tbuckley/cabot-search huggingface dataset:
Post-discharge kidney function is associated with subsequent ten-year renal progression risk among survivors of acute kidney injury
Authors: Simon Sawhney, Angharad Marks, Nick Fluck, Adeera Levin, David McLernon, Gordon Prescott, Corri Black
Journal: Kidney International (2017)

The extent to which renal progression after acute kidney injury (AKI) arises from an initial step drop in kidney function (incomplete recovery), or from a long-term trajectory of subsequent decline, is unclear. This makes it challenging to plan or time post-discharge follow-up. This study of 14651 hospital survivors in 2003 (1966 with AKI, 12685 no AKI) separates incomplete recovery from subsequent renal decline by using the post-discharge estimated glomerular filtration rate (eGFR) rather than the pre-admission as a new reference point for determining subsequent renal outcomes. Outcomes were sustained 30% renal decline and de novo CKD stage 4, followed from 2003-2013. Death was a competing risk. Overall, death was more common than subsequent renal decline (37.5% vs 11.3%) and CKD stage 4 (4.5%). Overall, 25.7% of AKI patients had non-recovery. Subsequent renal decline was greater after AKI (vs no AKI) (14.8% vs 10.8%). Renal decline after AKI (vs no AKI) was greatest among those with higher post-discharge eGFRs with multivariable hazard ratios of 2.29 (1.88-2.78); 1.50 (1.13-2.00); 0.94 (0.68-1.32) and 0.95 (0.64-1.41) at eGFRs of 60 or more; 45-59; 30-44 and under 30, respectively. The excess risk after AKI persisted over ten years of study, irrespective of AKI severity, or post-episode proteinuria. Thus, even if post-discharge kidney function returns to normal, hospital admission with AKI is associated with increased renal progression that persists for up to ten years. Follow-up plans should avoid false reassurance when eGFR after AKI returns to normal.
Abstract 423: Proteasome Priming by Protein Kinase G Protects Against Myocardial Ischemia-reperfusion Injury
Authors: Xuejun Wang, Erin J Terpstra, Eduardo Callegari, Chengjun Hu, Hanming Zhang, Xuejun "XJ" Wang
Journal: Circulation Research (2015)

Cardiac proteasome functional insufficiency is implicated in a large subset of heart disease and has been experimentally demonstrated to play an essential role in cardiac proteotoxicity, including desmin-related cardiomyopathy and myocardial ischemia-reperfusion (I-R) injury. Pharmacological inhibition of phosphodiesterase 5 (PDE5) via sildenafil for example, which can stabilize cGMP and thereby increase cGMP-dependent protein kinase (PKG) activity, is consistently reported to protect against I-R injury; however, the underlying mechanism is not fully understood. We have recently discovered that PKG activation enhances proteasomal degradation of misfolded proteins (Ranek, et al. Circulation 2013), prompting us to hypothesize that proteasome-priming may contribute to cardioprotection-induced by PDE5 inhibition. Here we used a cardiomyocyte-restricted proteasome inhibition transgenic mouse line (Tg) and non-Tg (Ntg) littermates to interrogate the action of sildenafil on I-R injury created by left anterior descending artery (LAD) ligation (30 min) and release (24 hr). Sildenafil was administered 30 min before LAD ligation. Results showed that (1) the 26S proteasome activity of the Ntg I-R hearts was significantly elevated by sildenafil but this elevation was blocked in the Tg line; (2) the infarct size reduction by sildenafil treatment in Ntg mice was completely abolished in the Tg mice with the same treatment; and (3) systolic and diastolic function impairment after I/R was markedly attenuated in sildenafil-treated Ntg mice, but not in the sildenafil-treated Tg mice. Additionally, immunoprecipitation assays show that PKG interacted with the proteasome in cultured cardiomyocytes, and this interaction appeared to be augmented by sildenafil treatment. Moreover, in vitro incubation of active PKG with purified human 26S proteasomes increased proteasome peptidase activities and the phosphorylation at specific serine residues of a 19S proteasome subunit as revealed by “gel-free” nano-LC-MS/MS. We conclude that active PKG directly interacts with, phosphorylates, and increases the activities of, the proteasome and that proteasome priming mediates to cardioprotection of PDE5 inhibition against I-R injury.
BMI and All-Cause Mortality in Normoglycemia, Impaired Fasting Glucose, Newly Diagnosed Diabetes, and Prevalent Diabetes: A Cohort Study
Authors: Eun Young Lee, Yong-ho Lee, Sang-Wook Yi, Soon-Ae Shin, Jee-Jeon Yi
Journal: Diabetes Care (2017)

OBJECTIVE This study examined associations between BMI and mortality in individuals with normoglycemia, impaired fasting glucose (IFG), newly diagnosed diabetes, and prevalent diabetes and identified BMI ranges associated with the lowest mortality in each group. RESEARCH DESIGN AND METHODS A total of 12,815,006 adults were prospectively monitored until 2013. Diabetes status was defined as follows: normoglycemia (fasting glucose &amp;lt;100 mg/dL), IFG (100–125 mg/dL), newly diagnosed diabetes (≥126 mg/dL), and prevalent diabetes (self-reported). BMI (kg/m2) was measured. Cox proportional hazards model hazard ratios were calculated after adjusting for confounders. RESULTS During a mean follow-up period of 10.5 years, 454,546 men and 239,877 women died. U-shaped associations were observed regardless of diabetes status, sex, age, and smoking history. Optimal BMI (kg/m2) for the lowest mortality by group was 23.5–27.9 (normoglycemia), 25–27.9 (IFG), 25–29.4 (newly diagnosed diabetes), and 26.5–29.4 (prevalent diabetes). Higher optimal BMI by worsening diabetes status was more prominent in younger ages, especially in women. The relationship between worsening diabetes status and higher mortality was stronger with lower BMI, especially at younger ages. Given the same BMI, people with prevalent diabetes had higher mortality compared with those with newly diagnosed diabetes, and this was more striking in women than men. CONCLUSIONS U-curve relationships existed regardless of diabetes status. Optimal BMI for lowest mortality became gradually higher with worsening diabetes for each sex and each age-group.
TCTAP C-039 Directional Coronary Atherectomy in a Patient Who Was Intolerant for Dual Anti-platelet Therapy Due to Coexistent Malignancy yet Niche but Necessary Option
Authors: Kotaro Miyashita, Nobuhiko Ogata, Naoki Masuda, Hideaki Kido
Journal: Journal of the American College of Cardiology (2017)
Investigating in vitro and in vivo αvβ6 integrin receptor-targeting liposomal alendronate for combinatory γδ T cell immunotherapy
Authors: Naomi O. Hodgins, Wafa' T. Al-Jamal, Julie T.-W. Wang, Rebecca Klippstein, Pedro M. Costa, Jane K. Sosabowski, John F. Marshall, John Maher, Khuloud T. Al-Jamal
Journal: Journal of Controlled Release (2017)

The αvβ6 integrin receptor has been shown to be overexpressed on many types of cancer cells, resulting in a more pro-invasive and aggressive phenotype, this makes it an attractive target for selective drug delivery. In tumours that over-express the αvβ6 receptor, cellular uptake of liposomes can be enhanced using ligand-targeted liposomes. It has previously been shown in both in vitro and in vivo studies that liposomal alendronate (L-ALD) can sensitise cancer cells to destruction by Vγ9Vδ2 T cells. It is hypothesised that by using the αvβ6-specific peptide A20FMDV2 as a targeting moiety for L-ALD, the therapeutic efficacy of this therapy can be increased in αvβ6 positive tumours. Targeted liposomes (t-L) were formulated and the targeting efficacy of targeted liposomes (t-L) was assessed by cell uptake and cytotoxicity studies in the αvβ6 positive cells line A375Pβ6. Bio-distribution of both L and t-L were carried out in αvβ6 positive (A375Pβ6 and PANC0403) and αvβ6 negative (A375Ppuro and PANC-1) subcutaneous tumour mouse models. Immuno-compromised mice bearing A375Pβ6 experimental metastatic lung tumours were treated with L-ALD or t-L-ALD as monotherapies or in combination with ex vivo-expanded Vγ9Vδ2 T cells. In vitro, αvβ6-dependant uptake of t-L was observed, with t-L-ALD being more effective than L-ALD at sensitising A375Pβ6 to γδ T cells. Interestingly, t-L-ALD led to slightly higher but not significant reduction in tumour growth compared to L-ALD, when used as monotherapy in vivo. Moreover, both L-ALD and t-L-ALD led to significant reductions in tumour growth when used in combination with γδ T cells in vivo but t-L-ALD offered no added advantage compared to L-ALD.
Making the NHS and social care system sustainable
Authors: Jennifer Dixon
Journal: BMJ (2017)

The House of Lords has made a start on a longer term strategy

The UK is currently facing numerous complex challenges. A cross party House of Lords select committee has examined one—how the NHS and adult social care could best be sustained in the next 10-20 years. Drawing on evidence from hearings and written contributions over a year, the committee reported its recommendations earlier this month.1

The healthcare budget constitutes a sizeable and growing share of government spending—about one fifth in England, one third in Scotland, and one half in Wales—and the NHS consistently remains among the public’s top priorities.2 Governments will therefore have to be active in shaping the agenda. But the Lords’ report notes the endemic problem: governments have a tendency to short termism. The Department of Health is “unable or unwilling” to think beyond the next few years, and the NHS is often absorbed in everyday struggles, leaving the future to “take care of itself.” Traditional approaches—such as reactive and tactical …
TCTAP A-173 Clinical Outcomes of Successful Chronic Total Occlusion Percutaneous Coronary Intervention Using the Retrograde Approach
Authors: Osung Kwon, Do-Yoon Kang, Se Hun Kang, Pil Hyung Lee, Jung-Min Ahn, Duk-Woo Park, Soo-Jin Kang, Seung-Whan Lee, Young-Hak Kim, Cheol Whan Lee, Seong-Wook Park, Seung-Jung Park
Journal: Journal of the American College of Cardiology (2017)
IFN-λ3, not IFN-λ4, likely mediates IFNL3–IFNL4 haplotype–dependent hepatic inflammation and fibrosis
Authors: Mohammed Eslam, Duncan McLeod, Kebitsaone Simon Kelaeng, Alessandra Mangia, Thomas Berg, Khaled Thabet, William L Irving, Gregory J Dore, David Sheridan, Henning Grønbæk, Maria Lorena Abate, Rune Hartmann, Elisabetta Bugianesi, Ulrich Spengler, Angela Rojas, David R Booth, Martin Weltman, Lindsay Mollison, Wendy Cheng, Stephen Riordan, Hema Mahajan, Janett Fischer, Jacob Nattermann, Mark W Douglas, Christopher Liddle, Elizabeth Powell, Manuel Romero-Gomez, Jacob George
Journal: Nature Genetics (2017)
THE FUNCTIONAL MOVEMENT TEST 9+ IS A POOR SCREENING TEST FOR LOWER EXTREMITY INJURIES IN PROFESSIONAL MALE FOOTBALL
Authors: Arnhild Bakken, Stephen Targett, Tone Bere, Eirale Cristiano, Farooq Aziz, Tol Johannes, Whiteley Rod, Khan Karim, Bahr Roald
Journal: British Journal of Sports Medicine (2017)

Background The Nine Plus screening battery test (9+) is a series of 11 tests, used to assess limitations in fundamental movement patterns assumed to predispose athletes for injury. Objective To examine the association of the 9+ with lower extremity injuries, and to identify the optimal cut-off point for risk screening. Design Prospective cohort study. Setting Professional football league. Participants Male professional football players in Qatar. Interventions The 9+ test was performed prior to the 2013 and 2014 seasons. Time-loss injuries and exposure in training and matches were registered prospectively by club medical staff during 2 consecutive seasons. Univariate and multivariate regression analyses were used to calculate odds ratios (ORs), risk ratios (RR) and 95% confidence intervals (CIs). Receiver operating characteristics (ROC) curves were calculated to determine sensitivity and specificity, and identify the optimal cut-off point for risk assessment. Main Outcome Measurement Lower extremity injuries. Results In total, 363 players completed the 9+ and had injury and exposure registration. There were 527 injuries among 204 players (56.2%) during the 2 seasons; injuries to the thigh were most frequent. There was no association between 9+ total score and the risk of lower extremity injuries (OR, 1.02; 95% CI, 0.98–1.06; P =0.44), even when adjusted for exposure (RR, 1.04; 95% CI, 0.98–1.12; P =0.21) or other factors in a multivariate analysis (OR, 1.04; 95% CI, 0.97–1.06; P=0.60). ROC curve analysis revealed an area under the curve of 0.48 for lower extremity injury. No optimal cut-off point to distinguish between injured and non-injured players could be determined. Conclusions The 9+ total score was not associated with lower extremity injury. The 9+ total score was no better than chance for classifying injured and non-injured players. Therefore, the 9+ test cannot be recommended as a screening tool in this population.
Molecular imaging of activated platelets via antibody-targeted ultra-small iron oxide nanoparticles displaying unique dual MRI contrast
Authors: Hang T. Ta, Zhen Li, Christoph E. Hagemeyer, Gary Cowin, Shaohua Zhang, Jathushan Palasubramaniam, Karen Alt, Xiaowei Wang, Karlheinz Peter, Andrew K. Whittaker
Journal: Biomaterials (2017)
Updated review of genetic reticulate pigmentary disorders
Authors: J. Zhang, M. Li, Z. Yao
Journal: British Journal of Dermatology (2017)

Reticulate pigmentary disorders are a group of disorders characterized by hyper- and/or hypopigmented macules with varying sizes and amounts of pigment. Some of the disorders are heritable, such as Dowling-Degos disease, dyschromatosis universalis hereditaria, dyschromatosis symmetrica hereditaria, reticulate acropigmentation of Kitamura and X-linked reticulate pigmentary disorder. Although each condition possesses unique phenotypic characteristics and the prognosis for each is somewhat different, there is a large degree of overlap between the disorders and therefore they are difficult to differentiate in the clinical setting. This updated review provides a clinical and molecular delineation of these genetic reticulate pigmentary disorders and aims to establish a concise diagnostic strategy to allow clinical dermatologists to make an accurate diagnosis, as well as to provide useful information for clinical and genetic counselling.
Rare Genetic Variants in <i>PARN</i> Are Associated with Pulmonary Fibrosis in Families
Authors: Jonathan A. Kropski, Sara Reiss, Cheryl Markin, Kevin K. Brown, David A. Schwartz, Marvin I. Schwarz, James E. Loyd, John A. Phillips, Timothy S. Blackwell, Joy D. Cogan
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Review: HbA<sub>1c</sub> has low accuracy for prediabetes; lifestyle programs and metformin reduce progression to T2DM
Authors: Dennis G. Maki
Journal: Annals of Internal Medicine (2017)

Source Citation Barry E, Roberts S, Oke J, et al. Efficacy and effectiveness of screen and treat policies in prevention of type 2 diabetes: systematic review and meta-analysis of screening tests and interventions. BMJ. 2017;356:i6538. 28052845
TCTAP A-045 Use of Local Intracoronary Single Bolus Administration of Eptifibatide, Streptokinase and Nitroglycerine in Primary Percutaneous Coronary Intervention
Authors: Zulfikri Mukhtar, Sutomo Kasiman, Amran Lubis, Nizam Zikri Akbar, Andika Sitepu, Cut Aryfa Andra, Teuku Bob Haykal, Miharza Aminunsyah, Depri Sumantha, Tengku Winda A, None Novia -, Tawanita Brahmana, Hilfan Ade Putra Lubis
Journal: Journal of the American College of Cardiology (2017)
A Detailed Evaluation of Transplant-Related Toxicities and Outcome for Patients with CNS Lymphoma (CNSL) Consolidated with High-Dose Therapy and Autologous Stem Cell Transplantation (HDT-ASCT) Using Thiotepa, Busulfan (Bu), Cyclophosphamide (TBC) Conditioning
Authors: Michael Scordo, Valkal Bhatt, Meier Hsu, Antonio M. Omuro, Matthew J. Matasar, Lisa DeAngelis, Parastoo B. Dahi, Craig H. Moskowitz, Sergio A. Giralt, Craig S. Sauter
Journal: Blood (2015)
Interruptions in Supplies of Second-Line Antituberculosis Drugs—United States, 2005-2012
Journal: JAMA (2013)

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TCTAP A-023 Percutaneous Coronary Intervention in Acute Myocardial Infarction with Cardiogenic Shock or Cardiac Arrest: Perspective from a Single Center Experience
Authors: Anwar Irawan Ruhani, Siti Khairani Zainal Abidin, Shahidi Jamaludin, Jen Lim Chong
Journal: Journal of the American College of Cardiology (2017)
Abstract 46: RSK4 Is a Novel Negative Regulator of Endothelial Differentiation via Direct Suppression of Protein Kinase A Activity
Authors: Taichi Matsunaga, Kohei Yamamizu, Kazuko K Takeuchi, Mizuyo Kojima, Jun K Takeuchi, Jun K Yamashita
Journal: Circulation Research (2012)

Endothelial cells (ECs) differentiation is strictly regulated to generate functional blood vessels. Previously, we demonstrated that Flk1+ cells derived from embryonic stem (ES) cells serve as vascular progenitors and can constructively reproduce the early differentiation of both ECs and Mural cells (MCs; vascular smooth muscle cells and pericytes). We recently reported that cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling enhanced EC differentiation from Flk1+ vascular progenitors via induction of vascular endothelial growth factor (VEGF) receptors expression. To identify a novel molecule involved in EC differentiation, we performed microarray analyses at various differentiation stages from ES cells to vascular cells; undifferentiated ES cells, Flk1+ vascular progenitors, ECs and MCs. Then, we found that mRNA of p90 ribosomal protein S6 kinase 4 (RSK4) was highly expressed in Flk1+ vascular progenitors and almost diminished during EC differentiation, whereas it remained being expressed in MCs. The addition of a broad-spectrum RSK inhibitor, SL0101, to Flk1+ vascular progenitors enhanced VEGF receptor expression and EC differentiation specifically in the presence of the simultaneous cAMP signal activation. SL0101-elicited EC differentiation was abolished by PKA catalytic subunit alpha (PKAc) knockdown. Specific RSK4 knockdown in Flk1+ vascular progenitors reproduced the effects of SL0101 on EC differentiation via increasing Flk1 expression. RSK4 had potential to bind with PKAc and inhibited PKA activity. Furthermore, an ex vivo whole embryo culture assay showed that SL0101 treatment drastically resulted in increased CD31+ vasculature area, enlarged vessel diameter and defected vascular remodeling in yolk sac. Taken together, these results indicate that RSK4 acts as a novel negative regulator for EC differentiation via inhibition of PKA function. Fine tuning of PKA and Flk1 signaling by RSK4 is critical to normal vascular development. Elucidation of the new-mode cell fate determination by RSK4 would provide novel insights in developmental biology, stem cell biology, and regenerative medicine.
A novel dual-ratiometric-response fluorescent probe for SO2/ClO− detection in cells and in vivo and its application in exploring the dichotomous role of SO2 under the ClO− induced oxidative stress
Authors: Kun Dou, Qiang Fu, Guang Chen, Fabiao Yu, Yuxia Liu, Ziping Cao, Guoliang Li, Xianen Zhao, Lian Xia, Lingxin Chen, Hua Wang, Jinmao You
Journal: Biomaterials (2017)
DEPTOR maintains plasma cell differentiation and favorably affects prognosis in multiple myeloma
Authors: Dalia Quwaider, Luis A. Corchete, Irena Misiewicz-Krzeminska, María E. Sarasquete, José J. Pérez, Patryk Krzeminski, Noemí Puig, María Victoria Mateos, Ramón García-Sanz, Ana B. Herrero, Norma C. Gutiérrez
Journal: Journal of Hematology & Oncology (2017)

The B cell maturation process involves multiple steps, which are controlled by relevant pathways and transcription factors. The understanding of the final stages of plasma cell (PC) differentiation could provide new insights for therapeutic strategies in multiple myeloma (MM). Here, we explore the role of DEPTOR, an mTOR inhibitor, in the terminal differentiation of myeloma cells, and its potential impact on patient survival. The expression level of DEPTOR in MM cell lines and B cell populations was measured by real-time RT-PCR, and/or Western blot analysis. DEPTOR protein level in MM patients was quantified by capillary electrophoresis immunoassay. RNA interference was used to downregulate DEPTOR in MM cell lines. DEPTOR knockdown in H929 and MM1S cell lines induced dedifferentiation of myeloma cells, as demonstrated by the upregulation of PAX5 and BCL6, the downregulation of IRF4, and a clear reduction in cell size and endoplasmic reticulum mass. This effect seemed to be independent of mTOR signaling, since mTOR substrates were not affected by DEPTOR knockdown. Additionally, the potential for DEPTOR to be deregulated in MM by particular miRNAs was investigated. The ectopic expression of miR-135b and miR-642a in myeloma cell lines substantially diminished DEPTOR protein levels, and caused dedifferentiation of myeloma cells. Interestingly, the level of expression of DEPTOR protein in myeloma patients was highly variable, the highest levels being associated with longer progression-free survival. Our results demonstrate for the first time that DEPTOR expression is required to maintain myeloma cell differentiation and that high level of its expression are associated with better outcome. Primary samples used in this study correspond to patients entered into GEM2010 trial (registered at www.clinicaltrials.gov as #NCT01237249, 4 November 2010).