tbuckley/cabot-search huggingface dataset:
Місце фосфатидилхоліну в лікуванні запального ураження кишечника
Authors: A.E. Dorofeev, N.N. Rudenko, N.I. Shvets, A.A. Dorofeeva
Journal: GASTROENTEROLOGY (2017)

У патогенезі більшості захворювань кишечника важливе, а часто вирішальне значення має запалення. Широко і всебічно його патогенетична роль вивчена при ЗЗК. В останні роки розпочато дослідження його вкладу в по­шкодження кишечника при функціональній патології — синдромі подразненої кишки (СПК). Парадоксальною здається участь запалення в розвитку ерозивно-виразкових уражень нижніх відділів шлунково-кишкового тракту на тлі прийому нестероїдних протизапальних препаратів (НПЗП-ентероколопатії). Добре відома роль фосфоліпідів у побудові клітинних мембран. Одним з основних мембранних фосфоліпідів більшості живих організмів (за винятком бактерій) є фосфатидилхолін (ФХ). У мембранах кишкового епітелію вміст ФХ збільшується з 10 до 50 % у напрямку від апікальної поверхні до базальної, причому максимальна кількість ФХ розташовується із зовнішнього боку клітинних мембран. Фосфатидилхолін показав свою високу ефективність і безпеку в лікуванні такого запального захворювання кишечника, як неспецифічний виразковий коліт. У людей, що приймають нестероїдні протизапальні засоби, доведена протективна роль ФХ у попередженні пошкодження верхніх і нижніх відділів шлунково-кишкового тракту. З огляду на загальні патогенетичні механізми цих захворювань і СПК нам представляється перспективним використання ФХ у хворих із СПК, особливо його постінфекційним варіантом.
Regional Variation of Computed Tomographic Imaging in the United States and the Risk of Nephrectomy
Authors: H. Gilbert Welch, Jonathan S. Skinner, Florian R. Schroeck, Weiping Zhou, William C. Black
Journal: JAMA Internal Medicine (2017)

<h3>Importance</h3> While computed tomography (CT) represents a tremendous advance in diagnostic imaging, it also creates the problem of incidental detection—the identification of tumors unrelated to the clinical symptoms that initiate the test. <h3>Objective</h3> To determine the geographic variation in the United States in CT imaging and the corresponding association with one of the most consequential sequelae of incidental detection: nephrectomy. <h3>Design, Setting, and Participants</h3> This study is a cross-sectional analysis of age-, sex-, and race-adjusted Medicare data (January 2010-December 2014) from 306 hospital referral regions (HRRs) in the United States and includes information from 15 million fee-for-service Medicare beneficiaries age 65 to 85 years. <h3>Exposures</h3> Regional CT risk (ie, the proportion of the population receiving either a chest or abdominal CT over 5 years). <h3>Main Outcomes and Measures</h3> Five-year risk of nephrectomy (partial or total). <h3>Results</h3> Data from 15 million fee-for-service Medicare beneficiaries age 65 to 85 years were gathered and illustrate that 43% of Medicare beneficiaries age 65 to 85 years received either a chest or abdominal CT from January 2010 to December 2014. This risk varied across the HRRs, ranging from 31% in Santa Cruz, California, to 52% in Sun City, Arizona. Increased regional CT risk was associated with a higher nephrectomy risk (<i>r</i> = 0.38; 95% CI, 0.28-0.47), particularly among HRRs with more than 50 000 beneficiaries (<i>r</i> = 0.47; 95% CI, 0.31-0.61). After controlling for HRR adult smoking rates, imaging an additional 1000 beneficiaries was associated with 4 additional nephrectomies (95% CI, 3-5). Case-fatality rates for those who underwent nephrectomy were 2.1% at 30 days and 4.3% at 90 days. <h3>Conclusions and Relevance</h3> Fee-for-service Medicare beneficiaries are commonly exposed to CT imaging. Those residing in high-scanning regions face a higher risk of nephrectomy, presumably reflecting the incidental detection of renal masses. Additional surgery should be considered one of the risks of excessive CT imaging.
Therapeutic Activity of Peg Albumin in Transgenic Mouse Model of Sickle Cell Disease Is a Function of the Pattern of Pegylation
Authors: Devendra Lingojwar, Savita Bhutoria, Fantao Meng, Sangeetha Thangaswamy, Henny H Billett, Caterina Minniti, Amy Tsai, Marcos Intaglietta, Craig A Branch, Seetharama A Acharya
Journal: Blood (2016)
Evidence Required for Drugs Granted Accelerated Approval—Reply
Authors: Huseyin Naci, Aaron S. Kesselheim
Journal: JAMA (2017)

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Cell membrane-based nanoparticles: a new biomimetic platform for tumor diagnosis and treatment
Authors: Ruixiang Li, Yuwei He, Shuya Zhang, Jing Qin, Jianxin Wang
Journal: Acta Pharmaceutica Sinica B (2017)

Taking inspiration from nature, the biomimetic concept has been integrated into drug delivery systems in cancer therapy. Disguised with cell membranes, the nanoparticles can acquire various functions of natural cells. The cell membrane-coating technology has pushed the limits of common nano-systems (fast elimination in circulation) to more effectively navigate within the body. Moreover, because of the various functional molecules on the surface, cell membrane-based nanoparticles (CMBNPs) are capable of interacting with the complex biological microenvironment of the tumor. Various sources of cell membranes have been explored to camouflage CMBNPs and different tumor-targeting strategies have been developed to enhance the anti-tumor drug delivery therapy. In this review article we highlight the most recent advances in CMBNP-based cancer targeting systems and address the challenges and opportunities in this field.
Everolimus (RAD) as treatment in breast cancer patients with bone metastases only: Results of the phase II RADAR study.
Authors: Nicolai Maass, Nadia Harbeck, Christoph Mundhenke, Christian A. Lerchenmuller, Jana Barinoff, Hans-Joachim Lueck, Johannes Ettl, Bahriye Aktas, Sherko Kuemmel, Siegfried Roesel, Steffen Wagner, Lothar Müller, Joachim Bischoff, Kristina Luebbe, Kathrin Schwedler, Marcus Schmidt, Dirk Bauerschlag, Valentina Nekljudova, Sibylle Loibl, Gunter Von Minckwitz
Journal: Journal of Clinical Oncology (2012)

556 Background: RAD001 is an orally bioavailable rapamycin ester analogue, which acts by selectively inhibiting mTOR (mammalian target of rapamycin), a key player in downstream signaling of different pathways. In vitro, RAD stops formation and activity of osteoclasts. Treating progressive bone metastases in breast cancer (bc) with RAD seems reasonable. Methods: We evaluated RAD in a placebo-controlled, phase II, randomized discontinuation study in bc patients (pts) with bone metastases only. Pts were eligible if they had HER2-negative, hormone-receptor (HR)-positive or –negative bc, with a maximum of 2 previous lines of endocrine therapy (ET) and 1 previous line of chemotherapy (CT). All pts received zoledronate and pts with HR-positive bc could receive ET. All pts started with RAD during a run-in phase of 8 weeks. Pts with stable disease were randomized to RAD or placebo; pts with response continued with RAD and pts with progression went off study. Primary outcome was time to progression (TTP) in pts being stable on 8 weeks of RAD. It was assumed that placebo would obtain a median TTP of 8 weeks which would be increased to 16 weeks, thus requiring 76 randomized pts. It was expected that 70% of all pts would have stable disease after the run-in phase. Overall, 110 pts were needed. Due to slow recruitment and dysbalance between randomized and discontinued pts, recruitment stopped in 12/ 2010. Results: From 11/06 until 12/10, 89 pts were enrolled. Median age was 59.5 years. 93% had HR-positive disease. 15% had prior chemotherapy; 58% had prior ET for metastases. 1/3 received concomitant ET. Three pts did not start therapy, 41 discontinued during run-in phase, 32 due to progression. Six continued as responder. 39 pts with SD after run in phase were randomized to RAD or placebo. Twenty-seven stopped due to progression; 9 discontinued due to AE, 4 are still on treatment. 15 pts had 20 serious adverse events; 1 hyperglycemia and one alveolitis. The TTP in patients with RAD was 8.5 months vs. 2.9 months with placebo (HR: 0.559; 95% CI [0.284-1.10] p=0.092. Conclusions: Pts with bone metastases only had a longer TTP on RAD compared to pts on placebo. Overall 7/89 showed a sustained response on RAD + zoledronate ± ET.
Abstract 17047: SnoRNA33 as a New Therapeutic Target in Ischemia/Reperfusion Induced Myocardial Injury
Authors: Shui Q Ye, Daniel Heruth, Min Xiong, Li Q Zhang
Journal: Circulation (2016)

Introduction:  SnoRNA33 is a H/ACA RNA, which is predicted to guide the pseudouridylation of 28S rRNA U4966. Other than this information, roles and mechanisms of snoRA33 in human physiology and pathology are largely unknown. Our preliminary data showed that snoRNA33 expression was highly upregulated in mouse myocardial ischemic/reperfusion (I/R) injury. This study is intended to evaluate the utility of snoRNA33 as a new preventive and therapeutic target in I/R induced mouse myocardial injury and to investigate underlying cell and molecular mechanisms.   Hypothesis:  We hypothesize that snoRNA33 may be a genetic risk factor and therapeutic target in CAD.   Methods:  Male C57BL/6J mice, 8-12week-old, were subjected to either sham operation or myocardial I/R by a 40 min occlusion of the left anterior descending coronary artery followed by 3 h reperfusion without or with i.v. morpholino-snoRNA33 antisense oligo (MAO), or its scrambled control (MAOsc) either prior to or during the operation. 24 h later, mice were sacrificed and their hearts and sera were harvested for further analyses including assessing infarct size, assaying apoptosis and serum troponin-I levels. The mechanisms underlying the effect of snoRNA33 were also investigated in  in vitro  cell culture system by the TUNEL staining and RNA-seq analysis.   Results:  The size of myocardial infarction/area at risk or myocardial apoptosis was significantly smaller or less severe in MAO mouse group than in MAOsc mouse group administered either prior to or during the operation. Serum tCTn1 levels were significantly lower in the  MAO group  than the MAOsc group (%cTn-1: 60±20 vs. 100±1.1,  p   N=5/group ). Overexpression of snoRNA33 augmented apoptosis while inhibition of snoRNA33 expression reduced staurosporine induced apoptosis in cultured mouse HL-1 cardiomyocytes. RNA-seq analysis revealed that out of 890 differentially expressed genes, Wnt/β-catenin signaling pathway was the top involved canonical pathway with 21 genes in the pathway downregulated in the MAO group vs MAOsc group.   Conclusions:  Inhibition of SnoRNA 33 could attenuate IR induced myocardial injury preventively and therapeutically. SnoRNA33 is promising as a new therapeutic target in CAD.
Abstract 119: Tempol Pre-treatment Restores Isoflurane Preconditioning in the Aged Cardiomyocytes: Involvement of Pink1/Parkin-mediated Mitophagy
Authors: Li Ma, Qun Gao, Mario J Rebecchi, Lixin Liu
Journal: Circulation Research (2016)

Background: Aging is associated with chronic oxidative stress and impaired cardiac preconditioning. Four-week pre-treatment with TEMPOL, an antioxidant, improves mitochondrial functions and restores isoflurane (ISO) preconditioning in the aging rat heart. Because mitophagy is implicated in cardiac preconditioning and declines with age, this study was designed to investigate how age influence mitophagy in response to preconditioning and whether TEMPOL pre-treatment improves it. Methods: Male Fischer 344 old (22-24 months) rats treated with or without 4-week TEMPOL (2 mM in drinking water) and young (4-6 months) untreated rats were used. Cardiomyocytes isolated from these rats were preconditioned with ISO and then collected for Western blot analyses of mitochondrial PINK1, Parkin and ubiquitination, or fixed for IF staining of co-localization of PINK1/Parkin with mitochondria. Autophagic flux was determined by IF staining of LC3 puncta, membrane-associated LC3-II and p62 in the presence and absences of bafilomycin A1, an autophagy inhibitor. ISO preconditioning was assessed by LDH release in a simulated hypoxia/reoxygenation model. Results: ISO protected young but not old cardiomyocytes. Four-week pre-treatment with TEMPOL in vivo restored ISO preconditioning in the old cardiomyocytes. In addition, ISO increased mitochondrial PINK1 and Parkin levels and promoted mitochondrial protein ubiquitination in the young, but not the old cardiomyocytes. TEMPOL pre-treatment improved these responses in the old cardiomyocytes. Aging impaired both baseline and ISO-induced autophagic flux, which was restored by TEMPOL pre-treatment. Inhibition of autophagy by bafilomycin abolished ISO preconditioning in the cardiomyocytes from the young and TEMPOL-pre-treated old rats. Conclusion: Aging reduces PINK1/Parkin-mediated mitophagy in response to ISO and impairs baseline as well as preconditioning-induced autophagic flux. A 4-week pre-treatment of TEMPOL reverses these changes and restores ISO preconditioning in the old cardiomyocytes. Our results may explain why cardiac preconditioning has failed in some clinical trials, because most patients were with pathologies, such as diabetes and advanced age, in which mitophagy is disrupted.
<i>PIK3CA</i> C2 Domain Deletions Hyperactivate Phosphoinositide 3-kinase (PI3K), Generate Oncogene Dependence, and Are Exquisitely Sensitive to PI3K<b>α</b> Inhibitors
Authors: Sarah Croessmann, Jonathan H. Sheehan, Kyung-min Lee, Gregory Sliwoski, Jie He, Rebecca Nagy, David Riddle, Ingrid A. Mayer, Justin M. Balko, Richard Lanman, Vincent A. Miller, Lewis C. Cantley, Jens Meiler, Carlos L. Arteaga
Journal: Clinical Cancer Research (2017)

Abstract Purpose: We describe herein a novel P447_L455 deletion in the C2 domain of PIK3CA in a patient with an ER+ breast cancer with an excellent response to the PI3Kα inhibitor alpelisib. Although PIK3CA deletions are relatively rare, a significant portion of deletions cluster within amino acids 446–460 of the C2 domain, suggesting these residues are critical for p110α function. Experimental Design: A computational structural model of PIK3CAdelP447-L455 in complex with the p85 regulatory subunit and MCF10A cells expressing PIK3CAdelP447-L455 and PIK3CAH450_P458del were used to understand the phenotype of C2 domain deletions. Results: Computational modeling revealed specific favorable inter-residue contacts that would be lost as a result of the deletion, predicting a significant decrease in binding energy. Coimmunoprecipitation experiments showed reduced binding of the C2 deletion mutants with p85 compared with wild-type p110α. The MCF10A cells expressing PIK3CA C2 deletions exhibited growth factor–independent growth, an invasive phenotype, and higher phosphorylation of AKT, ERK, and S6 compared with parental MCF10A cells. All these changes were ablated by alpelisib treatment. Conclusions: C2 domain deletions in PIK3CA generate PI3K dependence and should be considered biomarkers of sensitivity to PI3K inhibitors. Clin Cancer Res; 24(6); 1426–35. ©2017 AACR.
Lymphoedema in patients with lentigo maligna treated with imiquimod: a long-term adverse effect
Authors: D. Tio, G. Kirtschig, R. Hoekzema, C. van Montfrans
Journal: British Journal of Dermatology (2017)

Lymphoedema in patients with lentigo maligna treated with imiquimod: a long-term adverse effect
Lower Risk of Death With SGLT2 Inhibitors in Observational Studies: Real or Bias?
Authors: Samy Suissa
Journal: Diabetes Care (2017)

Two recent observational studies reported a remarkably lower rate of all-cause death associated with sodium-glucose cotransporter 2 inhibitor (-SGLT2i) use in all patients with type 2 diabetes and not only those at increased cardiovascular risk. The >50% lower mortality rates reported in these studies are much greater than those found in the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and CANagliflozin cardioVascular Assessment Study (CANVAS) randomized trials. We show that these observational studies are affected by time-related biases, including immortal time bias and time-lag bias, which tend to exaggerate the benefits observed with a drug. The Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL) study, based on 166,033 users of SGLT2i and 1,226,221 users of other glucose-lowering drugs (oGLD) identified from health care databases of six countries, was affected by immortal time bias. Indeed, the immortal time between the first oGLD prescription and the first SGLT2i prescription was omitted from the analysis, which resulted in increasing the rate of death in the oGLD group and thus producing the appearance of a lower risk of death with SGLT2i use. The Swedish study compared 10,879 SGLT2i/dipeptidyl peptidase 4 inhibitor (DPP-4i) users with 10,879 matched insulin users. Such comparisons involving second-line therapies with a third-line therapy can introduce time-lag bias, as the patients may not be at the same stage of diabetes. This bias is compounded by the fact that the users of insulin had already started their insulin before cohort entry, unlike the new users of SGLT2i. Finally, the study also introduces immortal time bias with respect to the effects of SGLT2i relative to DPP-4i. In conclusion, the >50% lower rate of death with SGLT2i in type 2 diabetes reported by two recent observational studies is likely exaggerated by immortal time and time-lag biases. It thus remains uncertain whether the benefit seen with empagliflozin in the EMPA-REG OUTCOME trial applies to all SGLT2i and to all patients with type 2 diabetes, not only those at increased cardiovascular risk. While observational studies can provide crucial real-world evidence for the effects of medications, they need to be carefully conducted to avoid such major time-related biases.
Low Prevalence of Hepatitis B Vaccination Among Patients Receiving Medical Care for HIV Infection in the United States, 2009 to 2012
Authors: John Weiser, Alejandro Perez, Heather Bradley, Hope King, R. Luke Shouse
Journal: Annals of Internal Medicine (2017)

Persons with HIV infection are at increased risk for hepatitis B virus infection. In 2016, the World Health Organization resolved to eliminate hepatitis B as a public health threat by 2030.To estimate the prevalence of hepatitis B vaccination among U.S. patients receiving medical care for HIV infection ("HIV patients").Nationally representative cross-sectional survey.United States.18 089 adults receiving HIV medical care who participated in the Medical Monitoring Project during 2009 to 2012.Primary outcomes were prevalence of 1) no documentation of hepatitis B vaccination or laboratory evidence of immunity or infection (candidates to initiate vaccination), and 2) initiation of vaccination among candidates, defined as documentation of at least 1 vaccine dose in a 1-year surveillance period during which patients received ongoing HIV medical care.At the beginning of the surveillance period, 44.2% (95% CI, 42.2% to 46.2%) of U.S. HIV patients were candidates to initiate vaccination. By the end of the surveillance period, 9.6% (CI, 8.4% to 10.8%) of candidates were vaccinated, 7.5% (CI, 6.4% to 8.6%) had no documented vaccination but had documented infection or immunity, and 82.9% (CI, 81.1% to 84.7%) remained candidates. Among patients at facilities funded by the Ryan White HIV/AIDS Program (RWHAP), 12.5% (CI, 11.1% to 13.9%) were vaccinated during the surveillance period versus 3.7% (CI, 2.6% to 4.7%) at facilities not funded by RWHAP. At the end of surveillance, 36.7% (CI, 34.4% to 38.9%) of HIV patients were candidates to initiate vaccination.The study was not designed to describe vaccine series completion or actual prevalence of immunity.More than one third of U.S. HIV patients had missed opportunities to initiate hepatitis B vaccination. Meeting goals for hepatitis B elimination will require increased vaccination of HIV patients in all practice settings, particularly at facilities not funded by RWHAP.Centers for Disease Control and Prevention.
Review: In HF with preserved EF, β-blockers reduced mortality; drug treatment overall did not
Authors: Harriette G.C. Van Spall
Journal: Annals of Internal Medicine (2017)

Source Citation Zheng SL; Chan FT; Nabeebaccus AA; et al. Drug treatment effects on outcomes in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Heart. 2017. [Epub ahead of print]. 28780577
Familial and Somatic <i>BAP1</i> Mutations Inactivate ASXL1/2-Mediated Allosteric Regulation of BAP1 Deubiquitinase by Targeting Multiple Independent Domains
Authors: Hongzhuang Peng, Jeremy Prokop, Jayashree Karar, Kyewon Park, Li Cao, J. William Harbour, Anne M. Bowcock, S. Bruce Malkowicz, Mitchell Cheung, Joseph R. Testa, Frank J. Rauscher
Journal: Cancer Research (2017)

Deleterious mutations of the ubiquitin carboxy-terminal hydrolase BAP1 found in cancers are predicted to encode inactive truncated proteins, suggesting that loss of enzyme function is a primary tumorigenic mechanism. However, many tumors exhibit missense mutations or in-frame deletions or insertions, often outside the functionally critical UCH domain in this tumor suppressor protein. Thus, precisely how these mutations inactivate BAP1 is unknown. Here, we show how these mutations affect BAP1 interactions with the Polycomb group-like protein, ASXL2, using combinations of computational modeling technology, molecular biology, and in vitro reconstitution biochemistry. We found that the BAP1-ASXL2 interaction is direct and high affinity, occurring through the ASXH domain of ASXL2, an obligate partner for BAP1 enzymatic activity. The ASXH domain was the minimal domain for binding the BAP1 ULD domain, and mutations on the surfaces of predicted helices of ASXH abolished BAP1 association and stimulation of BAP1 enzymatic activity. The BAP1-UCH, BAP1-ULD, and ASXH domains formed a cooperative stable ternary complex required for deubiquitination. We defined four classes of alterations in BAP1 outside the UCH domain, each failing to productively recruit ASXH to the wild-type BAP1 catalytic site via the ULD, resulting in loss of BAP1 ubiquitin hydrolase activity. Our results indicate that many BAP1 mutations act allosterically to inhibit ASXH binding, thereby leading to loss of enzyme activity. Small-molecule approaches to reactivate latent wild-type UCH activity of these mutants might be therapeutically viable.Significance: Combined computational and biochemical approaches demonstrate that the BAP1-ASXL2 interaction is direct and high affinity and that many BAP1 mutations act allosterically to inhibit BAP1-ASXL2 binding. Cancer Res; 78(5); 1200-13. ©2017 AACR.