tbuckley/cabot-search huggingface dataset:
Share research profits with NHS trusts to encourage innovation, says NHS Confederation
Authors: Gareth Iacobucci
Journal: BMJ (2017)

Profits from new medical discoveries could be shared with the NHS trusts most heavily involved in their development to encourage more NHS institutions to participate in research, the NHS Confederation has said.

To fulfil the promise of the government’s life sciences industrial strategy, launched this week, the confederation’s chief executive said that the NHS must be supported, encouraged, and resourced to play its part in spearheading new discoveries. Writing in The Telegraph ,1 Niall Dickson said that a key part of this was creating the right conditions to encourage NHS institutions to take part in research and innovation.

Citing recent plans where national leaders have allowed NHS trusts to benefit financially …
The Hyperpolarization-Activated Cyclic Nucleotide–Gated Channels: from Biophysics to Pharmacology of a Unique Family of Ion Channels
Authors: Laura Sartiani, Guido Mannaioni, Alessio Masi, Maria Novella Romanelli, Elisabetta Cerbai
Journal: Pharmacological Reviews (2017)

Hyperpolarization-activated, cyclic nucleotide–gated (HCN) channels are important members of the voltage-gated pore loop channels family. They show unique features: they open at hyperpolarizing potential, carry a mixed Na/K current, and are regulated by cyclic nucleotides. Four different isoforms have been cloned (HCN1–4) that can assemble to form homo- or heterotetramers, characterized by different biophysical properties. These proteins are widely distributed throughout the body and involved in different physiologic processes, the most important being the generation of spontaneous electrical activity in the heart and the regulation of synaptic transmission in the brain. Their role in heart rate, neuronal pacemaking, dendritic integration, learning and memory, and visual and pain perceptions has been extensively studied; these channels have been found also in some peripheral tissues, where their functions still need to be fully elucidated. Genetic defects and altered expression of HCN channels are linked to several pathologies, which makes these proteins attractive targets for translational research; at the moment only one drug (ivabradine), which specifically blocks the hyperpolarization-activated current, is clinically available. This review discusses current knowledge about HCN channels, starting from their biophysical properties, origin, and developmental features, to (patho)physiologic role in different tissues and pharmacological modulation, ending with their present and future relevance as drug targets.
CD73 Promotes Resistance to HER2/ErbB2 Antibody Therapy
Authors: Martin Turcotte, David Allard, Deepak Mittal, Yacine Bareche, Laurence Buisseret, Vinu José, Sandra Pommey, Vincent Delisle, Sherene Loi, Heikki Joensuu, Pirkko-Liisa Kellokumpu-Lehtinen, Christos Sotiriou, Mark J. Smyth, John Stagg
Journal: Cancer Research (2017)

Expression of the ectonucleotidase CD73 by tumor cells, stromal cells, and immune cells is associated in cancer with immune suppression. In this study, we investigated the role of CD73 on the activity of the anti-HER2/ErbB2 monoclonal antibody (mAb) trastuzumab. In a prospective, randomized phase III clinical trial evaluating the activity of trastuzumab, high levels of CD73 gene expression were associated significantly with poor clinical outcome. In contrast, high levels of PD-1 and PD-L1 were associated with improved clinical outcome. In immunocompetent mouse models of HER2/ErbB2-driven breast cancer, CD73 expression by tumor cells and host cells significantly suppressed immune-mediated responses mediated by anti-ErbB2 mAb. Furthermore, anti-CD73 mAb therapy enhanced the activity of anti-ErbB2 mAb to treat engrafted or spontaneous tumors as well as lung metastases. Gene ontology enrichment analysis from gene-expression data revealed a positive association of CD73 expression with extracellular matrix organization, TGFβ genes, epithelial-to-mesenchymal transition (EMT) transcription factors and hypoxia-inducible-factor (HIF)-1 gene signature. Human mammary cells treated with TGFβ or undergoing EMT upregulated CD73 cell-surface expression, confirming roles for these pathways. In conclusion, our findings establish CD73 in mediating resistance to trastuzumab and provide new insights into how CD73 is regulated in breast cancer. Cancer Res; 77(20); 5652-63. ©2017 AACR.
Over 65s flu vaccination programme was ineffective, data show
Authors: Nigel Hawkes
Journal: BMJ (2017)

Last winter’s flu vaccination programme in the over-65s was ineffective, according to new data from Public Health England (PHE).1

Provisional estimates show that for all age groups combined, the vaccine effectiveness against influenza A and B was 39.8% (85% CI 23.1 to 52.8). But for the over-65s, the principal target of the campaign, effectiveness was −6.3% (CI −95.5 to 42.0).

PHE said that the failure of the campaign in older people meant that better vaccines were needed for them. “It is increasingly recognised that the current generation of flu vaccines often work less well in the elderly, likely because of factors such as the weaker immune systems in this population,” a statement said in response to questions from The BMJ . “Nonetheless, over a number of years, …
Reply
Authors: Bing‐liang Lin
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. Thank you very much to the readers and editors for their constructive questions and valuable suggestions in response to our article. None of the patients in our study had received any antiviral treatment before enrollment; therefore, the confounding effect of lamivudine on entecavir is not an issue. The comparison of subsequent viral load between the two groups was not included in the original protocol, because the 24 weeks of follow‐up is relatively short. In addition, studies have shown that entecavir is a highly effective antivirus with a low resistance rate of 1.2% over 5 years in nucleoside‐naïve patients.1 Nevertheless, we concede that this could be a limitation that we would definitely improve in further studies. As for the antibiotic treatment, it was difficult for us to develop a standard protocol for patients with infections, because infection sites and pathogens could vary. Most hepatitis B virus–related acute‐on‐chronic liver failure (ACLF) patients suffered from one or more complications of infection, such as spontaneous bacterial peritonitis, bile tract infection, lung infection, and digestive tract infection, and the common pathogens included G− bacilli, candida, aspergillus, and so on. We selected antibiotics based primarily on the results of the pathogens' culture and drug sensitivity. If the drug sensitivity results were not available, antibiotics were administrated according to clinical experience. Studies have shown that mesenchymal stem cells (MSCs) adopt immunomodulatory properties by way of the paracrine pathway.3 In addition, our study shows that MSC infusion could upgrade the frequency of natural killer cells and KIR3DL1 expression (data not yet published). Therefore, we speculated that immunomodulation could be the potential mechanism of MSCs reducing infection in ACLF patients.
The brain-computer interface researcher’s questionnaire: from research to application
Authors: M. J. Vansteensel, G. Kristo, E. J. Aarnoutse, N. F. Ramsey
Journal: Brain-Computer Interfaces (2017)

Over the last decades, the brain-computer interface (BCI) research field has seen steep progress and now recognizes several types of applications, each with its own target population. Despite this evolution, BCIs seem to remain a research application, and are hardly used in daily life at home, work or in the clinic. Therefore, as a field, we need to take the next step and make sure that we develop BCIs that can, and will, be used outside the laboratory. To this purpose, BCI researchers worldwide were approached by email with the request to fill out a questionnaire, aimed at laying out the near and far future of the BCI field. We show that researchers are quite optimistic about the feasibility of having BCIs applied in real life. Also, we identify the hurdles that need to be taken before these applications become commercial products and the research activities required to accomplish this.
Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury
Authors: Christopher R. Heery, Claudia Palena, Sheri McMahon, Renee N. Donahue, Lauren M. Lepone, Italia Grenga, Ulrike Dirmeier, Lisa Cordes, Jenn Marté, William Dahut, Harpreet Singh, Ravi A. Madan, Romaine I. Fernando, Duane H. Hamilton, Jeffrey Schlom, James L. Gulley
Journal: Clinical Cancer Research (2017)

Purpose: The transcription factor brachyury has been shown in preclinical studies to be a driver of the epithelial-to-mesenchymal transition (EMT) and resistance to therapy of human tumor cells. This study describes the characterization of a Modified Vaccinia Ankara (MVA) vector-based vaccine expressing the transgenes for brachyury and three human costimulatory molecules (B7.1, ICAM-1, and LFA-3, designated TRICOM) and a phase I study with this vaccine.Experimental Design: Human dendritic cells (DC) were infected with MVA-brachyury-TRICOM to define their ability to activate brachyury-specific T cells. A dose-escalation phase I study (NCT02179515) was conducted in advanced cancer patients (n = 38) to define safety and to identify brachyury-specific T-cell responses.Results: MVA-brachyury-TRICOM-infected human DCs activated CD8+ and CD4+ T cells specific against the self-antigen brachyury in vitro No dose-limiting toxicities were observed due to vaccine in cancer patients at any of the three dose levels. One transient grade 3 adverse event (AE) possibly related to vaccine (diarrhea) resolved without intervention and did not recur with subsequent vaccine. All other AEs related to vaccine were transient and ≤grade 2. Brachyury-specific T-cell responses were observed at all dose levels and in most patients.Conclusions: The MVA-brachyury-TRICOM vaccine directed against a transcription factor known to mediate EMT can be administered safely in patients with advanced cancer and can activate brachyury-specific T cells in vitro and in patients. Further studies of this vaccine in combination therapies are warranted and planned. Clin Cancer Res; 23(22); 6833-45. ©2017 AACR.
Vitamin D Supplementation and Cardiovascular Disease Risk
Authors: Panagiotis Anagnostis, Stavroula A. Paschou, Dimitrios G. Goulis
Journal: JAMA Cardiology (2017)

To the Editor We read with great interest the results of the randomized, double-blind, placebo-controlled trial by Scragg et al.1 The authors reported that monthly vitamin D supplementation (at the dose of 100 000 IU) did not reduce the risk of cardiovascular disease (CVD) events.
Cytoprotective activated protein C averts Nlrp3 inflammasome–induced ischemia-reperfusion injury via mTORC1 inhibition
Authors: Sumra Nazir, Ihsan Gadi, Moh’d Mohanad Al-Dabet, Ahmed Elwakiel, Shrey Kohli, Sanchita Ghosh, Jayakumar Manoharan, Satish Ranjan, Fabian Bock, Ruediger C. Braun-Dullaeus, Charles T. Esmon, Tobias B. Huber, Eric Camerer, Chris Dockendorff, John H. Griffin, Berend Isermann, Khurrum Shahzad
Journal: Blood (2017)
scCO2浸透伝導ポリマーフィルムからのアセチルコリンの電気化学的に誘導した放出は神経学的に正常なSH‐SY5Y細胞で細胞内Ca2+シグナリングを誘導する
Authors: Loffler Susanne, Seyock Silke, Nybom Rolf, B Jacobson Gunilla, Richter-Dahlfors Agneta
Journal: Journal of Controlled Release (2016)
Long‐term survival of beta thalassemia major patients treated with hematopoietic stem cell transplantation compared with survival with conventional treatment
Authors: Giovanni Caocci, Maria Grazia Orofino, Adriana Vacca, Antonio Piroddi, Eugenia Piras, Maria Carmen Addari, Rossella Caria, Maria Paola Pilia, Raffaella Origa, Paolo Moi, Giorgio La Nasa
Journal: American Journal of Hematology (2017)

Allogeneic hematopoietic stem cell transplantation (HSCT) in thalassemia remains a challenge. We reported a single-centre case-control study of a large cohort of 516 children and adult patients treated with HSCT or blood transfusion support and iron chelation therapy; 258 patients (median age 12, range 1-45) underwent sibling (67%) or unrelated (33%) HSCT; 97 patients were adults (age ≥ 16 years). The median follow-up after HSCT was 11 years (range 1-30). The conditioning regimen was busulfan (80.6%) or treosulfan-based (19.4%). A cohort of 258 age-sex matched conventionally treated (CT) patients was randomly selected. In transplanted patients the 30-year overall survival (OS) and thalassemia-free survival (TFS) were 82.6 ± 2.7% and 77.8 ± 2.9%, compared to the OS of 85.3 ± 2.7% in CT patients (P = NS); The incidence of grade II-IV acute and chronic graft versus host disease (GvHD) was 23.6% and 12.9% respectively. The probability of rejection was 6.9%. Transplant-related mortality (TRM) (13.8%) was similar to the probability of dying of cardiovascular events in CT patients (12.2%). High-risk Pesaro score (class 3) was associated with lower OS (OR = 1.99, 95% C.I.=1.31-3.03) and TFS (OR = 1.54, 95% C.I.=1.12-2.12). In adult patients, the 23-years OS and TFS after HSCT were 70 ± 5% and 67.3 ± 5%, compared to 71.2 ± 5% of OS in CT (P = NS). Finally, treosulfan was associated with lower risk of acute GvHD (P = .004; OR = 0.28, 95% C.I.=0.12-0.67). In conclusion, the 30-year survival rate of ex-thalassemia patients after HSCT was similar to that expected in CT thalassemia patients, with the vast majority of HSCT survivors cured from thalassemia.
Concomitant 177Lu-DOTATATE and Capecitabine Therapy in Patients With Advanced Neuroendocrine Tumors
Authors: Sanjana Ballal, Madhav P. Yadav, Nishikant A. Damle, Ranjit K. Sahoo, Chandrasekhar Bal
Journal: Clinical Nuclear Medicine (2017)

Purpose The purpose of this study was to evaluate the outcome, toxicity, survival, and quality of life in patients with advanced neuroendocrine tumors. Methods One hundred sixty-seven patients were enrolled in the study. All patients underwent baseline 68 Ga-DOTANOC PET/CT scans. 177 Lu-DOTATATE therapy was administered quarterly along with oral capecitabine therapy in group 1 patients (n = 88), whereas group 2 patients (n = 79) were treated only with 177 Lu-DOTATATE. Hematologic, kidney function, liver function tests and chromogranin A levels were recorded before and after therapy at 2-week, 4-week, and 3-month intervals. Biochemical and morphological responses were assessed with the trend in chromogranin A levels and Response Evaluation Criteria in Solid Tumors 1.1 criteria, respectively. Results There was no significant difference in the hemoglobin levels after 177 Lu-DOTATATE therapy ( P = 0.4892). In most patients, there was a decrease in the platelet levels; however, all the patients had platelet counts greater than 100,000/μL with no platelet toxicity. There was no toxicity related to leukocytes. Two patients showed renal insufficiencies. No hepatotoxicity was observed in any of the patients. According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, in group 1 patients, the response was partial response in 34% of the patients, stable disease in 50.2%, and progressive disease in 6.8% versus partial response in 6.3%, stable disease in 60.9%, and progressive disease in 26.5% among group 2 patients. The median overall survival (OS) and progression-free survival (PFS) was not reached in group 1 patients. The median OS and PFS in group 2 patients were 48 months. Ki-67 tumor proliferation index was significantly associated with increased risk of disease progression. Conclusions Addition of capecitabine therapy with 177 Lu-DOTATATE therapy lengthens the OS and PFS. Patients with aggressive disease may benefit from this synergetic therapeutic approach.
Abstract 63: Reduction in Glucocorticoid Receptor Expression Attenuates Pressure Overload-induced Cardiac Hypertrophy and Promotes Heart Failure in Mice
Authors: Rongxue Wu, Maura Knapp, Mei Zheng, James K Liao
Journal: Circulation Research (2016)

Background: Left ventricular hypertrophy (LVH) is an independent risk factor for heart failure and sudden death. In addition, LVH is also a compensatory mechanism that helps the heart cope with pressure overload. Stress is considered one factor that is related to cardiac outcomes. Glucocorticoids are primary stress hormones, whose role in the heart is poorly understood. Here, we hypothesize that a reduction in the expression of the glucocorticoid receptor (GR) would decrease cardiac hypertrophy in response to pressure overload. Methods and Results: The GR homozygous mutation (GR-/-) is embryonic lethal. However, GR heterozygous mice (GR+/-) show a normal phenotype. We subjected GR+/- mice to transverse aortic constriction (TAC). At four weeks after TAC, the ratio of heart weight to tibia length increased significantly in wild-type mice (control) littermates compared with GR+/- mice. Cardiac myocyte size was also smaller in GR+/- mice vs controls, suggesting an attenuated cardiac growth response in these mice. In addition, GR+/- hearts displayed increased cell death and enhanced fibrosis in response to TAC. Cardiac function, determined by EF% and FS% (measured using the Vevo2100 imaging system), was significantly reduced in GR+/- mice compared with controls at eight weeks post-operation, while LVEDD was increased. Together, with the increased ratio of lung weight to body weight in GR+/- mice at eight weeks following TAC, this suggests an exaggerated heart failure in GR+/- mice. In vitro, hydrocortisone-induced cell growth in H9c2 cells was abolished by GR knockdown using siRNA. Finally, we looked at the mechanisms by which GR may play a role in the development of hypertrophy. We found reduced ERK-JNK activity in GR+/- hearts, suggesting that the reduced hypertrophic response in GR+/- mice occurs, at least partially, through abolished JNK and ERK activity. Conclusion: The glucocorticoid receptor is required for cardiac hypertrophy and protects the heart from heart failure during cardiac pressure overload.
Alternate dosing regimens of brentuximab vedotin for <scp>CD</scp> 30+ cutaneous T‐cell lymphoma: reply from the authors
Authors: R. Stranzenbach, E. Dippel, M. Schlaak, R. Stadler
Journal: British Journal of Dermatology (2017)

We thank the authors Lewis, Kim, and Duvic, for their reaction to our article.

The increasingly personalised medicine should also take into account individual tumour entities and their inter-individual pathways.

Therefore, we can only welcome and sustain the comments. As described in our article, it is possible, in some patients, to reduce the dose and interval frequency of Brentuximab Vedotin (BV), while continuing to have good efficacy.

This article is protected by copyright. All rights reserved.
Relationship Between Susceptibility to Induced Pulmonary Tumors and Certain Known Genes in Mice
Authors: W. E. Heston
Journal: JNCI Journal of the National Cancer Institute (1941)

Journal Article Relationship Between Susceptibility to Induced Pulmonary Tumors and Certain Known Genes in Mice Get access W. E. Heston W. E. Heston research fellow National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 2, Issue 2, October 1941, Pages 127–132, https://doi.org/10.1093/jnci/2.2.127 Published: 01 October 1941
重感染抵抗性安定パッケージング細胞株により産生されたアルファレトロウイルス自己不活性化ベクターは初代ヒトTリンパ球の遺伝的修飾を可能にする【Powered by NICT】
Authors: Labenski Verena, D Suerth Julia, Barczak Elke, Heckl Dirk, Levy Camille, Bernadin Ornellie, Charpentier Emmanuelle, A Williams David, Fehse Boris, Verhoeyen Els, Schambach Axel
Journal: Biomaterials (2016)
ナノカプセル官能化細胞傷害性T細胞により媒介される抗原認識トリガードラッグデリバリー【Powered by NICT】
Authors: Jones R. Brad, Mueller Stephanie, Kumari Sudha, Vrbanac Vlad, Genel Shy, M Tager Andrew, M Allen Todd, D Walker Bruce, J Irvine Darrell
Journal: Biomaterials (2017)
OP0079 Body fat percentage and waist circumference were associated with the development of rheumatoid arthritis – a danish follow-up study
Authors: A Linauskas, AL de Thurah, K Overvad, MB Johansen, K Stengaard-Pedersen
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Several studies have investigated the association between overweight and the development of rheumatoid arthritis (RA) and have come out with conflicting results. Body Mass Index (BMI) has been the preferred surrogate measure for overweight in these studies. However, BMI correlates only modestly with total amount of body fat and does not reflect fat distribution. <h3>Objectives</h3> To investigate the association between BMI, waist circumference, bio-impedance-derived total body fat percentage and the incidence of RA. <h3>Methods</h3> A population-based cohort study conducted within the Danish Diet, Cancer and Health cohort, which included individuals aged 50 to 64 years at the recruitment in the period between 1993 and 1997. Body fat composition measurements and data on lifestyle factors were collected at the enrolment into the cohort. The participants who subsequently developed RA were identified via linkage to The Danish National Patient Registry. The participants were followed until development of RA, death, loss to follow-up or October 2016, whichever came first. Data were analyzed by Cox proportional hazards regression model with delayed entry and age as the underlying time variable. Analyses were stratified by gender. Cox regression analyses with restricted cubic spline were carried out to elucidate the dose-response association between anthropometric measures and risk of RA. Smoking, socio-economic status, alcohol consumption, physical activity and intake of n-3 fatty acids were included in multivariate analyses as potential confounders. <h3>Results</h3> Data were available on 54 284 subjects (52% female). During follow-up (median 21 years), 283 women and 110 men developed RA. The median (IQR) time to onset of RA was 7 (4–11) years. The adjusted hazard ratio9s (HR) for developing RA are presented in Table 1. Restricted cubic spline analysis of body fat percentage displayed a positive slope in women (Image). There was no linear association between amount of fat and incidence of RA among men. <h3>Conclusions</h3> Overweight and obesity, defined by BMI, abdominal obesity and higher body fat percentage, especially above 30%, were in women associated with a higher risk for the development of RA. In men the associations were not consistent. <h3>Acknowledgements</h3> The Danish Rheumatism Association, The Danish Heart Foundation, Central Denmark Region, North Denmark Regional Hospital, Scandinavian Rheumatology Research Foundation <h3>Disclosure of Interest</h3> None declared
アミロイドβペプチドの神経毒性の治療のための模倣メタロペプチダーゼとしてのセリア/POMハイブリッドナノ粒子【Powered by NICT】
Authors: Guan Yijia, Li Meng, Dong Kai, Gao Nan, Ren Jinsong, Zheng Yongchen, Qu Xiaogang
Journal: Biomaterials (2016)