tbuckley/cabot-search huggingface dataset:
Abstract 16527: Transcript Profiling Indicates That Tissue Resident C-kit(+) Cells Express Cardiac Genes in Response to B-Catenin Inhibition in vivo
Authors: Conrad Hodgkinson, José Gomez, Alan Payne, Richard Pratt, Victor Dzau
Journal: Circulation (2017)

The mammalian heart lacks the capacity to repair itself following injury. Following injury, cardiomyocytes die but are not replaced. The inability to replace lost cardiomyocytes leads to a progress...
Emergency cancer diagnoses in England fall from 24% to 20% in 10 years
Authors: Nigel Hawkes
Journal: BMJ (2018)

The way in which cancer is diagnosed in England is showing a slow but steady improvement, according to the latest data published by Public Health England (PHE).1

Cancer survival rates in the UK lag behind other comparable European countries and one commonly cited reason is delay in diagnosis, which generally means poorer survival. To monitor improvements in diagnosis, PHE combines data from hospital episode statistics, cancer waiting times, data from screening programmes, and cancer registration data.

This enables every case of cancer arising since 2006 to be classified into one of eight routes to diagnosis, …
Inequalities in zoster disease burden: a population-based cohort study to identify social determinants using linked data from the U.K. Clinical Practice Research Datalink
Authors: A. Jain, A.J. van Hoek, J.L. Walker, H.J. Forbes, S.M. Langan, A. Root, L. Smeeth, S.L. Thomas
Journal: British Journal of Dermatology (2018)

Zoster vaccination was introduced in England in 2013, where tackling health inequalities is a statutory requirement. However, specific population groups with higher zoster burden remain largely unidentified. To evaluate health inequalities in zoster disease burden prior to zoster vaccine introduction in England. This population‐based cohort study used anonymized U.K. primary care data linked to hospitalization and deprivation data. Individuals aged ≥ 65 years without prior zoster history (N = 862 470) were followed from 1 September 2003 to 31 August 2013. Poisson regression was used to obtain adjusted rate ratios (ARRs) for the association of sociodemographic factors (ethnicity, immigration status, individuals' area‐level deprivation, care home residence, living arrangements) with first zoster episode. Possible mediation by comorbidities and immunosuppressive medications was also assessed. There were 37 014 first zoster episodes, with an incidence of 8·79 [95% confidence interval (CI) 8·70–8·88] per 1000 person‐years at risk. In multivariable analyses, factors associated with higher zoster rates included care home residence (10% higher vs. those not in care homes), being a woman (16% higher vs. men), nonimmigrants (~30% higher than immigrants) and white ethnicity (for example, twice the rate compared with those of black ethnicity). Zoster incidence decreased slightly with increasing deprivation (ARR most vs. least deprived 0·96 (95% CI 0·92–0·99) and among those living alone (ARR 0·96, 95% CI 0·94–0·98). Mediating variables made little difference to the ARR of social factors but were themselves associated with increased zoster burden (ARR varied from 1·11 to 3·84). The burden of zoster was higher in specific sociodemographic groups. Further study is needed to ascertain whether these individuals are attending for zoster vaccination.
Traumatic brain injury and the risk of dementia diagnosis: A nationwide cohort study
Authors: Anna Nordström, Peter Nordström
Journal: PLoS Medicine (2018)

Background Traumatic brain injury (TBI) has been associated with dementia. The questions of whether the risk of dementia decreases over time after TBI, whether it is similar for different TBI types, and whether it is influenced by familial aggregation are not well studied. Methods and findings The cohort considered for inclusion comprised all individuals in Sweden aged ≥50 years on December 31, 2005 (n = 3,329,360). Diagnoses of dementia and TBI were tracked through nationwide databases from 1964 until December 31, 2012. In a first cohort, individuals diagnosed with TBI (n = 164,334) were matched with up to two controls. A second cohort consisted of subjects diagnosed with dementia during follow-up (n = 136,233) matched with up to two controls. A third cohort consisted of 46,970 full sibling pairs with discordant TBI status. During a mean follow-up period of 15.3 (range, 0–49) years, 21,963 individuals in the first cohort (6.3% with TBI, 3.6% without TBI) were diagnosed with dementia (adjusted odds ratio [OR], 1.81; 95% confidence interval [CI], 1.75–1.86). The association was strongest in the first year after TBI (OR, 3.52; 95% CI, 3.23–3.84), but the risk remained significant >30 years (OR, 1.25; 95% CI, 1.11–1.41). Single mild TBI showed a weaker association with dementia (OR, 1.63; 95% CI, 1.57–1.70) than did more severe TBI (OR, 2.06; 95% CI, 1.95–2.19) and multiple TBIs (OR, 2.81; 95% CI, 2.51–3.15). These results were in general confirmed in the nested case-control cohort. TBI was also associated with an increased risk of dementia diagnosis in sibling pairs with discordant TBI status (OR, 1.89; 95% CI, 1.62–2.21). A main limitation of the present study is the observational design. Thus, no causal inferences can be made based on the associations found. Conclusions The risk of dementia diagnosis decreased over time after TBI, but it was still evident >30 years after the trauma. The association was stronger for more severe TBI and multiple TBIs, and it persisted after adjustment for familial factors.
Abstract 19037: Impact of the GNB3 C825T Polymorphism on Heart Failure Survival
Authors: Dennis M McNamara, Karen Hanley-Yanez, Indrani Halder, Richard Sheppard
Journal: Circulation (2015)

Introduction: Genetic background can influence heart failure survival and the impact of therapeutics. A polymorphism of a G protein beta subunit, GNB3 C825T, has been investigated extensively for its impact on the genomic risk of hypertension. The T allele is associated with low renin hypertension and increased alpha adrenergic tone. The T allele is more prevalant in African Americans and in the AHeFT trial was associated with a greater impact of therapy with a fixed dose combination of hydralazine and isosorbide dinitrates. We investigated the impact of GNB3 C825T on transplant free survival in systolic heart failure in GRACE (Genetic Risk Assessment of Cardiac Events), a singe center study based in an outpatient heart failure clinic. Methods: 944 subjects with systolic heart failure were enrolled from the Heart Failure Clinic at the University of Pittsburgh and followed for up to 5 years to an endpoint of death or cardiac transplantation. Demographic information was recorded at the time of enrollment and medical therapy reassessed annually. Blood was obtained at entry for DNA banking, and the GNB3 C825T genotype was determined. Transplant free survival was compared by Kaplan Meier log rank assessment. Results: The cohort was 28% female, 13% black, 48% ischemic, mean age 56 + 9, mean LVEF 0.25 + 0.09, and was NYHA class % 1/2/3/4=4%/52%/40%/4%. In terms of the GNB3 genotype the %TT/TC/CC were 16.5%/41.8%/41.7% and the frequency of the T allele differed significantly by race and was more common in Blacks (p&lt;0.001) . During follow up there were 236 (25%) death, and 126 transplants (13%). The T allele was associated with poor transplant free survival (Figure: p=0.025) driven primarily by poorer absolute survival (p=0.017). Conclusions: The GNB3 825T allele was associated with poorer survival in a cohort with chronic heart failure. Its role in racial differences in heart failure outcomes warrants futher investigation.
Genome-Wide Association Study Reveals Variants in CFH and CFHR4 Associated with Systemic Complement Activation
Authors: Laura Lorés-Motta, Constantin C. Paun, Jordi Corominas, Marc Pauper, Maartje J. Geerlings, Lebriz Altay, Tina Schick, Mohamed R. Daha, Sascha Fauser, Carel B. Hoyng, Anneke I. den Hollander, Eiko K. de Jong
Journal: Ophthalmology (2018)

To identify genetic variants associated with complement activation, which may help to select age-related macular degeneration (AMD) patients for complement-inhibiting therapies.Genome-wide association study (GWAS) followed by replication and meta-analysis.AMD patients and controls (n = 2245).A GWAS on serum C3d-to-C3 ratio was performed in 1548 AMD patients and controls. For replication and meta-analysis, 697 additional individuals were genotyped. A model for complement activation including genetic and non-genetic factors was built, and the variance explained was estimated. Haplotype analysis was performed for 8 SNPs across the CFH/CFHR locus. Association with AMD was performed for the variants and haplotypes found to influence complement activation.Normalized C3d/C3 ratio as a measure of systemic complement activation.Complement activation was associated independently with rs3753396 located in CFH (Pdiscovery = 1.09 × 10-15; Pmeta = 3.66 × 10-21; β = 0.141; standard error [SE] = 0.015) and rs6685931 located in CFHR4 (Pdiscovery = 8.18 × 10-7; Pmeta = 6.32 × 10-8; β = 0.054; SE = 0.010). A model including age, AMD disease status, body mass index, triglycerides, rs3753396, rs6685931, and previously identified SNPs explained 18.7% of the variability in complement activation. Haplotype analysis revealed 3 haplotypes (H1-2 and H6 containing rs6685931 and H3 containing rs3753396) associated with complement activation. Haplotypes H3 and H6 conferred stronger effects on complement activation compared with the single variants (P = 2.53 × 10-14; β = 0.183; SE = 0.024; and P = 4.28 × 10-4; β = 0.144; SE = 0.041; respectively). Association analyses with AMD revealed that SNP rs6685931 and haplotype H1-2 containing rs6685931 were associated with a risk for AMD development, whereas SNP rs3753396 and haplotypes H3 and H6 were not.The SNP rs3753396 in CFH and SNP rs6685931 in CFHR4 are associated with systemic complement activation levels. The SNP rs6685931 in CFHR4 and its linked haplotype H1-2 also conferred a risk for AMD development, and therefore could be used to identify AMD patients who would benefit most from complement-inhibiting therapies.
Successful closure of a refractory rectal anastomotic fistula using endoscopic submucosal dissection combined with an over-the-scope clip
Authors: Neven Barsic, Jérôme Rivory, Olivier Monneuse, Jean-Christophe Saurin, Thierry Ponchon, Mathieu Pioche
Journal: Endoscopy (2018)

Digestive endoscopy is increasingly replacing surgery in the treatment of postoperative leaks and fistulas. However, treatment of patients with these conditions remains challenging with many different methods being currently tested [1].
Towards the Next Generation CAR T Cells with TEGs: In Vivo Efficacy — Toxicity Profile in Xenografts of Primary Human AML Disease and Healthy Bone Marrow
Authors: Trudy Straetemans, Inez Johanna Gan, Sabine Heijhuurs, Guido Kierkels, Koen Jansen, Ruud Doorn, Tineke Aarts, Haakan Norrel, Zsolt Sebestyen, Jurgen Kuball
Journal: Blood (2017)
CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity
Authors: Naoto Fujiwara, Hayato Nakagawa, Kenichiro Enooku, Yotaro Kudo, Yuki Hayata, Takuma Nakatsuka, Yasuo Tanaka, Ryosuke Tateishi, Yohko Hikiba, Kento Misumi, Mariko Tanaka, Akimasa Hayashi, Junji Shibahara, Masashi Fukayama, Junichi Arita, Kiyoshi Hasegawa, Hadassa Hirschfield, Yujin Hoshida, Yoshihiro Hirata, Motoyuki Otsuka, Keisuke Tateishi, Kazuhiko Koike
Journal: Gut (2018)

Objective Metabolic reprogramming of tumour cells that allows for adaptation to their local environment is a hallmark of cancer. Interestingly, obesity-driven and non-alcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC) mouse models commonly exhibit strong steatosis in tumour cells as seen in human steatohepatitic HCC (SH-HCC), which may reflect a characteristic metabolic alteration. Design Non-tumour and HCC tissues obtained from diethylnitrosamine-injected mice fed either a normal or a high-fat diet (HFD) were subjected to comprehensive metabolome analysis, and the significance of obesity-mediated metabolic alteration in hepatocarcinogenesis was evaluated. Results The extensive accumulation of acylcarnitine species was seen in HCC tissues and in the serum of HFD-fed mice. A similar increase was found in the serum of patients with NASH-HCC. The accumulation of acylcarnitine could be attributed to the downregulation of carnitine palmitoyltransferase 2 (CPT2), which was also seen in human SH-HCC. CPT2 downregulation induced the suppression of fatty acid β-oxidation, which would account for the steatotic changes in HCC. CPT2 knockdown in HCC cells resulted in their resistance to lipotoxicity by inhibiting the Src-mediated JNK activation. Additionally, oleoylcarnitine enhanced sphere formation by HCC cells via STAT3 activation, suggesting that acylcarnitine accumulation was a surrogate marker of CPT2 downregulation and directly contributed to hepatocarcinogenesis. HFD feeding and carnitine supplementation synergistically enhanced HCC development accompanied by acylcarnitine accumulation in vivo. Conclusion In obesity-driven and NASH-driven HCC, metabolic reprogramming mediated by the downregulation of CPT2 enables HCC cells to escape lipotoxicity and promotes hepatocarcinogenesis.
Low-Dose Aspirin in Heart Failure Not Complicated by Atrial Fibrillation
Authors: Christian Madelaire, Gunnar Gislason, Søren L. Kristensen, Emil L. Fosbøl, Jenny Bjerre, Maria D’Souza, Finn Gustafsson, Lars Kober, Christian Torp-Pedersen, Morten Schou
Journal: JACC Heart Failure (2018)
STK11/LKB1 co-mutations to predict for de novo resistance to PD-1/PD-L1 axis blockade in KRAS-mutant lung adenocarcinoma.
Authors: Ferdinandos Skoulidis, Matthew David Hellmann, Mark M. Awad, Hira Rizvi, Brett W. Carter, Warren Denning, Yasir Elamin, Jianjun Zhang, Giulia Costanza Leonardi, Darragh Halpenny, Andrew Plodkowski, Niamh Long, Jeremy J. Erasmus, Vassiliki Papadimitrakopoulou, Kwok-Kin Wong, Ignacio Ivan Wistuba, Pasi A. Janne, Charles M. Rudin, John Heymach
Journal: Journal of Clinical Oncology (2017)

9016 Background: Identification of molecular predictors of response to PD-1/PD-L1 inhibitors is critical in order to maximize their therapeutic potential. We previously reported that KRAS-mutant lung adenocarcinomas (LUAC) with co-occurring genetic events in STK11/LKB1(KL) or TP53 (KP) define subgroups with marked differences in immune contexture, including a paucity of CD8+ TILs in KL LUAC. Here, we assess clinical responses to PD-1/PD-L1 therapy in KL and KP subsets, with data assembled under the auspices of the SU2C/ACS Lung Cancer Dream Team. Methods: Patients (pts) with metastatic KRAS-mutant LUAC who received at least one cycle of PD-1/PD-L1 therapy, were alive for ≥14 days thereafter, and had available molecular profiling were identified retrospectively. Efficacy assessment was based on RECIST v1.1. PD-L1 expression was tested using 22C3 pharmDx or E1L3N IHC assays and quantified as percent of staining tumor cell membranes. Isogenic derivatives of the LKR10 Kras LA1/+ murine LUAC cell line with CRISPR/Cas9-mediated Lkb1knockout were used in preclinical experiments. Results: 165 pts with KRAS-mutant LUAC who received PD-1/PD-L1 therapy were included [KL: 27%, KP: 36%, K-only: 37%]. Best overall response differed significantly in the KL (PR: 9.1%, SD: 15.9%, PD: 75%) and KP (PR: 33.3%, SD: 20%, PD: 46.7%) sub-groups (P = 0.005, Fisher’s exact test). PFS was significantly longer in KP compared to KL LUAC (median 12.9 wks vs 8.4 wks, HR = 0.64, 95% CI 0.39-0.95, P = 0.032, log-rank test). ORR in K-only tumors was 21.3% and median PFS 11.4 wks. PD-L1 positivity (≥1%) was more frequent in KP tumors compared to KL (75% vs 22%, P = 0.03, Fisher’s exact test). In syngeneic murine models of KRAS-mutant LUAC, loss of LKB1 promoted resistance to PD-1 inhibitor monotherapy, suggesting a causative role. Conclusions: Mutational inactivation of STK11/LKB1 represents a novel genomic predictor of de novo resistance to immune checkpoint blockade in KRAS-mutant LUAC, whereas TP53 co-mutations are associated with high likelihood of response. Precision immunotherapy will require tailoring to the co-mutation status of individual tumors.
Efficacy and safety of mechlorethamine (MCH) 0.04% gel in mycosis fungoides (MF) after treatment with topical MCH 0.02%.
Authors: Youn H. Kim, Madeleine Duvic, Joan Guitart, Stuart Lessin
Journal: Journal of Clinical Oncology (2014)

9093 Background: MF, the most common form of cutaneous T-cell lymphoma, is characterized by infiltration of the skin by malignant T cells and can further progress to other organs. Early stage disease (limited/localized skin involvement) is managed with skin-directed therapies. The first FDA approved topical formulation of MCH, MCH 0.02% gel (equivalent to 0.016% w/w MCH, mechlorethamine) was noninferior to MCH-Aquaphor (AP) 0.02% in a 12 mo study (Study 201). In clinical practice, patients (pts) who tolerate MCH 0.02% without complete response (CR) may have their dose increased to maximize response. Study 202 tested the efficacy and safety of MCH 0.04% gel after MCH 0.02%. Methods: Pts eligible for this 7 mo phase 2 extension study completed 12 mos of treatment with MCH 0.02% gel or AP without CR. All pts applied a thin layer of MCH 0.04% gel once daily. Application frequency could be reduced for toxicity. Primary endpoint was response rate defined as ≥ 50% improvement in composite assessment of index lesions score (CAILS) of up to 5 lesions, confirmed ≥ 4 weeks later. Results: 98 of 100 enrolled pts were treated in Study 202 (MCH 0.04%); 86.7% completed the trial. 26 pts (26.5% [18.6-35.9]) achieved confirmed CAILS response from Study 202 baseline, including 6 CR. Additionally, 14 pts (14.3%) had their first response at final visit—unconfirmed response rate, 40.8% (31.5-50.7). There was no difference in response by age, race, or gender. CAILS response rates were also assessed from Study 201 (MCH 0.02%) baseline for index lesions identified at the start of that trial, with confirmed responses occurring in 74 pts (75.5% [66.3-83.2]). By week 88, 33 pts (84.4%) who had previously received MCH 0.02% gel and 39 pts (67.9%) who had previously received MCH 0.02% AP in Study 201 had responses over the course of these sequential studies. Drug related skin adverse events in Study 202 were mostly mild to moderate and were reported by 31 pts (31.6%); the most common were skin irritation (11.2%), erythema (10.2%), and pruritus (6.1%). Conclusions: Pts with stage I or IIA MF who did not achieve CR after 12 mos of daily topical MCH 0.02% had additional clinical benefit with up to 7 mos of treatment with MCH 0.04% gel, which was well tolerated in these pts. Clinical trial information: NCT00535470.
非マキューン・アルブライト症候群による線維性骨異形成症(FD)組織におけるFGF-23の発現
Authors: Imanishi Y, Kobayashi K, Koshiyama H, Miyauchi A, Goto H, Yamamoto T, Ohashi H, Nakatsuka K, Inaba M, Ishimura E, Nishizawa Y
Journal: Journal of the American Society of Nephrology (2003)
Test patients with rheumatoid arthritis for anti-CCP antibodies, says NICE
Authors: Susan Mayor
Journal: BMJ (2018)

All adults diagnosed with rheumatoid arthritis (RA) should have a blood test for anti-cyclic citrullinated peptide (anti-CCP) antibodies to identify those at higher risk for more severe disease and who need active monitoring, says draft guidance from the National Institute for Health and Care Excellence (NICE).1

The guideline strengthens previous advice on anti-CCP antibody testing by recommending measuring levels in all patients as soon as possible after diagnosing RA. It is based on …
Noncanonical hedgehog pathway activation through SRF–MKL1 promotes drug resistance in basal cell carcinomas
Authors: Ramon J Whitson, Alex Lee, Nicole M Urman, Amar Mirza, Catherine Y Yao, Alexander S Brown, Jiang R Li, Gautam Shankar, Micah A Fry, Scott X Atwood, Eunice Y Lee, S Tyler Hollmig, Sumaira Z Aasi, Kavita Y Sarin, Matthew P Scott, Ervin H Epstein, Jean Y Tang, Anthony E Oro
Journal: Nature Medicine (2018)
Surgeon whose manslaughter conviction was quashed faces GMC hearing
Authors: Clare Dyer
Journal: BMJ (2018)

David Sellu, the senior colorectal surgeon who was jailed for gross negligence manslaughter after a patient died and who then had his conviction quashed by the Court of Appeal1 is to face a six week fitness to practise hearing starting on 29 January.

At the medical practitioners tribunal hearing in Manchester, Sellu faces charges of failing to provide good clinical care to James Hughes, the patient whose care was at the centre of the criminal case against him.

The tribunal will investigate Sellu’s actions during the days before Hughes died at …
Response to Open Peer Commentaries on “Resolving Ethical Dilemmas in a Tertiary Care Veterinary Specialty Hospital: Adaptation of the Human Clinical Consultation Committee Model”
Authors: Philip M. Rosoff, Rachel Ruderman, Jeannine Moga, Bruce Keene, Christopher Adin, Callie Fogle, Heather Hopkinson, Charity Weyhrauch
Journal: The American Journal of Bioethics (2018)

We are gratified that our article, “Resolving Ethical Dilemmas in a Tertiary Care Veterinary Specialty Hospital: Adaptation of the Human Clinical Consultation Committee Model” (Rosoff et al. 2018),...
Alda-1 shields endothelial cells against oxidative stress via activation of ALDH2
Authors: Sahebgowda S. Patil, Venkata Ramireddy Narala, Helena Hernández-Cuervo, Byeong J. Cha, Jutaro Fukumoto, Mason T. Breitzig, Richard F. Lockey, Narasaiah Kolliputi, Lakshmi Galam
Journal: Journal of Allergy and Clinical Immunology (2018)
Effectiveness of influenza vaccine in preventing medically-attended influenza virus infection in primary care, Israel, influenza seasons 2014/15 and 2015/16
Authors: Hamutal Yaron-Yakoby, Hanna Sefty, Rakefet Pando, Rita Dichtiar, Mark A Katz, Yaniv Stein, Michal Mandelboim, Ella Mendelson, Tamy Shohat, Aharona Glatman-Freedman
Journal: Eurosurveillance (2018)

IntroductionInfluenza vaccine is recommended for the entire population in Israel. We assessed influenza vaccine effectiveness (VE) for the 2014/15 and 2015/16 seasons in Israel, for the first time. Methods: Combined nose and throat swab specimens were collected from patients with influenza-like illness (ILI) presenting to sentinel primary care clinics and tested for influenza virus by RT-PCR. VE of the trivalent inactivated vaccine (TIV) was assessed using test-negative case-control design. Results: During the 2014/15 season 1,142 samples were collected; 327 (28.6%) were positive for influenza, 83.8% A(H3N2), 5.8% A(H1N1)pdm09, 9.2% B and 1.2% A un-subtyped. Adjusted VE against all influenza viruses for this influenza season was -4.8% (95% confidence interval (CI): -54.8 to 29.0) and against influenza A(H3N2), it was -15.8% (95% CI: -72.8 to 22.4). For the 2015/16 season, 1,919 samples were collected; 853 (44.4%) were positive for influenza, 43.5% A(H1N1)pdm09, 57% B, 0.7% A(H3N2) and 11 samples positive for both A(H1N1)pdm09 and B. Adjusted VE against all influenza viruses for this influenza season was 8.8% (95% CI: -25.1 to 33.5), against influenza A(H1N1)pdm09, it was 32.3% (95% CI: (-4.3 to 56.1) and against influenza B, it was -2.2% (95% CI: (-47.0 to 29.0). Conclusions: Using samples from patients with ILI visiting sentinel clinics in Israel, we demonstrated the feasibility of influenza VE estimation in Israel.
Airway inflammation after epicutaneous sensitization of mice requires protease activity of low-dose allergen inhalation
Authors: Izumi Nishioka, Toshiro Takai, Natsuko Maruyama, Seiji Kamijo, Punyada Suchiva, Mayu Suzuki, Shinya Kunimine, Hirono Ochi, Sakiko Shimura, Katsuko Sudo, Hideoki Ogawa, Ko Okumura, Shigaku Ikeda
Journal: Journal of Allergy and Clinical Immunology (2018)