tbuckley/cabot-search huggingface dataset:
Impact of PTEN/AKT/PI3K signal pathway on the chemotherapy for gastric cancer
Authors: E. Oki, Y. Kakeji, E. Tokunaga, K. Nishida, T. Koga, A. Egashira, M. Morita, Y. Maehara
Journal: Journal of Clinical Oncology (2006)

4034 Background: Growth factor receptor-mediated signal transduction has been recently implicated in conferring resistance to conventional chemotherapy on cancer cells. We have described a pathway that involves AKT/PI3K to mediate chemoresistance in gastric cancer patients. The phosphatase activity of PTEN is crucial in controlling the phosphatidylinositol-3 (PI-3) kinase signal transduction pathway and in the activation of the protein kinase B(PKB/Akt) proto-oncogene. This indicates that PTEN exerts its tumor-suppressor function by negatively regulating the anitapoptotic PI3-kinase/AKT signaling pathway. Methods: Primary gastric carcinoma tissues and corresponding normal mucosa were obtained from 119 gastric cancer patients who underwent surgery in the Department of Surgery II in Kyushu University Hospital from the years 1996 to 2000. Methylation of PTEN was studied with methylation-specific PCR and LOH (loss of heterozygosity) of PTEN was studied using a DNA sequencer with D10S796 and D10S1173 microsatellite marker in the same samples. AKT activation was investigated by immunostaining with a phosphorylation-specific antibody. The chemotherapeutic sensibilities of these patients were investigated using an MTT assay. Results: We found that methylation of PTEN was rarely recognized, However, the gastric cancer patients who had a higher AKT phosphorylation (activated AKT) appeared to have LOH of PTEN (p &lt; 0.0008), and the prognosis of the patient who has LOH of PTEN was significantly poor. When the chemotherapeutic sensibilities of these patients were studied in an MTT assay, it was found that the activated AKT was associated with increased resistance to multiple chemotherapeutic agents, which included those currently used on gastric cancer patients (5-fluorouracil, adriamycin, mitomycin C, and cis-platinum). Conclusions: The results of this study indicate that AKT activation and LOH of PTEN plays an important role in conferring a broad-spectrum chemoresistance in gastric cancer patients. It also indicates that clinical trials for an appropriate chemotherapy combination with conventional drugs and a new generation of signal transduction inhibitors that inhibit the PTEN/AKT pathway should be considered in treating gastric cancer in the near future. No significant financial relationships to disclose.
Role of c-MET in lung cancer, malignant mesothelioma, and head and neck cancer
Authors: P. C. Ma, M. S. Tretiakova, R. Jagadeeswaran, S. Jagadeesh, V. Nallasura, H. L. Kindler, M. Lingen, E. E. Vokes, A. Husain, R. Salgia
Journal: Journal of Clinical Oncology (2004)

9539 Background: c-MET is a potential therapeutic target with its aberrant signaling mediating invasive cellular program in cancers. Novel therapies are needed for lung cancer, mesothelioma and squamous cell carcinoma of head and neck (SCCHN) as their outcomes are poor despite standard therapy. Methods: We examined c-MET expression in cell lines and paraffin-embedded tumor tissues of lung cancer, mesothelioma and SCCHN using immunoblotting and immunohistochemistry (IHC) techniques. Activated-MET (pMET) was examined using phospho-MET antibodies in IHC in these tumor tissues, and using immunofluorescence (IF) in non-small cell lung cancer (NSCLC) A549 cells. Potential for targeted inhibition of c-MET was tested using small interfering RNA (siRNA) technique. siRNA-inhibition of c-MET expression was examined using immunoblotting, and the resultant inhibition of cell viability was studied using standard MTT assay. Results: There was varying c-MET expression in small cell lung cancer (SCLC) cell lines (N=10); and majority of the 9 NSCLC cell lines and 2 SCCHN cell lines had overexpression. In tumor tissues, c-MET expression was seen in 100% of thoracic malignancies (N=32). Strong expression was evident in 6/9 adenocarcinoma, 3/7 large cell, 3/7 squamous cell, and 3/5 carcinoid tumor). c-MET expression was also seen in tumor tissues of mesothelioma: 46% (N=13), and SCCHN: 54.5% (N=11). Activated pY1003-MET and pY1230/1234/1235-MET can also be demonstrated among all the tumor types. IF study showed that HGF dramatically increased pMET in A549 cells. c-MET expression was successfully inhibited using siRNA technique by >50% in the NSCLC A549 and mesothelioma H2373 cell lines. siRNA down-regulation of c-MET in A549 cells resulted in inhibition of viability (16.3±7.4% at 48hr; 57.1±7.2% at 72hr). Conclusions: c-MET is widely expressed in thoracic malignancies, mesothelioma and SCCHN with a potential role as novel therapeutic target. c-MET specific siRNA can successfully inhibit c-MET expression leading to significant inhibition of cell viability, and further inhibition strategies targeting the receptor will be sought for clinical applications. No significant financial relationships to disclose.
When Ebola came home
Authors: Rosa Escudero Sánchez, Javier Solano González
Journal: BMJ (2015)

Rosa Escudero Sanchez and Javier Solano Gonzalez reflect on the ramifications of treating Europe’s first patient 

We were responsible for admitting the first patient infected with the Ebola virus outside Africa.1 We were aware of our hospital’s protocol for dealing with suspected cases of Ebola infection,2 but the lack of experience with this disease, and the uneasiness of the non-medical staff, made clinical decision making difficult.

The patient had no fever on admission (necessary to fulfil the strict criteria for Ebola), but we considered her to be a suspected Ebola case because she had had contact with a confirmed case. On arrival, she was immediately placed in the isolation cubicle of our emergency department. We notified senior staff, which activated the epidemiological alert. Within hours, …
Feasibility of a multi-institutional liver cancer registry
Authors: W. Sun, J. Schwartz, A. Zhu, P. A. Philip, J. Metz, M. B. Thomas
Journal: Journal of Clinical Oncology (2006)

4146 Background: Hepatocellular carcinoma (HCC) is one of major causes of cancer-related death globally, with increasing incidence in the United States. There is still a lack of effective therapy for the disease. Many small phase II studies of systemic therapies for advanced HCC have been performed in the US. Most studies are too small to make definitive conclusions. This registry was developed to pool phase II studies from member institutions of the Liver Cancer Research Group (LCRG) to evaluate the characteristics and outcomes of patients receiving systemic treatments in an attempt to validate known and to identify potentially new prognostic factors in HCC. Methods: An Internet based registry was initiated on the OncoLink website ( https://www.oncolink.org ) and directed by the LCRG. This registry has undergone IRB approval. All data is password protected and maintained on physical and electronically secure servers. The registry contains 37 fields for each patient, which details demographics, tumor parameters, underlying liver disease, and detailed treatment information of chemotherapy and/or biological therapies. Results: As of 1/10/2006, 101 patients have been entered in the database from 5 institutions. The median age of patients in these studies is 59 years old (range 26–82) with 22 female (22%) patients. The racial distribution was: 67% of Caucasian, 15% African American, 11% Asian, and 6% Hispanic. The median performance status of patients included in these phase II studies was ECOG 1 (PS 0/1/2: 41/56/4). A variety of cytotoxic and biological agents (either as a single agent or as combination) were included in the analysis including doxorubicin, epirubicin, gemcitabine, oxaliplatin, capecitabine, thalidomide, erlotinib, and bevacizumab. All patients had extensive disease, most of them with multiple lesions (51% ≥ 5 lesions) and bilobar involvement (69%). The mean size of lesions was 8.3 cm (range 1–20 cm). Within the population, 25% patents have hepatitis B and 44% have hepatitis C as their background diseases. Conclusions: This multi-institutional database for HCC treated on phase II clinical trials in the US is feasible. This database continues to expand through the support of the LCRG. As the data matures, future studies on outcomes related to biological and chemotherapeutic regimens will be presented. No significant financial relationships to disclose.
비대상성 간경변증 환자의 예후지표로서 Model for End-stage Liver Disease와 간정맥압차의 비교
Authors: 이성화, 홍원기, 김영묵, 김성중, 백광호, 김진봉, 김동준, 박승하, 이우진, 류명신, 박규태, 이민영, 이찬우, 김진호
Journal: Clinical and Molecular Hepatology (2009)

목적: 비대상성 간경변증 환자에서 3개월과 12개월 시점의 간정맥압차와 MELD의 사망예측 정확도를 비교하여, HVPG의 예후인자로서의 역할을 확인하고자 하였다. 대상과 방법: 2006년 1월부터 2008년 6월까지 한림대학교부속 춘천성심병원에서 136명의 비대상성 간경변증 환자를 대상으로 HVPG를 측정하였다. 생존분석의 1차 결과 변수로서 3개월과 12개월에서의 사망 여부를 확인하였다. 결과: Cox 회귀분석 결과, MELD와 HVPG 모두 독립적인 예후인자로 확인되었다[각각 hazard ratio는 1.11(95% CI, 1.04 to 1.20)과 1.12(95% CI, 1.08 to 1.16)]. 두 변수의 ROC곡선의 AUC를 비교해 볼 때, 3개월에서 유의하진 않지만 MELD는 HVPG보다 사망예측에 있어서 정확도가 8% 정도 더 높게 보였다[0.76(95% CI, 0.62 to 0.89) 대 0.68(95% CI, 0.52 to 0.84), P=0.22]. 12개월에서는 MELD와 HVPG 모두 비슷한 사망예측의 정확도를 보였다[0.72(95% CI, 0.61 to 0.83) 대 0.73 (95% CI, 0.61 to 0.84), P=0.45,]. 결론: MELD와 HVPG는 비대상성 간경변증 환자에서 사망과 관련된 독립적인 예후인자로서 사망예측의 정확도에 있어서 유의한 차이를 보이지 않는다. 하지만 HVPG는 침습적이고 소수의 의료기관에서만 시행된다는 점에서 사망예측인자로서 HVPG의 역할은 제한적이라 판단된다. 그러나 HVPG의 다양한 예후인자로서의 임상적 역할을 규정하기 위해서는 폭넓은 환자군(원인, 성별, 지역, 등)을 대상으로 하는 전향연구가 필요하다.
Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial
Authors: David F. Penson, Andrew J. Armstrong, Raoul Concepcion, Neeraj Agarwal, Carl Olsson, Lawrence Karsh, Curtis Dunshee, Fong Wang, Kenneth Wu, Andrew Krivoshik, De Phung, Celestia S. Higano
Journal: Journal of Clinical Oncology (2016)

Purpose Enzalutamide, a potent oral androgen receptor inhibitor, improves survival in men with metastatic castration-resistant prostate cancer (CRPC) before and after chemotherapy. Bicalutamide, a nonsteroidal antiandrogen, is widely used to treat men with nonmetastatic or metastatic CRPC. The efficacy and safety of these drugs were compared in this randomized, double-blind, phase II study of men with CRPC. Patients and Methods A total of 396 men with nonmetastatic (n = 139) or metastatic (n = 257) CRPC were randomly assigned to enzalutamide 160 mg per day (n = 198) or bicalutamide 50 mg per day (n = 198). Androgen deprivation therapy was continued in both arms. The primary end point was progression-free survival (PFS). Results Enzalutamide reduced the risk of progression or death by 76% compared with bicalutamide (hazard ratio [HR], 0.24; 95% CI, 0.18 to 0.32; P &lt; .001). Median PFS was 19.4 months with enzalutamide versus 5.7 months with bicalutamide. Enzalutamide resulted in significant improvements in all key secondary end points: time to prostate-specific antigen progression (HR, 0.19; 95% CI, 0.14 to 0.26; P &lt; .001); proportion of patients with a ≥ 50% prostate-specific antigen response (81% v 31%; P &lt; .001); and radiographic PFS in metastatic patients (HR, 0.32; 95% CI, 0.21 to 0.50; P &lt; .001). Beneficial effects with enzalutamide were observed in both nonmetastatic and metastatic subgroups. The observed adverse event profile was consistent with that from phase III enzalutamide trials. Conclusion Enzalutamide significantly reduced risk of prostate cancer progression or death compared with bicalutamide in patients with nonmetastatic or metastatic CRPC.
<i>KRAS</i> mutation is highly predictive of cetuximab resistance in metastatic colorectal cancer
Authors: F. Di Fiore, F. Le Pessot, A. Lamy, F. Charbonnier, J. Sabourin, B. Paillot, T. Frebourg, P. Michel
Journal: Journal of Clinical Oncology (2007)

10502 Background: In metastatic colorectal cancer (MCRC), no molecular predictive markers to cetuximab response have been yet established. The aim was to evaluate whether KRAS gene mutations, EGFR immunochemistery (IHC) and EGFR gene copy number correlate with response to cetuximab. Methods: 59 patients with MCRC treated by cetuximab between July 2004 and December 2005 were retrospectively included. Clinical data were collected and tumour response was evaluated according to RECIST criteria. EGFR IHC was performed using the Dako kit. The EGFR gene copy number was determined by FISH (Fluorescence in-Situ Hybridization). Detection of KRAS gene mutations on exon 2 was performed by sequencing of extracted paraffin-embedded DNA and then by 2 methods, SNaPshot and PCR-LCR, specifically developed to detect small fractions of mutated tumor cells. Response to cetuximab was studied according to clinical data, IHC, FISH and KRAS mutation analysis using the Fischer exact test. Predictive factors of response were determined by logistic regression. Skin reactions were collected but not considered for this analysis as regards the lack of accurate grading in a retrospective study. Times to progression (TTP) were calculated using the Kaplan-Meier method and compared with log-rank test. Results: 12 patients (20.3%) responded to cetuximab (2 patients with complete response and 10 patients with partial response), 19 (32.2%) had stable disease and 28 (47.5%) were in disease progression. A KRAS mutation was detected in 22/59 tumours and, in 6 cases, was missed by sequencing analysis but detected using the SNaPshot and PCR-LCR assays. No KRAS mutation was found in responders patients. KRAS mutation was associated with disease progression (p = 0.0005) and TTP was significantly decreased in mutated KRAS patients (3 vs 5.5 months, p = 0.015). There was no correlation between EGFR IHC and cetuximab response. No EGFR gene copy number increase was detected in responders patients. Predictive factors of cetuximab resistance were KRAS mutation (p=0.003; OR:0.10; 95IC:0.22–0.40) and age&lt;60 (p=0.024; OR:0.13; 95IC:0.02–0.77). Conclusions: KRAS mutation is highly predictive of cetuximab resistance in MCRC. Our study also highlights the need of sensitive methods to ensure an efficient mutation detection. No significant financial relationships to disclose.
Quantitative assessment of AKT activation in melanoma
Authors: M. A. Davies, K. Stemke-Hale, T. Calderone, W. Deng, A. Lazar, V. G. Prieto, K. Aldape, G. B. Mills, J. E. Gershenwald
Journal: Journal of Clinical Oncology (2009)

9022 Background: Activating mutations of BRAF are highly prevalent in melanoma. However, multiple lines of evidence suggest that other pathways must also contribute to this disease. Activation of the PI3K-AKT pathway has been implicated in melanoma by mutations of NRAS and PTEN. Little direct information is known about the activation of the PI3K-AKT signaling pathway in melanoma, particularly in metastases. Methods: Proteins isolated from 99 frozen melanoma tumors were measured by reverse phase protein arrays (RRPA). A total of 53 proteins were assessed using validated antibodies. Activating mutations were assessed by mass spectroscopy-based genotyping. Activation of AKT (phospho-AKT) was compared to mutations and anatomic sites. Results: Samples from 75 regional metastases (LN or in-transit) and 24 distant metastases were analyzed. Technical replicates (same lysate) and biological replicates (same tumor, different lysates) demonstrated average Pearson correlation coefficients (r) of &gt; 0.90, supporting the high technical quality of the analysis. A positive correlation was observed between levels of p-AKT and known AKT substrates p-GSK3 and p-TSC2 (p&lt; 0.001 for both), and a negative correlation with PTEN (p &lt; 0.01), supporting the maintenance of phosphorylation events during sample processing. Relative differences in p-AKT by RPPA were also confirmed by immunohistochemistry of representative tumors. Tumors with BRAF mutations had higher levels of p-AKT than tumors with NRAS mutations (p = 0.03). Indeed, tumors with NRAS mutations had p-AKT levels similar to tumors wild-type for BRAF and NRAS (p =0.73). Detailed analysis demonstrated that all tumors with elevated p-AKT had low PTEN expression. Similar results were seen in human melanoma cell lines. Analysis of distant metastases demonstrated that brain metastases had higher levels of p-AKT, p-GSK3, and p-TSC2, and lower levels of PTEN, compared to metastases to the lung or liver. Conclusions: AKT activation in melanoma correlates with PTEN expression, and does not correlate with NRAS mutation. Activation of the PI3K-AKT pathway may contribute to the aggressiveness of brain metastases. These findings have clinical implications for targeting this pathway, and demonstrate the feasibility and potential of RPPA analysis of signaling pathways in melanoma. No significant financial relationships to disclose.
Comment on Hoffstad et al. Diabetes, Lower-Extremity Amputation, and Death. Diabetes Care 2015;38:1852–1857
Authors: Jaap J. van Netten, Lauren V. Fortington, Robert J. Hinchliffe
Journal: Diabetes Care (2016)

We read with great interest the article by Hoffstad et al. (1) that addressed the important topic of mortality risk following lower-extremity amputation in people with diabetes. At a time when amputation rates and outcomes are of increasing significance in guiding care, there are few data to underpin which outcomes should be reported following amputation and which are most relevant to patients. This also includes perhaps one of the simplest measures—mortality.

Hoffstad et al. sought to determine the variations in mortality rates after lower-extremity amputation. Although some of the variation is explained, the authors concluded that “there remains a large amount of unexplained …
But can someone like me do it? The importance of appropriate role modelling for safety behaviours in sports injury prevention
Authors: Peta White, Alex Donaldson, Caroline F Finch
Journal: British Journal of Sports Medicine (2015)

Preventing sports injuries requires behaviour change. Observational learning, or role modelling, is one way to develop self-efficacy, a key behavioural determinant. This premise underpins the social cognitive theory (SCT),1 and is the reason why role models have such a strong influence on behaviour. Most human behaviour is learned by observing others.2 Therefore, understanding role modelling and how to use it effectively could be important for sports injury prevention.

Self-efficacy refers to an individual's confidence in their ability to enact a particular behaviour. According to the SCT, people need sufficient self-efficacy before they adopt a particular behaviour. Individuals with high self-efficacy are more likely to engage in a given behaviour.3 In our study of what influences community-level Australian football (AF) and rugby league coaches’ and sports trainers’ intention to use concussion guidelines,4 self-efficacy was a significant predictor of intention.

Social modelling is one source of self-efficacy.5 Observing others can improve self-efficacy by altering perceptions of competency. Four processes govern observational learning: (1) attention: seeing and understanding …
A Retrospective Analysis of Irinotecan for Heavily Pretreated Esophageal Squamous Cell Carcinoma
Authors: Ryoko Fukushima, Satoru Iwasa, Hirokazu Shoji, Natsuko Okita, Atsuo Takashima, Yoshitaka Honma, Ken Kato, Tetsuya Hamaguchi, Yasuhide Yamada, Yasuhiro Shimada
Journal: Annals of Oncology (2014)
抗血栓治疗知识（七）——静脉血栓栓塞症：治疗策略
Authors: AlexanderGGTurpie, BernardSPChin, GregoryYHLip, 许晓岩, 翟振国
Journal: BMJ (2004)

肺栓塞（pulmonary cmbolism,PE)和深静脉血栓形成（deep vein thrombosis,DVT)在临床上治疗方法相似，包括药物和物理方法。1960年，一项随机试验首次证实了静脉输注普通肝素（unfractionatcd hcparin,UTH)的有效性；之后的研究多集中于药物剂量，疗程、给药方式以及与华法林联用；近期已有研究报道了低分子肝素（low molecular werght heparin,LMWH）与普通肝素有效性和成本-效益的比较。
Arterial Spin Labeling MRI Quantifies the Recovery of Myocardial Perfusion During Infarct Healing in Mice
Authors: Moriel H Vandsburger
Journal: Circulation (2009)

Abstract #253 Moriel H Vandsburger, Robert L Janiczek, Yaqin Xu, Brent A French, Craig H Meyer, Christopher M Kramer, Frederick H Epstein, Univ of Virginia, Charlottesville, VA Moriel H Vandsburger, 2009 Finalist and Presenting Author
Zymogen-like FXa Is a Potent Bypassing Agent for Reversal of Direct FXa Inhibitors in Vivo
Authors: Nabil K. Thalji, Lacramioara Ivanciu, Reema Jasuja, Sunita Patel-Hett, Joachim Fruebis, Debra Pittman, Rodney M. Camire
Journal: Blood (2014)
Abstract P037: Vitamin D and Insulin Resistance among Health Korean Adolescents
Authors: Dong Phil Choi, Hyeon Chang Kim
Journal: Circulation (2012)

BACKGROUND AND PURPOSE: Vitamin D deficiency is common in adults and has been associated with diabetes or insulin resistance. However the association between vitamin D and insulin resistance has not been fully studied. Thus we investigated the association between serum 25-hydroxyvitamin D level (serum 25(OH)D) and fasting glucose, fasting insulin and insulin resistance in healthy Korean adolescents. METHODS: Study participants included 258 (134 males and 124 females) in the first grade students (mean age, 15.5 years) at a rural high school in South Korea. Insulin resistance was calculated using homeostasis model assessment (HOMA-IR). Both categorical (Sex-specific quartiles groups) and continuous measure of serum 25(OH)D were assessed in association with fasting glucose, fasting insulin and HOMA-IR. RESULTS: Lower serum 25(OH)D level was significantly associated with fasting glucose, fasting insulin, HOMA-IR after adjustment for age and body mass index in males. But the associations were not significant in females (table). CONCLUSIONS: This study suggests that serum 25(OH)D level may be inversely associated with insulin resistance in healthy male adolescents. Table. Association between serum vitamin D and glucose metabolism. Variable Quartile of serum 25(OH)D Continuous measure of serum 25(OH)D Q1 Q2 Q3 Q4 P for trend β * P-value * Males N 33 34 33 34 Serum 25-OH-D (ng/mL, median(min, max)) 9.7 ( 5.4, 12.2 ) 14.2 (12.3, 15.8) 17.9 (15.9, 19.3) 24.8 (19.6, 40.9) Fasting glucose (mg/dL) 87.7 ± 5.4 85.7 ± 6.4 86.2 ± 6.7 85.0 ± 6.2 0.125 −0.138 0.004 Fasting insulin ( μ IU/ml) 9.9 ± 3.5 8.4 ± 3.3 8.8 ± 3.9 7.7 ± 2.8 0.022 −0.570 0.005 HOMA-IR 2.1 ± 0.8 1.8 ± 0.7 1.9 ± 0.9 1.6 ± 0.6 0.018 −2.518 0.004 Females N 31 31 31 31 Serum 25-OH-D (ng/mL, median(min, max)) 7.1(4.5, 8.3) 10.7(8.4, 12.8) 15.5(12.9, 18.5) 23.7(18.9, 36.1) Fasting glucose (mg/dL) 83.0 ± 5.1 83.0 ± 5.8 81.6 ± 5.9 84.0 ± 6.4 0.726 0.103 0.364 Fasting insulin ( μ IU/ml) 8.5 ± 2.6 9.0 ± 2.9 7.8 ± 2.6 8.6 ± 2.9 0.698 −0.009 0.970 HOMA-IR 1.7 ± 0.6 1.9 ± 0.6 1.6 ± 0.6 1.8 ± 0.7 0.831 0.316 0.781 * Adjusted for (sex), age, body mass index