tbuckley/cabot-search huggingface dataset:
A Pilot Trial of the Combination of Transgenic NY-ESO-1–reactive Adoptive Cellular Therapy with Dendritic Cell Vaccination with or without Ipilimumab
Authors: Theodore S. Nowicki, Beata Berent-Maoz, Gardenia Cheung-Lau, Rong Rong Huang, Xiaoyan Wang, Jennifer Tsoi, Paula Kaplan-Lefko, Paula Cabrera, Justin Tran, Jia Pang, Mignonette Macabali, Ivan Perez Garcilazo, Ignacio Baselga Carretero, Anusha Kalbasi, Alistair J. Cochran, Catherine S. Grasso, Siwen Hu-Lieskovan, Bartosz Chmielowski, Begoña Comin-Anduix, Arun Singh, Antoni Ribas
Journal: Clinical Cancer Research (2018)

Transgenic adoptive cell therapy (ACT) targeting the tumor antigen NY-ESO-1 can be effective for the treatment of sarcoma and melanoma. Preclinical models have shown that this therapy can be improved with the addition of dendritic cell (DC) vaccination and immune checkpoint blockade. We studied the safety, feasibility, and antitumor efficacy of transgenic ACT with DC vaccination, with and without CTLA-4 blockade with ipilimumab.Freshly prepared autologous NY-ESO-1-specific T-cell receptor (TCR) transgenic lymphocytes were adoptively transferred together with NY-ESO-1 peptide-pulsed DC vaccination in HLA-A2.1-positive subjects alone (ESO, NCT02070406) or with ipilimumab (INY, NCT01697527) in patients with advanced sarcoma or melanoma.Six patients were enrolled in the ESO cohort, and four were enrolled in the INY cohort. Four out of six patients treated per ESO (66%), and two out of four patients treated per INY (50%) displayed evidence of tumor regression. Peripheral blood reconstitution with NY-ESO-1-specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Tracking of transgenic T cells to the tumor sites was demonstrated in on-treatment biopsies via TCR sequencing. Multiparametric mass cytometry of transgenic cells demonstrated shifting of transgenic cells from memory phenotypes to more terminally differentiated effector phenotypes over time.ACT of fresh NY-ESO-1 transgenic T cells prepared via a short ex vivo protocol and given with DC vaccination, with or without ipilimumab, is feasible and results in transient antitumor activity, with no apparent clinical benefit of the addition of ipilimumab. Improvements are needed to maintain tumor responses.
Understanding the anti-tumor T cell responses modulation mediated by chemoradiation to improve immunotherapy efficacy
Authors: E. Lauret, C. Bonin, L. Rangan, L. Boullerot, J. Boustani, C. Fagnoni-Legat, S. Perrin, C. Mirjolet, M. Dosset, R. Boidot, S. Servagi, B. De Bari, O. Adotevi
Journal: Annals of Oncology (2018)

Background: The synergistic effect of concomitant chemoradiation (cRTCT) as standard of care in a broad range of cancers has been widely described. Recently, the combination of chemoradiation and immune checkpoint inhibitors raised great interest for the treatment of cancer patients. Although, previous studies have demonstrated the ability of chemotherapy (CT) or radiotherapy (RT) to improve host anti-tumor immunity, the immunological effects of concomitant chemoradiation are still poorly investigated. The main goal of this study was to understand how chemoradiation interplays with host anti-tumor T cell immunity. Methods: Mouse lung carcinoma and colorectal cancer models were used. Concomitant chemoradiation consisting in the combination of cisplatin (5mg/kg) plus 5-fluorouracil (25mg/kg) and radiation, at a single dose of 8Gy was delivered when tumors reached 90mm2. High throughput immunological analysis was performed on tumor infiltrating T lymphocytes (TILs) . Results: cRTCT promoted higher tumor infiltration by CD8 T cells as compared to CT or RT used as monotherapy. RNAsequencing analysis performed on TILs isolated from mice treated by cRTCT or CT or RT revealed that cRTCT promote immunological signatures characterized by strong Th1 polarization (T-bet, IFNg…) and high expression of T cells cytotoxicity markers (granzyme and perforin) as compared to CT or RT alone. Notably, immune checkpoint receptors such as CTLA-4, PD-1, TIM-3, TIGIT, and LAG-3 expression were highly upregulated by cRTCT. Kinetic monitoring of immune checkpoint receptors showed an early induction on TILs starting at day 3 and persisting over 15 days post cRTCT. This was concomitantly associated to PD-L1 induction on tumor cells and the tumor microenvironment and demonstrates the ability of cRTCT to promote a more suitable inflammatory tumor microenvironment than CT or RT alone. The association of anti-CTLA-4 and anti-PD-1 therapy with chemoradiation induced a strong tumor regression as compared to the immunotherapy combination alone. Conclusions: Our results demonstrate the ability of cRTCT to promote a high inflammatory tumor microenvironment and strongly support the rational to combine cRTCT with immune checkpoint inhibitors. Legal entity responsible for the study: UMR1098. Funding: Ligue contre le Cancer. Disclosure: All authors have declared no conflicts of interest.
Expression Profiling of Fibroblasts in Chronic and Acute Disease Models Reveals Novel Pathways in Kidney Fibrosis
Authors: Atsuko Y. Higashi, Bruce J. Aronow, Gregory R. Dressler
Journal: Journal of the American Society of Nephrology (2018)

Background Renal interstitial fibrosis results from activation and proliferation of fibroblasts to myofibroblasts, secretion and accumulation of extracellular matrix, and displacement of normal renal tubules. In contrast to chronic renal disease, acute injury may be repaired, a process that includes a decrease in the number of myofibroblasts in the interstitium and degradation of the accumulated extracellular matrix, leaving little evidence of prior injury. Methods To investigate whether activated fibroblasts demonstrate changes in gene expression that correspond with regression after acute injury but are not observed in chronic models of fibrosis, we used microarrays to analyze gene expression patterns among fibroblast populations at different stages of injury or repair. We then mined the data for signaling pathways in fibroblasts corresponding to the acute proliferative, regression, and chronic phases of renal injury. Results We identified multiple gene clusters with changes that correlate with the three phases of renal injury, including changes in levels of receptors for the antifibrotic factor PGE2. In adult renal fibroblast cultures, PGE2 was able to upregulate many genes that are suppressed by the profibrotic cytokine TGF- β , whereas many PGE2-downregulated genes were activated by TGF- β . High levels of TGF- β suppressed expression of a subset of PG receptors in fibroblast cultures, making these cells resistant to any effects of PGE2. Conclusions Inherent gene expression changes in activated fibroblasts accompany the transition from AKI to repair and regeneration. In chronic models, however, activated fibroblasts are resistant to the antifibrotic effects of PGE2 due to suppression of a subset of PGE receptors.
Human papillomavirus immunisation of adolescent girls: improving coverage through multisectoral collaboration in Malaysia
Authors: Saidatul N Buang, Safurah Ja’afar, Indra Pathmanathan, Victoria Saint
Journal: BMJ (2018)

Saidatul Buang and colleagues report on collaborative efforts to introduce HPV vaccination in Malaysia and increase coverage Cervical cancer is the fourth most common cancer in women globally.1 Human papillomavirus (HPV) types 16 and 18 collectively cause 70% of cervical cancers and precancerous cervical lesions.1 The UN joint global programme on cervical cancer prevention and control includes HPV immunisation for girls as one of its three priorities at country level, together with screening and treatment for cervical pre-cancer, and diagnosis and treatment of invasive cervical cancer.2 In Malaysia, the age standardised cervical cancer rate is 7.8 per 100 000 females, making it the third most common cancer in women, with 4352 new cases reported for 2007-11.3 Malaysia's HPV immunisation programme was introduced in 2010, within a healthcare system that has a credible track record (box 1, table 1). We present a case study of this programme and explore the role of multisectoral collaboration in achieving near universal immunisation of an estimated annual cohort of 250 000 13 year old girls. Box 1 ### Key facts about Malaysia #### Demographics4 #### Health7RETURN TO TEXT
Adalimumab as Treatment for Venous Thrombosis in Behçet's Syndrome: Comment on the Article by Emmi et al
Authors: Bayram Farisogullari, Alper Sari, Sefika Nur Ayar, Levent Kilic, Berkan Armagan, Omer Karadag
Journal: Arthritis & Rheumatology (2018)
Influenza Activity — United States, September 30–December 1, 2018
Authors: Alicia P. Budd, Anwar Isa Abd Elal, Noreen Alabi, John Barnes, Lenee Blanton, Lynnette Brammer, Erin Burns, Charisse N. Cummings, Vivien G. Dugan, Shikha Garg, Rebecca Garten, Lisa A. Grohskopf, Larisa Gubareva, Krista Kniss, Natalie Kramer, Alissa O’Halloran, Wendy Sessions, Calli Taylor, David E. Wentworth, Xiyan Xu, Alicia M. Fry, Jacqueline Katz, Daniel Jernigan
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Influenza activity in the United States was low during October 2018, and, although it increased slowly during November, activity remains low across most of the country.* During the week ending December 1, 2018, the percentage of outpatient visits for influenza-like illness† (ILI) was equal to the national baseline§ (Figure) and was at or slightly above the region-specific baseline in four of the 10 U.S. Department of Health and Human Services regions¶ (Regions 4 and 7-9). The majority of jurisdictions experienced minimal or low ILI activity since September 30; however, two experienced moderate ILI activity, and two experienced high ILI activity** during the week ending December 1. The percentage of deaths attributed to pneumonia and influenza remains below the epidemic threshold,†† and the rate of influenza-associated hospitalizations remains low. Five laboratory-confirmed, influenza-associated pediatric deaths occurring since September 30 have been reported to CDC. During the week ending December 1, the majority of jurisdictions (40 states, the District of Columbia, Puerto Rico, and U.S. Virgin Islands) reported sporadic or local geographic spread of influenza activity, nine states reported regional activity, and one state reported widespread activity.§§.
The <scp>FACE</scp> ‐Q Skin Cancer Module addresses post‐resection aesthetic and quality of life outcomes: reply from authors
Authors: T.D. Dobbs, H. Samarendra, S. Hughes, H.A. Hutchings, I.S. Whitaker
Journal: British Journal of Dermatology (2018)

Linked Articles: Dobbs et al. Br J Dermatol 2019; https://doi.org/10.1111/bjd.17342 and Lee et al. Br J Dermatol 2018; 179:88–94.
Domain-Focused CRISPR-Cas9 Screen Identifies the E3 Ubiquitin Ligase Substrate Adaptor Protein SPOP as a Novel Repressor of Fetal Hemoglobin
Authors: Xianjiang Lan, Eugene Khandros, Jeremy D. Grevet, Scott A. Peslak, Saurabh Bhardwaj, Cheryl A. Keller, Belinda Giardine, Ben A. Garcia, Ross C. Hardison, Junwei Shi, Gerd A. Blobel
Journal: Blood (2018)
Abstract 19936: Temporal Trend of High Intensity Statin Therapy Among Veterans Treated With Percutaneous Coronary Intervention: A Population Based Cohort Study
Authors: Aref A Bin Abdulhak, Mary Vaughan-Sarrzin, Peter Kaboli, Hilary Mosher, Jennifer G Robinson
Journal: Circulation (2017)

Introduction: The 2013 American College of Cardiology /American Heart Association (ACC/AHA) blood cholesterol guideline recommends high intensity statin therapy among certain groups of patients, bu...
The hereditary angioedema syndromes
Authors: Alvin H. Schmaier
Journal: Journal of Clinical Investigation (2018)

Hereditary angioedema (HAE) is a rare genetic disorder primarily caused by mutations in the SERPING1 gene encoding the C1 inhibitor (C1INH) that leads to plasma deficiency, resulting in recurrent attacks of severe swelling. In the current issue of the JCI, Haslund et al. show that in a subset of patients with type I HAE, mutated C1INH encoded by HAE-causing SERPING1 acts upon wildtype (WT) C1INH in a dominant-negative manner and forms intracellular C1INH aggregates. These aggregates lead to a reduction in the levels of secreted functional C1INH, thereby manifesting in the condition that allows the disease state. Interestingly, administration of WT SERPING1 gene is able to restore the levels of secreted C1INH, thereby opening up a novel mechanism justifying gene therapy for HAE.
Positive airway pressure for sleep-disordered breathing in acute quadriplegia: a randomised controlled trial
Authors: David J Berlowitz, Rachel Schembri, Marnie Graco, Jacqueline M Ross, Najib Ayas, Ian Gordon, Bonne Lee, Allison Graham, Susan V Cross, Martin McClelland, Paul Kennedy, Pradeep Thumbikat, Cynthia Bennett, Andrea Townson, Timothy J Geraghty, Sue Pieri-Davies, Raj Singhal, Karen Marshall, Deborah Short, Andrew Nunn, Duncan Mortimer, Doug Brown, Robert J Pierce, Peter A Cistulli
Journal: Thorax (2018)

Highly prevalent and severe sleep-disordered breathing caused by acute cervical spinal cord injury (quadriplegia) is associated with neurocognitive dysfunction and sleepiness and is likely to impair rehabilitation.To determine whether 3 months of autotitrating CPAP would improve neurocognitive function, sleepiness, quality of life, anxiety and depression more than usual care in acute quadriplegia.Multinational, randomised controlled trial (11 centres) from July 2009 to October 2015. The primary outcome was neurocognitive (attention and information processing as measure with the Paced Auditory Serial Addition Task). Daytime sleepiness (Karolinska Sleepiness Scale) was a priori identified as the most important secondary outcome.1810 incident cases were screened. 332 underwent full, portable polysomnography, 273 of whom had an apnoea hypopnoea index greater than 10. 160 tolerated at least 4 hours of CPAP during a 3-day run-in and were randomised. 149 participants (134 men, age 46±34 years, 81±57 days postinjury) completed the trial. CPAP use averaged 2.9±2.3 hours per night with 21% fully 'adherent' (at least 4 hours use on 5 days per week). Intention-to-treat analyses revealed no significant differences between groups in the Paced Auditory Serial Addition Task (mean improvement of 2.28, 95% CI -7.09 to 11.6; p=0.63). Controlling for premorbid intelligence, age and obstructive sleep apnoea severity (group effect -1.15, 95% CI -10 to 7.7) did not alter this finding. Sleepiness was significantly improved by CPAP on intention-to-treat analysis (mean difference -1.26, 95% CI -2.2 to -0.32; p=0.01).CPAP did not improve Paced Auditory Serial Addition Task scores but significantly reduced sleepiness after acute quadriplegia.ACTRN12605000799651.
In suspected ACS, care based on high-sensitivity vs standard cardiac troponin I assays did not improve 1-y outcomes
Authors: Christopher R. Carpenter
Journal: Annals of Internal Medicine (2018)

Source Citation Shah AS, Anand A, Strachan FE, et al; High-STEACS Investigators. High-sensitivity troponin in the evaluation of patients with suspected acute coronary syndrome: a stepped-wedge, cluster-randomised controlled trial. Lancet. 2018;392:919-28. 30170853
Abstract 18944: Efficacy of Clinical Notifications to Health Care Providers in Management of Heart Failure Patients
Authors: Reyhaneh M Akhavein, Jiri Sklenar, Jessica Minnier, Stephen Heitner
Journal: Circulation (2015)

Introduction: Adherence to guideline recommendations for patients with heart failure improves short and long-term outcomes, and can potentially reduce healthcare costs. Hypothesis: Written communication to care providers of individuals with heart failure with reduced systolic function (HFrEF) will result in better adherence to guidelines. Methods: We prospectively enrolled providers of all outpatients with HFrEF at Oregon Health and Science University in 2012. We reviewed adherence to six evidence-based HF therapies in each patient [ACE-I/ARB, beta blocker, aldosterone antagonist, anticoagulation therapy for atrial fibrillation or flutter, CRT, and ICD]. We excluded patients with destination therapy, resolution of HFrEF, lost to follow-up or death. After implementation of exclusion criteria, of 320 patients evaluated, 114 patients were ultimately included. These patients’ providers were randomized to either receiving a standardized written communication (intervention) or none (control). The letter highlighted 2013 ACCF/AHA heart failure management guidelines, and was sent by US mail to providers in intervention group. Six months later, we re-evaluated all patients according to the same criteria at the outset. Results: Optimal medical therapy (OMT) in intervention group improved in only 9% of patients who were previously sub-optimally treated (p 0.83), but 31% of patients who had already been on OMT experienced deescalated therapies despite no clear documentation (p 0.65). In control group, 11% of patients had increased treatment according to guidelines, and 9% of patients who had already been receiving OMT had deescalated treatment. There were no new ICDs implanted as a result of intervention, while 6.5% of patients in control group did receive ICD (p 0.46). Conclusions: Identification of patients with HFrEF and assessment of adherence to guideline-based therapies is now feasible via electronic medical record enquiry. Written notifications do not result in improved adherence to evidence-based guidelines, nor do these letters seem to alter provider behavior at all. We speculated that the lack of response is a direct result of “notification-fatigue”, and that alternative provider behavior modification techniques need to be evaluated.
Diagnostic Accuracy of 18F-FDG PET/CT in Patients With Biochemical Evidence of Recurrent, Residual, or Metastatic Medullary Thyroid Carcinoma
Authors: Laura Rodríguez-Bel, Aida Sabaté-Llobera, Susana Rossi-Seoane, Gabriel Reynés-Llompart, José Luis Vercher Conejero, Mònica Cos-Domingo, Pablo Moreno-Llorente, Manuel Pérez-Maraver, Montserrat Cortés-Romera, Cristina Gámez Cenzano
Journal: Clinical Nuclear Medicine (2018)

Medullary thyroid carcinoma (MTC) is a rare malignancy. Location of residual, recurrent, or metastatic disease is crucial to treatment management and outcome. We aimed to evaluate the use of F-FDG PET/CT in localizing MTC foci in patients with biochemical relapse.This is a retrospective cohort study. Review of 51 FDG PET/CT studies of 45 patients referred to restage MTC due to increased calcitonin (Ctn) and carcinoembryonic antigen (CEA) values at follow-up. FDG PET/CT diagnostic accuracy was determined through a patient-based analysis, using histology as criterion standard when available, or other imaging studies and clinical follow-up otherwise (mean, 4 years).There were 25 positive scans. Sensitivity, specificity, positive and negative predictive values, diagnostic accuracy, and positive likelihood ratio were 66.7%, 83.3%, 88.0%, 57.7%, 72.5%, and 4.0, respectively. Using a Ctn cutoff of 1000 pg/mL, sensitivity increased to 76.9%. There were significant differences of Ctn and CEA values between positive and negative FDG PET/CT (P < 0.05). Regarding true-positive studies, average SUVmax comparing locoregional and metastatic disease was at the limit of significance (P = 0.046).PET/CT can be useful to restage patients with biochemical relapse of MTC, with a better performance in higher Ctn levels. Its high positive predictive value (88%) may impact in the therapeutic management, although its low negative predictive value (57.7%) makes strict follow-up mandatory in examinations without pathologic findings.
Multi‐organ dysfunction/injury on admission identifies acute heart failure patients at high risk of poor outcome
Authors: Robert Zymliński, Mateusz Sokolski, Jan Biegus, Paweł Siwołowski, Sylwia Nawrocka‐Millward, Justyna M. Sokolska, Marta Dudkowiak, Dominik Marciniak, John Todd, Ewa A. Jankowska, Waldemar Banasiak, Piotr Ponikowski
Journal: European Journal of Heart Failure (2018)
Increased antitumour activity and extravasation of immune checkpoint inhibitor due to hyaluronidase expressed from oncolytic adenovirus VCN-01 and generation of new viruses with improved hyaluronidase activity
Authors: M. Farrera, A. Mato-Berciano, S. Morgado, R. Moreno, J. de Sostoa Pomes, R. Alemany, M. Bazan-Peregrino
Journal: Annals of Oncology (2018)

Background: Combined used of virotherapy and immune checkpoint inhibitors (ICI) has arisen as a promising treatment for cancer. VCN-01 is a selective oncolytic adenovirus (OAd) with hyaluronidase activity that can enhance the activity of ICIs as it can potentially increase their extravasation. The aims of this project are: to demonstrate that VCN01 is able to increase both ICI extravasation and antitumour activity, and to generate new OAds with potentiated hyal-related mechanisms of action. Methods: OAds were i.v. administered in NP-18 (PDL1+; human pancreatic cell line) xenograft male athymic mouse model. Fluorescently labelled anti-PD-L1 was used to assess its extravasation. TRAMP-C2 tumours were subcutaneously implanted in C57BL/6J. VCN01 was injected i.t alone or in combination with 5 doses i.p. of anti-PD-L1 antibody. New OAds were generated with two different hyalorunidase genes (A and B). Different locations within the viral genome and different splicing acceptors to express these hyaluronidases were tested. Results: VCN-01 significantly increased the extravasation of anti-PD-L1 antibodies into NP-18 tumours compared to a control oncolytic adenovirus ICOVIR15K and to control group, due to VCN-01’s capability to express hyaluronidase. Administration of VCN-01 within subcutaneous TRAMP-C2 tumours, alone or in combination with anti-PD-L1 antibody showed anti-tumour activity when compared with PBS or anti-PD-L1 treated tumours. The combined treatment showed increased anti-tumour activity, but not significant, when compared to VCN-01 alone. Most of the new hyal-OAds presented attenuated tumour cytotoxicity in vitro compared to VCN-01 except from VCNA and VCNB. Moreover, both candidates presented significantly higher hyalorunidase activity in vitro at 24h and 72h post infection compared to VCN-01. Conclusions: VCN-01 enhances the extravasation of anti-PD-L1 to tumours. Combination of VCN-01 with anti-PD-L1 antibody significantly delayed tumour growth over time when compared with PBS or anti-PD-L1 treated tumours. VCNA and VCNB maintain tumour cytotoxicity and show higher hyaluronidase activity compared to VCN-01. Legal entity responsible for the study: VCN Biosciences S.L. Funding: VCN Biosciences S.L. Disclosure: M. Farrera, A. Mato-Berciano, S. Morgado, S.L. M. Bazan-Peregrino: Employed by VCN Biosciences S.L. and presenting a company's product. R. Alemany: Founder and part of advisory board of VCN Biosciences. All other authors have declared no conflicts of interest.
<i>Notes from the Field</i>: Infections After Receipt of Bacterially Contaminated Umbilical Cord Blood–Derived Stem Cell Products for Other Than Hematopoietic or Immunologic Reconstitution — United States, 2018
Authors: Kiran M. Perkins, Samantha Spoto, Danielle A. Rankin, Nychie Q. Dotson, Mary Malarkey, Melissa Mendoza, Lorrie McNeill, Paige Gable, Krista M. Powell
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

On September 17, 2018, the Texas Department of State Health Services received notification of Enterobacter cloacae and Citrobacter freundii bloodstream infections in three patients who had received injections or infusions of non-FDAâapproved umbilical cord blood-derived stem cell products processed by Genetech, Inc., and distributed by Liveyon, LLC, for other than hematopoietic or immunologic reconstitution at an outpatient clinic on September 12.