tbuckley/cabot-search huggingface dataset:
Abstract 256: Ablation of 14-3-3 Protein Exacerbates Doxorubicin Induced Cardiomyopathy: Role of Apoptosis Signal Regulating Kinase-1
Authors: Vengadeshprabhu Karuppagounder, Somasundaram Arumugam, Remya Sreedhar, Vijayasree V Giridharan, Rejina Afrin, Meilei Harima, Kenji Suzuki, Kazuyuki Ueno, Rajarajan A Thandavarayan, Kenichi Watanabe
Journal: Circulation Research (2016)

Background: 14-3-3η family members are dimeric phosphoserine-binding proteins that participate in signal transduction and checkpoint control pathways. Anthracycline anticancer drug doxorubicin (Dox) can induce cardiotoxicity, which is believed to be based on inflammatory or oxidative injury. However, the role of 14-3-3η is not clear in Dox induced cardiac injury. We examined the role of 14-3-3η protein and apoptosis signal-regulating kinase-1 (Ask1) and inflammatory signaling by using transgenic mice with cardiac-specific expression of a dominant-negative 14-3-3η protein mutant (DN 14-3-3) in Dox induced cardiac injury. Methods: Cardiac dysfunction was induced by a single injection of Dox into wild-type (WT) and DN 14-3-3η mice. By the end of the study, echocardiography was performed to assess the cardiac function. The heart tissues were used for histopathology and western blotting. Results: Left ventricular (LV) fractional shortening and ejection fraction were dramatically decreased in DN 14-3-3η mice, when compared to WT mice after Dox injection. Inactivation of 14-3-3η protein significantly increased Dox induced mortality. Significant Ask1 activation in DN 14-3-3η after Dox injection was evidenced by pronounced de-phosphorylation at Ser-967 and intense immunofluorescence observed LV sections. Marked increase in myocardial apoptosis, cardiac hypertrophy, and fibrosis were observed with a corresponding up-regulation of proinflammatory factors and cytokine expression in DN 14-3-3η mice after Dox injection. Furthermore cardiac expression of high mobility group box (HMGB)1 and its cascade protein expressions were significantly up-regulated in DN 14-3-3η mice compared to WT mice after Dox injection. Conclusion: Taken together, these findings suggest that depletion of 14-3-3η protein causes reduce survival rate in mice with cardiac dysfunction, presumably via activation of downstream Ask1 signaling pathways. This may provide a novel therapeutic strategy against Dox-induced cardiac injury by regulating Ask1 signaling.
Cyclophosphamide with (+)/without (-) fluorouracil followed by subcutaneous or intravenous interleukin-2 in solid tumors: An off-label experience.
Authors: Giovanni Lo Re, Francesco Lo Re, Paolo Doretto, Alessandro Del Conte, Maria Amadio, Cinzia Cozzi, Valter Adamo, Daniele Maruzzi, Paolo Ubiali, Paolo Sandri
Journal: Journal of Clinical Oncology (2017)

e14621 Background: primary and acquired resistance cause treatment failure to several agents. Recently it is emerging the role of immune surveillance in the control of tumor progression. The immune tolerance correlates with disease progression and FOXP3+ regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC) play a relevant role in immunosuppression. Cyclophosphamide (C) and Fluorouracil (FU) seems to reduce these cell populations. Methods: Objective: safety, feasibility, pain control, activity and impact on immune system (Neutrophil/Lymphocyte (N/L), Platelet/L (P/L), Tregs %, Monocytes (M)(10 3 /μL) count.Treatment: 1) C 300 mg/sqm +/- FU 500 mg/sqm day (d) 1, Interleukin-2 (IL-2) 18 MUI/sqm intravenous continuous infusion (i.v.c.i) d 3-5, 17-19 q 29 or 2) C 300 mg/sqm + FU 500 mg/sqm day d 1, IL-2 4.5 MUI subcutaneous (s.c) d 3-6, 17-20 q 29 for 2 cycles. Stable or responding patients (pts) continue therapy for three cycles. Results: from February 2014 to December 2016, 13/14 pts were treated. M/F:1/1. Median age was 68 years and median PS 1 (range 0-2). The primary tumor was bladder, liver, pancreas, neuroendocrine carcinoma and ovary in 2, melanoma, prostate, GIST and breast in 1 pt respectively. Sites of metastases were: lung in 4, liver in 9, lymph’nodes in 9, bone in 5 and spleen in 1 pt respectively. Previous therapy: 1- 2 in 6, ≥ 3 in 8. Six and 7 pts performed treatment 1, 2 respectively. Median number of cycles administered was 2 (range 1-3). Median basal and post-treatment N/L, P/L, M and Treg values were 2, 130, 0.49, 2,9% and 2, 94, 0.55, 10.5%. Pain improvement was obtained on 7/8 pts. The toxicity was manageable as for i.v.c.i as for s.c administration. In addition to universal capillary like syndrome, G3-4 toxicities were diarrhea, bleeding, anemia in 2, proteinuria in 1 pt respectively. Response: 3 PR (2 HCC, 1 pancreas), 2 SD, 4 PD, 5 unevaluable. The duration of response was 2+ and 3 months in 2 HCC pts and 8+ months in pancreatic pt. The crude median PFS and OS was 1 (range1-8+) and 2+ (range 1-18) months Conclusions: C- FU- IL-2 can be considered safe, feasible and meanly active in heavy pretreated pts. Except P/L, no reduction on Tregs, M counts and N/L was observed.
基底细胞癌光学相干断层成像:位置、亚型、观察者变化和图像质量对诊断性能的影响
Authors: J. Holmes, T. von Braunmühl, C. Berking, E. Sattler, M. Ulrich, U. Reinhold, H. Kurzen, T. Dirschka, C. Kellner, S. Schuh, J. Welzel
Journal: British Journal of Dermatology (2018)

非黑色素瘤皮肤癌(NMSC)是影响全球白皮肤人群的最常见癌症,患者数量超过所有其他癌症患者的总和。基底细胞癌(BCC)是最常见的NMSC,英国每年至少确诊100000个新病例,每年增长4%~10%,对医疗服务构成的负担越来越重。至少50%的BCC皮肤活体组织检查为阴性(未发现癌症肿瘤),因此皮肤科医生希望能有一种非侵入式成像工具(即使用图像,而非活检手术),提供更多信息来诊断,以避免不必要的活检。本研究共有256名BCC患者,地点位于德国的6家中心。研究分析了使用新型成像设备VivoSight Optical Coherence Tomography (OCT)扫描仪来诊断BCC的准确性。本研究2015年的一篇文章(Ulrich et al., Brit. J. Dermatology, (15), 173, pp 428~435)指出,使用OCT诊断的准确性较临床/皮肤镜检查(医生用肉眼检查或使用一种叫做皮血管镜的手持放大镜检查皮肤)有大幅提升。在本文中,作者们提供了进一步的数据分析:诊断性能(即诊断准确性)不取决于病变(受影响的皮肤部位)发生在身体的哪个部位;在病变有鳞屑/痂皮的情况下,诊断性能会下降(但仍优于临床/皮肤镜检查);不同医生之间的诊断表现一致(即其诊断大体上相同),且他们在对其自己的诊断高度自信的情况下,更有可能作出正确诊断;以及BCC亚型可根据OCT诊断,准确性适中(62%~72%)。这些结论验证了OCT辅助诊断BCC的目标用途,其能够检测出更早期的BCC并支持非侵入式治疗方案,进而有可能改善护理标准。
A multifunctional nanotheranostic for the intelligent MRI diagnosis and synergistic treatment of hypoxic tumor
Authors: Ruixue Song, Meng Zhang, Yanyan Liu, Zhaowen Cui, Hua Zhang, Zhongmin Tang, Xiaoyan Chen, Haihong Wu, Zhenwei Yao, Mingyuan He, Wenbo Bu
Journal: Biomaterials (2018)
Phase II Study of Taselisib (GDC-0032) in Combination with Fulvestrant in Patients with HER2-Negative, Hormone Receptor–Positive Advanced Breast Cancer
Authors: Maura N. Dickler, Cristina Saura, Donald A. Richards, Ian E. Krop, Andrés Cervantes, Philippe L. Bedard, Manish R. Patel, Lajos Pusztai, Mafalda Oliveira, Alison K. Cardenas, Na Cui, Timothy R. Wilson, Thomas J. Stout, Michael C. Wei, Jerry Y. Hsu, José Baselga
Journal: Clinical Cancer Research (2018)

Abstract Purpose: This single-arm, open-label phase II study evaluated the safety and efficacy of taselisib (GDC-0032) plus fulvestrant in postmenopausal women with locally advanced or metastatic HER2-negative, hormone receptor (HR)-positive breast cancer. Patients and Methods: Patients received 6-mg oral taselisib capsules daily plus intramuscular fulvestrant (500 mg) until disease progression or unacceptable toxicity. Tumor tissue (if available) was centrally evaluated for PIK3CA mutations. Adverse events (AE) were recorded using NCI-CTCAE v4.0. Tumor response was investigator-determined using RECIST v1.1. Results: Median treatment duration was 4.6 (range: 0.9–40.5) months. All patients experienced ≥1 AE, 30 (50.0%) had grade ≥3 AEs, and 19 (31.7%) experienced 35 serious AEs. Forty-seven of 60 patients had evaluable tissue for central PIK3CA mutation testing [20 had mutations, 27 had no mutation detected (MND)]. In patients with baseline measurable disease, clinical activity was observed in tumors with PIK3CA mutations [best confirmed response rate: 38.5% (5/13; 95% CI, 13.9–68.4); clinical benefit rate (CBR): 38.5% (5/13; 95% CI, 13.9–68.4)], PIK3CA-MND [best confirmed response rate: 14.3% (3/21; 95% CI, 3.0–36.3); CBR: 23.8% (5/21; 95% CI, 8.2–47.2)], and unknown PIK3CA mutation status [best confirmed response rate: 20.0% (2/10; 95% CI, 2.5–55.6); CBR: 30.0% (3/10; 95% CI, 6.7–65.2)]. Conclusions: Taselisib plus fulvestrant had clinical activity irrespective of PIK3CA mutation status, with numerically higher objective response rate and CBR in patients with PIK3CA-mutated (vs. -MND) locally advanced or metastatic HER2-negative, HR-positive breast cancer. No new safety signals were reported. A confirmatory phase III trial is ongoing. Clin Cancer Res; 24(18); 4380–7. ©2018 AACR.
Targeting the <i>IDH2</i> Pathway in Acute Myeloid Leukemia
Authors: Maria L. Amaya, Daniel A. Pollyea
Journal: Clinical Cancer Research (2018)

Acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis. A large percentage of patients succumb to this disease in spite of aggressive treatments with chemotherapy. Recent advances with mutational analysis led to the discovery of isocitrate dehydrogenase (IDH) mutations in AML. IDH2 is an enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate; its mutated version leads to the accumulation of the oncometabolite (R)-2 hydroxyglutarate, which disrupts several cell processes and leads to a blockage in differentiation. Targeting IDH2 is compelling, as it is an early and stable mutation in AML. Enasidenib, a specific small-molecule inhibitor of IDH2, recently gained FDA approval for the treatment of patients with relapsed/refractory IDH2-mutated AML. In this review, we will focus on the indications and efficacy of enasidenib in the treatment of patients with IDH2-mutated AML. Clin Cancer Res; 24(20); 4931-6. ©2018 AACR.
Balancing risks versus benefits of anticoagulants in stroke prevention
Authors: Charlotte Cordonnier
Journal: The Lancet Neurology (2018)

Evidence at the population level shows that giving oral anticoagulants has a clear long-term benefit in preventing recurrent ischaemic stroke in people with ischaemic stroke and atrial fibrillation. However, when it comes to an individualised treatment decision, many doctors are still reluctant to prescribe oral anticoagulants because of the associated risk of bleeding. We can be, as one of my colleagues says, “haemophobic”. Intracranial haemorrhage associated with use of oral anticoagulants is indeed a serious condition but the benefit of oral anticoagulation has to be considered.
Abstract B07: Role of lysyl hydroxylases in metastatic lung cancer
Authors: Wei Liu, Ting Zhang, Lixia Guo, Yuanyuan Wang, Yanan Yang
Journal: Cancer Research (2018)

Abstract Lung cancer remains the leading cause of cancer-related death, partly due to the fact that most patients are diagnosed with metastatic disease, which is the main cause of death, yet effective therapeutics are lacking. Utilizing mouse models of metastatic lung adenocarcinomas, we report that the transcription factor GATA3 and its cofactor FOG2 play critical roles in lung adenocarcinoma metastasis by promoting the expression of the lysyl hydroxylase (LH) family members, which in turn regulate the tumorigenicity and motility of lung tumor cells through both EMT and EMT-independent mechanisms. In vivo, LHs are elevated in human lung adenocarcinomas and are associated with worse patient survival. Collectively, our data suggest that targeting LHs may be useful for treating metastatic lung cancer. Citation Format: Wei Liu, Ting Zhang, Lixia Guo, Yuanyuan Wang, Yanan Yang. Role of lysyl hydroxylases in metastatic lung cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B07.
Th2 cytokines orchestrate the secretion of <scp>MUC</scp>5<scp>AC</scp> and <scp>MUC</scp>5B in <scp>IL</scp>‐5‐positive chronic rhinosinusitis with nasal polyps
Authors: Y. Zhang, L. Derycke, G. Holtappels, X. D. Wang, L. Zhang, C. Bachert, N. Zhang
Journal: Allergy (2018)

Abstract Background Mucin over‐secretion is a significant characteristic of chronic rhinosinusitis with nasal polyps ( CRS w NP ). This study aimed to investigate the relationship between Th2 cytokines and MUC 5 AC or MUC 5B, and the mechanism of mucin over‐secretion in the type‐2 inflammatory endotype of CRS w NP . Methods Main Th‐cell cytokines, associated mediators, and mucins were determined in the homogenates of nasal polyp samples from 21 CRS w NP patients and inferior turbinate samples from 8 controls, by ELISA or Uni CAP system. Secretion of MUC 5 AC and MUC 5B was measured in the supernatants of IL ‐5, IL ‐4, or IL ‐13 primed nasal polyp fragments. Co‐localization of MUC 5 AC , MUC 5B, and IL ‐4 receptor α ( IL ‐4Rα) in CRS w NP and controls was evaluated by immunohistochemistry. Gene expression of IL ‐4Rα in the samples was measured by real‐time reverse transcription‐polymerase chain reaction. Results Baseline protein levels of the Th2‐cytokines IL ‐4, IL ‐5, and IL ‐13, and mucins MUC 5 AC and MUC 5B were significantly higher in the IL ‐5(+) CRS w NP group, compared to control and IL ‐5(−) CRS w NP groups. MUC 5 AC and MUC 5B secretions were significantly increased in IL ‐4‐ or IL ‐13‐primed, but not IL ‐5‐primed fragments of nasal polyps. Immuno‐stained serial sections demonstrated that IL ‐4Rα was widely expressed in the epithelium and submucosal glands in control and nasal polyp tissues. Gene expression of IL ‐4Rα was elevated in nasal polyp tissues, specifically in the IL ‐5(+) CRS w NP group. Conclusions In type‐2 inflammatory nasal polyps, characterized by the tissue expression of IL ‐5, MUC 5 AC and MUC 5B are overexpressed. Both IL ‐4 and IL ‐13 may upregulate mucin expression via IL ‐4Rα, which is also overexpressed in IL ‐5(+) CRS w NP .
LncRNA MT1JP functions as a ceRNA in regulating FBXW7 through competitively binding to miR-92a-3p in gastric cancer
Authors: Gang Zhang, Shuwei Li, Jiafei Lu, Yuqiu Ge, Qiaoyan Wang, Gaoxiang Ma, Qinghong Zhao, Dongdong Wu, Weida Gong, Mulong Du, Haiyan Chu, Meilin Wang, Aihua Zhang, Zhengdong Zhang
Journal: Molecular Cancer (2018)

Emerging evidence has shown that dysregulation function of long non-coding RNAs (lncRNAs) implicated in gastric cancer (GC). However, the role of the differentially expressed lncRNAs in GC has not fully explained.LncRNA expression profiles were determined by lncRNA microarray in five pairs of normal and GC tissues, further validated in another 75 paired tissues by quantitative real-time PCR (qRT-PCR). Overexpression of lncRNA MT1JP was conducted to assess the effect of MT1JP in vitro and in vivo. The biological functions were demonstrated by luciferase reporter assay, western blotting and rescue experiments.LncRNA MT1JP was significantly lower in GC tissues than adjacent normal tissues, and higher MT1JP was remarkably related to lymph node metastasis and advance stage. Besides, GC patients with higher MT1JP expression had a well survival. Functionally, overexpression of lncRNA MT1JP inhibited cell proliferation, migration, invasion and promoted cell apoptosis in vitro, and inhibited tumor growth and metastasis in vivo. Functional analysis showed that lncRNA MT1JP regulated FBXW7 expression by competitively binding to miR-92a-3p. MiR-92a-3p and down-regulated FBXW7 reversed cell phenotypes caused by lncRNA MT1JP by rescue analysis.MT1JP, a down-regulated lncRNA in GC, was associated with malignant tumor phenotypes and survival of GC. MT1JP regulated the progression of GC by functioning as a competing endogenous RNA (ceRNA) to competitively bind to miR-92a-3p and regulate FBXW7 expression. Our study provided new insight into the post-transcriptional regulation mechanism of lncRNA MT1JP, and suggested that MT1JP may act as a potential therapeutic target and prognosis biomarker for GC.
US approves first monoclonal antibody to prevent migraines
Authors: Owen Dyer
Journal: BMJ (2018)

The first of a new class of drugs for prevention of headaches in adults has won approval by the US Food and Drug Administration.

Amgen’s monoclonal antibody Aimovig (erenumab) comes in a disposable auto injector for home use once a month. It blocks receptors to the protein fragment CGRP (calcitonin gene related peptide), which has been known for decades to be overproduced in people with chronic migraine. It will be available to patients by the end of this week, Amgen said.

In phase IIIb results presented last month at the American Academy of Neurology’s annual meeting erenumab cut the number of days …
Sex and BMI Alter the Benefits and Risks of Sulfonylureas and Thiazolidinediones in Type 2 Diabetes: A Framework for Evaluating Stratification Using Routine Clinical and Individual Trial Data
Authors: John M. Dennis, William E. Henley, Michael N. Weedon, Mike Lonergan, Lauren R. Rodgers, Angus G. Jones, William T. Hamilton, Naveed Sattar, Salim Janmohamed, Rury R. Holman, Ewan R. Pearson, Beverley M. Shields, Andrew T. Hattersley, Catherine Angwin, Kennedy J. Cruickshank, Andrew J. Farmer, Stephen C.L. Gough, Alastair M. Gray, Christopher Hyde, Christopher Jennison, Mark Walker
Journal: Diabetes Care (2018)

OBJECTIVE The choice of therapy for type 2 diabetes after metformin is guided by overall estimates of glycemic response and side effects seen in large cohorts. A stratified approach to therapy would aim to improve on this by identifying subgroups of patients whose glycemic response or risk of side effects differs markedly. We assessed whether simple clinical characteristics could identify patients with differing glycemic response and side effects with sulfonylureas and thiazolidinediones. RESEARCH DESIGN AND METHODS We studied 22,379 patients starting sulfonylurea or thiazolidinedione therapy in the U.K. Clinical Practice Research Datalink (CPRD) to identify features associated with increased 1-year HbA1c fall with one therapy class and reduced fall with the second. We then assessed whether prespecified patient subgroups defined by the differential clinical factors showed differing 5-year glycemic response and side effects with sulfonylureas and thiazolidinediones using individual randomized trial data from ADOPT (A Diabetes Outcome Progression Trial) (first-line therapy, n = 2,725) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes) (second-line therapy, n = 2,222). Further replication was conducted using routine clinical data from GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) (n = 1,977). RESULTS In CPRD, male sex and lower BMI were associated with greater glycemic response with sulfonylureas and a lesser response with thiazolidinediones (both P &amp;lt; 0.001). In ADOPT and RECORD, nonobese males had a greater overall HbA1c reduction with sulfonylureas than with thiazolidinediones (P &amp;lt; 0.001); in contrast, obese females had a greater HbA1c reduction with thiazolidinediones than with sulfonylureas (P &amp;lt; 0.001). Weight gain and edema risk with thiazolidinediones were greatest in obese females; however, hypoglycemia risk with sulfonylureas was similar across all subgroups. CONCLUSIONS Patient subgroups defined by sex and BMI have different patterns of benefits and risks on thiazolidinedione and sulfonylurea therapy. Subgroup-specific estimates can inform discussion about the choice of therapy after metformin for an individual patient. Our approach using routine and shared trial data provides a framework for future stratification research in type 2 diabetes.
Dialysis versus Medical Management at Different Ages and Levels of Kidney Function in Veterans with Advanced CKD
Authors: Manjula Kurella Tamura, Manisha Desai, Kristopher I. Kapphahn, I-Chun Thomas, Steven M. Asch, Glenn M. Chertow
Journal: Journal of the American Society of Nephrology (2018)

Background Appropriate patient selection and optimal timing of dialysis initiation among older adults with advanced CKD are uncertain. We determined the association between dialysis versus medical management and survival at different ages and levels of kidney function. Methods We assembled a nationally representative 20% sample of United States veterans with eGFR&lt;30 ml/min per 1.73 m 2 between 2005 and 2010 ( n =73,349), with follow-up through 2012. We used an extended Cox model to determine associations among the time-varying exposures, age (&lt;65, 65–74, 75–84, and ≥85 years), eGFR (&lt;6, 6–&lt;9, 9–&lt;12, 12–&lt;15, and 15–&lt;29 ml/min per 1.73 m 2 ), and provision of dialysis, and survival. Result Over the mean±SEM follow-up of 3.4±2.2 years, 15% of patients started dialysis and 52% died. The eGFR at which dialysis, compared with medical management, associated with lower mortality varied by age ( P &lt;0.001). For patients aged &lt;65, 65–74, 75–84, and ≥85 years, dialysis associated with lower mortality for those with eGFR not exceeding 6–&lt;9, &lt;6, 9–&lt;12, and 9–&lt;12 ml/min per 1.73 m 2 , respectively. Dialysis initiation at eGFR&lt;6 ml/min per 1.73 m 2 associated with a higher median life expectancy of 26, 25, and 19 months for patients aged 65, 75, and 85 years, respectively. When dialysis was initiated at eGFR 9–&lt;12 ml/min per 1.73 m 2 , the estimated difference in median life expectancy was &lt;1 year for these patients. Conclusions Provision of dialysis at higher levels of kidney function may extend survival for some older patients.
The Milroy Lectures on the Value of Isolation and its Difficulties: Delivered before the Royal College of Physicians of London
Authors: E. Seaton
Journal: BMJ (1896)

not even forming a contraindication; indeed, Genzmer goes so far as to advocate the operation even though there are already metastatic deposits in the liver.As even in Ger- many about 20 per cent.to 25 per cent. of the cases applying for relief are not deemed fit for the radical operation, we may say that taking all patients together as they come to the surgeon.not more than 20 per cent.will be benefited by the radical operation; the remainder will do better with colotomy.
Assessment of Smartphone Application for Teaching Intuitive Visual Diagnosis of Melanoma
Authors: Frank A. Lacy, Garrett C. Coman, Alex C. Holliday, Michael S. Kolodney
Journal: JAMA Dermatology (2018)

NCT01728805) studies demonstrate that mogamulizumab may be an effective agent for disease reduction in patients with CTCL, mogamulizumab will likely be used as a bridge to allo-HSCT when it is made more available.Future prospective studies should monitor concentrations of mogamulizumab and regulatory T cells following treatment to determine whether shorter time inter vals between mogamulizumab and allo-HSCT increases risk of acute GVHD.
Externalization is common to all value judgments, and norms are motivating because of their intersubjective grounding
Authors: Carme Isern-Mas, Antoni Gomila
Journal: Behavioral and Brain Sciences (2018)

We show that externalization is a feature not only of moral judgment, but also of value judgment in general. It follows that the evolution of externalization was not specific to moral judgment. Second, we argue that value judgments cannot be decoupled from the level of motivations and preferences, which, in the moral case, rely on intersubjective bonds and claims.