biopsy and 78 (43%) had GG≥2 PCa. Application of Proclarix in all 282 men undergoing mpMRI resulted in a sensitivity for clinically significant PCa (GG≥2) of 91%, a negative predictive value (NPV) of 92% and 38% specificity. When normalized to the same sensitivity of 91%, %fPSA resulted in both lower NPV (89%) and specificity (28%) when compared to Proclarix. 144 (51%) men had an indeterminate mpMRI of whom 84 (58%) had a biopsy and 13 (15%) had GG≥2 PCa. In these men, Proclarix had an NPV of 100%, at 100% sensitivity and a specificity of 34%. When results were compared using equal sensitivity, PSA density (cut-off 0.05 ng/mL), which is frequently used to inform the need for biopsy, had 10% specificity. Conclusions: The use of Proclarix could potentially allow 38% of men to avoid undergoing an mpMRI. In men with an indeterminate mpMRI, Proclarix could allow one-third to safely avoid biopsies without missing any clinically significant cancer.
Dual Vascular Endothelial Growth Factor Receptor and Fibroblast Growth Factor Receptor Inhibition Elicits Antitumor Immunity and Enhances Programmed Cell Death-1 Checkpoint Blockade in Hepatocellular Carcinoma
Authors: Haijing Deng, Anna Kan, Ning Lyu, Luwen Mu, Yi Han, Longzhong Liu, Yanyu Zhang, Youfa Duan, Shuangye Liao, Shaolong Li, Qiankun Xie, Tianxiao Gao, Yanrong Li, Zhenfeng Zhang, Ming Zhao
Journal: Liver Cancer (2020)

Combining anti-angiogenic therapy with immune checkpoint blockade with anti-programmed cell death-1 (PD-1) antibodies is a promising treatment for hepatocellular carcinoma (HCC). Tyrosine kinase inhibitors are well-known anti-angiogenic agents and offer potential for combination with anti-PD-1 antibodies. This study investigated the possible underlying immunomodulatory mechanisms of combined therapy.HCC tissue samples for RNA-sequencing (RNA-seq) were obtained from patients with differential prognoses following anti-PD-1 treatment. Recombinant basic fibroblast growth factor (bFGF) and vascular endothelial growth factor A (VEGFA) were used to stimulate T cells following lenvatinib or sorafenib treatment, respectively. T cell function was analyzed by flow cytometry and lactate dehydrogenase assay. In vivo experiments were conducted in murine H22 and Hepa 1-6 competent models of HCC. Local immune infiltration in the tumor microenvironment (TME) was assessed using multicolor flow cytometry. Gene regulation was evaluated by RNA-seq. Microvascular density was measured by immunohistochemistry, and PD-1 ligand (PD-L1) induction was quantified by western blot.The baseline expression of VEGF and fibroblast growth factor (FGF) in patients with progressive disease was significantly higher than in patients achieving stable disease following anti-PD-1 treatment. VEGFA and bFGF significantly upregulated the expression of PD-1, cytotoxic T-lymphocyte-associated protein-4, and Tim-3 on T cells, while inhibiting the secretion of interferon gamma (IFNG) and granzyme B and suppressing T cell cytotoxicity. This immunosuppressive effect was reverted by lenvatinib but not sorafenib. Furthermore, dual lenvatinib/anti-PD-1 antibody therapy led to better antitumor effects than either sorafenib or fibroblast growth factor receptor (FGFR) inhibitor (BGJ398) in H22 murine models of HCC. Combined lenvatinib/anti-PD-1 treatment also led to long-term immune memory formation, while synergistically modulating the TME and enhancing the cytotoxic effect of T cells. Finally, lenvatinib inhibited PD-L1 expression on human umbilical vein endothelial cells, which improved the function of T cells.Inhibition of vascular endothelial growth factor receptor and FGFR augmented the efficacy of anti-PD-1 antibodies. Combined lenvatinib/anti-PD-1 treatment appears to exert antitumor activity by synergistically modulating effector T cell function in the TME and by mutually regulating tumor vessel normalization.
Positive Effects of a Young Systemic Environment and High Growth Differentiation Factor 11 Levels on Chondrocyte Proliferation and Cartilage Matrix Synthesis in Old Mice
Authors: Lu Li, Xiaochun Wei, Dongming Wang, Zhi Lv, Xiang Geng, Pengcui Li, Jiangong Lu, Kaihang Wang, Xiaohu Wang, Jian Sun, Xiaoming Cao, Lei Wei
Journal: Arthritis & Rheumatology (2020)

To investigate the effects of a young systemic environment and growth differentiation factor 11 (GDF-11) on aging cartilage. A heterochronic parabiosis model (2-month-old mouse and 12-month-old mouse [Y/O]), an isochronic parabiosis model (12-month-old mouse and 12-month-old mouse [O/O]), and 12-month-old mice alone (O) were evaluated. Knee joints and chondrocytes from old mice were examined by radiography, histology, cell proliferation assays, immunohistochemistry, Western blotting, and quantitative reverse transcriptase-polymerase chain reaction 16 weeks after parabiosis surgery. GDF-11 was injected into 12-month-old mouse joints daily for 16 weeks. Cartilage degeneration, cell proliferation, and osteoarthritis-related gene expression were evaluated. Osteoarthritis Research Society International scores in old mice were significantly lower in the Y/O group than in the O/O and O groups (both P < 0.05). The percentage of 5-ethynyl-2'-deoxyuridine-positive chondrocytes in old mice was significantly higher in the Y/O group than in the other groups (P < 0.05). Type II collagen (CII) and SOX9 messenger RNA levels differed in cartilage from old mice in the Y/O group compared to the O/O and O groups (both P < 0.05). RUNX-2, CX, and matrix metalloproteinase 13 levels were significantly lower in cartilage from old mice in the Y/O group compared to the O/O and O groups (both P < 0.05). Similar results were obtained for protein expression levels and after GDF-11 treatment in vitro and in vivo. Phosphorylated Smad2/3 (pSmad2/3) levels were higher in the recombinant GDF-11-treated group than in the control group. A young systemic environment promotes chondrocyte proliferation and cartilage matrix synthesis in old mice. GDF-11, a "young factor," contributes to these effects through the up-regulation of pSmad2/3.
Safety and effectiveness of radium-223 dichloride (Ra-223) in patients with mCRPC in real-world setting: A Japanese post-marketing study (PMS).
Authors: Shunji Takahashi, Yoshiyuki Kakehi, Naoya Masumori, Makoto Hosono, Seigo Kinuya, Yutaka Okayama, Toshiyuki Sunaya, Masafumi Okumura, Hirotsugu Uemura
Journal: Journal of Clinical Oncology (2020)

236 Background: In order to assess safety and effectiveness of Ra-223 in real-world setting, a PMS has been conducted under Japanese regulation for Good Post-marketing Study Practice. Methods: This was a prospective, single-arm, observational study of patients (pts) with mCRPC. The planned sample size was 300. In this primary analysis, clinical outcomes during the 6 month observational period up to 1 month after the last injection of Ra-223 were assessed. An exploratory subgroup analysis was performed according to symptom status at baseline (asymptomatic (AS) or symptomatic (S): WHO's cancer pain ladder 0 or &gt;1). Results: A total of 334 pts were enrolled from Jun 2016 to Nov 2017. As of May 2019, data for 273 pts were available (table). The incidence of drug-related any treatment-emergent adverse events (TEAEs), hematologic TEAEs, and skeletal-related events were 27%, 18%, and 3%, respectively. Fractures were reported in 3 pts, but all were judged not related to Ra-223 by investigators. At the subgroup analysis, baseline characteristics for AS-group seemed more favorable than those in S-group (table). More pts in AS-group completed 6 cycles of Ra-223, and incidence of drug-related TEAEs appeared lower in AS-group compared with S-group. More than 90% of pts did not experience pain progression during 24 weeks, regardless of their symptoms status. Conclusions: During the 6 month observational period, no new safety concerns related to Ra-223 treatment were reported. Asymptomatic patients were more likely to complete treatment and experience fewer TEAEs, possibly reflecting less advanced disease. A follow-up observation up to 3 years is on-going.[Table: see text]
TMEM30A loss-of-function mutations drive lymphomagenesis and confer therapeutically exploitable vulnerability in B-cell lymphoma
Authors: Daisuke Ennishi, Shannon Healy, Ali Bashashati, Saeed Saberi, Christoffer Hother, Anja Mottok, Fong Chun Chan, Lauren Chong, Libin Abraham, Robert Kridel, Merrill Boyle, Barbara Meissner, Tomohiro Aoki, Katsuyoshi Takata, Bruce W. Woolcock, Elena Viganò, Michael Gold, Laurie L. Molday, Robert S. Molday, Adele Telenius, Michael Y. Li, Nicole Wretham, Nancy Dos Santos, Mark Wong, Natasja N. Viller, Robert A. Uger, Gerben Duns, Abigail Baticados, Angel Madero, Brianna N. Bristow, Pedro Farinha, Graham W. Slack, Susana Ben-Neriah, Daniel Lai, Allen W. Zhang, Sohrab Salehi, Hennady P. Shulha, Derek S. Chiu, Sara Mostafavi, Alina S. Gerrie, Da Wei Huang, Christopher Rushton, Diego Villa, Laurie H. Sehn, Kerry J. Savage, Andrew J. Mungall, Andrew P. Weng, Marcel B. Bally, Ryan D. Morin, Gabriela V. Cohen Freue, Louis M. Staudt, Joseph M. Connors, Marco A. Marra, Sohrab P. Shah, Randy D. Gascoyne, David W. Scott, Christian Steidl
Journal: Nature Medicine (2020)
Efficacy of atezolizumab concurrent with radiotherapy in patients with muscle-invasive bladder cancer (MIBC) (SOGUG-2017-A-IEC(VEJ)-4).
Authors: Sergio Vázquez-Estévez, Ovidio Fernandez Calvo, Carlos Alvarez-Fernandez, Teresa Bonfill, Montserrat Domenech, JosE GarcIa SAnchez, José Miguel Jurado García, Francisca Martínez Madueño, Nuria Romero-Laorden, Elena Sevillano, Cristina Núñez
Journal: Journal of Clinical Oncology (2020)

TPS601 Background: Radical cystectomy (RC) is the standard of care for patients with T2-T4a MIBC. Organ-preserving treatment is an alternative for patients who wish to attempt bladder preservation therapy or are ineligible for cystectomy. This includes maximal transurethral resection of bladder tumour, external beam radiation therapy (EBRT) and concurrent chemotherapy. The 5 and 10 year OS and disease specific survival (DSS) rates in contemporary RC series are comparable to that reported in bladder-preserving series. Due to EBRT can mediate inmunoestimulatory effects and that radiotherapy has been used in combination with different treatment regimens, a considerable interest has been attracted by combinatorial regimens involving EBRT plus checkpoint inhibitors. The purpose of the present study is to explore feasibility and activity of the combination of atezolizumab associated with EBRT after TURBT in the treatment of localized MIBC with preservation intent. Methods: The primary endpoint of this study is to assess the efficacy of atezolizumab concurrent with EBRT in terms of pathological complete response. The secondary endpoints include OS, DSS, disease free survival, bladder intact disease-free survival, number of patients (pts) with muscle invasive and non-muscle invasive local failure, the rate of distance metastases, the rate of pts with bladder preserved, the rate of immediate or late salvage cystectomy and safety profile and tolerability of the combination. Biomarkers will be evaluated as exploratory endpoints. Elegibility criteria include pts with histologically-confirmed diagnosis of MIBC in clinical stages T2-4a N0 M0, who are not candidates for radical cystectomy by medical reasons, refusal or patient’s choice, unfit for cisplatin and PS (ECOG) 0-2. Pts will receive atezolizumab 1.200 mg by IV infusion on Day1 of each cycle every 3 weeks for a total of 6 treatment courses, concurrent with EBRT 60 Gy in 30 fractions over 6 weeks at 2 Gy/day. With 35 evaluable pts and a pCR of 80%, the 95%CI of the estimation would be 0.62–0.92. The study will be stopped if we do not achieve at least 9 pCR among the first 13 evaluable pts. Otherwise, the study will continue until 39 pts. Clinical trial information: 2018-004348-47.
Metabolome analysis reveals excessive glycolysis via PI3K/AKT/mTOR and RAS/MAPK signaling in methotrexate-resistant primary CNS lymphoma-derived cells
Authors: Yasuo Takashima, Azusa Hayano, Ryuya Yamanaka
Journal: Clinical Cancer Research (2020)

Metabolome analysis is an emerging method that provides insight into intracellular and physiologic responses. Methotrexate (MTX) is an antifolate that suppresses DNA syntheses by inhibiting dihydrofolate reductase. High-dose methotrexate treatment with deferred radiotherapy is a standard protocol in primary central nervous system lymphoma (PCNSL) treatments. However, most cases come to relapse-acquired resistance, in which the role of metabolic pathways is largely unknown.Metabolome analysis in methotrexate-resistant PCNSL-derived cells (designated as TK-MTX and HKBML-MTX) was performed to detect alternative metabolites and pathways.The metabolomic analyses using capillary electrophoresis-time-of-flight mass spectrometry detected 188 and 169 peaks in TK- and HKBML-derived cells, respectively, including suppression of central carbon metabolism, lipid metabolism, nucleic acid metabolism, urea cycle, branched chain and aromatic amino acids, and coenzyme metabolism. Particularly, whole suppressive metabolic pathways were demonstrated in TK-MTX, whereas HKBML-MTX indicated partially enhanced pathways of the urea cycle, amino acid metabolism, and coenzyme metabolism. Reciprocally detected metabolites for glycolysis, including induced glucose and reduced glycogen, and induced lactate and reduced pyruvate, in addition to increased lactate dehydrogenase activity, which is involved in Warburg effect. Thereby, ATP was increased in both methotrexate-resistant PCNSL-derived cells. Furthermore, we specifically found that PI3K/AKT/mTOR and RAS/MAPK signaling pathways were activated in TK-MTX but not in HKBML-MTX by growth rate with inhibitors and gene expression analysis, suggestive of cell type-specific methotrexate-resistant metabolic pathways.These results can help us understand targeted therapies with selective anticancer drugs in recurrent CNS lymphoma-acquired resistance against methotrexate.
N95 Respirators vs Medical Masks in Outpatient Settings
Authors: Melissa McDiarmid, Robert Harrison, Mark Nicas
Journal: JAMA (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Liver macrophages inhibit the endogenous antioxidant response in obesity-associated insulin resistance
Authors: Valerio Azzimato, Jennifer Jager, Ping Chen, Cecilia Morgantini, Laura Levi, Emelie Barreby, André Sulen, Carolina Oses, Joost Willerbrords, Connie Xu, Xidan Li, Joanne X. Shen, Naveed Akbar, Lars Haag, Ewa Ellis, Kerstin Wålhen, Erik Näslund, Anders Thorell, Robin P. Choudhury, Volker M. Lauschke, Mikael Rydén, Siobhan M. Craige, Myriam Aouadi
Journal: Science Translational Medicine (2020)

Liver macrophages exacerbate oxidative stress in obesity-induced hepatic steatosis by blocking the endogenous antioxidant response.
Double-tunnel circumferential endoscopic submucosal dissection with double clip-band-line traction for an esophageal squamous neoplasm
Authors: Miguel Fraile-López, Adolfo Parra-Blanco
Journal: Endoscopy (2020)

Esophageal endoscopic submucosal dissection (ESD) is technically challenging [1] [2] [3] [4] [5]. We report a successful circumferential esophageal ESD procedure using the double-tunnel and double-traction method with the clip-band-line technique applied on both pillars.
Tofacitinib in refractory adult-onset Still’s disease: 14 cases from a single centre in China
Authors: Qiongyi Hu, Mengyan Wang, Jinchao Jia, Jialin Teng, Huihui Chi, Tingting Liu, Hong-lei Liu, Xiaobing Cheng, Junna Ye, Yutong Su, Yue Sun, Zhuochao Zhou, Liyan Wan, Zhihong Wang, Fan Wang, Hui Shi, Chengde Yang
Journal: Annals of the Rheumatic Diseases (2020)

times per day 24Effective
Tivozanib as first-line treatment of metastatic renal cell carcinoma: A real-world outcome review in North-West of England, United Kingdom.
Authors: Sam Wong, Kellati Prasad, Tom Waddell, Natalie Charnley, Helen Wong, Andrea Law, Omi Parikh, Manon Pillai, Richard Griffiths, Shien Chow
Journal: Journal of Clinical Oncology (2020)

638 Background: Tivozanib is a selective tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor and has been shown to offer PFS and tolerance advantage compared to sorafenib among patients with mRCC. In this retrospective review, we aim to investigate the real world efficacy and tolerance of tivozanib delivered in four cancer hospital in the Northwest of England. Methods: mRCC patients started tivozanib in first line setting were identified and reviewed. Primary outcomes of interest include overall response rate (ORR), survival (OS, PFS where possible) and treatment tolerance. Results: A total of 113 patients were identified between March 2017 and May 2019. Median follow up was 200 days (15-792). 26% were switched from other prior TKI due to intolerance. 28%, 48% and 24% had Favourable (F), Intermediate (I) and Poor(P) IMDC risk category respectively. ORR was 29% (CR 0%, PR29%, SD38%, PD26%, NE 7%). Median PFS (after 53 events) was 9 months (F = NR, I = 7 months, P = 3 months p value &lt; 0.0001) with estimated 6 and 12 months OS of 80% and 67 % respectively. At cut-off, 26/32 with F IMDC risk remaining on treatment c.f. 24/54 (I) and 6/27 (P). Median treatment received was 5 cycles and 65% still on full dose at end of observation. Dose reduction was necessary in 31% while treatment was stopped in 15% due to toxicity. 46% received subsequent therapy post- progression. The commonest adverse events were fatigue (32%, G3 0%), diarrhoea (15%, G3 1.7%), mucositis (15%, G3 &lt; 1%), and anorexia (7%, G3 1.7%). Conclusions: Preliminary findings from this review suggests similar clinical efficacy of tivozanib compared to agents such as pazopanib or sunitinib in real-world setting particularly among patient with Favourable IMDC category however longer follow up is required to fully evaluate this. Treatment is well tolerated with low incidence of severe grade toxicities and may be a good monotherapy option in patient of Favourable IMDC category unsuitable for combination therapies.
Tumor neoantigenicity assessment with CSiN score incorporates clonality and immunogenicity to predict immunotherapy outcomes
Authors: Tianshi Lu, Shidan Wang, Lin Xu, Qinbo Zhou, Nirmish Singla, Jianjun Gao, Subrata Manna, Laurentiu Pop, Zhiqun Xie, Mingyi Chen, Jason J. Luke, James Brugarolas, Raquibul Hannan, Tao Wang
Journal: Science Immunology (2020)

CSiN score is an improved tool to assess the overall quality of tumor neoantigens that predicts response to immunotherapy.
An Updated Model For Prediction Of Asthma Exacerbations Using Albuterol Electronic Multi-dose Dry Powder Inhaler
Authors: Rajan Merchant, Guilherme Safioti, Lena Granovsky, Michael Reich, Thomas Li, Tanisha Hill, Roy Pleasants, Giselle Mosnaim, Michael Depietro
Journal: Journal of Allergy and Clinical Immunology (2020)
Nox2+ myeloid cells drive vascular inflammation and endothelial dysfunction in heart failure after myocardial infarction via angiotensin II receptor type 1
Authors: Michael Molitor, Wolf-Stephan Rudi, Venkata Garlapati, Stefanie Finger, Rebecca Schüler, Sabine Kossmann, Jeremy Lagrange, Thanh Son Nguyen, Johannes Wild, Tanja Knopp, Susanne H Karbach, Maike Knorr, Wolfram Ruf, Thomas Münzel, Philip Wenzel
Journal: Cardiovascular Research (2020)

Abstract Aims Heart failure (HF) ensuing myocardial infarction (MI) is characterized by the initiation of a systemic inflammatory response. We aimed to elucidate the impact of myelomonocytic cells and their activation by angiotensin II on vascular endothelial function in a mouse model of HF after MI. Methods and results HF was induced in male C57BL/6J mice by permanent ligation of the left anterior descending coronary artery. Compared to sham, HF mice had significantly impaired endothelial function accompanied by enhanced mobilization of Sca-1+c-Kit+ haematopoietic stem cells and Sca-1−c-Kit+ common myeloid and granulocyte-macrophage progenitors in the bone marrow as well as increased vascular infiltration of CD11b+Ly6G−Ly6Chigh monocytes and accumulation of CD11b+ F4/80+ macrophages, assessed by flow cytometry. Using mice with Cre-inducible expression of diphtheria toxin receptor in myeloid cells, we selectively depleted lysozyme M+ myelomonocytic cells for 10 days starting 28 days after MI. While the cardiac phenotype remained unaltered until 38 days post-MI, myeloid cell depletion attenuated vascular accumulation of Nox2+CD45+ cells, endothelial dysfunction, oxidative stress, and vascular expression of adhesion molecules and angiotensin II receptor type 1 (AT1R). Pharmacological blockade of this receptor for 4 weeks did not significantly alter cardiac function, but mimicked the effects of myeloid cell depletion: telmisartan (20 mg/kg/day, fed to C57BL/6J mice) diminished bone marrow myelopoesis and myeloid reactive oxygen species production, attenuated endothelial leucocyte rolling and vascular accumulation of CD11b+Ly6G−Ly6Chigh monocytes and macrophages, resulting in improved vascular function with less abundance of Nox2+CD45+ cells. Conclusion Endothelial dysfunction in HF ensuing MI is mediated by inflammatory Nox2+ myeloid cells infiltrating the vessel wall that can be targeted by AT1R blockade.