tbuckley/cabot-search huggingface dataset:
Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer
Authors: Thomas J. Morrison, Megan V. Jackson, Erin K. Cunningham, Adrien Kissenpfennig, Daniel F. McAuley, Cecilia M. O’Kane, Anna D. Krasnodembskaya
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Rationale: Acute respiratory distress syndrome (ARDS) remains a major cause of respiratory failure in critically ill patients. Mesenchymal stromal cells (MSCs) are a promising candidate for a cell-based therapy. However, the mechanisms of MSCs’ effects in ARDS are not well understood. In this study, we focused on the paracrine effect of MSCs on macrophage polarization and the role of extracellular vesicle (EV)-mediated mitochondrial transfer.Objectives: To determine the effects of human MSCs on macrophage function in the ARDS environment and to elucidate the mechanisms of these effects.Methods: Human monocyte–derived macrophages (MDMs) were studied in noncontact coculture with human MSCs when stimulated with LPS or bronchoalveolar lavage fluid (BALF) from patients with ARDS. Murine alveolar macrophages (AMs) were cultured ex vivo with/without human MSC-derived EVs before adoptive transfer to LPS-injured mice.Measurements and Main Results: MSCs suppressed cytokine production, increased M2 macrophage marker expression, and augmented phagocytic capacity of human MDMs stimulated with LPS or ARDS BALF. These effects were partially mediated by CD44-expressing EVs. Adoptive transfer of AMs pretreated with MSC-derived EVs reduced inflammation and lung injury in LPS-injured mice. Inhibition of oxidative phosphorylation in MDMs prevented the modulatory effects of MSCs. Generating dysfunctional mitochondria in MSCs using rhodamine 6G pretreatment also abrogated these effects.Conclusions: In the ARDS environment, MSCs promote an antiinflammatory and highly phagocytic macrophage phenotype through EV-mediated mitochondrial transfer. MSC-induced changes in macrophage phenotype critically depend on enhancement of macrophage oxidative phosphorylation. AMs treated with MSC-derived EVs ameliorate lung injury in vivo.
Publisher&amp;rsquo;s Note / Editor&amp;rsquo;s Note
Authors: P.E. Sifneos, U. Rosin, G.-K. Köhler, Tatjana M. Sivik, Thomas N. Wise, Lee S. Mann, Steven Epstein, Egon Stenager, Lone Knudsen, Knud Jensen, Robert H. Bull, Gabriela Legorreta, Gabriella Ba, Julian Hafner, Manuel Battegay, Rainer Weber, Jürg Willi, Dominique Eich, Walter Siegenthaler, Ruedi Lüthy, Clá;udio Laks Eizirik, Flá;via Costa, Flá;vio Kapczinski, Renato Piltcher, Rosane Gauer, Zelig Libermann
Journal: Psychotherapy and Psychosomatics (1991)
Hypertrophic cardiomyopathy in mitochondrial disorders: description of an uncommon clinical case
Authors: Fabio Marsico, Claudia D'Andrea, Antonio Parente, Fabiana De Martino, Letizia Capasso, Francesco Raimondi, Stefania Paolillo, Santo Dellegrottaglie, Caterina Marciano, Bruno Trimarco, Pasquale Perrone Filardi
Journal: European Journal of Heart Failure (2017)
Effect of obesity on the toxicity profile of patients with breast cancer treated with adjuvant chemotherapy.
Authors: Vijay Kumar Srinivasalu, Annu Susan George, Arun Philip, Sanketh Kotne, Sahil Bamroo, Vijaykumar D.K., Ranjini Pillai, Beena K, Wesley M Jose, Keechilat Pavithran
Journal: Journal of Clinical Oncology (2017)

e12033 Background: There is increasing evidence that obesity is strongly associated with breast cancer (BC) and has a major impact on the patient tolerance, overall survival (OS) and progression free survival (PFS). Chemotherapy dosing as per body surface area (BSA) or the actual body weight is a major dilemma among the oncologists. Moreover, the side effects of chemotherapy in obese patients in an Indian population has not been described previously in literature. We intended to evaluate the major toxicity, OS and PFS in obese BC patients who received adjuvant chemotherapy (ADC) with Adriamycin/cyclophosphamide (AC) and paclitaxel (T). Methods: A retrospective analysis of 331 patients of BC who received 4 cycles of adjuvant AC + T from a single tertiary centre in South India between 2006-2014 were included . All patients were treated as per their BSA which were capped at 2. Body Mass Index (BMI) was divided into normal (18-22.99), Overweight (23-24.99) and Obese ( ≥25 as per Asian guidelines). The toxicity was scored as per NCI-CTCAE criteria. Results: Out of 331 patients, 213 were obese. On comparison of normal and over weight with obese patients, 65 (30.5%) in obese group had significant all grade neuropathy (p = 0.027), 65 (30.5%) had Grade 2 and 3 myelosuppression (p &lt;0.001), 31 (14.5%) had all grade emesis (p = 0.031) and 28 (13.1%) had myalgia (0.001). The 5 year OS and PFS were 93.7% and 82.3% respectively in obese patients, higher than the patients with normal weight with a 5 year OS and PFS of 92.4 % and 76.9% , but was not statistically significant. Conclusions: Higher rates of severe toxicities were seen in obese BC patients who received ADC as per their BSA. The 5 year OS and PFS was better in obese BC patients, but was not statistically significant. [Table: see text]
‘Whoever has will be given more’ (Matthew 13:12): authorship of systematic reviews and clinical trials in the biological age
Authors: R.S. Stern
Journal: British Journal of Dermatology (2017)

Linked Article: Gómez‐García et al. Br J Dermatol 2017; 176:1633–1644. Tauber and Paul. Br J Dermatol 2017; 176:1669–1671.
Incidence of Anterior Cruciate Ligament Reconstruction Among Adolescent Females in the United States, 2002 Through 2014
Authors: Mackenzie M. Herzog, Stephen W. Marshall, Jennifer L. Lund, Virginia Pate, Christina D. Mack, Jeffrey T. Spang
Journal: JAMA Pediatrics (2017)

This study explores sex disparities among 13- to 17-year-olds who undergo anterior cruciate ligament reconstruction.
Improved Control of GvHD with Rabbit ATG, Rituximab and Bortezomib Among Pediatric Leukemia Patients after Tcrαβ/CD19-Depletion of Transplant from Matched Unrelated and Haploidentical Family Donors: A Single-Center Retrospective Analysis of Two Gvhd-Prophylaxis Regimens
Authors: Zhanna Shekhovtsova, Larisa Shelikhova, Dmitry Balashov, Elena Kurnikova, Iakov Muzalevskyi, Alexey Kazachenok, Yuliya Skvortsova, Maria Ilyushina, Daria Shasheleva, Rimma Khismatullina, Sergey Blagov, Dmitry Litvinov, Galina Novichkova, Alexey Maschan, Julia Starichkova, Michael Maschan
Journal: Blood (2016)
Karen Litzy #StrongSmart #DavidButlerSavedMyLife
Authors: Johann Windt
Journal: British Journal of Sports Medicine (2017)

I would tell my high school self to not worry too much about failure. It’s going to happen and it will make you stronger, smarter and better prepared for the next adventure. I was, and continue to be, a bit of a perfectionist so this whole failure thing was, at times, a bitter pill to swallow. Now I know that failures are there for a reason and there is always something better waiting if you take action to go out, find it and make it happen.

The first time I met Dr David Butler. I went to an ’Explain Pain' lecture he gave at an American Physical Therapy Association event and it not only completely changed the way I treated my patients with pain but it changed my life. I now had the knowledge and mentorship to overcome my own persistent pain issues. Learning more about the science behind pain has been such an empowering process for me and has become a huge part of my practice.

The 1996 Olympic games when Kerri Strug landed her vault to secure the gold medal for the US women’s gymnastics team. After her landing she needed to be carried off of the mat by her coach. I thought she was one of the strongest athletes I had ever seen.

I treated a patient few years ago with a fractured tibial plateau, ACL tear, MCL tear and medial meniscus damage. Terrible skiing accident. She was non-weight bearing for 12 weeks post-surgery and had two children under the age of five to care for. Her rehabilitation took several months, lots of hard work from the patient …
Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity
Authors: Ryu Watanabe, Tsuyoshi Shirai, Hong Namkoong, Hui Zhang, Gerald J. Berry, Barbara B. Wallis, Benedikt Schaefgen, David G. Harrison, Jennifer A. Tremmel, John C. Giacomini, Jörg J. Goronzy, Cornelia M. Weyand
Journal: Journal of Clinical Investigation (2017)

Patients with coronary artery disease (CAD) are at high risk for reactivation of the varicella zoster virus (VZV) and development of herpes zoster (HZ). Here, we found that macrophages from patients with CAD actively suppress T cell activation and expansion, leading to defective VZV-specific T cell immunity. Monocyte-derived and plaque-infiltrating macrophages from patients with CAD spontaneously expressed high surface density of the immunoinhibitory ligand programmed death ligand-1 (PD-L1), thereby providing negative signals to programmed death-1+ (PD-1+) T cells. We determined that aberrant PD-L1 expression in patient-derived macrophages was metabolically controlled. Oversupply of the glycolytic intermediate pyruvate in mitochondria from CAD macrophages promoted expression of PD-L1 via induction of the bone morphogenetic protein 4/phosphorylated SMAD1/5/IFN regulatory factor 1 (BMP4/p-SMAD1/5/IRF1) signaling pathway. Thus, CAD macrophages respond to nutrient excess by activating the immunoinhibitory PD-1/PD-L1 checkpoint, leading to impaired T cell immunity. This finding indicates that metabolite-based immunotherapy may be a potential strategy for restoring adaptive immunity in CAD.
Disparities in next generation sequencing in a population-based community cohort of patients with advanced non-small cell lung cancer.
Authors: Carolyn Jean Presley, Pamela R. Soulos, Anne C. Chiang, Janina A Longtine, Kerin B. Adelson, Roy S. Herbst, Nathan C Nussbaum, Rachael Sorg, Amy Pickar Abernethy, Vineeta Agarwala, Cary Philip Gross
Journal: Journal of Clinical Oncology (2017)

6563 Background: The use of next generation sequencing (NGS) in patients with advanced non-small cell lung cancer (NSCLC) is increasing. This study explored disparities in the use of NGS testing. Methods: This retrospective observational study utilized Flatiron Health’s longitudinal, demographically and geographically diverse database containing electronic health record data from 191 oncology practices across the U.S. We identified patients diagnosed with advanced (stages IIIB/IV or recurrent) non-squamous NSCLC who received first line treatment and either NGS testing or standard biomarker testing (e.g., EGFR, ALK) alone. NGS included any multi-gene panel testing &gt; 30 genes. Logistic regression modeled the association between patient characteristics and receipt of NGS testing, accounting for clustering of patients by oncology practice. Results: Among 5,688 adults with advanced NSCLC, 4,813 (84.6%) patients received standard biomarker testing alone and 875 (15.4%) patients received NGS testing. The median age of the sample was 67y (IQR: 41-85), the majority was white (63.6%) vs. black (7.5%) vs. unknown (13.4%), and had a history of smoking (79.9%). Among the youngest patients ( &lt; 45y), 31.5% received NGS compared to 11.3% among the oldest (76-85y; P &lt; .001). Approximately 16% of white patients received testing, compared to 11.4% of black patients (P &lt; .001). Patients with Medicaid received testing less often than commercially insured patients (11.7% vs 17.0%; P = .10). Patients had significantly lower odds of receiving NGS testing if they were older (≥75 vs. &lt; 45 years of age; adjusted OR: 0.21, 95% CI: 0.13-0.34), black vs. white race (aOR: 0.63, 95% CI: 0.44-0.90) or were Medicaid vs. commercially insured (aOR: 0.54, 95% CI: 0.30-0.97). Conclusions: Significant age, race, and insurance-related disparities exist in the receipt of NGS testing among patients with advanced lung cancer in real world clinical practice.
Abstract 229: TNF Receptor 1 Signaling Is Critically Involved in Mediating Angiotensin II-Induced Cardiac Fibrosis and Dysfunction
Authors: Sandra B Haudek, Jeff Crawford, Erin Reineke, Alberto A Allegre, George E Taffet, JoAnn Trial, Mark L Entman
Journal: Circulation Research (2012)

Angiotensin-II (Ang-II) plays a key role in the development of cardiomyopathies, as it is associated with many conditions involving heart failure and pathologic hypertrophy. Using a murine model of Ang-II infusion, we found that Ang-II induced the synthesis of monocyte chemoattractant protein 1 (MCP-1) that mediated the uptake of CD34 + /CD45 + monocytic cells into the heart. These precursor cells differentiated into collagen-producing fibroblasts and were responsible for the Ang-II-induced development of reactive fibrosis. Preliminary in vitro data using our monocyte-to-fibroblast differentiation model, suggested that Ang-II required the presence of TNF to induce fibroblast maturation from monocytes. In vivo, they indicated that in mice deficient of both TNF receptors (TNFR1 and TNFR2), Ang-II-induced fibrosis was absent. We now assessed the hypothesis that specific TNFR1 signaling is necessary for Ang-II-mediated cardiac fibrosis. Mice deficient in either TNFR1 (TNFR1-KO) or TNFR2 (TNFR2-KO) were subjected to continuous infusion of Ang-II for 1 to 6 weeks (n=6-8/group). Compared to wild-type, we found that in TNFR1-KO, but not in TNFR2-KO mouse hearts, collagen deposition was attenuated, as was cardiac α-smooth muscle actin protein (a marker for activated fibroblasts). When we isolated viable cardiac fibroblasts and characterized them by flow cytometry, we found that Ang-II infusion in TNFR1-KO, but not in TNFR2-KO, resulted in a marked decrease of CD34 + /CD45 + cells. Quantitative RT-PCR demonstrated a striking reduction of type 1 and 3 collagen, as well of MCP-1 mRNA expression in TNFR1-KO mouse hearts. Further measurements of cardiovascular parameters indicated that TNFR1-KO animals developed lesser Ang-II-mediated LV remodeling, smaller changes in E-linear deceleration times/rates over time, and displayed a lower Tei index (a heart rate independent marker of cardiac function), indicating less stiffness in TNFR1-KO hearts compared to wild-type and TNFR2-KO hearts. The data suggest that Ang-II-dependent cardiac fibrosis requires TNF and its signaling through TNFR1 which enhances the induction of MCP-1 and uptake of monocytic fibroblast precursors that are associated with reactive fibrosis and cardiac remodeling and function.
Weight trajectories during first two years of endocrine treatment: Premenopausal compared to postmenopausal early breast cancer survivors.
Authors: Kirsten A Nyrop, Allison Mary Deal, Jordan T Lee, Hyman B. Muss, Seul Ki Choi, Amy Wheless, Lisa A. Carey, Shlomit S. Shachar
Journal: Journal of Clinical Oncology (2017)

e12069 Background: Obesity and weight gain in breast cancer survivors (BCS) can impact prognosis, survival, and quality of life. Women who were premenopausal (PreBCS) or postmenopausal (PostBCS) at BC diagnosis are compared regarding weight change during the first 2 years of endocrine treatment (ET) and factors associated with &gt; 2kg weight gain. Methods: Data were gathered by retrospective chart review, with weights assessed by nursing staff during routine clinic visits. Chi-squared and t-tests were used to compare PostBCS and PreBCS characteristics, and log-binomial regression models to evaluate factors associated with &gt; 2kg weight gain. Results: In a final sample of N = 447 BCS, 33% were PreBCS (mean age 44) and 67% were PostBCS (mean age 65). PreBCS had lower BMI at diagnosis (p = 0.003), lower proportion of white (p = 0.04), fewer comorbidities (p &lt; 0.0001); higher stage (p &lt; 0.0001), grade (p = 0.008), node positive (p &lt; 0.0001), PR positive (p = 0.03), and HER2 positive (p = 0.03) BC tumors; higher proportion of mastectomies (p &lt; 0.0001), axillary node dissection (p = 0.005), chemotherapy (p &lt; 0.0001), radiation treatment (p = 0.009), and Tamoxifen use (p &lt; 0.0001); and less weight loss between diagnosis and start of ET (p = 0.013). After 2 years of ET, 48% of PreBCS and 39% of PostBCS had gained &gt; 2kg (p = 0.08). In univariate analysis, factors associated with &gt; 2kg weight gain were: weight loss between BC diagnosis and ET start (p &lt; .0001), lower age at start of ET (p = .002), higher tumor size (p = .003), increasing stage (p &lt; .0001), mastectomy (p = .0002), axillary node dissection (p = .005), positive nodal status (p = 0.0003), and chemotherapy (p &lt; .0001). In multivariable analysis controlling for covariates that differed between PreBCS/PostBCS, only weight change between BC diagnosis and ET start was associated with &gt; 2kg weight gain (p = 0.0005). Conclusions: In our sample, neither menopausal status nor type of ET was significantly associated with weight gain during ET. Our research suggests that BC survivors with higher risk tumors and associated treatments may experience higher weight gain during ET and warrant weight management counseling.
Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial
Authors: Alice T Shaw, Tae Min Kim, Lucio Crinò, Cesare Gridelli, Katsuyuki Kiura, Geoffrey Liu, Silvia Novello, Alessandra Bearz, Oliver Gautschi, Tony Mok, Makoto Nishio, Giorgio Scagliotti, David R Spigel, Stéphanie Deudon, Cheng Zheng, Serafino Pantano, Patrick Urban, Cristian Massacesi, Kalyanee Viraswami-Appanna, Enriqueta Felip
Journal: The Lancet Oncology (2017)
Abstract 49: Prolyl Isomerase Pin1 Regulates Cardiac Hypertrophy via Controlling Phosphorylation of Akt and MEK
Authors: Haruhiro Toko, Mathias Konstandin, Natalie Gude, Mark Sussman
Journal: Circulation Research (2012)

Rationale: Kinases and phosphatases regulate crucial aspects of growth and survival through phosphorylation and dephosphorylation of target substrates. Processes of cardiac hypertrophy, myocardial infarction, and heart failure are dictated in part by which kinases or phosphatases are involved and also by the intensity and duration of specific enzymatic activities. While research has identified numerous critical regulatory kinases and phosphatases in the myocardium, the intracellular mechanism for temporal regulation of signaling duration and intensity remains obscure. In the non-myocyte context, control of folding, activity, stability, and subcellular localization of proteins responsible for growth and survival is mediated by the prolyl isomerase Pin1. Objective: To establish the role of Pin1 in the heart. Method and Results: Initial characterization of myocardial Pin1 involved assessment of expression and localization during postnatal development or pathological challenge. Pin1 protein level was decreased and the location of Pin1 was changed from nucleus to cytoplasm with increasing age. Next, Pin1 protein expression and localization were assessed in the pathological challenged heart. Pin1 protein expression increases with pressure overload and ischemia, particularly in perivascular areas and in border zone myocytes, respectively. To determine the role of Pin1 on cardiac hypertrophy, siRNA to Pin1 (siPin1) was applied to neonatal rat cardiomyocytes. Western blot analysis showed that siPin1 decreased phosphorylation of Akt, and immunohistochemical analysis showed that siPin1 reduced cardiomyocyte size in response to high serum. siPin1 also decreased phosphorylation of MEK and reduced cardiomyocyte size in response to phenylephrine treatment. Furthermore, cardiac hypertrophy induced by transaortic constriction was ameliorated in Pin1 knockout mice, compared with littermate wild type mice. Conclusion: Expression and location of Pin1 during development and in response to pathologic challenge point to an important role for Pin1 in adaptation to myocardial growth or stress. Collective evidence indicates that Pin1 controls cardiac hypertrophy at least in part via regulating phosphorylation of Akt and MEK.
Response by Simpson et al to Letter Regarding Article, “Adrenergic Receptors in Individual Ventricular Myocytes: the Beta-1 and Alpha-1B Are in All Cells, the Alpha-1A Is in a Subpopulation, and the Beta-2 and Beta-3 Are Mostly Absent”
Authors: Paul C. Simpson, Bat-Erdene Myagmar, Philip M. Swigart, Simon Melov, Anthony J. Baker
Journal: Circulation Research (2017)
Antipsychotics vary in preventing treatment relapse in schizophrenia, study finds
Authors: Susan Mayor
Journal: BMJ (2017)

People with schizophrenia who are treated with long acting injectable antipsychotics have a 20-30% lower risk of relapse requiring readmission to hospital than people treated with equivalent oral formulations, a nationwide study assessing the real world effectiveness of these drugs has found.1

The comparative effectiveness of antipsychotics in patients with schizophrenia is not clear despite extensive research. Randomised trials have suggested that …
FOXM1 in Cancer: Interactions and Vulnerabilities
Authors: Andrei L. Gartel
Journal: Cancer Research (2017)

Abstract FOXM1 is a transcription factor of the Forkhead family that is required for cell proliferation of normal cells. However, FOXM1 is repeatedly overexpressed in a variety of human cancers, and it has been implicated in all major hallmarks of cancer delineated by Hanahan and Weinberg. It has been postulated that the oncogenic potential of FOXM1 is determined by its capacity to transactivate target genes that are implicated in different phases of cancer development. However, FOXM1 may also play an oncogenic role by interacting with other proteins, such as β-catenin or SMAD3 to induce oncogenic WNT and TGFβ signaling pathways, respectively. In this review, I will discuss the protein–protein interactions of FOXM1 that are critical for cancer development and may represent novel targets for anticancer drugs. Cancer Res; 77(12); 3135–9. ©2017 AACR.