tbuckley/cabot-search huggingface dataset:
Considering the Source of Information in the Evaluation of Maltreatment Experiences—Reply
Authors: Jessie R. Baldwin, Andrea Danese
Journal: JAMA Psychiatry (2019)

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Leukotriene Synthesis Is Critical for Medulloblastoma Progression
Authors: Fang Du, Larra Yuelling, Eric H. Lee, Yuan Wang, Shengyou Liao, Yan Cheng, Li Zhang, Chaonan Zheng, Suraj Peri, Kathy Q. Cai, Jessica M.Y. Ng, Tom Curran, Peng Li, Zeng-jie Yang
Journal: Clinical Cancer Research (2019)

Here, we examined the role of leukotrienes, well-known inflammatory mediators, in the tumorigenesis of hedgehog pathway-associated medulloblastoma, and tested the efficacies of antagonists of leukotriene biosynthesis in medulloblastoma treatment.Experimental Design: We examined the leukotriene levels in medulloblastoma cells by ELISA. We next tested whether leukotriene synthesis in medulloblastoma cells relied on activation of hedgehog pathway, or the presence of hedgehog ligand secreted by astrocytes. We then investigated whether leukotriene mediated hedgehog-induced Nestin expression in tumor cells. The functions of leukotriene in tumor cell proliferation and tumor growth in medulloblastoma were determined through knocking down 5-lipoxygenase (a critical enzyme for leukotriene synthesis) by shRNAs, or using 5-lipoxygenase-deficient mice. Finally, the efficacies of antagonists of leukotriene synthesis in medulloblastoma treatment were tested in vivo and in vitro.Leukotriene was significantly upregulated in medulloblastoma cells. Increased leukotriene synthesis relied on hedgehog ligand secreted by astrocytes, a major component of medulloblastoma microenvironment. Leukotriene stimulated tumor cells to express Nestin, a cytoskeletal protein essential for medulloblastoma growth. Genetic blockage of leukotriene synthesis dramatically suppressed medulloblastoma cell proliferation and tumor growth in vivo. Pharmaceutical inhibition of leukotriene synthesis markedly repressed medulloblastoma cell proliferation, but had no effect on proliferation of normal neuronal progenitors. Moreover, antagonists of leukotriene synthesis exhibited promising tumor inhibitory efficacies on drug-resistant medulloblastoma.Our findings reveal a novel signaling pathway that is critical for medulloblastoma cell proliferation and tumor progression, and that leukotriene biosynthesis represents a promising therapeutic target for medulloblastoma treatment.
Gata6+ Pericardial Cavity Macrophages Relocate to the Injured Heart and Prevent Cardiac Fibrosis
Authors: Justin F. Deniset, Darrell Belke, Woo-Yong Lee, Selina K. Jorch, Carsten Deppermann, Ali Fatehi Hassanabad, Jeannine D. Turnbull, Guoqi Teng, Isaiah Rozich, Kelly Hudspeth, Yuka Kanno, Stephen R. Brooks, Anna-Katerina Hadjantonakis, John J. O’Shea, Georg F. Weber, Paul W.M. Fedak, Paul Kubes
Journal: Immunity (2019)

Macrophages play an important role in structural cardiac remodeling and the transition to heart failure following myocardial infarction (MI). Previous research has focused on the impact of blood-derived monocytes on cardiac repair. Here we examined the contribution of resident cavity macrophages located in the pericardial space adjacent to the site of injury. We found that disruption of the pericardial cavity accelerated maladaptive post-MI cardiac remodeling. Gata6+ macrophages in mouse pericardial fluid contributed to the reparative immune response. Following experimental MI, these macrophages invaded the epicardium and lost Gata6 expression but continued to perform anti-fibrotic functions. Loss of this specialized macrophage population enhanced interstitial fibrosis after ischemic injury. Gata6+ macrophages were present in human pericardial fluid, supporting the notion that this reparative function is relevant in human disease. Our findings uncover an immune cardioprotective role for the pericardial tissue compartment and argue for the reevaluation of surgical procedures that remove the pericardium.
Gaps between fruit and vegetable production, demand, and recommended consumption at global and national levels: an integrated modelling study
Authors: Daniel Mason-D'Croz, Jessica R Bogard, Timothy B Sulser, Nicola Cenacchi, Shahnila Dunston, Mario Herrero, Keith Wiebe
Journal: The Lancet Planetary Health (2019)

Current diets are detrimental to both human and planetary health and shifting towards more balanced, predominantly plant-based diets is seen as crucial to improving both. Low fruit and vegetable consumption is itself a major nutritional problem. We aim to better quantify the gap between future fruit and vegetable supply and recommended consumption levels by exploring the interactions between supply and demand in more than 150 countries from 1961 to 2050.
Stratifying Bronchiectasis: Getting to within a <i>Zone</i>’s Throw
Authors: Sanjay H. Chotirmall
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

as to cross-sectional and longitudinal (1-yr) follow-up data on asthma control and exacerbation frequency.In addition, it will be of interest to use the CT-based model to connect changes in airway caliber in different locations of the reconstructed bronchial tree to other small airway parameters such as multiple breath nitrogen washout, FEF, alveolar nitric oxide, and lung hyperinflation.This will improve understanding of how currently available physiological and imaging tests reflect small airway disease in different locations of the bronchial tree, and may identify new small airway disease subtypes with possible clinical relevance in the context of treatment such as biologicals.The ongoing discussion of proving the added value of extra-fine particles, and a range of particle sizes in an administration, could also profit from this new technique.
Inhaled corticosteroids attenuate epithelial mesenchymal transition: implications for COPD and lung cancer prophylaxis
Authors: Wenying Lu, Pawan Sharma, Mathew Suji Eapen, Sukhwinder Singh Sohal
Journal: European Respiratory Journal (2019)

We read with great interest the recent original research article by Raymakers et al . [1] published in the European Respiratory Journal , regarding the beneficial effects of inhaled corticosteroids (ICS) in reducing the lung cancer risk in patients with chronic obstructive pulmonary disease (COPD). In their discussion, the authors mentioned that the mechanisms by which COPD is associated with an increased risk of lung cancer are not well-established. We do not know which mechanisms ICS inhibit for an appreciable reduction in lung cancer risk. This is a hugely important area and it is encouraging that leading respiratory journals are recognising this. Understanding these interactive mechanisms, we believe, is very important for better future translational approaches to establish early and preventive therapy [2, 3]. We would like to take this further and suggest a broader discussion on the latest findings in COPD pathology involving processes such as epithelial mesenchymal transition (EMT), angiogenesis and airway wall cellularity, and the effects of ICS on these aspects in COPD. Inhaled corticosteroids protect against lung cancer by inhibiting epithelial mesenchymal transition (EMT) in COPD <http://bit.ly/2WG682I>
Abstract 16725: Polarized Macrophages by Exosomes From Adipose-Derived Stem Cells Promote Angiogenesis
Authors: Dihan Zhu, Takerra Johnson, Xin Dai, Dong Liu
Journal: Circulation (2017)

Beneficial effects through the administration of stem cells have been reported to stimulate therapeutic angiogenesis for ischemic disease. However, the underlying mechanisms are still poorly define...
Activity of sirolimus in advanced epithelioid hemangioendothelioma (EHE): A retrospective analysis within the Italian Rare Tumor Network (RTR).
Authors: Noemi Simeone, Giacomo Giulio Baldi, Anna Maria Frezza, Elena Palassini, Bruna Bianca Lopes David, Bruno Vincenzi, Antonella Brunello, Gianpaolo Dagrada, Paola Collini, Carlo Morosi, Angelo Paolo Dei Tos, Paolo Giovanni Casali, Silvia Stacchiotti
Journal: Journal of Clinical Oncology (2019)

11065 Background: EHE is an exceedingly rare soft tissue sarcoma (STS) with no active standard treatment available in advanced patients (pts). We already reported on the activity of sirolimus in a retrospective series of 18 EHE treated within the RTR. We herein update this series on a longer follow-up in a larger number of pts. Methods: Adult pts affected by an advanced, progressive and centrally confirmed EHE treated with sirolimus within the RTR from 2006 to 2018 were retrospectively reviewed. Sirolimus was administered at the starting dose of 5 mg/day, until toxicity or progression. Sirolimus dose was adjusted according to plasma levels (target: 15–20 ng/dL). Response was assessed by RECIST 1.1. Survival was estimated by Kaplan-Meier method. Results: 33 patients were retrospectively identified (median age = 47 years, female = 20 (60%), male = 13 (40%); pretreated = 8, naïve = 25; presence of pleural effusion at baseline = 6). All patients had metastatic disease and evidence of disease progression before starting sirolimus. Mean sirolimus daily dose was 5 mg (range 2-10). 9 pts are still on therapy, 24 stopped sirolimus (13 progression, 5 toxicity, 6 other). 31 pts were evaluable for response (2 pts too early). Best RECIST response was: 1 (3.2%), PR, 26 (83.8%) SD, 4 (12.9%) progression. At a 14-mo median FU, median PFS (m-PFS) was 12.3 mos (range 8–15) and median OS (m-OS) was 19 mos (range 1–40). Pleural effusion correlated with a short m-PFS (3.4 vs 14.3 mos in patients without pleural effusion, p = 0.006) and m-OS (10.6 vs 40 mos in patients without pleural effusion, p &lt;0.0001). Amongst those without pleural effusion, the proportion of pts being progression free at &gt; 24 mos was 23%, with 54 % being alive. Conclusions: We selected pts with advanced EHE with clear evidence of disease progression. This singles out a subgroup of EHE pts with a bad prognosis. Prognosis was shown to be exceedingly bad when there was evidence of serosal effusion, and sirolimus was not effective. Though in an uncontrolled setting, apparently sirolimus is able to slightly prolong PFS and, above all, to allow mid-term freedom of progression in roughly 25% of pts.
Hematopoietic recovery and immune reconstitution after axi-cel CAR T-cell therapy in patients with relapsed/refractory large B-cell lymphoma.
Authors: Paolo Strati, Sherry Adkins, Loretta J. Nastoupil, Jason Westin, Fredrick B. Hagemeister, Nathan Hale Fowler, Hun Ju Lee, Luis Fayad, Felipe Samaniego, Sairah Ahmed, Ankur Varma, Sara Arafat, Swapna Johncy, Partow Kebriaei, Victor Mulanovich, Ella Ariza-Heredia, Sattva Swarup Neelapu
Journal: Journal of Clinical Oncology (2019)

7545 Background: Cytopenia lasting beyond 30 days has been observed after CAR T cell therapy. Here, we describe the hematopoietic recovery and immune reconstitution following axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory large B-cell lymphoma. Methods: Patients with available complete blood counts 30 days after axi-cel infusion were eligible for the analysis. Results: Of 31 patients treated on ZUMA-1 (=24) and ZUMA-9 (=7) trials at our institution, grade ≥3 cytopenias were observed in 15 (48%) patients at day 30 (d30), represented by neutropenia in 9 (29%), anemia in 5 (16%), and thrombocytopenia in 13 (42%). Baseline (d-5) characteristics associated with d30 grade ≥3 cytopenia on univariate analysis were ECOG performance status &gt;0 (60% vs 19%, p=0.03) and &gt;3 prior therapies (67% vs 25%, p=0.03). While on study, patients with d30 grade ≥3 cytopenia had a significantly higher need for intravenous immunoglobulins (Ig) (67% vs 25%, p=0.03) and platelet transfusion (73% vs 25%, p=0.01). No significant association was observed between d30 grade ≥3 cytopenia and subsequent grade ≥3 infections (27% vs 31%, p=1), need for growth factor support (both 100%), red blood cell transfusions or diagnosis of myelodysplastic syndromes. At a median follow-up of 2.7 years, a trend for a higher 3-year PFS was observed for patients with d30 grade ≥3 cytopenia (63% vs 35%, p=0.18). Among patients with ongoing response at most recent follow-up, resolution of grade ≥3 cytopenia was observed in 75% of patients at 1 year and 86% at 2 years; recovery in CD4, CD8, CD56, CD19, and IgG was observed in 63%, 100%, 100%, 29%, and 58% of patients at 1 year, and 86%, 100%, 100%, 25% and 50% of patients at 2 years. Among patients with d30 cytopenia, a significant correlation was observed between platelet count and CD56 count (r=+0.64, p&lt;0.001). Conclusions: Grade &gt; 3 cytopenias are common after axi-cel therapy, but resolve in most patients by 1 year. Recovery of CD4 T cells appears to be delayed beyond 1 year in 1/3 of the patients, highlighting the need for prolonged prophylaxis for opportunistic infections.
Evaluation of Lung Cancer and Neuroendocrine Neoplasm in a Single Scan by Targeting Both Somatostatin Receptor and Integrin αvβ3
Authors: Yumin Zheng, Hanping Wang, Huangying Tan, Xiaoxia Cui, Shaobo Yao, Jie Zang, Li Zhang, Zhaohui Zhu
Journal: Clinical Nuclear Medicine (2019)

This pilot study aimed to prove the complementary value of a novel Gallium-labeled heterodimeric peptide, Ga-NOTA-3P-TATE-RGD, in detection and evaluation of tumors with somatostatin receptor subtype 2 or integrin αvβ3 overexpression, including non-small cell lung cancer (NSCLC), small-cell lung cancer (SCLC), neuroendocrine tumor (NET), and neuroendocrine carcinoma (NEC).With institute review board approval and written informed consent, 32 patients with pathologically diagnosed lung cancer (18 NSCLC, 14 SCLC) and 12 patients with neuroendocrine neoplasm (8 NET, 4 NEC) patients were recruited to undergo Ga-NOTA-3P-TATE-RGD PET/CT. For comparison, the NSCLC patients also underwent Ga-NOTA-TATE PET/CT, the SCLC patients underwent Ga-NOTA-RGD PET/CT, and the neuroendocrine neoplasm patients underwent F-FDG PET/CT within 3 days. The maximum standardized uptake value (SUV) of the primary tumor (T) and mean SUV of the blood pool (B) were measured, and the T/B ratios were calculated for comparison.In the primary tumors of NSCLC, the T/B ratios of Ga-NOTA-3P-TATE-RGD were significantly higher than those of Ga-NOTA-TATE (4.54 ± 3.00 versus 4.10 ± 2.83, P = 0.0058). In SCLC, the T/B ratios of Ga-NOTA-3P-TATE-RGD were significantly higher than those of Ga-NOTA-RGD (6.06 ± 6.09 versus 2.65 ± 1.19, P = 0.0344). In NET, the T/B ratios of Ga-NOTA-3P-TATE-RGD were 36.13 ± 33.84, significantly higher than those of F-FDG (2.91 ± 1.71, P = 0.0234). In NEC, there were no significant difference between the T/B ratios of Ga-NOTA-3P-TATE-RGD (4.80 ± 0.85) and those of F-FDG (3.56 ± 0.74, P = 0.1833).This proof-of-concept study preliminarily demonstrates the efficacy of the dual targeting Ga-NOTA-3P-TATE-RGD PET/CT in the evaluation of lung cancer and neuroendocrine neoplasm in a single scan.
Effect of dose modifications on response to duvelisib in patients with relapsed/refractory (R/R) CLL/SLL in the DUO trial.
Authors: Ian Flinn, Marco Montillo, Árpád Illés, Gabriel Etienne, Julio Delgado, Bryone J. Kuss, Constantine Si Lun Tam, Fritz Offner, Francesc Bosch, Matthew Steven Davids, Ulrich Jäger, Paolo Ghia, Florence Cymbalista, David T. Weaver, Stephanie Lustgarten, Hagop Youssoufian, Stephan Stilgenbauer, Nicole Lamanna
Journal: Journal of Clinical Oncology (2019)

7523 Background: Duvelisib (DUV), a first-in-class oral dual PI3K-δ,γ inhibitor, is approved for treatment (tx) of R/R CLL/SLL after ≥ 2 prior therapies. In the phase 3 DUO trial, DUV 25 mg BID significantly improved efficacy vs ofatumumab (OFA; mPFS, 13.3 vs 9.9 mo; HR, 0.52 [ P &lt; .0001]; ORR, 74% vs 45% [ P &lt; .0001]) in pts with R/R CLL/SLL. Tx-emergent AEs (TEAEs) of special interest (AESIs) such as infections, diarrhea, colitis, neutropenia, rash, ALT/AST elevation, and pneumonitis, were moderate and manageable with early intervention and dose modification. We examined dose-modification patterns and their impact on response to DUV in the DUO trial. Methods: Dose interruptions (DI) or reductions (DR) to 15, 10, or 5 mg BID were permitted per study protocol to manage TEAEs. Responses were assessed by IRC. Results: Among 158 DUV-treated pts, median duration of DUV exposure was 11.6 mo (vs 5.3 mo, OFA). DI and DR occurred in 80% (126/158) and 27% (43/158) of pts, respectively. The most common cause of DI was diarrhea (23%), followed by neutropenia (12%) and pneumonia or colitis (11% each). Among responders (n = 118), median time to first response on DUV was 1.9 mo and estimated median duration of response was 11.1 mo. Median time to first DI was 3.9 mo and median duration of DI was 15 d (range, 1-133 d). Response to DUV was improved or maintained in most pts evaluated for response who had ≥ 1 DI for &gt; 1 wk (84% [42/50]) or &gt; 2 wk (82% [31/38]) followed by ≥ 3 wk on DUV. In a landmark analysis, median PFS was similar in pts with DI and those without DI for &gt; 1 wk (17.8 vs 16.3 mo) or &gt; 2 wk (17.8 vs 16.3 mo) within the first 3 mo. The median time to DR after CR/PR was 5.6 mo (n = 25) and median duration was 3.4 mo. Median time to onset across AESIs after starting DUV ranged from 2.2 to 4.3 mo; median time to resolution was within 4 wk across AESIs. Proportions of pts experiencing AESIs were stable or decreased over time after 3-6 mo: 0-3 mo, 64% (101/158); &gt; 3-6 mo, 63% (86/137); &gt; 6-9 mo, 47% (54/114); &gt; 9-12 mo, 52% (52/100), and seldom led to discontinuation of DUV (≤ 10%). Conclusions: DI/DR can contribute to the effective management of TEAEs with DUV. These findings suggest that DI of &gt; 1-2 weeks or more do not appear to significantly impact response to DUV or PFS. Clinical trial information: NCT02004522.
Developing a new urine cell flow cytometry analysis of PD-L1 expression and DNA content for diagnosis of bladder cancer.
Authors: Shaheen Riadh Alanee, Mustafa Deebajah, Pin-I Chen, Alice (Xiaoyang) Wang, Bruce Kendrick Patterson
Journal: Journal of Clinical Oncology (2019)

60 Background: Bladder cancer is the fifth most common cancer in the United States. PD-1/PD-L1, a pathway used by cancer cells to evade immune response, correlates with bladder cancer severity and has emerged as a target in bladder cancer treatment. Chromosomal instability is also a prominent feature associated with the development of bladder cancer. A method for unbiased analysis of PD-L1 expression and DNA content in cells from urine samples promises to be a new test for diagnosis of bladder cancer. Methods: To evaluate the PD-L1 expression and DNA content, we developed a 4-color flow assay. Cells in voided urine samples were pelleted, fixed in incellMAX (IncellDx Inc.) and stained with antibodies against pan-cytokeratin (CK), CD45, PD-L1 and a cell cycle dye. The stained samples were analyzed by a flow cytometer alongside stained control cells. Results: Fifty bladder cancer patient and 15 normal donor urine samples were collected and tested with this assay. We could distinguish epithelial cells (pan-CK+) and white blood cells (WBCs, CD45+) in urine samples and obtain PD-L1 expression and DNA content information simultaneously from these cell populations. The patient samples showed a significantly higher percentage of WBCs with substantial PD-L1 expression (P &lt; 0.001). The percentage of PD-L1 positive epithelial cells was not distinguishable between normal donor and patient samples. However increased post G1 epithelial cells ( &gt; 5%) were observed in a majority of bladder cancer patients, with around 25% of samples showing a DNA index above 1.05. Conclusions: We developed a flow cytometry-based method to investigate PD-L1 and DNA content simultaneously in cells from urine samples that could provide us with a new method to accurately identify bladder cancer patients through urine testing.
GMC loses right to appeal tribunal decisions or ask for doctors’ reflective notes
Authors: Clare Dyer
Journal: BMJ (2019)

The General Medical Council (GMC) will lose the legal power to require doctors to produce any reflective notes they have made about their practice, under legislative plans to shake up the system of healthcare regulation.1

It will also be stripped of its right to appeal against medical practitioners tribunal decisions that it considers to have treated doctors too leniently, as part of a UK-wide plan to speed up fitness to practise hearings for the nine health and social care regulators and make their procedures less adversarial and legalistic.

The two proposals come from the Williams review of gross negligence manslaughter,2 which the government commissioned …
Bevacizumab improves efficacy of trifluridine/tipiracil (TAS-102) in patients with chemorefractory metastatic colorectal cancer: a Danish randomized trial
Authors: P. Pfeiffer, M. Yilmaz, S. Möller, D. Zitnjak, L. Maltha, M. Krogh, S. Winther, L. Petersen, F. Hejlersen, K. Thomsen, C. Qvortrup
Journal: Annals of Oncology (2019)