tbuckley/cabot-search huggingface dataset:
Novel CD19/CD22 Bicistronic Chimeric Antigen Receptors Outperform Single or Bivalent Cars in Eradicating CD19+CD22+, CD19-, and CD22- Pre-B Leukemia
Authors: Haiying Qin, Sang M Nguyen, Sneha Ramakrishna, Samiksha Tarun, Lila Yang, Nicholas Peter Verdini, Waleed Haso, Terry J. Fry
Journal: Blood (2017)
Abstract 13545: ST2 in Heart Failure With Preserved Ejection Fraction
Authors: Omar F AbouEzzeddine, Paul M McKie, Shannon M Dunlay, Susanna R Stevens, G M Felker, Barry A Borlaug, Horng H Chen, Russell P Tracy, Eugene Braunwald, Margaret M Redfield
Journal: Circulation (2015)

Introduction: In vitro, ST2 is a marker of myocyte stress and inflammation but in vivo, there is no trans-cardiac ST2 concentration step-up to support cardiac ST2 activation in human heart failure (HF) calling into question the source of ST2 in HF. While ST2 is predictive of adverse outcomes in HF, the relationship between ST2 and key pathophysiologic domains in HF with preserved ejection fraction (HFpEF) is not well characterized. Hypothesis: ST2 levels increase in proportion to the severity of left ventricular (LV) remodeling and dysfunction in HFpEF. Methods: At enrollment, patients (n=174) from the RELAX trial testing sildenafil in HFpEF had serum ST2 levels measured and underwent assessment of pathophysiologic domains including congestion, cardiac structure and function, exercise performance (peak oxygen consumption (VO2)) and biomarkers of neurohumoral activation (NT-proBNP, aldosterone, endothelin-1), renal dysfunction (cystatin-C), fibrosis (pro-collagen III N-terminal peptide [NTP], C-telopeptide for type I collagen [CITP]), inflammation (high-sensitivity CRP [hsCRP]) and myocardial necrosis (high-sensitivity troponin-I [hsTnI]). Analysis adjusted for sex, a covariate associated with ST2 levels in normal persons. Results: See table. ST2 was associated with greater congestion, worse right ventricular (RV) pressure overload and dysfunction, lower peak VO2 and biomarkers of neurohumoral activation, renal dysfunction, fibrosis and myocardial necrosis and tended to be associated with systemic inflammation (hsCRP). ST2 was not associated with LV structure or LV systolic or diastolic function. Conclusions: In HFpEF, ST2 was associated with measures of right sided congestion, RV overload and dysfunction, exercise intolerance and other systemic markers of more advanced HF but not with LV structure or LV systolic or diastolic function. These data suggest that mechanisms distinct from LV stress stimulate ST2 activation in HFpEF.
Dosing modifications to increase tolerability of gemcitabine and nab-paclitaxel in treatment of pancreatic cancer in the elderly.
Authors: Jasmine L Martin, Simran Sidhu, Nabil Benhayoun, Michael Dedonno, Warren S. Brenner
Journal: Journal of Clinical Oncology (2019)

441 Background: Gemcitabine and nab-paclitaxel has been reported to prolong survival in patients with metastatic pancreatic cancer. This drug combination was studied in such patients in the MPACT trial with an average age of enrolled patients being 63. Pancreatic cancer, however, is a disease of the aging with a median age at diagnosis of 70. Reductions in dosing by 20% or more in one or both components and has been shown to improve the tolerability of this regimen, thereby increasing treatment exposure. Our study aims to examine the efficacy and tolerability of this drug combination in an elderly population and how this is affected by schedule and dosing modifications. Methods: A retrospective chart review was performed of 83 patients over the age of 70 with a median age of 79 who received this drug combination as first-line treatment for pancreatic adenocarcinoma at a single institution. Overall survival and progression-free survival were assessed as well as schedule modification, dose reduction, and rates of adverse events. Results: For patients with metastatic or non-metastatic disease, the mean overall survival and progression-free survival were found to be 10.57 months and 6.63 months, respectively. When only patients with metastatic disease are analyzed, these values were found to be 9.26 months and 6.05 months, respectively, which are similar to those observed in the MPACT trial. The most common adverse events of grade 3 or greater were fatigue in 34.9% of patients and hematologic adverse events including neutropenia in 27.7% and leukopenia in 25.3% of patients. Dose reductions were commonly used to mitigate adverse events. Reductions in either one or both drugs by at least 20% occurred in 84.3% of patients. Conclusions: Gemcitabine and nab-paclitaxel in treatment of pancreatic cancer is well tolerated in an elderly population with similar rates of adverse effects when compared with previous studies, though this population experienced a significantly higher rate of fatigue. Dose reductions were used frequently in this population to improve tolerability, which may have contributed to the observed increase in overall survival in this population.
Oral Plasma Kallikrein Inhibitor BCX7353 is Safe and Effective as an On-Demand Treatment of Angioedema Attacks in Hereditary Angioedema (HAE) Patients: Results of the ZENITH-1 Trial
Authors: Hilary Longhurst, Dumitru Moldovan, Anette Bygum, Marco Cicardi, Aarnoud Huissoon, Emel Aygoren-Pursun, Vesna Grivcheva-Panovska, David Hagin, Urs Steiner, Marcin Stobiecki, Werner Aberer, Claire Bethune, Saul N. Faust, Sorena Kiani, David Launay, Marcus Maurer, William Rae, Avner Reshef, Melanie T. Cornpropst, Sylvia M. Dobo, Sharon VanDyke, Sharon Murray, Phillip J. Collis, William P. Sheridan, Henriette Farkas
Journal: Journal of Allergy and Clinical Immunology (2019)
Circadian-Regulated Cell Death in Cardiovascular Diseases
Authors: Inna Rabinovich-Nikitin, Brooke Lieberman, Tami A. Martino, Lorrie A. Kirshenbaum
Journal: Circulation (2019)

Background: Over the past several years, a variety of human and animal studies have shown that circadian clocks regulate biological cardiovascular rhythms in both health and disease. For example, heart rate and blood pressure fluctuate over 24-hour daily periods, such that levels are higher in the morning and progressively decline in the evening. Methods and Results: It is interesting to note that the timing of the administration of various cardiac treatments can also benefit some cardiovascular outcomes. Circadian rhythms have been implicated in the pathogenesis of a number of cardiovascular diseases, including myocardial infarction, ischemia-reperfusion injury after myocardial infarction, and heart failure. Cell death is a major component of ischemia-reperfusion injury and posited as the central underlying cause of ventricular remodeling and cardiac dysfunction following myocardial infarction. It is notable that the time of day profoundly influences cardiac tolerance and sensitivity to cardiac injury. Conclusions: Herein, we highlight the novel relationship between circadian rhythms and homeostatic processes that governs cell fate by apoptosis, necrosis, and autophagy. Understanding how these intricate processes interconnect at the cellular level is of paramount clinical importance for optimizing treatment strategies to achieve maximum cardiovascular outcome.
Open-label phase II/III study of nivolumab plus standard of care versus standard of care for first-line treatment of metastatic colorectal cancer: Checkmate-9X8.
Authors: Josep Tabernero, Takayuki Yoshino, Allen Lee Cohn, Mark D. Kochenderfer, Regan C. Holdridge, Felix Couture, Elena Elez, Johanna C. Bendell, Ming Zhou, Dana Cullen, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2019)

TPS718 Background: 5-FU-containing regimens with oxaliplatin or irinotecan and a biologic agent such as the VEGF inhibitor bevacizumab (BEV) are standard-of-care (SOC) options for the treatment of first-line (1L) metastatic colorectal cancer (mCRC). However, the objective response rate (ORR) with these regimens is 38%, and median progression-free survival (PFS) and median overall survival (OS) are 9.4 months and 21.3 months, respectively (Saltz et al. JCO 2007). Thus, there is a need for therapies that will provide durable clinical responses and improved survival. mCRC tumors represent classic “cold” tumors characterized by low expression of inflammatory and immune signatures. Emerging evidence suggests that there may be subtypes of mCRC that could benefit from synergistic immunogenic stimuli with immunotherapy agents combined with other compounds. The immune checkpoint inhibitor nivolumab (NIVO) enhances antitumor T-cell activity through the inhibition of the programmed death-1 receptor. Chemotherapy and BEV may have potential synergistic immune-stimulatory effect on the tumor and its microenvironment. Therefore, combining NIVO with SOC may enhance the antitumor immune response and improve clinical activity in 1L mCRC. The international, multicenter, open-label phase 2/3 CheckMate-9X8 (NCT03414983) trial will evaluate efficacy and safety of the combination of NIVO+SOC, compared with SOC alone, in previously untreated patients with mCRC. Methods: An estimated 180 patients aged ≥ 18 years with histologically confirmed mCRC, no prior therapy for mCRC, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and an adequate tissue sample, will be randomized to receive either NIVO+SOC or SOC alone. Patients who have had prior treatment with a checkpoint inhibitor; have autoimmune, cardiovascular, or hepatic disease; or test positive for hepatitis B or C (indicating detectable virus) will be excluded. The primary endpoint is PFS assessed by blinded independent central review (BICR) using RECIST v1.1. Secondary endpoints include ORR, disease control rate, duration of response, and time to response, all by BICR; OS; and safety. Clinical trial information: NCT03414983.
Patient-Reported Outcome Driven Case Management System for Hematology — a Prospective Study
Authors: Rahma Warsame, Briant Fruth, Katrina Croghan, Ann Engebretson, Taxiarchis Kourelis, Sarah Aug, Sara Ellingson, Colleen Irlbeck, Morie A. Gertz, Francis K. Buadi, Ronald S. Go, Wilson I Gonsalves, Eli Muchtar, Shaji K. Kumar, S. Vincent Rajkumar, John A. Lust, Nelson Leung, David Dingli, Yi Lin, Suzanne R. Hayman, Martha Q. Lacy, Amie Fonder, Miriam Hobbs, Yi Lisa Hwa, Carrie A. Thompson, Robert A. Kyle, Jan Buckner, Angela Dispenzieri, Jeff A. Sloan
Journal: Blood (2018)
Organoids — Preclinical Models of Human Disease
Authors: Mo Li, Juan C. Izpisua Belmonte
Journal: New England Journal of Medicine (2019)

Interview with Dr. Benjamin S. Freedman on organoids as preclinical models of human diseases. (07:11)Download An organoid is a three-dimensional construct composed of multiple cell types that originates from stem cells through self-organization and can simulate the architecture and functionality of native organs. This article reviews the common platforms of organoid technology and its application.
Orange-red plaques in an older patient
Authors: Angela Tewari, Janakan Natkunarajah,
Journal: BMJ (2019)

A 91 year old white woman presented with a four month history of an asymmetrical non-itchy eruption on her face, forearms, and hands. She was otherwise well. She had no history of cough, fever, night sweats, or weight loss. Her medical history included hypertension for which she took ramipril and she had no history of tuberculosis (TB). On examination, there were scattered violaceous papules and plaques over her forearms, orange-red plaques over the left side of her temple (fig 1) and over an old surgery scar site on the bridge of her nose and an old site of trauma on the right forearm. There was no palpable lymphadenopathy or organomegaly.



Fig 1 
Red plaque on the left temple



Dermoscopy of the lesions showed yellow-brown homogeneous patches.

The quantiFERON gold test and ACE level were normal. However, multiple miliary opacities on chest radiography raised the suspicion of TB (fig 2), so an urgent respiratory opinion was sought.



Fig 2 
Chest radiography



Bronchial lavage for cytology and microbiology were negative for malignancy and TB, respectively.

A skin biopsy showed basal cell degeneration and an inflammatory infiltrate …
Abstract 12344: Suboptimal Control of Lipid Levels: Results From 29 Countries Participating in the Centralized Pan-Regional Surveys on the Undertreatment of Hypercholesterolemia (CEPHEUS)
Authors: Chern-En Chiang, Jean Ferrières, Nina N Gotcheva, Frederick J Raal, Abdulla Shehab, Jidong Sung, Karin Henriksson, Michel P Hermans
Journal: Circulation (2014)

Background: Five multicentre, cross-sectional Centralized Pan-regional Surveys on the Undertreatment of Hypercholesterolemia (CEPHEUS) were conducted in 29 countries across Asia, Western Europe, Ea...
Abstract 18718: Can We Predict Long-term Mortality Post Primary Takotsubo Syndrome via In-hospital Events?
Authors: Thanh H Nguyen, Jeanette Stansborough, Gao Ong, Sven Surikow, Michael Frenneaux, John D Horowitz
Journal: Circulation (2017)

Background: Some patients with Takotsubo syndrome (TS) develop this form of acute catecholamine-induced myocardial inflammation secondary to life-threatening extra-cardiac disease (TSsec), but in t...
Multi-agent neoadjuvant chemotherapy improves response and survival in patients with resectable pancreatic cancer.
Authors: Taylor Maramara, Jamie Huston, Ravi Shridhar, Kenneth L Meredith
Journal: Journal of Clinical Oncology (2019)

409 Background: Neoadjuvant therapy (NT) for resectable pancreatic adenocarcinoma (PAC) continues to be debated. We sought to establish the impact of single agent (SAC) versus multi-agent chemotherapy (MAC) with or without radiation (RT) on survival in patients with resectable pancreatic cancer. Methods: Utilizing the National Cancer Database we identified patients with PAC who underwent up front surgery (UFS), SAC, or MAC ± RT followed by surgery. Patient characteristics and survival were compared with Mann-Whitney U, Pearson’s Chi-square, and the Kaplan-Meier method. Multivariable analysis (MVA) was developed to identify predictors of survival. All tests were two-sided and α &lt; 0.05 was significant. Results: We identified 26,563 patients of which, 23,877 (89.9%) UFS, 1,482 (5.6%) NT+RT (SAC+RT 768, MAC+RT 560), and 1,204 (4.5%) chemo only (SAC 262, MAC 864) with a median age of 66 (25-90). The median tumor size was smaller, p = 0.003 and Charlson/Deyo was lower, p = 0.008 in the UFS. Despite this, the 90 day mortality was higher at 8% versus 7.5% in NT+RT and 4.8% in NT, p = 0.003. There were higher R0 resections in the NT+RT versus NT-RT or UFS, 82.4%, 80.5%, and 76%, p &lt; 0.001. Additionally, there were less N1 disease in NT+RT 35.4%, 59.5%, and 68.1%, p &lt; 0.001. Pathologic complete response (pCR) rates were higher in the NT+RT versus NT-RT, 3.1% versus 1.7%, p &lt; 0.001. Examining the response rates by SAC±RT and MAC±RT, pCR was 0.5% in SAC, 2.8% SAC+RT, 2.2% MAC, and 3.3 MAC+RT, p = 0.004. The median survival was 22.2 mo in UFS, 23.1 mo in SAC, 26 mo in SAC+RT, 27.9 mo in MAC+RT, and 29.8 mo in MAC, p &lt; 0.001. On multivariable analysis, age, Chalson/Deyo score, tumor size, grade, margin status, facility volume, and MAC were predictors of survival. Conclusions: Multi-agent chemotherapy with or without radiation improves overall survival, R0 resections rates, and complete pathological response rates in patients undergoing neoadjuvant therapy for resectable pancreatic cancer.
Abolition of aberrant neurogenesis ameliorates cognitive impairment after stroke in mice
Authors: María Isabel Cuartero, Juan de la Parra, Alberto Pérez-Ruiz, Isabel Bravo-Ferrer, Violeta Durán-Laforet, Alicia García-Culebras, Juan Manuel García-Segura, Jagroop Dhaliwal, Paul W. Frankland, Ignacio Lizasoain, María Ángeles Moro
Journal: Journal of Clinical Investigation (2019)

Poststroke cognitive impairment is considered one of the main complications during the chronic phase of ischemic stroke. In the adult brain, the hippocampus regulates both encoding and retrieval of new information through adult neurogenesis. Nevertheless, the lack of predictive models and studies based on the forgetting processes hinders the understanding of memory alterations after stroke. Our aim was to explore whether poststroke neurogenesis participates in the development of long-term memory impairment. Here, we show a hippocampal neurogenesis burst that persisted 1 month after stroke and that correlated with an impaired contextual and spatial memory performance. Furthermore, we demonstrate that the enhancement of hippocampal neurogenesis after stroke by physical activity or memantine treatment weakened existing memories. More importantly, stroke-induced newborn neurons promoted an aberrant hippocampal circuitry remodeling with differential features at ipsi- and contralesional levels. Strikingly, inhibition of stroke-induced hippocampal neurogenesis by temozolomide treatment or using a genetic approach (Nestin-CreERT2/NSE-DTA mice) impeded the forgetting of old memories. These results suggest that hippocampal neurogenesis modulation could be considered as a potential approach for treatment of poststroke cognitive impairment.
Back pain management: patients receive £10.5m of “limited value” injections
Authors: Jacqui Wise
Journal: BMJ (2019)

Patients with lower back pain are still receiving injections of local anaesthetic or steroids with “limited clinical value” rather than physical and psychological rehabilitation as recommended by the National Institute for Health and Care Excellence (NICE).

A Getting it Right First Time (GIRFT) report on spinal surgery found wide variation in NHS trusts’ management of lower back and radicular pain in England.1 From 2015 to 2018 an average of 5.7% of patients with back pain received three or more facet joint injections in a year despite evidence and guidance advising against them. The annual cost of repeat injections is estimated at £10.5m (€12m; $13.8m).

The report said …
Feedback-Driven Mechanisms between Microtubules and the Endoplasmic Reticulum Instruct Neuronal Polarity
Authors: Ginny G. Farías, Amélie Fréal, Elena Tortosa, Riccardo Stucchi, Xingxiu Pan, Sybren Portegies, Lena Will, Maarten Altelaar, Casper C. Hoogenraad
Journal: Neuron (2019)
Bosutinib or Imatinib in Older Vs Younger Patients with Newly Diagnosed Chronic Myeloid Leukemia in the Phase 3 BFORE Trial
Authors: Michael W. Deininger, Vamsi Kota, Jeff H. Lipton, Dragana Milojkovic, Valentín García Gutiérrez, Eric Leip, Sonja Nick, Andreas Hochhaus, Carlo Gambacorti-Passerini, Jorge E. Cortes, Tim H. Brummendorf
Journal: Blood (2018)
Reply
Authors: Agustín Albillos, Leticia Muñoz, Melchor Álvarez‐Mon
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. We read with interest the letter by Dey regarding our article which addresses the role of microbiome in driving intestinal inflammation, barrier disruption, and bacterial translocation in CCl4 cirrhosis.1 Dey claims that dysbiosis and inflammation in this model can be attributed, rather than to cirrhosis, to the effects of CCl4 on the gut microbiome and that the resultant dysbiosis becomes the major driver of CCl4 liver damage. Our results indicate that the observed immune system dysregulation at the intestinal level can be ascribed to cirrhosis and its associated consequences (i.e., dysbiosis) and not to the hepatotoxin. (1) There were no significant changes in intestinal immune cell populations or in the gut microbiome after a short course of CCl4 before liver fibrosis onset, as shown in the Supporting Information.1 For this control, we delivered three weekly doses of CCl4 as at least four week of twice‐weekly dosing are needed for liver fibrosis to commence.2 Moreover, we have shown the absence of mesenteric and systemic immune system dysfunction after such a short CCl4 course.3 (2) More importantly, the observed disturbance in the intestinal immune system cell subset distribution is already present at the preascitic stage, and this imbalance progresses as gut dysbiosis does in the ascitic stage. In addition, massive 16S ribosomal DNA sequencing revealed clear differences in the ileum microbiota of rats with cirrhosis and those receiving a short CCl4 course, with an increased Proteobacteria abundance as the most characteristic feature of the former.1 Thus, the distinctive immunological and microbiome changes of our rats with cirrhosis cannot be ascribed to a direct effect of CCl4 on intestinal immune system or bacterial populations as they only appeared once cirrhosis was present and then continued as dysbiosis worsened. Our findings also support a causal relationship between the gut microbiome and immune phenotype changes at the different stages of cirrhosis: (1) significant correlations between the abundance and frequency of bacterial genera and key immune cell subsets and (2) reversibility of most intestinal immune abnormalities and associated increased permeability through antibiotic‐induced microbiome reorganization.
Clinical risk factors for Achilles tendinopathy: a systematic review
Authors: Arco C van der Vlist, Stephan J Breda, Edwin H G Oei, Jan A N Verhaar, Robert-Jan de Vos
Journal: British Journal of Sports Medicine (2019)

Achilles tendinopathy is a common problem, but its exact aetiology remains unclear.To evaluate the association between potential clinical risk factors and Achilles tendinopathy.Systematic review.The databases Embase, MEDLINE Ovid, Web of Science, Cochrane Library and Google Scholar were searched up to February 2018.To answer our research question, cohort studies investigating risk factors for Achilles tendinopathy in humans were included. We restricted our search to potential clinical risk factors (imaging studies were excluded).We included 10 cohort studies, all with a high risk of bias, from 5111 publications identified. There is limited evidence for nine risk factors: (1) prior lower limb tendinopathy or fracture, (2) use of ofloxacin (quinolone) antibiotics, (3) an increased time between heart transplantation and initiation of quinolone treatment for infectious disease, (4) moderate alcohol use, (5) training during cold weather, (6) decreased isokinetic plantar flexor strength, (7) abnormal gait pattern with decreased forward progression of propulsion, (8) more lateral foot roll-over at the forefoot flat phase and (9) creatinine clearance of <60 mL/min in heart transplant patients. Twenty-six other putative risk factors were not associated with Achilles tendinopathy, including being overweight, static foot posture and physical activity level.From an ocean of studies with high levels of bias, we extracted nine clinical risk factors that may increase a person's risk of Achilles tendinopathy. Clinicians may consider ofloxacin use, alcohol consumption and a reduced plantar flexor strength as modifiable risk factors when treating patients with Achilles tendinopathy.CRD42017053258.
Abstract 14277: Institution Wide QT Alert System Identifies Patients with High Risk of Mortality
Authors: Kristina H Haugaa, J. M Bos, Robert F Tarrell, Bruce W Morlan, Pedro J Caraballo, Michael J Ackerman
Journal: Circulation (2012)

Objectives QT prolongation is an independent risk factor for cardiovascular mortality. Because QT prolonging medications and conditions cross all disciplines of medicine, an institution wide comput...
The NIH BRAIN Initiative: Integrating Neuroethics and Neuroscience
Authors: Khara M. Ramos, Christine Grady, Henry T. Greely, Winston Chiong, James Eberwine, Nita A. Farahany, L.Syd M. Johnson, Bradley T. Hyman, Steven E. Hyman, Karen S. Rommelfanger, Elba E. Serrano, James D. Churchill, Joshua A. Gordon, Walter J. Koroshetz
Journal: Neuron (2019)