tbuckley/cabot-search huggingface dataset:
Cryotherapy for nodal metastasis in NSCLC with acquired resistance to immunotherapy
Authors: Lucas C. Adam, Junaid Raja, Johannes M. Ludwig, Adebowale Adeniran, Scott N. Gettinger, Hyun S. Kim
Journal: Journal for ImmunoTherapy of Cancer (2018)

Novel approaches with checkpoint inhibitors in immunotherapy continue to be essential in the treatment of non-small cell lung cancer (NSCLC). However, the low rate of primary response and the development of acquired resistance during the immunotherapy limit their long-term effectiveness. The underlying cause of acquired resistance is poorly understood; potential management strategies for patients with acquired resistance are even less clear. Here, we report the case of a 75-year-old female smoker with cough, fatigue, and weight loss that was found to have an 8.6 cm right upper lobe lung lesion with local invasion, adenopathy, and a malignant pericardial effusion. This lesion was biopsied and identified to be cT3N3M1b squamous cell cancer of the lung without any recognizable PD-L1 expression on tumor cells. For her metastatic NSCLC, the patient underwent two lines of conventional chemotherapy before initiation of combination immunotherapy with an anti-PD-L1 and anti-CTLA-4 antibody. Though she initially achieved a response, she thereafter progressed and developed immunotherapy resistant lymph nodal metastasis. While cervical lymph nodes could be surgically removed, another metastasis in an aortocaval area required a more sensitive therapy like thermal ablation. The aortocaval node was partially treated with a single treatment of cryotherapy and demonstrated durable complete response. Cryotherapy for checkpoint immunotherapy resistant metastasis appears to be a safe and feasible treatment for treating metastatic disease in non-small cell lung cancer. The prospect of cryotherapy adjuvancy may enable local control of metastatic disease after initial response to immune checkpoint immunotherapy and may impact on overall outcomes.
Abstract 14784: Effect of Lifestyles of Children and Their Parents on the Levels of Cardiovascular Risk Factors in Elementary School Children
Authors: Masao Yoshinaga, Ayumi Miyazaki, Machiko Aoki, Yoshiya Ito, Toshihide Kubo, Takashi Hamajima, Hitoshi Horigome, Hideto Takahashi, Mari Iwamoto, Hiromitus Ogata, Masakuni Tokuda, Tomoko Tachikawa, Nobuyuki Koriyama, Mitsuhiko Hara, Masaki Shinomiya, Masami Nagashima, Masami Nagashima
Journal: Circulation (2014)

Background and Objectives: Recently, the prevalence of obese children is declining in Japan; however, longitudinal studies showed that the prevalence of obesity is still increasing during elementary school periods. Therefore, the present study aimed to evaluate the effect of lifestyles of children and their parents on the levels of cardiovascular (CV) risk factors in elementary school children. Subjects: The study have conducted since 2012 and announced through the local boards of education in seven areas in Japan. The study was included 1114 healthy volunteers (540 boys, 574 girls) aged from 6 to 12 years with a medical examination and a questionnaire. The medical examination included the measurement of height, weight, waist circumference, and blood pressures, and blood sampling for CV risk factors. The questionnaire collected data on the lifestyles of the subjects and their parents. Screen time included time spent watching TV and playing games. The subjects were asked to walk with pedometer for 7 days. Obesity in the present study was defined using the age- and sex-specific International Obesity Task Force standard. Results: Multivariate regression analyses showed that number of steps by pedometer measurement, screen time, sleeping time, and parental BMI were significantly and independently associated with the levels of one or more CV risk factors in elementary school children. Among these, screen time had a profound adverse effect on CV risk factor levels. Number of steps was positively associated with sleeping time and negatively associated with screen time. Screen time in children was strongly associated with parental screen time. The risk of obesity in boys was associated with paternal obesity (p=0.000), but not with maternal obesity (p=0.95). On the other hand, the risk of obesity in girls was associated with both paternal and maternal obesity (both p=0.000). Conclusions: Increase in number of steps and sleeping time and decrease in screen time may be the first-line approach for elementary school children to maintain favorable CV risk factor levels. An association between childhood obesity and paternal or maternal obesity and differs between genders in Japan; thus, approaches focusing on parents should take the gender of children into consideration.
Cytokine-induced endogenous production of prostaglandin D2 is essential for human group 2 innate lymphoid cell activation
Authors: Jovana Maric, Avinash Ravindran, Luca Mazzurana, Aline Van Acker, Anna Rao, Efthymia Kokkinou, Maria Ekoff, Dominique Thomas, Alexander Fauland, Gunnar Nilsson, Craig E. Wheelock, Sven-Erik Dahlén, Nerea Ferreirós, Gerd Geisslinger, Danielle Friberg, Akos Heinemann, Viktoria Konya, Jenny Mjösberg
Journal: Journal of Allergy and Clinical Immunology (2018)
P089 An EGFR KDD Data in the Chinese NSCLC Population and the Response to EGFR-TKIs: A Multicenter Study
Authors: W. Wang, C. Xu, Y. Zhu, M. Fang, W. Zhuang, Y. Chen, G. Chen, T. Lv, Y. Song
Journal: Journal of Thoracic Oncology (2018)
Blood endotyping distinguishes the profile of vitiligo from that of other inflammatory and autoimmune skin diseases
Authors: Tali Czarnowicki, Helen He, Alexandra Leonard, Hyun Je Kim, Naoya Kameyama, Ana B. Pavel, Randall Li, Yeriel Estrada, Huei-Chi Wen, Grace W. Kimmel, Hee J. Kim, Margot Chima, Mark Lebwohl, James G. Krueger, Emma Guttman-Yassky
Journal: Journal of Allergy and Clinical Immunology (2018)
A Horizon Scan of Emerging Issues for Global Conservation in 2019
Authors: William J. Sutherland, Steven Broad, Stuart H.M. Butchart, Stewart J. Clarke, Alexandra M. Collins, Lynn V. Dicks, Helen Doran, Nafeesa Esmail, Erica Fleishman, Nicola Frost, Kevin J. Gaston, David W. Gibbons, Alice C. Hughes, Zhigang Jiang, Ruth Kelman, Becky LeAnstey, Xavier le Roux, Fiona A. Lickorish, Kathryn A. Monk, Diana Mortimer, James W. Pearce-Higgins, Lloyd S. Peck, Nathalie Pettorelli, Jules Pretty, Colleen L. Seymour, Mark D. Spalding, Jonathan Wentworth, Nancy Ockendon
Journal: Trends in Ecology & Evolution (2018)
Abstract 18471: Risk of Ventricular Arrhythmias, ICD Shock, and Death According to Diuretic Therapy in Patients With Mild Systolic Heart Failure and Prolonged QRS
Authors: Jason Costa, Yitschak Biton, Valentina Kutyifa, Scott McNitt, Slava Polonsky, Arthur J Moss
Journal: Circulation (2017)

Introduction: Chronic loop diuretic therapy has been associated with increased risk of adverse outcomes in patients with systolic heart failure, including sudden cardiac death. Conversely, there is...
A Phase I, Open-Label Study to Evaluate the Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity of PF-06863135, a B-Cell Maturation Antigen/CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Advanced Multiple Myeloma
Authors: Alexander M. Lesokhin, Noopur Raje, Cristina J Gasparetto, Justine Walker, Heike I. Krupka, Tenshang Joh, Carrie T. Taylor, Andrzej Jakubowiak
Journal: Blood (2018)
Intratumoral G100 Induces Systemic Immunity and Abscopal Tumor Regression in Patients with Follicular Lymphoma: Results of a Phase 1/ 2 Study Examining G100 Alone and in Combination with Pembrolizumab
Authors: Christopher Flowers, Carlos Panizo, Iris Isufi, Alex F. Herrera, Craig Okada, Elizabeth H. Cull, Bela Kis, Jorge M. Chaves, Nancy L. Bartlett, Weiyun Ai, Luis de la Cruz-Merino, Locke J. Bryan, Roch Houot, Kim Linton, Javier Briones, Ian Chau, Gottfried R. von Keudell, Hailing Lu, Frank J Hsu, Ahmad S. Halwani
Journal: Blood (2017)
Updated 18-Month Results from Dasfree: A Study Evaluating Dasatinib Discontinuation in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and Deep Molecular Response (DMR)
Authors: Neil P. Shah, Jose Valentín García Gutiérrez, Antonio Jiménez-Velasco, Sarah Larson, Susanne Saussele, Delphine Rea, François-Xavier Mahon, Moshe Yair Levy, María Teresa Gómez-Casares, Fabrizio Pane, Franck-Emmanuel Nicolini, Michael J. Mauro, Oumar Sy, Patricia Martin Regueira, Jeffrey H. Lipton
Journal: Blood (2018)
Abstract 17250: Ranolazine Use Following Initial Anti-anginal Therapy Is Associated With Lower Health Resource Utilization Among U.S. Veterans With Chronic Stable Angina
Authors: Adam Bress, John Dodson, Brian Sauer, Scott DuVall, Jacob Crook, Thomas Reese, Cindy Hartsfield, Bruce Koch, Richard Nelson, Joanne LaFleur
Journal: Circulation (2015)

Introduction: While clinical trials show improvement in angina symptoms with ranolazine, it is unclear whether this improvement translates into reduced health resource utilization (HRU). We, therefore, sought to analyze whether HRU declined at one year after ranolazine initiation within a large integrated health system. Methods: This was a historical cohort study using nationwide Department of Veterans Affairs (VA) data. We compared participants with a diagnosis of coronary artery disease and chronic stable angina who were prescribed ranolazine, as monotherapy or add-on, following an initial trial of ≥ 1 anti-anginal agent versus alternative secondary agents between 01/01/2006 and 12/31/2013. We addressed confounding through inverse probability (IP) of treatment weighting. We used IP-weighted regression models to evaluate adjusted risk ratios and incident rate ratios for coronary revascularizations, hospitalizations, emergency room (ER) visits, and costs within one year. Results: Of 37,060 patients identified, IP weighted treatment groups comprised 4,766 patients prescribed ranolazine and 32,261 prescribed an alternative agent as their second or third anti-anginal. There were no significant differences in baseline characteristics between treatment groups after IP weighting. In the IP-weighted outcome analysis, coronary artery bypass graft surgeries were significantly lower with ranolazine. All-cause, atrial fibrillation (AF) and heart failure (HF) specific hospitalizations, and total costs were significantly lower in the ranolazine group. Conclusions: Among patients with CSA prescribed a second or third anti-anginal pharmacotherapy, ranolazine was associated with fewer all-cause hospitalizations, hospitalizations for AF and HF, ER visits and total costs. These findings suggest that the reduction in angina symptoms seen in other studies of ranolazine may translate into lower HRU compared to conventional pharmacotherapies.
An overview of the 6th World Symposium on Pulmonary Hypertension
Authors: Nazzareno Galiè, Vallerie V. McLaughlin, Lewis J. Rubin, Gerald Simonneau
Journal: European Respiratory Journal (2018)

Since 1973 the World Symposia on Pulmonary Hypertension (WSPH) proceedings have summarised the scientific advances and future needs in this field through the efforts of multiple task forces, each focusing on a different aspect of pulmonary hypertension (PH) [1]. The 6th WSPH comprised 124 experts, divided into 13 task forces, that began their work in January 2017 and presented their consensus opinions to an audience of 1376 participant attendees between February 27 and March 1, 2018 in Nice, France. A newly created task force dedicated to patients' perspectives, including representatives of patients' associations worldwide, was added for the 6th WSPH. State of the art summary on diagnosis, prognosis, therapy and future perspectives of pulmonary hypertension <http://ow.ly/8MHN30mGtqs>
Kir4.1/Kir5.1 Activity Is Essential for Dietary Sodium Intake–Induced Modulation of Na-Cl Cotransporter
Authors: Peng Wu, Zhong-Xiuzi Gao, Xiao-Tong Su, Ming-Xiao Wang, Wen-Hui Wang, Dao-Hong Lin
Journal: Journal of the American Society of Nephrology (2018)

Significance Statement Considerable evidence indicates that basolateral inwardly rectifying potassium channel Kir4.1/Kir5.1 is essential for membrane transport in the distal convoluted tubule (DCT), and that dietary sodium and potassium are important in regulating activity of the thiazide-sensitive Na-Cl cotransporter (NCC). In mouse studies, the authors found that stimulation of NCC induced by sodium restriction was associated with increasing Kir4.1/Kir5.1 activity in the DCT and membrane hyperpolarization; NCC inhibition induced by high sodium intake was associated with decreasing Kir4.1/Kir5.1 activity in the DCT and membrane depolarization. In kidney-specific Kir4.1 knockout mice, the effect of dietary sodium on NCC activity was largely abolished, as were its effects on DCT membrane conductance and potential. The findings indicate that Kir4.1/Kir5.1 is essential for mediating dietary sodium intake–induced modulation of NCC function. Background Dietary sodium intake regulates the thiazide-sensitive Na-Cl cotransporter (NCC) in the distal convoluted tubule (DCT). Whether the basolateral, inwardly rectifying potassium channel Kir4.1/Kir5.1 (a heterotetramer of Kir4.1/Kir5.1) in the DCT is essential for mediating the effect of dietary sodium intake on NCC activity is unknown. Methods We used electrophysiology, renal clearance techniques, and immunoblotting to examine effects of Kir4.1/Kir5.1 in the DCT and NCC in wild-type and kidney-specific Kir4.1 knockout mice. Results Low sodium intake stimulated basolateral Kir4.1/Kir5.1 activity, increased basolateral K + conductance, and hyperpolarized the membrane. Conversely, high sodium intake inhibited the potassium channel, decreased basolateral K + currents, and depolarized the membrane. Low sodium intake increased total and phosphorylated NCC expression and augmented hydrochlorothiazide-induced natriuresis; high sodium intake had opposite effects. Thus, elevated NCC activity induced by low sodium intake was associated with upregulation of Kir4.1/Kir5.1 activity in the DCT, whereas inhibition of NCC activity by high sodium intake was associated with diminished Kir4.1/Kir5.1 activity. In contrast, dietary sodium intake did not affect NCC activity in knockout mice. Further, Kir4.1 deletion not only abolished basolateral K + conductance and depolarized the DCT membrane, but also abrogated the stimulating effects induced by low sodium intake on basolateral K + conductance and hyperpolarization. Finally, dietary sodium intake did not alter urinary potassium excretion rate in hypokalemic knockout and wild-type mice. Conclusions Stimulation of Kir4.1/Kir5.1 by low intake of dietary sodium is essential for NCC upregulation, and inhibition of Kir4.1/Kir5.1 induced by high sodium intake is a key step for downregulation of NCC.
Abstract 14673: Imaging of Hypoxia and Inflammation in Carotid Atherosclerosis With 18F-Fluoromisonidazole and 18F-Fluorodeoxyglucose Positron Emission Tomography
Authors: Francis R Joshi, Roido Manavaki, Tim D Fryer, John R Buscombe, Rob Smith, Nichola Figg, Jonathan H Gillard, Victoria E Young, Martin J Graves, Franklin I Aigbirhio, Anthony Davenport, Peter J Kirkpatrick, Elizabeth A Warburton, James H Rudd
Journal: Circulation (2013)

Background: Positron emission tomography (PET) imaging of atherosclerosis with 18F-fluorodeoxyglucose (FDG) gives a non-invasive surrogate of inflammation. FDG PET can be used to track the response...
Abstract 14037: Impact of Medication Synchronization Programs on Adherence, Clinical Outcomes, and Healthcare Resource Utilization
Authors: Alexis A Krumme, Robert J Glynn, Sebastian Schneeweiss, Joshua J Gagne, J. S Dougherty, Gregory Brill, Niteesh K Choudhry
Journal: Circulation (2017)

Introduction: The burden of filling complex cardiovascular medication regimens is an important barrier to adherence. Pharmacy-based medication synchronization programs simplify the refill process b...
A Matching-Adjusted Indirect Treatment Comparison of Daratumumab-Bortezomib-Melphalan-Prednisone Versus Lenalidomide-Dexamethasone Continuous, Lenalidomide-Dexamethasone 18 Months, and Melphalan-Prednisone-Thalidomide
Authors: Meletios A Dimopoulos, Michele Cavo, Maria-Victoria Mateos, Thierry Facon, Bart Heeg, Sophie van Beekhuizen, Sandhya Nair, Marta Pisini, Annette Lam, Mary Slavcev
Journal: Blood (2018)
Abstract 19083: Macrophage Expression of Pcsk9 Influences Atherosclerosis Development
Authors: Ilaria Giunzioni, Hagai Tavori, Roman Covarrubias, Amy Major, MacRae F Linton, Sergio Fazio
Journal: Circulation (2013)

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory protein that regulates low-density lipoprotein (LDL) cholesterol levels by binding and degrading hepatic LDL receptor (LDLR), thus contributing to atherosclerosis. Little is known of PCSK9 effect in macrophages and whether this contributes to the development of the atheroma. First, we demonstrated that murine peritoneal macrophages (MPM) express endogenous (m) PCSK9 both at the mRNA and protein level. Then, to test the effect of human (h) PCSK9 on atherosclerosis we developed transgenic mice expressing hPCSK9 from multiple tissues and cells, including macrophages. As it occurs in hepatocytes, hPCSK9 reduced LDLR levels in MPM. The effect on LDLR was more evident in resident than in elicited MPM, and was completely abolished after culturing MPM in medium containing FBS or LPDS, that cause LDLR upregulation. Co-immunoprecipitation experiments showed a direct interaction of hPCSK9 with LDL-R. In addition, we found that PCSK9 also interacts with LRP-1, a member of the LDL-R gene family involved in modulation of inflammatory responses and cell survival. It has been recently reported that PCSK9 reduces LRP1 levels in transduced renal HEK293T cells. However, we found that the interaction of hPCSK9 with LRP1 did not affect either total or membrane levels of the receptor. Surprisingly, analyses of spleen lysates from hPCSK9 transgenics revealed an increase in the percentage of Ly6C hi and CD11b positive cells compared with WT. To study the effect of macrophage PCSK9 in the atheroma, bone marrow from hPCSK9/apoE -/- or apoE -/- mice was transplanted into apoE -/- recipients. Low levels of hPCSK9 were detected in serum of hPCSK9/apoE -/- marrow recipients, but no effects on cholesterol were noted. Although lesion size was not different, lesion composition analyses showed a higher percentage of Ly6C hi positive cells in recipients of hPCSK9/apoE -/- marrow compared to controls (7.4±1.5% vs. 5.6±1.1%, respectively, p &lt;0.05). Our results show for first time that PCSK9 expression by macrophages directly influences atherosclerotic plaque composition in the absence of changes in serum cholesterol levels, suggesting a direct effect of macrophage PCSK9 in inflammation and plaque development.
Manchester’s landmark devolution deal needs more teeth to succeed, say researchers
Authors: Gareth Iacobucci
Journal: BMJ (2018)

A landmark devolution deal that gave Manchester control of its £6bn health and social care budget will require legislation from central government to fully realise its potential, researchers have concluded.1

The Greater Manchester Health and Social Care Partnership was formed in 2016 to develop a shared plan to integrate health and social care for a population of 2.8 million across Greater Manchester.2 Comprising 35 organisations, including 10 clinical commissioning groups and local authorities, it set out to improve health outcomes with the backing of £450m in transformation funding from NHS England over a five year period.

But a report by University of Manchester experts has concluded that it is too soon to …
A point-of-care diagnostic for differentiating Ebola from endemic febrile diseases
Authors: David Sebba, Alexander G. Lastovich, Melody Kuroda, Eric Fallows, Joshua Johnson, Ambroise Ahouidi, Anna N. Honko, Henry Fu, Rex Nielson, Erin Carruthers, Cyrille Diédhiou, Doré Ahmadou, Barré Soropogui, John Ruedas, Kristen Peters, Miroslaw Bartkowiak, N’Faly Magassouba, Souleymane Mboup, Yanis Ben Amor, John H. Connor, Kristin Weidemaier
Journal: Science Translational Medicine (2018)

A multiplexed point-of-care diagnostic using surface-enhanced Raman scattering detects Ebola, Lassa, and malaria in blood and serum samples.
Alpelisib Plus Fulvestrant in <i>PIK3CA</i>-Altered and <i>PIK3CA</i>-Wild-Type Estrogen Receptor–Positive Advanced Breast Cancer
Authors: Dejan Juric, Filip Janku, Jordi Rodón, Howard A. Burris, Ingrid A. Mayer, Martin Schuler, Ruth Seggewiss-Bernhardt, Marta Gil-Martin, Mark R. Middleton, José Baselga, Douglas Bootle, David Demanse, Lars Blumenstein, Karl Schumacher, Alan Huang, Cornelia Quadt, Hope S. Rugo
Journal: JAMA Oncology (2018)

The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in patients with estrogen receptor-positive (ER+), endocrine therapy-resistant breast cancers.To assess the maximum tolerated dose (MTD), safety, and activity of alpelisib, an oral, PI3Kα-specific inhibitor, plus fulvestrant in patients with ER+ advanced breast cancer (ABC).An open-label, single-arm, phase 1b study of alpelisib plus fulvestrant was conducted at 10 centers in 5 countries. Participants were 87 postmenopausal women with PIK3CA-altered or PIK3CA-wild-type ER+ ABC, whose cancer progressed during or after antiestrogen therapy. The study began enrolling patients October 5, 2010, and the data cutoff was March 22, 2017.Escalating doses of alpelisib were administered once daily, starting at 300 mg, plus fixed-dose fulvestrant, 500 mg, in the dose-escalation phase; alpelisib at the recommended phase 2 dose plus fulvestrant in the dose-expansion phase.The primary end point was determination of the MTD of once-daily alpelisib plus fulvestrant. Secondary end points included safety and preliminary activity.From October 5, 2010, to March 22, 2017, 87 women (median age: 58 years [range, 37-79 years]; median of 5 prior lines of antineoplastic therapy) received escalating once-daily doses of alpelisib (300 mg, n = 9; 350 mg, n = 8; 400 mg, n = 70) plus fixed-dose fulvestrant (500 mg). During dose escalation, dose-limiting toxic effects were reported in 1 patient (alpelisib, 400 mg): diarrhea (grade 2), vomiting, fatigue, and decreased appetite (all grade 3). The MTD of alpelisib when combined with fulvestrant was 400 mg once daily, and the recommended phase 2 dose was 300 mg once daily. Overall, the most frequent grade 3/4 adverse events with alpelisib, 400 mg, once daily (≥10% of patients), regardless of causality, were hyperglycemia (19 [22%]) and maculopapular rash (11 [13%]); 9 patients permanently discontinued therapy owing to adverse events. Median progression-free survival at the MTD was 5.4 months (95% CI, 4.6-9.0 months). Median progression-free survival with alpelisib, 300 to 400 mg, once daily plus fulvestrant was longer in patients with PIK3CA-altered tumors (9.1 months; 95% CI, 6.6-14.6 months) vs wild-type tumors (4.7 months; 95% CI, 1.9-5.6 months). Overall response rate in the PIK3CA-altered group was 29% (95% CI, 17%-43%), with no objective tumor responses in the wild-type group.Alpelisib plus fulvestrant has a manageable safety profile in patients with ER+ ABC, and data suggest that this combination may have greater clinical activity in PIK3CA-altered vs wild-type tumors.ClinicalTrials.gov identifier: NCT01219699.