tbuckley/cabot-search huggingface dataset:
<i>PIK3CA</i> Amplification Associates with Aggressive Phenotype but Not Markers of AKT-MTOR Signaling in Endometrial Carcinoma
Authors: Frederik Holst, Henrica M.J. Werner, Siv Mjøs, Erling A. Hoivik, Kanthida Kusonmano, Elisabeth Wik, Anna Berg, Even Birkeland, William J. Gibson, Mari K. Halle, Jone Trovik, Andrew D. Cherniack, Karl-Henning Kalland, Gordon B. Mills, Christian F. Singer, Camilla Krakstad, Rameen Beroukhim, Helga B. Salvesen
Journal: Clinical Cancer Research (2018)

Amplification of PIK3CA, encoding the PI3K catalytic subunit alpha, is common in uterine corpus endometrial carcinoma (UCEC) and linked to an aggressive phenotype. However, it is unclear whether PIK3CA amplification acts via PI3K activation. We investigated the association between PIK3CA amplification, markers of PI3K activity, and prognosis in a large cohort of UCEC specimens.UCECs from 591 clinically annotated patients including 83 tumors with matching metastasis (n = 188) were analyzed by FISH to determine PIK3CA copy-number status. These data were integrated with mRNA and protein expression and clinicopathologic data. Results were verified in The Cancer Genome Atlas dataset.PIK3CA amplifications were associated with disease-specific mortality and with other markers of aggressive disease. PIK3CA amplifications were also associated with other amplifications characteristic of the serous-like somatic copy-number alteration (SCNA)-high subgroup of UCEC. Tumors with PIK3CA amplification also demonstrated an increase in phospho-p70S6K but had decreased levels of activated phospho-AKT1-3 as assessed by Reverse Phase Protein Arrays and an mRNA signature of MTOR inhibition.PIK3CA amplification is a strong prognostic marker and a potential marker for the aggressive SCNA-high subgroup of UCEC. Although PIK3CA amplification associates with some surrogate measures of increased PI3K activity, markers for AKT1-3 and MTOR signaling are decreased, suggesting that this signaling is not a predominant pathway to promote cancer growth of aggressive serous-like UCEC. Moreover, these associations may reflect features of the SCNA-high subgroup of UCEC rather than effects of PIK3CA amplification itself.
AB0964 The role of mtor gene expression, apoptosis and inflammation in obese patients with knee osteoarthritis
Authors: E. Strebkova, E. Chetina, L. Alekseeva
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Metabolic osteoarthritis (OA) has been identified in rheumatology as a specific phenotype due to the growing rates of obesity and other comorbidities, with meta-inflammation as the key factor in its'pathogenesis. On the other hand, OA progression is associated with altered regulation of chondrocytes' metabolism, namely, with up-regulated expression of genes encoding m-TOR, apoptosis, cartilage degeneration and inflammation. <h3>Objectives</h3> To measure the expression levels of genes encoding mTOR, apoptosis (caspase-3), cartilage destruction (cathepsin К), and inflammation (TNF-α) in patients with knee OA (KOA) and obesity. <h3>Methods</h3> 50 female patients (45–65 y.o.) with Kellgren-Lawrence stage II-III KOA and obesity (BMI &gt;30 kg/m<sup>2</sup>;) were randomised into 2 groups. Pts in Group 1 (n=25) were administered orlistat as a specific therapy for obesity for the period of 6 months, and life-style modifications including low caloric diet and physical exercises for 12 months, pts in Group 2 were recommended to observe the diet and physical exercises during 12 months. Peripheral blood samples were obtained at Mo12 for PCR evaluation of gene expression. <h3>Results</h3> Following orlistat therapy pts from Group 1 managed to reduce their body weight by 10,07% at Mo 6 (p&lt;0,05), while pts from Group 2 lost only 0,88% (p=0,8) of their body weight versus the baseline values. During the following 6 months pts from Group 2 on life-modifying regimen continued to lose their body weight, achieving 3,5% (<i>p</i>&gt;0,05) weight reduction versus baseline values, while pts from Group 1 gained weight by 5,6% as compared to the values at Mo 6 during the study (figure 1). Expression of genes encoding inflammation, apoptosis and cell proliferation was assessed at Mo12 to evaluate possible correlation with the dynamics of body weight. Up-regulated expression (p&lt;0,05) of genes encoding inflammation (TNF-α), cartilage destruction (cathepsin K), apoptosis (caspase-3) and cell proliferation (m-TOR) was documented in KOA obese pts from Group 1, gaining body weight during the second stage of the study, as compared to the expression values in pts from Group 2 (figure 1). The analysis demonstrated direct positive correlation (<i>p</i>&lt;0,05) between expression of genes encoding inflammation, cartilage destruction and apoptosis and pain intensity in knee joints assessed by VAS and WOMAC scales. <h3>Conclusions</h3> Therefore up-regulation of m-TOR, caspase-3, TNF-α and cathepsin K gene expression is observed in obese pts with KOA following weight gain and worsening of clinical parameters, which is suggestive of aggravated apoptosis, inflammation and cartilage destruction, providing further KOA progression. <h3>Disclosure of Interest</h3> None declared
Abstract 19384: The Association Between Cognitive Impairment and Mortality Among the Oldest-Old
Authors: Heng Jiang, Enying Gong, Qiqiang He, Xiaoyang Guo, Lijing L Yan
Journal: Circulation (2017)

Background: The oldest-old (adults 80 years old or older) are the fastest growing population segment and also the most vulnerable to cognitive impairment. We aimed to estimate the relationship betw...
Multiplex CRISPR/Cas9-Based Genome Editing of Mouse Hematopoietic Stem Cells Recapitulates Acute Erythroid Leukemia and Identifies Therapeutic Targets
Authors: Ilaria Iacobucci, Elena Varotto, Chunxu Qu, Laura Janke, Aman Seth, Anang Shelat, Burgess Freeman, James Kennedy, Adam S Sperling, R. Coleman Lindsley, Kirsten Dickerson, Debbie Payne-Turner, Sarah M Morris, Nina Ghosn, Benjamin L. Ebert, Charles G. Mullighan
Journal: Blood (2018)
Application of flash nanoprecipitation to fabricate poorly water-soluble drug nanoparticles
Authors: Jinsong Tao, Shing Fung Chow, Ying Zheng
Journal: Acta Pharmaceutica Sinica B (2018)

Nanoparticles are considered to be a powerful approach for the delivery of poorly water-soluble drugs. One of the main challenges is developing an appropriate method for preparation of drug nanoparticles. As a simple, rapid and scalable method, the flash nanoprecipitation (FNP) has been widely used to fabricate these drug nanoparticles, including pure drug nanocrystals, polymeric micelles, polymeric nanoparticles, solid lipid nanoparticles, and polyelectrolyte complexes. This review introduces the application of FNP to produce poorly water-soluble drug nanoparticles by controllable mixing devices, such as confined impinging jets mixer (CIJM), multi-inlet vortex mixer (MIVM) and many other microfluidic mixer systems. The formation mechanisms and processes of drug nanoparticles by FNP are described in detail. Then, the controlling of supersaturation level and mixing rate during the FNP process to tailor the ultrafine drug nanoparticles as well as the influence of drugs, solvent, anti-solvent, stabilizers and temperature on the fabrication are discussed. The ultrafine and uniform nanoparticles of poorly water-soluble drug nanoparticles prepared by CIJM, MIVM and microfluidic mixer systems are reviewed briefly. We believe that the application of microfluidic mixing devices in laboratory with continuous process control and good reproducibility will be benefit for industrial formulation scale-up.
Abstract 17226: Left Ventricular Mechanics in Patients With Pulmonary Arterial Hypertension: Relationship With Outcomes
Authors: Kanako Kishiki, Amita Singh, Akhil Narang, Mardi Gomberg-Maitland, Victor Mor-Avi, Roberto M Lang, Karima Addetia
Journal: Circulation (2016)

Background: Patients with severe pulmonary arterial hypertension (PAH) frequently present with a severely dilated and dysfunctional right ventricle (RV) together with a small left ventricle (LV) with apparently preserved performance. We hypothesized that these changes in RV geometry and function would adversely impact left ventricular mechanics and have a negative influence on outcomes. Methods: We studied 50 patients (55±14 years, 18% male) with severe PAH (pulmonary arterial pressure 82±19mmHg and D-shaped septum) and 40 age- and gender-matched controls (CTRL) with normal LV ejection fraction (LVEF>55%) based on biplane Simpson analysis (Table). LV apical 4-, 2-, and 3-chamber and mid short-axis views were analyzed using 2D speckle-tracking to obtain LV global longitudinal, circumferential and radial strain (LS, CS, RS) (Epsilon). Measurements were compared between PAH patients and CTRL. PAH patients were divided into survivors and non-survivors (follow-up 2.4±1.6 years) and Kaplan-Meier curves were con...
Blood Group Genotyping Test Goes Beyond A, B, and O
Authors: Rebecca Voelker
Journal: JAMA (2018)

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Sixty seconds on . . . rainbow badges
Authors: Abi Rimmer
Journal: BMJ (2018)

Nope. We’re talking about little pin badges that feature the NHS logo on a rainbow flag background, the like of which are associated with the LGBT+ pride movement.

Yes, exactly! But these badges are more than just colourful accessories. They’re a sign that the wearer is a safe person for patients, both young and old, to talk to about matters of gender identity and sexuality. They also show that …
C-MYC overexpression is required for continuous suppression of senescence in melanoma cells
Authors: Mikhail Nikiforov, Wen-Hua Tang, Suresh Patil, Thomas J. Giordano, Dazhong Zhuang, Sudha Mannava, Vladimir Grachtcho
Journal: Cancer Research (2008)

4476  Malignant melanomas often harbor activating mutations in BRAF(V600E) or, less frequently, in NRAS (Q61R). Intriguingly, the same mutations have been detected at higher incidences in benign nevi, which are largely composed of senescent melanocytes. Overexpression of BRAFV600E or NRASQ61R in human melanocytes in vitro has also been shown to induce senescence, albeit via different mechanisms. How oncogene-induced senescence is overcome during melanoma progression remains unclear. Here, we report that C-MYC protein levels are higher in metastatic melanoma tissues and cell lines compared to benign nevi and normal melanocytes, respectively. In the majority of analyzed BRAFV600E- or NRASQ61R-expressing melanoma cells, C-MYC depletion induced different yet overlapping sets of senescence phenotypes characteristic for normal melanocytes undergoing senescence due to overexpression of BRAFV600E or NRASQ61R, respectively. These senescence phenotypes were p16- or p53-independent, however in melanoma cells several of them were suppressed by inhibition of MEK or PI3K kinases. Reciprocally, overexpression of C-MYC in normal melanocytes suppressed BRAFV600E-induced senescence more efficiently than NRASQ61R-induced senescence, which agrees with the generally higher rates of activating mutations in BRAF gene than NRAS genein human cutaneous melanomas. Our data suggest that one of the major functions of C-MYC overexpression in melanoma progression is to suppress BRAFV600E- or NRASQ61R-dependent senescence programs.
National estimates and risk factors associated with early mother-to-child transmission of HIV after implementation of option B+: a cross-sectional analysis
Authors: Beth A Tippett Barr, Monique van Lettow, Joep J van Oosterhout, Megan Landes, Ray W Shiraishi, Ermias Amene, Erik Schouten, Nellie Wadonda-Kabondo, Sundeep Gupta, Andrew F Auld, Thokozani Kalua, Andreas Jahn
Journal: The Lancet HIV (2018)
The Gp1ba-Cre transgenic mouse: a new model to delineate platelet and leukocyte functions
Authors: Zoltan Nagy, Timo Vögtle, Mitchell J. Geer, Jun Mori, Silke Heising, Giada Di Nunzio, Ralph Gareus, Alexander Tarakhovsky, Arthur Weiss, Benjamin G. Neel, Guillaume E. Desanti, Alexandra Mazharian, Yotis A. Senis
Journal: Blood (2018)
Сонологічні методи діагностики стеатозу та фіброзу печінки в дітей
Authors: Yu.M. Stepanov, N.Yu. Zavhorodnia, O.Yu. Lukianenko, V.B. Yahmur, I.S. Konenko, O.P. Petishko
Journal: GASTROENTEROLOGY (2018)

Актуальність. Ультразвукове дослідження є найбільш поширеним методом візуалізації, що використовується для діагностики стеатозу печінки. Метою нашої роботи є порівняння можливостей діагностики стеатозу й фіброзу печінки за допомогою стандартного ультразвукового дослідження, зсувнохвильової еластографії зі стеатометрією та транзієнтною еластографією з визначенням САР. Матеріали та методи. В обстеження включено 90 пацієнтів віком від 5 до 17 років, середній вік пацієнтів становив (12,08 ± 2,71) року. Визначення наявності й ступеня стеатозу печінки проводилось за допомогою апарата FibroScan 502 Touch F60156 (Echosens, Франція) з дослідженням САР. Усім дітям проводилось ультразвукове дослідження паренхіми печінки В-методом з одночасною зсувнохвильовою еластографією й стеатометрією на апараті Ultima PA («Радмір», Харків). Залежно від наявності стеатозу, що визначався за показником САР, й надмірної ваги й ожиріння пацієнти були розподілені на 3 групи: 1 групу становили 45 пацієнтів зі стеатозом печінки й надмірною вагою та ожирінням (50,0 %), 2 групу — 35 пацієнтів із надмірною вагою та ожирінням без стеатозу (38,9 %), 3 групу (група контролю) — 10 пацієнтів із нормальною вагою без стеатозу (11,1 %). Результати. Для хворих зі стеатозом було характерним підвищення ехогенності печінки (75,0 % пацієнтів). У дітей 1 групи в 2,2 раза частіше спостерігалась змінена структура паренхіми печінки порівняно з показниками дітей 2 і 3 груп. Жорсткість тканини печінки в обстежених хворих коливалась від 2,3 до 8,8 кПа, а показник САР — від 108 до 349 дБ/м. У переважної більшості (96,1 %) пацієнтів фіброз був відсутнім; перший та другий ступінь фіброзу реєструвався лише в 3 пацієнтів (3,9 %) першої групи. За даними стеатометрії печінки середні показники коефіцієнта затухання ультразвуку в дітей 1 групи були вірогідно вищими порівняно з контрольною групою (p &lt; 0,05). Чутливість методу зсувнохвильової еластографії щодо виявлення фіброзу печінки порівняно з транзієнтною еластографією становила 83,33 %, специфічність — 60,0 %, позитивна прогностична цінність — 15,15 %, негативна прогностична цінність — 97,67 %. При порівнянні методів стеатометрії та САР-функції транзієнтної еластографії в діагностиці стеатозу печінки в дітей 1 групи було виявлено збіг у 15 з 26 випадків, що відповідає діагностичній ефективності 57,7 %. Висновки. Таким чином, поєднання ультразвукових режимів оцінки структурних змін печінки із зсувнохвильовою еластографією та стеатометрією дає можливість оцінити стадію фіброзу й ступінь стеатозу в контексті мультипараметричного ультразвукового дослідження в дітей із дифузними змінами паренхіми печінки.
A feasibility study of edoxaban for the cancer-associated asymptomatic venous thromboembolism in Japanese gastrointestinal cancer patients receiving chemotherapy (ExCAVE study)
Authors: M. Nakamura, M. Yagisawa, T. Saiki, A. Ishiguro, K. Sawada, S. Yuki, T. Sasaki, T. Ando, H. Ohori, M. Kotaka, O. Muto, Y. Shindo, K. Nakashima, A. Hosokawa, A. Doi, N. Izawa, Y. Sunakawa, A. Satoh, K. Ono, Y. Komatsu
Journal: Annals of Oncology (2018)
Immobilization of cadmium and lead by <i>Lactobacillus rhamnosus</i> GR-1 mitigates apical-to-basolateral heavy metal translocation in a Caco-2 model of the intestinal epithelium
Authors: Brendan A. Daisley, Marc Monachese, Mark Trinder, Jordan E. Bisanz, John A. Chmiel, Jeremy P. Burton, Gregor Reid
Journal: Gut Microbes (2018)

Heavy metals are highly toxic elements that contaminate the global food supply and affect human and wildlife health. Purification technologies are often too expensive or not practically applicable for large-scale implementation, especially in impoverished nations where heavy metal contamination is widespread. Lactobacillus rhamnosus GR-1 (LGR-1) was shown in previous work to reduce heavy metal bioaccumulation in a Tanzanian cohort of women and children through indeterminant mechanisms. Here, it was hypothesized that LGR-1 could sequester the heavy metals lead (Pb) and cadmium (Cd), thereby reducing their absorption across intestinal epithelium. LGR-1 and other lactobacilli significantly reduced the amount of Pb and Cd in solution at all concentrations tested (0.5 mg/L – 50 mg/L) and exhibited sustained binding profiles over a 48-hour period. Relative binding efficiency of LGR-1 decreased as Pb concentration increased, with an absolute minimum binding threshold apparent at concentrations of 2 mg/L and above. Electron microscopy revealed that Pb formed irregular cell-surface clusters on LGR-1, while Cd appeared to form intracellular polymeric clusters. Additionally, LGR-1 was able to significantly reduce apical-to-basolateral translocation of Pb and Cd in a Caco-2 model of the intestinal epithelium. These findings demonstrate the absorbent properties of LGR-1 can immobilize Pb and Cd, effectively reducing their translocation across the intestinal epithelium in vitro. Oral administration of heavy metal-binding Lactobacillus spp. (many of which are known human symbionts and strains of established probiotics) may offer a simple and effective means to reduce the amount of heavy metals absorbed from foods in contaminated regions of the world.
Abstract P235: Superior Mesenteric Artery Calcification is Associated with Cardiovascular Risk Factors, Systemic Calcified Atherosclerosis and Mortality in Asymptomatic Adults
Authors: Timothy C Lin, C. Michael Wright, Michael H Criqui, Matthew A Allison
Journal: Circulation (2016)

Arterial calcification is a hallmark of atherosclerosis and can be detected by computed tomography (CT). There are few epidemiological data regarding the superior mesenteric artery, the atherosclerotic occlusion of which contributes to mesenteric ischemia that may, in turn, lead to increased morbidity or mortality. This study tested the hypothesis that superior mesenteric artery calcification (SMAC) is associated with cardiovascular disease (CVD) risk factors, systemic calcified atherosclerosis, and both cardiovascular and all-cause mortality. The presence and amount of arterial calcification was evaluated by CT in 4302 adults with no known CVD who were physician- or self-referred to obtain preventative health testing at a university-affiliated outpatient center. Laboratory data and medical histories were obtained concomitantly. A multiple logistic regression model was used to determine risk factor associations for SMAC presence, adjusted for calcification in five other arterial beds. In a separate logistic regression model adjusted for CVD risk factors, SMAC presence was used as a predictor for systemic calcified atherosclerosis, represented as having calcification in all five other arterial beds. Cox models, adjusted for CVD risk factors and calcification in other arterial beds, were used to examine the association of SMAC presence and amount (expressed as log[Agatston score+1]) with cardiovascular and all-cause mortality. In the study sample, the average age was 56 years, 43.7% (1879 of 4302) were women, and 6.7% (290 of 4302) had SMAC. Age (OR=1.08, 95%CI [1.06 to 1.10]), male sex (OR=1.97, 95%CI [1.43 to 2.71]), dyslipidemia (OR=1.38, 95% CI [1.01 to 1.88]) and any smoking (OR=1.60, 95% CI [1.20 to 2.14]) were associated with SMAC presence. Moreover, SMAC presence was associated with higher odds for calcification in all five other arterial beds (OR=5.96, 95%CI [3.72-9.54]). Over a median follow-up time of 9.4 years, there were 234 (5.4%) deaths, 76 of which were CVD-related. SMAC presence (HR=1.57, 95%CI [0.93-2.68]) and amount (HR=1.30 per unit increase in log[Agatston score+1], 95%CI [1.00-1.68]) were each associated with a greater risk for CVD mortality. Similarly, SMAC presence (HR=1.52, 95%CI [1.10-2.12]) and amount (HR=1.25, 95%CI [1.06-1.48]) were each associated with a greater risk for all-cause mortality. In conclusion, age, male sex, dyslipidemia, and any smoking were significant risk factors for the presence of SMAC. The association of SMAC presence with greatly increased odds for calcification in all other vascular beds suggests that calcification of the superior mesenteric artery occurs with subclinical, yet widely-manifest, systemic atherosclerosis. Finally, SMAC amount was significantly associated with incident cardiovascular mortality, while both SMAC presence and amount were significantly associated with all-cause mortality.
Inhibition of LEF1-Mediated DCLK1 by Niclosamide Attenuates Colorectal Cancer Stemness
Authors: So-Yeon Park, Ji-Young Kim, Jang-Hyun Choi, Jee-Heun Kim, Choong-Jae Lee, Pomila Singh, Shubhashish Sarkar, Jeong-Heum Baek, Jeong-Seok Nam
Journal: Clinical Cancer Research (2018)

Niclosamide, an FDA-approved anthelmintic drug, has been characterized as a potent Wnt inhibitor that can suppress tumor growth and cancer stem-like cell (CSC) populations. However, the underlying molecular mechanisms remain poorly understood. This study aimed to examine how Wnt inhibition by niclosamide preferentially targets CSCs.The mechanistic role of niclosamide in CSC inhibition was examined in public databases, human colorectal cancer cells, colorectal cancer xenografts, and azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colorectal cancer model.Niclosamide suppresses CSC populations and their self-renewal activities in colorectal cancer cells, and this CSC-targeting effect leads to irreversible disruption of tumor-initiating potential in vivo. Mechanistically, niclosamide downregulates multiple signaling components of the Wnt pathway, specifically lymphoid enhancer-binding factor 1 (LEF1) expression, which is critical for regulating stemness. Subsequently, we identified that the doublecortin-like kinase 1 (DCLK1)-B is a target of LEF1 and upregulates cancer stemness in colorectal cancer cells. We first documented that niclosamide blocks the transcription of DCLK1-B by interrupting the binding of LEF1 to DCLK1-B promoter. DCLK1-B depletion impairs cancer stemness resulting in reduced survival potential and increased apoptosis, thus sensitizing colorectal cancer to chemoradiation.Disruption of the LEF1/DCLK1-B axis by niclosamide eradicates cancer stemness and elicits therapeutic effects on colorectal cancer initiation, progression, and resistance. These findings provide a preclinical rationale to broaden the clinical evaluation of niclosamide for the treatment of colorectal cancer.