tbuckley/cabot-search huggingface dataset:
Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma
Authors: Wantae Kim, Sanjoy Kumar Khan, Yuchen Liu, Ruoshi Xu, Ogyi Park, Yong He, Boksik Cha, Bin Gao, Yingzi Yang
Journal: Gut (2017)

Objective Hippo signalling is a recently identified major oncosuppressive pathway that plays critical roles in inhibiting hepatocyte proliferation, survival and hepatocellular carcinoma (HCC) formation. Hippo kinase (Mst1 and Mst2) inhibits HCC proliferation by suppressing Yap/Taz transcription activities. As human HCC is mainly driven by chronic liver inflammation, it is not clear whether Hippo signalling inhibits HCC by shaping its inflammatory microenvironment. Design We have established a genetic HCC model by deleting Mst1 and Mst2 in hepatocytes. Functions of inflammatory responses in this model were characterised by molecular, cellular and FACS analysis, immunohistochemistry and genetic deletion of monocyte chemoattractant protein-1 ( Mcp1 ) or Yap . Human HCC databases and human HCC samples were analysed by immunohistochemistry. Results Genetic deletion of Mst1 and Mst2 in hepatocytes (DKO) led to HCC development, highly upregulated Mcp1 expression and massive infiltration of macrophages with mixed M1 and M2 phenotypes. Macrophage ablation or deletion of Mcp1 in DKO mice markedly reduced hepatic inflammation and HCC development. Moreover, Yap removal abolished induction of Mcp1 expression and restored normal liver growth in the Mst1/Mst2 DKO mice. Finally, we showed that MCP1 is a direct transcription target of YAP in hepatocytes and identified a strong gene expression correlation between YAP targets and MCP-1 in human HCCs. Conclusions Hippo signalling in hepatocytes maintains normal liver growth by suppressing macrophage infiltration during protumoural microenvironment formation through the inhibition of Yap-dependent Mcp1 expression, providing new targets and strategies to treat HCCs.
Implementation of Xpert MTB/RIF in 22 high tuberculosis burden countries: are we making progress?
Authors: Danielle Cazabon, Anita Suresh, Collins Oghor, Zhi Zhen Qin, Sandra V. Kik, Claudia M. Denkinger, Madhukar Pai
Journal: European Respiratory Journal (2017)

By the end of 2016, approximately 23 million Xpert MTB/RIF® (Xpert; Cepheid, Sunnyvale, CA, USA) cartridges for tuberculosis (TB) diagnosis had been procured by the public sector in 130 countries at concessional pricing [1], but smear microscopy continues to be the most widely used test for TB [2]. To understand the true market penetration of Xpert in TB high burden countries (HBCs), we surveyed National TB Programmes (NTPs) or their partnering organisations in 22 HBCs to obtain Xpert data from 2015 and to assess dynamic trends from 2014 to 2015. These 22 countries had been previously surveyed by us in 2014 [3]. Uptake of Xpert in 22 high burden countries has progressed well since 2014, although more can be done to reach scale <http://ow.ly/Whvu30dpqVI> We are grateful to survey respondents from 22 countries for their time and support.
Overdosing on immediate-release morphine solution has predictable adverse effects
Authors: David C. Currow, Magnus Ekström, Miriam J. Johnson
Journal: European Respiratory Journal (2017)

Prescribing responsibility inherently includes adequate ongoing monitoring for medication. The adverse effects of an overdose of immediate-release morphine in a recent letter to the ERJ are well known <http://ow.ly/71D130dMLYd>
AB0447 Antimalarials improve survival of systemic lupus erythematosus on cholesterol: results of a fifteen-year chinese multicenter retrospective study in jiangsu province
Authors: F Wang, W Zhang, S Wang, W Pan, L Liu, M Wu, X Ding, H Wei, Y Zou, X Feng, L Sun
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Nowadays the importance of antimalarials, especially hydroxychloroquine (HCQ) and chloroquine (CQ), in treatment of systemic lupus erythematosus (SLE) has been demonstrated. However, few have examined the efficacy of HCQ and CQ on eastern Chinese SLE patients. <h3>Methods</h3> The analysis is based on 1372 patients who were enrolled in a retrospective study of 26 centers from January 1st, 1999 through December 31st, 2009, during which time is their first hospitalization. Baseline and follow-up clinical, laboratory and therapeutic data and survival status before April 30th, 2015 were recorded. Statistical analysis consist of Chi-square test, <i>t</i>-test, Kaplan-Meier curves and logrank test. <h3>Results</h3> Compared with 562 patients without HCQ or CQ treatment, the hazard ratio (HR) of deaths in 810 patients taking those was reduced (HR 0.52, 95% CI 0.38–0.70, p&lt;0.001). 376 of these 1372 patients experienced their second hospitalization, during which treating group (165 of 376) showed lower blood level of total cholesterol (TG), compared to control group (4.47 (0.13) vs 5.03 (0.21), p=0.027), while no statistical difference of TG exists between the two groups9 first hospitalization (p&gt;0.05). Other metabolic data, such as systolic and diastolic blood pressure, fasting blood sugar, Triglyceride and uric acid were similar between the two groups in two times of hospitalization. On second inpatient visit, disease activity (SLEDAI, blood sedimentation rate, complement) and organ involvements (SLICC) of those who took antimalarials and no users have no significant differences. <h3>Conclusions</h3> Use of HCQ or CQ lower the risk of mortality and TG levels of eastern Chinese SLE patients. <h3>Disclosure of Interest</h3> None declared
Tamoxifen facilitates translocation of ERα to the cytoplasm and enhances interaction between EGF receptor and ERα in MCF-7 breast cancer cells
Authors: Ping Fan, Jiping Wang, Richard J. Santen, Wei Yue
Journal: Cancer Research (2006)

419   Patients with hormone-dependent breast cancer experience tumor regression in response to tamoxifen (TAM) treatment. Unfortunately the disease inevitably relapses in 12-18 months. Up-regulation of growth factor signaling pathways is associated with development of tamoxifen resistance but the precise mechanisms are still unclear. To investigate mechanisms responsible for acquired tamoxifen resistance, we cultured MCF-7 breast cancer cells in medium containing TAM (10 -7  M) for up to 12 months. Six months after TAM treatment, growth of these cells was no longer inhibited by TAM. These cells were named tamoxifen resistant cells, TAM-R. While the basal levels of activated MAP kinase in TAM-R cells were similar to that in the control cells, TAM-R cells exhibited enhanced sensitivity to E2 and EGF stimulated activation of MAPK. Blockade of the EGFR/MAPK pathway caused more dramatic inhibition of growth of TAM-R cells than the control cells. It was interestingly found that an increased amount of ERα was co-immunoprecipitated with EGFR from TAM-R cells even though there was no increase in the levels of these receptors compared to the control cells. There was an increased immunoreactivity with ERα antibody in the cytoplasm and plasma membrane of TAM-R cells by fluorescent microscopy and Western analysis of cellular fractions. Interaction between growth factor receptors and ERα usually requires an adaptor protein. In TAM-R cells the amount of c-Src co-precipitated with EGFR or ERα was significantly increased. The interaction between EGFR and ERα could be reduced by the anti-estrogen fulvestrant. Notably the c-Src inhibitor PP2 caused redistribution of ERα back to the nucleus whereas the EGFR tyrosine kinase inhibitor AG1478 did not. Our results suggest that cytoplasmic translocation of ERα increases its interaction with EGFR which may result in enhanced activation of MAPK signaling pathway in TAM-R cells. Activation of the EGFR/MAPK pathway allows the cells to grow in the presence of TAM. Kinase active c-Src plays a critical role in retaining ERα in the cytoplasm and in serving as an adaptor of EGFR/ERα complex.
Increased IgE levels are linked to faster relapse in patients with omalizumab-discontinued chronic spontaneous urticaria
Authors: Ragip Ertas, Kemal Ozyurt, Emin Ozlu, Yilmaz Ulas, Atil Avci, Mustafa Atasoy, Tomasz Hawro, Marcus Maurer
Journal: Journal of Allergy and Clinical Immunology (2017)
miR-193b–Regulated Signaling Networks Serve as Tumor Suppressors in Liposarcoma and Promote Adipogenesis in Adipose-Derived Stem Cells
Authors: Ying Z. Mazzu, Yulan Hu, Rajesh K. Soni, Kelly M. Mojica, Li-Xuan Qin, Phaedra Agius, Zachary M. Waxman, Aleksandra Mihailovic, Nicholas D. Socci, Ronald C. Hendrickson, Thomas Tuschl, Samuel Singer
Journal: Cancer Research (2017)

Well-differentiated and dedifferentiated liposarcomas (WDLS/DDLS) account for approximately 13% of all soft tissue sarcoma in adults and cause substantial morbidity or mortality in the majority of patients. In this study, we evaluated the functions of miRNA (miR-193b) in liposarcoma in vitro and in vivo Deep RNA sequencing on 93 WDLS, 145 DDLS, and 12 normal fat samples demonstrated that miR-193b was significantly underexpressed in DDLS compared with normal fat. Reintroduction of miR-193b induced apoptosis in liposarcoma cells and promoted adipogenesis in human adipose-derived stem cells (ASC). Integrative transcriptomic and proteomic analysis of miR-193b-target networks identified novel direct targets, including CRK-like proto-oncogene (CRKL) and focal adhesion kinase (FAK). miR-193b was found to regulate FAK-SRC-CRKL signaling through CRKL and FAK. miR-193b also stimulated reactive oxygen species signaling by targeting the antioxidant methionine sulfoxide reductase A to modulate liposarcoma cell survival and ASC differentiation state. Expression of miR-193b in liposarcoma cells was downregulated by promoter methylation, resulting at least in part from increased expression of the DNA methyltransferase DNMT1 in WDLS/DDLS. In vivo, miR-193b mimetics and FAK inhibitor (PF-562271) each inhibited liposarcoma xenograft growth. In summary, miR-193b not only functions as a tumor suppressor in liposarcoma but also promotes adipogenesis in ASC. Furthermore, this study reveals key tyrosine kinase and DNA methylation pathways in liposarcoma, some with immediate implications for therapeutic exploration. Cancer Res; 77(21); 5728-40. ©2017 AACR.
Somatic Mutations in Epigenetic Modifiers Identified Using Next Generation Sequencing (NGS) in Diagnostic Samples of CML-CP Can Predict Poor Outcome on Imatinib Which Is Abrogated By Frontline 2G-TKI Therapy
Authors: Georgios Nteliopoulos, Alexandra Bazeos, Gareth Gerrard, Simone Claudiani, Ed Curry, Mary Alikian, Hui En Foong, Letizia Foroni, Jane F. Apperley
Journal: Blood (2016)
SERVE-HF on-treatment analysis: does the on-treatment analysis SERVE its purpose?
Authors: T. Douglas Bradley
Journal: European Respiratory Journal (2017)

The randomised clinical trial (RCT) is the best-accepted means to assess the effectiveness of a treatment for a given disease because treatment allocation is not influenced by non-random factors such as patient or physician preference. Conversely, observational trials, in which treatment allocations are not randomised, can be, and often are, subject to patient or physician preference. For this reason, the results of observational trials of various interventions are not considered to carry as much weight as those of RCTs, and results of such trials are often considered to be only suggestive or hypothesis generating, rather than definitive. Indeed, in several instances, the positive treatment results of observational trials have not been borne out by RCTs. For example, in the field of sleep apnoea and cardiovascular diseases, several non-randomised observational studies reported reduced fatal and non-fatal cardiovascular events rates among obstructive sleep apnoea (OSA) patients who elected to be treated by, and to continue on, continuous positive airway pressure (CPAP) compared to those who elected not to be treated by, or who discontinued, such treatment [1–3]. In contrast, several large-scale RCTs of treatment of OSA by CPAP demonstrated no beneficial effect of CPAP on fatal or non-fatal cardiovascular events [4–6]. Nevertheless, the reliability of the results of an RCT depends on the degree of adherence to the treatment allocation: the greater the adherence, the more reliable the results, and vice versa . For these reasons, there are various means by which RCTs can be analysed that take into account treatment adherence. Minute-ventilation triggered ASV increases mortality in heart failure patients with central sleep apnoea <http://ow.ly/wIcr30dXlu7>
Large measles outbreak introduced by asylum seekers and spread among the insufficiently vaccinated resident population, Berlin, October 2014 to August 2015
Authors: Dirk Werber, Alexandra Hoffmann, Sabine Santibanez, Annette Mankertz, Daniel Sagebiel
Journal: Eurosurveillance (2017)

The largest measles outbreak in Berlin since 2001 occurred from October 2014 to August 2015. Overall, 1,344 cases were ascertained, 86% (with available information) unvaccinated, including 146 (12%) asylum seekers. Median age was 17 years (interquartile range: 4–29 years), 26% were hospitalised and a 1-year-old child died. Measles virus genotyping uniformly revealed the variant ‘D8-Rostov-Don’ and descendants. The virus was likely introduced by and initially spread among asylum seekers before affecting Berlin’s resident population. Among Berlin residents, the highest incidence was in children aged &lt; 2 years, yet most cases (52%) were adults. Post-exposure vaccinations in homes for asylum seekers, not always conducted, occurred later (median: 7.5 days) than the recommended 72 hours after onset of the first case and reached only half of potential contacts. Asylum seekers should not only have non-discriminatory, equitable access to vaccination, they also need to be offered measles vaccination in a timely fashion, i.e. immediately upon arrival in the receiving country. Supplementary immunisation activities targeting the resident population, particularly adults, are urgently needed in Berlin.
Immunofluorescent Studies of Human Articular Cartilage
Authors: Peter Barland, Rosamond Janis, John Sandson
Journal: Annals of the Rheumatic Diseases (1966)

The matrix of articular cartilage is produced by chondrocytes and is composed of chondromuco- protein (CMP) enmeshed in a network of coUlagen fibres.Native CMP consists of chains of chon- droitin sulphate and keratin sulphate combined with protein to form large complexes.These complexes can be extracted from cartilage by high- speed homogenization in water (Malawista and Schubert, 1958).Ultracentrifugation of CMP from human articular cartilage at 105,000 G. yields two proteinpolysaccharide fractions; one sedimentable, PP-H, and one non-sedimentable, PP-L (Gerber, Franklin, and Schubert, 1960).PP-L is the purer of these fractions and in the adult is composed of approximately equal parts of protein, chondroitin sulphate, and keratin sulphate.Previous histological studies of the distribution of CMP in articular cartilage have depended upon the metachromatic or other anionic staining properties of chondroitin sulphate and keratin sulphate.In normal human articular cartilage there is diffuse metachromatic staining of the matrix with a slight diminution in the intensity of the staining in the most superficial zone adjacent to the joint space.In osteo-arthritis the superficial zone of articular cartilage becomes fibrillated and vacuolated, and exhibits a striking loss of metachromatic staining (Collins, 1949).In this paper we describe the use of an immunofluorescent technique to study the distribution of CMP in normal and osteo-arthritic articular cartilage.Specific antisera to CMP were prepared in rabbits and an indirect fluorescent antibody tech- nique was used to localize the CMP in sections of cartilage.The immunofluorescent and metachro- matic staining patterns of normal cartilage were
Spinal Manipulative Therapy for Low Back Pain—Reply
Authors: Neil M. Paige, Sally C. Morton, Paul G. Shekelle
Journal: JAMA (2017)

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No evidence of HIV replication in children on antiretroviral therapy
Authors: Gert U. Van Zyl, Mary Grace Katusiime, Ann Wiegand, William R. McManus, Michael J. Bale, Elias K. Halvas, Brian Luke, Valerie F. Boltz, Jonathan Spindler, Barbara Laughton, Susan Engelbrecht, John M. Coffin, Mark F. Cotton, Wei Shao, John W. Mellors, Mary F. Kearney
Journal: Journal of Clinical Investigation (2017)

It remains controversial whether current antiretroviral therapy (ART) fully suppresses the cycles of HIV replication and viral evolution in vivo. If replication persists in sanctuary sites such as the lymph nodes, a high priority should be placed on improving ART regimes to target these sites. To investigate the question of ongoing viral replication on current ART regimens, we analyzed HIV populations in longitudinal samples from 10 HIV-1–infected children who initiated ART when viral diversity was low. Eight children started ART at less than ten months of age and showed suppression of plasma viremia for seven to nine years. Two children had uncontrolled viremia for fifteen and thirty months, respectively, before viremia suppression, and served as positive controls for HIV replication and evolution. These latter 2 children showed clear evidence of virus evolution, whereas multiple methods of analysis bore no evidence of virus evolution in any of the 8 children with viremia suppression on ART. Phylogenetic trees simulated with the recently reported evolutionary rate of HIV-1 on ART of 6 × 10–4 substitutions/site/month bore no resemblance to the observed data. Taken together, these data refute the concept that ongoing HIV replication is common with ART and is the major barrier to curing HIV-1 infection.
Abstract 20133: Not All ST Elevations Mandate Emergent Catheterization: A Case Report of Brugada Syndrome Induced by Severe Hyponatremia
Authors: Jasmin Martinez, Sandeep Dayanand, Mohamad Kabach, Pradeep Dayanand, Steven Borzak
Journal: Circulation (2015)

Introduction: Brugada syndrome is a rare channelopathy, which is familial or sporadic in occurrence. Typical ECG findings of Brugada pattern consist of a pseudo-right bundle branch block and persistent ST segment elevation in leads V1 to V2. While fever, stressors and sodium channel blockers have been implicated in unmasking the underlying rhythm, only 2 cases of hyponatremia precipitating Brugada Syndrome have been reported to date. Here in, we report a case of a 61 y/o woman who underwent emergent cardiac catheterization after her EKG demonstrated ST elevation in the anterior leads. Eventual work up revealed Brugada Syndrome induced by hyponatremia. Case: A 61 y/o woman with a known medical history of hyponatremia from chronic alcohol abuse was found to be unresponsive at home. EKG performed by paramedics revealed ST elevation in anterior leads. Based on the EKG and the patient’s presentation, a probable diagnosis of cardiac arrest from ischemic heart disease was made and a decision for emergent cardiac catheterization was made. Catheterization revealed, mild non-obstructive coronary artery disease. The patient was transferred to ICU for further care where she continued to remain unresponsive. Initial work up revealed severe hyponatremia, with a serum sodium of 103. The rest of her electrolytes were within normal limits. Detailed review of her presenting EKG revealed that she had “coved” pattern of ST elevation in the anterior leads. Her severe hyponatremia was corrected with hypertonic saline. Subsequent EKG’s after partial correction of hyponatremia demonstrated resolution of abnormal EKG changes. Conclusion: The patient described in this case had a cardiac arrest most likely from sustained ventricular tachycardia secondary to a brugada pattern. Hence, hyponatremia should be recognized as an important etiology in the list of causes that unmask a Brugada pattern in patients with this channelopathy.
標的神経内分泌癌治療のための新規H DAC阻害剤thailandepsin Aを負荷したKE108共役単分子ミセル【Powered by NICT】
Authors: Chen Guojun, Jaskula-Sztul Renata, Harrison April, Dammalapati Ajitha, Xu Wenjin, Cheng Yiqiang, Chen Herbert, Gong Shaoqin
Journal: Biomaterials (2016)
Intensive cholesterol control in high risk patients can reduce cardiovascular events by 20%
Authors: Susan Mayor
Journal: BMJ (2017)

Reducing cholesterol to very low levels by treating high risk patients with a statin as well as a proprotein convertase subtilisin-kexin type 9 (PSCK9) inhibitor is associated with a 20% reduction in cardiovascular events, a secondary analysis of a randomised study has reported.1

“Our findings demonstrate that there is essentially no floor effect, and that lower levels translated to a greater reduction in risk,” said lead author Robert Giugliano, from the Brigham and Women’s Hospital in Boston, US. He added, “Among …
The effect of oral vinorelbine and capecitabine in patients with metastatic breast cancer
Authors: J. Finek, L. Holubec, L. Elgrova, M. Pesta, M. Votavova, I. Pavlikova, M. Frank, I. Bustova, H. Siffnerova, M. Sediva
Journal: Journal of Clinical Oncology (2006)

10605 Background: Optimal chemotherapy (CT) for advanced breast cancer treatment should be effective, well tolerated and convenient. Although the optimum CT is not defined, oral chemotherapy is an attractive option for many patients. Methods: We report a phase II multicentric study, first and second line metastatic breast cancer (MBC) treatment, at least one measurable lesion, prospectively collected data between 2003 and 2005. Treatment schedule: vinorelbine 60 mg/m 2 p.o. day 1 and 8, capecitabine 1000 mg/m 2 twice daily, day 1–14 q 21 days. Patients: 84 patients with MBC have been registered. Mean age 58.1 years, ranges (39.7 years–71.9 years). All patients had received prior adjuvant anthracycline based chemotherapy (CT). No adjuvant or palliative CT within the last 12 months, no concomitant hormonal treatment. Results: The median number of oral chemotherapy cycles vinorelbine plus capecitabine was 6 cycles (ranges 1 cycle - 19 cycles), total number of cycles was 550. In 84 evaluable pts the objective tumor response was achieved in 46 pts 55%, (ORR = CR + PR), complete response CR was achieved in 11 (13%) pts, partial response in 35 pts (42%), stable disease in 26 pts (31%). Median follow up was 9.7 months. In the intent-to-treat analysis, median time to progression was 6.7 months, median survival not reached, 58 pts (69%) are still alive. Reported NCI grade 3 - 4 toxicities: neutropenia in 4 pts (5%), febrile neutropenia in 4 pts (5%), vomiting in 6 pts (7%) Conclusion: Oral vinorelbine-capecitabine combination shows very promising activity and low toxicity in the MBC treatment. No significant financial relationships to disclose.
Drug Sensitivity Across Acute Myeloid Leukemia Subtypes Using an in Vitro Assay
Authors: Levanto Schachter, Irene M. Hutchins, Jill Waalen, Carol Burian, Darren Finlay, Kristiina Vuori, Giovanni Paternostro, Marin F. Xavier, Carrie L. Costantini, William E. Miller, Jeffrey Andrey, James Mason
Journal: Blood (2016)