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Identification of neuron selective androgen receptor inhibitors

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World Journal of Biological Chemistry 2017年第2期8卷 138-150页

作者： Maya Otto-Duessel Ben Yi Tew Steven Vonderfecht Roger Moore jeremy O jones Department of Cancer Biology Beckman Research Institute City of Hope National Medical Center Division of Comparative Medicine Beck-man Research Institute City of Hope National Medical Center Department of Molecular Immunology Beckman Research Institute City of Hope National Medical Center

AIM To identify neuron-selective androgen receptor(AR) signaling inhibitors, which could be useful in the treatment of spinal and bulbar muscular atrophy(SBMA), or Kennedy's disease, a neuromuscular disorder in which deterioration of motor neurons leads to progressive muscle weakness. METHODS Cell lines representing prostate, kidney, neuron, adipose, and muscle tissue were developed that stably expressed the CFP-AR-YFP FRET reporter. We used these cells to screen a library of small molecules for cell typeselective AR inhibitors. Secondary screening in luciferase assays was used to identify the best cell-type specific AR inhibitors. The mechanism of action of a neuronselective AR inhibitor was examined in vitro using luciferase reporter assays, immunofluorescence microscopy, and immunoprecipitations. Rats were treated with the most potent compound and tissue-selective AR inhibition was examined using RT-q PCR of AR-regulated genes and *** We identified the thiazole class of antibiotics as com-pounds able to inhibit AR signaling in a neuronal cell line but not a muscle cell line. One of these antibiotics, thiostrepton is able to inhibit the activity of both wild type and polyglutamine expanded AR in neuronal GT1-7 cells with nanomolar potency. The thiazole antibiotics are known to inhibit FOXM1 activity and accordingly, a novel FOXM1 inhibitor FDI-6 also inhibited AR activity in a neuron-selective fashion. The selective inhibition of AR is likely indirect as the varied structures of these compounds would not suggest that they are competitive antagonists. Indeed, we found that FOXM1 expression correlates with cell-type selectivity, FOXM1 co-localizes with AR in the nucleus, and that sh RNA-mediated knock down of FOXM1 reduces AR activity and thiostrepton sensitivity in a neuronal cell line. Thiostrepton treatment reduces FOXM1 levels and the nuclear localization of beta-catenin, a known co-activator of both FOXM1 and AR, and reduces the associa

关键词： Androgen receptor Selective androgen receptor modulator Spinal and bulbar muscular atrophy Kennedy’s disease

Targeting KRAS in pancreatic adenocarcinoma:Progress in demystifying the holy grail

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World Journal of Clinical Oncology 2023年第8期14卷 285-296页

作者： Ahmed Elhariri Ahmed Alhaj Daniel Ahn Mohamad Bassam Sonbol Tanios Bekaii-Saab Christina Wu Michael Scott Rutenberg John Stauffer Jason Starr Umair Majeed jeremy jones Mitesh Borad Hani Babiker Division of Hematology-Oncology Department of MedicineMayo Clinic FloridaMayo Clinic Cancer CenterJacksonvilleFL 32224United States Division of Hematology-Oncology Department of MedicineMayo Clinic ArizonaMayo Clinic Cancer CenterPhoenixAZ 85054United States Department of Radiation-Oncology Mayo Clinic FloridaMayo Clinic Cancer CenterJacksonvilleFL 32224United States Department of Surgical Oncology Hepatopancreatobiliary SurgeryMayo Clinic FloridaJacksonvilleFL 32224United States

Pancreatic cancer(PC)remains one of the most challenging diseases,with a very poor 5-year overall survival of around 11.5%.Kirsten rat sarcoma virus(KRAS)mutation is seen in 90%-95%of PC patients and plays an important role in cancer cell proliferation,differentiation,metabolism,and survival,making it an essential mutation for targeted *** extensive efforts in studying this oncogene,there has been little success in finding a drug to target this pathway,labelling it for decades as“undruggable”.In this article we summarize some of the efforts made to target the KRAS pathway in PC,discuss the challenges,and shed light on promising clinical trials.

关键词： Kirsten rat sarcoma virus Targeted therapy Pancreatic cancer Drug resistance Next generation sequencing Clustered regularly interspaced short palindromic repeats

Extramural vascular invasion and response to neoadjuvant chemoradiotherapy in rectal cancer: influence of the CpG island methylator phenotype

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World Journal of Gastrointestinal Oncology 2017年第5期9卷 209-217页

作者： jeremy Stuart Williamson Huw Geraint jones Namor Williams Anthony Paul Griffiths Gareth Jenkins John Beynon Dean Anthony Harris Department of General and Colorectal Surgery Singleton Hospital Department of Pathology Singleton Hospital Department of Life Sciences Swansea University

To identify whether CpG island methylator phenotype (CIMP) is predictive of response to neoadjuvant chemoradiotherapy (NACRT) and outcomes in rectal cancer. METHODSPatients undergoing NACRT and surgical resection for rectal cancer in a tertiary referral centre between 2002-2011 were identified. Pre-treatment tumour biopsies were analysed for CIMP status (high, intermediate or low) using methylation specific PCR. KRAS and BRAF status were also determined using pyrosequencing analysis. Clinical information was extracted from case records and cancer services databases. Response to radiotherapy was measured by tumour regression scores determined upon histological examination of the resected specimen. The relationship between these molecular features, response to NACRT and oncological outcomes were analysed. RESULTSThere were 160 patients analysed with a median follow-up time of 46.4 mo. Twenty-one (13%) patients demonstrated high levels of CIMP methylation (CIMP-H) and this was significantly associated with increased risk of extramural vascular invasion (EMVI) compared with CIMP-L [8/21 (38%) vs 15/99 (15%), P = 0.028]. CIMP status was not related to tumour regression after radiotherapy or survival, however EMVI was significantly associated with adverse survival (P < 0.001). Intermediate CIMP status was significantly associated with KRAS mutation (P = 0.01). There were 14 (9%) patients with a pathological complete response (pCR) compared to 116 (73%) patients having no or minimal regression after neoadjuvant chemoradiotherapy. Those patients with pCR had median survival of 106 mo compared to 65.8 mo with minimal regression, although this was not statistically significant (P = 0.26). Binary logistic regression analysis of the relationship between EMVI and other prognostic features revealed, EMVI positivity was associated with poor overall survival, advanced “T” stage and CIMP-H but not nodal status, age, sex, KRAS mutation status and presence of local or systemic recurre

关键词： Rectal cancer CpG islands Methylation

AML presenting as a mediastinal mass and right ventricular failure

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Case Reports in Clinical Medicine 2013年第1期2卷 35-37页

作者： jeremy B. Moad Kellie R. jones Pulmonary and Critical Care Medicine Department of Medicine University of Oklahoma Health Sciences Center Oklahoma City USA

Extrinsic compression of the pulmonary arteries by mediastinal masses, while rare, is the most common cause of non-congenital peripheral pulmonary artery stenosis. Granulocytic myeloid sarcomas are an extramedullary manifestation of acute myeloid leukemia, with a wide variability in their presentation. They can present either de novo as soft tissue masses or in conjunction with acute myeloid leukemia. Myeloid sarcomas are uncommon and their prognosis is generally considered poor when present in patients with acute myeloid leukemia (AML). We present a case of a granulocytic myeloid sarcoma causing pulmonary artery stenosis and right ventricular failure. This case represents a unique cause of pulmonary arterial stenosis.

关键词： Granulocytic Myeloid Sarcoma Myeloid Sarcoma Right Heart Failure Pulmonary Artery Stenosis

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作为医学人文教育核心的历史学

广西民族大学学报（哲学社会科学版） 2018年第2期40卷 114-128页

作者： [美]David S. jones [美]jeremy A. Greene [美]Jacalyn Duffin [美]John Harley Warner 方芗(译) 美国哈佛大学历史系约翰斯·霍普金斯大学皇后大学耶鲁大学医学史系中山大学社会学与人类学学院广东广州510275

尝试从不同的角度讨论史学对于医学核心能力在知识、论证和操作上所发挥的作用。史学对于了解疾病的成因(如非还原论机制需要计算疾病长期以来的变化量)、疗效(如为什么医生认为他们的治疗方案有效,还有就是他们在不同时期的评估方式的... 详细信息

尝试从不同的角度讨论史学对于医学核心能力在知识、论证和操作上所发挥的作用。史学对于了解疾病的成因(如非还原论机制需要计算疾病长期以来的变化量)、疗效(如为什么医生认为他们的治疗方案有效,还有就是他们在不同时期的评估方式的变化)有核心贡献。同时有助于了解医学知识和实际操作在不同的社会、经济和政治背景中的偶然性。这些都是医生作为诊断者和治疗者需要知道的。因此史学恰恰能被纳入医学教育中最为盛行的核心技能的培养。

关键词：医学史医学教育医学人文

这些手机应用软件获取了你的电话号码（英文）

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大学英语 2017年第3期 50-52页

作者： Rory Cellan-jones 杰西

The mobile phone numbers of former Prime Minister David Cameron^1,Labour leader jeremy Corbyn^2,celebrities and millions of other people are being stored in databases that can be searched by the *** the numbers cannot... 详细信息

关键词：高等教育英语阅读理解