tbuckley/cabot-search huggingface dataset:
Protective and Detrimental Roles of p38α Mitogen‐Activated Protein Kinase in Different Stages of Nonalcoholic Fatty Liver Disease
Authors: Seonghwan Hwang, Xiaolin Wang, Robim M. Rodrigues, Jing Ma, Yong He, Wonhyo Seo, Seol Hee Park, Seung‐Jin Kim, Dechun Feng, Bin Gao
Journal: Hepatology (2020)

Background and Aims Neutrophil infiltration is a hallmark of nonalcoholic steatohepatitis (NASH), but how this occurs during the progression from steatosis to NASH remains obscure. Human NASH features hepatic neutrophil infiltration and up‐regulation of major neutrophil‐recruiting chemokines (e.g., chemokine [C‐X‐C motif] ligand 1 [CXCL1] and interleukin [IL]‐8). However, mice fed a high‐fat diet (HFD) only develop fatty liver without significant neutrophil infiltration or elevation of chemokines. The aim of this study was to determine why mice are resistant to NASH development and the involvement of p38 mitogen‐activated protein kinase (p38) activated by neutrophil‐derived oxidative stress in the pathogenesis of NASH. Approach and Results Inflamed human hepatocytes attracted neutrophils more effectively than inflamed mouse hepatocytes because of the greater induction of CXCL1 and IL‐8 in human hepatocytes. Hepatic overexpression of Cxcl1 and/or IL‐8 promoted steatosis‐to‐NASH progression in HFD‐fed mice by inducing liver inflammation, injury, and p38 activation. Pharmacological inhibition of p38α/β or hepatocyte‐specific deletion of p38a (a predominant form in the liver) attenuated liver injury and fibrosis in the HFD +Cxcl1 ‐induced NASH model that is associated with strong hepatic p38α activation. In contrast, hepatocyte‐specific deletion of p38a in HFD‐induced fatty liver where p38α activation is relatively weak exacerbated steatosis and liver injury. Mechanistically, weak p38α activation in fatty liver up‐regulated the genes involved in fatty acid β‐oxidation through peroxisome proliferator‐activated receptor alpha phosphorylation, thereby reducing steatosis. Conversely, strong p38α activation in NASH promoted caspase‐3 cleavage, CCAAT‐enhancer‐binding proteins homologous protein expression, and B cell lymphoma 2 phosphorylation, thereby exacerbating hepatocyte death. Conclusions Genetic ablation of hepatic p38a increases simple steatosis but ameliorates oxidative stress‐driven NASH, indicating that p38α plays distinct roles depending on the disease stages, which may set the stage for investigating p38α as a therapeutic target for the treatment of NASH.
Prognostic value of SOX2 and CD8+TIL in limited stage small cell lung cancer.
Authors: Jinsoo Lee, Soon Auck Hong, Hye Won Hwang, Se Jun Park, Kabsoo Shin, Joori Kim, Seung-Hwan Lee, Jieun Lee, In-Ho Kim, Sook-Hee Hong
Journal: Journal of Clinical Oncology (2020)

e21108 Background: SOX2 is a transcriptional factor that drives embryonic stem cell to neuroendocrine cells in lung development and is highly expressed in SCLC. The serum SOX2 antibody in SCLC has been known to mediate neurologic paraneoplastic syndrome. In this study, we evaluated the expression of SOX2 and CD8+ tumor infiltrating lymphocyte (TIL) in LS-SCLC from clinical tumor tissue and their impact on PFS and OS. Methods: Among the total 245 patients with SCLC treated between 2010 and 2018, 75 patients with LS-SCLC with available tumor tissue were enrolled. SOX2 and CD8+ TIL were evaluated by immunohistochemistry. High SOX2 expression was defined as above 100 of H score that was derived from multiplying intensity by the proportion of stained tumor cells. The number of CD8+TILs was counted under high magnification (x400) with four fields in intratumoral area. The cut value for high CD8+TIL was the above the median of total case. Results: 64 patients (85.4%) received etoposide/platinum and definite local therapy (radiation therapy or surgery) and 18 patients (24.0%) received surgical resection. High expression of CD8+ TIL was related to significantly longer PFS (13.9 vs. 8.0 months, P = 0.014) and tended to related to longer OS (32.1 vs. 17.4 months, P = 0.056) than low expression. High expression of SOX2 was tended to related with longer OS and PFS compared to low expression of SOX2 (median, 21.7 vs. 17.1 months, P = 0.118; 12.7 vs. 9.0 months, P = 0.110, respectively) without statistical significance. 29 patients with high CD8+TIL among 52 patients with high SOX2 had significantly longer PFS and OS compared to the other groups (median PFS 19.3 vs. 8.4 months, P = 0.002 and median OS 35.7 vs. 17.4 months, P = 0.004, respectively). Multivariate Cox regression analysis showed that combined high expression SOX2 and CD8+ TIL was an independent good prognostic factor for OS (HR = 0.449, P = 0.018) and PFS of SCLC (HR = 0.481, P = 0.021). Conclusions: In our study, high expression level of combined SOX2 and CD8+ TIL were related to longer OS and PFS, and it could be used as a prognostic biomarker for LS-SCLC. [Table: see text]
65岁以上急性胆囊炎并胆囊结石患者的临床特点与处理
Authors: 刁红亮, 乌尔班, 黄先国
Journal: BMJ (2006)

回顾性分析我院收治的267例65岁以上老年急性胆囊炎并胆囊结石患者的临床资料,其中69例保守治疗,198例行手术治疗.55例发生胆囊坏疽,31例发生胆囊穿孔,231例痊愈,28例缓解,死亡8例(5例为手术治疗,3例为保守治疗).对老年急性胆囊炎胆囊结石患者,选择适当的手术时机、手术方式并加强围手术期处理是提高疗效的关键。
Andrew Veitch Foote
Authors: George G Youngson, J Nelson Norman
Journal: BMJ (2020)

Andrew Veitch Foote was brought up in Lochgelly, Fife, where his father was the provost and a local general practitioner. He studied medicine at the University of Edinburgh. After a period of national service in the Royal Air Force, he entered surgical training in Yorkshire, thereafter moving to Edinburgh as registrar in cardiothoracic surgery to Andrew Logan. He then undertook research—initially in the cardiac surgery department UCLA, Los Angeles, and subsequently under the watchful gaze of Sir John Bruce at the gastrointestinal unit, Western General Hospital. Although he …
Diabetes-related hearing loss
Authors: Jin Hao, Xinxing Fu, Lin Hua, Yongxin Li
Journal: BMJ (2018)

中国已成为超越印度的糖尿病第一人口大国，糖尿病相关听力下降作为新的糖尿病并发症逐渐引起关注。本文从流行病学及其影响因素、糖尿病相关听力下降的危害、临床听力学特点及其诊断和筛查进行阐述，并对未来研究提出展望。
How to better anticipate innovative anticancer drugs and their potential challenges: A European survey from the iPAAC WP9.
Authors: Hélène Denis, Elisabeth Bermudez, Krol Aurélie, Marianne Duperray, Sophie Negellen, Thierry Breton, Norbert Ifrah
Journal: Journal of Clinical Oncology (2020)

e14134 Background: The European joint action iPAAC, funded by the European Commission, aims to develop innovative approaches to advances in cancer control. The field of anticancer drugs has strongly evolved over the past years and the clinical development remains very important. Horizon scanning systems (HSS) help policy makers and healthcare professionals to anticipate new medicines and their main impacts before their marketing authorization. The Work package 9 (WP9) of iPAAC, dedicated to innovative therapies in cancer, wanted to evaluate the need for more finesse in the anticipation of innovative therapies in the oncology field. Methods: A survey among organizations in charge of an HSS was conducted to point out methodologic features needed to enable a better anticipation of anticancer drugs, gene and cell therapies, biomarkers and pediatric indications. In addition, a retrospective analysis of the efficiency of HSS was conducted based on the review of 11 approved indications of checkpoint inhibitors and CAR-T cells. For each indication, organizations indicated if it was anticipated via their HSS and provided eventual challenges encountered. Results: Eleven main organizations in charge of HSS were identified in Europe, from which 9 participated to the iPAAC WP9 study. Time frames of these HSS ranged from 3 years to only a few months prior marketing authorizations. While most of the organizations included all innovative drugs in their scope, 2 were focusing only on oncology drugs and had developed specific methods to prioritize innovative medicines. To enable a good anticipation of biomarkers and gene &amp; cell therapies, it appeared important to screen earlier phases clinical trials and to collect additional data. The retrospective analysis showed that biomarker expression threshold and centers authorized to provide gene and cell therapies or biomarker tests were some of the hardest parameters to anticipate. Having a structured database in the HSS process was seen as helpful, as it allowed the generation of ad hoc queries. Involving the expertise of practicing clinicians for prioritizing and assessing the innovative therapies was seen as an important asset for predicting clinically impacting drugs. Conclusions: Anticipating innovative drugs in oncology requires specific characteristics, especially given the variety of drugs, the earliness of data supporting marketing authorization and the dynamics of this therapeutic area. HSS is a valuable resource for the proper introduction and diffusion of innovative drugs.
Peutz-Jephers 综合征二例并文献复习
Authors: 杨建萍, 张洪波, 杨勤兵
Journal: BMJ (2012)

回顾性分析2例Peutz-Jeghers综合征患者的临床资料,并结合相关文献探讨其临床特征及诊断与治疗,提示内镜下息肉电切术为治疗有效方法,同时此类患者发生肿瘤的危险性较高,应加强术后随访,定期复查内镜和筛查肿瘤。
Safety and clinical activity of gene-engineered T-cell therapy targeting HPV-16 E7 for epithelial cancers.
Authors: Scott Norberg, Nisha Nagarsheth, Andrew Sinkoe, Sabina Adhikary, Thomas Meyer, Justin Lack, Jennifer Ann Kanakry, Mohammadhadi Bagheri, Colleen Schweitzer, Stephanie H. Astrow, Adrian Bot, David Stroncek, Nikolaos Gkitsas, Steven Highfill, Christian S. Hinrichs
Journal: Journal of Clinical Oncology (2020)

101 Background: Genetically engineered T-cell therapy has shown remarkable clinical activity in hematologic malignancies. It is not known if this type of treatment can be applied effectively to epithelial cancers, which account for 80% to 90% of human malignancies. Methods: We conducted a phase I clinical trial with a 3 + 3 dose escalation in which patients with metastatic HPV-16+ epithelial cancers were treated with a one-time infusion of genetically engineered T cells expressing a T-cell receptor targeting an HLA-A*02:01-restricted epitope of HPV-16 E7 (E7 TCR-T cells). A lymphocyte-depleting conditioning regimen was administered before cell infusion, and high-dose systemic aldesleukin was administered after cell infusion. Results: Twelve patients, previously treated with a median of 4 (range, 3 to 7) anticancer agents, were treated. The cell dose was not limited by toxicity. Six patients demonstrated objective clinical responses, which included regression of bulky tumors and complete elimination of some tumors. Responses occurred in patients with vulvar, anal, head and neck, and cervical cancer. Four patients who previously received PD-1-based therapy responded. Response duration ranged from 3 to 9 months. Sustained, high-level engraftment of E7 TCR-T cells in peripheral blood was observed (median after approximately 6 weeks, 66% of total T cells, range 1% to 88%) and correlated with cell dose but not with clinical response. Infused T cell characteristics did not correlate strongly with response. Of the 4 resistant tumors that were studied, 3 demonstrated genetic defects in HLA-A*02:01 or B2M (necessary components of the target complex) and 1 demonstrated copy loss with decreased expression of antigen presentation and interferon response molecules (i.e. TAP1, TAP2, IFNGR1, IFNGR2). Of the 3 sensitive tumors studied, 0 showed genetic defects in these molecules. Conclusions: E7 TCR-T cells demonstrated safety and clinical activity in the treatment of highly refractory metastatic HPV-16+ cancers. Treatment resistance was linked to definitive genetic defects in the targeted peptide-HLA complex and to manifold defects in antigen processing and interferon response. Clinical trial information: NCT02858310.
Gastrointestinal bleeding as initial presentation in a case of ectopic parathyroid adenoma complicated with hypercalcemic crisis
Authors: Rui Yang, Rongping Chen
Journal: BMJ (2018)

报道1例以消化道出血为主要表现的异位甲状旁腺腺瘤伴高钙危象患者的临床资料。患者女性，38岁。因解脓血便2周，恶心、呕吐2 d入院。查血钙3.27 mmol/L，胃镜示十二指肠溃疡(S2期)；甲状腺B超检查示左侧颈动脉旁包块，甲状旁腺核素显像示左颈动脉旁放射性浓聚影，以左颈动脉旁异位甲状旁腺腺瘤并甲状旁腺功能亢进而手术切除腺瘤。术后血钙、磷水平正常。
Foley尿管在腺样体切除术出血中的临床应用
Authors: 刘磊, 刘飞, 李冰, 渠倩, 庞宗领, 林均武, 王绪增, 徐鹏, 刘领兵
Journal: BMJ (2011)

儿童因鼾症常需行腺样体和扁桃体切除术,目前报道的腺样体切除术式较多,但无论哪种术式都会存在顽同性出血的情况.我科自2007年1月至2010年4月采用Foley尿管治疗23例腺样体切除术常规止血效果不佳的病例,取得显著效果。
Tolerability of enzalutamide in prostate cancer: A meta-analysis.
Authors: Tejas Karawadia, Shenhong Wu
Journal: Journal of Clinical Oncology (2020)

e15629 Background: Enzalutamide, a second-generation androgen receptor inhibitor widely used in the treatment of prostate cancer, is often discontinued due to adverse events. A meta-analysis of randomized controlled trials was performed to examine the overall tolerability of enzalutamide in prostate cancer in comparison with controls. Methods: Databases including PubMed (up to December 2019) and Google scholar (up to December 2019) were searched to identify all phase II and III randomized controlled trials that compared enzalutamide with placebo (with or without other anti androgen drugs) along with reported data regarding drug discontinuation due to adverse events with enzalutamide and placebo. A random- or fixed-effects model was used to determine summary incidences, relative risks (RR), and 95% confidence intervals depending on the heterogeneity of included studies. Results: A total of 7 RCTs were eligible for analysis which included 7,343 patients (enzalutamide: n = 4116, control: n = 3227). The summary incidence of tolerability measured as discontinuation rate due to adverse events was 7.3% (95% CI: 6.1-8.7%) with enzalutamide and 5.7% (95% CI: 4.3-7.5%) with placebo or first-generation antiandrogens including bicalutamide, nilutamide or flutamide. The tolerability of enzalutamide varied with stage of prostate cancer with significantly higher incidence of discontinuation (9.8%, 95% CI: 8.0-11.9%) in non-metastatic prostate cancer group than metastatic prostate cancer group (6.7%, 95% CI: 5.8-7.6%). In comparison with controls, enzalutamide did not significantly affect the tolerability with an RR of 1.25 (95% CI: 0.95-1.66, P = 0.12). In addition, enzalutamide did not significantly affect the tolerability with an RR of 1.11 (95% CI: 0.80-1.53, P = 0.54) when compared to placebo. Conclusions: Enzalutamide may be comparable to placebo or first-generation antiandrogens in the tolerability for prostate cancer patients. Cautions should be taken to avoid unnecessary discontinuation.
Abstract 18615: Impact of Peripheral Atherectomy Utilization on the Outcomes of Lower Extremity Arterial Intervention - A Cross-sectional US Experience
Authors: Shilpkumar Arora, Sopan Lahewala, Nilay Patel, Kanishk Agnihotri, Sidakpal Panaich, Nileshkumar J Patel, Chirag Savani, Abhishek Dave, Badal Thakkar, Achint Patel, Samir V Patel, Parth Bhatt, Sanskruti Patel, Aashay Patel, Rajesh Sonani, Ankit Chothani, Vikas Singh, Sunny Jhamnani, Abhishek Deshmukh, Apurva O Badheka
Journal: Circulation (2015)

Background: Contemporary outcome data regarding effects of atherectomy in lower extremity arterial revascularization is lacking. Methods: We queried HCUP’s Nationwide Inpatient Sample (NIS) for 2012 using the appropriate primary ICD 9-CM diagnostic code for peripheral vascular disease and procedural codes 39.90 (bare metal stent - BMS), 00.55 (drug eluting stent - DES), 17.56 (peripheral artherectomy) and 39.50 for angioplasty. Only procedures performed in patients &gt;= 18 years were included. Hierarchical mixed effects logistic regression models were generated to evaluate multivariate predictors of outcomes. Results: In total 13,206 (weighted: 66,030) lower extremity arterial revascularization were analyzed (65.5% white, 56.2% Male &amp; 97.4% angioplasty). Atherectomy utilization (23.2%) was associated with significant reduction in amputation (11.5% vs 13.4%), any complications (13.2% vs 16.3%) and in hospital morality (0.8% vs 1.4%) compared to no atherectomy group (p &lt; 0.001). Multivariate analysis showed similar results with decrease amputation (OR, 95% CI; p - value) (0.83, 0.71 - 0.97, p = 0.02) and in hospital mortality/any complication (0.79, 0.69 - 0.90, p = 0.001) with atherectomy (similar results were observed with propensity score matching). “Atherectomy only” was utilized only in 2.3%. post-hoc analysis also shows better outcomes when atherectomy was used with either angioplasty or stenting (figure a &amp; b). subgroup multivariate analysis shows significant reduction in amputation when atherectomy was utilized in chronic limb ischemia (0.74, 0.59 - 0.93, p = 0.01) and with angioplasty (0.72, 0.60 - 0.87, p = 0.001) and trend towards advantage while used along with stents but not reaching statistical significant. Conclusion: Lower extremity atherectomy utilization was associated with significant reduction in amputation and overall complication. We observed better outcomes when atherectomy was used in conjunction with angioplasty.
Innovation in resident oncology education: Switching from an inpatient ward rotation to a hybrid model of inpatient consultations and outpatient clinics.
Authors: Jennifer King, Antoine Saliba, Reem Akel, Cynthia Wei, Naveen Manchanda, Noelle Sinex, Sara Jo Grethlein, Mitchell Goldman
Journal: Journal of Clinical Oncology (2020)

11006 Background: Interest in pursuing a career in oncology has decreased among internal medicine residents completing an inpatient oncology rotation. Over several years, our institutional data at Indiana University School of Medicine reflected lower resident satisfaction with the oncology inpatient ward rotation compared to other rotations. Methods: A hybrid model of inpatient consultations and outpatient clinics replaced the traditional inpatient oncology rotation at our institution. Over a six-month period preceding and following the change in format, residents completed anonymous rotation assessments and rated their experiences on a 5-point Likert scale (low 1 to high 5). Areas assessed included: patient load, educational value of patient mix, quality of didactics and teaching, quality of patient care delivery, adequacy of time for reading, and overall educational quality of the rotation. Results: The hybrid oncology rotation (8 respondents out of 10 residents approached) was rated as significantly superior to the traditional ward format (15 respondents out of 16 residents approached) in six out of eight areas. Improvements in the perceived quality of patient care delivery (p=0.139) and quality of didactics (p=0.058) were also observed without reaching statistical significance. The balance of inpatient and outpatient experiences with the hybrid rotation was highly rated (4.5 ± 0.5). Conclusions: The implementation of a hybrid oncology rotation was associated with perceived improvement in educational value, patient mix, and time for reflection and study without apparent compromise in the quality of patient care delivery. [Table: see text]
Effect and mechanism of ikkβ on proliferation, apoptosis, and metastasis of breast cancer cells with different expression levels of leptin and its receptors.
Authors: Yan Kong, Qian Dong, Cuizhi Geng, Da Jiang
Journal: Journal of Clinical Oncology (2020)

e15592 Background: To investigate the effect and mechanism of IKKβ on proliferation, apoptosis, invasion and metastasis of breast cancer cells with different expression levels of leptin and ObR. Methods: IKKβ in breast cancer cells was knocked down via virus transfection technology. MTT, flow cytometry, cell scratch test and clone formation test were used to observe the effect of IKKβ on proliferation, apoptosis and metastasis of breast cancer cells with different expression levels of leptin and ObR. RT-PCR was used to detect the downstream genes expressions in IKKβ signaling pathway. Results: The expression levels of leptin and ObR in MDA-MB-231 cells were higher than those in MCF-7 cells. Lentivirus can successfully infect breast cancer cells in vitro and knock down the expression of IKKβ. Knocking down IKKβ reduced the viability of MDA-MB-231 cells, but had little effect on MCF-7, and had an effect on the cell cycle of both cells. After knocking down IKKβ, the apoptotic rate of MDA-MB-231 cells increased. There was no significant difference in the apoptotic rate of MCF-7 cells. The number of clones of MCF-7 and MDA-MB-231 cells decreased, and the difference was significant. The effect on MDA-MB-231 cells was more significant. The scratch mobility of MDA-MB-231 cells decreased significantly, with significant difference.After knocking down IKKβ, the expressions of leptin and ObR, IKBKG, P65 and HIF in MCF-7 cells were significantly decreased, and there was statistical significance. However, the above indicators were significantly increased in MDA-MB-231 cells. The expression level of IKBKG was increased significantly, whereas that of HIF did not differ significantly, as compared with that of control group. Conclusions: The proliferation, metastasis and apoptosis of MDA-MB-231 cells were inhibited after blocking the IKKβ pathway, while the proliferation of MCF-7 cells was inhibited, and the apoptosis did not change significantly. The difference between the two cells may be related to the different expression levels of leptin and ObR.After blocking the IKKβ signaling pathway, the expressions of genes related to the IKKβ signaling pathway in MDA-MB-231 cells were increased, whereas those in MCF-7 cells were decreased, which might be related to the different expression levels of leptin and ObR.After knocking down IKKβ, the expressions of HIF gene in MCF-7 cells were decreased, whereas those in MDA-MB-231 cell lines were not affected. It needs to be verified whether this difference is related to leptin and ObR.
Parental history of type 2 diabetes is associated with lower resting energy expenditure in normoglycemic subjects
Authors: Nyenwe Ebenezer A, Ogwo Cherechi C, Owei Ibiye, Wan Jim Y, Dagogo-Jack Samuel, 范丽君, 巩纯秀
Journal: BMJ (2018)

目的
静息能量消耗（REE）与肥胖、胰岛素抵抗和2型糖尿病（T2DM）相关。REE和T2DM均为遗传性状。因此，我们研究父母T2DM对正常血糖子代的静息能量消耗的影响。


方法
将父母T2DM血糖正常的受试者87名，与父母无糖尿病的正常血糖受试者83名相比较，他们的年龄、性别、种族、体质指数（BMI）、体重和腰围进行匹配。研究他们的75 g口服葡萄糖耐量试验；并使用间接测热法测定静息能量消耗，用双能X线吸收测定法评估体组分。使用Student t-检验、方差分析和回归分析进行统计分析。


结果
平均年龄为（38.8±11.3）岁，57%为女性，53%为非洲裔美国人。平均BMI为（28.5±6.1）kg/m2，腰围（91.8±15.1）cm，体质量（83.9±20.3）kg，体脂含量31.0%±10.0%，平均去脂体质量（FFM）为（54.4±12.9）kg。父母糖尿病家族史阳性与阴性受试者的REE相比显著降低，标准化REE为（1 364.4±263.4）kcal/天比（1 489.4±323.2）kcal/天，P=0.006；（29.2±5.3）kcal/kg FFM/天比（31.9±6.0）kcal/kg FFM/天，P=0.002。非洲裔美国人比高加索人REE低，为（28.6±5.4）kcal/kg FFM/天比（32.6±5.5）kcal/kg FFM/天，P<0.000 1。在多元回归模型中，种族（P<0.000 1）、父母T2DM家族史（P=0.006）和FFM（P=0.021）均为REE的独立预测因子。


结论
与无父母糖尿病家族史的受试者相比，家族史阳性的受试者具有较低的REE，这在非洲裔美国人中更为明显。这种代谢改变可能增加肥胖、胰岛素抵抗和血糖代谢紊乱的风险。