tbuckley/cabot-search huggingface dataset:
Mycolactone subverts immunity by selectively blocking the Sec61 translocon
Authors: Ludivine Baron, Anja Onerva Paatero, Jean-David Morel, Francis Impens, Laure Guenin-Macé, Sarah Saint-Auret, Nicolas Blanchard, Rabea Dillmann, Fatoumata Niang, Sandra Pellegrini, Jack Taunton, Ville O. Paavilainen, Caroline Demangel
Journal: The Journal of Experimental Medicine (2016)

Mycolactone, an immunosuppressive macrolide released by the human pathogen Mycobacterium ulcerans, was previously shown to impair Sec61-dependent protein translocation, but the underlying molecular mechanism was not identified. In this study, we show that mycolactone directly targets the α subunit of the Sec61 translocon to block the production of secreted and integral membrane proteins with high potency. We identify a single–amino acid mutation conferring resistance to mycolactone, which localizes its interaction site near the lumenal plug of Sec61α. Quantitative proteomics reveals that during T cell activation, mycolactone-mediated Sec61 blockade affects a selective subset of secretory proteins including key signal-transmitting receptors and adhesion molecules. Expression of mutant Sec61α in mycolactone-treated T cells rescued their homing potential and effector functions. Furthermore, when expressed in macrophages, the mycolactone-resistant mutant restored IFN-γ receptor–mediated antimicrobial responses. Thus, our data provide definitive genetic evidence that Sec61 is the host receptor mediating the diverse immunomodulatory effects of mycolactone and identify Sec61 as a novel regulator of immune cell functions.
High Frequency and Poor Outcome of Philadelphia Chromosome–Like Acute Lymphoblastic Leukemia in Adults
Authors: Kathryn G. Roberts, Zhaohui Gu, Debbie Payne-Turner, Kelly McCastlain, Richard C. Harvey, I-Ming Chen, Deqing Pei, Ilaria Iacobucci, Marcus Valentine, Stanley B. Pounds, Lei Shi, Yongjin Li, Jinghui Zhang, Cheng Cheng, Alessandro Rambaldi, Manuela Tosi, Orietta Spinelli, Jerald P. Radich, Mark D. Minden, Jacob M. Rowe, Selina Luger, Mark R. Litzow, Martin S. Tallman, Peter H. Wiernik, Ravi Bhatia, Ibrahim Aldoss, Jessica Kohlschmidt, Krzysztof Mrózek, Guido Marcucci, Clara D. Bloomfield, Wendy Stock, Stephen Kornblau, Hagop M. Kantarjian, Marina Konopleva, Elisabeth Paietta, Cheryl L. Willman, Charles G. Mullighan
Journal: Journal of Clinical Oncology (2017)

Purpose Philadelphia chromosome (Ph) –like acute lymphoblastic leukemia (ALL) is a high-risk subtype of childhood ALL characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. We sought to define the prevalence and genomic landscape of Ph-like ALL in adults and assess response to conventional chemotherapy. Patients and Methods The frequency of Ph-like ALL was assessed by gene expression profiling of 798 patients with B-cell ALL age 21 to 86 years. Event-free survival and overall survival were determined for Ph-like ALL versus non–Ph-like ALL patients. Detailed genomic analysis was performed on 180 of 194 patients with Ph-like ALL. Results Patients with Ph-like ALL accounted for more than 20% of adults with ALL, including 27.9% of young adults (age 21 to 39 years), 20.4% of adults (age 40 to 59 years), and 24.0% of older adults (age 60 to 86 years). Overall, patients with Ph-like ALL had an inferior 5-year event-free survival compared with patients with non–Ph-like ALL (22.5% [95% CI, 14.9% to 29.3%; n = 155] v 49.3% [95% CI, 42.8% to 56.2%; n = 247], respectively; P &lt; .001). We identified kinase-activating alterations in 88% of patients with Ph-like ALL, including CRLF2 rearrangements (51%), ABL class fusions (9.8%), JAK2 or EPOR rearrangements (12.4%), other JAK-STAT sequence mutations (7.2%), other kinase alterations (4.1%), and Ras pathway mutations (3.6%). Eleven new kinase rearrangements were identified, including four involving new kinase or cytokine receptor genes and seven involving new partners for previously identified genes. Conclusion Ph-like ALL is a highly prevalent subtype of ALL in adults and is associated with poor outcome. The diverse range of kinase-activating alterations in Ph-like ALL has important therapeutic implications. Trials comparing the addition of tyrosine kinase inhibitors to conventional therapy are required to evaluate the clinical utility of these agents in the treatment of Ph-like ALL.
THU0481 Prevalence of Asymptomatic Morphometric Vertebral Deformities in HIV-Infected Patients: Table 1.
Authors: M. Llop Vilaltella, W.A. Sifuentes Giraldo, M. Vázquez Díaz, C. Medina Quiñones, C.C. Macía Villa, S. Bañόn-Escandell, J.L. Casado Osorio
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Patients infected with the human immunodeficiency virus (HIV) have a high rate of low bone mineral density (BMD) of multifactorial origin, that involve traditional risk factors, activity of the infection and highly active antiretroviral therapy (HAART). An increased risk of fractures has been reported in these patients but few studies have estimated the true prevalence of asymptomatic morphometric vertebral deformities (MVD). <h3>Objectives</h3> To determine the prevalence of MVD in HIV-infected patients followed in a Spanish tertiary center, taking into account both traditional risk factors as those associated with their underlying disease. <h3>Methods</h3> We performed a cross-sectional study in HIV-infected patients with age 50 years treated in our center during the period 2014–2015. Demographics and traditional risk factors were collected through a specific survey. BMD was determined by X-ray absorptiometry dual-energy (DXA) at the lumbar spine and hip. Blood and urine samples were collected for biochemical analysis of bone metabolism. WHO definitions were used to classify DXA results. MVD were assessed on lateral X-rays of thoracic and lumbar spine using the Genant9s semiquantitative method: 1) reduction of any height of the vertebral body between 20–25%: grade I (mild); 2) between 26–40%: grade II (moderate); and 3) &gt;40%: grade III (severe). <h3>Results</h3> A total of 75 patients were included, 54 males (72%), with a mean age of 54.8 years (range: 50–70). MVD was detected in 15 cases (20%): 4 grade I, 6 grade II and 5 grade III. All patients received HAART during the study period. Femoral neck BMD was normal in 39%, 52% were in range of osteopenia and 9% osteoporosis. Variables independently associated with development of MVD were female gender (13% vs 31%, p=0.13), daily calcium intake (490 mg/d vs 594 mg/d, p=0.16), serum phosphorus (2.79 mg/dL vs 3.17 mg/dL, p=0.02) and low BMD in total hip (0.69 vs 0.75, p=0.05) (Table 1). Significant association was also found with disease duration (mean time in patients with MVD: 264.7 months, p=0.09). No correlation was found with age, a fact that can be attributed to limited sample size and age of patients (50–70 years). <h3>Conclusions</h3> We found a high prevalence of asymptomatic MVD in our series (20%). X-rays of thoracic and lumbar spine should be performed as a screening method in HIV-infected patients with risk factors, such as long-term infection, low calcium intake, low serum phosphorus levels and female gender. <h3>Disclosure of Interest</h3> None declared
The Addition of CT Scans to NCI-96 Chronic Lymphocytic Leukemia (CLL) Response Criteria Fails To Improve the Predictive Power of Complete Response (CR) and Partial Response (PR) as Assessed by Improvement in Progression-Free (PFS) and Overall Survival (OS) .
Authors: Kristie A. Blum, Donn Young, Sarah Broering, Margaret S. Lucas, Thomas S. Lin, Michael R. Grever, John C. Byrd
Journal: Blood (2006)
Making An Impact on Clinical Practice and Research in China
Authors: Rui-Ping Xiao, Gary W.K. Wong, Jacqueline M. Prince, Maro Gartside, Jianfei Zhao, Jiping Wang, Getu Zhaori, Jeffrey M. Drazen
Journal: New England Journal of Medicine (2016)

Two weeks ago, NEJM Group launched a collaboration with Jiahui Medical Research and Education (JMRE) of Shanghai: NEJM医学前沿 (Yi Xue Qian Yan), or NEJM Frontiers in Medicine. This online medical resource, now available at www.nejmqianyan.cn and by mobile app, provides an archive of key New England Journal of Medicine and NEJM Journal Watch articles fully translated into Chinese, with new articles being added each week. Many of the new Journal articles will appear with original commentary from China-based experts. China has made substantial advances in medical research and patient care in recent decades, but its expanding economy, changes in lifestyle, . . .
Arsenic Trioxide (Trisenox®) with/without Thalidomide in Patients with Myelodysplastic Syndromes (MDS) Produces Hematologic Improvement (HI).
Authors: Azra Raza, Laurie Lisak, Jennifer Billmeier, Samreen Akbar, Khalid Washeed, Mohammad Mumtaz, Poluru Reddy, Naomi Galili
Journal: Blood (2004)
Intradermal grass pollen immunotherapy increases T H 2 and IgE responses and worsens respiratory allergic symptoms
Authors: Anna Slovick, Abdel Douiri, Rachel Muir, Andrea Guerra, Konstantinos Tsioulos, Evie Hay, Emily P.S. Lam, Joanna Kelly, Janet L. Peacock, Sun Ying, Mohamed H. Shamji, David J. Cousins, Stephen R. Durham, Stephen J. Till
Journal: Journal of Allergy and Clinical Immunology (2016)

BackgroundRepeated low-dose grass pollen intradermal allergen injection suppresses allergen-induced cutaneous late-phase responses comparably with conventional subcutaneous and sublingual immunotherapy.ObjectiveWe sought to evaluate the efficacy and safety of grass pollen intradermal immunotherapy in the treatment of allergic rhinitis.MethodsWe randomly assigned 93 adults with grass pollen–induced allergic rhinitis to receive 7 preseasonal intradermal allergen injections (containing 7 ng of Phl p 5 major allergen) or a histamine control. The primary end point was daily combined symptom-medication scores during the 2013 pollen season (area under the curve). Analysis was by intention to treat. Skin biopsy specimens were collected after intradermal allergen challenges, and late-phase responses were measured 4 and 7, 10, or 13 months after treatment.ResultsThere was no significant difference in the primary end point between treatment arms (active, n = 46; control, n = 47; median difference, 14; 95% CI, −172.5 to 215.1; P = .80). Among secondary end points, nasal symptoms were worse in the intradermal treatment group, as measured based on daily (median difference, 35; 95% CI, 4.0-67.5; P = .03) and visual analog scale (median difference, 53; 95% CI, −11.6 to 125.2; P = .05) scores. In a per-protocol analysis intradermal immunotherapy was further associated with worse asthma symptoms and fewer symptom-free days. Intradermal immunotherapy increased serum Phleum pratense–specific IgE levels (P = .001) compared with those in the control arm. T cells cultured from biopsy specimens of subjects undergoing intradermal immunotherapy had higher expression of the TH2 surface marker CRTH2 (P = .04) and lower expression of the TH1 marker CXCR3 (P = .01), respectively. Late-phase responses remained inhibited 7 months after treatment (P = .03).ConclusionIntradermal allergen immunotherapy suppressed skin late-phase responses but was not clinically effective and resulted in worsening of respiratory allergic symptoms.
PTH-151 Improving Patient Care: Nurse-Led Therapeutic Paracentesis Service
Authors: N Summers, S Khalid, T Patani, C McEvoy
Journal: Gut (2016)

<h3>Introduction</h3> Warrington is home to more patients with a history of alcohol excess and chronic liver disease than the national average. In Warrington hospital we have a cohort of patients dependent on regular therapeutic abdominal paracentesis who traditionally were admitted via A&amp;E. In the trust paracentesis can only be performed on the gastroenterology ward, and so awaiting transfer led to increased length of stay. Once admitted, patients would wait for consultant review and for a junior doctor to finish their ward work before inserting their drain, causing further delay in treatment. Following this we developed a protocol and training scheme to allow band 6 nurses to safely perform the procedure and co-ordinate admissions directly. The aim of this service was to improve access for patients who require regular paracentesis and reduce length of stay, whilst maintaining patient safety. <h3>Methods</h3> The nurses who volunteered for training began with tutorials, then with demonstration and direct supervision by three gastroenterology consultants. The nurses observed 3 drains inserted by a consultant or registrar, then assisted for 3 procedures, and finally inserted drains themselves under direct supervision. The nurses were assessed at 10, 15, 20 and 25 drains using an assessment tool based on the Paracentesis DOPS assessment form used for doctors. Following this they were deemed competent to perform the task independently. We carried out a prospective audit of all patients involved and analysed the data after 9 months of the service being established. Mean length of stay was calculated using inpatient discharge letters. Patients who had issues not directly related to the insertion of their drain were discounted from the results. <h3>Results</h3> Since April 2015, a total of 114 drains have been performed in 25 patients. The majority of patients were male (76%). Interestingly we noticed two peaks in age distribution: the majority in the older age group 66–75 years (40%) which were more likely to have NAFLD aetiology; the younger group age 46–55 years (28%) and were shown to be majority ALD patients. We noted that in those elective patients admitted directly to the gastroenterology ward for nurse-led management, mean length of stay was less than 24 hours, compared with 4.5 days for the patients admitted via A&amp;E. The latter was the path of all patients prior to April 2015. There have been no documented complications following any of the procedures performed by nurses. <h3>Conclusion</h3> Therapeutic abdominal paracentesis in elective patients can be carried out safely by nurses, improves patient experience and drastically reduces length of stay. We feel this service has greatly improved the care of our outpatients with ascites and we would recommend implementation of this service in other trusts. <h3>Disclosure of Interest</h3> None Declared
Inhibition of Hexokinase II Inactivates ABC Transporters and Restores Drug Sensitivity in Myeloma Cells
Authors: Ayako Nakano, Masahiro Abe, Daisuke Tsuji, Hirokazu Miki, Akishige Ikegame, Shingen Nakamura, Takeshi Harada, Shiro Fujii, Kumiko Kagawa, Kyoko Takeuchi, Shuji Ozaki, Kohji Itoh, Toshio Matsumoto
Journal: Blood (2011)
Analysis of the Expression of PHTF1 and Related Genes in Acute Lymphoblastic Leukemia
Authors: Xin Huang, Suxia Geng, Jianyu Weng, Zesheng Lu, Linji Zeng, Minming Li, Chengxin Deng, Xiuli Wu, Yangqiu Li, Xin Du
Journal: Blood (2015)
Targeting the Tetramerization by a Specific Peptide Abrogates the Transformation Potential of BCR/ABL and Some of Its Imatinib-Resistant Mutants.
Authors: Tim Beissert, Alena Hundertmark, Velina Kaburova, Afsar A. Mian, Lorena Travaglini, Oliver G. Ottmann, Dieter Hoelzer, Clara Nervi, Martin Ruthardt
Journal: Blood (2006)
Body-mass index adjustments to increase the validity of body fatness assessment in UK black African and South Asian children: a cross-sectional calibration study
Authors: Mohammed T Hudda, Claire M Nightingale, Angela S Donin, Mary S Fewtrell, Dalia Haroun, Sooky Lum, Jane E Williams, Christopher G Owen, Alicja R Rudnicka, Jonathan C K Wells, Derek G Cook, Peter H Whincup
Journal: The Lancet (2016)
Outcome with Lenalidomide Plus Dexamethasone Followed by Early Autologous Stem Cell Transplantation In the ECOG E4A03 Randomized Clinical Trial
Authors: David Samuel diCapua Siegel, Susanna Jacobus, S. Vincent Rajkumar, Rafat Abonour, Natalie Scott Callander, Michael S Katz, Rafael Fonseca, David H. Vesole, On behalf of the Eastern Cooperative Oncology Group
Journal: Blood (2010)
Idelalisib Plus Bendamustine and Rituximab (BR) Is Superior to BR Alone in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Results of a Phase 3 Randomized Double-Blind Placebo-Controlled Study
Authors: Andrew D Zelenetz, Tadeusz Robak, Bertrand Coiffier, Julio Delgado, Paula Marlton, Adeboye H Adewoye, Yeonhee Kim, Lyndah K. Dreiling, Peter Hillmen
Journal: Blood (2015)
AB0151 Diprospan efficacy in periarticular symptoms of ostearthritis
Authors: RA Khabirov, LG Salikhov, SA Lapshina, KN Agisheva, RG Mukhina, LI Myasoutova
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Complex clinical and instrumental investigations (kinesthesical method, electromyography (EMG), thermovision, ultrasonography) showed significant involvement (up to 80%) of periarticular structures (muscles, tendons) in osteoarthritis (OA) aggravating the clinical picture of the disease and leading to the decrease of life quality of the patients. The substrate of myofascial pain syndrome are local densities in muscular tissue and in the places of detachment of tendons to the bones. <h3>Objectives</h3> The goal of investigation was to study the diprospan efficacy in treatment of 30 patients with OA with muscular syndrome. The treatment efficacy was estimated by Lee and Reachy indices of muscular syndrome, the volume of active and passive movements of joints and by EMG. <h3>Methods</h3> In case of revealing of painful trigger zones in the muscles surrounding the joints we injected locally 1 ml of diprospan. In order to increase the volume of medication we added 5–10 ml of 0.5% novocaine solution into the syringe. <h3>Results</h3> During the first 24–36 h after the periarticular injection of diprospan there was found decrease of myalgias and arthralgias. Further on the volume of movements in joints increased and functional activity of patients improved as well. No local side effects after periarticular diprospan injections were noted in contrast to kenalog injections. The diprospan injections were repeated if necessary depending on clinical picture of OA. <h3>Conclusion</h3> Periarcicular diprospan injections are effective and safe in patients with OA with myofascial pain syndrome.
Impact on Progression Free Survival of Autologous Stem Cell transplantation after Consolidation with Alemtuzumab in Chronic Lymphocytic Leukemia.
Authors: Marco Montillo, Francesca Ricci, Alessandra Tedeschi, Sara Miqueleiz, Giovanni Grillo, Eleonora Vismara, Antonino Greco, Silvio Veronese, Enrica Morra
Journal: Blood (2008)
Prognostic Correlation Between Neutrophilic Leukocytosis, VEGF, VEGFR and ERCC1 in Advanced Non-Small Cell Lung Cancer (NSCLC)
Authors: Nagla F. Abdel Karim, Hai Bui, Marshall Anderson, Ninad Patil, Peterson Pathrose, Nadia Osman, M.B Rao, Apurva Mehta
Journal: Blood (2008)
Randomized Trial of Bilateral versus Single Internal-Thoracic-Artery Grafts
Authors: David P. Taggart, Douglas G. Altman, Alastair M. Gray, Belinda Lees, Stephen Gerry, Umberto Benedetto, Marcus Flather
Journal: New England Journal of Medicine (2016)

The use of bilateral internal thoracic (mammary) arteries for coronary-artery bypass grafting (CABG) may improve long-term outcomes as compared with the use of a single internal-thoracic-artery plus vein grafts.
AB0309 Value of The Clinical Meetings for An Accurate Biological Therapy Assessment in Rheumatic Diseases. The Experience of The Biological Therapy Assessment Committee at A Tertiary Hospital:
Authors: E. Grau Garcia, J. Ivorra Cortés, L. González Puig, I. Chalmeta Verdejo, C. Feced Olmos, E. Labrador Sánchez, F.M. Ortiz Sanjuan, K. Arévalo Ruales, R. Negueroles Albuixech, J. Fragio Gil, I. Martínez Cordellat, J. Valero Sanz, C. Alcañiz Escandell, G. Poveda Marín, C. Nájera Herranz, E. Monte Boquet, V. Fornes Ferrer, J. Román Ivorra
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Given the increasing use of biological therapies in rheumatologic diseases and the importance of their secondary effects, it has been promoted clinical Meetings for an accurate Biological Therapy Assessment (BTAM). In the BTAM rheumatologists consider the need to initiating biological therapy, changes in biological therapeutic targets, sustained biological treatment or their suspension. <h3>Objectives</h3> To assess the BTAM effectiveness in patients with rheumatic diseases in a Rheumatology Department in a tertiary-level hospital. <h3>Methods</h3> Prospective study including all consultations to BTAM between 2013 and 2015 in the Rheumatology Department of La Fe Hospital. Consultations were classified as: “therapeutic target modification”, “route of administration modification”, “dose treatment modification”, “new biological treatment”, “treatment continuation” and “treatment suspension”. In order to evaluate disease activity, we used DAS28, BASDAI, serum C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Biostatistical analysis was performed using R software 3.2.3. <h3>Results</h3> We included 1683 BTAM consultations, corresponding to 517 patients with rheumatic diseases with a mean age of 39.94±14.88 and 13.37±8.75 years of disease progression. 51.6% of patients were rheumatoid arthritis, 27.9% spondyloarthritis, 15.3% psoriatic arthritis and 5.2% other diagnosis. 116 patients received a prior biological treatment. Disease activity evaluation of the 1683 BTAM consultations for the main categories is shown in the table. Biostatistic analysis shows significant differences in Das28, BASDAI, CRP and ESR values between BTAM consultations for initiating new treatment or modify therapeutic target, and treatment continuation consultations (P&lt;0.0001). There was also a significant association between the number of biological targets administered and the increase of DAS28 (P&lt;0.0001) and BASDAI (P=0.014). <h3>Conclusions</h3> We observed a increased disease activity in cases where a new biological treatment or different therapeutic target is administrated, and values of disease activity in treatment continuation are compatible with low activity. In the 5.2% of consultations it has prescribed modification treatment, in order to avoid treatment ineffectiveness. Moreover, some continuation treatment consultations showed low activity scores, leading to a therapeutic optimization. BTAM consultations are useful for optimal management of these patients with biological therapy <h3>Disclosure of Interest</h3> None declared
Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer
Authors: Vikram B. Wali, Casey G. Langdon, Matthew A. Held, James T. Platt, Gauri A. Patwardhan, Anton Safonov, Bilge Aktas, Lajos Pusztai, David F. Stern, Christos Hatzis
Journal: Cancer Research (2016)

Abstract Triple-negative breast cancer (TNBC) remains an aggressive disease without effective targeted therapies. In this study, we addressed this challenge by testing 128 FDA-approved or investigational drugs as either single agents or in 768 pairwise drug combinations in TNBC cell lines to identify synergistic combinations tractable to clinical translation. Medium-throughput results were scrutinized and extensively analyzed for sensitivity patterns, synergy, anticancer activity, and were validated in low-throughput experiments. Principal component analysis revealed that a fraction of all upregulated or downregulated genes of a particular targeted pathway could partly explain cell sensitivity toward agents targeting that pathway. Combination therapies deemed immediately tractable to translation included ABT-263/crizotinib, ABT-263/paclitaxel, paclitaxel/JQ1, ABT-263/XL-184, and paclitaxel/nutlin-3, all of which exhibited synergistic antiproliferative and apoptotic activity in multiple TNBC backgrounds. Mechanistic investigations of the ABT-263/crizotinib combination offering a potentially rapid path to clinic demonstrated RTK blockade, inhibition of mitogenic signaling, and proapoptotic signal induction in basal and mesenchymal stem–like TNBC. Our findings provide preclinical proof of concept for several combination treatments of TNBC, which offer near-term prospects for clinical translation. Cancer Res; 77(2); 566–78. ©2016 AACR.