tbuckley/cabot-search huggingface dataset:
Robust suppression of cardiac energy catabolism with marked accumulation of energy substrates during lipopolysaccharide-induced cardiac dysfunction in mice
Authors: Yogi Umbarawan, Mas Rizky A.A. Syamsunarno, Hideru Obinata, Aiko Yamaguchi, Hiroaki Sunaga, Hiroki Matsui, Takako Hishiki, Tomomi Matsuura, Norimichi Koitabashi, Masaru Obokata, Hirofumi Hanaoka, Anwarul Haque, Fumio Kunimoto, Yoshito Tsushima, Makoto Suematsu, Masahiko Kurabayashi, Tatsuya Iso
Journal: Metabolism (2017)

Myocardial contractile dysfunction in sepsis has been attributed mainly to increased inflammatory cytokines, insulin resistance, and impaired oxidative phosphorylation of fatty acids (FAs). However, precise molecular mechanisms underlying the cardiac dysfunction in sepsis remain to be determined. We previously reported major shift in myocardial energy substrates from FAs to glucose, and increased hepatic ketogenesis in mice lacking fatty acid-binding protein 4 (FABP4) and FABP5 (DKO).We sought to determine whether a shift of energy substrates from FAs to glucose and increased availability of ketone bodies are beneficial or detrimental to cardiac function under the septic condition.Lipopolysaccharide (LPS, 10mg/kg) was intraperitoneally injected into wild-type (WT) and DKO mice. Twelve hours after injection, cardiac function was assessed by echocardiography and serum and hearts were collected for further analyses.Cardiac contractile function was more deteriorated by LPS injection in DKO mice than WT mice despite comparable changes in pro-inflammatory cytokine production. LPS injection reduced myocardial uptake of FA tracer by 30% in both types of mice, while uptake of the glucose tracer did not significantly change in either group of mice in sepsis. Storage of glycogen and triacylglycerol in hearts was remarkably increased by LPS injection in both mice. Metabolome analysis revealed that LPS-induced suppression of pool size in the TCA cycle was more enhanced in DKO hearts. A tracing study with 13C6-glucose further revealed that LPS injection substantially reduced glucose-derived metabolites in the TCA cycle and related amino acids in DKO hearts. Consistent with these findings, glucose oxidation in vitro was similarly and markedly reduced in both mice. Serum concentration of β-hydroxybutyrate and cardiac expression of genes associated with ketolysis were reduced in septic mice.Our study demonstrated that LPS-induced cardiac contractile dysfunction is associated with the robust suppression of catabolism of energy substrates including FAs, glucose and ketone bodies and accumulation of glycogen and triacylglycerol in the heart. Thus, a fuel shift from FAs to glucose and/or ketone bodies may be detrimental rather than protective under septic conditions.
The Use of PET Imaging for Prognostic Integrin α<sub>2</sub>β<sub>1</sub> Phenotyping to Detect Non-Small Cell Lung Cancer and Monitor Drug Resistance Responses
Authors: Chiun-Wei Huang, Wen-Chuan Hsieh, Shih-Ting Hsu, Yi-Wen Lin, Yi-Hsiu Chung, Wen-Chi Chang, Han Chiu, Yun Han Lin, Chung-Pu Wu, Tzu-Chen Yen, Feng-Ting Huang
Journal: Theranostics (2017)

PURPOSE: Growing evidence has demonstrated that aberrant expression of integrin α2β1 might contribute to the invasion, metastasis and drug resistance of non-small cell lung cancer (NSCLC).Thus, the integrin α2β1 targeting 68 Ga-DOTA-A2B1 tracer was validated in NSCLC in contrast to accumulation of the clinically used 18 F-FDG PET tracer to see if 68 Ga-DOTA-A2B1-PET imaging can offer a valuable and critical diagnostic imaging criterion for the identification of phenotypes of aggressive lung cancer.METHODS: To verify the prognostic value of integrin α2β1, several quantitative and functional in vitro assays were validated in different NSCLC cell lines (CL1-0, CL1-5, A549 and selected A549 ++ cells).Positron emission tomography (PET) imaging studies using both standard 18 F-FDG and a newly developed 68 Ga-labeled integrin α2β1 ( 68 Ga-DOTA-A2B1) tracer were sequentially performed on mice with lung tumor xenografts in different anatomic locations (subcutaneous, orthotopic and osseous) to validate the targeting capability of the 68 Ga-DOTA-A2B1 tracers.Treatment responses were monitored by injecting animals with metastatic bone tumors with 5 mg/kg doxorubicin.All in vivo treatment responses in each treatment subgroup were monitored with a PET imaging system to evaluate the up-regulation of integrin expression at the earliest stage of treatment (6 h).RESULTS: The PET and computed tomography (CT) images from NSCLC xenograft animals unambiguously demonstrated accumulation of the integrin tracer 68 Ga-DOTA-A2B1 in the tumor lesions at all locations.The average tumor uptake and tumor-to-normal (T/N) ratio were 2.51 ± 0.56 %ID/g and T/N = 2.82, 3.40 ± 0.42 %ID/g and T/N = 1.52, and 1.58 ± 0.108 %ID/g and T/N = 2.31 in subcutaneous, orthotopic and osseous tumors, respectively (n = 5; p < 0.05).The xenograft tumors were all clearly visible.In contrast, the accumulation of 18 F-FDG reached 3.6 ± 0.76 %ID/g, 1.39 ± 0.075 %ID/g and 3.78 ± 0.73 %ID/g in subcutaneous, orthotopic and osseous tumors, respectively (n = 5; p < 0.05).However, due to the high background uptake by normal tissue, the T/N values were less than or close to 1, making the tumors almost indistinguishable in the PET imaging analysis.Furthermore, 68 Ga-DOTA-A2B1-PET imaging of the treated osseous tumor model demonstrated more than 19% tracer uptake in A549 lesions (1.72 ± 0.95 %ID/g vs. pretreatment 1.44 ± 0.12 %ID/g,p = 0. 015) 6 h post-treatment with doxorubicin.The elevated intensity of tracer uptake was in accordance with the results of in vitroWestern blot and ex vivo integrin staining, demonstrating elevated integrin α2β1 expression.
An older woman with spontaneous bruising
Authors: Muhajir Mohamed, Ajay Prakash
Journal: BMJ (2017)

An 85 year old woman attended the emergency department with large bruises on her right forearm and left leg, which had appeared four days earlier. She had not sustained any injuries to account for the bruising. There was no bleeding from any other sites. Her only medical history was hypertension. Her medications included amlodipine and calcium supplements and she wasn’t taking aspirin, anticoagulants, or any over-the-counter medications. On examination there were extensive subcutaneous haematomas on the right forearm extending up to the upper arm and on the left leg extending up to the thigh (fig 1, 2⇓). Initial investigations showed low haemoglobin of 95 g/L with a normal platelet count (369 × 109/L). Coagulation assays showed markedly elevated activated partial thromboplastin time of 74 seconds (reference range 25 to 35 seconds). Prothrombin time was normal (12.2 seconds, reference range: 11 to 13 seconds), however, and fibrinogen assay was within normal limits (3.8 g/L, reference range 1.5 to 4.0 g/L). Mixing studies with 1 part of patient’s plasma and 1 part of pooled normal plasma (1:1 mix) showed no correction of elevated activated partial thromboplastin time. Further tests were performed to determine the reason for the elevated activated partial thromboplastin time. Factor assays revealed very low level of factor VIII (<1 IU/dL, reference range 50 – 150 IU/dL), and factors IX, XI, and XII were within normal ranges.



Fig 1  Large subcutaneous haematoma in the right forearm extending to the upper arm





Fig 2  Extensive subcutaneous haematoma in the left foot …
Blood hemoglobin A1c levels and amyotrophic lateral sclerosis survival
Authors: Qian Qian Wei, Yongping Chen, Bei Cao, Ru Wei Ou, Lingyu Zhang, Yanbing Hou, Xiang Gao, Huifang Shang
Journal: Molecular Neurodegeneration (2017)

There are inconsistences regarding the correlation between diabetes or fasting blood glucose concentrations and the risk and survival of amyotrophic lateral sclerosis (ALS) in the previous studies. Moreover, the association between hemoglobin A1c (HbA1c) levels, which reflect long-term glycemic status, and ALS survival was not examined. A prospective cohort study including 450 Chinese sporadic ALS patients (254 men and 196 women; mean age: 55.4 y). We identified 223 deaths during average 1.6 years of follow-up. We assessed levels of fasting HbA1c (primary exposure) and glucose (secondary exposure) via ion exchange high-performance liquid chromatography and hexokinase/glucose-6-pgosphate dehydrogenase methods, respectively. Multivariate Cox proportional hazards regression model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of ALS mortality across the exposures. Our results indicated that, higher levels of HbA1c, but not fasting blood glucose concentrations, were significantly associated with higher risks of mortality. The adjusted HR was 1.40 (95% confidence interval (95% CI): 1.02–1.99) for HbA1c of 5.7–6.4%, and 2.06 (95% CI: 1.07–3.96) for HbA1c ≥6.5%, relative to HbA1c <5.7% (P trend =0.01), after adjustment for age, smoking, obesity, disease severity, site of onset, lifestyle, and other potential confounders. The adjusted HR was 1.38 (95% CI: 0.81–2.35, P trend =0.13) for fasting glucose concentrations ≥7.0 mmol/L vs <5.6 mmol/L. We did not observe any significant interactions between HbA1c levels and age, sex, smoking, body mass index, rate of disease progression of ALS, and site of onset (P-interactions >0.05 for all). In this prospective study, we observed that individuals with higher HbA1c levels at the baseline had higher risk of mortality, which is independent of other known risk factors.
Diabetes Treatments and Risks of Adverse Breast Cancer Outcomes among Early-Stage Breast Cancer Patients: A SEER-Medicare Analysis
Authors: Lu Chen, Jessica Chubak, Denise M. Boudreau, William E. Barlow, Noel S. Weiss, Christopher I. Li
Journal: Cancer Research (2017)

Abstract The widely prescribed diabetes medicine metformin has been reported to lower the risk of incident breast cancer, but it is unclear whether it affects malignant progression after diagnosis. In this study, we conducted a retrospective cohort study using the linked Surveillance, Epidemiology, and End-Results (SEER)-Medicare database. Women were included in the study if they were aged 66 to 80 years, newly diagnosed with stage I or II breast cancer, and enrolled in Medicare Parts A, B, and D during 2007 to 2011. Information on dispensed diabetes-related medications was obtained from Medicare Part D claims data. Our primary outcomes were second breast cancer events (SBCE), breast cancer recurrence, and breast cancer death. Time-varying Cox proportional hazard models were used to estimate HRs and their 95% confidence intervals (CI). Among 14,766 women included in the study, 791 experienced SBCE, 627 had a recurrence, and 237 died from breast cancer. Use of metformin (n = 2,558) was associated with 28% (95% CI, 0.57–0.92), 31% (95% CI, 0.53–0.90), and 49% (95% CI, 0.33–0.78) lower risks of an SBCE, breast cancer recurrence, and breast cancer death. Use of sulfonylureas or insulin was associated with 1.49- (95% CI, 1.00–2.23) and 2.58-fold (95% CI, 1.72–3.90) higher risks of breast cancer death. Further research may be warranted to determine whether metformin is a preferred treatment for diabetes among breast cancer survivors and whether it benefits breast cancer patients without diabetes. Cancer Res; 77(21); 6033–41. ©2017 AACR.
Reply
Authors: Xavier Puéchal, Christian Pagnoux, Loïc Guillevin
Journal: Arthritis & Rheumatology (2017)

Dr. Smitienko and colleagues commented on our trial on the interest of azathioprine (AZA) adjunction to glucocorticoids to induce remission of systemic necrotizing vasculitides (SNVs) without poor-prognosis factors, more specifically on eosinophilic granulomatosis with polyangiitis (EGPA). We fully agree that EGPA is a heterogenous disease. Indeed, we (1) and others (2) demonstrated that antineutrophil cytoplasm antibody (ANCA)-positive and ANCA-negative EGPA differ phenotypically. Among the CHUSPAN2 trial's 95 patients, 51 had new-onset EGPA, 19 (37%) of which were anti-myeloperoxidase–positive. Our trial was not designed to evaluate AZA efficacy according to EGPA phenotypes and too few EGPA patients were enrolled to conduct any valid comparison between subgroups. Because our CHUSPAN2 study addressed the efficacy of 1-year of adjunctive AZA as induction and maintenance therapy, data are lacking to determine whether a more prolonged AZA regimen would be beneficial for some patients.

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Response to ‘Analysis of learning curves in gastroscopy training: the need for composite measures for defining competence’ by Siau <i>et al</i>
Authors: Stephen Thomas Ward, Paul Dunckley
Journal: Gut (2017)

We are thankful for the letter of Siau et al 1 in response to our article describing the learning curve to satisfactory completion rates in upper GI endoscopy.2 

We agree that D2 intubation and successful J manoeuvre are insufficient to define competence. Our article’s title stated that we focused on completion rates. We specifically mentioned in our discussion that it is necessary to comply with a host of other measures to be competent. For example, procedural completion and successful J manoeuvre do not ensure complete inspection of the mucosa, nor do they result in correct identification of pathology. We welcome the introduction by Joint Advisory Group of assessment of endoscopic non-technical skills and support direct observation of procedural skills …
The implementation of the Plan Esperanza and response to the imPACT Review
Authors: Tatiana Vidaurre, Carlos Santos, Henry Gómez, Gustavo Sarria, Edgar Amorin, Marga López, Roxana Regalado, Javier Manrique, Duniska Tarco, Carlos Ayestas, Mónica Calderón, Luis Mas, Silvia Neciosup, Miriam Salazar, Juan Carlos Chávez, Milward Ubillus, Abel Limache, José Carlos Ubillus, Jeannie Navarro, Kavita Sarwal, Simon Sutcliffe, Alfonso Gutiérrez-Aguado, Marianela Silva, Amalia Mena, María Eugenia Guillén, Carlos Castañeda, Julio Abugattas
Journal: The Lancet Oncology (2017)
Clinical and molecular characterization of patients with cancer of unknown primary in the modern era
Authors: A.M. Varghese, A. Arora, M. Capanu, N. Camacho, H.H. Won, A. Zehir, J. Gao, D. Chakravarty, N. Schultz, D.S. Klimstra, M. Ladanyi, D.M. Hyman, D.B. Solit, M.F. Berger, L.B. Saltz
Journal: Annals of Oncology (2017)
Combined Prenatal Pesticide Exposure and Folic Acid Intake in Relation to Autism Spectrum Disorder
Authors: Rebecca J. Schmidt, Vladimir Kogan, Janie F. Shelton, Lora Delwiche, Robin L. Hansen, Sally Ozonoff, Claudia C. Ma, Erin C. McCanlies, Deborah H. Bennett, Irva Hertz-Picciotto, Daniel J. Tancredi, Heather E. Volk
Journal: Environmental Health Perspectives (2017)

Maternal folic acid (FA) protects against developmental toxicity from certain environmental chemicals.We examined combined exposures to maternal FA and pesticides in relation to autism spectrum disorder (ASD).Participants were California children born from 2000-2007 who were enrolled in the Childhood Autism Risks from Genetics and the Environment (CHARGE) case-control study at age 2-5 y, were clinically confirmed to have ASD (n=296) or typical development (n=220), and had information on maternal supplemental FA and pesticide exposures. Maternal supplemental FA and household pesticide product use were retrospectively collected in telephone interviews from 2003-2011. High vs. low daily FA intake was dichotomized at 800μg (median). Mothers' addresses were linked to a statewide database of commercial applications to estimate agricultural pesticide exposure.High FA intake (≥800μg) during the first pregnancy month and no known pesticide exposure was the reference group for all analyses. Compared with this group, ASD was increased in association with <800μg FA and any indoor pesticide exposure {adjusted odds ratio [OR]=2.5 [95% confidence interval (CI): 1.3, 4.7]} compared with low FA [OR=1.2 (95% CI: 0.7, 2.2)] or indoor pesticides [OR=1.7 (95% CI: 1.1, 2.8)] alone. ORs for the combination of low FA and regular pregnancy exposure (≥6 mo) to pet pesticides or to outdoor sprays and foggers were 3.9 (95% CI: 1.4, 11.5) and 4.1 (95% CI: 1.7, 10.1), respectively. ORs for low maternal FA and agricultural pesticide exposure 3 mo before or after conception were 2.2 (95% CI: 0.7, 6.5) for chlorpyrifos, 2.3 (95% CI: 0.98, 5.3) for organophosphates, 2.1 (95% CI: 0.9, 4.8) for pyrethroids, and 1.5 (95% CI: 0.5, 4.8) for carbamates. Except for carbamates, these ORs were approximately two times greater than those for either exposure alone or for the expected ORs for combined exposures under multiplicative or additive models.In this study population, associations between pesticide exposures and ASD were attenuated among those with high versus low FA intake during the first month of pregnancy. Confirmatory and mechanistic studies are needed. https://doi.org/10.1289/EHP604.
Staging in bipolar disorder: from theoretical framework to clinical utility
Authors: Michael Berk, Robert Post, Aswin Ratheesh, Emma Gliddon, Ajeet Singh, Eduard Vieta, Andre F. Carvalho, Melanie M. Ashton, Lesley Berk, Susan M. Cotton, Patrick D. McGorry, Brisa S. Fernandes, Lakshmi N. Yatham, Seetal Dodd
Journal: World Psychiatry (2017)

Illness staging is widely utilized in several medical disciplines to help predict course or prognosis, and optimize treatment. Staging models in psychiatry in general, and bipolar disorder in particular, depend on the premise that psychopathology moves along a predictable path: an at-risk or latency stage, a prodrome progressing to a first clinical threshold episode, and one or more recurrences with the potential to revert or progress to late or end-stage manifestations. The utility and validity of a staging model for bipolar disorder depend on its linking to clinical outcome, treatment response and neurobiological measures. These include progressive biochemical, neuroimaging and cognitive changes, and potentially stage-specific differences in response to pharmacological and psychosocial treatments. Mechanistically, staging models imply the presence of an active disease process that, if not remediated, can lead to neuroprogression, a more malignant disease course and functional deterioration. Biological elements thought to be operative in bipolar disorder include a genetic diathesis, physical and psychic trauma, epigenetic changes, altered neurogenesis and apoptosis, mitochondrial dysfunction, inflammation, and oxidative stress. Many available agents, such as lithium, have effects on these targets. Staging models also suggest the utility of stage-specific treatment approaches that may not only target symptom reduction, but also impede illness neuroprogression. These treatment approaches range from prevention for at-risk individuals, to early intervention strategies for prodromal and newly diagnosed individuals, complex combination therapy for rapidly recurrent illness, and palliative-type approaches for those at chronic, late stages of illness. There is hope that prompt initiation of potentially disease modifying therapies may preclude or attenuate the cognitive and structural changes seen in the later stages of bipolar disorder. The aims of this paper are to: a) explore the current level of evidence supporting the descriptive staging of the syndromal pattern of bipolar disorder; b) describe preliminary attempts at validation; c) make recommendations for the direction of further studies; and d) provide a distillation of the potential clinical implications of staging in bipolar disorder within a broader transdiagnostic framework.
BMA urges more career flexibility and better occupational support to fight workforce crisis
Authors: Abi Rimmer
Journal: BMJ (2017)

Doctors’ career flexibility must be increased, such as more options to work part time, and their health and wellbeing services improved to stop the staff shortage worsening, the BMA has said in a new briefing on the state of medical recruitment.1

To tackle what it described as a workforce crisis in medicine, the BMA also said that after Brexit the immigration system should enable the UK to recruit and retain the numbers of doctors it required if it couldn’t find enough in the country.

The BMA has gathered figures …
Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy
Authors: Jingying Zhou, Man Liu, Hanyong Sun, Yu Feng, Liangliang Xu, Anthony W H Chan, Joanna H Tong, John Wong, Charing Ching Ning Chong, Paul B S Lai, Hector Kwong-Sang Wang, Shun-Wa Tsang, Tyler Goodwin, Rihe Liu, Leaf Huang, Zhiwei Chen, Joseph JY Sung, King Lau Chow, Ka Fai To, Alfred Sze-Lok Cheng
Journal: Gut (2017)

Objective Myeloid-derived suppressor cells (MDSCs) contribute to tumour immunosuppressive microenvironment and immune-checkpoint blockade resistance. Emerging evidence highlights the pivotal functions of cyclin-dependent kinases (CDKs) in tumour immunity. Here we elucidated the role of tumour-intrinsic CDK20, or cell cycle-related kinase (CCRK) on immunosuppression in hepatocellular carcinoma (HCC). Design Immunosuppression of MDSCs derived from patients with HCC and relationship with CCRK were determined by flow cytometry, expression analyses and co-culture systems. Mechanistic studies were also conducted in liver-specific CCRK -inducible transgenic (TG) mice and Hepa1–6 orthotopic HCC models using CRISPR/Cas9-mediated Ccrk depletion and liver-targeted nanoparticles for interleukin (IL) 6 trapping. Tumorigenicity and immunophenotype were assessed on single or combined antiprogrammed death-1-ligand 1 (PD-L1) therapy. Results Tumour-infiltrating CD11b + CD33 + HLA-DR − MDSCs from patients with HCC potently inhibited autologous CD8 + T cell proliferation. Concordant overexpression of CCRK and MDSC markers (CD11b/CD33) positively correlated with poorer survival rates. Hepatocellular CCRK stimulated immunosuppressive CD11b + CD33 + HLA-DR − MDSC expansion from human peripheral blood mononuclear cells through upregulating IL-6. Mechanistically, CCRK activated nuclear factor-κB (NF-κB) via enhancer of zeste homolog 2 (EZH2) and facilitated NF-κB-EZH2 co-binding to IL-6 promoter. Hepatic CCRK induction in TG mice activated the EZH2/NF-κB/IL-6 cascade, leading to accumulation of polymorphonuclear (PMN) MDSCs with potent T cell suppressive activity. In contrast, inhibiting tumorous Ccrk or hepatic IL-6 increased interferon γ + tumour necrosis factor-α + CD8 + T cell infiltration and impaired tumorigenicity, which was rescued by restoring PMN-MDSCs. Notably, tumorous Ccrk depletion upregulated PD-L1 expression and increased intratumorous CD8 + T cells, thus enhancing PD-L1 blockade efficacy to eradicate HCC. Conclusion Our results delineate an immunosuppressive mechanism of the hepatoma-intrinsic CCRK signalling and highlight an overexpressed kinase target whose inhibition might empower HCC immunotherapy.
Abstract P101: Unprocessed and Processed Red Meat Consumption and Self-reported Hypertension among French Women
Authors: Martin Lajous, Anne Bijon, Guy Fagherazzi, Beverley Balkau, Marie-Christine Boutron-Ruault, Francoise Clavel-Chapelon
Journal: Circulation (2013)

Background—Unprocessed and processed red meat consumption have been hypothesized to have differential effects on cardiovascular disease due to differences in constituents. Long-term intake of high ...
IL-33 exacerbates liver sterile inflammation by amplifying neutrophil extracellular trap formation
Authors: Hamza O. Yazdani, Hui-Wei Chen, Samer Tohme, Sheng Tai, Dirk J. van der Windt, Patricia Loughran, Brian R. Rosborough, Vikas Sud, Donna Beer-Stolz, Heth R. Turnquist, Allan Tsung, Hai Huang
Journal: Journal of Hepatology (2017)