tbuckley/cabot-search huggingface dataset:
Adverse respiratory effects of opioids for chronic breathlessness: to what extent can we learn lessons from chronic pain?
Authors: Cornelia A. Verberkt, Marieke H.J. van den Beuken-van Everdingen, Jos M.G.A. Schols, Sushma Datla, Carmen D. Dirksen, Miriam J. Johnson, Sander M.J. van Kuijk, Emiel F.M. Wouters, Daisy J.A. Janssen
Journal: European Respiratory Journal (2018)

We would like to thank K.T.S. Pattinson and colleagues for their interest in our review and their comprehensive comments [1]. We agree that the quality of the included studies was low, and the studies were small and not designed to examine the safety of opioids, as stated in our discussion [2]. Indeed, respiratory depression was not included as an outcome in over half of the studies. Of note, in the 25 studies that did include the outcome, only 11 stated a definition. Therefore, we recommended in our review to include "a common respiratory outcome set in all trials of opioids for breathlessness, so that a more robust synthesis could be conducted". Although chemoreflex response is useful in laboratory research, measurement of blood gases remains the basis for evaluation in clinical practice, with the assessment of arterial blood gases being more reliable than the assessment of capillary blood gases [3] or transcutaneous measurement [4]. Chronic breathlessness: care must be taken not to generalise evidence on adverse effects of opioids from chronic pain inappropriately <http://ow.ly/D7sR30kfskS>
Tumor Mutation Burden and Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with <i>EGFR</i>-Mutant Lung Cancers
Authors: Michael Offin, Hira Rizvi, Megan Tenet, Andy Ni, Francisco Sanchez-Vega, Bob T. Li, Alexander Drilon, Mark G. Kris, Charles M. Rudin, Nikolaus Schultz, Maria E. Arcila, Marc Ladanyi, Gregory J. Riely, Helena Yu, Matthew D. Hellmann
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Tumor mutation burden (TMB) is a biomarker of response to immune checkpoint blockade (ICB). The impact of TMB on outcomes with targeted therapies has not been explored. Experimental Design: We identified all patients with metastatic EGFR exon19del or L858R-mutant lung cancers treated with first/second-generation EGFR tyrosine kinase inhibitors (TKIs) with pretreatment next-generation sequencing data (MSK-IMPACT assay). The effect of TMB on time-to-treatment discontinuation (TTD) and overall survival (OS) were evaluated in univariate and multivariate analyses. EGFR wild-type lung adenocarcinoma samples were used for comparison. Results: Among 153 patients with EGFR-mutant lung cancer, TMB was lower compared with EGFR wild-type (n = 1,849; median 3.77 vs. 6.12 mutations/Mb; P &amp;lt; 0.0001) with a broad range (0.82–17.9 mutations/Mb). Patients with EGFR-mutant lung cancer whose tumors had TMB in the high tertile had shorter TTD (HR, 0.46; P = 0.0008) and OS (HR, 0.40; P = 0.006) compared with patients with low/intermediate TMB. Evaluating by median TMB, there was significantly shorter TTD and OS for patients with higher TMB (TTD, P = 0.006; OS, P = 0.03). In multivariate analysis, TTD and OS remained significantly longer in the low/intermediate tertile compared with high TMB (HR = 0.57, P = 0.01; HR = 0.50, P = 0.02, respectively). In paired pretreatment and postprogression samples, TMB was increased at resistance (median 3.42 vs. 6.56 mutations/Mb; P = 0.008). Conclusions: TMB is negatively associated with clinical outcomes in metastatic patients with EGFR-mutant lung cancer treated with EGFR-TKI. This relationship contrasts with that seen in lung cancers treated with immunotherapy. See related commentary by Cheng and Oxnard, p. 899
Dual Angiogenic and Neurotrophic Effects of Bone Marrow–Derived Endothelial Progenitor Cells on Diabetic Neuropathy
Authors: Jin-OkJeong, Mee-OhkKim, HyongbumKim, Min-YoungLee, Sung-WhanKim, MasaakiIi, Jung-uekLee, JiyoonLee, Yong JinChoi, Hyun-JaiCho, NamhoLee, MarcySilver, AndreaWecker, Dong-WookKim, Young-supYoon
Journal: Circulation (2009)

Background— Endothelial progenitor cells (EPCs) are known to promote neovascularization in ischemic diseases. Recent evidence suggested that diabetic neuropathy is causally related to impaired angiogenesis and deficient growth factors. Accordingly, we investigated whether diabetic neuropathy could be reversed by local transplantation of EPCs. Methods and Results— We found that motor and sensory nerve conduction velocities, blood flow, and capillary density were reduced in sciatic nerves of streptozotocin-induced diabetic mice but recovered to normal levels after hind-limb injection of bone marrow–derived EPCs. Injected EPCs were preferentially and durably engrafted in the sciatic nerves. A portion of engrafted EPCs were uniquely localized in close proximity to vasa nervorum, and a smaller portion of these EPCs were colocalized with endothelial cells. Multiple angiogenic and neurotrophic factors were significantly increased in the EPC-injected nerves. These dual angiogenic and neurotrophic effects of EPCs ...
Optimal bone fracture repair requires 24R,25-dihydroxyvitamin D3 and its effector molecule FAM57B2
Authors: Corine Martineau, Roy Pascal Naja, Abdallah Husseini, Bachar Hamade, Martin Kaufmann, Omar Akhouayri, Alice Arabian, Glenville Jones, René St-Arnaud
Journal: Journal of Clinical Investigation (2018)

The biological activity of 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] remains controversial, but it has been suggested that it contributes to fracture healing. Cyp24a1–/– mice, synthesizing no 24R,25(OH)2D3, show suboptimal endochondral ossification during fracture repair, with smaller callus and reduced stiffness. These defects were corrected by 24R,25(OH)2D3 treatment, but not by 1,25-dihydroxyvitamin D3. Microarrays with Cyp24a1–/– callus mRNA identified FAM57B2 as a mediator of the 24R,25(OH)2D3 effect. FAM57B2 produced lactosylceramide (LacCer) upon specific binding of 24R,25(OH)2D3. Fam57b inactivation in chondrocytes (Col2-Cre Fam57bfl/fl) phenocopied the callus formation defect of Cyp24a1–/– mice. LacCer or 24R,25(OH)2D3 injections restored callus volume, stiffness, and mineralized cartilage area in Cyp24a1-null mice, but only LacCer rescued Col2-Cre Fam57bfl/fl mice. Gene expression in callus tissue suggested that the 24R,25(OH)2D3/FAM57B2 cascade affects cartilage maturation. We describe a previously unrecognized pathway influencing endochondral ossification during bone repair through LacCer production upon binding of 24R,25(OH)2D3 to FAM57B2. Our results identify potential new approaches to ameliorate fracture healing.
Huntingtin-interacting protein 1 (HIP1) regulates arthritis severity and synovial fibroblast invasiveness by altering PDGFR and Rac1 signalling
Authors: Teresina Laragione, Max Brenner, Amit Lahiri, Erjing Gao, Carolyn Harris, Percio S Gulko
Journal: Annals of the Rheumatic Diseases (2018)

Objectives While new treatments for rheumatoid arthritis (RA) have markedly improved disease control by targeting immune/inflammatory pathways, current treatments rarely induce remission, underscoring the need for therapies that target other aspects of the disease. Little is known about the regulation of disease severity and joint damage, which are major predictors of disease outcome, and might be better or complementary targets for therapy. In this study, we aimed to discover and characterise a new arthritis severity gene. Methods An unbiased and phenotype-driven strategy including studies of unique congenic rat strains was used to identify new arthritis severity and joint damage genes. Fibroblast-like synoviocytes (FLS) from rats and patients with RA expressing or not Huntingtin-interacting protein 1 (HIP1) were studied for invasiveness, morphology and cell signalling. HIP1 knockout mice were used in in vivo confirmatory studies. Paired t-test was used. Results DNA sequencing and subcongenic strains studied in pristane-induced arthritis identified a new amino acid changing functional variant in HIP1. HIP1 was required for the increased invasiveness of FLS from arthritic rats and from patients with RA. Knocking down HIP1 expression reduced receptor tyrosine kinase-mediated responses in RA FLS, including RAC1 activation, affecting actin cytoskeleton and cell morphology and interfering with the formation of lamellipodia, consistent with reduced invasiveness. HIP1 knockout mice were protected in KRN serum-induced arthritis and developed milder disease. Conclusion HIP1 is a new arthritis severity gene and a potential novel prognostic biomarker and target for therapy in RA.
Expression of stathmin in tumor to predict response to neoadjuvant chemotherapy with docetaxel-containing regimens in locally advanced breast cancer.
Authors: Xuli Meng
Journal: Journal of Clinical Oncology (2012)

e11566 Background: We performed this retrospective study to evaluate the value of clinicopathological factors and a novel molecular marker stathmin in predicting treatment response to neoadjuvant chemotherapy (NCT) with docetaxel-containing regimens in patients with locally advanced breast cancer. Methods: Fifty-four consecutive locally advanced patients receiving docetaxel-containing NCT between January 2006 and July 2010 in Zhejiang Cancer Hospital were included. The expression levels of estrogen receptor (ER), progesterone receptor (PR), epidermal growth factor receptor-2 (HER-2), and p53 were detected by immunohistochemistry, while expression of stathmin mRNA was measured by Quanti-Gene assay. Results: The overall clinical objective response (cOR) rate was 75.9% (41/54) in breast. A total of 34 patients (63.0%) experienced pathological OR (pOR), with pathological complete remission (pCR) rate of 20.4% (11/54) in breast and 16.7% (9/54) in both breast and axilla. In univariate analysis, there were associations of pOR in both breast and axilla with age (P=0.054), ER status (P=0.059), subtypes (P=0.062), p53 (P=0.030), and stathmin expression (three terciles) (P=0.039). Mean expression of stathmin in pOR group was 0.410, compared with that in no response group of 0.556 (P=0.051 by Student’s t-test). Similarly, a lower expression of stathmin might represent a higher pCR rate (P=0.061). Moreover, the LOWESS smoothing plot showed the same trend, i.e., that tumor with a lower level of stathmin expression had a higher probability of response to docetaxel-containing NCT. After multivariate adjustment, both ER and stathmin kept being significant with hazard ratio of 4.58 (95% CI: 1.11-18.94, P=0.036) and 2.94 (95% CI: 1.26-6.86, P=0.012), respectively. Conclusions: ER and stathmin were independent predictive factors for NCT with docetaxel-containing regimens.
Metabolic Response to BRAF-MEK Combination Therapy in Cecal Neuroendocrine Carcinoma With BRAFV600E Mutation and Refractory Lactic Acidosis
Authors: Alessio Imperiale, Adrien Latgé, Frédérique Schaff-Wendling, Bernard Goichot, Jean-Emmanuel Kurtz, Gabriel G. Malouf
Journal: Clinical Nuclear Medicine (2018)

We report the results of serial F-FDG PET/CT investigations in a 49-year-old woman presenting with an advanced cecal high-grade neuroendocrine carcinoma harboring a somatic BRAF mutation. Patient was refractory to standard chemotherapy regimen showing life-threatening hyperlactatemia. Early after the beginning of BRAF-MEK therapy (dabrafenib and trametinib), impressive improvement in PET/CT imaging was achieved. The pathological F-FDG uptake in cecal primary tumor as well as in nodal, hepatic, and bone metastases drastically decreased. Moreover, the reduction of total lesion glycolysis on PET/CT images was strictly related to extraordinary patient clinical response and lactic acid level normalization.
ADAM15 in Apoptosis Resistance of Synovial Fibroblasts: Converting Fas/CD95 Death Signals Into the Activation of Prosurvival Pathways by Calmodulin Recruitment
Authors: Tomasz Janczi, Beate B. Böhm, Yuliya Fehrl, Pangrazio DeGiacomo, Raimund W. Kinne, Harald Burkhardt
Journal: Arthritis & Rheumatology (2018)

To investigate mechanisms underlying the capability of ADAM15 to transform FasL-mediated death-inducing signals into prosurvival activation of Src and focal adhesion kinase (FAK) in rheumatoid arthritis synovial fibroblasts (RASFs).Caspase 3/7 activity and apoptosis rate were determined in RASFs and ADAM15-transfected T/C28a4 cells upon Fas/CD95 triggering using enzyme assays and annexin V staining. Phosphorylated Src and FAK were analyzed by immunoblotting. Interactions of ADAM15 and CD95 with calmodulin (CaM), Src, or FAK were analyzed by pull-downs using CaM-Sepharose and coimmunoprecipitations with specific antibodies. Protein binding assays were performed using recombinant CaM and ADAM15. Immunofluorescence was performed to investigate subcellular colocalization of ADAM15, Fas/CD95, and CaM.The antiapoptotic effect of ADAM15 in FasL-stimulated cells was demonstrated either by increased apoptosis of cells transfected with an ADAM15 construct lacking the cytoplasmic domain compared to cells transfected with full-length ADAM15 or by reduced apoptosis resistance of RASFs upon RNA interference silencing of ADAM15. Fas ligation triggered a Ca2+ release-activated Ca2+ /calcium release-activated calcium channel protein 1 (CRAC/Orai1) channel-dependent CaM recruitment to Fas/CD95 and ADAM15 in the cell membrane. Simultaneously, Src associated with CaM was shown to become engaged in the ADAM15 complex also containing cytoplasmic-bound FAK. Accordingly, Fas ligation in RASFs led to ADAM15-dependent phosphorylation of Src and FAK, which was associated with increased survival. Pharmacologic interference with either the CaM inhibitor trifluoperazine or the CRAC/Orai inhibitor BTP-2 simultaneously applied with FasL synergistically enhanced Fas-mediated apoptosis in RASFs.ADAM15 provides a scaffold for formation of CaM-dependent prosurvival signaling complexes upon CRAC/Orai coactivation by FasL-induced death signals and a potential therapeutic target to break apoptosis resistance in RASFs.
Abstract 282: Inhibition of Inducible Nitric Oxide Synthase Improves Heart Rate Variability During Sepsis
Authors: Michael E Kwiatt, Joe LaChant, Sergio Zanotti, Steven M Hollenberg
Journal: Circulation (2011)

Background Nonlinear hemodynamic variables such as blood pressure and heart rate variability are abnormal in sepsis. Nitric oxide has a complex role in hemodynamic alterations in sepsis. The role of inducible nitric oxide synthase (iNOS) on nonlinear hemodynamic parameters is unknown. Hypothesis Selective inhibition of iNOS will alter the response of nonlinear hemodynamic parameters in a murine model of sepsis. Methods Radio-transmitters were implanted into the aorta of C57/BL6 wild type (n=15) and C57/BL6 NOS 2 (iNOS knockout) (n=8) mice for continuous hemodynamic monitoring. After 72 hours of recovery, baseline heart rate recordings were captured for 24 hours. Sepsis was induced by cecal ligation and puncture and continuous recordings were taken for the next 48 hours. All mice received antibiotics (ceftriaxone and clindamycin) and fluids (35mg/kg 0.9% NaCl) every 6 hours. Volatility was used as a measurement of variability. Heart rate volatility (HRV) and blood pressure volatility (BPV) measurements were compared between groups. Results At baseline the iNOS knockout mice had a higher mean systolic blood pressure (135 vs. 126 mmHg, p&lt;0.001) and lower mean heart rate (504 vs. 534, p&lt;0.001) compared to wild type mice. Following induction of sepsis, heart rate and blood pressure were similar between the two groups. During sepsis the iNOS knockout mice had more frequent normal HRV intervals (48.9 vs. 33.3%, p&lt;0.001) but fewer normal BPV intervals (39.7 vs. 62.8%, p&lt;0.001) than the wild type mice. Survival was significantly higher in the iNOS knockout mice compared to wild type mice (75 vs. 26.7%, p= 0.039). Conclusions In conclusion, selective inhibition of iNOS was associated with alterations in nonlinear hemodynamics during sepsis. Heart rate variability was improved in iNOS knockouts and correlated with improved survival. Our findings suggest a complex role of iNOS in nonlinear hemodynamics during sepsis. Heart rate variability may provide unique prognostic information in sepsis.
European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias
Authors: Maria Gavriatopoulou, Pellegrino Musto, Jo Caers, Giampaolo Merlini, Efstathios Kastritis, Niels van de Donk, Francesca Gay, Ute Hegenbart, Roman Hajek, Sonja Zweegman, Benedetto Bruno, Christian Straka, Meletios A. Dimopoulos, Hermann Einsele, Mario Boccadoro, Pieter Sonneveld, Monika Engelhardt, Evangelos Terpos
Journal: Leukemia (2018)
Guided chemotherapy based on patient‐derived mini‐xenograft models improves survival of gallbladder carcinoma patients
Authors: Ming Zhan, Rui‐meng Yang, Hui Wang, Min He, Wei Chen, Sun‐wang Xu, Lin‐hua Yang, Qiang Liu, Man‐mei Long, Jian Wang
Journal: Cancer Communications (2018)

Abstract Background Gallbladder carcinoma is highly aggressive and resistant to chemotherapy, with no consistent strategy to guide first line chemotherapy. However, patient‐derived xenograft (PDX) model has been increasingly used as an effective model for in preclinical study of chemosensitivity. Methods Mini‐PDX model was established using freshly resected primary lesions from 12 patients with gallbladder to examine the sensitivity with five of the most commonly used chemotherapeutic agents, namely gemcitabine, oxaliplatin, 5‐fluorouracil, nanoparticle albumin‐bound (nab)‐paclitaxel, and irinotecan. The results were used to guide the selection of chemotherapeutic agents for adjunctive treatment after the surgery. Kaplan–Meier method was used to compare overall survival (OS) and disease free survival (DFS) with 45 patients who received conventional chemotherapy with gemcitabine and oxaliplatin. Results Cell viability assays based on mini‐PDX model revealed significant heterogeneities in drug responsiveness. Kaplan–Meier analysis showed that patients in the PDX‐guided chemotherapy group had significantly longer median OS (18.6 months; 95% CI 15.9–21.3 months) than patients in the conventional chemotherapy group (13.9 months; 95% CI 11.7–16.2 months) ( P = 0.030; HR 3.18; 95% CI 1.47–6.91). Patients in the PDX‐guided chemotherapy group also had significantly longer median DFS (17.6 months; 95% CI 14.5–20.6 months) than patients in the conventional chemotherapy group (12.0 months; 95% CI 9.7–14.4 months) ( P = 0.014; HR 3.37; 95% CI 1.67–6.79). Conclusion The use of mini‐PDX model to guide selection of chemotherapeutic regimens could improve the outcome in patients with gallbladder carcinoma.
Abstract 14200: The Association Between Markers of Preclinical Cardiovascular Disease and Incident Diabetes is Mediated by the Insulin Resistance Syndrome: The Strong Heart Study
Authors: Giovanni de Simone, Wenyu Wang, Lyle G Best, Fawn Yeh, Raffaele Izzo, Mary J. Roman, Elisa T Lee, Barbara V. Howard, Richard B. Devereux
Journal: Circulation (2016)

Introduction:  Hypertensive left ventricular [LV] hypertrophy (LVH) precedes and independently predicts incident type 2 diabetes (DM).   Hypothesis:  Target organ damage (TOD, i.e. LVH and urinary albumin/creatinine excretion [UACr]) precede incident DM in a population-based cohort, independently of measures of adiposity, body composition and circulating insulin.   Methods:  We assess 4-year predictors of DM in non-diabetic participants (ADA criteria) from the Strong Heart Study (2 nd  exam) and the Strong Heart Family Study (4 th  exam), in relation to initial glucose profile (i.e., normal [NFG] or impaired fasting glucose [IFG]), obesity, central fat distribution (by waist circumference), body composition (by bioelectric impedance analysis), and markers of TOD.   Results:  Of 3385 participants, 235 died during follow-up and 263 were unclassified at the follow-up. Thus, after 4 years, the glucose status was available in 2887 participants (1721 or 60% women; median age=48 yrs, IQR=30-57 yrs, range=14-93 yrs; 37% with IFG at baseline, 36% hypertensive, 47% obese, 63% with central fat distribution). At follow-up, 20% with baseline IFG had DM vs 4% of participants with NFG (p   Conclusions:  TOD conventionally attributed to diabetes precedes its clinical appearance. This association substantially depends on obesity-related abnormalities. Substantial part of the TOD attributable to diabetes is due to metabolic alterations related to the preceding obesity and insulin resistance.
Fluorescent 2D WS<sub>2</sub> Nanosheets Bearing Chemical Affinity Elements for the Recognition of Glycated Hemoglobin
Authors: Jin‐Kyoung Yang, Hye‐Rim Lee, In‐Jun Hwang, Hye‐In Kim, DaBin Yim, Jong‐Ho Kim
Journal: Advanced Healthcare Materials (2018)

Abstract It is required to exfoliate and functionalize 2D transition metal dichalcogenides (TMDs) in an aqueous solution for biological and medical applications. Herein, the approach for the simultaneous exfoliation and functionalization of 2D WS 2 nanosheets using boronic acid‐modified poly(vinyl alcohol) (B‐PVA) in an aqueous solution is reported, and the B‐PVA‐functionalized WS 2 nanosheets (B‐PVA‐WS 2 ) are exploited as a fluorescent biosensor for the detection of glycated hemoglobin, HbA1c. The synthetic B‐PVA polymer facilitates the exfoliation and functionalization of WS 2 nanosheets from the bulk counterpart in the aqueous solution via a pulsed sonication process, resulting in fluorescent B‐PVA‐WS 2 nanohybrids with a specific recognition of HbA1c. The fluorescence of the B‐PVA‐WS 2 is quenched in the presence of HbA1c, whereas PVA‐functionalized WS 2 (PVA‐WS 2 ), not bearing boronic acid as a recognition moiety, shows no fluorescence changes upon the addition of the target. The B‐PVA‐WS 2 is able to selectively detect HbA1c at the concentration as low as 3.3 × 10 −8 m based on its specific fluorescence quenching.
Association Between Intestinal Microbiota Collected at Hospital Admission and Outcomes of Patients With Cirrhosis
Authors: Jasmohan S. Bajaj, Hugo E. Vargas, K. Rajender Reddy, Jennifer C. Lai, Jacqueline G. O’Leary, Puneeta Tandon, Florence Wong, Robert Mitrani, Melanie B. White, Megan Kelly, Andrew Fagan, Rohan Patil, Shaimaa Sait, Masoumeh Sikaroodi, Leroy R. Thacker, Patrick M. Gillevet
Journal: Clinical Gastroenterology and Hepatology (2018)
Review of David Benatar, <i>The Human Predicament: A Candid Guide to Life’s Biggest Questions</i>
Authors: Ema Sullivan-Bissett
Journal: The American Journal of Bioethics (2018)

"Review of David Benatar, The Human Predicament: A Candid Guide to Life’s Biggest Questions." The American Journal of Bioethics, 18(7), pp. W4–W6