tbuckley/cabot-search huggingface dataset:
Abstract 18134: Cardiomyocyte Overexpression of the alpha1A-Adrenergic Receptor in the Rat Protects Post-Infarct Heart Failure through Angiogenesis and the MEK-ERK Pathway
Authors: Xin Zhao, Ronald Pachon, Lin Yan, Grace Lee, Xiangzhen Sui, Daniella Beniamen, Poornima Balaji, David Ho, Dorothy E Vatner, Robert M Graham, Stephen F Vatner
Journal: Circulation (2014)

α1A-Adrenergic receptors (α1A-AR) are important for regulating cardiac contractility, but whether they regulate coronary vessels is not known. To examine this we investigated the effects of chronic, complete coronary artery occlusion (CAO) in rats with cardiac myocyte-restricted transgenic (TG) α1A-AR overexpression, since protection of the heart with complete CAO requires increased blood flow. 4 weeks after permanent left anterior descending CAO TG rats displayed improved contractility vs. non-transgenic littermates (NTL) (n=8/group, p&lt;0.05): 23% higher in LV dP/dt (7188±167mmHg/s), 13% higher in LV ejection fraction (57±0.9) and 23% lower in end-systolic wall stress (LVSWS) (79±6dynes/cm2) compared to NTLs. The scar size at 4 wks after CAO was significantly smaller in TG rats (18±2%) compared to NTL rats (28±3%), p&lt;0.05, but more importantly there were increased blood vessels within the scar in the TG rat hearts suggesting angiogenesis. This was confirmed using colored microspheres to measure coronary blood flow, which was higher in area at risk in TGs (1.4±0.2ml/min/g) as compared to NTLs (0.5±0.08ml/min/g), p&lt;0.05. This increased blood flow was further supported by a 41% increase in arterial density within the ischemic zone compared to NTLs at 2 weeks after CAO. In addition, capillary density was also found to be significantly increased, by 18% in the remote zone, compared to 2109 caps/mm2 in NTL. Utilizing an In vitro model, treatment with 25μM A61603 for 48 hours in cultured NTL neonatal myocytes resulted in an increase in VEGF-A secretion into the culture media and 26% increase in vascular tubule formation in HUVECs by a paracrine mechanism coinciding with an increased VEGF-A concentration compared to vehicle treated myocytes. Since VEGF is linked to the MEK-ERK signaling pathway, we blocked this mechanism by chronically administering the MEK blocker, U0126, sc. In these rats LV function was no longer different after 4 wks permanent CAO in TG and WTL treated with the blocker. Therefore, overexpression of cardiac myocyte specific α1A-AR in rats protected against cardiac dysfunction and remodeling associated with chronic myocardial infarction through the MEK-ERK pathway and via angiogenesis with a VEGF-A related paracrine mechanism.
Epiproteomic Landscape and Histone Code of Cutaneous T-Cell Lymphoma/Sézary Syndrome
Authors: Ozlem Onder, Rui Wu, Maria Wysocka, Paul L. Haun, Ellen Kim, Benjamin A Garcia, David Bahler, Alain Rook, Megan S. Lim, Kojo S.J. Elenitoba-Johnson
Journal: Blood (2018)
Erythrocyte ATP, a possible therapeutic approach for sickle cell disease
Authors: Joseph F. Hoffman
Journal: American Journal of Hematology (2019)

To the Editor: This letter presents some suggestions of possible therapies for sickle cell disease that are based on interpretations of presumed effects of different substrates that alter the cellular levels of ATP. A prevailing idea is that the shrinkage of sickle cells is the result of an increase in intracellular Ca that turns on the Ca-activated K channel (Gardos channel1) which causes the cells to shrink and become sickled. The presumption is that the sickled cells can lead to capillary flow blockage resulting in a patient's clinical crisis. If the cellular shrinkage could be prevented the ensuing crisis might be mitigated. The approaches discussed below might be candidates that keep the cells from shrinking. Walter Wilbrandt reported in 19372 that red blood cells exposed to fluoride shrink as a result of the loss of K. This type of K+ loss was later shown to be by the Gardos channel. Importantly, he found that the shrinkage of the cells could be prevented by the addition of pyruvate to the medium. It occurred to me that the effect of pyruvate might be due to the synthesis of ATP by the cell's redox system, which prevented the activity of the Gardos channel. This inhibition could occur by preventing the accumulation of cellular Ca by ATP acting to stimulate the cell's Ca pump.3 This interpretation has yet to be tested. A second possible approach emanates from a paper from the Agios Pharmaceuticals, Inc.,4 in which they report that their drug, AG-348, significantly increased the intracellular concentration of ATP in normal cells. Obviously, if the idea that the action of pyruvate was via ATP, then the AG-348 drug is a better choice over pyruvate. A third possibility arose with the publication of a clinical trial of testing the effect of glutamine therapy on sickle cell patients.5 It is thought that the effect of glutamine is to act on the cell's redox system, NAD/NADH. If this is so, then a possible result is that this could increase the cell's ATP concentration by stimulating glycolysis. This could mimic the effect of pyruvate considered above. It is obvious that the underlying suggestion in all of the above approaches relies on the central role of cellular ATP. It seems straight forward that these effects are easily testable on sickle cells as a function of aerobic/anaerobic conditions. Perhaps these types of results will be soon forthcoming. The author declare that they have no financial conflicts or conflicts of interest with the contents of this article.
β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer
Authors: Bernhard W. Renz, Ryota Takahashi, Takayuki Tanaka, Marina Macchini, Yoku Hayakawa, Zahra Dantes, H. Carlo Maurer, Xiaowei Chen, Zhengyu Jiang, C. Benedikt Westphalen, Matthias Ilmer, Giovanni Valenti, Sarajo K. Mohanta, Andreas J.R. Habenicht, Moritz Middelhoff, Timothy Chu, Karan Nagar, Yagnesh Tailor, Riccardo Casadei, Mariacristina Di Marco, Axel Kleespies, Richard A. Friedman, Helen Remotti, Maximilian Reichert, Daniel L. Worthley, Jens Neumann, Jens Werner, Alina C. Iuga, Kenneth P. Olive, Timothy C. Wang
Journal: Cancer Cell (2018)
Elevated IL-1Ra Levels in the Stem Cell Product Is Associated with the Development of Engraftment Syndrome Following Autologous Stem Cell Transplantation for the Treatment of Multiple Myeloma and Lymphoma
Authors: Stacey L. Fanning, Kira Goldgirsh, Dante B. Descalzi-Montoya, Rena Feinman, David S Siegel, Noa Biran, David H. Vesole, Andre Goy, Tatyana A. Feldman, Lori A. Leslie, Scott D. Rowley, Alan P Skarbnik, Phyllis McKiernan, Melissa Baker, Michele L. Donato, Robert Korngold
Journal: Blood (2018)
Exposure and Sensitization to Formaldehyde of Urban Children at Risk of Asthma and Rhinitis
Authors: Dong Keon Yon, Seung Won Lee, Hye mi Jee, Kyung Suk Lee, Young-Ho Jung, Youn Ho Sheen, Sun Hee Choi, Man Yong Han
Journal: Journal of Allergy and Clinical Immunology (2019)
Faecal microbiota transplant for eradication of multidrug-resistant Enterobacteriaceae: a lesson in applying best practice? Re: ‘A five-day course of oral antibiotics followed by faecal transplantation to eradicate carriage of multidrug-resistant Enterobacteriaceae: A Randomized Clinical Trial’
Authors: B.H. Mullish, R. Ghani, J.A.K. McDonald, J.R. Marchesi
Journal: Clinical Microbiology and Infection (2019)
Efficacy and safety of nivolumab in first-line or further treatment of advanced metastatic biliary tract cancer.
Authors: Miaomiao Gou, Yong Zhang, Haiyan Si, Guanghai Dai
Journal: Journal of Clinical Oncology (2019)

315 Background: PD-1 inhibitors have improved efficacy in many cancers. There are few report of nivolumab for metastatic biliary tract cancer (MBTC). This study reviewed the efficacy and safety of nivolumab for MBTC to improve efficacy and survival. Methods: Thirty patients with MBTC were voluntarily treated with non-clinical nivolumab at the PLA General Hospital. Nivolumab 200 mg or 180 mg was administered according to patient tolerance. Progression free survival (PFS), overall survival (OS) was evaluated by kaplan-meier and univariate analysis were carried out among clinical characteristics. Objective response rates (ORR), disease control rates (DCR), and treatment-related adverse events (AEs) were also evaluated. Results: The median treatment cycle is 4 cycles. One case was complete response (CR), 5 cases partial response (PR), 12 cases stable (SD). ORR was 20%, DCR was 60%. PFS was 3.1m (95% CI: 2.13~4.06 months). The AEs of nivolumab monothrapy were fatigue (3 cases), fever (2 cases), hypothyroidism (1 case), skin reaction (1 case). Nivolumab combined with chemotherapy related 1-2 hematologic toxicity were leukopenia (5 cases), thrombocytopenia (2 cases), and grade 3-4 were leukopenia (3 cases). Non-hematologic toxicity grade 1-2 were nausea and vomiting (4 cases), fatigue (4 cases), fever (3 cases), peripheral neurotoxicity (3 cases), and hypothyroidism (1 case). Univariate analysis showed that PFS was 4.20m in patients older than 53 years, slightly higher than those younger than 53 years (3.0 m, P = 0.047). PFS of nivolumab combined with chemotherapy was statistically significant compared with nivolumab monothrapy (4.1 m vs 2.3 m, p = 0.031). Patients with metastatic number &gt; 2 had a shorter PFS than those &lt; 2 (1.4 m vs 4.1 m, P = 0.05). PD-L1 expression positive have no better PFS compared with PD-L1 negative (3.6 m vs 3.1 m , p = 0.801). Multivariate analysis show nivolumab combined with chemotherapy was only independent factor for longer PFS (HR: 0.432, P &lt; 0.05). Conclusions: the safety of nivolumab in MBTC is controllable. Subgroup analysis suggests that further selection of superior populations is needed and sample size need to be expanded to improve the efficacy of nivolumab in MBTC.
The JAK Inhibitor Blocks PD-L1, PD-L2 and CD44 Expression in Multiple Myeloma (MM) and Sensitizes MM Cells to Lenalidomide and Steroids
Authors: Haiming Chen, Mingjie Li, Eric Sanchez, Camilia M. Soof, Sean Bujarski, Nicole Ng, Jasmin Cao, Tara Hekmati, Edward J Tanenbaum, Brian Zahab, Cathy S. Wang, George Y Tang, Ning Xu, James R Berenson
Journal: Blood (2018)
Retrospective multicenter study for assessment of association between imaging change and outcome after treatment of regorafenib: KSCC1603.
Authors: Taito Esaki, Masahiro Kawahira, Tetsuya Kusumoto, Satoshi Yuki, Kazuteru Hatanaka, Yoshimitsu Kobayashi, Akihiro Nishie, Satoshi Kawanami, Akitaka Makiyama, Hiroshi Saeki, Mototsugu Shimokawa, Eiji Oki, Yoshihiko Maehara
Journal: Journal of Clinical Oncology (2019)

509 Background: Molecular-targeted drugs are known to have angiogenesis-inhibiting properties, and thus can inhibit angiogenesis inside the tumor tissue to cause necrosis, even if the tumor diameter is unchanged. We retrospectively investigated relationship between imaging change associated with regorafenib (REGO) treatment and the treatment outcome in Japanese mCRC. Methods: Eligibility included ECOG-PS 0 or 1, treated with REGO with lung or liver metastasis, started dose with 120 or 160mg/day of regorafenib and duration of treatment (DOT) must be 35 days or more (excluding interruption). Patients (Pts) were performed baseline CT within 28 days before and first CT assessment were between eight and 12 weeks after start of regorafenib. The main objective of this analysis is to investigate the correlation between the imaging change and outcome. As imaging change, onset or increase of Cavitation of lung lesion (CLL), morphologic response of liver lesion (MRL), Change of liver metastasis density (CLD) were evaluated. In all cases, independent two radiologists are evaluating radiological change after regorafenib treatment. Results: We finally screened 671 cases and 231 cases were eligible. The pts background was male/female 147/84, median age 64.0 (range: 32-83), median DOT of REGO 86 days (range: 35-818). The pts with lung metastasis were 153, and with liver metastasis were 166. CLL were positive in 69 (40.0%) pts. The median progression free survival (PFS) of the pts with/without CLL were 3.2/2.4 months (HR 0.794; 95% CI 0.584-1.080). Median overall survival (OS) of the pts with/without CLL were 10.5/9.0 months (HR 1.058; 95% CI 0.751-1.489). Median OS of pts with/without CLL in female were 11.4/7.9 months (HR 0.630; 95% CI 0.352-1.127). The MRL and CLD of liver metastasis were analyzed in 147 / 91 pt. Median OS of pts with/without MRL were 9.9/8.2 months (HR 1.015; 95% CI 0.581-1.774) and Median OS with/ without CLD were 11.6/7.0 months (HR 0.604; 95% CI 0.353-1.031). Conclusions: Cavitation of lung metastasis may predict PFS of the pts but not OS. Change of Liver metastasis density were predictor of favorable outcome to regorafenib. (UMIN000023329).
Who Are the Type 2 Von Willebrand Disease Patients? Results from Interim Analysis of the French HRQoL Study: Wish-Qol.
Authors: Annie Borel-Derlon, Jenny Goudemand, Dominique Desprez, Céline Falaise, Fabienne Genre Volot, Laurent Ardillon, Brigitte Pan-Petesch, Catherine Chatelanaz, Catherine Doriat-Robin, Agnès Veyradier, Sylvia Von Mackensen
Journal: Blood (2018)
Impact of Concomitant Administration of Gastric Acid–Suppressive Agents and Pazopanib on Outcomes in Soft-Tissue Sarcoma Patients Treated within the EORTC 62043/62072 Trials
Authors: Olivier Mir, Nathan Touati, Michela Lia, Saskia Litière, Axel Le Cesne, Stefan Sleijfer, Jean-Yves Blay, Michael Leahy, Robin Young, Ron H.J. Mathijssen, Nielka P. Van Erp, Hans Gelderblom, Winette T. Van der Graaf, Alessandro Gronchi
Journal: Clinical Cancer Research (2019)

Pazopanib is active in soft-tissue sarcoma (STS). Because pazopanib absorption is pH-dependent, coadministration with gastric acid-suppressive (GAS) agents such as proton pump inhibitors could affect exposure of pazopanib, and thereby its therapeutic effects.The EORTC 62043 and 62072 were single-arm phase II and placebo-controlled phase III studies, respectively, of pazopanib in advanced STS. We first compared the outcome of patients treated with pazopanib with or without GAS agents for ≥80% of treatment duration, and subsequently using various thresholds. The impact of concomitant GAS therapy was assessed on progression-free survival (PFS) and overall survival (OS) using multivariate Cox models, exploring and comparing also the potential effect on placebo-treated patients.Of 333 eligible patients, 59 (17.7%) received concomitant GAS therapy for >80% of pazopanib treatment duration. Median PFS was shorter in GAS therapy users versus nonusers: 2.8 vs. 4.6 months, respectively [HR, 1.49; 95% confidence interval (CI), 1.11-1.99; P = 0.01]. Concomitant administration of GAS therapy was also associated with a shorter median OS: 8.0 vs. 12.6 months (HR, 1.81; 95% CI, 1.31-2.49; P < 0.01). The longer the overlapping use of GAS agents and pazopanib, the worse the outcome with pazopanib. These effects were not observed in placebo-treated patients (HR, 0.82; 95% CI, 0.51-1.34; P = 0.43 for PFS and HR, 0.84; 95% CI, 0.48-1.48; P = 0.54 for OS).Coadministration of long-term GAS therapy with pazopanib was associated with significantly shortened PFS and OS. Withdrawal of GAS agents must be considered whenever possible. Therapeutic drug monitoring of pazopanib plasma concentrations may be helpful for patients on pazopanib and GAS therapy.
Growth trajectories of breastfed HIV-exposed uninfected and HIV-unexposed children under conditions of universal maternal antiretroviral therapy: a prospective study
Authors: Stanzi M le Roux, Elaine J Abrams, Kirsten A Donald, Kirsty Brittain, Tamsin K Phillips, Kelly K Nguyen, Allison Zerbe, Max Kroon, Landon Myer
Journal: The Lancet Child & Adolescent Health (2019)
Is retinal microvascular damage an early manifestation of systemic sclerosis?
Authors: Florenzo Iannone, Cinzia Rotondo
Journal: Annals of the Rheumatic Diseases (2019)

We read with great interest the paper by Rothe et al , recently published on Annals of the Rheumatic Diseases,1 who provided evidence that patients affected with systemic sclerosis (SSc) had impaired retinal microvascular perfusion, despite the lack of ocular symptoms. Angiograms of the full retina were obtained by optical coherent tomography (OCTA) in 12 patients with SSc with established disease and 12 matched healthy subjects in a case-control cross-sectional …
Prognostic Relevance of Neutrophil to Lymphocyte Ratio (NLR) and Lymphocyte to Monocyte Ratio (LMR) in Newly Diagnosed Advanced-Stage Hodgkin Lymphoma Patients Treated up-Front with a PET-2 Risk Adapted Protocol
Authors: Alessandra Romano, Francesco Di Raimondo, Chiara Pavoni, Corrado Tarella, Simonetta Viviani, Andrea Rossi, Caterina Patti, Marco Picardi, Maria Cantonetti, Giorgio La Nasa, Livio Trentin, Silvia Bolis, Valerio Zoli, Paolo Gavarotti, Paolo Corradini, Michele Cimminiello, Corrado Schiavotto, Guido Eugenio Parvis, Roberta Zanotti, Guido Gini, Andres J M Ferreri, Piera Viero, Alberto Biggi, Alessandro M. Gianni, Andrea Gallamini, Alessandro Rambaldi
Journal: Blood (2018)
Navigating Loneliness in the Era of Virtual Care
Authors: Ameya Kulkarni
Journal: New England Journal of Medicine (2019)

Dr. Ameya Kulkarni on drivers of physician loneliness and opportunities for meaningful interaction. (08:42)Download The transition away from routine interaction with patients and colleagues toward more individual activities has contributed to loneliness and burnout. Addressing physicians' loneliness in the 21st century requires finding innovative ways to interact with each other.
Distribution and Clinical Features of NOTCH1 Signaling Activating Alterations in Pediatric T-Cell Acute Lymphoblastic Leukemia (T-ALL)
Authors: Shunsuke Kimura, Masafumi Seki, Kenichi Yoshida, Hiroo Ueno, Yasuhito Nannya, Kentaro Ohki, Motohiro Kato, Katsuyoshi Koh, Ryoji Kobayashi, Takao Deguchi, Yoshiko Hashii, Toshihiko Imamura, Atsushi Sato, Nobutaka Kiyokawa, Atsushi Manabe, Keizo Horibe, Akira Ohara, Masashi Sanada, Mitsuteru Hiwatari, Masao Kobayashi, Akira Oka, Satoru Miyano, Seishi Ogawa, Junko Takita
Journal: Blood (2018)
The Rap1-RIAM Pathway Regulates the Expression of Integrins αEβ7(CD103) and α4β7, Which Guide T Cell Homing to Intestinal Compartments
Authors: Yavuz-Furkan Yazicioglu, Halil-Ibrahim Aksoylar, Rinku Pal, Nikolaos Patsoukis, Vassiliki A Boussiotis
Journal: Blood (2018)
The Global POLAR program: Calmangafodipir used on top of modified FOLFOX6 (5-FU/FA and oxaliplatin) to prevent chemotherapy induced peripheral neuropathy (CIPN).
Authors: Per Pfeiffer, Camilla Qvortrup, Kei Muro, Maryam B. Lustberg, Fumiko Nagahama, Yusuke Sonehara, Marie Helene Bengtson, Malin Nittve, Christian Sonesson, Carl Stefan Carlsson
Journal: Journal of Clinical Oncology (2019)

TPS722 Background: Oxaliplatin (OXA), is approved in combination with 5-FU/FA (5-fluorouracil/folinic acid; FOLFOX) for metastatic as well as in adjuvant colo-rectal cancer (CRC) treatment. CIPN is a common adverse event, after OXA treatment. The incidence of chronic CIPN is approximately 15% after a cumulative dose of 780 to 850 mg/m² and 50% after a cumulative dose of 1170 mg/m². OXA induced neuropathy, results in greatly reduced nitrated manganese superoxide dismutase (MnSOD) activity. Treatment with a superoxide dismutase mimetic, such as calmangafodipir (CAL), prevents and reverses oxaliplatin-induced neuropathies. This has been demonstrated in the PLIANT study (Glimelius et al. 2017). Methods: The POLAR program is a phase III, multicenter, placebo (PLC)-controlled program of CAL to prevent CIPN, initiated in US, Europe and Asia: POLAR A patients with CRC, treatment of patients with stage III or high-risk stage II who are indicated for adjuvant modified FOLFOX6 (mFOLFOX6) chemotherapy for up to 6 months, randomized in a 1:1 ratio, each arm n = 140: A: CAL (5 µmol/kg) + mFOLFOX6 chemotherapy B: PLC + mFOLFOX6 chemotherapy POLAR M Patients with metastatic colorectal cancer (mCRC), who are indicated for first-line mFOLFOX6 chemotherapy for at least 3 months, without any pre-planned treatment breaks and will be randomized in a 1:1:1 ratio, each arm n = 140: A: CAL (2 µmol/kg) + mFOLFOX6 chemotherapy B: CAL (5 µmol/kg) + mFOLFOX6 chemotherapy C: PLC + mFOLFOX6 chemotherapy. Primary objective is to compare CAL versus PLC with respect to the proportion of patients with moderate or severe chronic CIPN. The primary endpoint is; patient reported symptoms as proportion of patients scoring 3 or 4 in at least 1 of the first 4 items of the FACT/GOG-NTX-13 (i.e., FACT/GOG-NTX-4), targeting numbness, tingling or discomfort in hands and/or feet, assessed 9 months after the first dose of chemotherapy. In addition to conventional safety endpoints, Progressive Free Survival and Overall Survival are assessed in the POLAR M study. In the POLAR A study Disease Free Survival is one additional safety endpoint assessed. Results are expected during second half of 2020. Clinical trial information: NCT03654729.
Lectin-Mediated pH-Sensitive Doxorubicin Prodrug for Pre-Targeted Chemotherapy of Colorectal Cancer with Enhanced Efficacy and Reduced Side Effects
Authors: Meinan Yao, Xiaotu Ma, Xin Zhang, Linqing Shi, Tianyu Liu, Xiaolong Liang, Huiyun Zhao, Xiaoda Li, Liqiang Li, Hannan Gao, Bing Jia, Fan Wang
Journal: Theranostics (2019)

Doxorubicin (DOX) has been clinically used as a broad-spectrum chemotherapeutic agent for decades, but its clinical application is hindered by the lack of tumour specificity, severe cardiotoxicity and haematotoxicity.Pre-targeted strategies are highly tumour-specific, therapeutic approaches.Herein, a novel pre-targeted system was constructed, aiming to enhance anticancer efficacy of DOX and maximally reduce its side effects.Methods: The DOX prodrug (bDOX) was first synthesized by conjugating DOX with mini-PEGylated (mPEGylated) biotin through a pH-sensitive bond.During the pre-targeted treatment, avidin was first administrated.After an optimized interval, bDOX was second administrated.The nontoxic prodrug bDOX was eventually transformed into the toxic anticancer form (DOX) by a pH-triggered cleavage specifically in tumour cells.The drug efficacy and side effect of the two-step, pre-targeted treatment were fully compared with free DOX in vitro and in vivo.Results: The prodrug bDOX was quite stable under neutral conditions and nearly nontoxic, but was immediately transformed into the toxic anticancer form (DOX) under acidic conditions.Compared to free DOX, the pre-targeted bDOX exhibited a higher cellular uptake by human colorectal tumour cells (LS180 and HT-29 cells).In vivo evaluation performed on LS180 xenograft animal model demonstrated that the pre-targeted bDOX achieved a much more significant tumour inhibition than free DOX.The largely decreased, unwanted bystander toxicity was demonstrated by changes in body weight, cardiomyocyte apoptosis, blood routine examination and splenic pathological changes. Conclusion:The high therapeutic efficacy, together with the minimal side effects, of this easily synthesized, pre-targeted system exhibited immense potentiality for the clinical application of DOX delivery.