tbuckley/cabot-search huggingface dataset:
Interactive Associations of Vascular Risk and β-Amyloid Burden With Cognitive Decline in Clinically Normal Elderly Individuals
Authors: Jennifer S. Rabin, Aaron P. Schultz, Trey Hedden, Anand Viswanathan, Gad A. Marshall, Emily Kilpatrick, Hannah Klein, Rachel F. Buckley, Hyun-Sik Yang, Michael Properzi, Vaishnavi Rao, Dylan R. Kirn, Kathryn V. Papp, Dorene M. Rentz, Keith A. Johnson, Reisa A. Sperling, Jasmeer P. Chhatwal
Journal: JAMA Neurology (2018)

Identifying asymptomatic individuals at high risk of impending cognitive decline because of Alzheimer disease is crucial for successful prevention of dementia. Vascular risk and β-amyloid (Aβ) pathology commonly co-occur in older adults and are significant causes of cognitive impairment.To determine whether vascular risk and Aβ burden act additively or synergistically to promote cognitive decline in clinically normal older adults; and, secondarily, to evaluate the unique influence of vascular risk on prospective cognitive decline beyond that of commonly used imaging biomarkers, including Aβ burden, hippocampal volume, fludeoxyglucose F18-labeled (FDG) positron emission tomography (PET), and white matter hyperintensities, a marker of cerebrovascular disease.In this longitudinal observational study, we examined clinically normal older adults from the Harvard Aging Brain Study. Participants were required to have baseline imaging data (FDG-PET, Aβ-PET, and magnetic resonance imaging), baseline medical data to quantify vascular risk, and at least 1 follow-up neuropsychological visit. Data collection began in 2010 and is ongoing. Data analysis was performed on data collected between 2010 and 2017.Vascular risk was quantified using the Framingham Heart Study general cardiovascular disease (FHS-CVD) risk score. We measured Aβ burden with Pittsburgh Compound-B PET. Cognition was measured annually with the Preclinical Alzheimer Cognitive Composite. Models were corrected for baseline age, sex, years of education, and apolipoprotein E ε4 status.Of the 223 participants, 130 (58.3%) were women. The mean (SD) age was 73.7 (6.0) years, and the mean (SD) follow-up time was 3.7 (1.2) years. Faster cognitive decline was associated with both a higher FHS-CVD risk score (β = -0.064; 95% CI, -0.094 to -0.033; P < .001) and higher Aβ burden (β = -0.058; 95% CI, -0.079 to -0.037; P < .001). The interaction of the FHS-CVD risk score and Aβ burden with time was significant (β = -0.040, 95% CI, -0.062 to -0.018; P < .001), suggesting a synergistic effect. The FHS-CVD risk score remained robustly associated with prospective cognitive decline (β = -0.055; 95% CI, -0.086 to -0.024; P < .001), even after adjustment for Aβ burden, hippocampal volume, FDG-PET uptake, and white matter hyperintensities.In this study, vascular risk was associated with prospective cognitive decline in clinically normal older adults, both alone and synergistically with Aβ burden. Vascular risk may complement imaging biomarkers in assessing risk of prospective cognitive decline in preclinical Alzheimer disease.
Metabolism within the tumor microenvironment and its implication on cancer progression: An ongoing therapeutic target
Authors: Ma Carmen Ocaña, Beatriz Martínez‐Poveda, Ana R. Quesada, Miguel Ángel Medina
Journal: Medicinal Research Reviews (2018)

Abstract Since reprogramming energy metabolism is considered a new hallmark of cancer, tumor metabolism is again in the spotlight of cancer research. Many studies have been carried out and many possible therapies have been developed in the last years. However, tumor cells are not alone. A series of extracellular components and stromal cells, such as endothelial cells, cancer‐associated fibroblasts, tumor‐associated macrophages, and tumor‐infiltrating T cells, surround tumor cells in the so‐called tumor microenvironment (TME). Metabolic features of these cells are being studied in deep in order to find relationships between metabolism within the TME and tumor progression. Moreover, it cannot be forgotten that tumor growth is able to modulate host metabolism and homeostasis, so that TME is not the whole story. Importantly, the metabolic switch in cancer is just a consequence of the flexibility and adaptability of metabolism and should not be surprising. Treatments of cancer patients with combined therapies including antitumor agents with those targeting stromal cell metabolism, antiangiogenic drugs, and/or immunotherapy are being developed as promising therapeutics.
Contribution of Lynch syndrome to early onset malignancy in Ireland.
Authors: Alice Talbot, David James Gallagher
Journal: Journal of Clinical Oncology (2018)

586 Background: Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome responsible for 2 -6% of hereditary colorectal cancers. LS is caused by germ-line mutations in mismatch repair genes (MMR): MLH1, MSH2, MSH6, PMS2 or EPCAM. This results in microsatellite instability, a phenotypic hallmark of LS-associated colorectal cancer. The aim of this study was to construct and analyse a database of Irish MMR mutation carriers. Methods: Records were from two of the three existing cancer genetics clinics in Ireland. Clinicopathological data of all probands (n=57) including names, dates of birth and death, carrier status and phenotype were recorded. Death certificates were used to confirm information regarding deceased mutation carriers. An ANOVA test was used to establish statistical significance of variations in age by gene. Length of survival based on stage was assessed using Kaplain Meier curves. Results: 345 affected individuals were identified. The most common cancers recorded were colorectal (53%), breast (12%) and endometrial (10%). 138 confirmed carriers were identified: 65 MLH1 (47%), 43 MSH2 (31%), 11 MSH6 (8%), 17 PMS2 (12%), and 2 EPCAM (1%). 22 patients have died since confirmation of Lynch Syndrome, 50% of whom died within 2.5 years of first diagnosis. All deceased carriers had at least one cancer diagnosis and 50% had developed multiple cancers. 59% of deaths were directly related to cancer. 7 of these patients had Stage 4 cancer at diagnosis. There was a significant difference in length of survival based on stage. (p=.048) Phenotype frequencies varied significantly by gene. (see table 1) Median age of first diagnosis of any cancer was 44.5 years (range 23-81). There was no difference in age at presentation by gene mutated. Conclusions: Under-diagnosis of LS misses a powerful preventive and therapeutic opportunity. LS causes early onset cancer diagnosis with substantial societal impact. A significant number of Lynch Syndrome cases have poor clinical outcomes. Genotype/Phenotype frequencies. [Table: see text]
Abstract 16278: Outcomes of Concomitant Use of Mechanical Circulatory Support in Patients Undergoing Therapeutic Hypothermia: A Propensity Score Weighted Regression Analysis
Authors: Nirmanmoh Bhatia, Arash Nayeri, Benjamin Holmes, William Armstrong, Nyal Borges, Michael Young, Shi Huang, John McPherson
Journal: Circulation (2016)

Introduction:  Use of mechanical circulatory support (MCS) is rising. There is limited data to support or refute the use of MCS in patients (pts) undergoing therapeutic hypothermia (TH).   Hypothesis:  We hypothesized that use of MCS is safe in pts undergoing TH.   Methods:  We retrospectively reviewed 336 consecutive pts (mean age 57.9 ± 14.9 years) treated with TH at our center from 2007-2014. We used a propensity score weighted logistic/ordinal regression analysis to identify association of MCS use with significant bleeding requiring transfusion, length of intensive care unit (ICU) stay, neurologic outcome (Cerebral Performance Category [CPC] score 1-2=good; 3-5=poor), time from arrest to initiation of TH protocol and in-hospital death.   Results:  MCS was used in 61/336 (18%) pts; 43/61 (71%) were men. Devices included: intra-aortic balloon pump (53 pts; 87%); Impella (3 pts; 5%); Tandem Heart (2 pts; 3%); and extracorporeal membrane oxygenation (14 pts; 23%). Univariate analysis revealed that significant bleeding was more common (25% vs. 8%, p   Conclusions:  Use of MCS in conjunction with TH is associated with a higher risk of significant bleeding and higher likelihood of longer ICU stay but a lower likelihood of good neurologic outcome (CPC ≤ 2) at discharge. MCS use was not associated with a delay in initiation of TH protocol or a higher risk of death. Future prospective studies assessing the efficacy of MCS in TH are needed.
Cardiomyopathy in patients with epidermolysis bullosa simplex with mutations in <i>KLHL24</i>
Authors: V.K. Yenamandra, P.C. van den Akker, H.H. Lemmink, S.Z. Jan, G.F.H. Diercks, M. Vermeer, M.P. van den Berg, P. van der Meer, A.M.G. Pasmooij, R.J. Sinke, M.F. Jonkman, M.C. Bolling
Journal: British Journal of Dermatology (2018)

DEAR EDITOR, Dominant mutations in KLHL24, encoding for kelch-like protein 24 (KLHL24), have been implicated in the pathogenesis of epidermolysis bullosa simplex (EBS).So far, 26 patients from different ethnicities have been reported and all of them harboured a heterozygous KLHL24 start codon mutation, with c.1A>G;p.Met1?][3] We aimed to expand the phenotypic spectrum by incorporating additional findings, in particular dilated cardiomyopathy, seen in a Dutch family.
Inhibition of Cyclic <scp>GMP</scp>‐<scp>AMP</scp> Synthase Using a Novel Antimalarial Drug Derivative in <i>Trex1</i>‐Deficient Mice
Authors: Jie An, Joshua J. Woodward, Weinan Lai, Mark Minie, Xizhang Sun, Lena Tanaka, Jessica M. Snyder, Tomikazu Sasaki, Keith B. Elkon
Journal: Arthritis & Rheumatology (2018)

Objective Type I interferon ( IFN ) is strongly implicated in the pathogenesis of systemic lupus erythematosus ( SLE ) as well as rare monogenic interferonopathies such as Aicardi‐Goutières syndrome ( AGS ), a disease attributed to mutations in the DNA exonuclease TREX 1 . The DNA ‐activated type I IFN pathway cyclic GMP ‐ AMP ( cGAMP ) synthase ( cGAS ) is linked to subsets of AGS and lupus. This study was undertaken to identify inhibitors of the DNA – cGAS interaction, and to test the lead candidate drug, X6, in a mouse model of AGS. Methods Trex1 −/− mice were treated orally from birth with either X6 or hydroxychloroquine ( HCQ ) for 8 weeks. Expression of IFN ‐stimulated genes ( ISG s) was quantified by quantitative polymerase chain reaction. Multiple reaction monitoring by ultra‐performance liquid chromatography coupled with tandem mass spectrometry was used to quantify the production of cGAMP and X6 drug concentrations in the serum and heart tissue of Trex1 −/− mice. Results On the basis of the efficacy‐to‐toxicity ratio established in vitro, drug X6 was selected as the lead candidate for treatment of Trex1 −/− mice. X6 was significantly more effective than HCQ in attenuating ISG expression in mouse spleens ( P &lt; 0.01 for Isg15 and Isg20 ) and hearts ( P &lt; 0.05 for Isg15 , Mx1 , and Ifnb, and P &lt; 0.01 for Cxcl10 ), and in reducing the production of cGAMP in mouse heart tissue ( P &lt; 0.05), thus demonstrating target engagement by the X6 compound. Of note, X6 was also more effective than HCQ in reducing ISG expression in vitro ( P &lt; 0.05 for IFI 27 and MX 1 , and P &lt; 0.01 for IFI 44L and PKR ) in human peripheral blood mononuclear cells from patients with SLE . Conclusion This study demonstrates that X6 is superior to HCQ for the treatment of an experimental autoimmune myocarditis mediated in vivo by the cGAS /stimulator of IFN genes ( cGAS / STING ) pathway. The findings suggest that drug X6 could be developed as a novel treatment for AGS and/or lupus to inhibit activation of the cGAS / STING pathway.
Role of Resident Stem Cells in Vessel Formation and Arteriosclerosis
Authors: Li Zhang, Shirin Issa Bhaloo, Ting Chen, Bin Zhou, Qingbo Xu
Journal: Circulation Research (2018)

Vascular, resident stem cells are present in all 3 layers of the vessel wall; they play a role in vascular formation under physiological conditions and in remodeling in pathological situations. Throughout development and adult early life, resident stem cells participate in vessel formation through vasculogenesis and angiogenesis. In adults, the vascular stem cells are mostly quiescent in their niches but can be activated in response to injury and participate in endothelial repair and smooth muscle cell accumulation to form neointima. However, delineation of the characteristics and of the migration and differentiation behaviors of these stem cells is an area of ongoing investigation. A set of genetic mouse models for cell lineage tracing has been developed to specifically address the nature of these cells and both migration and differentiation processes during physiological angiogenesis and in vascular diseases. This review summarizes the current knowledge on resident stem cells, which has become more defined and refined in vascular biology research, thus contributing to the development of new potential therapeutic strategies to promote endothelial regeneration and ameliorate vascular disease development.
Abstract 13194: The Effects of Methotrexate Therapy on Myocardial Infarction With ST-Segment Elevation (TETHYS Trial)
Authors: Daniel M Moreira, Roberto L da Silva, Maria E Lueneberg, Tammuz Fattah, Carlos A Gottschall
Journal: Circulation (2015)

Introduction: Acute myocardial infarction provokes inflammatory activation. Methotrexate is one drug that has been shown to have anti-ischemic effects in experimental studies. Hypothesis: Methotrexate could reduce inflammation and the ischemia area in acute myocardial infarction Methods: We randomly assigned patients with myocardial infarction with ST-segment elevation to receive either methotrexate (0.05 mg/kg bolus followed by 0.05 mg/kg/h for 6 h) or matching placebo (riboflavin sodium phosphate 0.1%, in order to preserve double-blinding) at a ratio of 1:1. Patients in both groups were given a 5mg single dose of folic acid. The primary endpoint was infarct size, determined by the area under the curve (AUC) for creatine kinase (CK) release. Secondary endpoints were AUC of CK-MB and AUC of troponin I; peak CK, peak CK-MB and troponin I; B-type natriuretic peptide (BNP) level, high-sensitivity C-reactive protein (hsCRP) result and erythrocyte sedimentation rate (ESR); left ventricular ejection fraction (LVEF); TIMI frame count; Killip score; mortality and reinfarction incidence. The safety endpoint was the incidence of adverse reactions. Results: We included 84 patients. The AUC of CK was 78,861.00 in the methotrexate group and 68,088.00 in the placebo group (P=0.10). Patients given methotrexate and placebo exhibited, respectively, AUC for CK-MB of 9,803.40 and 8,037.00 (P=0.42); AUC for troponin I of 3,691.11 and 2,132.63 (P=0.09); peak CK of 2,806.00 and 2,147.00 (P=0.05), peak CK-MB of 516.00 and 462.25 (P=0.25) and peak troponin I of 121.00 and 85.05 (P=0,06). At 3 months, LVEF was lower in patients who received methotrexate (48.97±14.09%) than in patients given placebo (56.37±9.97%) (P=0.01). There were no differences in hsCRP, ESR, BNP, Killip scores or TIMI frame count. There were also no differences in reinfarction or mortality rates or in incidence of side effects, with the exception of higher median serum glutamic-pyruvic transaminase (SGPT) levels in the methotrexate group. Conclusions: Methotrexate did not reduce infarction size and worsened LVEF at 3 months.
Abstract 3250: Low-does Of Amiodarone For The Prevention Of Atrial Fibrillation After Coronary Artery Bypass Grafting
Authors: Song Gu, Pi-xiong Su, Yan Liu
Journal: Circulation (2007)

Aim: to identify the risk factors associated with atrial fibrillation after CABG and to evaluate the necessity, anti-arrhythmic efficacy and safty of low-does of amiodarone for AF. Methods: Between April 2005 and April 2007, 480 adult patients underwent CABG were randomly divided into two groups. They were given 0.6 g of amiodarone (220 cases) or placebo (260 cases) daily in 7 days before surgery and 0.2 g of amiodarone or placebo daily for 30 days postoperatively. Electrocardiograms were monitored over 14-day postoperative period. Results : Of 480 patients, there were 85 patients(17.7%) occurred AF. The recurrent AF usually developed within 1–3 days after operation, and continued for 0.5–24 hours. The incidence of postoperative AF was significantly (p &lt; 0.001) lower in patients on low-does of amiodarone (9.55%) as compared with placebo (24.62%). Heart rate at onset of atrial fibrillation were 131.4 ± 28.9 beats/min for amiodarone compared with 144.1 ± 30.7 for placebo (P &lt; 0.05). Duration of AF were 12.8 ± 6.7 hours in amiodarone group compared with 18.2 ± 11.6 hours in placebo group(P &lt; 0.05). Conclusion: The strongest independent preoperative predictors for AF after CABG were the patients’age(≥ 70 ys), heart failure(EF ≤ 40% and/or FS ≤ 24%) and hypokalemia; Postoperative administration of Low-does of amiodarone reduced the occurrence of AF by 27.97% and prevented sudden death by 17.02% after CABG surgery; Amiodarone is the safest in four groups of anti-arrhythmic drugs, Preventive trials of low does of amiodarone significantly reduces the incidence, ventricular rate, and duration of AF after CABG, and seems to be of similar efficacy with the trials of large does amiodarone. Furthermore, low-dose amiodarone is well tolerated and decreases the risks of severe side effects and proarrhythmic effects, especially for these patients with high risk factors at peroperative period.
Abstract A17: Novel patient-derived xenograft (PDX) models from peritoneal metastasis of colorectal carcinoma for drug testing and biomarker analysis
Authors: Wolfgang Walther, Eva Pachmayr, Bernadette Brzezicha, Britta Büttner, Beate Rau, Ulrike Stein
Journal: Cancer Research (2018)

Abstract Peritoneal metastasis (PM) represents a terminal tumor stage with limited therapy options for patients with colorectal cancer (CRC). To improve therapeutic efficacy and overall survival, availability of appropriate in vivo models of PM could improve the evaluation of chemosensitivity as well as identification of novel biomarkers and therapeutic targets to improve the therapeutic outcome of PM patients. In this context, we generated the first patient-derived xenograft (PDX) models of PM from CRC as platform to test chemotherapy response and to potentially analyze biomarkers. For the PDX establishment colorectal surgical specimens were subcutaneously (s.c.) transplanted onto immunocompromised NOG mice. The engrafted tumors were transferred to NMRI nu/nu mice for further passaging. They were characterized by histopathology, immunohistochemistry, and gene expression analyses using real-time RT-PCR. Chemosensitivity of PDX models was evaluated in vivo by application of a panel of conventional chemotherapeutic and of targeted drugs. For PDX establishment 68 CRC surgical specimens (taken from peritoneum and omentum) were transplanted, from which 22 PDX have engrafted. From those, 13 models of 10 patients have been analyzed. Their tumor doubling times ranged between 4 to 28 days. The histopathologic evaluation revealed maintenance of the original CRC histology in the PDX. The chemosensitivity testing of conventional and of targeted drugs in the 13 PM PDX models revealed the individual, diverging response of the PDX, such as for 5-FU, irinotecan, oxaliplatin, cetuximab, and erlotinib. More interestingly, different responses were observed in PDX of the omentum vs. peritoneum, which were derived from the same patient. Our results demonstrate that this novel panel of PDX maintains the morphology of the patient tumor in early passages, reflect heterogeneous response rates, and can be used as a preclinical in vivo platform for translational studies of potential clinical use. In conclusion, this PDX panel of PM of the CRC can be used for further studies to evaluate new biomarkers and to test novel therapies or combinations for PM of CRC. Citation Format: Wolfgang Walther, Eva Pachmayr, Bernadette Brzezicha, Britta Büttner, Beate Rau, Ulrike Stein. Novel patient-derived xenograft (PDX) models from peritoneal metastasis of colorectal carcinoma for drug testing and biomarker analysis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A17.
3 Mortality on orthotopic liver transplantation waiting list at national liver transplant unit ireland
Authors: BT Christopher, Ismail, C Kiat, E Tatro, Y McGarry, R MacNicholas, PA McCormick, D Houlihan
Journal: Gut (2017)

Background  Orthotopic liver transplantation is indicated in patients with end-stage liver disease, hepatocellular carcinoma (HCC) within transplant criteria and acute fulminant hepatic failure. Progression to end stage liver failure with high mortality is inevitable without transplantation.  Aim  Our aim is to analyse mortality aspects on our OLT waiting list. This retrospective study included patients’ cohort over 3 years from January 2014 to December 2016. During this time period, there were 163 patients transplanted.  Method  Data was collected from database and patients’ medical records.  Results  There were 21 deaths (6 females, 15 males) with 8 patients delisted and 4 suspended. The median patients’ age was 50. Nine patients (43%) died on waiting list. Of these, three were listed as super-urgent for fulminant hepatic failure (2 acetaminophen overdose1 autoimmune hepatitis). Median duration on waiting list to death was 3.6 months. There was one patient followed up regularly with 16 months duration on waiting list. The remainder waiting duration was single figured in months. The average MELD score at time of listing was 19(7-53). Causes of death include multi-organ failure (n=5), coroner’s case (n=4), end stage liver failure progression (n=4), bleeding oesophageal varices and sepsis (n=1), metastatic cancer recurrence (n=1) and not documented in 6 others. Aetiology of liver disease subgroups are shown in Table 1 (attached). There were 10 patients each in blood group O and A and 1 in blood group B.  Conclusions  Limited organ availability and increasing demand for organ transplantation has extended transplant waiting times, thus increased morbidity and mortality for potential recipients.
Gold and gold-silver alloy nanoparticles enhance the myogenic differentiation of myoblasts through p38 MAPK signaling pathway and promote in vivo skeletal muscle regeneration
Authors: Juan Ge, Kai Liu, Wen Niu, Mi Chen, Min Wang, Yumeng Xue, Chuanbo Gao, Peter X. Ma, Bo Lei
Journal: Biomaterials (2018)
Grizel D'Rastricke Stewart
Authors: Ailbe Beirne, Désirée Mules
Journal: BMJ (2018)

Grizel D'Rastricke Stewart (nee Carr) qualified with distinction in medicinal therapeutic chemistry. From January to December 1947 she was casualty officer and house surgeon at St Bartholomew’s Hospital in Rochester, Kent. In early 1948 she accompanied her husband to Burma, where he was in the oil industry.

Her only child, Desiree (“Daisy”), was born in December 1949, in Omagh …
Assisted dying: Guernsey rejects proposal to move towards legalisation
Authors: Adrian O’Dowd
Journal: BMJ (2018)

A majority of politicians in Guernsey have voted against a proposal that would have approved moves towards legalising assisted dying—a change that would have created the first such regime in the British Isles.

After a highly charged three day debate held on 16-18 May a proposal made by Gavin St Pier, chief minister at Guernsey’s parliament and president of the policy and resources committee, was defeated by 24 votes to 14.

His “Requete”1—the closest equivalent to a private member’s bill in Westminster—had proposed agreeing, in principle, to developing a suitable legal regime to permit assisted dying in Guernsey for people who are terminally ill and mentally competent, as …