tbuckley/cabot-search huggingface dataset:
Randomized study evaluating trifluridine/tipiracil (TAS-102) versus + trifluridine/tipiracil + bevacizumab as last-line therapy in patients with chemorefractory unresectable metastatic colorectal cancer (mCRC).
Authors: Per Pfeiffer, Mette Yilmaz, Sören Möller, Line Maltha, Merete Krogh, Daniela Zitnjak, Caroline Lemb Szameitat, Finn Hejlesen, Karina Gravgaard Thomsen, Camilla Qvortrup
Journal: Journal of Clinical Oncology (2019)

637 Background: Trifluridine/tipiracil (FTD/TPI, also known as TAS-102) is approved for the use in patients with chemorefractory mCRC. Inspired by the encouraging results of a small phase I/II study, C-TASK FORCE, evaluating the combination of FTD/TPI and bevacizumab in chemorefractory mCRC patients (Kuboki et al, 2017), we designed the present randomized trial. Methods: This randomized study enrolled as planned 80 mCRC patients. The main inclusion criteria were: histologically confirmed and chemorefractory mCRC; PD during or after therapy with fluoropyrimidine, irinotecan, oxaliplatin, EGFR-inhibitor (RAS wildtype), and bevacizumab was optional; PS 0-1. In arm A, FTD/TPI was administered orally at the dose of 35 mg/m²/dose bid from day 1 to day 5 and from day 8 to day 12 and in arm B the same dose of FTD/TPI was combined with bevacizumab at a dose of 5 mg/kg on day 1 and on day 15 of a 28-day treatment cycle. The primary endpoint was to increase progression-free survival (PFS) from 1.8 months to 3.8 months. Secondary objectives included overall survival (OS) and safety. Results: Eighty patients with chemorefractory mCRC were randomized from September 2017 to August 2018. The median PFS was significantly improved from 2.6 months (arm A) to 5.9 months (arm B) with a hazard ratio (HR) 0.51 (95% CI, 0.28 to 0.92; P &lt; 0.03) and median OS was significantly improved from 7.3 months (arm A) to 10.3 months (arm B) with HR 0.42 (95% CI, 0.18 to 0.99; P &lt; 0.05). After median follow-up for OS of 5.6 months, 57 patients were alive at September 7th, 2018. Therapy was well tolerated with adverse events as expected, patients receiving FTD/TPI + bevacizumab had more grade 3-4 neutropenia (56% in arm B vs 30% in arm A, p = 0.03) and three patients in arm B (vs zero in arm A ) developed febrile neutropenia. SAEs were observed in 13 (arm A) and 11 patients (arm B), respectively. Conclusions: In patients with chemorefractory mCRC, FTD/TPI + bevacizumab, as compared with FTD/TPI monotherapy, was associated with a significant and clinical relevant improvement in PFS and OS with tolerable toxicity. Clinical trial information: 2016-005241-23.
Delayed drug hypersensitivity to bortezomib: Desensitization and tolerance to its analogue carfilzomib
Authors: Paula Galvan‐Blasco, Mar Guilarte, Victoria Cardona, Moises Labrador‐Horrillo, Anna Sala‐Cunill, Ingrid Johana Gil‐Serrano, Olga Luengo
Journal: Allergy (2019)
Epidemiological trends of small bowel tumors and changing incidence in Utah.
Authors: Ramya Thota, Kim Herget, William T. Sause, Karen Curtin, Carol Sweeney, Deborah Wood Neklason
Journal: Journal of Clinical Oncology (2019)

245 Background: The incidence and prevalence of small bowel tumors in particular adenocarcinomas are thought to be rising but updated epidemiological data is lacking. Therefore, in this study we explored the evolving epidemiology of small bowel tumors. Methods: This is a retrospective population based study using Utah Cancer Registry (UCR) and Surveillance Epidemiology, and End Results program (SEER) conducted between 1973-2015. The age adjusted incidence and prevalence was determined. The incidence and prevalence rates were compared to other SEER residents diagnosed with invasive small bowel tumors using ICD codes C17.0 – C17.9). Results: The small bowel tumors have steadily increased from 1990 to 2015. In the UCR, the highest incidence of and small bowel tumors was reported 1.7 per 100,000 in 2015. The prevalence of small bowel tumors in the state of Utah from 1973 – 2014 was 616 including 41 adenocarcinomas, 327 with carcinoid tumors and 248 with other histology’s. There was 1.67% increase in incidence of small bowel tumors in SEER while in Utah we noted 2.81 % annual increase of incidence from 1990 to 2015. Especially, for small bowel adenocarcinomas, Utah has an annual increase of 2.43% from 1990-2015, and SEER had a smaller increase of 0.71% per year over the same time frame. Conclusions: The incidence of small bowel adenocarcinomas between 1995 and 2015 show a steady increase in both UCR and SEER databases. Despite the rarity of these tumors rising incidence warrants increasing awareness and need for better treatments to improve the survival outcomes of these under-studied tumors.
CD133-directed CAR T-cells for MLL leukemia: on-target, off-tumor myeloablative toxicity
Authors: Clara Bueno, Talia Velasco-Hernandez, Francisco Gutiérrez-Agüera, Samanta Romina Zanetti, Matteo L. Baroni, Diego Sánchez-Martínez, Oscar Molina, Adria Closa, Antonio Agraz-Doblás, Pedro Marín, Eduardo Eyras, Ignacio Varela, Pablo Menéndez
Journal: Leukemia (2019)

Acknowledgements: We thank the Interfant treatment protocol and local physicians for contributing patient samples: Dr. Ronald W Stam (Princess Maxima Centre, Utrech), Dr. Mireia Camos and Dr. Jose Luis Fuster (Spanish Society of Pediatric Hematoncology), Dr. Paola Ballerini (A. Trousseau Hospital, Paris). We also thank Prof. Paresh Vyas (Oxford Univeristy, UK) and Prof. Kajsa Paulsson (Lund University, Sweden) for facilitating access to their RNA-seq database. This work has been supported by the European Research Council (CoG-2014-646903, PoC-2018-811220) to PM, the Spanish Ministry of Economy and Competitiveness (MINECO, SAF-SAF2016-80481-R, BIO2017-85364-R) to PM and EE, the Generalitat de Catalunya (SGR330, SGR102 and PERIS) to PM and EE, the Spanish Association against cancer (AECC-CI-2015) to CB, and the Health Institute Carlos III (ISCIII/FEDER, PI14-01191) to CB. PM also acknowledges financial support from the Obra Social La Caixa-Fundacio Josep Carreras. SRZ and TV are supported by a Marie Curie fellowships. OM is supported by the Catalan Government through a Beatriu de Pinos fellowship. MB is supported by MINECO through a PhD scholarship. PM is an investigator of the Spanish Cell Therapy cooperative network (TERCEL).
Abstract 13390: Nitrite Ameliorates Sepsis-Induced Myocardial Dysfunction via Mitochondrial Protection
Authors: Ryoichi Kawaguchi, Naoyuki Hirata, Yusuke Yoshikawa, Tomohiro Chaki, Michiaki Yamakage
Journal: Circulation (2015)

Introduction: Mitochondrial impairment plays an important role in septic myocardial dysfunction. Several studies have shown that nitrite can ameliorate myocardial ischemia-reperfusion injury via mitochondrial protection. However, the effect of nitrite on septic myocardium has not been investigated in detail. Hypothesis: Nitrite therapy will improve cardiac contractility via mitochondrial function in a murine model of polymicrobial sepsis. Methods: Sepsis was induced in Wistar rats by cecal ligation and puncture (CLP). After CLP, we administered saline (NS group, n=8) or saline with nitrite (Nit group, n=8) subcutaneously. No procedure was performed in the control group. First, to determine the most effective dose of nitrite in septic rats, we administered different doses of nitrite (0.1, 0.3, 1, 3, 10 mg/kg) and examined cardiac function in an isolated heart experiment after 8 hours. The most effective dose of nitrite (1 mg/kg) was used in subsequent experiments. For an in vitro study, hearts were removed and cardiac mitochondria were isolated by differential centrifugation. We measured mitochondrial oxygen consumption and determined the respiratory control ratio (RCR). We also assessed protein expression by ELISA and immunoblotting. Results: In the isolated heart experiment, left ventricular developed pressure in the Nit group (dose of 1 mg/kg) was significantly higher than that in the NS group (Fig. 1). Although RCR in the NS group was significantly decreased compared to that in control group, RCR in the Nit group was preserved (Fig. 2). Myocardial nitrotyrosine levels were comparable in the NS group and the Nit group. In the Nit group, Akt phosphorylation was preserved and activation of NF-κB was inhibited. Conclusions: Nitrite therapy preserved mitochondrial oxidative phosphorylation in the septic myocardium and improved contractility. Nitrite affects the stress response signaling pathway and may be novel treatment for septic myocardial dysfunction.
Nitric Oxide and Cardiac Function
Authors: P.B. Massion, O. Feron, C. Dessy, J.-L. Balligand
Journal: Circulation Research (2003)

Nitric oxide (NO) is produced from virtually all cell types composing the myocardium and regulates cardiac function through both vascular-dependent and -independent effects. The former include regulation of coronary vessel tone, thrombogenicity, and proliferative and inflammatory properties as well as cellular cross-talk supporting angiogenesis. The latter comprise the direct effects of NO on several aspects of cardiomyocyte contractility, from the fine regulation of excitation-contraction coupling to modulation of (presynaptic and postsynaptic) autonomic signaling and mitochondrial respiration. This multifaceted involvement of NO in cardiac physiology is supported by a tight molecular regulation of the three NO synthases, from cellular spatial confinement to posttranslational allosteric modulation by specific interacting proteins, acting in concert to restrict the influence of NO to a particular intracellular target in a stimulus-specific manner. Loss of this specificity, such as produced on excessive NO delivery from inflammatory cells (or cytokine-stimulated cardiomyocytes themselves), may result in profound cellular disturbances leading to heart failure. Future therapeutic manipulations of cardiac NO synthesis will necessarily draw on additional characterization of the cellular and molecular determinants for the net effect of this versatile radical on the cardiomyocyte biology.
Multimodal Single-Cell Analysis Reveals Physiological Maturation in the Developing Human Neocortex
Authors: Simone Mayer, Jiadong Chen, Dmitry Velmeshev, Andreas Mayer, Ugomma C. Eze, Aparna Bhaduri, Carlos E. Cunha, Diane Jung, Arpana Arjun, Emmy Li, Beatriz Alvarado, Shaohui Wang, Nils Lovegren, Michael L. Gonzales, Lukasz Szpankowski, Anne Leyrat, Jay A.A. West, Georgia Panagiotakos, Arturo Alvarez-Buylla, Mercedes F. Paredes, Tomasz J. Nowakowski, Alex A. Pollen, Arnold R. Kriegstein
Journal: Neuron (2019)
Impact of Genetic Profile on Clinical Outcomes in Adults ≥60 with AML: The Princess Margaret Cancer Centre Experience
Authors: Georgina S Daher-Reyes, Caroline J McNamara, Manjula Maganti, Tracy L. Stockley, Jose Mario Capo-Chichi, Reem Abdulrahman Alkharras, Andrea Arruda, Jaime Claudio, Steven M Chan, Aaron D Schimmer, Mark D. Minden, Hassan Sibai, Karen W.L. Yee, Vikas Gupta, Suzanne Kamel-Reid, Dawn Maze, Andre Schuh
Journal: Blood (2018)
Abstract 20536: Desmoplakin Deficient Epicardial Progenitor Cells Mediate the Development of Fibroadiposis in Arrhythmogenic Cardiomyopathy
Authors: Raffaella Lombardi, Suet N Chen, Priyatansh Gurha, Grazyna Z Czernuszewicz, James T Willerson, Ali J Marian
Journal: Circulation (2017)

Background: Arrhythmogenic cardiomyopathy (AC), a hereditary disease caused by mutations in desmosome genes, presents with ventricular arrhythmias, sudden death and heart failure. A pathological feature of AC is myocardial fibrofatty replacement, typically originating from the epicardium. We have implicated fibroadipocyte progenitors as a source of fibroadiposis; however, the epicardial origin of excess fibroadipocytes in AC remains unknown. Hypothesis: Epicardial progenitor cells (EPCs) have cell junctions and differentiate to several cell types. We hypothesized that EPCs express desmosome proteins and are responsible for the epicardial origin of fibroadiposis in AC. Methods: We deleted desmoplakin (Dsp), an AC causal gene, and expressed the enhanced yellow fluorescence protein (EYFP) post-natally (P7) in EPCs in vivo using an inducible Cre recombinase transcriptionally regulated by the Wt1 (Wilms tumor) locus. Results: Recombination efficiency was about 80%. WT1posEYFPpos cells represented 5-10% of the ...
Anti-CUB1 or Anti-Spacer Antibodies That Increase ADAMTS13 Activity Act By Allosterically Enhancing Metalloprotease Domain Function
Authors: An-Sofie Schelpe, Anastasis Petri, Nele Vandeputte, Hans Deckmyn, Simon F De Meyer, James TB Crawley, Karen Vanhoorelbeke
Journal: Blood (2018)
Individual difference in acts of self-sacrifice
Authors: Michael N. Stagnaro, Rebecca Littman, David G. Rand
Journal: Behavioral and Brain Sciences (2018)

Abstract Whitehouse's model explains when people engage in self-sacrifice, but not who is most likely to do so. We propose incorporating individual differences, such as cognitive style (one's inclination toward intuition versus deliberation), and argue that individuals who rely on intuition may be more likely to (1) develop group identity fusion after an emotional experience and (2) engage in pro-social self-sacrifice.
Phosphodiesterases as therapeutic targets for respiratory diseases
Authors: Haoxiao Zuo, Isabella Cattani-Cavalieri, Nshunge Musheshe, Viacheslav O. Nikolaev, Martina Schmidt
Journal: Pharmacology & Therapeutics (2019)

Chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and asthma, affect millions of people all over the world. Cyclic adenosine monophosphate (cAMP) which is one of the most important second messengers, plays a vital role in relaxing airway smooth muscles and suppressing inflammation. Given its vast role in regulating intracellular responses, cAMP provides an attractive pharmaceutical target in the treatment of chronic respiratory diseases. Phosphodiesterases (PDEs) are enzymes that hydrolyze cyclic nucleotides and help control cyclic nucleotide signals in a compartmentalized manner. Currently, the selective PDE4 inhibitor, roflumilast, is used as an add-on treatment for patients with severe COPD associated with bronchitis and a history of frequent exacerbations. In addition, other novel PDE inhibitors are in different phases of clinical trials. The current review provides an overview of the regulation of various PDEs and the potential application of selective PDE inhibitors in the treatment of COPD and asthma. The possibility to combine various PDE inhibitors as a way to increase their therapeutic effectiveness is also emphasized.
The standard Bayesian model is normatively invalid for biological brains
Authors: Rani Moran, Konstantinos Tsetsos
Journal: Behavioral and Brain Sciences (2018)

We show that the benchmark Bayesian framework that Rahnev &amp; Denison (R&amp;D) used to assess optimality is actually suboptimal under realistic assumptions about how noise corrupts decision making in biological brains. This model is therefore invalid qua normative standard. We advise against generally forsaking optimality and argue that a biologically constrained definition of optimality could serve as an important driver for scientific progress.
Allergic contact dermatitis in psoriasis
Authors: A. Claßen, T. Buhl, S. Schubert, M. Worm, A. Bauer, J. Geier, S. Molin
Journal: British Journal of Dermatology (2019)

Recent research suggests that people with the skin disease psoriasis may be at less risk of developing contact dermatitis, which is an eczema‐like reaction in response to the skin coming into contact with an irritant (irritant contact dermatitis) or allergen (allergic contact dermatitis, or ACD). This study looked at the prevalence of ACD specifically, in 2387 people with psoriasis who had been patch tested, compared to 161 981 patch tested people without psoriasis. Patch testing is used to find out which potential allergens cause a skin reaction in a person. Overall, 25.2% of the people with psoriasis and 38.9% of people without psoriasis showed at least one reaction to the allergens used in patch testing. These findings revealed a significantly lower overall risk for ACD in individuals with psoriasis. Taken together, psoriasis and contact dermatitis both involve complex processes of the body's immune system that make it difficult to understand what happens when both occur together. This research helps further our understanding on the topic.
Role of Monthly High-Dose Vitamin D Supplementation in Cancer Prevention—In Reply
Authors: Robert Scragg, Carlos A. Camargo
Journal: JAMA Oncology (2019)

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Toxicity of FOLFOX-abraxane (FOLFOX-A) on phase II Brown University Oncology Group (BrUOG) trials.
Authors: Howard Safran, Rimini Breakstone, Kevin Charpentier, John Vatkevich, Eric I Marks, Lindsey Cavanagh, Kristen Mitchell, Jen Renaud, Rachel Beard, Kayla Rosati
Journal: Journal of Clinical Oncology (2019)

354 Background: FOLFIRINOX increases survival in pancreatic cancer. The Brown University Oncology Group developed the FOLFOX-A regimen in a phase I study. (Am J Clin Oncol, 2016). We subsequently opened phase II studies of FOLFOX-A in patients with metastatic pancreatic cancer (BrUOG 292), locally advanced/borderline pancreatic cancer (BrUOG 318) and adjuvant disease following resection (BrUOG 295). The BrUOG Data Safety Monitoring Committee met on May 22, 2018. Toxicity of FOLFOX-A reviewed at the May meeting aligned with data lock in April on phase II FOLFOX-A studies and is summarized. Methods: Patients received oxaliplatin, 85mg/m2 day 1, nab-paclitaxel, 150mg/m2 and leucovorin 400mg/m2 day 1 and fluorouracil 2400mg/m2 by continuous IV infusion over 46 hours. Myeloid growth factor support was optional. Cycles were repeated every 14 days for up to 10-12 cycles. Oxaliplatin was dose reduced to 68mg/m2 for grade 2 neurotoxicity. CTCAE version 4 toxicity scales were utilized. Results: A total of 81 patients were accrued, (22 adjuvant, 36 metastatic, 23 locally advanced disease). Cumulative fatigue was the most common toxicity and required dose reduction in 50% of patients. The incidences of grade 2, 3 and 4 neutropenia were 26%, 17% and 6%, respectively. Grade 2,3 and 4 diarrhea were 9%, 15% and 0%. The rates of grade 2,3 and 4 neuropathy were 29%, 2% and 0%. Conclusions: FOLFOX-A is well tolerated with low incidences of grade 3 neuropathy and gastrointestinal toxicity. Toxicities were less frequent in patients treated in the adjuvant setting. Clinical trial information: NCT02080221, NCT02022033, NCT02578732.
Abstract 16137: Essential Role of Cdc42 in Cardiomyocyte Proliferation and Cell-cell Adhesion During Heart Development
Authors: Jieli Li, Yang Liu, Yixin Jin, Rui Wang, Vincent VanBuren, David E Dostal, Shenyuan L Zhang, Xu Peng
Journal: Circulation (2015)

Cdc42 is a member of the Rho GTPase family and functions as a molecular switch in regulating cell migration, proliferation, differentiation and survival. However, the role of Cdc42 in heart development remains largely unknown. To determine the function of Cdc42 in heart formation, we have generated a Cdc42 cardiomyocyte knockout (CCKO) mouse line by crossing Cdc42 flox mice with myosin light chain (MLC) 2a-Cre mice. The inactivation of Cdc42 in embryonic cardiomyocytes induced lethality after embryonic day 12.5. Histological analysis of CCKO embryos showed cardiac developmental defects that included thin ventricular walls and ventricular septum defects. Microarray and real-time PCR data also revealed that the expression level of p21 was significantly increased and cyclin B1 was dramatically decreased, suggesting that Cdc42 is required for cardiomyocyte proliferation. Phosphorylated Histone H3 staining confirmed that the inactivation of Cdc42 inhibited cardiomyocytes proliferation. In addition, transmission electron microscope studies showed disorganized sarcomere structure and disruption of cell-cell contact among cardiomyocytes in CCKO hearts. Accordingly, we found that the distribution of N-cadherin/β-Catenin in CCKO cardiomyocytes was impaired. Taken together, our data indicate that Cdc42 is essential for cardiomyocyte proliferation, sarcomere organization and cell-cell adhesion during heart development.
Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease
Authors: Evandro F. Fang, Yujun Hou, Konstantinos Palikaras, Bryan A. Adriaanse, Jesse S. Kerr, Beimeng Yang, Sofie Lautrup, Md Mahdi Hasan-Olive, Domenica Caponio, Xiuli Dan, Paula Rocktäschel, Deborah L. Croteau, Mansour Akbari, Nigel H. Greig, Tormod Fladby, Hilde Nilsen, M. Zameel Cader, Mark P. Mattson, Nektarios Tavernarakis, Vilhelm A. Bohr
Journal: Nature Neuroscience (2019)