tbuckley/cabot-search huggingface dataset:
Interest and potential of genetically engineered cord blood derived T cells for cancer immunotherapy
Authors: C. Marton, P. Mercier-Letondal, M. Deschamps, C. Ferrand, O. Adotevi, C. Borg, J. Galaine, Y. Godet
Journal: Annals of Oncology (2018)

Background: The use of engineered T cells has proven to be successful in the field of cancer therapy. In vivo persistence of these genetically redirected T cells, which depends on their differentiation profile, plays a central role in the achievement of treatment efficacy. Indeed, less differentiated T cells proliferate and persist longer in vivo compared to their more differentiated counterparts, while having functional antitumor capacities. In this view, cord blood derived T cells display a more naïve phenotype compared to peripheral blood derived T cells. Hence, cord blood could be used as a source of T cells in order to generate gene-modified cancer-targeting cells able to persist in vivo, with the ability to ensure immunosurveillance in treated patients. Methods: Cord blood derived T cells were isolated, activated and cultured with IL-2 or IL-7 and IL-15, before a retroviral transduction with a vector encoding a TCR targeting HPV16-E7/HLA-DR4. Transgenic T cell functional capacities were then evaluated by flow cytometry. The differentiation profile of cord blood derived T cells, genetically redirected or not and cultured in different conditions, were also analyzed. Results: The IL-7 and IL-15 culture condition resulted in the generation of gene-modified T cells maintaining a higher transgenic TCR expression over time compared with the IL-2 culture condition. Functional assays revealed that genetically redirected T cells cultured in both conditions were reactive against HLA-DR4+ BLCL pulsed with an E7-derived peptide. Both T cell products lead to comparable interferon-γ, tumor necrosis factor-α and interleukine-2 secretion. These results are consistent with the fact that no outstanding difference was detected between both culture conditions regarding transduced and untransduced T cell differentiation profile. Conclusions: In conclusion, we were able to generate cord blood derived transgenic T cells which were specific for an HPV16-E7 peptide, with a higher TCR expression over time when cultured with IL-7 and IL-15. Our study supports that cord blood units could be used as a source of T cells to develop cost-reducing and easy to access adoptive cancer immunotherapy. Legal entity responsible for the study: UMR1098: INSERM, EFS BFC, Univ. Bourgogne Franche-Comté. Funding: This work was supported by the Ligue Nationale Contre le Cancer, and by the MiMedi project funded by BPI France (grant No. DOS0060162/00) and the European Union through the European Regional Development Fund of the Region Bourgogne-Franche-Comte (grant No. FC0013440). C.M. has benefited from a fellowship from Nancy Regional University Hospital. Disclosure: All authors have declared no conflicts of interest.
Alternative Acts: Oncogenic Splicing of Steroidogenic Enzymes in Prostate Cancer
Authors: Elahe A. Mostaghel
Journal: Clinical Cancer Research (2018)

Castration-resistant prostate cancer is characterized by loss of the androgen inactivation enzyme HSD17B2, emphasizing the importance of intratumoral androgens in tumor progression. Inactive isoforms generated by alternative splicing destabilize the wild-type enzyme, adding steroidogenesis to other prostate cancer drivers that undergo oncogenic splicing, highlighting aberrant splicing as a therapeutic target.See related article by Gao et al., p. 1291.
Abstract 10302: Brachial Artery Intima-Media Thickness and Grayscale Texture Changes in Peripheral Arterial Disease Patients Receiving Supervised Exercise Training in the PROPEL Randomized Clinical Trial
Authors: Jack Berroug, Claudia E Korcarz, Carol K Mitchell, Mary M McDermott, James H Stein
Journal: Circulation (2018)

Background: In individuals with peripheral artery disease (PAD), supervised treadmill exercise improves walking performance. We performed an exploratory analysis to evaluate the biological effects ...
Prevalence of human papillomavirus DNA and p16INK4a in penile cancer and penile intraepithelial neoplasia: a systematic review and meta-analysis
Authors: Tina Bech Olesen, Freja Lærke Sand, Christina Louise Rasmussen, Vanna Albieri, Birgitte Grønkær Toft, Bodil Norrild, Christian Munk, Susanne Krüger Kjær
Journal: The Lancet Oncology (2018)
Metabolic regulation of dermal fibroblasts contributes to skin extracellular matrix homeostasis and fibrosis
Authors: Xiao Zhao, Pamela Psarianos, Laleh Soltan Ghoraie, Kenneth Yip, David Goldstein, Ralph Gilbert, Ian Witterick, Hilary Pang, Ali Hussain, Ju Hee Lee, Justin Williams, Scott V. Bratman, Laurie Ailles, Benjamin Haibe-Kains, Fei-Fei Liu
Journal: Nature Metabolism (2018)
The Epidemiology of Sexual Partnerships—It’s Complicated
Authors: Ashleigh R. Tuite, David N. Fisman, Minttu M. Rönn
Journal: JAMA Network Open (2018)

Catherine H. Mercer, PhD; Kyle G. Jones, MSc; Rebecca S. Geary, PhD; Nigel Field, PhD; Clare Tanton, PhD; Sarah Burkill, MSc; Soazig Clifton, MSc; Pam Sonnenberg, PhD; Kirstin R. Mitchell, PhD; Kirsten Gravningen, PhD; Anne M. Johnson, MD
CHECK'UP: A prospective cohort study to identify predictive factors of response and mechanisms of resistance to PD-1 and PD-L1 antagonists
Authors: F. Penault-Llorca, C. Caux, S. Depil, C. Le Tourneau, M. Pérol, C. Robert, V. Soumelis, D. Couch, N. Isambert, Y. Fernandez, T. Filleron, G. Vassal
Journal: Annals of Oncology (2018)

Background: Immune checkpoint blockade represents a major breakthrough in cancer therapy with recent approvals of PD-1 or PD-L1 antagonists in a range of indications. Phase 3 studies have demonstrated response rates varying from 13% (head and neck squamous cell carcinoma [HNSCC]) to 40% (melanoma) in sensitive diseases, and impressively durable responses in individual patients. The overall rate of response remains relatively low however. Even in immune-sensitive diseases such as melanoma the majority of tumours do not respond to immunotherapy alone and most tumours will eventually develop resistance to the treatment. Furthermore, although PD-1/PD-L1 antagonists are generally well tolerated, a small but significant number of patients experience severe immune-related toxicity, the risk factors of which are poorly understood. Identifying which patients will most benefit from PD-1/PD-L1 antagonist therapy and the mechanisms of resistance are of critical importance for clinicians. The CHECK'UP trial aims to address this question by studying approved PD-1/PD-L1 antagonist treatment across three cancer indications: melanoma, non-small cell lung cancer (NSCLC) and HNSCC. Trial design: This prospective, multicentre cohort trial will study 670 patients in 3 parallel groups set to receive one of the single agent PD-1 or PD-L1 antagonists authorised for use in France as standard care for melanoma, NSCLC or HNSCC. Clinical and biological sample data (tumour, blood, microbiome) collected at study entry and throughout the treatment period will be analysed to identify potential response biomarkers. Patients will be followed for 5 years. A penalized logistic regression model will be used to identify associations between different parameters and response to treatment in a training cohort, made up of the first patients included, and to develop a predictive response signature for each indication. The performance of this signature will then be tested in an independent validation cohort comprised of the remaining patients. Mechanisms of primary and acquired resistance, occurrence of long-term treatment related toxicity and a cost/benefit assessment of treatment in a real-life setting will also be explored. Legal entity responsible for the study: UNICANCER. Funding: Fondation ARC pour la recherche sur le cancer. Disclosure: All authors have declared no conflicts of interest.
Alan Edward Andrew Ridgway
Authors: Ian Christopher Lloyd
Journal: BMJ (2018)

Alan Edward Andrew Ridgway attended Downside School, from where he won a place to study medicine at Jesus College, Cambridge, in 1958. He qualified in 1964 after undertaking his clinical studies at the London Hospital in Whitechapel. After senior house officer and registrar posts in ophthalmology at Oxford Eye Hospital and Cardiff Royal Infirmary, he was appointed senior registrar to Birmingham and Midland Eye Hospital in 1970. It was there that he began to develop his interests in the surgical management of conditions mainly affecting the anterior segment of the eye, including cataract, corneal disease, and glaucoma.

He started his consultant career at Manchester Royal Eye Hospital in April 1974. This included regular outreach clinics in Trafford General Hospital, Stretford Memorial Hospital, and Altrincham General Hospital.

Alan brought with him huge reserves of energy, drive, and determination and set about making his mark. At that time (1974) Manchester Royal Eye Hospital had a proud history and a huge patient base, but had perhaps been underperforming on the national stage for some years.

Alan was an immensely skilled surgeon and a strong proponent of what was at the time innovative capsule preserving (extracapsular) cataract and intraocular lens implant surgery. Extracapsular surgery evolved in the 1990s via the use of ultrasonic phacoemulsification. Late …
Prognostic implications of markers of the metabolic phenotype in human cutaneous melanoma
Authors: L. Nájera, M. Alonso‐Juarranz, M. Garrido, C. Ballestín, L. Moya, M. Martínez‐Díaz, R. Carrillo, A. Juarranz, F. Rojo, J.M. Cuezva, J.L. Rodríguez‐Peralto
Journal: British Journal of Dermatology (2018)

Reprogramming of energy metabolism to enhanced aerobic glycolysis has been defined as a hallmark of cancer. To investigate the role of the mitochondrial proteins, β‐subunit of the H+‐ATP synthase (β‐F1‐ATPase), and heat‐shock protein 60 (HSP60), and the glycolytic markers, glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) and pyruvate kinase M2 (PKM2), as well as the bioenergetic cellular (BEC) index, in melanoma progression. The expression of energy metabolism proteins was assessed on a set of different melanoma cells representing the natural biological history of the disease: primary cultures of melanocytes, radial (WM35) and vertical (WM278) growth phases, and poorly (C81‐61‐PA) and highly (C8161‐HA) aggressive melanoma cells. Cohorts of 63 melanocytic naevi, 55 primary melanomas and 35 metastases were used; and 113 primary melanoma and 33 metastases were used for validation. The BEC index was significantly reduced in melanoma cells and correlated with their aggressive characteristics. Overexpression of HSP60, GAPDH and PKM2 was detected in melanoma human samples compared with naevi, showing a gradient of increased expression from radial growth phase to metastatic melanoma. The BEC index was also significantly reduced in melanoma samples and correlated with worse overall and disease‐free survival; the multivariate Cox analysis showed that the BEC index (hazard ratio 0·64; 95% confidence interval 0·4–1·2) is an independent predictor for overall survival. A profound alteration in the mitochondrial and glycolytic proteins and in the BEC index occurs in the progression of melanoma, which correlates with worse outcome, supporting that the alteration of the metabolic phenotype is crucial in melanoma transformation.
Ductular Reaction Cells Display an Inflammatory Profile and Recruit Neutrophils in Alcoholic Hepatitis
Authors: Beatriz Aguilar‐Bravo, Daniel Rodrigo‐Torres, Silvia Ariño, Mar Coll, Elisa Pose, Delia Blaya, Isabel Graupera, Luis Perea, Júlia Vallverdú, Teresa Rubio‐Tomás, Laurent Dubuquoy, Carolina Armengol, Antonio Lo Nigro, Peter Stärkel, Philippe Mathurin, Ramon Bataller, Joan Caballería, Juan José Lozano, Pere Ginès, Pau Sancho‐Bru
Journal: Hepatology (2018)

Chronic liver diseases are characterized by the expansion of ductular reaction (DR) cells and the expression of liver progenitor cell (LPC) markers. In alcoholic hepatitis (AH), the degree of DR expansion correlates with disease progression and short‐term survival. However, little is known about the biological properties of DR cells, their impact on the pathogenesis of human liver disease, and their contribution to tissue repair. In this study, we have evaluated the transcriptomic profile of DR cells by laser capture microdissection in patients with AH and assessed its association with disease progression. The transcriptome analysis of cytokeratin 7‐positive (KRT7 + ) DR cells uncovered intrinsic gene pathways expressed in DR and genes associated with alcoholic liver disease progression. Importantly, DR presented a proinflammatory profile with expression of neutrophil recruiting C‐X‐C motif chemokine ligand (CXC) and C‐C motif chemokine ligand chemokines. Moreover, LPC markers correlated with liver expression and circulating levels of inflammatory mediators such as CXCL5. Histologically, DR was associated with neutrophil infiltration at the periportal area. In order to model the DR and to assess its functional role, we generated LPC organoids derived from patients with cirrhosis. Liver organoids mimicked the transcriptomic and proinflammatory profile of DR cells. Conditioned medium from organoids induced neutrophil migration and enhanced cytokine expression in neutrophils. Likewise, neutrophils promoted the proinflammatory profile and the expression of chemokines of liver organoids. Conclusion : Transcriptomic and functional analysis of KRT7 + cells indicate that DR has a proinflammatory profile and promote neutrophil recruitment. These results indicate that DR may be involved in the liver inflammatory response in AH, and suggest that therapeutic strategies targeting DR cells may be useful to mitigate the inflammatory cell recruitment in AH.
Systemic Mastocytosis, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology
Authors: Jason Gotlib, Aaron T. Gerds, Prithviraj Bose, Mariana C. Castells, Michael W. Deininger, Ivana Gojo, Krishna Gundabolu, Gabriela Hobbs, Catriona Jamieson, Brandon McMahon, Sanjay R. Mohan, Vivian Oehler, Stephen Oh, Eric Padron, Philip Pancari, Nikolaos Papadantonakis, Animesh Pardanani, Nikolai Podoltsev, Raajit Rampal, Erik Ranheim, Lindsay Rein, David S. Snyder, Brady L. Stein, Moshe Talpaz, Swapna Thota, Martha Wadleigh, Katherine Walsh, Mary Anne Bergman, Hema Sundar
Journal: Journal of the National Comprehensive Cancer Network (2018)

Mastocytosis is a group of heterogeneous disorders resulting from the clonal proliferation of abnormal mast cells and their accumulation in the skin and/or in various extracutaneous organs. Systemic mastocytosis is the most common form of mastocytosis diagnosed in adults, characterized by mast cell infiltration of one or more extracutaneous organs (with or without skin involvement). The identification of KIT D816V mutation and the emergence of novel targeted therapies have significantly improved the diagnosis and treatment of systemic mastocytosis. However, certain aspects of clinical care, particularly the diagnosis, assessment, and management of mediator-related symptoms continue to present challenges. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with systemic mastocytosis.
Abstract 050: Fine-mapping and Bioinformatics Characterization of QT Interval Loci in African Americans: The Population Architecture Using Genomics and Epidemiology (PAGE) Study
Authors: Christy L Avery, Praveen Sethupathy, Steven Buyske, Q. C He, Dan Y Lin, Dan E Arking, David Duggan, Ervin R Fox, Garnet Anderson, Ewa Deelman, Megan Fesinmeyer, Lucia A Hindorff, Janina Jeff, Liviu Klein, Kristen K Patton, Ralph Shohet, Nona Sotoodehnia, Alicia M Young, Teri A Manolio, Karen L Mohlke, Eric A Whitsel, Kari E North
Journal: Circulation (2012)

The QT interval (QT) is a heritable trait and its prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Most genetic studies of QT have examined populations of European ancestry, although the increased genetic diversity in populations of African descent provides opportunity for fine-mapping, which can help narrow association signals and identify candidates for functional characterization. We examined whether eleven previously identified QT loci comprising 6,681 variants on the Illumina Metabochip array were associated with QT in 7,516 African American participants from the Atherosclerosis Risk in Communities study and Women’s Health Initiative clinical trial. Among associated loci, we used conditional analyses and queried bioinformatics databases to identify and functionally categorize signals. We identified nine of the eleven QT loci in African American populations ( P &lt;0.0045 under an additive genetic model adjusting for ancestry and demographic characteristics: NOS1AP, ATP1B1, SCN5A, SLC35F1, KCNH2, KCNQ1, LITAF, NDRG4, and RFFL ). We also identified two independent secondary signals in NOS1AP and ATP1B1 ( P &lt; 7.4x10 −6 ). Conditional analyses adjusting for published loci in European populations demonstrated that eight of these eleven SNPs (nine primary; two secondary) were independent of previously reported SNPs. We then performed the first bioinformatics-based functional characterization of QT loci using the eleven primary and secondary variants and SNPs in strong LD (r 2 &gt; 0.5) among these African American participants. Only the SCN5A locus included a non-synonymous coding variant (rs1805124, H558R, r 2 = 0.7 with primary SNP rs9871385, P = 4.7x10 −4 ). The remaining ten loci harbored variants located exclusively within non-coding regions. Specifically, three contained SNPs within candidate long-range regulatory elements in human cardiomyocytes, five were in or near annotated promoter regions, and the remaining two were in un-annotated, but highly conserved non-coding elements. Several of the QT risk alleles at these SNPs significantly alter the predicted binding affinity for transcription factors, such as TBX5 and AhR, which have been previously implicated in cardiac formation and function. In summary, the findings provide compelling evidence that the same genes influence variation in QT across global populations and that additional, independent signals exist in African Americans. Moreover, of those SNPs identified as strong candidates for functional evaluation, the majority implicate gene regulatory dysfunction in QT prolongation.
Tac1-Expressing Neurons in the Periaqueductal Gray Facilitate the Itch-Scratching Cycle via Descending Regulation
Authors: Zheng-Run Gao, Wen-Zhen Chen, Ming-Zhe Liu, Xiao-Jun Chen, Li Wan, Xin-Yan Zhang, Lei Yuan, Jun-Kai Lin, Meng Wang, Li Zhou, Xiao-Hong Xu, Yan-Gang Sun
Journal: Neuron (2018)
Longer Term Follow up of the Â Randomized Phase III Trial SWOG S0777: Bortezomib, Lenalidomide and Dexamethasone Vs. Lenalidomide and Dexamethasone in Patients (Pts) with Previously Untreated Multiple Myeloma without an Intent for Immediate Autologous Stem Cell Transplant (ASCT)
Authors: Brian GM Durie, Antje Hoering, Rachael Sexton, Muneer H. Abidi, Joshua Epstein, S. Vincent Rajkumar, Angela Dispenzieri, Stephen P. Kahanic, Mohan C. Thakuri, Frederic J. Reu, Christopher M. Reynolds, Robert Z. Orlowski, Bart Barlogie
Journal: Blood (2018)
Striving for Evidence-Based Postoperative Opioid Prescribing While Optimizing Perioperative Pain Management—Shifting to Conservative Prescribing
Authors: Jennifer M. Hah
Journal: JAMA Network Open (2018)

The study by Mark et al 1 presents the findings of a case-control cohort study of gynecologic oncology patients receiving ambulatory or minimally invasive surgery highlighting the effects of an ultrarestrictive opioid prescription protocol (UROPP).All patients receiving ambulatory or minimally invasive surgery were not prescribed opioids at hospital discharge unless they required more than 5 doses of oral or intravenous opioids in the 24 hours prior to discharge.Patients receiving laparotomy were prescribed either a 3-or 6-day supply of opioids at discharge based on whether they similarly required more than 5 opioid doses in the 24 hours prior to discharge.Overall, there were significant decreases in the mean number of opioid tablets prescribed at discharge comparing cases with controls after laparotomy (12.1 vs 43.6 tablets; P < .001),after major laparoscopic or robotic operations (1.3 vs 38.4 tablets; P < .001),and after ambulatory surgery (0.2 vs 13.9 tablets; P < .001).In the context of an overall 89% reduction in dispensed opioids, the UROPP did not increase the number of refill requests within the first 30 days, postoperative visit pain scores in the first 2 weeks, or postoperative complications.The authors described a promising strategy for markedly decreasing postoperative opioid prescribing without increasing pain.These actions greatly limit the potential for diversion and opioid misuse that can result from opioid overprescribing.In the context of the current opioid crisis, much attention is likely to be focused on the opioid prescribing aspects of the protocol.However, it is important to emphasize that the protocol encompasses more than personalized opioid prescribing.
Abstract 18743: Lack of Evidence of Higher 30-day All-cause Readmission Among Older African American (vs. White) Medicare Beneficiaries Hospitalized for Heart Failure
Authors: Ali Ahmed, Shervin AhmadBeygi, Helen Sheriff, Charity Morgan, Sijian Zhang, Ross D Fletcher, Marc Blackman, Wen-Chih Wu, Javed Butler, Gregg C Fonarow, Prakash Deedwania, Michel White, Wilbert S Aronow, Richard M Allman
Journal: Circulation (2015)

Background: A recent study using administrative data suggested that older African American heart failure (HF) patients may have higher 30-day readmissions than whites do (PMC3332042). However, to what extent these associations are intrinsic remains unclear. Methods: Of the 8042 Medicare beneficiaries hospitalized for HF and discharged alive from 106 U.S. hospitals (1998-2001), 1994 were African American and 6048 were white. Using propensity scores for being an African American, we assembled a matched cohort of 1799 pairs of African American and white patients balanced on 33 baseline characteristics. Results: Matched patients (N=3598) had a mean age of 74 (±11) years with no racial difference (p=0.599). 30-day all-cause readmission occurred in 20% and 22% of matched African Americans and whites, respectively (HR, 0.89; 95% CI, 0.77-1.03; p=0.110; Figure, left panel). In the pre-match cohort (N=8042), African Americans were younger (77 v 72 years for whites; p&lt;0.001) and had similar unadjusted 30-day all-cause readmission (20% v. 20% for whites; p=0.075), but had significantly lower risk when adjusted for age and sex (HR, 0.87; 95% CI, 0.77-0.98; p=0.018; Figure, right panel) but not for propensity scores (HR, 0.90; 95% CI, 0.80-1.02; p=0.101). Among matched patients, race had no association with 30-day HF readmission or all-cause mortality. Conclusions: Findings from our propensity-matched study suggest that in a cohort of hospitalized African American and white HF patients who were balanced on 33 baseline characteristics, race had no independent association with 30-day all-cause or HF readmissions or all-cause mortality.
Endoscopic technique for closure of a large gastric tube perforation by using endoclips with line-assisted complete closure
Authors: Masaki Ominami, Yasuaki Nagami, Chieko Tanaka, Taishi Sakai, Shusei Fukunaga, Toshio Watanabe, Yasuhiro Fujiwara
Journal: Endoscopy (2018)

Endoscopic submucosal dissection (ESD) is an acceptable treatment for gastric tube cancer after an esophagectomy [1]. However, treatment of lesions on the suture line is difficult and may cause perforations. It is sometimes difficult to close a large perforation with endoclips. We report an endoscopic technique that enabled the closure of a large perforation by using the line-assisted complete closure (LACC) method [2] [3] [4] [5].
OA12 A Phase I Study of Novel Bcl-2/Bcl-xL Inhibitor APG-1252 in Patients with Advanced SCLC or Other Solid Tumor
Authors: Y. Wu, N.J. Lakhani, M. Boyer, Q. Zhou, D.W. Rasco, Y. Huang, L. Men, Y. Li, Z. Xia, H. Wang, J. Ji, B. Lu, Z. He, Q. Dong, D. Yang, Y. Zhai
Journal: Journal of Thoracic Oncology (2018)