tbuckley/cabot-search huggingface dataset:
The adrenergic nervous system as a therapeutic target in pulmonary arterial hypertension: a cautionary tale
Authors: Lewis J. Rubin
Journal: European Respiratory Journal (2016)

While the role of the adrenergic nervous system in the progression of left ventricular failure has been well established, its contribution to the pathogenesis of pulmonary arterial hypertension (PAH) and the resultant right ventricular failure is far less clear. The earliest attempts to treat PAH included drugs that were α-adrenergic agonists such as tolazoline [1] and isoproterenol [2]; unfortunately, their administration usually resulted in systemic hypotension and little evidence of a beneficial effect on pulmonary circulatory or right ventricular dynamics. More recently, interest has shifted towards targeting the β-adrenergic pathway as a therapeutic strategy for PAH. Nebivolol, a β1 antagonist and β2–3 agonist, inhibits proliferation of pulmonary vascular cells and produces endothelial and nitric oxide-dependent relaxation of pulmonary artery rings [3]; both nebivolol and pulmonary artery sympathetic denervation (PADN) attenuate vascular remodelling in monocrotaline-treated rats [3, 4], and single-centre preliminary results of PADN in PAH patients are of considerable interest [5]. In this issue of the European Respiratory Journal , van Campen et al. [6] report the results of their single-centre study of the effects of β-adrenergic blockade in patients with PAH. Their results reinforce the notion that the pulmonary and systemic circulations and their respective ventricles behave very differently both in the pathogenesis of disease states and in response to targeted therapies. A study of beta-adrenergic blockade in patients with PAH demonstrated no benefit but some serious adverse effects <http://ow.ly/xeJy302c69b>
Genetic-Based Dissection Unveils the Inputs and Outputs of Striatal Patch and Matrix Compartments
Authors: Jared B. Smith, Jason R. Klug, Danica L. Ross, Christopher D. Howard, Nick G. Hollon, Vivian I. Ko, Hilary Hoffman, Edward M. Callaway, Charles R. Gerfen, Xin Jin
Journal: Neuron (2016)
Clapd (Clarithromycin, Pomalidomide, Dexamethasone) Therapy in Relapsed or Refractory Multiple Myeloma Overcomes Negative Prognostic Impact of Adverse Cytogenetics and Prior Resistance to Lenalidomide and Bortezomib
Authors: Tomer M Mark, Angelique Boyer, Sujitha Yadlapati, Adriana C Rossi, Roger N Pearse, Karen Pekle, Arthur Perry, Kathleen Pogonowski, Ekta Aneja, Linda Tegnestam, David Jayabalan, Scott Ely, Morton Coleman, Xiangao Huang, Maurizio Di Liberto, Selina Chen-Kiang, Ruben Niesvizky
Journal: Blood (2015)
Long-term outcomes in patients with septic shock transfused at a lower versus a higher haemoglobin threshold: the TRISS randomised, multicentre clinical trial
Authors: Sofie L. Rygård, Lars B. Holst, Jørn Wetterslev, Per Winkel, Pär I. Johansson, Jan Wernerman, Anne B. Guttormsen, Sari Karlsson, Anders Perner
Journal: Intensive Care Medicine (2016)
Expression patterns of a taxane sensitivity panel in 25,000 cancer patients.
Authors: Brian L. Abbott, Rebecca Feldman, Sandeep K. Reddy, Michael Castro
Journal: Journal of Clinical Oncology (2015)

e22235 Background: Taxanes are microtubule poisons that have cytotoxic applications across a wide range of cancer types. Taxanes block cell division by binding to tubulin and disrupting the function of the mitotic spindle thereby inducing cell death. Clinical data exist to support the role of various predictive markers for taxane response, including low or negative class III beta tubulin (TUBB3), positive transducin-like enhancer of split 3 (TLE3) and low or negative p-glycoprotein (PGP/ABCB1). We explored the expression patterns of these proteins across tumor types. Methods: 25,312 patients molecularly profiled with a commercial multiplatform service (Caris Life Sciences) were evaluated. Protein expression by immunohistochemistry (IHC) was assessed. Results: A range of response categories were identified based on patterns of PGP, TLE3 and TUBB3. The “favorable response” category (all 3 markers in the favorable direction) accounts for 11% (2722/25,312), whereas the “unfavorable response” category (all 3 markers in the unfavorable direction) accounts for 6% (1412/25,312) of the population studied. 83% of studied patients fall within a spectrum of potentially mixed responses, based on these markers. Results with tumor type and in decreasing order of frequency for the “favorable response” category are shown. Conclusions: Taxanes are the backbone to many antineoplastic regimens used across many tumor types. Further investigations into defining categories of patients that have favorable or unfavorable responses to taxane therapy, (based on biomarker guidance) are warranted. % Exhibiting Favorable Response Expression % Exhibiting Unfavorable Response Expression Taxanes- NCCN? Tumor Type N PGP-/TLE3+/TUBB3- PGP+/TLE3-/TUBB3+ Prostate 213 35% 1% Y Breast 2704 30% 2% Y Thymic cancers 46 28% 0% Y Cervical 271 23% 2% Y HNSCC 304 18% 0% Y Bone 48 17% 0% Y Bladder 245 15% 6% Y Thyroid cancers 78 13% 3% N Sarcoma 822 13% 3% Y NSCLC 2270 11% 7% Y Kidney 221 10% 9% Y GE/GEJ 341 9% 8% Y Gastric 268 9% 4% Y Epithelial Ovarian 7610 7% 4% Y CUP 736 9% 14% Y Uterine/Endometrial 2179 7% 3% Y CRC 2182 7% 12% N Melanoma 560 5% 3% Y Pancreatic 909 5% 16% Y Glioblastoma 515 5% 3% N SCLC 172 3% 5% Y Cholangiocarcinoma 270 4% 20% N Liver (HCC) 126 2% 7% N Extrahepatic bile duct 39 0% 51% N
A phase I study of PF-05082566 (anti-4-1BB) + rituximab in patients with CD20+ NHL.
Authors: Ajay K. Gopal, Nancy L. Bartlett, Ronald Levy, Roch Houot, Stephen Douglas Smith, Neil Howard Segal, Aron D. Thall, Ganesh Mugundu, Bo Huang, Craig Davis, Holbrook Edwin Kohrt
Journal: Journal of Clinical Oncology (2015)

3004 Background: 4-1BB agonists enhance cytotoxic T-cell and NK cell responses, including antibody-dependent cellular cytotoxicity, resulting in anti-tumor activity in preclinical models. PF-05082566 (PF-566), a fully humanized IgG2 monoclonal antibody, activates 4-1BB while blocking binding to endogenous 4-1BBL. Methods: This Phase I study evaluated PF-566 in doses ranging from 0.03-10 mg/kg in combination with 375 mg/m2 rituximab (R) in patients (pts) with relapsed or refractory CD20+ NHL. Patients were treated using a Time-To-Event Continuous-Reassessment-Method design. Pts received PF-566 from D1 Q4 weeks up to 24 mo. and R from D-7 Q1W X4. The 1o endpoint was first 2-cycle DLT with PK/PD, safety, and anti-tumor activity as 2o endpoints. Results: 35 pts with CD20 + NHL were treated with PF-566 combined with R: Follicular (FL) (n = 22), mantle cell (MCL) (n = 5), diffuse large B cell (n = 3), marginal zone (n = 2), small lymphocytic (n = 2) and nodular lymphocyte predominant Hodgkin's (n = 1), 34 (97%) with prior R, and 20 (57%) with R-refractory disease. The median number of prior regimens was 3 (range of 1 - 9). No DLTs were observed and no pts discontinued treatment due to treatment-related AEs. The MTD was estimated as ≥ 10 mg/kg. No severe immune-related AEs were observed. PK data show a dose proportional increase in exposure and a half-life of ~10 days. Increases in soluble 4-1BB, memory T cells, and activated NK cells were observed. For pts up to 2.4 mg/kg (higher doses under evaluation for efficacy), the ORR was 21% (6/28), and in R-refractory pts the ORR was 29% (4/14), with 2 CR (0.03 and 0.12 mg/kg, both FL) with a duration of response > 2 years and 2 PR (FL and MCL). Enrollment into an expansion cohort is ongoing. The PFS for all of the R-refractory responders was > 6 mo and for all R-refractory pts the 6 mo PFS rate was 66% by Kaplan-Meier. Conclusions: PF-05082566 in combination with rituximab was well tolerated, with anti-tumor activity in R-refractory NHL patients, along with biomarker modulation consistent with 4-1BB agonist activity. In these R-refractory patients, the durability of anti-tumor activity appeared greater than their previous therapy. Further clinical studies of this combination in R-refractory indolent NHL patients are warranted. Clinical trial information: NCT01307267.
8P Organic cation transporter 6 directly confers resistance to anticancer platinum drugs
Authors: T. Oguri, E. Kunii, S. Fukuda, T. Uemura, O. Takakuwa, K. Maeno, Y. Kanemitsu, H. Ohkubo, M. Takemura, Y. Ito, A. Niimi
Journal: Annals of Oncology (2015)
Carbapenem-Resistant Enterobacteriaceae Transmission in Health Care Facilities — Wisconsin, February–May 2015
Authors: Lina I. Elbadawi, Gwen Borlaug, Kristin M. Gundlach, Timothy Monson, David Warshauer, Maroya S Walters, Alexander Kallen, Christopher A. Gulvik, Jeffrey P. Davis
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Carbapenem-resistant Enterobacteriaceae (CRE) are multidrug-resistant gram-negative bacilli that can cause infections associated with high case fatality rates, and are emerging as epidemiologically important health care-associated pathogens in the United States (1). Prevention of CRE transmission in health care settings is dependent on recognition of cases, isolation of colonized and infected patients, effective use of infection control measures, and the correct use of antibiotics. The use of molecular technologies, including polymerase chain reaction (PCR) testing, pulsed-field gel electrophoresis (PFGE), and whole genome sequencing (WGS), can lead to detection of transmission events and interruption of transmission. In Wisconsin, acute care and critical access hospitals report laboratory-identified CRE to the Wisconsin Division of Public Health (WDPH), and clinical laboratories submit CRE isolates to the Wisconsin State Laboratory of Hygiene (WSLH) for molecular testing. During February-May 2015, a total of 49 CRE isolates from 46 patients were submitted to WSLH. On June 8, WSLH informed WDPH of five carbapenemase-producing CRE isolates with closely related PFGE patterns identified among four inpatients at two hospitals in southeastern Wisconsin. An investigation revealed a high degree of genetic relatedness among the patients' isolates, but did not identify the mechanism of transmission between the two facilities. No breaches in recommended practices were identified; after reviewing respiratory care procedures, no further cases were identified. Routine hospital- and laboratory-based surveillance can detect and prevent health care transmission of CRE.
P0707 : Differences in the intestinal microbiota in patients with chronic hepatitis C
Authors: B. Heidrich, I. Plumeier, S. Kahl, R. Jauregui, W.I. Barrantes-Bustinza, J. Kirschner, L. Sollik, S. Ziegert, M.P. Manns, H. Wedemeyer, D.H. Pieper
Journal: Journal of Hepatology (2015)
Respiratory manifestations of eosinophilic granulomatosis with polyangiitis (Churg–Strauss)
Authors: Vincent Cottin, Elisabeth Bel, Paolo Bottero, Klaus Dalhoff, Marc Humbert, Romain Lazor, Renato A. Sinico, Pasupathy Sivasothy, Michael E. Wechsler, Matthieu Groh, Sylvain Marchand-Adam, Chahéra Khouatra, Benoit Wallaert, Camille Taillé, Philippe Delaval, Jacques Cadranel, Philippe Bonniaud, Grégoire Prévot, Sandrine Hirschi, Anne Gondouin, Bertrand Dunogué, Gérard Chatté, Amandine Briault, David Jayne, Loïc Guillevin, Jean-François Cordier
Journal: European Respiratory Journal (2016)

The respiratory manifestations of eosinophilic granulomatosis with polyangiitis (EGPA) have not been studied in detail. In this retrospective multicentre study, EGPA was defined by asthma, eosinophilia and at least one new onset extra-bronchopulmonary organ manifestation of disease. The study population included 157 patients (mean± sd age 49.4±14.1 years), with a mean± sd blood eosinophil count of 7.4±6.4×10 9 L −1 at diagnosis. There was a mean± sd of 11.8±18.2 years from the onset of asthma to the diagnosis of EGPA, of 1.4±8.4 years from the first onset of peripheral eosinophilia to the diagnosis of EGPA, and of 7.4±6.4 years from EGPA diagnosis to the final visit. Despite inhaled and oral corticosteroid treatment, the severity of asthma increased 3–6 months before the onset of the systemic manifestations. Asthma was severe in 57%, 48%, and 56% of patients at diagnosis, at 3 years, and at the final visit, respectively. Persistent airflow obstruction was present in 38%, 30%, and 46% at diagnosis, at 3 years, and at the final visit, respectively. In EGPA, asthma is severe, antedates systemic manifestations by a mean of 12 years, and progresses to long-term persistent airflow obstruction despite corticosteroids in a large proportion of patients, which affects long-term management and morbidity.
Phase 1 dose escalation, food effect, and biomarker study of RG7388, a more potent second-generation MDM2 antagonist, in patients (pts) with solid tumors.
Authors: Lillian L. Siu, Antoine Italiano, Wilson H. Miller, Jean-Yves Blay, Jourik A. Gietema, Yung-Jue Bang, Linda R. Mileshkin, Hal W. Hirte, Monica Reckner, Brian Higgins, Lori Jukofsky, Steven Blotner, Jianguo Zhi, Steven Middleton, Gwen L. Nichols, Lin Chi Chen
Journal: Journal of Clinical Oncology (2014)

2535 Background: RG7388 is an oral pyrrolidine designed as a potent antagonist of MDM2. Preclinical studies demonstrate p53 activation, tumor growth inhibition, & increased life span in xenograft models. Methods: A phase 1 study in solid tumor pts was conducted to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), food-effect (FE) & biomarker (BM) activity of RG7388. Administration schedules of once weekly (qwk) x 3, & daily (3 or 5d) every 28d were evaluated. Following initial accelerated titration, a modified continual reassessment method-escalation with overdose control (EWOC) requiring at least 2 DLT evaluable pts per cohort, was used to guide escalation. Enrolment in BM cohorts was initiated at the prior dose level once EWOC was triggered. PK, baseline p53 & MDM2 status, & serum MIC-1 (a marker for p53 activation) were measured for all pts. The FE cohort consisted of 10 pts in a randomized, 3-way crossover, partial-replicate design. In BM cohorts, tumor biopsies were collected pre-dose & during cycle 1 for analysis of p53 activation, anti-proliferative & pro-apoptotic effects of RG7388. Correlative changes in FLT-PET imaging were also assessed. Results: Accrual to dose escalation, FE & core BM cohorts is complete: 46 pts enrolled on the qwk schedule (7 dose levels from 100 - 3200 mg qwk x 3); 49 pts enrolled on the daily schedule: 34 pts treated for 5d at 8 dose levels (100 - 1200 mg daily) & 15 pts treated for 3d at 2 dose levels (1000 & 1600 mg daily). Nausea/vomiting & myelosuppression (more frequent in the daily dosing schedule & associated with PK exposure) were the DLTs. MTD per schedule was: 1600 mg bid qwk x 3; 500 mg bid x 3d & 500 mg qd x 5d. Dose-PK exposure was proportional up to 2,400 mg/d; t½: ~ 1 d. No major effect of high-fat food on PK exposure was seen. MIC-1 activation was seen at the lowest dose evaluated. Preliminary BM results suggest that p53 activation is greater with 5d dosing than with other schedules at respective MTDs. Stable disease for 17, 22 & 23+ months has been seen in sarcoma pts. Conclusions: RG7388 demonstrates p53 activation which may be dose & schedule dependent and warrants further evaluation. Safety, PK, FE, PD & BM results will be presented. Clinical trial information: NCT01462175.
Increased Activity or Energy as a Primary Criterion for the Diagnosis of Bipolar Mania in DSM-5: Findings From the STEP-BD Study
Authors: Rodrigo Machado-Vieira, David A. Luckenbaugh, Elizabeth D. Ballard, Ioline D. Henter, Mauricio Tohen, Trisha Suppes, Carlos A. Zarate
Journal: American Journal of Psychiatry (2016)

Objective: DSM-5 describes "a distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy" as a primary criterion for mania. Thus, increased energy or activity is now considered a core symptom of manic and hypomanic episodes. Using data from the Systematic Treatment Enhancement Program for Bipolar Disorder study, the authors analyzed point prevalence data obtained at the initial visit to assess the diagnostic validity of this new DSM-5 criterion. The study hypothesis was that the DSM-5 criterion would alter the prevalence of mania and/or hypomania. Method: The authors compared prevalence, clinical characteristics, validators, and outcome in patients meeting the DSM-5 criteria (i.e., DSM-IV criteria plus the DSM-5 criterion of increased activity or energy) and those who did not meet the new DSM-5 criterion (i.e., who only met DSM-IV criteria). Results: All 4,360 participants met DSM-IV criteria for bipolar disorder, and 310 met DSM-IV criteria for a manic or hypomanic episode. When the new DSM-5 criterion of increased activity or energy was added as a coprimary symptom, the prevalence of mania and hypomania was reduced. Although minor differences were noted in clinical and concurrent validators, no changes were observed in longitudinal outcomes. Conclusions: The findings confirm that including increased activity or energy as part of DSM-5 criterion A decreases the prevalence of manic and hypomanic episodes but does not affect longitudinal clinical outcomes.
Pathway Targeted Immunotherapy: Rationale and Evidence of Durable Clinical Responses with a Novel, EGF-directed Agent for Advanced NSCLC
Authors: Rafael Rosell, Elia Neninger, Marianne Nicolson, Rudolf M. Huber, Sumitra Thongprasert, Purvish M. Parikh, Erik D’Hondt
Journal: Journal of Thoracic Oncology (2016)
Abstract 3385: Role Of Regional Geometric Dyssynchrony By Real-time Three-dimensional Echocardiography As A Determinant Of Functional Mitral Regurgitation In Patients With Acute Myocardial Infarction
Authors: Chung-Lieh Hung, Anil Verma, Rahman Shah, Charles Jia-Yin Hou, Hung-I Yeh, Cheng-Ho Tsai
Journal: Circulation (2007)

Background: Functional mitral regurgitation (FMR) after myocardial infarction (MI) is associated with left ventricular (LV) dys-synchrony and increased mortality. However, determinants of FMR severity after acute MI are poorly defined. Our aim was (1) to test whether real-time Three-Dimensional echocardiography (RT-3DE) can provide insights into the mechanism of LV dys-synchrony on MR severity after MI (2) to investigate role of selective regional dys-synchrony index (DI) in prediction of FMR. Method: RT-3DE and Doppler echo was performed on 64 consecutive patients (mean age 62.2 ± 12.5 yrs) following acute MI without cardiogenic shock and with narrow QRS complex (&lt; 120 ms). MR Severity was assessed by vena contracta, and MR jet area/LA area. Dyssynchrony index (DI) was derived from the dispersion of time to minimum regional volume for all 16 LV segments. Pearson’s correlation and multiple linear regression analysis were used to identify the relationship between FMR and DI. Different models of LV dys-synchrony including global index and selective ring-defined (basal, middle and apical ring) regional index were all analyzed and compared. Results: The mean LVEF was 49.6 ± 11.9% and LV end-diastolic volume (EDV) was 93.1 ± 23.8ml. All regional and global DIs were significantly correlated with FMR even after adjusting for age, LVEF and EDV (table 1 ), with mid-wall DI being most strongly associated with MR severity. Conclusion: RT-3DE determined mid-wall DI following MI is strongly associated with FMR. Our results suggest that selective geometric ring-defined DI has better FMR severity prediction and may provide specific approaches to the treatment of FMR complicating MI.
NLRC4 suppresses melanoma tumor progression independently of inflammasome activation
Authors: Ann M. Janowski, Oscar R. Colegio, Emma E. Hornick, Jennifer M. McNiff, Matthew D. Martin, Vladimir P. Badovinac, Lyse A. Norian, Weizhou Zhang, Suzanne L. Cassel, Fayyaz S. Sutterwala
Journal: Journal of Clinical Investigation (2016)

Members of the NLR family can assemble inflammasome complexes with the adaptor protein ASC and caspase-1 that result in the activation of caspase-1 and the release of IL-1β and IL-18. Although the NLRC4 inflammasome is known to have a protective role in tumorigenesis, there is an increased appreciation for the inflammasome-independent actions of NLRC4. Here, we utilized a syngeneic subcutaneous murine model of B16F10 melanoma to explore the role of NLRC4 in tumor suppression. We found that NLRC4-deficient mice exhibited enhanced tumor growth that was independent of the inflammasome components ASC and caspase-1. Nlrc4 expression was critical for cytokine and chemokine production in tumor-associated macrophages and was necessary for the generation of protective IFN-γ–producing CD4+ and CD8+ T cells. Tumor progression was diminished when WT or caspase-1–deficient, but not NLRC4-deficient, macrophages were coinjected with B16F10 tumor cells in NLRC4-deficient mice. Finally, examination of human primary melanomas revealed the extensive presence of NLRC4+ tumor-associated macrophages. In contrast, there was a paucity of NLRC4+ tumor-associated macrophages observed in human metastatic melanoma, supporting the concept that NLRC4 expression controls tumor growth. These results reveal a critical role for NLRC4 in suppressing tumor growth in an inflammasome-independent manner.
Safety and antitumor activity of hypofractionated stereotactic irradiation (HFSRT) with pembrolizumab (Pembro) and bevacizumab (Bev) in patients (pts) with recurrent high grade gliomas: Preliminary results from phase I study.
Authors: Solmaz Sahebjam, Peter A. Johnstone, Peter A. J. Forsyth, John Arrington, Frank D Vrionis, Arnold B Etame, Nam D. Tran, Pranali H Dalvi, Sungjune Kim, Robert J Macaulay, Prakash Chinnaiyan, Michael Yu
Journal: Journal of Clinical Oncology (2016)

2041 Background: High grade gliomas carry a grim prognosis despite current therapies. Several studies have shown that the combination of anti-PD-1 antibody with stereotactic radiosurgery generates robust and durable responses and improves survival in preclinical models of glioma. Pembro is a highly selective humanized monoclonal antibody against PD-1. This study evaluates the safety and anti-tumor activity of Pembro administered in combination with Bev and HFSRT in pts with recurrent high grade gliomas. Methods: This phase I study (3+3 design) explores the safety, tolerability, recommended phase II dose (RP2D), and antitumor activity of Pembro administered concurrently with HFSRT and Bev (NCT02313272). Adult pts with recurrent glioblastoma (GBM) or anaplastic astrocytoma (maximum diameter of target lesion ≤ 3.5 cm) are eligible. Eligible patients receive HFSRT to the recurrent tumor (30 Gy delivered in 5 fractions) combined with Bev (10 mg/kg, intravenously Q2W) and Pembro (100 mg or 200 mg intravenously based on dose level, Q3W). Two dose levels of Pembro (100 mg and 200 mg Q3W) are explored. Once the RP2D is determined, an additional 20 patients will be enrolled in an expansion cohort. Response is assessed every 6W per RANO criteria. Effect of treatment on quality of life measures are evaluated. Results: As of Feb 2016, 6 pts with GBM were enrolled: 3 at Pembro 100 mg, 3 at Pembro 200 mg dose levels. No dose limiting toxicity or dose modifications were reported. Permanent discontinuation due to treatment-related AEs has not occurred. No treatment related neurologic AEs were observed. The most common drug-related AE was grade 1 fatigue (2 out of 6). At the time of abstract submission, all pts are continuing on study treatment and 3 pts (at Pembro 100 mg dose level) are evaluable for response. Durable disease control is seen in all 3 pts, including 1 CR (24+W) and 2 SDs (24+ W and 22+ W). Conclusions: Preliminary data demonstrate an acceptable toxicity profile for combination of HFSRT with Pembro and Bev in pts with recurrent high grade gliomas. Updated safety, efficacy data will be presented. Clinical trial information: NCT02313272.