tbuckley/cabot-search huggingface dataset:
The administration route is decisive for the ability of the vaccine adjuvant CAF09 to induce antigen-specific CD8 + T-cell responses: The immunological consequences of the biodistribution profile
Authors: Signe Tandrup Schmidt, Swapnil Khadke, Karen Smith Korsholm, Yvonne Perrie, Thomas Rades, Peter Andersen, Camilla Foged, Dennis Christensen
Journal: Journal of Controlled Release (2016)

A prerequisite for vaccine-mediated induction of CD8+ T-cell responses is the targeting of dendritic cell (DC) subsets specifically capable of cross-presenting antigen epitopes to CD8+ T cells. Administration of a number of cationic adjuvants via the intraperitoneal (i.p.) route has been shown to result in strong CD8+ T-cell responses, whereas immunization via e.g. the intramuscular (i.m.) or subcutaneous (s.c.) routes often stimulate weak CD8+ T-cell responses. The hypothesis for this is that self-drainage of the adjuvant/antigen to the lymphoid organs, which takes place upon i.p. immunization, is required for the subsequent activation of cross-presenting lymphoid organ-resident CD8α+ DCs. In contrast, s.c. or i.m. immunization usually results in the formation of a depot at the site of injection (SOI), which hinders the self-drainage and targeting of the vaccine to cross-presenting CD8α+ DCs. We investigated this hypothesis by correlating the biodistribution pattern and the adjuvanticity of the strong CD8+ T-cell inducing liposomal cationic adjuvant formulation 09 (CAF09), which is composed of dimethyldioctadecylammonium bromide/monomycoloyl glycerol liposomes with polyinosinic:polycytidylic acid electrostatically adsorbed to the surface. Biodistribution studies with radiolabeled CAF09 and a surface-adsorbed model antigen [ovalbumin (OVA)] showed that a significantly larger fraction of the vaccine dose localized in the draining lymph nodes (dLNs) and the spleen 6 h after i.p. immunization, as compared to after i.m. immunization. Studies with fluorescently labelled OVA + CAF09 demonstrated a preferential association of OVA + CAF09 to DCs/monocytes, as compared to macrophages and B cells, following i.p. immunization. Administration of OVA + CAF09 via the i.p. route did also result in DC activation, whereas no DC activation could be measured within the same period with unadjuvanted OVA and OVA + CAF09 administered via the s.c. or i.m. routes. In the dLNs, the highest level of activated, cross-presenting CD8α+ DCs was detected at 24 h post immunization, whereas an influx of activated, migrating and cross-presenting CD103+ DCs to the dLNs could be measured after 48 h. This suggests that the CD8α+ DCs are activated by self-draining OVA + CAF09 in the lymphoid organs, whereas the CD103+ DCs are stimulated by the OVA + CAF09 at the SOI. These results support the hypothesis that the self-drainage of OVA + CAF09 to the draining LNs is required for the activation of CD8α+ DCs, while the migratory CD103+ DCs may play a role in sustaining the subsequent induction of strong CD8+ T-cell responses.
Prospective Evaluation Of Alternative Donor Availability In 708 Patients: Improved Allograft Access With Enlarging CB Inventory For All Patients Including Racial and Ethnic Minorities
Authors: Parastoo B. Dahi, Doris M. Ponce, Courtney Byam, Sean Devlin, Marissa N. Lubin, Katherine L. Evans, Anne Marie R. Gonzales, Melissa Sideroff, Deborah Wells, Sergio A. Giralt, James W. Young, Esperanza B. Papadopoulos, Nancy A. Kernan, Andromachi Scaradavou, Juliet N. Barker
Journal: Blood (2013)
Drug appraisal issues must be resolved at policy level
Authors: Katharina Kieslich, Peter Littlejohns, Albert Weale
Journal: BMJ (2016)

Gornall and colleagues’ investigation shows that stakeholders blame NHS England (NHSE) for slow and limited access to new hepatitis C medicines.1 However, NHSE’s tactics reflect a fundamental challenge that the medicines appraisal system in England faces: the new hepatitis C medicines have, in one fell swoop, challenged the cost effectiveness paradigm that is perceived as …
Former faculty member is charged with attempted murder of medical school dean
Authors: Michael McCarthy
Journal: BMJ (2016)

A fired faculty member of the Icahn School of Medicine at Mount Sinai, New York City, has been charged with attempted second degree murder for allegedly shooting the school’s dean outside a delicatessen in the community of Chappaqua in New Castle, New York, about 40 miles (64 km) north of New York City.

Police said that the suspect, Hengjun Chao, 49, used a shotgun loaded with buckshot to shoot Dennis S Charney, 65, dean of the Icahn School of Medicine, …
Targeting Alpha-Fetoprotein (AFP)–MHC Complex with CAR T-Cell Therapy for Liver Cancer
Authors: Hong Liu, Yiyang Xu, Jingyi Xiang, Li Long, Shon Green, Zhiyuan Yang, Bryan Zimdahl, Jingwei Lu, Neal Cheng, Lucas H. Horan, Bin Liu, Su Yan, Pei Wang, Juan Diaz, Lu Jin, Yoko Nakano, Javier F. Morales, Pengbo Zhang, Lian-xing Liu, Binnaz K. Staley, Saul J. Priceman, Christine E. Brown, Stephen J. Forman, Vivien W. Chan, Cheng Liu
Journal: Clinical Cancer Research (2016)

Abstract Purpose: The majority of tumor-specific antigens are intracellular and/or secreted and therefore inaccessible by conventional chimeric antigen receptor (CAR) T-cell therapy. Given that all intracellular/secreted proteins are processed into peptides and presented by class I MHC on the surface of tumor cells, we used alpha-fetoprotein (AFP), a specific liver cancer marker, as an example to determine whether peptide–MHC complexes can be targets for CAR T-cell therapy against solid tumors. Experimental Design: We generated a fully human chimeric antigen receptor, ET1402L1-CAR (AFP-CAR), with exquisite selectivity and specificity for the AFP158–166 peptide complexed with human leukocyte antigen (HLA)-A*02:01. Results: We report that T cells expressing AFP-CAR selectively degranulated, released cytokines, and lysed liver cancer cells that were HLA-A*02:01+/AFP+ while sparing cells from multiple tissue types that were negative for either expressed proteins. In vivo, intratumoral injection of AFP-CAR T cells significantly regressed both Hep G2 and AFP158-expressing SK-HEP-1 tumors in SCID-Beige mice (n = 8 for each). Moreover, intravenous administration of AFP-CAR T cells in Hep G2 tumor-bearing NSG mice lead to rapid and profound tumor growth inhibition (n = 6). Finally, in an established intraperitoneal liver cancer xenograft model, AFP-CAR T cells showed robust antitumor activity (n = 6). Conclusions: This study demonstrates that CAR T-cell immunotherapy targeting intracellular/secreted solid tumor antigens can elicit a potent antitumor response. Our approach expands the spectrum of antigens available for redirected T-cell therapy against solid malignancies and offers a promising new avenue for liver cancer immunotherapy. Clin Cancer Res; 23(2); 478–88. ©2016 AACR.
High Dose Daunorubicin Improves Survival in AML up to Age 60, Across All Cytogenetic Risk Groups Including Patients with Unfavorable Cytogenetic Risk, and FLT3-ITD Mutant AML: Updated Analyses from Eastern Cooperative Oncology Trial E1900
Authors: Marlise R. Luskin, Ju-Whei Lee, Hugo F Fernandez, Hillard M. Lazarus, Jacob M. Rowe, Martin S. Tallman, Elisabeth M. Paietta, Mark Litzow, Omar Abdel-Wahab, Jay P. Patel, Ross L. Levine, Zhuoxin Sun, Selina M. Luger
Journal: Blood (2014)
Social correlates of mental, neurological, and substance use disorders in China and India: a review
Authors: Hui G Cheng, Rahul Shidhaye, Fiona Charlson, Fei Deng, Tanica Lyngdoh, Shengnan Chen, Sharmishtha Nanda, Kimberly Lacroix, Amanda Baxter, Harvey Whiteford
Journal: The Lancet Psychiatry (2016)
Performance measures for lower gastrointestinal endoscopy: a European Society of Gastrointestinal Endoscopy (ESGE) Quality Improvement Initiative
Authors: Michal Kaminski, Siwan Thomas-Gibson, Marek Bugajski, Michael Bretthauer, Colin Rees, Evelien Dekker, Geir Hoff, Rodrigo Jover, Stepan Suchanek, Monika Ferlitsch, John Anderson, Thomas Roesch, Rolf Hultcranz, Istvan Racz, Ernst Kuipers, Kjetil Garborg, James East, Maciej Rupinski, Birgitte Seip, Cathy Bennett, Carlo Senore, Silvia Minozzi, Raf Bisschops, Dirk Domagk, Roland Valori, Cristiano Spada, Cesare Hassan, Mario Dinis-Ribeiro, Matthew Rutter
Journal: Endoscopy (2017)

The European Society of Gastrointestinal Endoscopy and United European Gastroenterology present a short list of key performance measures for lower gastrointestinal endoscopy. We recommend that endoscopy services across Europe adopt the following seven key performance measures for lower gastrointestinal endoscopy for measurement and evaluation in daily practice at a center and endoscopist level: <b>1</b> Rate of adequate bowel preparation (minimum standard 90 %); <b>2</b> Cecal intubation rate (minimum standard 90 %); <b>3</b> Adenoma detection rate (minimum standard 25 %); <b>4 </b>Appropriate polypectomy technique (minimum standard 80 %); <b>5</b> Complication rate (minimum standard not set); <b>6</b> Patient experience (minimum standard not set); <b>7</b> Appropriate post-polypectomy surveillance recommendations (minimum standard not set). Other identified performance measures have been listed as less relevant based on an assessment of their importance, scientific acceptability, feasibility, usability, and comparison to competing measures.
Cyberknife in the management of metastatic melanoma: A feasibility study.
Authors: E. G. Elias, C. Aygen
Journal: Journal of Clinical Oncology (2010)

e19033 Background: Cyberknife is a robotic radiosurgery device coupled with synchrony respiratory tracking system. It can deliver precisely high-dose radiotherapy with low fractionation to any part in the body, including a moving organ. Methods: Thirteen consecutive patients with wide spread metastases were treated to the most life-threatening lesions that included 17 sites: 6 patients with brain metastases treated to 8 sites, 2 spines to 3 sites and one to each of the following sites: lung, liver, intra-abdominal, nasopharynx, retro-orbital and floor of the orbit. Their ages ranged from 24-88 (median 61). The dose of radiation ranged from 2,000 to 3,500 cGy, carried out on outpatient over 1-5 fractions per patient. Results: All treatments were well tolerated with excellent patients' compliance. Their survival ranged from 2-15 months with a median of 4 months. Four patients had documented complete response to the treated lesions; one by biopsy and 3 radiologically. Two patients lived for 13 and 15 months (lung/spine). However, most of the patients succumbed to progression of other metastases. Duration of therapy ranged from 1-5 days. Conclusions: Cyberknife is a new effective therapy in melanoma. It is non-toxic, bloodless, precise local therapy administered on outpatient over a short period of time, and with no age limitation. It can reach areas that are not amenable to surgical resections to eliminate immediate life- threatening lesions. It can be administered while the patient continues to receive systemic therapy. No significant financial relationships to disclose.
Acarbose and acetaminophen?a dangerous combination?
Authors: Akio Sato
Journal: Hepatology (1999)

concerning the study of Wang et al. 2 taught the readers of HEPATOLOGY a great deal about the mechanism of acetaminophen (AP)-induced hepatotoxicity.However, as the corresponding author for the paper of Wang et al., I feel obliged to respond to his comments concerning the dose of acarbose and ethanol used in our study.Dr. Kra ¨henbu ¨hl stated that the daily dose of alcohol and acarbose ingested by our rats, approximately 14 mL of 10% alcohol and 16 mg acarbose per day, corresponded to approximately 200 g of alcohol and 3 g of acarbose by a 70 kg human subject, and concluded that the doses of both ethanol and acarbose that we chose were substantially higher than those normally ingested. 1However, the extrapolation of the dose from rats to humans can also be made on the basis of body surface area, rather than on the conventional body weight basis. 3 In Wang et al., 2 21 to 22 mg/kg/d of acarbose evidently potentiated the hepatotoxicity of CC1 4 and/or AP, which was significantly increased when combined with 3.0 g/kg/d alcohol.This dose of acarbose is about four times higher than the recommended dose (5 mg/kg/d) for type 2 diabetics when calculated on the basis of body weight, which is a substantially high dose, as Dr. Kra ¨henbu ¨hl remarks. 1 However, the dose extrapolation based on body surface area produces a different result.Assuming that the body surface area is proportional to body weight (kg) to the power of 0.7, 4 i.e., (body weight) 0.7 , the doses of acarbose (21.5 mg/kg) and alcohol (3.0 g/kg) for a rat correspond to doses of only 421
P138 Early vs delayed rehabilitation: A randomised controlled trial: Abstract P138 Table 1
Authors: O Revitt, S Ward, MD Morgan, SJ Singh, SJ Singh
Journal: Thorax (2015)

<h3>Introduction</h3> Providing outpatient Pulmonary Rehabilitation (PR) following hospitalisation for an acute exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) has been found to improve exercise capacity, quality of life and a reduction in unplanned hospital admissions and mortality (Puhan, 2011). These positive effects, although studied in the short term, have led to national and international guidelines supporting the provision of post exacerbation PR (PEPR). However, uptake is poor with less than 10% of hospital discharges for AECOPD completing PEPR (Jones, 2014). The aim of this study was to establish whether delaying the offer of rehabilitation would be effective and acceptable to patients who have recently been hospitalised for an AE of their COPD. <h3>Methods</h3> A randomised controlled trial was conducted. Patients were randomised to PEPR or delayed PEPR (D-PEPR) following hospitalisation for an AECOPD. Both programmes were the same, consisting of twice weekly, six-week hospital based programme (exercise and education). PEPR commenced within four weeks of hospital discharge and D-PEPR commenced 7 weeks after this. The primary outcome was the Incremental Shuttle Walking test (ISWT), secondary measures were the Endurance Shuttle Walk Test (ESWT). <h3>Results</h3> Thirty six patients consented and were assessed (14 male, mean (SD) age 66.03 (7.64) years, FEV<sub>1</sub> 1.18 (0.48) litres, ISWT 225 (160.77) metres, ESWT 222 (151.09) seconds. We observed important improvements in the PEPR group. However, only 6 patients out of 12 assessed in the D-PEPR group remained during the control time prior to the programme commencing of which 3 patients went on to complete all of D-PEPR (Table 1). <h3>Conclusion</h3> PEPR is effective and no natural recovery was observed. Although small numbers, acceptability and completion for D-PEPR was even worse than PEPR. D-PEPR does not seem a feasible alternative to PEPR. <h3>Reference</h3> 1 Puhan MA, Gimeno-Santos E, Scharplatz M. <i>et al.</i> Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease.<i> Cochrane Database Syst Rev</i>. 2011;<b>10</b>:CD005305 2 Jones SE, Green SA, Clark AL. <i>et al.</i> Pulmonary rehabilitation following hospitalisation for acute exacerbation of COPD: referrals, uptake and adherence.<i> Thorax</i>. 2014;<b>69</b>:181–2
A phase I trial of the human double minute 2 inhibitor (MK-8242) in patients with refractory/recurrent acute myelogenous leukemia (AML).
Authors: Farhad Ravandi, Ivana Gojo, Mrinal Mahesh Patnaik, Mark D. Minden, Hagop M. Kantarjian, Amy Levonas, Craig Fancourt, Raymond Lam, Amy Meister, Mary Elizabeth Jones, Ramon Karmel Kemp, Clayton Knox, Shelonitda Rose, Payal Shah Patel, Raoul Tibes
Journal: Journal of Clinical Oncology (2015)

7070 Background: Human double minute 2 (HDM2) binds to and inhibits wild-type (WT) p53, thereby promoting oncogenesis. MK-8242 is a potent, orally bioavailable, small-molecule inhibitor of the HDM2:p53 protein-protein interaction being developed as a novel cancer therapy. Methods: This multi-center, non-randomized, open-label, 2-arm (A/monotherapy and B/combination therapy), 2-part (dose escalation and confirmation) study was designed to evaluate the safety/tolerability, pharmacokinetics (PK) and recommended phase 2 dose (RP2D) of MK-8242 +/- cytarabine in p53 WT patients (pts) with refractory/recurrent AML. The study was terminated for reasons unrelated to safety; only the monotherapy dose-escalation phase was completed. In Arm A, MK-8242 was initially dosed p.o. either QD (30 mg-250 mg) or BID (120 mg-250 mg) for 7 days on/7 days off (7on/7off) in a 28-day cycle The dosing schedule was later modified to 7on/14off in a 21-day cycle (210 mg or 300 mg BID) to improve the safety profile of the drug. Results: 26 pts enrolled (24 evaluable for response). Median age was 66 yrs (range: 29-81). All pts had ≥ 1 AE with 5 (19%) discontinuing due to AEs. There were 7 deaths (3 pneumonia-related; 2 AML progression; 1 sepsis; 1 respiratory failure); only 1 death (fungal pneumonia due to marrow aplasia) was deemed drug-related. With the initial 7on/7off regimen, DLTs occurred only in the 250 mg BID group in 2 pts (bone marrow failure, G1 and G4). After switching to the 7on/14off schedule, no DLTs were observed for the 210 mg BID or 300 mg BID groups (doses above 300 mg not tested). Across all dosing schedules, best responses were: 1/24 PR observed after 11 wks (120 mg QD, 7on/7off); 1/24 CRi observed after 2 wks (210 mg BID, 7on/14off); and 1/24 morphologic leukemia-free state after 4 wks (250 mg BID, 7on/7off). Plasma PK analysis on day 7 at the 210 mg BID dose revealed AUC0-12hr of 8.7 µM*hr, Cmax of 1.5 µM (n = 5, Tmax, 2-6 hr) and T1/2 of 7.9 hr. Conclusions: The modified 7on/14off regimen showed a more favorable safety profile than the 7on/7off schedule, and a MTD for this regimen was not established. Clinical activity was seen at 210 mg BID (7on/14off), providing impetus for further study of HDM2 inhibitors in pts with AML. Clinical trial information: NCT01451437.
Visual Acuity Is Correlated with the Area of the Foveal Avascular Zone in Diabetic Retinopathy and Retinal Vein Occlusion
Authors: Chandrakumar Balaratnasingam, Maiko Inoue, Seungjun Ahn, Jesse McCann, Elona Dhrami-Gavazi, Lawrence A. Yannuzzi, K. Bailey Freund
Journal: Ophthalmology (2016)
Resolving Lipid Mediators Maresin 1 and Resolvin D2 Prevent Atheroprogression in Mice
Authors: Joana R. Viola, Patricia Lemnitzer, Yvonne Jansen, Gergely Csaba, Carla Winter, Carlos Neideck, Carlos Silvestre-Roig, Gunnar Dittmar, Yvonne Döring, Maik Drechsler, Christian Weber, Ralf Zimmer, Nicolas Cenac, Oliver Soehnlein
Journal: Circulation Research (2016)

Atheroprogression is a consequence of nonresolved inflammation, and currently a comprehensive overview of the mechanisms preventing resolution is missing. However, in acute inflammation, resolution is known to be orchestrated by a switch from inflammatory to resolving lipid mediators. Therefore, we hypothesized that lesional lipid mediator imbalance favors atheroprogression.To understand the lipid mediator balance during atheroprogression and to establish an interventional strategy based on the delivery of resolving lipid mediators.Aortic lipid mediator profiling of aortas from Apoe-/- mice fed a high-fat diet for 4 weeks, 8 weeks, or 4 months revealed an expansion of inflammatory lipid mediators, Leukotriene B4 and Prostaglandin E2, and a concomitant decrease of resolving lipid mediators, Resolvin D2 (RvD2) and Maresin 1 (MaR1), during advanced atherosclerosis. Functionally, aortic Leukotriene B4 and Prostaglandin E2 levels correlated with traits of plaque instability, whereas RvD2 and MaR1 levels correlated with the signs of plaque stability. In a therapeutic context, repetitive RvD2 and MaR1 delivery prevented atheroprogression as characterized by halted expansion of the necrotic core and accumulation of macrophages along with increased fibrous cap thickness and smooth muscle cell numbers. Mechanistically, RvD2 and MaR1 induced a shift in macrophage profile toward a reparative phenotype, which secondarily stimulated collagen synthesis in smooth muscle cells.We present evidence for the imbalance between inflammatory and resolving lipid mediators during atheroprogression. Delivery of RvD2 and MaR1 successfully prevented atheroprogression, suggesting that resolving lipid mediators potentially represent an innovative strategy to resolve arterial inflammation.
Abstract 5006: Elucidating the mechanism of bile acid-induced activation of estrogen receptor β in colorectal adenocarcinoma
Authors: Jesse Trujillo
Journal: Cancer Research (2015)

Abstract In previous studies, Ursodeoxycholic Acid (UDCA) was investigated as a chemopreventive drug for the prevention of colorectal adenoma recurrence. These studies revealed that the efficacy of UDCA was gender-specific. The use of UDCA in men significantly lowered the odds of advanced lesions in men, but significantly increased the odds of advanced lesions in women, more specifically, in females who were younger, obese, or whose diet was high in fat. The gender specific role of UDCA led us to investigate this bile acids’, along with deoxycholic acid's (DCA), ability to activate the estrogen receptor in colon cancer. Estrogen receptor β (ERβ) is the predominant estrogen receptor in both normal and malignant human colon tissue, and loss of ERβ has been shown to be critical for tumor cell differentiation. Elevated concentrations of bile acids have previously been shown to promote colon cancer and growing evidence indicates that these molecules play a vital role in regulating cell signaling and gene expression. In our current studies, through western blot and qRT-PCR analysis, we have shown that DCA-treated HT-29 colorectal adenocarcinoma cells significantly induce the phosphorylation of ERβ, as well as increase gene expression of the pS2 estrogen response element (ERE). UDCA was also shown to induce phosphorylation of ERβ, but much later than DCA. However, UDCA increases gene expression of pS2 at much earlier time points than DCA. In addition, we have also shown that when pre-treating HT-29 cells with the MEK 1/2 inhibitor, PD98059, bile acid-induced phosphorylation of ERβ is significantly reduced, along with ERE gene up-regulation. Collectively, this data suggests that bile acids are inducing the activation of ERβ through a ligand-independent mechanism via the MAPK signaling cascade. Citation Format: Jesse Trujillo. Elucidating the mechanism of bile acid-induced activation of estrogen receptor β in colorectal adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5006. doi:10.1158/1538-7445.AM2015-5006