tbuckley/cabot-search huggingface dataset:
Titin splicing regulates cardiotoxicity associated with calpain 3 gene therapy for limb-girdle muscular dystrophy type 2A
Authors: William Lostal, Carinne Roudaut, Marine Faivre, Karine Charton, Laurence Suel, Nathalie Bourg, Heather Best, John Edward Smith, Jochen Gohlke, Guillaume Corre, Xidan Li, Zaher Elbeck, Ralph Knöll, Jack-Yves Deschamps, Henk Granzier, Isabelle Richard
Journal: Science Translational Medicine (2019)

Limb-girdle muscular dystrophy type 2A (LGMD2A or LGMDR1) is a neuromuscular disorder caused by mutations in the calpain 3 gene (CAPN3). Previous experiments using adeno-associated viral (AAV) vector-mediated calpain 3 gene transfer in mice indicated cardiac toxicity associated with the ectopic expression of the calpain 3 transgene. Here, we performed a preliminary dose study in a severe double-knockout mouse model deficient in calpain 3 and dysferlin. We evaluated safety and biodistribution of AAV9-desmin-hCAPN3 vector administration to nonhuman primates (NHPs) with a dose of 3 × 1013 viral genomes/kg. Vector administration did not lead to observable adverse effects or to detectable toxicity in NHP. Of note, the transgene expression did not produce any abnormal changes in cardiac morphology or function of injected animals while reaching therapeutic expression in skeletal muscle. Additional investigation on the underlying causes of cardiac toxicity observed after gene transfer in mice and the role of titin in this phenomenon suggest species-specific titin splicing. Mice have a reduced capacity for buffering calpain 3 activity compared to NHPs and humans. Our studies highlight a complex interplay between calpain 3 and titin binding sites and demonstrate an effective and safe profile for systemic calpain 3 vector delivery in NHP, providing critical support for the clinical potential of calpain 3 gene therapy in humans.
A phase II trial of adjuvant chemoradiotherapy for patients with high-risk rectal submucosal invasive cancer after local resection
Authors: M. Noguchi, K. Shitara, A. Kawazoe, D. Yamamoto, Y. Takii, Y. Saito, T. Sato, T. Horimatsu, H. Ishikawa, Y. Ito, M. Ito, H. Ikematsu
Journal: Annals of Oncology (2019)
What came first, the chicken or the egg?
Authors: Lionel Artige, Todd Lubart, Leif van Neuss
Journal: Behavioral and Brain Sciences (2019)

Abstract Current empirical evidence does not seem to confirm that an improvement in living conditions is the cause of the shift in the human mindset toward innovation and long-term risky investment. However, it may well be one of the conditions for greater tolerance of income inequality in exchange for a steady increase in average income.
Cognitive dysfunction in patients with cancer pain (CP): A multicenter cross-sectional study from China.
Authors: Rongbo Lin, Shen Zhao, Hongyu Zhu, Yan Lei, Xiaofang Wen, Yamei Deng, ShuFang Ruan, Tingting Hu, Wei Huang, Min Han, Jianyi Wang, Yuqiong Hu, Xiaohua He, Xi Ke, Guangfeng Wu, Huiyu Luo
Journal: Journal of Clinical Oncology (2019)

81 Background: Pain is one of the most common symptoms in cancer patients and often has a negative impact on patients’ functional status and quality of life. Cognitive dysfunction can impact the assessment and treatment of pain. Taking analgesics may worsen the cognitive dysfunction. The study of the prevalence of cognitive dysfunction and the association with analgesics in the CP patients is rare in China. This study aimed to investigate the prevalence of cognitive dysfunction in Chinese CP patients and analyze the related factors. Methods: A total of 220 Chinese CP patients in 9 first-grade hospitals received the following assessment: the functional assessment of cancer therapy-cognitive function (FACT-Cog) and numerical rating scale (NRS), Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7). ANOVA and multiple linear regression analysis were performed to explore the related factors. Results: A total of 220 Chinese CP patients received the assessment: The overall incidence of cognitive dysfunction in CP patients was 33.64%, with an average cognitive function score 105.93±21.39. The total cognitive function score and each dimension were negatively correlated with the pain, depression, and anxiety levels. The analgesics did not affect the cognitive function of CP patients. Sleep and smoking history were two key factors influencing the cognitive function. Conclusions: An effective management of pain, depression, anxiety, sleep, and smoking are recommended to protect the cognitive function of patients under CP stress. It is safe and reliable to regularly use the analgesics for CP patients. Clinical trial information: NCT03641820.
Targeting Myeloma Cell Metabolism Via Disruption of the Lnc-17-92 Transcriptional Program: Druggable New Vulnerability in Multiple Myeloma
Authors: Eugenio Morelli, Mariateresa Fulciniti, Mehmet Kemal Samur, Caroline Ribeiro, Leon Wert-Lamas, Annamaria Gulla, Anil Aktas Samur, Cinzia Federico, Francesca Scionti, Yao Yao, Nicola Amodio, Giada Bianchi, Yu-Tzu Tai, Pierfrancesco Tassone, Kenneth C. Anderson, Carl D. Novina, Massimo Loda, Nikhil C. Munshi
Journal: Blood (2019)
Implementation and dissemination of a shared mental model of palliative oncology.
Authors: Sarah F. D'Ambruoso, John A. Glaspy, Neil Wenger, Christopher Pietras, Kauser Ahmed, Sara A. Hurvitz, Alexandra Drakaki, Jonathan Wade Goldman, Sidharth Anand, Wendy Simon, Jennie Kung, Anne Coscarelli, Lee S. Rosen, Parvin F. Peddi, Deborah J.L. Wong, Peter Phung, Daniel Karlin, Anne M. Walling
Journal: Journal of Clinical Oncology (2019)

58 Background: American Society of Clinical Oncology guidelines support early integration of palliative care (PC) into standard oncology practice; however, little is known as to whether improved outcomes can be achieved by modifying health care delivery and training oncology providers. Methods: We report our five year experience of embedding a nurse practitioner (NP) in an oncology clinic (March 2014-March 2019) to develop a shared mental model (SMM) of early, concurrent advance care planning (ACP) and PC as well as the collaborative effort to further disseminate this SMM throughout the Division of Hematology-Oncology using communication training, quality measurement, audit and feedback, leadership support, and monthly collaborative meetings. We developed PC quality metrics (process measures and end of life utilization measures) using a validated advanced cancer denominator. We used these measures to evaluate the impact of the PC-NP program (2014-2019) and provide individualized metric packets to each oncologist in the context of an annual half-day interactive communication training sessions (1-hr didactic, 3-hr small group role-play) each spring and monthly implementation team meetings from 2017-2019. Results: Compared to patients with advanced cancer not seen by the PC-NP program, patients who are enrolled in the program have higher rates of goals of care note documentation (80% vs. 17%, p &lt; 0.01), higher rates of Physician Orders for Life Sustaining Treatment (POLST) completion (19% vs. 5%, p &lt; 0.01), higher referral rates to the psychosocial oncology program (51% vs. 25%, p &lt; 0.01), and higher referral rates to hospice (60% vs. 33%, p &lt; 0.01). Among decedents, there was less hospital use (12 vs. 18 days) and ICU use (1.5 vs. 2.6 days) in the last 6 months of life. Since spring 2017, 19/21 NP’s, 64/68 physicians, and 17/20 fellows have participated in communication training. Among all patients with advanced cancer, goals of care note documentation has improved from 3% in March 2014 to 21% in March 2019. Conclusions: Embedding a trained PC-NP in oncology clinics to deliver upstream PC to patients on active treatment can lead to opportunities for development and dissemination of a SMM that translates into better primary and specialist PC.
Declining US life expectancy is driven by more than just opioids, study finds
Authors: Owen Dyer
Journal: BMJ (2019)

The United States began to fall behind other rich countries in improving life expectancy long before the opioid epidemic gathered steam around the turn of the millennium, says an analysis published in JAMA ,1 and opioid deaths are just one of several factors contributing to increased mortality among US people of working age.

The country has matched other wealthy nations in cutting its death toll from big killers such as cancer, ischaemic heart disease, and AIDS, but these gains have been undermined by an increasing toll from drug overdose, suicide, liver disease, and lung diseases, the study finds.

“There has been an increase in death rates among working age Americans,” the lead author, Steven Woolf, told ABC News . “This is an emergent crisis, and it is a uniquely American problem since it is not seen in other …
Transcriptome reprogramming and myeloid skewing in haematopoietic stem and progenitor cells in systemic lupus erythematosus
Authors: Maria Grigoriou, Aggelos Banos, Anastasia Filia, Pavlos Pavlidis, Stavroula Giannouli, Vassiliki Karali, Dionysis Nikolopoulos, Antigone Pieta, George Bertsias, Panayotis Verginis, Ioannis Mitroulis, Dimitrios T Boumpas
Journal: Annals of the Rheumatic Diseases (2019)

Objectives Haematopoietic stem and progenitor cells (HSPCs) are multipotent cells giving rise to both myeloid and lymphoid cell lineages. We reasoned that the aberrancies of immune cells in systemic lupus erythematosus (SLE) could be traced back to HSPCs. Methods A global gene expression map of bone marrow (BM)-derived HSPCs was completed by RNA sequencing followed by pathway and enrichment analysis. The cell cycle status and apoptosis status of HSPCs were assessed by flow cytometry, while DNA damage was assessed via immunofluorescence. Results Transcriptomic analysis of Lin − Sca-1 + c-Kit + haematopoietic progenitors from diseased lupus mice demonstrated a strong myeloid signature with expanded frequencies of common myeloid progenitors (CMPs)—but not of common lymphoid progenitors—reminiscent of a ‘trained immunity’ signature. CMP profiling revealed an intense transcriptome reprogramming with suppression of granulocytic regulators indicative of a differentiation arrest with downregulation trend of major regulators such as Cebpe , Cebpd and Csf3r , and disturbed myelopoiesis. Despite the differentiation arrest, frequencies of BM neutrophils were markedly increased in diseased mice, suggesting an alternative granulopoiesis pathway. In patients with SLE with severe disease, haematopoietic progenitor cells (CD34 + ) demonstrated enhanced proliferation, cell differentiation and transcriptional activation of cytokines and chemokines that drive differentiation towards myelopoiesis, thus mirroring the murine data. Conclusions Aberrancies of immune cells in SLE can be traced back to the BM HSPCs. Priming of HSPCs and aberrant regulation of myelopoiesis may contribute to inflammation and risk of flare. Trial registration number 4948/19-07-2016.
Timing is everything: Evaluating behavioural causal theories of Britain's industrialisation
Authors: Judy Z Stephenson
Journal: Behavioral and Brain Sciences (2019)

Abstract Baumard's thesis that the English Industrial Revolution can be explained by Life History Theory's predictions for psychological development is a progression of much literature in economic and social history. However, the theory suffers from its reliance on increasingly fragile data indicators for “wealth” and its focus on “innovation” as new research begins to explore sectoral dynamics in long run growth.
CRISPR-Cas9 Screen Identifies Me2, a Mitochondrial Malic Enzyme, As a Molecule Relevant for MCL1 Inhibitor Resistance in AML
Authors: Fumihiko Nakao, Takuji Yamauchi, Yuichiro Semba, Jumpei Nogami, Koichi Akashi, Takahiro Maeda
Journal: Blood (2019)
The Role of Calreticulin in Normal Hematopoiesis and Neoplastic Hematopoiesis of Myeloproliferative Neoplasms
Authors: Kotaro Shide, Takuro Kameda, Ayako Kamiunten, Yoshinori Ozono, Yuki Tahira, Masaaki Sekine, Masaya Ono, Takako Yokomizo, Sho Kubota, Keiichi Akizuki, Yoko Kubuki, Tomonori Hidaka, Goro Sashida, Kazuya Shimoda
Journal: Blood (2019)
Eastern Equine Encephalitis Virus — Another Emergent Arbovirus in the United States
Authors: David M. Morens, Gregory K. Folkers, Anthony S. Fauci
Journal: New England Journal of Medicine (2019)

Eastern Equine Encephalitis Virus In the summer and fall of 2019, nine U.S. states reported 36 human cases (14 of them fatal) of EEE, an arthropod-borne viral (arboviral) disease transmitted by mos...
Activity of larotrectinib in TRK fusion cancer patients with primary central nervous system tumours
Authors: D.S. Ziegler, F. Doz, B. Geoerger, S. Dubois, J.E. Grilley-Olson, C. van Tilburg, A. Italiano, A. Lissat, J.-H. Kang, M. Tahara, V. Boni, S. Perreault, M. Capra, S. Nanda, N. Brega, A. Holynskyj, D.S. Hong, D. Hyman, A. Drilon
Journal: Annals of Oncology (2019)
Selinexor, Pomalidomide, and Dexamethasone (SPd) in Patients with Relapsed or Refractory Multiple Myeloma
Authors: Christine I Chen, Nizar Bahlis, Cristina Gasparetto, Sascha A Tuchman, Brea C. Lipe, Muhamed Baljevic, Rami Kotb, Heather J. Sutherland, William I. Bensinger, Michael Sebag, Richard Leblanc, Christopher P Venner, Gary J. Schiller, Suzanne Lentzsch, Natalie Scott Callander, Heidi Sheehan, Yi Chai, Kazuharu Kai, Jatin Shah, Sharon Shacham, Michael G. Kauffman, Darrell J White
Journal: Blood (2019)
HGG-43. SUSTAINED RESPONSE OF THREE PEDIATRIC BRAF MUTATED HIGH-GRADE GLIOMAS WITH BRAF AND MEK INHIBITOR THERAPY.
Authors: S Toll, J Cotter, A Judkins, B Tamrazi, J Biegel, P Patel, HN Tran, R Cooper, AS Margol
Journal: Neuro-Oncology (2018)

AbstractBACKGROUNDTreating high-grade gliomas in pediatric patients involves multimodal therapy with significant long-term sequelae. Despite this approach, these tumors have a high rate of recurrence. Genetic testing has allowed for targeted therapies to be investigated in tumors with BRAF mutations. While BRAF inhibitors have improved survival among patients with BRAF mutated melanoma, resistance develops quickly leading to trials combining BRAF and MEK inhibitors. The efficacy and side effect profile of this combination has yet to be determined in pediatric high-grade glioma patients.CASESWe describe three cases: a 12 year-old female with a high-grade glioma, a 13 year-old male with an astroblastoma and a 6 year-old female with an anaplastic ganglioglioma. All tumors demonstrated a BRAF mutation, and each patient received combined dabrafenib and trametinib therapy. The 12 year-old patient experienced a significant partial response and remains progression-free after a year of combination therapy. The 13 year-old remains disease free post radiation on combination therapy for 8 months. The final patient received combination targeted therapy upfront and after significant tumor response at 3 months, remains progression-free at 1 year. All patients were strictly monitored for side effects and remain free of complications.CONCLUSIONSTo our knowledge, this is the first report of sustained responses in pediatric patients with high-grade gliomas following combined BRAF and MEK inhibitor therapy. These responses highlight the potential use of these targeted agents in this population and suggest that targeted combination therapy is a well-tolerated option in pediatric patients with documented BRAF mutated high-grade gliomas.
Influenza imprinting in childhood and the influence on vaccine response later in life
Authors: Alyson A Kelvin, Maria Zambon
Journal: Eurosurveillance (2019)

Preview this article: Influenza imprinting in childhood and the influence on vaccine response later in life, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/eurosurveillance/24/48/eurosurv-24-48-1-1.gif
Physiological and psychological associations of early childhood adversity in lung cancer.
Authors: Daniel Curtis McFarland, Devika R Jutagir, Barry Rosenfeld, Christian J. Nelson
Journal: Journal of Clinical Oncology (2019)

80 Background: Early Childhood Adversity (ECA) explains the presence of psychological issues such as depression in many chronic disease settings but has not been measured in lung cancer. ECA may increase the positive predictive value for detecting lung cancer related psychological problems. ECA is associated with inflammation in adulthood independent of psychological outcomes or other chronic diseases. Similarly, depression is associated with inflammation. Patients with lung cancer have elevated physical symptoms, which are increased in the presence of depression, but have not been measured in the presence of ECA. We hypothesized that psychological issues and physical symptoms are worse in lung cancer patients who experienced ECA and that this relationship is explained by inflammation. Methods: Patients with stage IV lung cancer (n = 92) were evaluated for ECA using the Risky Families Questionnaire. Concomitant assessments were made of distress (Distress Thermometer and Problem List [DT&amp;PL]), anxiety (Generalized Anxiety Disorder-7), depression (Patient Hospital Questionniare-9), physical symptoms (DT&amp;PL), and inflammation (C-reactive protein [CRP]). Multivariate models were created to explain associations with depression, anxiety, and distress. Results: ECA was associated with younger age (p = .006), elevated CRP (p = .042), distress (p = .032), anxiety (p = .004), depression ( = .001) and greater physical problems (p = .025). Multivariate analyses of psychological outcomes found that ECA (p = .017) explained depression severity, but not distress or anxiety, while controlling for age, sex, and physical symptoms. No interaction effects were seen between inflammation, physical symptoms, and ECA. Conclusions: ECA places lung cancer patients at a higher risk of developing depression, which complicates lung cancer treatment, quality of life, and overall survival outcomes. ECA should be factored into lung cancer patient psychological assessments.
Association Between Obesity-Mediated Atrial Fibrillation and Therapy With Sodium Channel Blocker Antiarrhythmic Drugs
Authors: Aylin Ornelas-Loredo, Shinwan Kany, Vihas Abraham, Zain Alzahrani, Faisal A. Darbar, Arvind Sridhar, Maha Ahmed, Ihab Alamar, Ambili Menon, Meihang Zhang, Yining Chen, Liang Hong, Sreenivas Konda, Dawood Darbar
Journal: JAMA Cardiology (2019)

The association between obesity, an established risk factor for atrial fibrillation (AF), and response to antiarrhythmic drugs (AADs) remains unclear.To test the hypothesis that obesity differentially mediates response to AADs in patients with symptomatic AF and in mice with diet-induced obesity (DIO) and pacing induced AF.An observational cohort study was conducted including 311 patients enrolled in a clinical-genetic registry. Mice fed a high-fat diet for 10 weeks were also evaluated. The study was conducted from January 1, 2018, to June 2, 2019.Symptomatic response was defined as continuation of the same AAD for at least 3 months. Nonresponse was defined as discontinuation of the AAD within 3 months of initiation because of poor symptomatic control of AF necessitating alternative rhythm control therapy. Outcome measures in DIO mice were pacing-induced AF and suppression of AF after 2 weeks of treatment with flecainide acetate or sotalol hydrochloride.A total of 311 patients (mean [SD] age, 65 [12] years; 120 women [38.6%]) met the entry criteria and were treated with a class I or III AAD for symptomatic AF. Nonresponse to class I AADs in patients with obesity was less than in those without obesity (30% [obese] vs 6% [nonobese]; difference, 0.24; 95% CI, 0.11-0.37; P = .001). Both groups had similar symptomatic response to a potassium channel blocker AAD. On multivariate analysis, obesity, AAD class (class I vs III AAD [obese] odds ratio [OR], 4.54; 95% Wald CI, 1.84-11.20; P = .001), female vs male sex (OR, 2.31; 95% Wald CI, 1.07-4.99; P = .03), and hyperthyroidism (OR, 4.95; 95% Wald CI, 1.23-20.00; P = .02) were significant indicators of the probability of failure to respond to AADs. Pacing induced AF in 100% of DIO mice vs 30% (P < .001) in controls. Furthermore, DIO mice showed a greater reduction in AF burden when treated with sotalol compared with flecainide (85% vs 25%; P < .01).Results suggest that obesity differentially mediates response to AADs in patients and in mice with AF, possibly reducing the therapeutic effectiveness of sodium channel blockers. These findings may have implications for the management of AF in patients with obesity.
The effects of androgen deprivation therapy and radiation therapy on cancer-related fatigue.
Authors: Leorey Saligan
Journal: Journal of Clinical Oncology (2019)

10 Background: Fatigue is a common symptom characterized by incapacitating tiredness. Androgen deprivation therapy (ADT) in combination with radiotherapy (RT) is one of the standard treatments for prostate cancer. Fatigue often worsens during RT with concomitant ADT and it persists long after treatment completion. The purpose of this study is to examine the effects of combined ADT and RT on fatigue in prostate cancer men and in a fatigue mouse model. Methods: 64 participants were recruited and followed at baseline, midpoint, completion, and 1 year post-RT. Two cohorts of men: +ADT cotinued after RT (n=27), +ADT during RT only (n=20), and -ADT (n=17). Fatigue was measured using FACT-F. Male C57BI/6 mice (n=55) were randomly placed into 2 groups: +ADT and –ADT (control). Mice were further subdivided into +RT and –RT (sham) groups. Voluntary Wheel Running Activity (VWRA) data from all mice were recorded for 6 days post-irradiation and the total average of all 6 days was used for analysis. Results: Fatigue (n=64) worsened during RT ( p=.02 at midpoint, p=.04 at completion). ADT significantly affected fatigue development over time (F3,42 = 3.80, p=.02) with the most significant difference occurring at midpoint ( p&lt;.001) and completion of RT ( p&lt;0.001). VWRA significantly decreased in mice that received the combination of ADT and irradiation, compared to those that received only ADT + sham radiation ( p=.001) and no ADT + sham radiation ( p=.004). Transcription factor A, mitochondrial (TFAM) in brain cortical samples was significantly reduced in irradiated mice compared to control mice ( p=.014). Glucose transported type 4 (GLUT4) in brain cortices was significantly reduced in irradiated mice compared to non-irradiated mice ( p=.0057). GLUT4 was also significantly reduced in irradiated mice receiving ADT compared to control mice receiving sham RT ( p=.043). Conclusions: There is a significant combined effect of ADT and RT on fatigue in both humans and mice. Mitochondrial function/neuronal bioenergetic markers were altered in the cortices of irradiated mice that received concomitant ADT. These findings suggest that fatigue experienced by subjects who receive ADT + RT could be attributable to impaired cortical energy production.
Efficacy and Survival in Newly Diagnosed Advanced Extranodal Natural Killer/T-Cell Lymphoma: A Randomized, Controlled, Multicenter and Open-Labled Study with Ddgp Regimen Versus SMILE Regimen
Authors: Xinhua Wang, Lei Zhang, Xiangli Liu, Xin Li, Ling Li, Xiaorui Fu, Zhenchang Sun, Jingjing Wu, Xudong Zhang, Jiaqin Yan, Yu Chang, Feifei Nan, Zhiyuan Zhou, Xiaolong Wu, Li Tian, Wencai Li, Hongwei Xue, Jinghua Wang, Liqun Zou, Liping Su, Yi Lu, Yanzhen Guo, Ken H. Young, Mingzhi Zhang
Journal: Blood (2019)
Increasing Lengths of First Complete Remission with 7+3 Induction Chemotherapy for Acute Myeloid Leukemia over the Past Four Decades: Analysis of SWOG Trial Data
Authors: Megan Othus, Guillermo Garcia-Manero, John E. Godwin, James K. Weick, Frederick R. Appelbaum, Harry P. Erba, Elihu H. Estey
Journal: Blood (2019)