tbuckley/cabot-search huggingface dataset:
Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23
Authors: Maya Kansara, Kristian Thomson, Puiyi Pang, Aurelie Dutour, Lisa Mirabello, Francine Acher, Jean-Philippe Pin, Elizabeth G. Demicco, Juming Yan, Michele W.L. Teng, Mark J. Smyth, David M. Thomas
Journal: Cancer Discovery (2019)

Abstract The glutamate metabotropic receptor 4 (GRM4) locus is linked to susceptibility to human osteosarcoma, through unknown mechanisms. We show that Grm4−/− gene–targeted mice demonstrate accelerated radiation-induced tumor development to an extent comparable with Rb1+/− mice. GRM4 is expressed in myeloid cells, selectively regulating expression of IL23 and the related cytokine IL12. Osteosarcoma-conditioned media induce myeloid cell Il23 expression in a GRM4-dependent fashion, while suppressing the related cytokine Il12. Both human and mouse osteosarcomas express an increased IL23:IL12 ratio, whereas higher IL23 expression is associated with worse survival in humans. Consistent with an oncogenic role, Il23−/− mice are strikingly resistant to osteosarcoma development. Agonists of GRM4 or a neutralizing antibody to IL23 suppressed osteosarcoma growth in mice. These findings identify a novel, druggable myeloid suppressor pathway linking GRM4 to the proinflammatory IL23/IL12 axis. Significance: Few novel systemic therapies targeting osteosarcoma have emerged in the last four decades. Using insights gained from a genome-wide association study and mouse modeling, we show that GRM4 plays a role in driving osteosarcoma via a non–cell-autonomous mechanism regulating IL23, opening new avenues for therapeutic intervention. See related commentary by Jones, p. 1484. This article is highlighted in the In This Issue feature, p. 1469
The effects of marijuana smoking on lung function in older people
Authors: Wan C. Tan, Jean Bourbeau, Shawn D. Aaron, James C. Hogg, François Maltais, Paul Hernandez, Darcy D. Marciniuk, Kenneth R. Chapman, Teresa To, J. Mark FitzGerald, Brandie L. Walker, Jeremy Road, Liyun Zheng, Guohai Zhou, Trevor Yau, Andrea Benedetti, Denis O'Donnell, Don D. Sin
Journal: European Respiratory Journal (2019)

Background Previous studies have associated marijuana exposure with increased respiratory symptoms and chronic bronchitis among long-term cannabis smokers. The long-term effects of smoked marijuana on lung function remain unclear. Methods We determined the association of marijuana smoking with the risk of spirometrically defined chronic obstructive pulmonary disease (COPD) (post-bronchodilator forced expiratory volume in 1 s (FEV 1 )/forced vital capacity ratio &lt;0.7) in 5291 population-based individuals and the rate of decline in FEV 1 in a subset of 1285 males and females, aged ≥40 years, who self-reported use (or non-use) of marijuana and tobacco cigarettes and performed spirometry before and after inhaled bronchodilator on multiple occasions. Analysis for the decline in FEV 1 was performed using random mixed effects regression models adjusted for age, sex and body mass index. Heavy tobacco smoking and marijunana smoking was defined as &gt;20 pack-years and &gt;20 joint-years, respectively. Results ∼20% of participants had been or were current marijuana smokers with most having smoked tobacco cigarettes in addition (83%). Among heavy marijuana users, the risk of COPD was significantly increased (adjusted OR 2.45, 95% CI 1.55–3.88). Compared to never-smokers of marijuana and tobacco, heavy marijuana smokers and heavy tobacco smokers experienced a faster decline in FEV 1 by 29.5 mL·year −1 (p=0.0007) and 21.1 mL·year −1 (p&lt;0.0001), respectively. Those who smoked both substances experienced a decline of 32.31 mL·year −1 (p&lt;0.0001). Interpretation Heavy marijuana smoking increases the risk of COPD and accelerates FEV 1 decline in concomitant tobacco smokers beyond that observed with tobacco alone.
Current practice for screening and management of financial distress at NCCN member institutions.
Authors: Nandita Khera, Jessica Sugalski, Diana Krause, Richard Butterfield, Nan Zhang, Warren Smedley, F. Marc Stewart, Joan M. Griffin, Yousuf Zafar, Stephanie Lee
Journal: Journal of Clinical Oncology (2019)

11615 Background: Deficiencies and barriers exist to delivering comprehensive and affordable cancer care. Understanding the variation in organizational commitment, existing programs, and expected outcomes for screening and management of financial distress is needed. Methods: Representatives from 17 of 27 NCCN Member Institutions (63%) completed an online survey in November 2018 conducted by the NCCN Best Practices Committee. Centers were classified based on number of unique patients seen per year, as large ( &gt; 10,000) (76%), or small ( &lt; 10,000) (34%). The survey focused on institutions’ screening and management practices for patient financial distress, perceived barriers in implementation, and leadership attitudes. Results: Routine screening for financial distress was reported by 77% of centers, and most used social worker assessments (94%). 56% screened patients throughout the cancer journey. Help with drug costs, meal or gas vouchers and payment plans were offered by 100% of centers. Formal pre-authorization programs and assistance with claims and denials was offered by 81%. Charity care for medical costs was provided by 100% of the large centers compared to only 33% of small centers (p = 0.03). Median number of social workers (24 vs. 3; p = 0.01) and pharmacy representatives (6 vs. 2; p = 0.02) was also different between large and small centers. 76% evaluated the impact of financial advocacy services through number of patients assisted (85%), bad debt and charity write-offs (85%) or patient satisfaction surveys (54%). 6% and 12% reported overall effectiveness of institutional practice for screening and management of financial distress as poor/ very poor respectively. Inadequate staffing and real time resources (69%), limited institutional budget (50%), lack of reimbursement (50%), and clinical time constraints (50%) were reported as potential barriers in provision of these services. 94% agreed about stronger integration of financial advocacy services into oncology practice and 84% felt that success of these services should be a quality metric. 31% of large centers vs. 100% of small centers plan to increase staffing in this area in the next 5 years. Conclusions: Majority of NCCN Member Institutions report screening and management programs for financial distress, though the actual practices and range of services vary widely. Information from this study can help centers benchmark their performance relative to similar cancer programs and identify best practices in this area.
Economic burden of multimorbidity in patients with severe asthma: a 20-year population-based study
Authors: Wenjia Chen, Abdollah Safari, J Mark FitzGerald, Don D Sin, Hamid Tavakoli, Mohsen Sadatsafavi
Journal: Thorax (2019)

The economic impact of multimorbidity in severe or difficult-to-treat asthma has not been comprehensively investigated.To estimate the incremental healthcare costs of coexisting chronic conditions (comorbidities) in patients with severe asthma, compared with non-severe asthma and no asthma.Using health administrative data in British Columbia, Canada (1996-2016), we identified, based on the intensity of drug use and occurrence of exacerbations, individuals who experienced severe asthma in an incident year. We also constructed matched cohorts of individuals without an asthma diagnosis and those who had mild/dormant or moderate asthma (non-severe asthma) throughout their follow-up. Health service use records during follow-up were categorised into 16 major disease categories based on the International Classification of Diseases. Incremental costs (in 2016 Canadian Dollars, CAD$1=US$0.75=₤0.56=€0.68) were estimated as the adjusted difference in healthcare costs between individuals with severe asthma compared with those with non-severe asthma and non-asthma.Relative to no asthma, incremental costs of severe asthma were $2779 per person-year (95% CI 2514 to 3045), with 54% ($1508) being attributed to comorbidities. Relative to non-severe asthma, severe asthma was associated with incremental costs of $1922 per person-year (95% CI 1670 to 2174), with 52% ($1003) being attributed to comorbidities. In both cases, the most costly comorbidity was respiratory conditions other than asthma ($468 (17%) and $451 (23%), respectively).Comorbidities accounted for more than half of the incremental medical costs in patients with severe asthma. This highlights the importance of considering the burden of multimorbidity in evidence-informed decision making for patients with severe asthma.
RPB5‐Mediating Protein Promotes Cholangiocarcinoma Tumorigenesis and Drug Resistance by Competing With NRF2 for KEAP1 Binding
Authors: Zheng‐Hua Wan, Tian‐Yi Jiang, Yuan‐Yuan Shi, Yu‐Fei Pan, Yun‐Kai Lin, Yun‐Han Ma, Chun Yang, Xiao‐Fan Feng, Li‐Feng Huang, Xiao‐Ni Kong, Zhi‐Wen Ding, Ye‐Xiong Tan, Li‐Wei Dong, Hong‐Yang Wang
Journal: Hepatology (2019)

Background and Aims Cancer cell survival depends on the balance between reactive oxygen species production and scavenging, which is regulated primarily by NRF2 during tumorigenesis. Here, we demonstrate that deletion of RBP5‐mediating protein (RMP) in an autonomous mouse model of intrahepatic cholangiocarcinoma (ICC) delays tumor progression. Approach and Results RMP‐overexpressing tumor cells exhibited enhanced tolerance to oxidative stress and apoptosis. Mechanistically, RMP competes with NRF2 for binding to the Kelch domain of KEAP1 (Kelch‐like ECH‐associated protein 1) through the E**E motif, leading to decreased NRF2 degradation via ubiquitination, thus increasing NRF2 nuclear translocation and downstream transactivation of antioxidant genes. This RMP‐KEAP1‐NRF2 axis promotes ICC tumorigenesis, metastasis, and drug resistance. Consistent with these findings, the RMP level in human ICC is positively correlated with the protein level of NRF2 and is associated with poor prognosis. Conclusion These findings reveal that RMP is involved in the oxidative stress defense program and could be exploited for targeted cancer therapies.
In treatment-resistant depression, adding esketamine nasal spray to an oral antidepressant improved symptoms at 28 days
Authors: Hemraj Pal
Journal: Annals of Internal Medicine (2019)

Source Citation Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176:428-38. 31109201
Cardiac Magnetic Resonance Imaging Evaluation of Neonatal Bronchopulmonary Dysplasia–associated Pulmonary Hypertension
Authors: Paul J. Critser, Nara S. Higano, Jean A. Tkach, Emilia S. Olson, David R. Spielberg, Paul S. Kingma, Robert J. Fleck, Sean M. Lang, Ryan A. Moore, Michael D. Taylor, Jason C. Woods
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Patients with bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) have increased morbidity and mortality. Noninvasive assessment relies on echocardiograms (echos), which are technically challenging in this population. Improved assessment could augment decisions regarding PH therapies.
The importance of real-life research in respiratory medicine: manifesto of the Respiratory Effectiveness Group
Authors: Nicolas Roche, Antonio Anzueto, Sinthia Bosnic Anticevich, Alan Kaplan, Marc Miravitlles, Dermot Ryan, Joan B. Soriano, Omar Usmani, Nikolaos G. Papadopoulos, G. Walter Canonica
Journal: European Respiratory Journal (2019)

Randomised controlled trials (RCTs) are universally considered as the gold standard for evaluating the efficacy of treatments. Their main strength is that, through randomisation, they avoid any major imbalance between compared groups: therefore, observed outcome differences between groups at the end of the trial are most likely related to treatment effects. Since they are inherently prospective by design, they also permit stability throughout the study to ensure that all conditions remain optimal to test the hypothesis of interest. These include high-quality follow-up, reinforced adherence, etc . Consequently, these studies can reach the highest level of internal validity, provided that all quality standards are followed, such as those defined by CONSORT guidelines [1]. This document has been Endorsed by the International Primary Care Respiratory Group and the World Allergy Organization. The authors wish to thank the Respiratory Effectiveness Group Team (Michael Walker, CEO and Supporter Liaison, Naomi Launders, Senior Scientific Researcher and Sarah Lucas, Researcher) and Oversight Committee (Keith Allan, Trevor Lambert and Nick May).
PEG10 Promoter–Driven Expression of Reporter Genes Enables Molecular Imaging of Lethal Prostate Cancer
Authors: Mariya Shapovalova, John K. Lee, Yingming Li, Donald J. Vander Griend, Ilsa M. Coleman, Peter S. Nelson, Scott M. Dehm, Aaron M. LeBeau
Journal: Cancer Research (2019)

The retrotransposon-derived paternally expressed gene 10 (PEG10) protein is ordinarily expressed at high levels in the placenta. Recently, it was discovered that PEG10 isoforms promote the progression of prostate cancer to a highly lethal androgen receptor (AR)-negative phenotype. The presence of PEG10 in other subtypes of prostate cancer has not been explored and a utility for PEG10 overexpression has not been developed. Here, we found that in addition to AR-null disease, PEG10 was also expressed in prostate cancer with constitutively active AR-splice variants. A molecular genetic imaging strategy for noninvasive imaging of AR-splice variant prostate cancer was developed by utilizing the cancer specificity of the PEG10 promoter to drive the expression of reporter genes. Plasmid insertion of a PEG10 promoter sequence optimized for enhanced output upstream of a reporter gene allowed detection of prostate cancer by near-infrared and positron emission tomography imaging after systemic administration of the plasmid in vivo. PEG10 expressing subcutaneous xenograft and intratibial tumor models were imaged by both modalities using this molecular genetic imaging strategy. This study demonstrates a preclinical proof-of-concept that the PEG10 promoter is a powerful and specific tool that can be utilized for noninvasive detection of aggressive prostate cancer subtypes. SIGNIFICANCE: PEG10 is expressed by prostate cancer with constitutively active AR-splice variants that can be exploited for noninvasive molecular imaging of this aggressive prostate cancer subytpe.
Modulation of Mitochondrial ATP-Dependent K+ Channels by Protein Kinase C
Authors: ToshiakiSato, BrianO’Rourke, EduardoMarbán
Journal: Circulation Research (1998)

Abstract—Pharmacological openers of mitochondrial ATP-dependent K+ (mitoKATP) channels mimic ischemic preconditioning, and such cardioprotection can be prevented by mitoKATP channel blockers. It is also known that protein kinase C (PKC) plays a key role in the induction and maintenance of preconditioning. To look for possible mechanistic links between these 2 sets of observations, we measured mitochondrial matrix redox potential as an index of mitoKATP channel activity in rabbit ventricular myocytes. The mitoKATP channel opener diazoxide (100 μmol/L) partially oxidized the matrix redox potential. Exposure to phorbol 12-myristate 13-acetate (PMA, 100 nmol/L) potentiated and accelerated the effect of diazoxide. These effects of PMA were blocked by the mitoKATP channel blocker 5-hydroxydecanoate, which we verified to be a selective blocker of the mitoKATP channel in simultaneous recordings of membrane current and flavoprotein fluorescence. The inactive control compound 4α-phorbol (100 nmol/L) did not alter t...
Minimal residual disease undetectable by next-generation sequencing predicts improved outcome in CLL after chemoimmunotherapy
Authors: Philip A. Thompson, Jaya Srivastava, Christine Peterson, Paolo Strati, Jeffrey L. Jorgensen, Tyler Hether, Michael J. Keating, Susan M. O’Brien, Alessandra Ferrajoli, Jan A. Burger, Zeev Estrov, Nitin Jain, William G. Wierda
Journal: Blood (2019)
Functional evaluation of the pathological significance of MEFV variants using induced pluripotent stem cell–derived macrophages
Authors: Takeshi Shiba, Takayuki Tanaka, Hiroaki Ida, Misa Watanabe, Haruna Nakaseko, Mitsujiro Osawa, Hirofumi Shibata, Kazushi Izawa, Takahiro Yasumi, Yuri Kawasaki, Megumu K. Saito, Junko Takita, Toshio Heike, Ryuta Nishikomori
Journal: Journal of Allergy and Clinical Immunology (2019)
Effects of mandibular advancement device for obstructive sleep apnea on temporomandibular disorders: A systematic review and meta-analysis
Authors: Anna Alessandri-Bonetti, Francesco Bortolotti, Isabel Moreno-Hay, Ambra Michelotti, Massimo Cordaro, Giulio Alessandri-Bonetti, Jeffrey P. Okeson
Journal: Sleep Medicine Reviews (2019)
Distinct Physiological Characteristics of Isolated Laryngopharyngeal Reflux Symptoms
Authors: Han-Chung Lien, Chen-Chi Wang, John Y. Kao, Hong-Zen Yeh, Jeng-Yuan Hsu, Shou-Wu Lee, Chun-Yi Chuang, Yung-An Tsou, Jung-Der Wang, Michael F. Vaezi, Chi-Sen Chang
Journal: Clinical Gastroenterology and Hepatology (2019)
Treatment of afferent loop syndrome using digital cholangioscopy through the percutaneous transhepatic biliary drainage route
Authors: Ryunosuke Hakuta, Hirofumi Kogure, Yousuke Nakai, Tatsuya Sato, Naminatsu Takahara, Suguru Mizuno, Kazuhiko Koike
Journal: Endoscopy (2019)

A 75-year-old man with peritoneal recurrence of distal bile duct cancer after pancreaticoduodenectomy was admitted because of cholangitis. A computed tomography scan showed obstruction of the afferent limb by peritoneal metastasis and intrahepatic bile duct dilatation without stricture at the hepaticojejunostomy ([Fig. 1]). After the patient’s cholangitis had resolved with percutaneous transhepatic biliary drainage (PTBD), placement of a self-expandable metal stent (SEMS) was planned across the malignant afferent limb stricture through the PTBD route under fluoroscopic guidance. However, a guidewire could not be passed through the stricture because of the tightness of the stricture and the dilated proximal afferent limb ([Fig. 2 a]). Therefore, once the PTBD route had matured, we inserted the digital cholangioscope (SpyGlass DS Direct Visualization System; Boston Scientific Japan, Tokyo, Japan) through the bile duct. Guidewire passage was easily achieved under direct visualization ([Fig. 2 b]), and a SEMS was successfully placed across the stricture ([Fig. 2 c]; [Video 1]).
TIP regimen in metastatic or recurrent esophageal cancer: An Indian experience
Authors: U. Batra, D. C. Doval, V. Talwar, J. B. Sharma, R. Sherali
Journal: Journal of Clinical Oncology (2009)

e15664 Background: Currently, there is no standard regimen for metastatic or recurrent upper or middle squamous cell esophageal cancer. Multiple agents including Taxanes, Ifosfamide have shown significant single agent efficacy in this subset of patients. We therefore undertook this study to test the first-line combination of TIP regimen (Paclitaxel, Ifosfamide and cisplatinum) in patients with metastatic carcinoma of the esophagus. Methods: This study evaluated the efficacy, tolerability and toxicity profile of the TIP regimen in patients with metastatic or recurrent carcinoma of the upper or middle squamous cell carcinoma of esophagus. Patients received Paclitaxel 135 mg/m2, Ifosfamide 1.3 gm/m2 day1–3, CDDP 75 mg/m2( split in day 1–2). Granulocyte Colony stimulating factors were not administered until the patient had prolonged Gr IV neutropenia or febrile neutropenia. Patients were evaluated after 3 cycles and at completion of treatment. Results: A total of 32 patients were treated with TIP regimen. 24 patients completed a median of 4 cycles of which 21 were evaluable for response assessment. 13 patients achieved a major response of which 5 patients had complete response. The median time to tumor progression was 7 months and the median survival was 13 months (range 2–36 months). The regimen was well tolerated with only 1 patient requiring dose reduction.Febrile Neutropenia occurred in 8 patients, all of whom recovered after treatment with antibiotics. There were no reported events of Gr IV peripheral neuropathy or mucositis. There were no treatment related deaths. In addition to the radiological responses, patients who responded had a significant better quality of life. Conclusions: The combination of Paclitaxel, Ifosfamide and Cisplatinum has significant activity in metastatic or recurrent esophageal cancer. This regimen is well tolerated with a high response rate. The ease of administration, cost effectiveness and suitable safety profile makes it an ideal first line regimen in metastatic esophageal cancer. No significant financial relationships to disclose.
India bans e-cigarettes by executive order
Authors: Owen Dyer
Journal: BMJ (2019)

India’s government has announced that it will ban e-cigarettes by cabinet decree, capping a disastrous week for the industry that has seen its potential global market shrink dramatically.

Nirmala Sitharaman, finance minister, announced India’s ban on 18 September—the same day that the media companies CBS, Viacom, and WarnerMedia banned e-cigarette advertising from their channels. CNN also announced an advertising ban last week.

India’s ban came two days after the online stores of Juul Labs, an e-cigarette maker, were delisted without explanation from Chinese websites. Juul, which has been accused by the US Food and Drug Administration of targeting a young demographic, had entered the Chinese market just days before. …
TCT-160 Impact of White Blood Cell Count on Infarct Size and Clinical Outcomes Following Primary PCI: Patient-Level Analysis From 6 Randomized Trials
Authors: Bahira Shahim, Bjorn Redfors, Gennaro Giustino, Shmuel Chen, Ghazaleh Mehdipoor, Aaron Crowley, Manesh Patel, Ingo Eitel, Holger Thiele, Akiko Maehara, Ori Ben-Yehuda, Christopher Granger, E. Magnus Ohman, Gregg Stone
Journal: Journal of the American College of Cardiology (2019)
TCT-427 Meta-Analysis Comparing Safety and Outcomes After Transcatheter Aortic Valve Replacement in Bicuspid Aortic Stenosis
Authors: Srilekha Sridhara, Prajakta Gavhane, Bhavi Pandya, Arnav Kumar, Nidhi Kanwar, Janelle Rodriguez, Meghana Prakash Hiriyur Prakash, Hemang Panchal
Journal: Journal of the American College of Cardiology (2019)