tbuckley/cabot-search huggingface dataset:
Associations between Greenness, Impervious Surface Area, and Nighttime Lights on Biomarkers of Vascular Aging in Chennai, India
Authors: Kevin J. Lane, Eleanor C. Stokes, Karen C. Seto, Sadagopan Thanikachalam, Mohan Thanikachalam, Michelle L. Bell
Journal: Environmental Health Perspectives (2017)

Background: India is undergoing rapid urbanization with simultaneous increases in the prevalence of cardiovascular disease (CVD). As urban areas become home to an increasing share of the world’s population, it is important to understand relationships between the built environment and progression towards CVD. Objective: We assessed associations between multiple measures of the built environment and biomarkers of early vascular aging (EVA) in the Population Study of Urban, Rural and Semiurban Regions for the Detection of Endovascular Disease and Prevalence of Risk Factors and Holistic Intervention Study (PURSE-HIS) in Chennai, India. Methods: We performed a cross-sectional analysis of 3,150 study participants. EVA biomarkers included systolic and diastolic blood pressure (SBP and DBP), central pulse pressure (cPP) and flow-mediated dilatation (FMD). Multiple approaches were used to assign residential exposure to factors of the built environment: Moderate Resolution Imaging Spectroradiometer (MODIS)-derived normalized difference vegetation index (NDVI), a measure of vegetation health and greenness; Landsat-derived impervious surface area (ISA); and Visible Infrared Imaging Radiometer Suite (VIIRS)-derived nighttime lights (NTL). Multivariable regression models were used to assess associations between each built environment measure and biomarkers of EVA, adjusting for age, body mass index (BMI), cooking fuel type, energy intake, sex, physical activity, smoking, socioeconomic status, and stress. Results: Residing in areas with higher ISA or NTL, or lower greenness, was significantly associated with elevated SBP, DBP, and cPP, and with lower FMD, adjusting for age, BMI, sex, smoking status, and other CVD risk factors. An interquartile range decrease in greenness had the largest increase in SBP [4.3 mmHg (95% CI: 2.9, 5.6)], DBP [1.2 mmHg (95% CI: 0.4, 2.0)] and cPP [3.1 mmHg (95% CI: 2.0, 4.1)], and the largest decrease in FMD [−1.5% (95%CI: −2.2%, −0.9%]. Conclusion: Greenness, ISA, and NTL were associated with increased SBP, DBP, and cPP, and with reduced FMD, suggesting a possible additional EVA pathway for the relationship between urbanization and increased CVD prevalence in urban India. https://doi.org/10.1289/EHP541
Triggered intracellular calcium waves in dog and human left atrial myocytes from normal and failing hearts
Authors: Gary L. Aistrup, Rishi Arora, Søren Grubb, Shin Yoo, Benjamin Toren, Manvinder Kumar, Aaron Kunamalla, William Marszalec, Tej Motiwala, Shannon Tai, Sean Yamakawa, Satya Yerrabolu, Francisco J. Alvarado, Hector H. Valdivia, Jonathan M. Cordeiro, Yohannes Shiferaw, John Andrew Wasserstrom
Journal: Cardiovascular Research (2017)

Abnormal intracellular Ca2+ cycling contributes to triggered activity and arrhythmias in the heart. We investigated the properties and underlying mechanisms for systolic triggered Ca2+ waves in left atria from normal and failing dog hearts.Intracellular Ca2+ cycling was studied using confocal microscopy during rapid pacing of atrial myocytes (36 °C) isolated from normal and failing canine hearts (ventricular tachypacing model). In normal atrial myocytes (NAMs), Ca2+ waves developed during rapid pacing at rates ≥ 3.3 Hz and immediately disappeared upon cessation of pacing despite high sarcoplasmic reticulum (SR) load. In heart failure atrial myocytes (HFAMs), triggered Ca2+ waves (TCWs) developed at a higher incidence at slower rates. Because of their timing, TCW development relies upon action potential (AP)-evoked Ca2+ entry. The distribution of Ca2+ wave latencies indicated two populations of waves, with early events representing TCWs and late events representing conventional spontaneous Ca2+ waves. Latency analysis also demonstrated that TCWs arise after junctional Ca2+ release has occurred and spread to non-junctional (cell core) SR. TCWs also occurred in intact dog atrium and in myocytes from humans and pigs. β-adrenergic stimulation increased Ca2+ release and abolished TCWs in NAMs but was ineffective in HFAMs making this a potentially effective adaptive mechanism in normals but potentially arrhythmogenic in HF. Block of Ca-calmodulin kinase II also abolished TCWs, suggesting a role in TCW formation. Pharmacological manoeuvres that increased Ca2+ release suppressed TCWs as did interventions that decreased Ca2+ release but these also severely reduced excitation-contraction coupling.TCWs develop during the atrial AP and thus could affect AP duration, producing repolarization gradients and creating a substrate for reentry, particularly in HF where they develop at slower rates and a higher incidence. TCWs may represent a mechanism for the initiation of atrial fibrillation particularly in HF.
Reply to Alan Dal Pra, Stephane Supiot and Pirus Ghadjar's Letter to the Editor re: Giorgio Gandaglia, Stephen A. Boorjian, William P. Parker, et al. Impact of Postoperative Radiotherapy in Men with Persistently Elevated Prostate-specific Antigen After Radical Prostatectomy for Prostate Cancer: A Long-term Survival Analysis. Eur Urol 2017;72:910–7
Authors: Giorgio Gandaglia, Nicola Fossati, Francesco Montorsi, Alberto Briganti
Journal: European Urology (2017)
Mesenchymal Stromal Cells Expressing Interferon α Limit the Development of Acute Myeloid Leukemia, Inducing Apoptosis In Vitro and In Vivo
Authors: Laura M Desbourdes, Adam J Guess, Suheyla Hasgur, Kathleen M Overholt, Minjun Yu, Satoru Otsuru, Edwin M Horwitz
Journal: Blood (2016)
International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia
Authors: Antoni Torres, Michael S. Niederman, Jean Chastre, Santiago Ewig, Patricia Fernandez-Vandellos, Hakan Hanberger, Marin Kollef, Gianluigi Li Bassi, Carlos M. Luna, Ignacio Martin-Loeches, J. Artur Paiva, Robert C. Read, David Rigau, Jean François Timsit, Tobias Welte, Richard Wunderink
Journal: European Respiratory Journal (2017)

The most recent European guidelines and task force reports on hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) were published almost 10 years ago. Since then, further randomised clinical trials of HAP and VAP have been conducted and new information has become available. Studies of epidemiology, diagnosis, empiric treatment, response to treatment, new antibiotics or new forms of antibiotic administration and disease prevention have changed old paradigms. In addition, important differences between approaches in Europe and the USA have become apparent. The European Respiratory Society launched a project to develop new international guidelines for HAP and VAP. Other European societies, including the European Society of Intensive Care Medicine and the European Society of Clinical Microbiology and Infectious Diseases, were invited to participate and appointed their representatives. The Latin American Thoracic Association was also invited. A total of 15 experts and two methodologists made up the panel. Three experts from the USA were also invited (Michael S. Niederman, Marin Kollef and Richard Wunderink). Applying the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology, the panel selected seven PICO (population–intervention–comparison–outcome) questions that generated a series of recommendations for HAP/VAP diagnosis, treatment and prevention.
Empirical Antimicrobial Therapy in the Neutropenic Host
Authors: Lowell S. Young
Journal: New England Journal of Medicine (1986)

The definitive test of a new empirical antimicrobial regimen is the treatment of bacterial infection in a febrile patient with neutropenia. An increasing number of antimicrobial agents are used for empirical therapy in such patients, and controversy about their clinical use occupies much of the current literature on infectious diseases.1 Because of insecurity or because of theoretical, experimental, or clinical considerations, physicians have usually treated these critically ill patients initially with a combination of drugs — if not two drugs, sometimes three.2 Experimental and clinical evidence supports the use of combinations of drugs. Those that act synergistically in vitro have . . .
モジュール集合による生物医学的応用のための多機能プラットフォームとしての形状記憶特性を有する自己修復超分子bioelastomers【Powered by NICT】
Authors: Wu Yaobin, Wang Ling, Zhao Xin, Hou Sen, Guo Baolin, X Ma Peter
Journal: Biomaterials (2016)
SMCHD1のde novo変異はBosma無鼻小眼球症候群を引き起こし,鼻の発生を阻止する
Authors: Gordon Christopher T, Filali Hicham, Oufadem Myriam, Lyonnet Stanislas, Amiel Jeanne, Bole‐Feysot Christine, Nitschke Patrick, Xue Shifeng, Bonnard Carine, Kong Mung Kei, Reversade Bruno, Yigit Goekhan, Rosin Nadine, Wollnik Bernd, Ratbi Ilham, Elalaoui Siham Chafai, Sefiani Abdelaziz, Chen Kelan, Beck Tamara J, Gurzau Alexandra D, Murphy James M, Blewitt Marnie E, Yoshiura Koh‐ichiro, Mcgowan Ruth, Magee Alex C, Altmueller Janine, Thiele Holger, Nuernberg Peter, Dion Camille, Levy Nicolas, Magdinier Frederique, Meschede Dieter, Muehlbauer Wolfgang, Okamoto Nobuhiko, Varghese Vinod, Irving Rachel, Sigaudy Sabine, Williams Denise, Ragge Nicola, Ahmed S Faisal, Fejjal Nawfal, Fikri Meriem, Reigstad Hallvard, Tuncbilek Goekhan, Teo Audrey S M, Hillmer Axel M, Javed Asif, Cunningham Michael L, Kayserili Huelya, Chatdokmaiprai Chalermpong, Wattanasirichaigoon Duangrurdee
Journal: Nature Genetics (2017)
Prognostic Impact of Margin Distance and Tumor Spread Through Air Spaces in Limited Resection for Primary Lung Cancer
Authors: Kyohei Masai, Hiroyuki Sakurai, Aoi Sukeda, Shigeki Suzuki, Keisuke Asakura, Kazuo Nakagawa, Hisao Asamura, Shun-ichi Watanabe, Noriko Motoi, Nobuyoshi Hiraoka
Journal: Journal of Thoracic Oncology (2017)
Thermosensitive Hydrogel Containing Doxycycline Exerts Inhibitory Effects on Abdominal Aortic Aneurysm Induced By Pancreatic Elastase in Mice
Authors: Maomao Yu, Anjie Dong, Cong Chen, Shuxin Xu, Yini Cao, Shu Liu, Qiang Zhang, Rong Qi
Journal: Advanced Healthcare Materials (2017)

Doxycycline (DOX) is reported to exert therapeutic effects against abdominal aortic aneurysm (AAA), a severe degenerative disease. In this study, a DOX hydrogel formulation of DOX/PECTgel is studied, and its phase transition behavior and in vitro release profiles are explored. In addition, the anti-AAA effects and bioavailability of DOX/PECTgel are evaluated in an elastase induced AAA mouse model. The results show that the phase transition temperature of 30% poly(e-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT) solution is above 34 °C. In vitro release profiles of DOX/PECTgel indicate a fast release of DOX at the first two days, followed by a slow and sustained release for 14 d. In vivo single-dose single subcutaneous injection of DOX/PECTgel containing 8.4 or 4.2 mg mL-1 DOX presents comparatively preventive effects on AAA, compared to intraperitoneal injections of DOX alone at a dose of 15 mg kg-1 for seven injections, while DOX bioavailability of the DOX/PECTgel treated groups is 1.39 times or 1.19 times of the DOX alone treated group, respectively.
pH multistage responsive micellar system with charge-switch and PEG layer detachment for co-delivery of paclitaxel and curcumin to synergistically eliminate breast cancer stem cells
Authors: Zhe Yang, Na Sun, Rui Cheng, Chenyang Zhao, Zerong Liu, Xian Li, Jie Liu, Zhongmin Tian
Journal: Biomaterials (2017)
Novel Fusion Genes at CML Diagnosis Reveal a Complex Pattern of Genomic Rearrangements and Sequence Inversions Associated with the Philadelphia Chromosome in Patients with Early Blast Crisis
Authors: Justine E Marum, Paul PS Wang, Doris Stangl, David T. Yeung, Martin C. Mueller, Christian T. Dietz, Ieuan Walker, Nathalie Nataren, Zoe Donaldson, Wendy T Parker, David M. Ross, Hamish S Scott, Timothy P. Hughes, Andreas W Schreiber, Susan Branford
Journal: Blood (2016)
A phase Ib/II trial of lenvatinib (LEN) plus pembrolizumab (Pembro) in patients (Pts) with endometrial carcinoma.
Authors: Vicky Makker, Drew W. Rasco, Corina E Dutcus, Daniel E. Stepan, Di Li, Emmett V. Schmidt, Robert Charles Shumaker, Matthew H. Taylor
Journal: Journal of Clinical Oncology (2017)

5598 Background: LEN is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptor 1−3, fibroblast growth factor receptor 1−4, platelet-derived growth factor receptor α, RET, and KIT. Pembro, an antibody targeting programmed cell death protein 1 (PD-1), prevents T cell deactivation. In addition to its antiangiogenic effects, LEN may act in part by preventing VEGF-mediated immune suppression, suggesting combination with pembro could improve its activity. We report results in pts with endometrial carcinoma from a phase Ib/II trial of LEN + pembro. Methods: In this multicenter, open-label study, pts had confirmed metastatic endometrial cancer that progressed after approved therapy, measurable disease, and ECOG performance status ≤ 1. Pts received oral LEN 20 mg/day plus pembro 200 mg intravenously every 3 weeks. Tumor assessments were by the investigator. The primary phase II endpoint was objective response rate (ORR) based on immune-related RECIST (irRECIST). Secondary endpoints included progression-free survival (PFS), disease-control rate (DCR; complete response [CR] + partial response [PR] + stable disease [SD]), clinical-benefit rate (CBR; CR + PR + durable SD), and duration of response (DOR), all by irRECIST, and safety. Results: 23 Pts enrolled (phase II: 21; phase Ib: 2); median age was 64 years (range: 51−80); 87% were white; and all had ≥ 1 prior anticancer therapy. Confirmed ORR was 48% (all PR). Median PFS and DOR were not estimable (NE; see table). All pts had a treatment-emergent adverse event (TEAE). The most common TEAEs were hypertension, fatigue, arthralgia, diarrhea, and nausea. Toxicities were manageable with dose interruption and/or modification and no new safety signals were found. Updated data will be presented. Conclusions: Promising efficacy was observed in pts receiving LEN + pembro. In addition, toxicities were generally expected and manageable with dose modification. These results warrant further study of LEN + pembro in pts with endometrial carcinoma. Clinical trial information: NCT02501096. [Table: see text]
The Challenge for Development of Valuable Immuno-oncology Biomarkers
Authors: Janice M. Mehnert, Arta M. Monjazeb, Johanna M.T. Beerthuijzen, Deborah Collyar, Larry Rubinstein, Lyndsay N. Harris
Journal: Clinical Cancer Research (2017)

The development of immunotherapy is an important breakthrough for the treatment of cancer, with antitumor efficacy observed in a wide variety of tumors. To optimize immunotherapy use, approaches must be developed to identify which patients are likely to achieve benefit. To minimize therapeutic toxicities and costs, understanding the ideal choice and sequencing of the numerous immuno-oncology agents available for individual patients is thus critical, but fraught with challenges. The immune tumor microenvironment (TME) is a unique aspect of the response to immuno-oncology agents and measurement of single biomarkers does not adequately capture these complex interactions. Therefore, multiple potential biomarkers are likely needed. Current candidates in this area include PD-L1 expression, CD8+ tumor-infiltrating lymphocytes, tumor mutation load and neoantigen burden, immune-related gene signatures, and multiplex IHC assays that examine the pharmacodynamic and spatial interactions of the TME. The most fruitful investigations are likely to use several techniques to predict response and interrogate mechanisms of resistance. Immuno-oncology biomarker research must employ validated assays to ask focused research questions utilizing clinically annotated tissue collections and biomarker-focused clinical trial designs to investigate specific endpoints. Real-time input from patients and their advocates into biomarker discovery is necessary to ensure that the investigations pursued will improve both clinical outcomes and quality of life. We herein provide a framework of recommendations to guide the search for immuno-oncology biomarkers of value.
Ultrasound-induced mild hyperthermia improves the anticancer efficacy of both Taxol® and paclitaxel-loaded nanocapsules
Authors: Tanguy Boissenot, Alexandre Bordat, Benoît Larrat, Mariana Varna, Hélène Chacun, Angelo Paci, Vianney Poinsignon, Elias Fattal, Nicolas Tsapis
Journal: Journal of Controlled Release (2017)
First-in-Human Phase I Study of the Tamoxifen Metabolite Z-Endoxifen in Women With Endocrine-Refractory Metastatic Breast Cancer
Authors: Matthew P. Goetz, Vera J. Suman, Joel M. Reid, Don W. Northfelt, Michael A. Mahr, Andrew T. Ralya, Mary Kuffel, Sarah A. Buhrow, Stephanie L. Safgren, Renee M. McGovern, John Black, Travis Dockter, Tufia Haddad, Charles Erlichman, Alex A. Adjei, Dan Visscher, Zachary R. Chalmers, Garrett Frampton, Benjamin R. Kipp, Minetta C. Liu, John R. Hawse, James H. Doroshow, Jerry M. Collins, Howard Streicher, Matthew M. Ames, James N. Ingle
Journal: Journal of Clinical Oncology (2017)

Purpose Endoxifen is a tamoxifen metabolite with potent antiestrogenic activity. Patients and Methods We performed a phase I study of oral Z-endoxifen to determine its toxicities, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity. Eligibility included endocrine-refractory, estrogen receptor-positive metastatic breast cancer. An accelerated titration schedule was applied until moderate or dose-limiting toxicity occurred, followed by a 3+3 design and expansion at 40, 80, and 100 mg per day. Tumor DNA from serum (circulating cell free [cf); all patients] and biopsies [160 mg/day and expansion]) was sequenced. Results Of 41 enrolled patients, 38 were evaluable for MTD determination. Prior endocrine regimens during which progression occurred included aromatase inhibitor (n = 36), fulvestrant (n = 21), and tamoxifen (n = 15). Patients received endoxifen once daily at seven dose levels (20 to 160 mg). Dose escalation ceased at 160 mg per day given lack of MTD and endoxifen concentrations > 1,900 ng/mL. Endoxifen clearance was unaffected by CYP2D6 genotype. One patient (60 mg) had cycle 1 dose-limiting toxicity (pulmonary embolus). Overall clinical benefit rate (stable > 6 months [n = 7] or partial response by RECIST criteria [n = 3]) was 26.3% (95% CI, 13.4% to 43.1%) including prior tamoxifen progression (n = 3). cfDNA mutations were observed in 13 patients ( PIK3CA [n = 8], ESR1 [n = 5], TP53 [n = 4], and AKT [n = 1]) with shorter progression-free survival ( v those without cfDNA mutations; median, 61 v 132 days; log-rank P = .046). Clinical benefit was observed in those with ESR1 amplification (tumor; 80 mg/day) and ESR1 mutation (cfDNA; 160 mg/day). Comparing tumor biopsies and cfDNA, some mutations ( PIK3CA, TP53, and AKT) were undetected by cfDNA, whereas cfDNA mutations ( ESR1, TP53, and AKT) were undetected by biopsy. Conclusion In endocrine-refractory metastatic breast cancer, Z-endoxifen provides substantial drug exposure unaffected by CYP2D6 metabolism, acceptable toxicity, and promising antitumor activity.
Impact of combined PET/CT on radiotherapy treatment planning and outcomes in esophageal cancer.
Authors: Sweet Ping Ng, Jennifer Tan, Glen Osbourne, Luke Williams, Mathias Bressel, Rodney J Hicks, Eddie Lau, Julie Chu, Sam Ngan, Trevor Leong
Journal: Journal of Clinical Oncology (2016)

e15519 Background: To date, there is no universally accepted method to accurately delineate the gross tumor volume (GTV) of primary esophageal cancer in patients undergoing radiotherapy (RT). This prospective study aims to determine the impact of PET/CT on RT planning and outcomes in patients with localized esophageal cancer. Methods: 57 eligible patients with localized esophageal cancer were recruited between June 2003 and May 2008. All underwent PET/CT scanning in the RT treatment position and received treatment planned using the PET/CT dataset. Of these, 13 (23%) had metastatic disease detected on PET and 3 patients had no radical RT, while another 3 patients had missing planning PET/CT data (excluded from planning component analysis). GTV was defined separately on PET/CT (GTV-PET) and CT (GTV-CT) data sets. A corresponding planning target volume (PTV) was generated for each patient. Volumetric and spatial analysis quantified the proportion of FDG-avid disease not included in CT-based volumes. Clinical data was collected for 38 patients treated radically to determine locoregional control and overall survival rates. Results: Mean age was 67 years (range: 32 - 88). Median follow up was 4 years (range: 2.7 – 6.8). FDG-avid disease would have been excluded from GTV-CT in 29 patients (76%; median volume = 17%, range: 1-100%). In 5 patients, FDG-avid disease would have been completely excluded from the PTV-CT (Grade 1 geographic miss; median volume = 6%, range: 2-92%). For 8 patients, less than 95% of PTV-PET would have received at least 95% of prescription dose based on the CT-based plan (Grade 2 geographic miss). GTV-CT underestimated the cranial and caudal extent of FDG-avid tumor in 14 (37%) and 10 (26%) patients respectively. There were no significant differences in radiation doses to the lungs and liver. 5-year overall survival and locoregional failure free survival were 24% and 42% respectively. Conclusions: PET/CT prevented futile RT for 1 in 4 patients and avoided geographic misses without significant impact on dose-limiting tissues in apparently localized esophageal cancer. However, survival remains suboptimal and indicates the need for further improvement in planning and therapeutic paradigms.
Detection of minimal residual disease in FLT3/ITD AML.
Authors: Mark J. Levis, Jeffrey Edward Miller, Zhiyi Xie, Valerie McClain, Andrew R. Carson, Tim Stenzel
Journal: Journal of Clinical Oncology (2016)

7015 Background: FLT3/ITD mutations are common in AML and confer a poor prognosis. A sensitive, specific assay for the detection of minimal residual disease (MRD) in FLT3/ITD AML could guide decisions on transplant or maintenance therapy. To date, assays for MRD in FLT3/ITD AML have not been useful due to limited sensitivity. We have developed a sensitive and specific MRD assay for FLT3/ITD mutations using next-generation sequencing (NGS). Methods: Exons 14 and 15 are amplified by PCR and the products were detected by a refined NGS technique developed at Invivoscribe, Inc. Initial validation was carried out by spiking in fixed amounts of mutant DNA into wild type DNA to establish a sensitivity equivalent to detection of at least one ITD-containing cell out of 10,000 with a minimum input of 100,000 cell equivalents of DNA. We validated the assay using marrow from patients with FLT3/ITD AML in CR. The investigator conducting the MRD assay was blind to all clinical and laboratory data. Results: In all samples, the standard CLIA-certified assay for the FLT3/ITD mutation was negative and no leukemia was evident by morphology. In 4 samples from patients in first CR prior to consolidation, the mutation was detected with levels ranging from 1.35E-05 to 1.74E-04 mutant ITD reads/total reads. In 3 patients who had relapsed and had achieved CR2, the mutation was detected at levels ranging from 1.38E-06 to 1.11E-04. The next 6 samples were collected during post-transplant surveillance from patients who had undergone transplant in CR. No mutation was detected in any of these patients, all 6 of whom are alive and disease free 2.5-5.5 years after transplant. Finally, in 2 samples from patients transplanted in CR1 (both of whom were in morphologic CR with 100% donor chimerism in marrow and T-cells), the MRD assay detected the mutations at levels of 3.67E-03 and 1.04E-04, respectively. Both patients relapsed with FLT3/ITD AML within 6 months of these specimens being collected. Conclusions: This novel MRD assay is specific, and is 2 orders of magnitude more sensitive than current commercially available assays for FLT3/ITD mutations. We anticipate that this assay will be broadly available to the public soon, and will have a significant impact in the clinical management of this disease.