tbuckley/cabot-search huggingface dataset:
Tissue-Specific Transgene Expression in Induced Pluripotent Stem (iPS) Cell-Derived Megakaryocytes: Correction of Glanzmann Thrombasthenia (GT)
Authors: Spencer K. Sullivan, Jason A. Mills, Li Zhai, Prasuna Paluru, Karen Vo, Michele Lambert, Sevasti B. Koukouritaki, Juan Fang, David A. Wilcox, Deborah L. French, Mortimer Poncz, Paul Gadue
Journal: Blood (2012)
A Phase II Trial of the Oral mTOR Inhibitor Everolimus (RAD001) in Relapsed or Refractory Waldenstrom's Macroglobulinemia.
Authors: Irene M Ghobrial, Morie A Gertz, Betsy LaPlant, John Camoriano, Suzanne R. Hayman, Martha Q. Lacy, Stacey Chuma, Patricia Sheehy, Brianna Harris, Renee Leduc, Meghan Rourke, Stephen M Ansell, Daniel J DeAngelo, Angela Dispenzieri, Leif Bergsagel, Craig B. Reeder, Kenneth C. Anderson, Paul Richardson, Steven Treon, Thomas E Witzig
Journal: Blood (2009)
Hospital admissions reach record levels in England
Authors: Gareth Iacobucci
Journal: BMJ (2016)

Hospital admissions in England rose to record levels last year and are now almost 30% higher than a decade ago, figures show.

Statistics published in a new report by NHS Digital showed 16.2 million admissions during 2015-16—up from 12.7 million in 2005-06.1 Over the same 10 year period the population as a whole has grown much more slowly, rising by 8% from 50.6 million to 54.8 million. …
Randomized, multicenter, open-label, phase III study of the BTK inhibitor ibrutinib versus chlorambucil in patients 65 years or older with treatment-naive CLL/SLL (RESONATE-2, PCYC-1115-CA).
Authors: Jan Andreas Burger, Paolo Ghia, Aaron Polliack, Constantine Tam, Deepali Suri, Fong Clow, Silvija Kraljevic, Danelle Frances James, Thomas J. Kipps
Journal: Journal of Clinical Oncology (2013)

TPS7130 Background: There is an unmet need for safer and more effective therapies for CLL patients who are older/have comorbidites. Ibrutinib, a small molecule inhibitor of BTK, has demonstrated single-agent activity in CLL in the Ph 1b/2 study, PCYC-1102-CA. Treatment-naïve (TN) patients aged &gt;= 65 yrs (n=31) experienced an estimated PFS and OS of 96% at 26 months; ORRs per iwCLL were: 10% CR, 58% PR, and 13% PR with lymphocytosis (Byrd, ASH 2012). AEs were generally Grade 1/2, most commonly diarrhea. Incidence of Grade 3/4 hematologic toxicities was low. These findings support a phase III study of ibrutinib in older patients with treatment-naïve CLL/SLL. Methods: The ongoing study is a randomized, multicenter, open label Ph 3 study comparing safety and efficacy of ibrutinib vs. chlorambucil in TN patients aged &gt;= 65 yrs with CLL/SLL. Approximately 272 patients will be randomized in 1:1 ratio to receive either chlorambucil or ibrutinib, stratified for ECOG PS and Rai stage. Oral chlorambucil will be administered at 0.5 mg/kg on Days 1 and 15 of each 28-day cycle, for up to 12 cycles. Ibrutinib 420 mg q.d. will continue until PD or unacceptable toxicity. Key incl. criteria include age &gt;= 65 yrs, active disease requiring treatment per iwCLL, measurable nodal disease by CT, ECOG performance status 0-2, and adequate organ function (ANC ≥1,000/μL, platelets ≥50,000/μL, creatinine clearance ≥30 mL/min). Key excl. criteria include Richter’s transformation, del(17p13.1) or previous treatment for CLL/SLL. The primary endpoint of the study is PFS, assessed by Independent Review Committee (IRC). Secondary endpoints include ORR, MRD-negative CRs, fatigue by FACIT-F, hematological improvement, safety, and tolerability. Subjects who relapse on PCYC-1115 will be enrolled on PCYC-1116 for long term follow up. Second line therapy is investigator choice; ibrutinib will be made available for patients who experience IRC-confirmed PD ≤12 months of completing chlorambucil therapy, if they meet the treatment criteria. Approximately 85 sites will enroll patients in North America, Europe, Israel, Australia/New Zealand and China. Enrollment began in Q1 2013. Clinical trial information: NCT01722487.
Targeting the PI3K/AKT/mTOR Pathway for the Treatment of Mesenchymal Triple-Negative Breast Cancer
Authors: Reva K. Basho, Michael Gilcrease, Rashmi K. Murthy, Thorunn Helgason, Daniel D. Karp, Funda Meric-Bernstam, Kenneth R. Hess, Shelley M. Herbrich, Vicente Valero, Constance Albarracin, Jennifer K. Litton, Mariana Chavez-MacGregor, Nuhad K. Ibrahim, James L. Murray, Kimberly B. Koenig, David Hong, Vivek Subbiah, Razelle Kurzrock, Filip Janku, Stacy L. Moulder
Journal: JAMA Oncology (2016)

<h3>Importance</h3> Triple-negative breast cancer (TNBC) classified by transcriptional profiling as the mesenchymal subtype frequently harbors aberrations in the phosphoinositide 3-kinase (PI3K) pathway, raising the possibility of targeting this pathway to enhance chemotherapy response. Up to 30% of mesenchymal TNBC can be classified histologically as metaplastic breast cancer, a chemorefractory group of tumors with a mixture of epithelial and mesenchymal components identifiable by light microscopy. While assays to identify mesenchymal TNBC are under development, metaplastic breast cancer serves as a clinically identifiable surrogate to evaluate potential regimens for mesenchymal TNBC. <h3>Objective</h3> To assess safety and efficacy of mammalian target of rapamycin (mTOR) inhibition in combination with liposomal doxorubicin and bevacizumab in patients with advanced metaplastic TNBC. <h3>Design, Setting, and Participants</h3> Phase 1 study with dose escalation and dose expansion at the University of Texas MD Anderson Cancer Center of patients with advanced metaplastic TNBC. Patients were enrolled from April 16, 2009, to November 4, 2014, and followed for outcomes with a cutoff date of November 1, 2015, for data analysis. <h3>Interventions</h3> Liposomal doxorubicin, bevacizumab, and the mTOR inhibitors temsirolimus or everolimus using 21-day cycles. <h3>Main Outcomes and Measures</h3> Safety and response. When available, archived tissue was evaluated for aberrations in the PI3K pathway. <h3>Results</h3> Fifty-two women with metaplastic TNBC (median age, 58 years; range, 37-79 years) were treated with liposomal doxorubicin, bevacizumab, and temsirolimus (DAT) (N = 39) or liposomal doxorubicin, bevacizumab, and everolimus (DAE) (N = 13). The objective response rate was 21% (complete response = 4 [8%]; partial response = 7 [13%]) and 10 (19%) patients had stable disease for at least 6 months, for a clinical benefit rate of 40%. Tissue was available for testing in 43 patients, and 32 (74%) had a PI3K pathway aberration. Presence of PI3K pathway aberration was associated with a significant improvement in objective response rate (31% vs 0%;<i>P</i> = .04) but not clinical benefit rate (44% vs 45%;<i>P</i> &gt; .99). <h3>Conclusions and Relevance</h3> Using metaplastic TNBC as a surrogate for mesenchymal TNBC, DAT and DAE had notable activity in mesenchymal TNBC. Objective response was limited to patients with PI3K pathway aberration. A randomized trial should be performed to test DAT and DAE for metaplastic TNBC, as well as nonmetaplastic, mesenchymal TNBC, especially when PI3K pathway aberrations are identified.
Margaret McCartney: Innovation isn’t the same as evidence
Authors: Margaret McCartney
Journal: BMJ (2016)

The NHS is keen on innovation. “Innovation is not an option but a necessity if we are to build a sustainable NHS,” says Bruce Keogh, national medical director of NHS England. “Innovation is key to a viable NHS,” says Mahiben Maruthappu, cofounder of the NHS Innovation Accelerator.

NHS England has approved eight innovations that it says are “evidence-based and cost-saving and focus on providing solutions to key challenges facing the NHS, including better prevention of ill health, improved management of long term conditions, and early intervention into diseases.”1 Technology, early diagnosis, and innovation are the triumvirate of fashionable policy making.

The airwaves were saturated with pronouncements on an innovation that would, we were promised, be a step change in …
Clinical and Biologic Studies in Smoldering/Indolent Multiple Myeloma (SMM/IMM) Suggest That Therapies That Specifically Inhibit IL-6 Production Are More Effective at Targeting the Proliferative Myeloma Component Than Apoptosis Inducing Agents.
Authors: John A. Lust, Martha Q. Lacy, Steven R. Zeldenrust, Angela Dispenzieri, Morie A. Gertz, Philip R. Greipp, Thomas E. Witzig, Shaji Kumar, Susan M. Geyer, Laurie L. Moon-Tasson, S. Vincent Rajkumar, Kathleen A. Donovan
Journal: Blood (2006)
Expression of the Human PIM-2 (hPIM-2) Gene in Patients with Acute Myeloblastic Leukaemia (AML) and Acute Lymphoblastic Leukaemia (ALL).
Authors: Katarzyna L. Kapelko-Slowik, Donata M. Urbaniak-Kujda, Bozena Jazwiec, Jaroslaw Dybko, Dariusz Wolowiec, Miroslaw Slowik, Irena Frydecka, Kazimierz Kuliczkowski
Journal: Blood (2007)
Disruption of Autophagic Degradation with ROC-325 Antagonizes Renal Cell Carcinoma Pathogenesis
Authors: Jennifer S. Carew, Claudia M. Espitia, William Zhao, Yingchun Han, Valeria Visconte, James Phillips, Steffan T. Nawrocki
Journal: Clinical Cancer Research (2016)

Purpose: Although autophagy plays important roles in malignant pathogenesis and drug resistance, there are few clinical agents that disrupt this pathway, and the potential therapeutic benefit of autophagy inhibition remains undetermined. We used medicinal chemistry approaches to generate a series of novel agents that inhibit autophagic degradation.Experimental Design: ROC-325 was selected as a lead compound for further evaluation. Comprehensive in vitro and in vivo studies were conducted to evaluate the selectivity, tolerability, and efficacy of ROC-325 in preclinical models of renal cell carcinoma (RCC) with HCQ serving as a comparator. Markers of autophagy inhibition and cell death were evaluated in tumor specimens.Results: ROC-325 exhibited superior in vitro anticancer effects compared with the existing autophagy inhibitor hydroxychloroquine (HCQ) in 12 different cancer cell lines with diverse genetic backgrounds. Focused studies of the mechanism of action and efficacy of ROC-325 in RCC cells showed that drug treatment induced hallmark characteristics of autophagy inhibition, including accumulation of autophagosomes with undegraded cargo, lysosomal deacidification, p62 stabilization, and disruption of autophagic flux. Subsequent experiments showed that ROC-325 antagonized RCC growth and survival in an ATG5/7-dependent manner, induced apoptosis, and exhibited favorable selectivity. Oral administration of ROC-325 to mice bearing 786-0 RCC xenografts was well tolerated, was significantly more effective at inhibiting tumor progression than HCQ, and inhibited autophagy in vivoConclusions: Our findings demonstrate that ROC-325 has superior preclinical anticancer activity compared with HCQ and support the clinical investigation of its safety and preliminary efficacy in patients with RCC and other autophagy-dependent malignancies. Clin Cancer Res; 23(11); 2869-79. ©2016 AACR.
Potential of human twin embryos generated by embryo splitting in assisted reproduction and research
Authors: Laila Noli, Caroline Ogilvie, Yacoub Khalaf, Dusko Ilic
Journal: Human Reproduction Update (2016)

Embryo splitting or twinning has been widely used in veterinary medicine over 20 years to generate monozygotic twins with desirable genetic characteristics. The first human embryo splitting, reported in 1993, triggered fierce ethical debate on human embryo cloning. Since Dolly the sheep was born in 1997, the international community has acknowledged the complexity of the moral arguments related to this research and has expressed concerns about the potential for reproductive cloning in humans. A number of countries have formulated bans either through laws, decrees or official statements. However, in general, these laws specifically define cloning as an embryo that is generated via nuclear transfer (NT) and do not mention embryo splitting. Only the UK includes under cloning both embryo splitting and NT in the same legislation. On the contrary, the Ethics Committee of the American Society for Reproductive Medicine does not have a major ethical objection to transferring two or more artificially created embryos with the same genome with the aim of producing a single pregnancy, stating that 'since embryo splitting has the potential to improve the efficacy of IVF treatments for infertility, research to investigate the technique is ethically acceptable'. Embryo splitting has been introduced successfully to the veterinary medicine several decades ago and today is a part of standard practice. We present here an overview of embryo splitting experiments in humans and non-human primates and discuss the potential of this technology in assisted reproduction and research. A comprehensive literature search was carried out using PUBMED and Google Scholar databases to identify studies on embryo splitting in humans and non-human primates. 'Embryo splitting' and 'embryo twinning' were used as the keywords, alone or in combination with other search phrases relevant to the topics of biology of preimplantation embryos. A very limited number of studies have been conducted in humans and non-human primates. The published material, especially the studies with human embryos, is controversial. Some reports suggest that twinning technology will find clinical use in reproductive medicine in the future, whereas others conclude the opposite that human twin embryos created in vitro are unsuitable not only for clinical, but also for research, purposes. The blastomere biopsy technique of embryo splitting seems to be unsuitable for either clinical or research purposes; however, embryo bisection, a preferable method of cloning in veterinary medicine, has not yet been tested on human embryos.
A Meta-Analysis of Gene Expression Studies in Severe Sepsis and Septic Shock
Authors: Maiara M L Fiusa, Benilton S Carvalho, Rodolfo M E Hubert, Welliton Souza, Iscia Lopes-Cendes, Joyce M Annichino-Bizzacchi, Erich Vinicius De Paula
Journal: Blood (2014)
Erythrocyte Adenosine A2B Receptor-Mediated AMP-Activated Protein Kinase Prevents Hypoxia-Induced Tissue Injury in High Altitude By Inducing 2,3-Bisphosphoglycerate
Authors: Hong Liu, Yujin Zhang, Anren Song, Harry Karmouty Quintana, Almut Grenz, Hong Sun, Rodney E. Kellems, Holger Eltzschig, Robert Roach, Michael R. Blackburn, Yang Xia
Journal: Blood (2014)
Plasmodium Merozoite TRAP Family Protein Is Essential for Vacuole Membrane Disruption and Gamete Egress from Erythrocytes
Authors: Daniel Y. Bargieri, Sabine Thiberge, Chwen L. Tay, Alison F. Carey, Alice Rantz, Florian Hischen, Audrey Lorthiois, Ursula Straschil, Pallavi Singh, Shailja Singh, Tony Triglia, Takafumi Tsuboi, Alan Cowman, Chetan Chitnis, Pietro Alano, Jake Baum, Gabriele Pradel, Catherine Lavazec, Robert Ménard
Journal: Cell Host & Microbe (2016)

Surface-associated TRAP (thrombospondin-related anonymous protein) family proteins are conserved across the phylum of apicomplexan parasites. TRAP proteins are thought to play an integral role in parasite motility and cell invasion by linking the extracellular environment with the parasite submembrane actomyosin motor. Blood stage forms of the malaria parasite Plasmodium express a TRAP family protein called merozoite-TRAP (MTRAP) that has been implicated in erythrocyte invasion. Using MTRAP-deficient mutants of the rodent-infecting P. berghei and human-infecting P. falciparum parasites, we show that MTRAP is dispensable for erythrocyte invasion. Instead, MTRAP is essential for gamete egress from erythrocytes, where it is necessary for the disruption of the gamete-containing parasitophorous vacuole membrane, and thus for parasite transmission to mosquitoes. This indicates that motor-binding TRAP family members function not just in parasite motility and cell invasion but also in membrane disruption and cell egress.
First Symptoms In Idiopathic Thrombotic Thrombocytopenic Purpura (TTP): What Are They and When Do They Occur?.
Authors: Drees Griffin, Zayd al-Nouri, Darrshini Muthurajah, John Ross, Riley Ballard, Deirdra Terrel, Sara K. Vesely, James N. George, Marisa Marques
Journal: Blood (2010)
Genome-Wide Profiling of DNA Copy Number Abnormalities and Loss-Of-Heterozygosity in Pediatric Acute Myeloid Leukemia Using High-Resolution Single Nucleotide Polymorphism Microarrays.
Authors: Ina Radtke, Charles G. Mullighan, Salil Goorha, Jing Ma, Stanley B. Pounds, Xiaoping Su, Alyssa L. Kennedy, Susanna M. Downing, Jeffrey E. Rubnitz, Raul C. Ribeiro, Sheila A. Shurtleff, James R. Downing
Journal: Blood (2006)
Clofarabine, Melphalan, and Thiotepa, Followed by Allogeneic Unmodified Bone Marrow or Peripheral Blood Stem Cell Transplant, by Unmodified Double Cord Blood Transplant, or by CD34+ T-Cell Depleted Stem Cell Transplant for the Treatment of Hematologic Malignancies.
Authors: Farid Boulad, Guenther Koehne, Nancy A. Kernan, Susan E. Prockop, Trudy N. Small, Andromachi Scaradavou, Miguel-Angel Perales, Hugo R Castro-Malaspina, Esperanza B. Papadopoulos, Jenna D Goldberg, Elizabeth G Klein, Rachel Kobos, Ann A. Jakubowski, Doris Ponce, Juliet Barker, James W. Young, Craig S. Sauter, Sergio Giralt, Richard J. O'Reilly
Journal: Blood (2012)
Evidence for Increased Bone Marrow Lymphoplasmocytoid Cells and SDF1 Secretion in imatinib Treated CML. Relationship with Clinical/hemathological Response
Authors: Ivana Pierri, Silvia Catellani, Francesca Olcese, Raffaella Grasso, Nicoletta Colombo, Marco Gobbi, Alessandro Poggi, Maria Raffaella Zocchi
Journal: Blood (2008)
Validation of the Elderly IPI (E-IPI) for Patients with Diffuse Large B Cell Lymphoma Using An Independent Data Set From the RICOVER-60 Trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)
Authors: Ranjana H. Advani, Fangxin Hong, Hailun Li, Brad S. Kahl, Michael Pfreundschuh, Marita Ziepert
Journal: Blood (2011)
Immunotargetting of the Wilms’ Tumor WT1 Antigen for Dendritic Cell and B-Cell-Based Vaccination of Leukemia.
Authors: Zwi N. Berneman, Ann Van Driessche, Peter Ponsaerts, Liquan Gao, Hans J. Stauss, Wilfried A. Schroyens, Ann Van de Velde, Alain Gadisseur, Marc Lenjou, Griet Nijs, Dirk R. Van Bockstaele, Viggo F. Van Tendeloo
Journal: Blood (2004)
FRI0023 Effects of IL-33/ST2 Axis on Cytokine Gene Expression at The Site of Acute Inflammation
Authors: M. Stankovic, K. Janjetovic, N. Puskas, M. Milenkovic, I. Zaletel, S.R. De Luka, A.M. Trbovich, V. Trajkovic
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Acute inflammation is an early response to a cell injury. Interleukin (IL)-33 is a new member of IL-1 cytokine family. It was discovered that IL-33 and its receptor ST2 have a role not only in Th2 mediated diseases, as firstly reported, but also in other diseases, such as rheumatoid arthritis, autoimmune uveitis, and squamous cell carcinoma. Effects of IL-33/ST2 axis in acute inflammation are still not completely understood. <h3>Objectives</h3> The aim of this study was to examine effects of IL-33/ST2 axis on cytokine gene expression at the site of acute inflammation. <h3>Methods</h3> Male mice were divided in groups: wild-type control group (WT-C), wild-type inflammatory group (WT-I), ST2 knockout control group (KO-C), and ST2 knockout inflammatory group (KO-I). Acute inflammation was induced in WT-I and KO-I by intramuscular injection of turpentine oil, whereas animals in WT-C and KO-C were injected with saline. Mice were euthanized after 12 hours, and the treated tissue was collected for histopathological analysis, and gene expression determination (qRT-PCR) of IL-33, ST2 receptor, tumor necrosis factor alpha (TNF-alpha), IL-12p35, IL-23p19, and transforming growth factor-beta (TGF-beta). All experimental procedures were approved by the University of Belgrade School of Medicine Ethics Committee. <h3>Results</h3> Acute inflammation was histopathologicaly confirmed in WT-I and KO-I. IL-33 in the treated tissue was significantly higher in inflammatory groups, WT-I and KO-I, when compared to WT-C and KO-C, respectively. However, IL-33 was significantly higher in KO-I than in WT-I. ST2 significantly increased in inflamed tissue of wild-type mice, in comparison to WT-C. TNF-alpha, IL-12p35, and IL-23p19 in the treated tissue significantly increased in WT-I and KO-I, when compared to their corresponding control groups WT-C and KO-C. TGF-beta in the treated tissue was significantly higher in KO-I than in WT-I, whereas it did not significantly differ between WT-C and KO-C. <h3>Conclusions</h3> Results of this study indicated that IL-33/ST2-axis affected gene expression of cytokines at the site of acute inflammation, i.e. gene expression of IL-33, and anti-inflammatory cytokine TGF-beta. ST2 gene expression increased in acutely inflamed tissue, indicating importance of IL-33/ST2 axis in acute inflammation. <h3>References</h3> Verri et al. Ann Rheum Dis. 2010; 69(9):1697–1703; Barbour et al. Eur J Immunol. 2014; 44(11):3320–3329; Ishikawa et al. Auris Nasus Larynx. 2014; 41(6):552–557. Abbas et al. Cytokines. In Cellular and Molecular Immunology. 2010; 267–302. <h3>Acknowledgement</h3> This research was funded by Ministry of Education, Science and Technological Development (RS, grant III 41013). <h3>Disclosure of Interest</h3> None declared
The Biocompatibility and Security of Magnetic Nanoparticles Fe3O4-DNR Used In Hematologic Malignancies Therapy
Authors: Bao-An Chen, Wei-wei Wu, Jian Cheng, Jun Wang, Feng Gao, Wen-lin Xu, Chong Gao, Jia-hua Ding, Yun-yu Sun, Hui-hui Song, Wen Bao, Li-jie Liu, Guo-hua Xia, Xue-mei Wang
Journal: Blood (2010)
Ectopic HOXB4 Overcomes the Inhibitory Effect of TNFα on Hematopoietic Stem and Progenitor Cells in a Murine Fanconi Anemia Model.
Authors: Michael D. Milsom, Bernhard Schiedlmeier, Jeff Bailey, Abdullah Ali, MiOk Kim, Christopher Baum, Michael Jansen, David A. Williams
Journal: Blood (2008)
Association of Cardiovascular Risk Factors and Stroke With Alzheimer Disease
Authors: Priyanka Sivakumaran
Journal: JAMA Neurology (2016)

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