tbuckley/cabot-search huggingface dataset:
Identification and characterization of a novel class of JAK inhibitors and their application in targeting multiple myeloma
Authors: Pawel T. Dobrzanski
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

666 

Multiple myeloma (MM) is a B-cell neoplasm characterized by the accumulation of clonal malignant plasma cells in the bone marrow (BM). Adhesion of MM cells to stromal cells of BM induces IL-6 secretion, which plays a critical role in progression of MM. IL-6 activates multiple signaling pathways including Ras/MAPK, JAK/STAT and PI3-K/Akt, which mediate proliferation, survival and drug resistance of MM cells. JAK/STAT signaling, by upregulating expression of inhibitors of apoptosis including Bclxl, Mcl-1, survivin and XIAP, mediates cell survival and resistance to chemotherapies in MM cells. Thus, JAK/STAT pathway represents an attractive target for new MM therapies. Here we report identification and characterization of a novel class of JAK inhibitors, and demonstrate their ability to strongly (90% at 72h) suppress growth and induce apoptosis in MM cells. We show that treatment of U266 MM cells with these compounds inhibited JAK/STAT signaling and downregulated the expression of Bclxl and Mcl-1, antiapoptotic members of the Bcl2 family, as well as XIAP and survivin, members of the IAP family of caspase inhibitors. This resulted in activation of caspase-9 and caspase-3 and PARP cleavage, indicating induction of apoptosis. Furthermore, these JAK inhibitors significantly (3-10 fold) augmented the cytotoxicity of commonly used chemotherapeutic agents including cisplatin and fludarabine, highlighting their potential as chemosensitizers. The chemosensitizing efficacy of JAK inhibitors correlated with their ability to derepress mitochondrial pathway of apoptosis. In addition to inducing apoptosis, JAK inhibitors strongly downregulated expression of cyclinD1. Induction of apoptosis and suppression of cell growth correlated with ability of this class of compounds to inhibit JAK/STAT signaling, as structurally related, but nonactive compounds, showed no effects on growth of U266 cells. These results indicate a potential therapeutic application for JAK inhibitors in the treatment of MM and other tumor types, either as monotherapy or in combination with established treatment modalities.
Hypoplastic Left Heart Syndrome
Authors: Jeffrey A. Feinstein, D. Woodrow Benson, Anne M. Dubin, Meryl S. Cohen, Dawn M. Maxey, William T. Mahle, Elfriede Pahl, Juan Villafañe, Ami B. Bhatt, Lynn F. Peng, Beth Ann Johnson, Alison L. Marsden, Curt J. Daniels, Nancy A. Rudd, Christopher A. Caldarone, Kathleen A. Mussatto, David L. Morales, D. Dunbar Ivy, J. William Gaynor, James S. Tweddell, Barbara J. Deal, Anke K. Furck, Geoffrey L. Rosenthal, Richard G. Ohye, Nancy S. Ghanayem, John P. Cheatham, Wayne Tworetzky, Gerard R. Martin
Journal: Journal of the American College of Cardiology (2011)
Abstract 2865: Enhanced Left Ventricular Mass Regression Following Aortic Valve Replacement is Associated with Improved Long-Term Survival: A 15-year Study
Authors: Ayyaz Ali, Amit Patel, Yasir Abu-Omar, Anila Mehta, Ziad Ali, Sabine Bleiziffer, Darren Freed, Ahmad Y Sheikh, Thanos Athanasiou, John Pepper
Journal: Circulation (2008)

Background Aortic valve replacement (AVR) is followed by regression of LVH. More complete resolution of LVH is suggested to be associated with superior clinical outcomes, however its impact on long-term survival following AVR has not been investigated. Methods Demographic and clinical data were obtained retrospectively through casenote review. Transthoracic echocardiography was used to measure LVM pre-operatively and at annual follow-up visits. Patients were grouped according to their reduction in LVM at late follow-up: Group A &lt; 25 grams, Group B 25–150 grams and Group C &gt; 150 grams. Results 211 patients underwent AVR between 1 st January 1991 and 1 st January 2001. Pre-operative LVM was 295 ± 118 g in A (n=63), 346 ± 97 g in B (n=75) and 539 ± 175 g in C (n=73), P &lt;0.001. Mean time to last echocardiogram was 6.4 ± 3.3 years. LVM at late follow-up was 351 ± 160 g in A, 265 ± 95 g in B and 270 ± 90 g in C, P &lt;0.001. Transvalvular gradients at follow-up were not significantly differerent between groups (A: 21 ± 21 mm Hg, B: 20 ± 15 mm Hg, C: 14 ± 11 mm Hg), P = 0.10. There was no difference in the prevalence of other factors influencing LVM regression such as IHD or hypertension. Ten year actuarial survival was significantly greater in patients with enhanced LVM regression when compared with the log-rank test (A: 49% ± 7, B: 67%± 6, C: 75% ± 6), P =0.03 (Figure 1 ). LVM reduction &gt; 150 grams was an independent predictor of long-term survival on multivariate analysis (P = 0.03). Conclusion Enhanced LVM regression at late follow-up in patients undergoing AVR is associated with improved long-term survival. Strategies to optimize post-operative LVM regression should be considered in view of potential prognostic benefit.
Efficacy of Cabazitaxel in Castration-resistant Prostate Cancer Is Independent of the Presence of AR-V7 in Circulating Tumor Cells
Authors: Wendy Onstenk, Anieta M. Sieuwerts, Jaco Kraan, Mai Van, Annemieke J.M. Nieuweboer, Ron H.J. Mathijssen, Paul Hamberg, Hielke J. Meulenbeld, Bram De Laere, Luc Y. Dirix, Robert J. van Soest, Martijn P. Lolkema, John W.M. Martens, Wytske M. van Weerden, Guido W. Jenster, John A. Foekens, Ronald de Wit, Stefan Sleijfer
Journal: European Urology (2015)
Abstract 2844: Preload Augmentation by Leg Elevation is Helpful in Triaging the Patients with Grade 1 Diastolic Dysfunction
Authors: Eui-Young Choi, Sung-Ai Kim, Sang Jae Rhee, Ae Young Her, Chi Young Shim, Jong-Won Ha, Namsik Chung
Journal: Circulation (2008)

Grade 1 diastolic dysfunction (DD) is a spectrum of a variety of conditions. Objectives: We sought to investigate whether the responses of mitral inflow and annular velocity to leg elevation can provide additional information regarding triaging patients with grade 1 DD. One hundred fifty-four consecutive patients with hypertension with abnormal left ventricular (LV) relaxation on Doppler mitral inflow (early (E)/late (A) mitral inflow velocity &lt;0.75 or deceleration time &gt; 240 ms) were enrolled. Patients with LV ejection fractions less than 50%, a previous history of ischemic heart disease, inducible regional wall motion abnormality, valvular or myocardial disease, or any other volume overloading diseases were excluded. After resting evaluation, echo-Doppler measurements were performed during passive leg elevation and symptom-limited graded bicycle exercise. Patients were divided into two groups according to resting E/E’: Group I (E/E’&lt;15) and II (E/E’≥15, n=23). Group I subjects were further subdivided into IA (persistent E/E’ &lt;15, n=112) and IB (change to E/E’≥15, n=19) according to response to leg elevation. Group II had lower systolic (S’), early (E’), and late (A’) diastolic annular velocity, and diastolic reserve index to exercise (E’xΔE’50W) and higher LV elastance index (E/E’/stroke volume) than that of group IA; there was no significant difference compared to group IB. Group IB had more female predominance, older age, lower E’, higher diastolic elastance index, and higher E/E’ at 25W and 50W exercise accompanied by lower exercise capacity compared to group IA. Preload augmentation by leg elevation might provide additional information in triaging patients with grade 1 DD.
Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder
Authors: Alexander J Abrams, Robert B Hufnagel, Adriana Rebelo, Claudia Zanna, Neville Patel, Michael A Gonzalez, Ion J Campeanu, Laurie B Griffin, Saskia Groenewald, Alleene V Strickland, Feifei Tao, Fiorella Speziani, Lisa Abreu, Rebecca Schüle, Leonardo Caporali, Chiara La Morgia, Alessandra Maresca, Rocco Liguori, Raffaele Lodi, Zubair M Ahmed, Kristen L Sund, Xinjian Wang, Laura A Krueger, Yanyan Peng, Carlos E Prada, Cynthia A Prows, Elizabeth K Schorry, Anthony Antonellis, Holly H Zimmerman, Omar A Abdul-Rahman, Yaping Yang, Susan M Downes, Jeffery Prince, Flavia Fontanesi, Antonio Barrientos, Andrea H Németh, Valerio Carelli, Taosheng Huang, Stephan Zuchner, Julia E Dallman
Journal: Nature Genetics (2015)
Abstract 2256: Predictors of “Life-Threatening” Fast VT or VF in Arrhythmogenic Right Ventricular Dysplasia
Authors: Douglas W Laidlaw, David Lucier, James P Daubert, Frank I Marcus, Melvin M Scheinman, Wojciech Zareba, N.A. Mark Estes
Journal: Circulation (2007)

Introduction: The Multidisciplinary Study of Right Ventricular Dysplasia is an NIH-funded, multicenter, prospective registry of patients meeting Task-Force criteria for arrhythmogenic right ventricular dysplasia (ARVD). Previous studies have used the occurrence of “life-threatening” fast VT or VF as a surrogate for sudden cardiac death in patients with an ICD, however the patient characteristics associated with sudden cardiac death in ARVD remain poorly defined. Methods: All patients in the ARVD registry that underwent implantation of an ICD were studied. Baseline characteristics of patients who received ICD therapy for fast VT/VF (with a cycle length of &lt;250msec) were compared to those patients who did not receive ICD therapy. The cumulative risk of appropriate ICD therapy for fast VT/VF was determined by the Kaplan-Meier method for patients receiving an ICD for primary or secondary prevention. Results: 80 patients in the ARVD registry underwent implantation of an ICD. Of those, 61 patients (76%) had an ICD implanted for secondary prevention and 19 patients (24%) for primary prevention. Over a mean follow-up of 1.7 years, 17.5% of patients experienced appropriate ICD therapy for fast VT/VF, including 18% of patients with an ICD implanted for secondary prevention and 15.8% of patients with and ICD implanted for primary prevention. Among all baseline imaging, echocardiographic, and electrcardiographic characteristics, none were significantly associated with the occurance of fast VT/VF during follow-up. In a Kaplan-Meier analysis, there was no significant diffference in the cumulative risk of ICD therapy for fast VT/VF between primary or secondary prevention cohorts (log rank p-value = 0.69). Conclusions: In this registry of patients meeting the current Task Force criteria for ARVD, there is a high incidence of “life-threatening” fast VT/VF during follow-up, and the probability of fast VT/VF is similar in patients with an ICD for secondary prevention compared to those with an ICD for primary prevention. Furthermore, baseline characteristics do not reliably predict a future risk of life threatening arrhythmias in this cohort.
国际艾滋病大会呼吁：加强预防工作，防止艾滋病蔓延
Authors: Henry, Wasswa, 孙静
Journal: BMJ (2008)

上周在乌干达首都坎帕拉召开了2008年艾滋病防治执行者会议，有1700位医生和专家参加。大会共召开了大约60个专家委员会分会，就艾滋病防治的各项工作进行了充分的讨论．包括流行病学、关怀工作、人权保护、营养、项目合作、受性虐待艾滋病人的现状以及基金资助等内容。
Association Of Platelet Function Markers, Independent Of Platelet Count, With Bleeding Score In Patients With Immune Thrombocytopenia
Authors: Andrew L. Frelinger, Anja J Gerrits, Michelle A. Berny-Lang, Travis Brown, Sabrina L. Carmichael, Ellis J. Neufeld, Alan D. Michelson, Rachael F. Grace
Journal: Blood (2013)
Abstract 19809: Association between Jet Direction and Mitral Leaflet Tethering in Ischemic Mitral Regurgitation. An Echocardiographic Study
Authors: Eiji Kuwahara, Masaki Izumo, Yoko Fukuoka, Takahiro Shiota
Journal: Circulation (2010)

Background: Mitral regurgitant (MR) jet direction with ischemic etiology is usually central to posterior. However, few studies revealed the cause of jet direction in ischermic MR. We hypothesized t...
Abstract 15642: Relationship of Mechanical Dyssynchrony to QRS Morphology and CRT-D Efficacy in Patients with Heart Failure and Wide QRS: The MADIT-CRT Trial
Authors: Dorit Knappe, Anne-Catherine Pouleur, Wojciech Zareba, Arthur J Moss, Elyse Foster, Scott D Solomon
Journal: Circulation (2010)

Background: Cardiac resynchronization therapy (CRT) is effective for treating heart failure (HF) in patients (pts) with conduction delay and dyssynchronous contraction, although data from MADIT-CRT suggests that pts with LBBB derive considerably greater benefit than those with RBBB or IVCD. We assessed the relationship between mechanical dyssynchrony by 2D-speckle tracking imaging (2D-STI) and QRS morphology in MADIT-CRT. Methods: We studied 1,069 pts with NYHA class I/II HF, EF  or= 130ms enrolled in MADIT-CRT with adequate image quality. Dyssynchrony was defined as the standard deviation of time to peak transverse strain out of 12 segments from the apical 4- and 2-chamber views. Time to peak transverse strain for basal-septal and basal-lateral wall was recorded. QRS morphology was defined as LBBB, RBBB, or IVCD. We assessed the treatment effect on the primary outcome of death or HF based on QRS morphology. Results: Compared to the pts with RBBB (n = 126) or IVCD (n = 179), pts with LBBB...
Cytotoxic anthraquinones compounds revisited: Synthesis and preclinical testing in the BOT-2 human breast cancer cell line
Authors: Don R. Ishmael, John A. Nordquist, Robert E. Nordquist
Journal: Cancer Research (2005)

3948  Background: The anticancer anthraquinone mitoxantrone (5,8-dihydroxy-1,4-bis{[2-[(2- hydroxyethyl)amino]ethyl]amino}-9,10-anthracenedione hydrochloride) has been on the market for the treatment of various types of cancer for a number of years. The types approved by the FDA include: 1) acute myelogenous leukemia, 2) breast cancer, 3) high grade and low grade lymphomas, and 4) hormone refractory prostate cancer. The drug is used in high dose chemotherapy regimes with bone marrow or stem cell rescue. It is also used to treat the non-malignant condition, multiple sclerosis. However in most of its applications it is less active than the anthracycline hydroxydaunomycin (doxorubicin, adriamycin) as judged by response rate. We therefore decided to look at a variety of 1,4 aminoalkylanthraquinones to determine if a better cytotoxic compound was avaiable. Methods: Using this information of anthraquinone derivatives as background, a variety of anthraquinone derivatives were synthesized. Mitoxantrone was also synthesized and tested against material used in human cancer therapy (Novantrone® ). The method of preparation was modifications of Murdock et al and Zeecheng et al 1979. Cytotoxicity assay using the BOT-2 human breast cancer cell line was carried out for the compounds synthesized along with mitoxatrone (novantrone® ) and adriamycin. Results: Many compounds of the class 1,4-bis-hydroxyalkylaminoalkylamino and 1,4-bis-aminoalkylaminoanthraquinones had anti-cancer activity as judged by the MTT conversion assay. Three of the compounds were more active than mitoxantrone on a molar concentration basis in the cytotoxicity assay. These were 1,4-bis-{[2-[(2-hydroxyethylaminoethylamino-6,7-dichloroanthraquinone, 1,4-bis-{[2-[(2-aminoethylamino-5,8dihydroxyanthraquinone, and 1,4-bis-{[2-[(2-aminoethylamino-6,7-dichloroanthraquinone. In addition both the 1,4-bis-{[2-[(2-hydroxyethylaminoethylamino-6,7-dichloroanthraquinone and 1,4-bis-{[2-[(2-aminoethylamino-5,8dihydroxyanthraquinone demonstrated synergism with other cytotoxic agents particularly docetaxel and topotecan. This was an effect much greater than that seen with mitoxantrone. The 1,4-bis-hydroxyethylaminoethylamino-6,7-dichloroanthraquinone was tested in mice bearing B-16 melanoma. The compound had no observable toxicity at the doses tested.
A Phase 2 Study of Bortezomib as First-Line Therapy in Patients with Multiple Myeloma.
Authors: Sundar Jagannath, Durie Brian, Jeffrey L. Wolf, Elber Camacho, David Irwin, Jose Lutzky, Marti McKinley, Eli Gabayan, Amitabha Mazumder, John Crowley, David Schenkein
Journal: Blood (2004)
Comparison Of Treatment Outcomes with EPOCH-Rituximab Versus CHOP-Rituximab in Patients with De-novo Intermediate and High Risk International Prognostic Index(IPI)Diffuse Large B Cell Lymphoma(DLBCL): A Single Center Retrospective Analysis
Authors: Hasmukh Jain, Manju Sengar, Hari Menon, Uma Dangi, Bhausaheb Bagal, Navin Khattry, Sridhar Epari, Tanuja Shet, Sumeet Gujral, Venkatesh Rangarajan, Siddhartha Laskar
Journal: Blood (2013)
Population based assessment of surgical treatment trends for melanoma patients
Authors: J. N. Cormier, Y. Xing, M. Ding, M. I. Ross, J. E. Lee, P. F. Mansfield, J. E. Gershenwald, X. L. Du
Journal: Journal of Clinical Oncology (2005)

7509 Background: Since the introduction of sentinel lymph node (SLN) biopsy, the staging of melanoma patients has undergone dramatic change. There are currently no studies which examine whether these surgical techniques have been widely adopted. In this study, SEER data was used to assess how surgical treatment is being carried out in melanoma patients compared to national guidelines. Methods: A total of 17,954 melanoma patients were identified in SEER (1998–2001). Patients were classified according to disease stage. National Comprehensive Cancer Network guidelines were used to define optimal stage-specific surgical treatment: wide local excision of all primary tumors, SLN biopsy for tumors >1mm thick (Ib-IIC), and lymph node dissection for pathologic or clinical nodal disease. Treatment trends were summarized for patients with stages I - III disease and multivariate analyses were performed to assess factors associated with suboptimal treatment. Results: The total number of incident melanoma cases did not vary from 1998 to 2001. However, during that time the number of patients with stage IB decreased by 17% while those with stage III increased by 54% corresponding with an increase in the number of SLN biopsies performed. The percent of patients who received suboptimal surgical treatment by disease stage and year is summarized in the table. In multivariate analyses, age, race, marital status, geographic region, year of diagnosis, and disease stage were significant predictors for receiving suboptimal surgical treatment. The adjusted odds ratios for patients receiving suboptimal treatment were 2.57, 2.46 and 1.64 for stage IB, II, and III, respectively, compared to those patients with stage IA disease. Conclusions: Stage migration is evident in the SEER registries for patients with melanoma. Although treatment trends are improving, SLN biopsy continues to be underutilized, particularly in the elderly and minority populations, as well as in some geographic regions. No significant financial relationships to disclose.
Abstract 18899: Cardiovascular Benefits of Dietary Salt Reduction for US Adolescents
Authors: Kirsten Bibbins-Domingo, Pamela Coxson, Tekeshe Mekonnen, David Guzman, Lee Goldman
Journal: Circulation (2010)

Background: The US diet is high in salt, and adolescents consume more salt than other age groups (9.2 gm/day of salt or 3800 mg/day of sodium). Because processed foods account for the majority of s...
Abstract 652: Prevention Of Inappropriate ICD Therapy Due To Supraventricular Tachycardia In Patients With Brugada Syndrome - A Prospective Study
Authors: Christian Veltmann, Rainer Schimpf, Juergen Kuschyk, Florian Streitner, Martin Borggrefe, Christian Wolpert
Journal: Circulation (2008)

Implantable cardioverter-defibrillators (ICD) are implanted for primary and secondary prevention in patients with Brugada syndrome who are at high risk for sudden cardiac death. It has been reporte...
Control of antimicrobial resistance: time for action
Authors: P. Huovinen, O. Cars
Journal: BMJ (1998)

Until recently the medical community world wide has seemed incapable of reacting to the imminent crisis of antibiotic resistance. Several explanations exist for this lack of action, including the complex interaction between doctors, patients, and parents over antibiotic use 1 2 and the fact that the pharmaceutical industry has so far succeeded in developing new antibiotics when resistance to existing ones has emerged. Although we still need a better understanding of the factors involved in the emergence and spread of antibiotic resistance, action cannot wait until all the answers are available. The essentials of better control of antibiotic resistance are already well known.

Surveillance of bacterial resistance is a key element in understanding the size of the problem. The large number of existing networks for resistance surveillance need to be coordinated and the …
Characterization of HER2 testing and treatment patterns among patients with gastric cancer in the United States using the Oncology Services Comprehensive Electronic Records (OSCER) database.
Authors: Kimberly A Lowe, Adam Reich, Sarah Bobiak, Dina Chau, Jane M Quigley, Michael A. Kelsh
Journal: Journal of Clinical Oncology (2015)

36 Background: There is a paucity of data related to HER2 testing and treatment patterns among gastric cancer patients in a real-world setting. Our primary objectives were to (1) identify the proportion of gastric cancer patients who received HER2 testing, the proportion of patients with HER2+ve tumors, and the proportion of HER2+ve patients who received trastuzumab; (2) describe treatment patterns among gastric cancer patients, including the proportion of patients who received surgery and/or radiation with chemotherapy; (3) identify the proportion of patients who received singlet, doublet, or triplet chemotherapy treatments and specific first- and second-line regimens. Methods: The study participants were randomly selected to undergo a detailed chart review from a source population of patients included in the OSCER database who were diagnosed with gastric cancer from 2009 to 2013. OSCER is a data warehouse of electronic medical records from 565 community and hospital-affiliated oncology clinics in the U.S. from 2004 forward. All patients were required to have metastatic gastric cancer at the time of the chart review and have been treated with chemotherapy to be included. Descriptive statistics were used to characterize HER2 testing and treatment patterns. Results: The study patients (n=238) were mostly male (62%), Caucasian (58%), &gt;65 years of age (57%), with the following stage distribution at diagnosis (Stage II: 7%; Stage III: 11%; Stage IV: 63%; unknown: 19%). HER2 testing was documented in n=121/238 (51%), of which n=30/121(25%) were HER2+ve. Among HER2+ve patients, n=20/30 (67%) received trastuzumab. Of the total sample (n=238), 79% were treated with only chemotherapy, 4% received chemotherapy and surgery, 15% received chemotherapy and radiation, and 2% received all three treatments. First-line treatment was as follows: singlet (17%); doublet (33%), triplet (38%), other (12%). Conclusions: Only half of patients were tested for HER2 status; however, the use of trastuzumab among HER2+ve patients was high. Chemotherapy alone was the primary treatment in this population.
Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation
Authors: Ta-Ming Liu, Jennifer A. Woyach, Yiming Zhong, Arletta Lozanski, Gerard Lozanski, Shuai Dong, Ethan Strattan, Amy Lehman, Xiaoli Zhang, Jeffrey A. Jones, Joseph Flynn, Leslie A. Andritsos, Kami Maddocks, Samantha M. Jaglowski, Kristie A. Blum, John C. Byrd, Jason A. Dubovsky, Amy J. Johnson
Journal: Blood (2015)