tbuckley/cabot-search huggingface dataset:
Open-label, Multicenter, Phase II Study of RC48-ADC, a HER2-Targeting Antibody–Drug Conjugate, in Patients with Locally Advanced or Metastatic Urothelial Carcinoma
Authors: Xinan Sheng, Xieqiao Yan, Lin Wang, Yanxia Shi, Xin Yao, Hong Luo, Benkang Shi, Jiyan Liu, Zhisong He, Guohua Yu, Jianming Ying, Weiqing Han, Changlu Hu, Yun Ling, Zhihong Chi, Chuanliang Cui, Lu Si, Jianmin Fang, Aiping Zhou, Jun Guo
Journal: Clinical Cancer Research (2020)

Abstract Purpose: To evaluate the efficacy and safety of RC48-ADC, a novel humanized anti-HER2 antibody conjugated with monomethyl auristatin E, in patients with HER2+ locally advanced or metastatic urothelial carcinoma (mUC) refractory to standard therapies. Patients and Methods: This was a phase II, open-label, multicenter, single-arm study of patients with HER2+ (IHC status 3+ or 2+) locally advanced or mUC who previously failed at least one line of systemic chemotherapy. The primary endpoint was the objective response rate (ORR) assessed by a blinded independent review committee (BIRC). The secondary endpoint included progression-free survival (PFS), disease control rate, duration of response, overall survival (OS), and safety. Results: Forty-three patients were enrolled. The median follow-up was 20.3 months. The overall confirmed ORR as assessed by the BIRC was 51.2% [95% confidence interval (CI), 35.5%–66.7%]. Similar responses were observed in prespecified subgroups, such as those with liver metastasis and those previously treated with anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) therapies. The median PFS and OS were 6.9 months (95% CI, 5.6–8.9) and 13.9 months (95% CI, 9.1–NE), respectively. The most common treatment-related adverse events (TRAE) were hypoesthesia (60.5%), alopecia (55.8%), and leukopenia (55.8%). Twenty-five (58%) patients experienced grade 3 TRAEs, including hypoesthesia (23.3%) and neutropenia (14.0%). No grade 4 or grade 5 TRAEs occurred. Conclusions: RC48-ADC demonstrated a promising efficacy with a manageable safety profile in patients with HER2+ locally advanced or mUC who had failed at least one line of systemic chemotherapy.
Exploiting Protein Translation Dependence in Multiple Myeloma with Omacetaxine-Based Therapy
Authors: Zachary J. Walker, Beau M. Idler, Lorraine N. Davis, Brett M. Stevens, Michael J. VanWyngarden, Denis Ohlstrom, Shelby C. Bearrows, Andrew Hammes, Clayton A. Smith, Craig T. Jordan, Tomer M. Mark, Peter A. Forsberg, Daniel W. Sherbenou
Journal: Clinical Cancer Research (2020)

Abstract Purpose: The prognosis of patients with multiple myeloma who are resistant to proteasome inhibitors, immunomodulatory drugs (IMiD), and daratumumab is extremely poor. Even B-cell maturation antigen–specific chimeric antigen receptor T-cell therapies provide only a temporary benefit before patients succumb to their disease. In this article, we interrogate the unique sensitivity of multiple myeloma cells to the alternative strategy of blocking protein translation with omacetaxine. Experimental Design: We determined protein translation levels (n = 17) and sensitivity to omacetaxine (n = 51) of primary multiple myeloma patient samples. Synergy was evaluated between omacetaxine and IMiDs in vitro, ex vivo, and in vivo. Underlying mechanism was investigated via proteomic analysis. Results: Almost universally, primary patient multiple myeloma cells exhibit &amp;gt;2.5-fold increased rates of protein translation compared with normal marrow cells. Ex vivo treatment with omacetaxine resulted in &amp;gt;50% reduction in viable multiple myeloma cells. In this cohort, high levels of translation serve as a biomarker for patient multiple myeloma cell sensitivity to omacetaxine. Unexpectedly, omacetaxine demonstrated synergy with IMiDs in multiple myeloma cell lines in vitro. In addition, in an IMiD-resistant relapsed patient sample, omacetaxine/IMiD combination treatment resensitized the multiple myeloma cells to the IMiD. Proteomic analysis found that the omacetaxine/IMiD combination treatment produced a double-hit on the IRF4/c-MYC pathway, which is critical to multiple myeloma survival. Conclusions: Overall, protein translation inhibitors represent a potential new drug class for myeloma treatment and provide a rationale for conducting clinical trials with omacetaxine alone and in combination with IMiDs for patients with relapsed/refractory multiple myeloma.
Abstract 554: Reverse-mode Mitochondrial Na <sup>+</sup> / Ca2+ Mitochondrial Exchange, Not the Mcu, is the Primary Mode of Ca2+ Import Into the Mitochondria During Ischemia/ Reperfusion in Neonatal Cardiac Myocytes
Authors: Deepthi Ashok, Kyriakos Papanicolaou, Ting Liu, Brian O'Rourke
Journal: Circulation Research (2020)

Ca 2+ entry via the Mitochondrial Calcium Uniporter (MCU) participates in energetic adaption to workload under physiological conditions but is thought to contribute to cell death during ischemia-reperfusion (I/R) injury. We have previously shown that mitochondrial membrane potential (ΔΨm) instability contributes to early-reperfusion arrhythmias and contractile dysfunction; however, the role of mitochondrial Ca 2+ (mCa 2+ ) uptake in triggering ΔΨm oscillation is unclear. Here, by acutely knocking out MCU, we examine whether MCU-mediated mCa 2+ uptake is required to trigger ΔΨm loss or oscillation during early reperfusion in neonatal mouse ventricular myocyte (NMVM) monolayers. We monitored mCa 2+ (with MitoCam) and ΔΨm (with TMRM) in WT(MCU fl/fl ) and MCU-KO (MCU fl/fl +AdCre) NMVMs during in vitro I/R (previously described by Solhjoo et al JMCC, 2015) by confocal microscopy. Image sequences were analyzed for changes in mCa 2+ and ΔΨm by segmenting individual cells in ImageJ. To quantify ΔΨm oscillations in mitochondrial clusters during reperfusion, a new wavelet-transform-based analysis was developed using MATLAB’s wavelet toolbox. Surprisingly, our findings demonstrate that MCU knockout does not significantly alter mCa 2+ import during I/R, nor does it affect ΔΨm recovery during Reperfusion. In fact, MCU-KO moderately shortened the latency to Ischemic ΔΨm depolarization. In contrast, blocking the mitochondrial sodium-calcium exchanger (mNCLX) with CGP-37157 suppressed the mCa 2+ increase during Ischemia. Moreover, blocking mNCLX also did not affect ΔΨm recovery during Reperfusion or the frequency of ΔΨ m oscillations, confirming that mitochondrial ΔΨm instability on reperfusion is not triggered by mCa 2+ . Interestingly, inhibition of mitochondrial electron transport stabilized ΔΨm oscillations during reperfusion. The findings are consistent with mCa 2+ overload being mediated by reverse-mode mNCLX activity and support ROS-induced ROS release as the primary trigger of ΔΨm instability during reperfusion injury.
Abstract 10996: Inhibition of Thrombin-PARs Signaling by Dabigatran, a Direct Thrombin Inhibitor, Attenuates Endothelial Dysfunction in Diabetic Mice
Authors: Daiju Fukuda, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki, Masataka Sata
Journal: Circulation (2018)

Background: Vascular inflammation induced by diabetes causes endothelial dysfunction, an initial step of atherogenesis. Previous studies reported hypercoagulable state in diabetic patients. Thrombi...
Comprehensive Analysis of Factors Predictive for Time to Transformation and Risk of Transformation in Patients (pts) with Mantle Cell Lymphoma
Authors: Preetesh Jain, Rashmi Kanagal-Shamanna, Lucy Navsaria, Chi Young Ok, Holly Hill, Dayoung Jung, Graciela M. Nogueras González, Hun Ju Lee, Ranjit Nair, Sairah Ahmed, Raphael Eric Steiner, Guilin Tang, Shaoying Li, Keyur Patel, Selvi Thirumurthi, Pan Tinsu, Guofang Xu, Francisco Vega, Christopher Flowers, Michael Wang
Journal: Blood (2020)
Dichotomous Regulation of Lysosomes By MYC and Tfeb Controls Hematopoietic Stem Cell Fate
Authors: Laura Garcia Prat, Kerstin B Kaufmann, Florin Schneiter, Veronique Voisin, Alex Murison, Michelle Chan-Seng-Yue, Olga I. Gan, Jessica L. McLeod, Michelle Shoong, Kristele Pan, Kinam Gupta, Shin-Ichiro Takayanagi, Elvin Wagenblast, Weijia Wang, Timm Schroeder, Stephanie Zhi-Juan Xie, John E. Dick
Journal: Blood (2020)
Systematic Literature Review of the Clinical Efficacy, Safety, and Patient-Reported Outcomes of Treatments in Patients with Relapsed or Refractory Follicular Lymphoma after Two Prior Therapies
Authors: Qiufei Ma, Simarjeet Kaur, Angela Zhao, Jie Zhang, Roberto Javier Ramos, Dinesh Kumar, Lokho John, Lida Bubuteishvili Pacaud, Alessandra Forcina
Journal: Blood (2020)
Risk Prediction Modeling Based on a Combination of Initial Serum Biomarker Levels in Polymyositis/Dermatomyositis–Associated Interstitial Lung Disease
Authors: Takahisa Gono, Kenichi Masui, Naoshi Nishina, Yasushi Kawaguchi, Atsushi Kawakami, Kei Ikeda, Yohei Kirino, Yumiko Sugiyama, Yoshinori Tanino, Takahiro Nunokawa, Yuko Kaneko, Shinji Sato, Katsuaki Asakawa, Taro Ukichi, Shinjiro Kaieda, Taio Naniwa, Yutaka Okano, Masataka Kuwana
Journal: Arthritis & Rheumatology (2020)

To establish predictive models for mortality in patients with polymyositis/dermatomyositis-associated interstitial lung disease (PM/DM-ILD) using a combination of initial serum biomarker levels.The Multicenter Retrospective Cohort of Japanese Patients with Myositis-Associated ILD (JAMI) database of 497 incident cases of PM/DM-ILD was used as a derivation cohort, and 111 cases were additionally collected as a validation cohort. Risk factors predictive of all-cause mortality were identified by univariate and multivariable Cox regression analyses using candidate serum biomarkers as explanatory variables. The predictive models for mortality were generated in patients with and those without anti-melanoma differentiation-associated gene 5 (MDA-5) antibody, using a combination of risk factors. Cumulative survival rates were assessed using Kaplan-Meier analysis, and were compared between subgroups using the Breslow test.In the derivation cohort, C-reactive protein (CRP) and Krebs von den Lungen 6 (KL-6) levels were identified as independent risk factors for mortality in both anti-MDA-5-positive and anti-MDA-5-negative patients. We then developed a prediction model based on anti-MDA-5 antibody status, CRP level, and KL-6 level, termed the "MCK model," to identify patients at low (<15%), moderate (15-50%), or high (≥50%) risk of mortality, based on the number of risk factors. The MCK model successfully differentiated cumulative survival rates in anti-MDA-5-positive patients (P < 0.01 for low versus moderate risk and P = 0.03 for moderate versus high risk) and in anti-MDA-5-negative patients (P < 0.001 for low versus moderate risk). The utility of the MCK model was replicated in the validation cohort.Our findings indicate that an evidence-based risk prediction model using CRP and KL-6 levels combined with anti-MDA-5 antibody status might be useful for predicting prognosis in patients with PM/DM-ILD.
Targeting of Calbindin 1 (CALB1) Rescues Erythropoiesis in a Human Model of Diamond Blackfan Anemia: Implications for Novel Therapies
Authors: Nan of Wang, Corinne Marie Lavasseur, Hongxia Yan, Scott Younger, Bertil Glader, Kathleen M. Sakamoto, Lionel Blanc, Anupama Narla
Journal: Blood (2020)
Adoptive Therapy with Cord Blood T Regulatory Cells Enhances Anti-Myeloma Efficacy of T Cell Based Immunotherapies
Authors: Mitsutaka Nishimoto, Li Li, Meixian Huang, Mi-Ae Lyu, Ke Zeng, Hongbing Ma, Tara Sadeghi, Sairah Ahmed, Nina Shah, Krina K. Patel, Simrit Parmar
Journal: Blood (2020)
Azacitidine Maintenance Versus No Maintenance after Standard Therapy in Patientswith Acute Myeloid Leukemia, a Mexican Center Experience
Authors: Antonio De La Peña, Denisse J. Fermin-Caminero, Oscar Teomitzi-Sanchez, Luara Arana, Jose Alvarez, Juan Manuel Perez, María Eugenia Espitia, Eleazar Hernandez, Martha Alvarado
Journal: Blood (2020)
COVID-19 Infection in Patients with Paroxysmal Nocturnal Hemoglobinuria in Italy
Authors: Wilma Barcellini, Bruno Fattizzo, Luisa Quattrocchi, Juri Alessandro Giannotta, Semra Aydin, Federica Barone, Cecilia Carbone, Eloise Beggiato, Paola Bianchi, Eros Di Bona, Rosario Notaro, Anna Paola Iori
Journal: Blood (2020)
Association of Smoking with Advanced Stage and Survival Outcomes in Classic Hodgkin's Lymphoma
Authors: Samer Al Hadidi, Ranjit Nair, Raphael E Steiner, Sairah Ahmed, Paolo Strati, Simrit Parmar, Swami P. Iyer, Jillian R. Gunther, Chelsea C. Pinnix, Bouthaina S. Dabaja, Yago Nieto, Felipe Samaniego, Branko Cuglievan, Preetesh Jain, Penny Fang, Roberto N. Miranda, L. Jeffrey Medeiros, Lei Feng, Hubert Chuang, Michael Wang, Hun Ju Lee
Journal: Blood (2020)
Final Results of a Phase II Study of Fc Engineered, CD19 Antibody Tafasitamab in Combination with Lenalidomide or Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL)
Authors: Seema A Bhat, Ying Huang, Amy S. Ruppert, James S. Blachly, Michael R. Grever, Adam S. Kittai, Kerry A. Rogers, Gerard Lozanski, Nyla A Heerema, Lynne V. Abruzzo, Cecelia Miller, Jennifer Zvosec, Kasturi Ganesh-Barki, John C. Byrd, Jennifer A. Woyach
Journal: Blood (2020)
Abstract 347: Comparison of Six Minute Walk Test and Cardiopulmonary Exercise Test Results in Postural Orthostatic Tachycardia Syndrome Patients
Authors: Adeel Yousphi, Ayesha Bakhtiar, Adnaan Sheikh, Lan Yang, Shahkar A Khan, Esha Mahmood, Hemanshi Mistry, Amer Suleman
Journal: Circulation Research (2020)

Introduction: Postural orthostatic tachycardia syndrome (POTS) is a form of dysautonomia that can present as orthostatic tachycardia, dizziness, nausea, and anxiety, and many other symptoms that can be debilitating enough to cause functional impairment. The cardiopulmonary exercise test (CPET) has become a reliable test for evaluating the functional capacity (fc) in POTS patients. The test requires utilization of a bicycle ergometer, blood pressure apparatus, ECG, pulse oximeter, and a face mask that measures the oxygen uptake and carbon dioxide release. The 6-minute walk test (6MWT) is another test that can also be utilized to assess fc in patients. Objective: The aim of this study is to differentiate whether the 6MWT and CPET give similar results with regards to fc in POTS patients. Methods: A total of 27 POTS patients visiting the clinic consented to participate in the voluntary study. There were 2 males and 25 females, with ages between 16 to 58 years. For the 6MWT, we used wrist worn pulse oximeter, electronic tablet device, sphygmomanometer and a lap counter. Patients walked in a straight flat corridor which was marked at 3 meter intervals, for six minutes. At the end of 6 minutes, patients were asked to stop and the six minute walk distance (6MWD) was recorded. The predicted 6MWD, the distance the patient was expected to walk based on patient’s sex, age, height and weight was calculated by the application installed on the tablet. The percentage of the predicted 6MWD that was actually walked by the patients was calculated (6MWD % predicted), and considered as their fc. Using the electronic medical records, we obtained their CPET fc results, where fc was calculated as a percentage of the predicted maximal oxygen uptake per unit body weight per unit time (VO 2max ) that was actually consumed. The VO 2max measurement depends on patient’s sex, age, weight and height. Pearson correlation coefficient was used to compare the results of the 6MWT (6MWD % predicted) and CPET (fc). Results: Pearson correlation coefficient shows that there is no linear association between the CPET (fc) results and 6MWT (6MWD % predicted) results in POTS patients, with p=0.3368. Conclusion: The results convey no statistically significant association between the CPET (fc) results and the 6MWT (6MWD % predicted) results in POTS patients; the results of the 6MWT were not similar to that of the CPET in terms of fc testing in POTS patients. This suggests that the 6MWT has limited utility in POTS patients.
External Validation of Diffusion Weighted Whole Body MRI (DW-MRI) Response Assessment Category (RAC) Criteria Proposed By the Myeloma Response Assessment and Diagnosis System (MY-RADS) Imaging Recommendations: Prognostic Role of Imaging Response after Transplant in Multiple Myeloma and Comparison with MRD Evaluation By Flow Cytometry
Authors: Angelo Belotti, Rossella Ribolla, Valeria Cancelli, Alberta Villanacci, Valentina Angelini, Samantha Ferrari, Annalisa Peli, Chiara Cattaneo, Marco Chiarini, Luigi Grazioli, Giuseppe Rossi, Alessandra Tucci
Journal: Blood (2020)
Phazar: A Phase Ib Study to Assess the Safety and Tolerability of Ruxolitinib in Combination with Azacitidine in Advanced Phase Myeloproliferative Neoplasms (MPN), Including Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukaemia (AML) Arising from MPN [ISRCTN16783472]
Authors: Mark W. Drummond, Charlotte Gaskell, Claire Harrison, Adam J. Mead, Christina Yap, Aimee E Jackson, Jennifer Byrne, Fiona J Clark, Srinivasan Narayanan, David Bowen, Tim C.P Somervaille, Emma Gudgin, Dragana Milojkovic, Rachel S Fletcher, Charlotte K Brierley, Steve Knapper
Journal: Blood (2020)
Multiple Myeloma Mortality Incidence Prevalence of Disease - <i>Mmy Mind Study</i>
Authors: Humberto Martínez Cordero, Jessica Zapata Malagon, Lorena Cubillos Osorio, Alejandro Rico Mendoza, Alexandra Porras Ramírez, Juan Ospina Idarraga, Henry Idrobo, Viviana Olaya, Kenny Galvez, Sergio Cancelado, Juan Manuel Herrera, Leonardo Bautista Toloza
Journal: Blood (2020)
AB0508 EFFICACY AND SAFETY OF TNF-Α ANTAGONISTS AND TOCILIZUMAB IN TAKAYASU ARTERITIS: MULTICENTER EUROPEAN RETROSPECTIVE STUDY OF 203 PATIENTS.
Authors: A. Mekinian, M. Vautier, M. Resche-Rigon, L. Dagna, S. Sciascia, O. E. N. F. Olivier.Espitia@chu-Nantes.Fr, P. Cacoub, O. Fain, D. Saadoun
Journal: Annals of the Rheumatic Diseases (2020)

Background: Takayasu arteritis (TA) is a chronic inflammatory large-vessel vasculitis, predominantly affecting the aorta and its main branches Objectives: To assess safety and efficacy of biologics (i.e. TNF-α antagonists and tocilizumab) in patients with Takayasu arteritis (TA). Methods: We conducted a retrospective multicenter study in referral centers from Europe and several countries in the world about biological-targeted therapies in Takayasu arteritis during the period from January 2017 to September 2019. Results: Retrospective multicenter study of characteristics and outcome of 49 TA patients [80% of females; median age 42 [20-55] years] treated by TNF-α antagonists (80%) or tocilizumab (20%)] and fulfilling ACR and/or Ishikawa criteria. Factors associated with complete response were assessed. Eighty-eight percent of TA patients were inadequately controlled with, or intolerant to, conventional immunosuppressive therapy [median number of 3 (1-5)]. Overall response (i.e. complete and partial) to biological-targeted treatments at 6 and 12 months was of 75% and 83%, respectively. There were a significantly lower C-reactive protein levels at initiation of biological-targeted treatments [22 [10-46] mg/l vs 58 [26-76] mg/l, (p=0.006)] and a trend toward lower immunosuppressants drugs used prior biologics (p=0.054) in responders (i.e. complete and/or partial responders) relative to non-responders to biological-targeted treatments. C-reactive protein levels and daily prednisone dosage significantly decreased after 12 months of biological-targeted treatments [30 vs 6 mg/l, p&lt;0.05 and 15 vs 7.5 mg, p&lt;0.05, at baseline and at 12 months, respectively]. The 3-year relapse free survival was of 90.9% (83.5-99) over biologic treatment period compared to 58.7% (43.3-79.7) (p=0.0025) with DMARDs. No difference was found relative to efficacy between TNF-α antagonists and tocilizumab. After a median follow-up of 24 [2-95] months, 21% of adverse effects occurred, with biological-targeted treatments discontinuation in 6.6% of cases. Conclusion: This nationwide study shows high efficacy of biological-targeted treatments in refractory TA patients with an acceptable safety profile. Acknowledgments: NO Disclosure of Interests: Arsene Mekinian: None declared, Mathieu Vautier: None declared, Matthieu resche-rigon: None declared, Lorenzo Dagna Grant/research support from: Abbvie, BMS, Celgene, Janssen, MSD, Mundipharma Pharmaceuticals, Novartis, Pfizer, Roche, SG, SOBI, Consultant of: Abbvie, Amgen, Biogen, BMS, Celltrion, Novartis, Pfizer, Roche, SG, and SOBI, Savino Sciascia: None declared, olivier.espitia@chu-nantes.fr olivier.espitia@chu-nantes.fr: None declared, Patrice cacoub: None declared, olivier fain: None declared, david Saadoun: None declared
Daratumumab, lenalidomide, and dexamethasone in relapsed/refractory myeloma: a cytogenetic subgroup analysis of POLLUX
Authors: Jonathan L. Kaufman, Meletios A. Dimopoulos, Darrell White, Lotfi Benboubker, Gordon Cook, Merav Leiba, James Morton, P. Joy Ho, Kihyun Kim, Naoki Takezako, Philippe Moreau, Heather J. Sutherland, Hila Magen, Shinsuke Iida, Jin Seok Kim, H. Miles Prince, Tara Cochrane, Albert Oriol, Nizar J. Bahlis, Ajai Chari, Lisa O’Rourke, Sonali Trivedi, Tineke Casneuf, Maria Krevvata, Jon Ukropec, Rachel Kobos, Hervé Avet-Loiseau, Saad Z. Usmani, Jesus San-Miguel
Journal: Blood Cancer Journal (2020)

Abstract High cytogenetic risk abnormalities confer poor outcomes in multiple myeloma patients. In POLLUX, daratumumab/lenalidomide/dexamethasone (D-Rd) demonstrated significant clinical benefit versus lenalidomide/dexamethasone (Rd) in relapsed/refractory multiple myeloma (RRMM) patients. We report an updated subgroup analysis of POLLUX based on cytogenetic risk. The cytogenetic risk was determined using fluorescence in situ hybridization/karyotyping; patients with high cytogenetic risk had t (4;14), t (14;16), or del17p abnormalities. Minimal residual disease (MRD; 10 –5 ) was assessed via the clonoSEQ ® assay V2.0. 569 patients were randomized (D-Rd, n = 286; Rd, n = 283); 35 (12%) patients per group had high cytogenetic risk. After a median follow-up of 44.3 months, D-Rd prolonged progression-free survival (PFS) versus Rd in standard cytogenetic risk (median: not estimable vs 18.6 months; hazard ratio [HR], 0.43; P &lt; 0.0001) and high cytogenetic risk (median: 26.8 vs 8.3 months; HR, 0.34; P = 0.0035) patients. Responses with D-Rd were deep, including higher MRD negativity and sustained MRD-negativity rates versus Rd, regardless of cytogenetic risk. PFS on subsequent line of therapy was improved with D-Rd versus Rd in both cytogenetic risk subgroups. The safety profile of D-Rd by cytogenetic risk was consistent with the overall population. These findings demonstrate the improved efficacy of daratumumab plus standard of care versus standard of care in RRMM, regardless of cytogenetic risk.