tbuckley/cabot-search huggingface dataset:
Vaccination to improve the persistence of CD19CAR gene-modified T cells in relapsed pediatric acute lymphoblastic leukemia
Authors: C Rossig, M Pule, B Altvater, S Saiagh, G Wright, S Ghorashian, L Clifton-Hadley, K Champion, Z Sattar, B Popova, A Hackshaw, P Smith, T Roberts, E Biagi, B Dreno, R Rousseau, S Kailayangiri, M Ahlmann, R Hough, B Kremens, M G Sauer, P Veys, N Goulden, M Cummins, P J Amrolia
Journal: Leukemia (2017)
Plasma kallikrein mediates brain hemorrhage and edema caused by tissue plasminogen activator therapy in mice after stroke
Authors: Fabrício Simão, Tuna Ustunkaya, Allen C. Clermont, Edward P. Feener
Journal: Blood (2017)

Thrombolytic therapy using tissue plasminogen activator (tPA) in acute stroke is associated with increased risks of cerebral hemorrhagic transformation and angioedema. Although plasma kallikrein (PKal) has been implicated in contributing to both hematoma expansion and thrombosis in stroke, its role in the complications associated with the therapeutic use of tPA in stroke is not yet available. We investigated the effects of tPA on plasma prekallikrein (PPK) activation and the role of PKal on cerebral outcomes in a murine thrombotic stroke model treated with tPA. We show that tPA increases PKal activity in vitro in both murine and human plasma, via a factor XII (FXII)-dependent mechanism. Intravenous administration of tPA increased circulating PKal activity in mice. In mice with thrombotic occlusion of the middle cerebral artery, tPA administration increased brain hemorrhage transformation, infarct volume, and edema. These adverse effects of tPA were ameliorated in PPK (Klkb1)-deficient and FXII-deficient mice and in wild-type (WT) mice pretreated with a PKal inhibitor prior to tPA. tPA-induced brain hemisphere reperfusion after photothrombolic middle cerebral artery occlusion was increased in Klkb1-/- mice compared with WT mice. In addition, PKal inhibition reduced matrix metalloproteinase-9 activity in brain following stroke and tPA therapy. These data demonstrate that tPA activates PPK in plasma and PKal inhibition reduces cerebral complications associated with tPA-mediated thrombolysis in stroke.
Is Conventional Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) an Optimal Long-Term Strategy for Non Hodgkin Lymphomas: A Retrospective Study from 1987 to 2004.
Authors: Anne-Sophie A.S. Michallet, Sophie S. Tartas, Quoc-Hung Q.H. Le, Franck F. Nicolini, Nicole N. Raus, Anne A. Thiebaut, Xavier X. Thomas, Francoise F. Berger, Pascale P. Felman, Gilles G. Salles, Bertrand B. Coiffier, Mauricette M. Michallet
Journal: Blood (2004)
Effectiveness of personalised risk information and taster sessions to increase the uptake of smoking cessation services (Start2quit): a randomised controlled trial
Authors: Hazel Gilbert, Stephen Sutton, Richard Morris, Irene Petersen, Simon Galton, Qi Wu, Steve Parrott, Irwin Nazareth
Journal: The Lancet (2017)

BackgroundNational Health Service Stop Smoking Services (SSSs) offer help to smokers motivated to quit; however, attendance rates are low and recent figures show a downward trend. We aimed to assess the effectiveness of a two-component personalised intervention on attendance at SSSs.MethodsWe did this randomised controlled trial in 18 SSSs in England. Current smokers (aged ≥16 years) were identified from medical records in 99 general practices and invited to participate by their general practitioner. Individuals who gave consent, were motivated to quit, and had not attended the SSS within the past 12 months, were randomly assigned (3:2), via computer-generated randomisation with permuted blocks (block size of five), to receive either an individually tailored risk letter and invitation to attend a no-commitment introductory session run by the local SSS (intervention group) or a standard generic letter advertising the local SSS (control group). Randomisation was stratified by sex. Masking of participants to receipt of a personal letter and invitation to a taster session was not possible. The personal letter was generated by a research assistant, but the remainder of the research team were masked to group allocation. General practitioners, practice staff, and SSS advisers were unaware of their patients' allocation. The primary outcome was attendance at the first session of an SSS course within 6 months from randomisation. We did analysis by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN 76561916.FindingsRecruitment, collection of baseline data, delivery of the intervention, and follow up of participants took place between Jan 31, 2011, and July 12, 2014. We randomly assigned 4384 smokers to the intervention group (n=2636) or the control group (n=1748); 4383 participants comprised the intention-to-treat population. Attendance at the first session of an SSS course was significantly higher in the intervention group than in the control group (458 [17·4%] vs 158 [9·0%] participants; unadjusted odds ratio 2·12 [95% CI 1·75–2·57]; p<0·0001).InterpretationDelivery of personalised risk information alongside an invitation to an introductory session more than doubled the odds of attending the SSS compared with a standard generic invitation to contact the service. This result suggests that a more proactive approach, combined with an opportunity to experience local services, can reduce patient barriers to receiving treatment and has high potential to increase uptake.FundingNational Institutes of Health Research Health Technology Assessment.
Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs
Authors: Divya Prakash Gnanadhas, Prasanta K. Dash, Brady Sillman, Aditya N. Bade, Zhiyi Lin, Diana L. Palandri, Nagsen Gautam, Yazen Alnouti, Harris A. Gelbard, JoEllyn McMillan, R. Lee Mosley, Benson Edagwa, Howard E. Gendelman, Santhi Gorantla
Journal: Journal of Clinical Investigation (2017)

Long-acting anti-HIV products can substantively change the standard of care for patients with HIV/AIDS. To this end, hydrophobic antiretroviral drugs (ARVs) were recently developed for parenteral administration at monthly or longer intervals. While shorter-acting hydrophilic drugs can be made into nanocarrier-encased prodrugs, the nanocarrier encasement must be boosted to establish long-acting ARV depots. The mixed-lineage kinase 3 (MLK-3) inhibitor URMC-099 provides this function by affecting autophagy. Here, we have shown that URMC-099 facilitates ARV sequestration and its antiretroviral responses by promoting the nuclear translocation of the transcription factor EB (TFEB). In monocyte-derived macrophages, URMC-099 induction of autophagy led to retention of nanoparticles containing the antiretroviral protease inhibitor atazanavir. These nanoparticles were localized within macrophage autophagosomes, leading to a 4-fold enhancement of mitochondrial and cell vitality. In rodents, URMC-099 activation of autophagy led to 50-fold increases in the plasma drug concentration of the viral integrase inhibitor dolutegravir. These data paralleled URMC-099–mediated induction of autophagy and the previously reported antiretroviral responses in HIV-1–infected humanized mice. We conclude that pharmacologic induction of autophagy provides a means to extend the action of a long-acting, slow, effective release of antiretroviral therapy.
The MLL1-H3K4me3 Axis-Mediated PD-L1 Expression and Pancreatic Cancer Immune Evasion
Authors: Chunwan Lu, Amy V. Paschall, Huidong Shi, Natasha Savage, Jennifer L. Waller, Maria E. Sabbatini, Nicholas H. Oberlies, Cedric Pearce, Kebin Liu
Journal: JNCI Journal of the National Cancer Institute (2016)

Pancreatic cancer is one of the cancers where anti-PD-L1/PD-1 immunotherapy has been unsuccessful. What confers pancreatic cancer resistance to checkpoint immunotherapy is unknown. The aim of this study is to elucidate the underlying mechanism of PD-L1 expression regulation in the context of pancreatic cancer immune evasion.Pancreatic cancer mouse models and human specimens were used to determine PD-L1 and PD-1 expression and cancer immune evasion. Histone methyltransferase inhibitors, RNAi, and overexpression were used to elucidate the underlying molecular mechanism of PD-L1 expression regulation. All statistical tests were two-sided.PD-L1 is expressed in 60% to 90% of tumor cells in human pancreatic carcinomas and in nine of 10 human pancreatic cancer cell lines. PD-1 is expressed in 51.2% to 52.1% of pancreatic tumor-infiltrating cytotoxic T lymphocytes (CTLs). Tumors grow statistically significantly faster in FasL-deficient mice than in wild-type mice (P = .03-.001) and when CTLs are neutralized (P = .03-<.001). H3K4 trimethylation (H3K4me3) is enriched in the cd274 promoter in pancreatic tumor cells. MLL1 directly binds to the cd274 promoter to catalyze H3K4me3 to activate PD-L1 transcription in tumor cells. Inhibition or silencing of MLL1 decreases the H3K4me3 level in the cd274 promoter and PD-L1 expression in tumor cells. Accordingly, inhibition of MLL1 in combination with anti-PD-L1 or anti-PD-1 antibody immunotherapy effectively suppresses pancreatic tumor growth in a FasL- and CTL-dependent manner.The Fas-FasL/CTLs and the MLL1-H3K4me3-PD-L1 axis play contrasting roles in pancreatic cancer immune surveillance and evasion. Targeting the MLL1-H3K4me3 axis is an effective approach to enhance the efficacy of checkpoint immunotherapy against pancreatic cancer.
Allergen exposure chambers: harmonizing current concepts and projecting the needs for the future – an <scp>EAACI</scp> Position Paper
Authors: O. Pfaar, M. A. Calderon, C. P. Andrews, E. Angjeli, K. C. Bergmann, J. H. Bønløkke, F. de Blay, P. Devillier, A. K. Ellis, R. Gerth van Wijk, J. M. Hohlfeld, F. Horak, R. L. Jacobs, L. Jacobsen, M. Jutel, S. Kaul, M. Larché, D. Larenas‐Linnemann, R. Mösges, H. Nolte, P. Patel, L. Peoples, R. L. Rabin, C. Rather, A. M. Salapatek, T. Sigsgaard, S. Thaarup, J. Yang, P. Zieglmayer, T. Zuberbier, P. Demoly
Journal: Allergy (2017)

Allergen exposure chambers (AECs) are clinical facilities allowing for controlled exposure of subjects to allergens in an enclosed environment. AECs have contributed towards characterizing the pathophysiology of respiratory allergic diseases and the pharmacological properties of new therapies. In addition, they are complementary to and offer some advantages over traditional multicentre field trials for evaluation of novel therapeutics. To date, AEC studies conducted have been monocentric and have followed protocols unique to each centre. Because there are technical differences among AECs, it may be necessary to define parameters to standardize the AECs so that studies may be extrapolated for driving basic immunological research and for marketing authorization purposes by regulatory authorities.For this task force initiative of the European Academy of Allergy and Clinical Immunology (EAACI), experts from academia and regulatory agencies met with chamber operators to list technical, clinical and regulatory unmet needs as well as the prerequisites for clinical validation.The latter covered the validation process, standardization of challenges and outcomes, intra- and interchamber variability and reproducibility, in addition to comparability with field trials and specifics of paediatric trials and regulatory issues.This EAACI Position Paper aims to harmonize current concepts in AECs and to project unmet needs with the intent to enhance progress towards use of these facilities in determining safety and efficacy of new therapeutics in the future.
Skin manifestation with imatinib mesylate: Experience from India
Authors: S. Mukhopadhyay, S. Dey, S. Koner, C. Bhattacharjee, A. Mukhopadhyay
Journal: Journal of Clinical Oncology (2008)

20682 Background: The majority of the patients notice the pigmentary changes at the time of treatment with imatinib mesylate in western world. There is one reputed case of imatinib mesylate induced hypopigmentation in the literature that occurred in a Caucasian male with involvement of the distal aspects both hands and the penis. In the Indian-African ethnicity, the skin toxicity is not specific to one ethnic background and most likely the skin changes are more noticeable and therefore more likely to be reported among patients with darker skin. Till now no published data available for skin pigmentation from eastern India. The aim of our study was to see the skin manifestation of imatinib mesylate in India-Asian population. Methods: During period from January 2002 to December 2007, we selected consecutive 320 patients with chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST) in the hemato-oncology department of Netaji Subhash Chandra Bose Cancer Research Institute. Out of them 240 were bcr-abl positive CML and 80 were C-Kit positive GIST. The age range of the patients was 18 years to 76 years (median age of 42 years). The performance status was more than 60% (Karnofsky). They were started with 400mg imatinib mesylate (Veenat, Natco Pharma), 200mg dose was increased every two weekly up to 800mg if the patient could tolerate. Results: Two hundred fifty patients (78.12%) showed whitish discoloration of skin out of 320 patients. Only 12 patients (3.75%) observed skin manifestation. One patient had hypopigmentation while other had severe excoriation of the facial, palm, and sole skin. Four patients were of GIST (3 patients on 800mg and 1 patient on 600mg dose), the other eight patients were of CML (3 patients on 800mg and 5 patients on 600mg dose). Both the skin manifestation were reduced after withholding imatinib temporarily and reducing the dose later on. Conclusions: Imatinib is a very safe drug in Indian-Asian population and skin manifestation is negligible in contrast to western literature. No significant financial relationships to disclose.
A phase I trial of bortezomib in combination with fludarabine in patients with lymphoproliferative neoplasms
Authors: O. N. Koc, N. J. Bahlis, L. Liu, H. M. Lazarus, B. W. Cooper, S. L. Gerson, M. J. Laughlin, J. W. Jacobberger, N. Horvath, S. Remick
Journal: Journal of Clinical Oncology (2005)

6647 Background: Bortezomib has been shown to be safe and effective single agent in the treatment of relapsed and refractory hematological malignancies. Fludarabine also is an active agent in treatment of indolent non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Bortezomib may potentiate fludarabine activity by inhibiting DNA repair and inducing apoptosis in Bcl-2 overexpressing cells. Methods: A phase I study combining bortezomib and fludarabine is being performed to determine the MTD/toxicities of this combination in patients with relapsed or refractory (progressive) indolent NHL or CLL. Cohorts of 3 patients received fludarabine 25mg/m2 days 1–3 and escalating doses of bortezomib on days 1,4,8 and 11 in 3 week cycles. Results: Thus far 7 patients (indolent NHL=4, CLL=2, Mantle Cell NHL=1) are evaluated in 3 of 4 planned dose cohorts of bortezomib (0.7, 1.0 and 1.3 mg/m2). All patients were treated with 2–6 prior regimens (median 4). A total of 27 cycles of therapy has been given and the DLT has not been reached. All 7 patients experienced grade 3 lymphopenia, 1 had reversible grade 3 thrombocytopenia 1 had transient grade 3 neutropenia and 2 had grade 3 diarrhea unrelated to treatment. Grade 1 and 2 neurotoxicity was seen in 2 patients. One patient achieved CRu (follicular lymphoma), 1 PR (mantle Cell) and 4 had SD. One patient with CLL progressed after 1 cycle of therapy. There was no detectable change in levels of DNA-PKc, bcl-2, p27, p21, caspase 3, or ATM proteins in CLL cells of this patient on day 8 compared to day 1 at bortezomib dose of 1.0 mg/m2. Conclusions: Combination of bortezomib and fludarabine is feasible and appears to be active in heavily pre-treated patients with indolent NHL. Dose escalation of bortezomib above 1.0 mg/m2 continues to determine the MTD. No significant financial relationships to disclose.
Bone Marrow Stroma (BMS) Prevents Apoptosis of Lymphoma Cells by Upregulation of BMS-Derived B-Cell Activating Factor (BAFF) and Activation of NF-kB.
Authors: Tint Lwin, Lori A. Hazlehurst, Lynn C. Moscinski, William S. Dalton, Jianguo Tao
Journal: Blood (2006)
Predictors of Dyslipidemia Over Time in Youth With Type 1 Diabetes: For the SEARCH for Diabetes in Youth Study
Authors: Amy S. Shah, David M. Maahs, Jeanette M. Stafford, Lawrence M. Dolan, Wei Lang, Giuseppina Imperatore, Ronny A. Bell, Angela D. Liese, Kristi Reynolds, Catherine Pihoker, Santica Marcovina, Ralph B. D’Agostino, Dana Dabelea
Journal: Diabetes Care (2017)

Understanding the risk factors associated with progression and regression of dyslipidemia in youth with type 1 diabetes may guide treatments.We studied 1,478 youth with type 1 diabetes (age 10.8 ± 3.9 years, 50% male, 77% non-Hispanic white, not on lipid-lowering medications) at baseline and at a mean follow-up of 7.1 ± 1.9 years in the SEARCH for Diabetes in Youth (SEARCH) study. Progression to dyslipidemia was defined as normal lipid concentrations at baseline and abnormal at follow-up (non-HDL-cholesterol [C] >130 mg/dL or HDL-C <35 mg/dL). Regression was defined as abnormal lipids at baseline and normal at follow-up. Multivariable logistic regression was used to evaluate factors associated with progression and regression compared with stable normal and stable abnormal, respectively. An area under the curve (AUC) variable was used for the time-varying covariates A1C and waist-to-height ratio (WHtR).Non-HDL-C progressed, regressed, was stable normal, and stable abnormal in 19%, 5%, 69%, and 7% of youth with type 1 diabetes, respectively. Corresponding percentages for HDL-C were 3%, 3%, 94%, and 1%, respectively. Factors associated with non-HDL-C progression were higher A1C AUC and higher WHtR AUC in males. Non-HDL-C regression was associated with lower WHtR AUC, and HDL-C progression was associated with male sex and higher WHtR AUC. HDL-C regression was not modeled due to small numbers.A1C and WHtR are modifiable risk factors associated with change in dyslipidemia over time in youth with type 1 diabetes.
Hyaluronidase and IFN-γ from Activated T-Cells Are Key Mediators To Induce Immunosuppressive Activity of Mesenchymal Stem Cells.
Authors: Kazuya Sato, Ozaki Katsutoshi, Iekuni Oh, Haruko Matsu, Raine Tatara, Akiko Meguro, Keiko Hatanaka, Tadashi Nagai, Kazuo Muroi, Keiya Ozawa
Journal: Blood (2007)
Comparison of 12 current staging systems for advanced hepatocellular carcinoma not amendable to locoregional therapy as inclusion criteria for clinical trials.
Authors: X. Li, Q. Lin, M. Dong, X. Wu, L. Wei, J. Wen, X. Ma, Z. Chen
Journal: Journal of Clinical Oncology (2011)

2567 Background: The life expectancy of patients with advanced hepatocellular carcinoma (HCC) enrolled in clinical trials should be at least 3 month to test drug response. However, the prognosis of these patients was poor with median overall survival (OS) shorter than 3 months. This study was aimed to evaluate different prognosis score systems for HCC in predicting prognosis and 3-month OS of patients with advanced HCC. Methods: From November 2008 to April 2010, a total of 208 patients with advanced HCC who were not amendable to locoregional therapy were included in this study. Data were collected to classify patients according to Japan Integrated Staging scoring system, TNM stage by liver Cancer Study Group of Japan criteria, National Comprehensive Cancer Network Stage system, Cancer of the liver Italian Program scoring system for hepatocelluar carcinoma (CLIP), Advanced Liver Cancer Prognostic System (ALCPS), model of end-stage liver disease, French scoring system, Chinese University Prognostic Index staging system for HCC (CUPI), OKUDA score system, Tokyo score system, Barcelona Clinic Liver Cancer staging for hepatocelluar carcinoma at diagnosis. OS and 3-month OS were the end points used in the analysis. Survival analysis, Cox regression, relative operating characteristic (ROC), and logistic regression were utilized to access the prognostic value of each score system. Results: ROC analysis confirmed that ALCPS was the best prognostic system for 3-month OS. The cut-off point for ALCPS was 14 with sensitivity of 81.82% and specificity of 79.01%, which was reinforced by the survival variation on the two subgroups divided by ROC analysis generated cutoff point. CLIP and CUPI presented no statistical difference in prognostic discrimination with ALCPS, however, with relatively lower accuracy. Conclusions: ALCPS was the best score system in prediction of OS and 3-month OS among the 12 systems analyzed and a proper inclusion criteria for clinical trials for Chinese advanced HCC patients.
HCP-22TOPICALLY APPLIED VANCOMYCIN POWDER REDUCES THE RATE OF SURGICAL SITE INFECTION IN PATIENTS UNDERGOING CRANIOTOMIES FOR PRIMARY BRAIN TUMORS
Authors: Andrew Banz, Anthony Clark, Corin Agoris, Muhammad Imam, Nam D. Tran
Journal: Neuro-Oncology (2015)

BACKGROUND: Surgical site infections (SSI) can increase postoperative morbidity, mortality and lead to increased health care costs. The rates of SSI can be as high as 5.8% in patients undergoing craniotomies for tumors. Local application of vancomycin powder has been shown to be effective in reducing SSI in spine surgery; however, the effectiveness and safety of vancomycin powder in craniotomy in unclear. METHODS: The authors performed a retrospective chart review of all patients who underwent craniotomies for resection of primary brain glioma at the Moffitt Cancer Center from 2004-2014. A protocol consisting of 1 g of intrawound vancomycin powder application was initiated at our institution in 2010. Patient demographics (age, gender), clinical characteristics (comorbidities, steroid dose, KPS), tumor characteristics (tumor type, location), surgical factors (primary or redo, length of surgery, blood loss), SSI rates were assessed. Multivariate analysis was performed to determine risk factors associated with SSI and rates. RESULTS: A total of 864 patients underwent craniotomies for primary brain tumors. The cohorts were similar in demographics and baseline comorbidities, KPS, tumor characteristics, and surgical factors. SSI rates at 90 days were reduced after the implementation of vancomycin powder. CONCLUSIONS: The use of vancomycin powder application in craniotomy led to a reduction in SSI. No significant adverse events were observed.