tbuckley/cabot-search huggingface dataset:
A phase 2 trial of regorafenib as a single agent in patients with chemotherapy refractory advanced and metastatic biliary adenocarcinoma/cholangiocarcinoma.
Authors: Weijing Sun, Daniel Paul Normolle, Nathan Bahary, James Ohr, Barry C. Lembersky, Krishna Patel, Anuj K. Patel, James J. Lee, Edward Chu, Natalie Streeter, Summer Drummond, John P. Morcos, Matthew Gerard Sulecki, David A. Geller, J. Wallis Marsh, Allan Tsung, Herbert Zeh
Journal: Journal of Clinical Oncology (2017)

4081 Background: Biliary adenocarcinoma/cholangiocarcinoma is a rare but aggressive neoplasm. Most patients present with unresectable or metastatic disease with 5-year survival rate ~5%. No second-line regimen has demonstrated clinical benefit in this disease. Regorafenib is an oral multi-kinase inhibitor with potent antitumor activity. This single arm phase II study evaluates the efficacy and safety of regorafenib as a single agent in advanced or metastatic biliary carcinoma/cholangiocarcinoma pts who failed systemic chemotherapy. Methods: Patients with ECOG PS 0-1and adequate liver, kidney and bone marrow function were given regorafenib orally once daily, 21 days on and 7 days off in a 28-day cycle. The initial dose of 160 mg was given to the first 3 patients. After toxicity assessment, the dose was reduced to 120 mg for the subsequent pts. The primary endpoint is PFS with the null hypotheses of 2.0 months, and median PFS ≥3.5 months as evidence of the study drug activity (α = 0.10, 80% power). Secondary objectives include OS, RR, and DCR. Results: Thirty-seven patients received at least one dose of regorafenib, of whom 28 were evaluable for efficacy. All had previous gemcitabine/cisplatin treatment. The mean age was 62.5 (34.5-82.8) with 17 (46%) females. PR was achieved in 3 (10.7%), SD in 18 (64.3%, with DCR of 75%), and PD in 7 (25%). For all 37 patients, median PFS was 3.55 months (95% CI = 2.1- 5.72) and mOS was 5.55 months (95% CI = 4.04 -NA) with survival rate of 42 % at 12 months, and 38% at 18 months. Medan PFS and OS of 30 patients who had ≥1 cycle were 3.91 months (95% CI = 3.55-9.79) and 13.4 months (95% CI = 5.06 - NA), respectively. The overall toxicity profile was as expected, with G3/4 AE’s of 40.5%. The most common toxicities were HTN, hypophosphatemia, hand-foot skin reaction, and increased serum bilirubin. Dose modification was required in 11 (30.6%) patients. Tumor samples were collected in 80% of patients, with planned correlative studies underway. Conclusions: This study showed promising efficacy of regorafenib in chemotherapy refractory advanced/metastatic cholangiocarcinoma. Further studies to confirm the clinic efficacy are recommended. Clinical trial information: NCT02053376.
Exposure to Road, Railway, and Aircraft Noise and Arterial Stiffness in the SAPALDIA Study: Annual Average Noise Levels and Temporal Noise Characteristics
Authors: Maria Foraster, Ikenna C. Eze, Emmanuel Schaffner, Danielle Vienneau, Harris Héritier, Simon Endes, Franziska Rudzik, Laurie Thiesse, Reto Pieren, Christian Schindler, Arno Schmidt-Trucksäss, Mark Brink, Christian Cajochen, Jean Marc Wunderli, Martin Röösli, Nicole Probst-Hensch
Journal: Environmental Health Perspectives (2017)

The impact of different transportation noise sources and noise environments on arterial stiffness remains unknown.We evaluated the association between residential outdoor exposure to annual average road, railway, and aircraft noise levels, total noise intermittency (IR), and total number of noise events (NE) and brachial-ankle pulse wave velocity (baPWV) following a cross-sectional design.We measured baPWV (meters/second) in 2,775 participants (49-81 y old) at the second follow-up (2010-2011) of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA). We assigned annual average road, railway, and aircraft noise levels (Ldensource), total day- and nighttime NEtime and IRtime (percent fluctuation=0%, none or constant noise; percent fluctuation=100%, high fluctuation) at the most exposed façade using 2011 Swiss noise models. We applied multivariable linear mixed regression models to analyze associations.Medians [interquartile ranges (IQRs)] were baPWV=13.4 (3.1) m/s; Ldenair (57.6% exposed)=32.8 (8.0) dB; Ldenrail (44.6% exposed)=30.0 (8.1) dB; Ldenroad (99.7% exposed): 54.2 (10.6) dB; NEnight=123 (179); NEday=433 (870); IRnight=73% (27); and IRday=63.8% (40.3). We observed a 0.87% (95% CI: 0.31, 1.43%) increase in baPWV per IQR of Ldenrail, which was greater with IRnight>80% or with daytime sleepiness. We observed a nonsignificant positive association between Ldenroad and baPWV in urban areas and a negative tendency in rural areas. NEnight, but not NEday, was associated with baPWV. Associations were independent of the other noise sources and air pollution.Long-term exposure to railway noise, particularly in an intermittent nighttime noise environment, and to nighttime noise events, mainly related to road noise, may affect arterial stiffness, a major determinant of cardiovascular disease. Ascertaining noise exposure characteristics beyond average noise levels may be relevant to better understand noise-related health effects. https://doi.org/10.1289/EHP1136.
Regional Variation in Technetium Pyrophosphate Uptake in Transthyretin Cardiac Amyloidosis and Impact on Mortality
Authors: Brett W. Sperry, Michael N. Vranian, Albree Tower-Rader, Rory Hachamovitch, Mazen Hanna, Richard Brunken, Dermot Phelan, Manuel D. Cerqueira, Wael A. Jaber
Journal: JACC. Cardiovascular imaging (2017)
Erratum: Corrigendum: L1-associated genomic regions are deleted in somatic cells of the healthy human brain
Authors: Jennifer A Erwin, Apuã C M Paquola, Tatjana Singer, Iryna Gallina, Mark Novotny, Carolina Quayle, Tracy A Bedrosian, Francisco I A Alves, Cheyenne R Butcher, Joseph R Herdy, Anindita Sarkar, Roger S Lasken, Alysson R Muotri, Fred H Gage
Journal: Nature Neuroscience (2017)
A phase II, open-label, randomized study to evaluate the efficacy and safety of andecaliximab combined with nivolumab versus nivolumab alone in subjects with unresectable or recurrent gastric or gastroesophageal junction adenocarcinoma.
Authors: Manish A. Shah, Jean-Philippe Metges, David Cunningham, Kai-Keen Shiu, Lucjan Wyrwicz, Dung Thai, Carrie Brachmann, Pankaj Bhargava, Daniel V.T. Catenacci, Zev A. Wainberg
Journal: Journal of Clinical Oncology (2019)

75 Background: Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9). Preclinical studies suggest that MMP9 inhibition relieves immune suppression and promotes T-cell infiltration to potentiate checkpoint blockade. Methods: Phase 2, open-label, randomized study of the efficacy and safety of ADX + nivolumab (NIVO) vs. NIVO alone in patients with pre-treated metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. Patients were randomized to either ADX 800 mg IV + NIVO 3 mg/kg IV, or NIVO 3 mg/kg IV alone, and stratified by tumor PD-L1 status. Treatment was administered every 2 weeks. Re-staging CT scans were performed every 8 weeks to evaluate response. Primary endpoint: objective response rate (ORR). Secondary endpoints: progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results: Of the 144 patients randomized, 141 were treated, 109 (76%) completed tumor assessment. 81% of patients were white, with 69% male and a mean (SD) age of 59 (12) years. ORR (95% CI) was 11.1% (4.9–20.7%) in patients receiving ADX + NIVO, and 6.9% (2.3–15.5%) in those receiving NIVO alone, p = 0.6. Kaplan-Meier estimated median (95% CI) PFS was 1.8 (1.8–2.0) months in patients receiving ADX + NIVO, and 1.9 (1.7–1.9) months in those receiving NIVO alone, p = 0.2. Kaplan-Meier estimated median (95% CI) OS was 7.2 (5.2–9.1) months in patients receiving ADX + NIVO, and 5.9 (3.5–8.6) months in those receiving NIVO alone, p = 0.4. AEs leading to treatment discontinuation occurred in 1 patient in the ADX + NIVO group, and in 1 patient in NIVO-only group. PD-L1 and mismatch repair deficient subgroup analyses will be presented. Exploratory biomarker analyses will be submitted separately. Conclusions: Addition of ADX to NIVO did not improve ORR, PFS, or OS compared with NIVO alone in patients with pre-treated metastatic gastric or GEJ adenocarcinoma. Combination of ADX with NIVO had a favorable safety and tolerability profile. Clinical trial information: NCT02864381.
Neutrophil macroaggregates promote widespread pulmonary thrombosis after gut ischemia
Authors: Yuping Yuan, Imala Alwis, Mike C. L. Wu, Zane Kaplan, Katrina Ashworth, David Bark, Alan Pham, James Mcfadyen, Simone M. Schoenwaelder, Emma C. Josefsson, Benjamin T. Kile, Shaun P. Jackson
Journal: Science Translational Medicine (2017)

Gut ischemia is common in critically ill patients, promoting thrombosis and inflammation in distant organs. The mechanisms linking hemodynamic changes in the gut to remote organ thrombosis remain ill-defined. We demonstrate that gut ischemia in the mouse induces a distinct pulmonary thrombotic disorder triggered by neutrophil macroaggregates. These neutrophil aggregates lead to widespread occlusion of pulmonary arteries, veins, and the microvasculature. A similar pulmonary neutrophil-rich thrombotic response occurred in humans with the acute respiratory distress syndrome. Intravital microscopy during gut ischemia-reperfusion injury revealed that rolling neutrophils extract large membrane fragments from remnant dying platelets in multiple organs. These platelet fragments bridge adjacent neutrophils to facilitate macroaggregation. Platelet-specific deletion of cyclophilin D, a mitochondrial regulator of cell necrosis, prevented neutrophil macroaggregation and pulmonary thrombosis. Our studies demonstrate the existence of a distinct pulmonary thrombotic disorder triggered by dying platelets and neutrophil macroaggregates. Therapeutic targeting of platelet death pathways may reduce pulmonary thrombosis in critically ill patients.
Nano-delivery system targeting to cancer stem cell cluster of differentiation biomarkers
Authors: Ahad Mokhtarzadeh, Soodabeh Hassanpour, Zahra Farajzadeh Vahid, Maryam Hejazi, Maryam Hashemi, Javad Ranjbari, Maryam Tabarzad, Saeed Noorolyai, Miguel de la Guardia
Journal: Journal of Controlled Release (2017)
Esterase (Butyric Esterase) Activity of Normal and Neoplastic Tissues of the Mouse
Authors: Jesse P. Greenstein
Journal: JNCI Journal of the National Cancer Institute (1944)

Esterase (Butyric Esterase) Activity of Normal and Neoplastic Tissues of the Mouse Get access Jesse P. Greenstein Jesse P. Greenstein senior biochemist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 5, Issue 1, August 1944, Pages 31–34, https://doi.org/10.1093/jnci/5.1.31 Published: 01 August 1944
Patient-reported outcomes from a phase 2 study of copanlisib in patients with relapsed/refractory indolent B-cell non-Hodgkin lymphoma (iNHL).
Authors: Karen N. Keating, Florian Hiemeyer, Jose E. Garcia-Vargas, Barrett H. Childs, Martin H. Dreyling, Pier Luigi Zinzani
Journal: Journal of Clinical Oncology (2017)

e18123 Background: Information on the degree to which treatment of iNHL impacts health-related quality of life in terms of disease- and treatment-related symptoms is limited. Copanlisib is an investigational pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor. In a phase II study in patients with relapsed/refractory iNHL, copanlisib treatment resulted in a high response rate and durable responses. We report here on patient-reported outcomes (PRO) from this trial (NCT01660451, part B). Methods: Patients with 4 subtypes of iNHL were eligible: follicular, marginal zone, small lymphocytic and lymphoplasmacytoid/Waldenstrӧm macroglobulinemia. Patients had to have received ≥2 prior lines of treatment, including rituximab and an alkylating agent. Copanlisib (60 mg, I.V.) was intermittently administered on days 1, 8 and 15 of a 28-day cycle. Health-related quality of life questionnaire FACT-Lym questionnaire (with focus on Total and Lymphoma subscale [FACT-LymS] and LOCF-method applied) was evaluated with Hodges-Lehmann estimate for change in median until week 16, including 95% confidence intervals. EQ-5D and visual analogue scale (EQ-5D VAS) were statistically described. All questionnaires were compiled at baseline and every other cycle in the first year of the study (aligned with radiological imaging). Results: A total of 141 iNHL patients were treated, with completed questionnaires received from 132 patients at baseline and 86 at week 16. The mean±SD (and median) for FACT-Lym LymS score at baseline was 45.27 ± 9.55 (46.5), and 47.20 ± 8.69 (49.0) at 16 weeks. The estimated change in median was +1.0 with 95% CI: [0.5; 2.5] and min: -13.0, max: 23.0, representing an improvement in lymphoma-related symptoms. Accordingly, the FACT-Lym total score was 126.59 ± 22.96 (127.5) at baseline and 127.99 ± 23.60 (130.8) at 16 weeks. Estimated change in median was 0.0 with 95% CI: [-0.5; 3.2] and min: -38.0, max 42.5. Conclusions: This study demonstrated the favorable impact of copanlisib treatment on disease-related symptoms and HRQoL in patients with relapsed/refractory iNHL.
Abstract #1692: Sulfhydryl-modulated mechanisms of the cytotoxicity of cadmium and inhibition of DNA topoisomerase II\#945;
Authors: Xing Wu, Brian Hasinoff
Journal: Cancer Research (2009)

Cadmium (Cd 2+ ) is a highly toxic carcinogenic metal that is an environmental and occupational hazard. It also causes severe damage to many organs including the liver, kidney and lung. The molecular and cellular mechanisms responsible for its toxicity and carcinogenicity are not known. In this study we showed that divalent cadmium chloride strongly inhibited the DNA decatenation catalytic activity of human topoisomerase II\#945; (topo II) in the low micromolar concentration range. However, cadmium did not stabilize the DNA-topo II covalent complex, and thus may not act as a topo II poison. We also showed that cadmium inhibited the growth of human erythroleukemic K562 and CHO cells in the low micromolar concentration range. The growth inhibitory effects of cadmium on K562 and K/VP.5 cells (an etoposide-resistant cell line containing one-fifth the topo II content of the parental K562 cells) were not significantly different; a result which also suggested that cadmium is not a topo II poison. We and others have shown that the catalytic activity of topo II is strongly inhibited by sulfhydryl-reactive compounds that react with critical topo II cysteine sulfhydryl groups. Divalent cadmium forms a strong complex with cysteine. Consistent with the idea that cadmium may have its cytotoxicity modulated by GSH levels, buthionine sulfoximine (BSO) pretreatment to decrease GSH levels resulted in a greatly increased cadmium-induced cytotoxicity in K562 cells. Thus cellular GSH levels may be a key regulator of cellular toxicity of cadmium. The results of this study suggest that cadmium may exert some of its cell growth inhibitory and possibly its carcinogenic effects by inhibiting topo II through reaction with critical enzyme sulfhydryl groups.  Support: CIHR and a Canada Research Chair in Drug Development.    Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1692.
Dissecting COPD exacerbations: time to rethink our definition
Authors: Bartolome R. Celli
Journal: European Respiratory Journal (2017)

"Measure what is measurable, and make measurable what is not so." Galileo Galilei (1564–1642)The Age of Enlightenment reminded humans of the importance of critical and innovative thinking that had been lost during the middle ages. The cited phrase of Galileo is very appropriate when referring to the field of exacerbations of chronic obstructive pulmonary disease (COPD). Variables measured during COPD exacerbations inform about their relationships and exacerbation definition <http://ow.ly/3mdc30etU3s>
Lost in Thought — The Limits of the Human Mind and the Future of Medicine
Authors: Ziad Obermeyer, Thomas H. Lee
Journal: New England Journal of Medicine (2017)

Interview with Dr. Ziad Obermeyer on how collaboration between doctors and computers will help improve medical care. (11:26)Download The complexity of medicine now exceeds the capacity of the human mind. Computers are the solution, but using them to manage this complexity will require fundamental changes in the way we think about thinking, and in the structure of medical education and research.
Association of subungual melanoma and subungual squamous cell carcinoma: A case series
Authors: Amélie Boespflug, Sébastien Debarbieux, Lauriane Depaepe, Brigitte Chouvet, Delphine Maucort-Boulch, Stéphane Dalle, Brigitte Balme, Luc Thomas
Journal: Journal of the American Academy of Dermatology (2017)
Abstract 15150: Triidothyronine and Dexamethasone Improve Electrophysiological Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Authors: Lili Wang, Shan Parikh, Maria de las Nieves Gomez-Hurtado, Kyunsoo Kim, Bjorn C. Knollmann
Journal: Circulation (2016)

Introduction:  Although human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used for disease modeling, a major limitation are their relative electrophysiological immaturity (i.e., spontaneous electrical activity, low levels of inward rectifier current (I K1 ), and high levels of pacemaker current (I f )). Triiodothyronine (T 3 ) plays an important role for heart development and combined with Dexamethasone has been reported to improve functional properties of hiPSC-CMs but its effect on I K1  and I f  is unknown.   Objective:  To test whether addition of T 3  & Dexamethasone to standard hiPSC cardiac induction media enhances electrophysiological maturation of hiPSC-CM without increasing culturing time.   Methods:  T 3  & Dexamethasone or vehicle was added to cardiac induction media from day 16 to day 30. Day 30 th  hiPSC-CMs were dissociated, plated at single cell density for 5 days on a flexible matrigel substrate and studied using voltage clamp and confocal imaging.   Results:  Spontaneous beating rate was significantly reduced in hormone-treated compared to vehicle-treated hiPSC-CM (10±1.7 b/min  vs.  23±1.9 b/min, n=10, p f  density was three-fold decreased by hormone treatment (-2.7±0.35 pA/pF  vs.  -6.2±1.3 pA/pF at -120 mV, n=6, p Figure , I K1  density was four-time higher in hormone-treated hiPSC-CM than in control (-19.3±2.2 pA/pF  vs.  -4.4±0.5 pA/pF at -120 mV, n=7, p   Conclusion:  Addition of T 3  & Dexamethasone to standard protocols may be an effective approach for rapidly enhancing electrophysiological and ultrastructural maturity of hiPSC-CMs.
Tumor mutation burden derived from large NGS panel as biomarker for immunotherapy response.
Authors: Dana Vuzman, Winslow Powers, Xiu Huang, Ruobai Sun, Cheryl Eifert, Pablo Cingolani, Andrew Bjonnes, Stephen Lyle, Alexei Protopopov
Journal: Journal of Clinical Oncology (2017)

e23077 Background: Tumor mutation burden (TMB) is an informative biomarker for predicting response to immunotherapy in a growing number of malignancies. The TMB clinical applicability is limited due to cost and bioinformatics requirements of sequencing and analyis of whole exome/gemone. Here, we demonstrate that a large next generation sequencing (NGS) panel can accurately identify hypermutation status. Methods: A novel algorithmic approach to derive the predicted total mutation load (PTML) described in J Roszik et al, BMC Med, 2016, was applied to our large NGS panel, CANCERPLEX. Statistical weights were calculated for each of the genes using publically available TCGA database. The algorithm was tested using CANCERPLEX data of stomach adenocarcinoma (199), colorectal cancer (59), and lung cancer (60) cohorts (n = 318). The correlation of PTML status with mismatch repair (MMR) status (n = 11) was also tested. The correlation of PTML status with clinical outcome was assessed using WES data following distinct immunotherapies (n = 16). The actual total mutation load (ATML) was compared to PTML by downsampling the WES data to our region of interest. Results: The mean values of PTML were evaluated for stomach adenocarcinoma (199), colorectal cancer (59), and lung cancer (60) cohorts. The PTML results for these 3 cancer types were statistically similar, and therefore the cohorts were combined into one dataset (n = 318). The hypermutation threshold was calculated from the PTML distribution of the three cancer types. This hypermutation threshold was in high concordance with our MMR validation set (n = 11), and also correlated (0.86) with an independent validation set of clinical outcome data from WES, which had undergone treatment with distinct immunotherapies (n = 16). This threshold predicts response to immunotherapy with 90% accuracy. Conclusions: NGS across a large gene panel captures sufficient information to predict tumor mutation burden with a single threshold for hypermutation status for stomach adenocarcinoma, colorectal, and lung cancers. This threshold highly correlates with MMR status and clinical outcome for immunotherapy response. Additional cancer types are currently being tested for inclusion in this study.
Investigating the Effect of Chemical Structure of Semiconducting Polymer Nanoparticle on Photothermal Therapy and Photoacoustic Imaging
Authors: Dongdong Li, Guobing Zhang, Weiguo Xu, Junxia Wang, Yucai Wang, Longzhen Qiu, Jianxun Ding, Xianzhu Yang
Journal: Theranostics (2017)

The donor-acceptor semiconducting polymers (SPs) have robust absorbance in near-infrared (NIR) region, great photostability, high photothermal conversion efficiency, and good biocompatibility.Thus, the SPs exhibit great potentials for photothermal therapy (PTT) and photoacoustic imaging (PAI).However, poor understanding of the underlying mechanisms and the correlation between the SP polymer chemical structures and their performances of PTT and PAI have significantly hindered their biomedical application.Herein, a series of acceptor-π-acceptor type (A1-π-A2) type SPs were synthesized.The diketopyrrolopyrrole (DPP) and thiophene are used as A1 electron accepting block and π-bridge, and the chemical structure of A2 unit was variable.The SPs were formulated into PEGylated nanoparticles, which ensured these SP-based nanoparticles (SP@NPs) exhibited similar size, shape, and physiological stability.Thus, the chemical structure of A2 unit was the only variable.The effects of the SP chemical structures are carefully and comprehensively evaluated through both in vitro and in vivo experiments.Our results demonstrated the chemical structure of A2 unit simultaneously impact their absorption spectra and photothermal (PT) conversion efficiency, which finally determined their PTT and PAI performances.Among these A2 acceptors, thieno[3,2-b]thiophene (TT) unit exhibited the best in vitro and in vivo anticancer efficacies and PAI performances.This study not only provides molecular insights into the design of efficient SPs for PTT and PAI but also highlights the flexibility and potential of SP@NPs for biomedical application.Thus, SP@NPs can act as a versatile nanoplatform for the development of novel light intensive imaging and therapeutic approaches.