tbuckley/cabot-search huggingface dataset:
Epidemiology of intra-abdominal infection and sepsis in critically ill patients: “AbSeS”, a multinational observational cohort study and ESICM Trials Group Project
Authors: Stijn Blot, Massimo Antonelli, Kostoula Arvaniti, Koen Blot, Ben Creagh-Brown, Dylan de Lange, Jan De Waele, Mieke Deschepper, Yalim Dikmen, George Dimopoulos, Christian Eckmann, Guy Francois, Massimo Girardis, Despoina Koulenti, Sonia Labeau, Jeffrey Lipman, Fernando Lipovestky, Emilio Maseda, Philippe Montravers, Adam Mikstacki, José-Artur Paiva, Cecilia Pereyra, Jordi Rello, Jean-Francois Timsit, Dirk Vogelaers
Journal: Intensive Care Medicine (2019)

To describe the epidemiology of intra-abdominal infection in an international cohort of ICU patients according to a new system that classifies cases according to setting of infection acquisition (community-acquired, early onset hospital-acquired, and late-onset hospital-acquired), anatomical disruption (absent or present with localized or diffuse peritonitis), and severity of disease expression (infection, sepsis, and septic shock). We performed a multicenter (n = 309), observational, epidemiological study including adult ICU patients diagnosed with intra-abdominal infection. Risk factors for mortality were assessed by logistic regression analysis. The cohort included 2621 patients. Setting of infection acquisition was community-acquired in 31.6%, early onset hospital-acquired in 25%, and late-onset hospital-acquired in 43.4% of patients. Overall prevalence of antimicrobial resistance was 26.3% and difficult-to-treat resistant Gram-negative bacteria 4.3%, with great variation according to geographic region. No difference in prevalence of antimicrobial resistance was observed according to setting of infection acquisition. Overall mortality was 29.1%. Independent risk factors for mortality included late-onset hospital-acquired infection, diffuse peritonitis, sepsis, septic shock, older age, malnutrition, liver failure, congestive heart failure, antimicrobial resistance (either methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing Gram-negative bacteria, or carbapenem-resistant Gram-negative bacteria) and source control failure evidenced by either the need for surgical revision or persistent inflammation. This multinational, heterogeneous cohort of ICU patients with intra-abdominal infection revealed that setting of infection acquisition, anatomical disruption, and severity of disease expression are disease-specific phenotypic characteristics associated with outcome, irrespective of the type of infection. Antimicrobial resistance is equally common in community-acquired as in hospital-acquired infection.
CACYBP Enhances Cytoplasmic Retention of P27<sup>Kip1</sup> to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation
Authors: Yi-Fan Lian, Yan-Lin Huang, Yao-Jun Zhang, Dong-Mei Chen, Jia-Liang Wang, Huan Wei, Yan-Hua Bi, Zhi-Wu Jiang, Peng Li, Min-Shan Chen, Yue-Hua Huang
Journal: Theranostics (2019)

Calcyclin-binding protein (CACYBP) is a multi-ligand protein implicated in the progression of various human cancers.However, its function in hepatocellular carcinoma (HCC) remains unknown.Methods: The expression of CACYBP and RNF41 (RING finger protein 41) in HCC cancer and adjacent non-tumor tissues was detected by immunohistochemistry. CCK-8 assays, colony formation assays, flow cytometry detection and xenograft models were used to evaluate the impact of CACYBP expression on HCC cell growth, apoptosis and cell cycle regulation.Immunoprecipitation and ubiquitination assays were performed to determine how RNF41 regulates CACYBP.The regulatory mechanism of RNF41-CACYBP signaling axis on P27 Kip1 was investigated by western blotting and immunofluorescence.Results: CACYBP was highly expressed and associated with poor prognosis in HCC.CACYBP expression was required for HCC cell growth in vitro and in vivo.Moreover, we identified RNF41 as a specific binding partner of CACYBP at exogenous and endogenous levels.RNF41 recruited CACYBP by its C-terminal substrate binding domain, subsequently ubiquitinating CACYBP and promoting its degradation in both proteasome-and lysosome-dependent pathways.In HCC tissues, RNF41 expression was reduced and conferred a negative correlation with CACYBP expression.Mechanistically, CACYBP overexpression stimulated the Ser10, Thr157 and Thr198 phosphorylation of P27 Kip1 and its cytoplasmic retention, and RNF41 co-expression attenuated this phenomenon.CACYBP depletion led to decreased levels of cyclin D1, cyclin A2, CDK2 and CDK4, causing a typical cell cycle arrest at G1/S phase and increasing apoptosis in HCC cells.P27 Kip1 -S10D but not P27 Kip1 -S10A reconstitution rescued partially the cell cycle function and apoptotic feature after CACYBP depletion.Conclusion: Our findings provide novel insights into the functional role and regulatory mechanism of CACYBP in HCC.
Assessment of phosphatidylinositol-3 kinase (PI3K) as a prognostic marker in head and neck squamous cell carcinoma (HNSCC)
Authors: E. Pectasides, G. Founztilas, C. Sasaki, B. Burtness, A. Psyrri
Journal: Journal of Clinical Oncology (2009)

e17028 Background: Deregulated signaling through phosphatidylinositol 3’-kinase (PI3K) pathway is common in several cancers, including HNSCC. In the present study we investigated the relationship between PI3K protein expression and outcome in patients with HNSCC. Methods: A tissue microarray composed of 122 specimens from primary HNSCC cases treated with either external beam radiotherapy (EBRT) or gross total surgical resection and EBRT was constructed. Protein expression levels for PI3K were analyzed using an immunofluorescence-based assay that provides an automated, quantitative analysis of expression within subcellular compartments (AQUA). Primary endpoints were progression-free survival (PFS) and overall survival (OS). Survival analysis was performed by Kaplan-Meier method with log-rank test for assessing statistical significance. Results: Mean follow-up time for the cohort was 40 months. Ninety-seven of 122 cases had sufficient tissue for analysis and continuous AQUA scores were divided into quartiles. Survival analysis showed that patients in the top and bottom quartile had a significantly shorter OS (p = 0.015). In multivariable analysis, adjusting for well-characterized prognostic variables, PI3K expression retained its prognostic significance. Conclusions: Our study suggests that in situ quantitative measurement of PI3K stratifies HNSCC into four expression levels where both low and high levels are associated with a worse outcome. We speculate that transmission of growth factor receptor signals that promote tumor aggression in these low expressers may occur via PI3K/Akt independent mechanisms. It is possible that activation of such alternate pathways in some tumors results in the down-regulation of PI3K expression via a feedback mechanism, producing aggressive tumors bearing a PI3K-low phenotype. No significant financial relationships to disclose.
Theranostic application of <i>miR-429</i> in HER2+ breast cancer
Authors: Claudia Cava, Chiara Novello, Cristina Martelli, Alessia Lodico, Luisa Ottobrini, Francesca Piccotti, Marta Truffi, Fabio Corsi, Gloria Bertoli, Isabella Castiglioni
Journal: Theranostics (2019)

Human epidermal growth factor receptor 2 (HER2) is overexpressed/amplified in one third of breast cancers (BCs), and is associated with the poorer prognosis and the higher metastatic potential in BC.Emerging evidences highlight the role of microRNAs (miRNAs) in the regulation of several cellular processes, including BC. Methods: Here we identified, by in silico approach, a group of three miRNAs with central biological role (high degree centrality) in HER2+ BC.We validated their dysregulation in HER2+ BC and we analysed their functional role by in vitro approaches on selected cell lines and by in vivo experiments in an animal model.Results: We found that their expression is dysregulated in both HER2+ BC cell lines and human samples.Focusing our study on the only upregulated miRNA, miR-429, we discovered that it acts as an oncogene and its upregulation is required for HER2+ cell proliferation.It controls the metastatic potential of HER2+ BC subtype by regulating migration and invasion of the cell. Conclusions:In HER2+ BC oncogenic miR-429 is able to regulate HIF1α pathway by directly targeting VHL mRNA, a molecule important for the degradation of HIF1α.The overexpression of miR-429, observed in HER2+ BC, causes increased proliferation and migration of the BC cells.More important, silencing miR-429 succeeds in delaying tumor growth, thus miR-429 could be proposed as a therapeutic probe in HER2+ BC tumors.
A novel method for engineering autologous non-thrombogenic in situ tissue-engineered blood vessels for arteriovenous grafting
Authors: W.J. Geelhoed, K.E.A. van der Bogt, T.C. Rothuizen, F.F.R. Damanik, J.F. Hamming, C.D. Mota, M.S. van Agen, H.C. de Boer, M. Tobón Restrepo, B. Hinz, A. Kislaya, C. Poelma, A.J. van Zonneveld, T.J. Rabelink, L. Moroni, J.I. Rotmans
Journal: Biomaterials (2019)
Initiation of Angiotensin Receptor-Neprilysin Inhibitor in Heart Failure With Low Cardiac Output
Authors: Trejeeve Martyn, Kathleen D. Faulkenberg, Dmitry M. Yaranov, Chonyang L. Albert, Colleen Hutchinson, Venu Menon, Jerry D. Estep, Steven E. Nissen, W.H. Wilson Tang, Randall C. Starling
Journal: Journal of the American College of Cardiology (2019)
Cost-Effectiveness Analysis of Screening for Hepatitis B Virus Infection in Patients With Solid Tumors Before Initiating Chemotherapy
Authors: Gauree G. Konijeti, Sirisha Grandhe, Monica Tincopa, Jill A. Lane, Mark G. Shrime, Siddharth Singh, Rohit Loomba
Journal: Clinical Gastroenterology and Hepatology (2019)
Biology vs Access to Care—Relative Contribution to Racial Disparities in Prostate Cancer
Authors: Travis Gerke, Shivanshu Awasthi, Kosj Yamoah
Journal: JAMA Oncology (2019)

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Mesenchymal stem cell transplantation alleviates experimental Sjögren's syndrome through IFN-β/IL-27 signaling axis
Authors: Genhong Yao, Jingjing Qi, Jun Liang, Bingyu Shi, Weiwei Chen, Wenchao Li, Xiaojun Tang, Dandan Wang, Liwei Lu, Wanjun Chen, Songtao Shi, Yayi Hou, Lingyun Sun
Journal: Theranostics (2019)

Rationale: Although mesenchymal stem cell (MSC) transplantation has been proved to be an effective therapeutic approach to treat experimental Sjögren's syndrome (SS), the detailed underlying mechanisms remains unknown. IL-27 has diverse influences on the regulation of T cell differentiation and was involved in SS through modulating immune response. Here we aimed to explore whether IL-27-mediated regulation of immune cells was responsible for the beneficial effects of MSC transplantation on SS. Methods: The SS-like symptoms were evaluated in IL-27 deficient and recombinant IL-27-treated NOD mice. The MSCs were infused into NOD mice via the tail vein. The histological features of submandibular glands, saliva flow rate and serum IL-27 were examined. The effects of MSCs on the IL-27 production and Th17/Treg cell in SS patients and mice in vitro and in vivo were determined for the mechanistic study. Results: This study showed that SS patients had decreased IL-27 level and increased ratio of Th17/Treg cells. Consistently, exacerbated SS-like symptoms were observed in IL-27 deficient NOD mice, along with increased ratio of Th17/Treg cells. Importantly, MSC transplantation alleviated SS-like symptoms by elevating the level of IL-27 to restore Th17/Treg balance in NOD mice. Mechanistically, MSC-secreted interferon-β (IFN-β) promote dendritic cells to produce IL-27. Conclusions: Thus, we have revealed a previously unrecognized function of MSC-mediated IL-27 production by DCs in suppressing SS-like syndrome, which provided evidences for clinical application of MSC in patients with SS.
David Oliver: Reducing emergency admissions from care homes
Authors: David Oliver
Journal: BMJ (2019)

The Health Foundation recently published a report on emergency hospital admissions from care homes.1 The analysis, coproduced with NHS England, found that 41% were for “potentially avoidable conditions,” such as respiratory infections, pressure sores, and urinary tract infections. It estimated that one in every 12 patients admitted to emergency wards is a care home resident—around 192 000 a year.

Care home residents are often in the final phase of life: median survival from entry is around two years (less in nursing homes than residential homes), with a 55% chance of surviving the first year.2 Advance care planning and support at the end of life should surely …
Heart rate and metabolic profile in relation to estradiol and progesterone in premenopausal women- possible biomarkers for breast cancer?
Authors: Emaus Aina, Marit Bragelien Veierod, Christine Friedenreich, Sissi Espetvedt, Peter Ellison, Grazyna Jasienska, Inger Thune
Journal: Cancer Research (2008)

3075  Background: To study whether women with a tendency to develop metabolic syndrome, have high levels of 17β-estradiol (E2) and mid-luteal progesterone (P) of importance for breast cancer risk.  Methods: 204 healthy women of reproductive age were assessed for resting heart rate (HR), blood pressure (BP), anthropometry, and glucose, lipids and insulin. E2 and P were measured in daily saliva samples throughout an entire menstrual cycle and analyzed using radio immune assay (RIA). A clustered metabolic risk score, zMS, was defined and included; total cholesterol:HDL-C-ratio, insulin resistance, total fat tissue, BP and triglycerides. Linear regression and linear mixed models were used and confounding factors were tested.  Results: We estimated an increase in E2 of 1.27 pmol/L (95% CI, 0.06-2.47) for each 11.7 beats/min (1SD) increase in HR, and this correspond to 7% change in mean concentration of E2 for the total group. Associations with E2 was also found for fat tissue, total cholesterol:HDL-C-ratio, insulin resistance and triglycerides. We found no association between P and the same factors. A dose-response relationship was observed among three levels of HR (tertiles) and zMS (ptrend=0.004). Women in the highest tertile of the clustered metabolic risk score had average salivary E2 profiles that were markedly higher, throughout the cycle, than those of the other groups, with a cycle peak-day difference in E2 of 22-29%.  Conclusion: Daily level of 17β-estradiol was found to be associated with a clustered metabolic risk score, pointing to important biologic mechanisms of importance for breast cancer risk.
Medicine and the Mind — The Consequences of Psychiatry’s Identity Crisis
Authors: Caleb Gardner, Arthur Kleinman
Journal: New England Journal of Medicine (2019)

Interview with Dr. Caleb Gardner on the limitations of an increasing focus on biologic knowledge in psychiatry. (11:22)Download In psychiatry, checklists of symptoms now take the place of thoughtful diagnosis, and trial-and-error "medication management" dominates practice. We face stark limitations of biologic treatments, while finding less time to work with patients on difficult problems.
Cell‐of‐origin determined by both gene expression profiling and immunohistochemistry is the strongest predictor of survival in patients with diffuse large B‐cell lymphoma
Authors: Maysaa Abdulla, Peter Hollander, Tatjana Pandzic, Larry Mansouri, Susanne Bram Ednersson, Per‐Ola Andersson, Magnus Hultdin, Maja Fors, Martin Erlanson, Sofie Degerman, Helga Munch Petersen, Fazila Asmar, Kirsten Grønbæk, Gunilla Enblad, Lucia Cavelier, Richard Rosenquist, Rose‐Marie Amini
Journal: American Journal of Hematology (2019)

The tumor cells in diffuse large B-cell lymphomas (DLBCL) are considered to originate from germinal center derived B-cells (GCB) or activated B-cells (ABC). Gene expression profiling (GEP) is preferably used to determine the cell of origin (COO). However, GEP is not widely applied in clinical practice and consequently, several algorithms based on immunohistochemistry (IHC) have been developed. Our aim was to evaluate the concordance of COO assignment between the Lymph2Cx GEP assay and the IHC-based Hans algorithm, to decide which model is the best survival predictor. Both GEP and IHC were performed in 359 homogenously treated Swedish and Danish DLBCL patients, in a retrospective multicenter cohort. The overall concordance between GEP and IHC algorithm was 72%; GEP classified 85% of cases assigned as GCB by IHC, as GCB, while 58% classified as non-GCB by IHC, were categorized as ABC by GEP. There were significant survival differences (overall survival and progression-free survival) if cases were classified by GEP, whereas if cases were categorized by IHC only progression-free survival differed significantly. Importantly, patients assigned as non-GCB/ABC both by IHC and GEP had the worst prognosis, which was also significant in multivariate analyses. Double expression of MYC and BCL2 was more common in ABC cases and was associated with a dismal outcome. In conclusion, to determine COO both by IHC and GEP is the strongest outcome predictor to identify DLBCL patients with the worst outcome.
Assessment of Caregiver-Targeted Interventions for Use of Motor Vehicle Passenger Safety Systems for Children
Authors: Emma Sartin, Tyler R. Bell, Catherine C. McDonald, Jessica Hafetz Mirman
Journal: JAMA Network Open (2019)

Caregiver-targeted interventions to improve the use of child restraint systems (CRS) in motor vehicles are common and heterogeneous in their implementation. The effectiveness of these interventions is unknown.To quantify the effects of caregiver-targeted interventions using meta-analytic methods, assess the quality of published studies, and assess for publication bias.PubMed and PsychINFO (January 1, 2004, to April 1, 2019) were searched for English-language studies using a list of search terms. The search and screening process was completed between May 25, 2018, and April 1, 2019.Studies met inclusion criteria if they included a caregiver-targeted intervention that focused on increasing CRS use for children (age, ≤9 years) and report the use of CRS before and after the intervention.Cochrane and PRISMA guidelines were used for the meta-analysis and risk-of-bias review. Information was extracted on intervention type, setting, implementation, and attributes of the study independently between 2 coders. Data were pooled from independent samples, with 1 outcome measure from each intervention implementation or study.This study was an exploratory random-effects meta-analysis. Unadjusted odds ratios were calculated using the sample size and the observed number of children in incorrect or correct restraints in motor vehicles before and after the intervention to determine the odds of incorrect CRS use after completing an intervention. Setting, measurement method, randomization, use of vouchers, and types of restraint were tested as moderators. A funnel plot was used to assess for publication bias.Of 1240 potential articles, 51 were deemed eligible for screening and 10 (8238 participants total) were included in the meta-analysis. Caregiver-targeted interventions were associated with a reduction in the number of children not riding in a CRS (odds ratio, 0.51; 95% CI, 0.36-0.71; P < .001). Variance in the averaged effect size was driven by self-report methods (when removed from analyses, I2 = 61.8%; R2 change = 26.3; P = .02) and hospital settings (when removed from analyses, I2 = 70.7%; R2 change = 17.4; P = .002). Risk of bias was high in most studies; however, there was low evidence for publication bias.In this meta-analysis, caregiver-targeted interventions were associated with a reduction in the number of children not riding in a CRS in motor vehicles; however, the methodological rigor of intervention studies should be enhanced.
Optogenetic control of mesenchymal cell fate towards precise bone regeneration
Authors: Weicai Wang, Delan Huang, Jianhan Ren, Runze Li, Zhicai Feng, Chenyu Guan, Baicheng Bao, Bin Cai, Junqi Ling, Chen Zhou
Journal: Theranostics (2019)

Rationale: Spatial-temporal control of cell fate in vivo is of great importance for regenerative medicine. Currently, there remain no practical strategies to tune cell-fate spatial-temporally. Optogenetics is a biological technique that widely used to control cell activity in genetically defined neurons in a spatiotemporal-specific manner by light. In this study, optogenetics was repurposed for precise bone tissue regeneration. Methods: Lhx8 and BMP2 genes, which are considered as the master genes for mesenchymal stem cell proliferation and differentiation respectively, were recombined into a customized optogenetic control system. In the system, Lhx8 was constitutively expressed, while BMP2 together with shLhx8 expression was driven by blue light. Results: As expected, blue light induced BMP2 expression and inactivated Lhx8 expression in cells infected with the optogenetic control system. Optogenetic control of BMP2 and Lhx8 expression inversely regulates MSC fate in vitro. By animal study, we found that blue light could fine-tune the regeneration in vivo. Blue light illumination significantly promotes bone regeneration when the scaffold was loaded with MSCs infected with adeno-Lhx8, GI-Gal4DBD, LOV-VP16, and BMP2-shLhx8. Conclusions: Together, our study revealed that optogenetic control of the master genes for mesenchymal stem cell proliferation and differentiation would be such a candidate strategy for precise regenerative medicine.