tbuckley/cabot-search huggingface dataset:
mTOR signaling is regulated by TSC2 at the peroxisome
Authors: Angela Alexander, Jinhee Kim, Sheng-Li Cai, Michael Kastan, Mustafa Sahin, Cheryl Walker
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

2729 

The TSC2 tumor suppressor regulates mTOR activity and plays a central role in integrating energy sensing by the AMPK pathway with signals from mitogenic pathways such as PI3K to coordinate cell growth with available energy. While it is known that TSC2 is active when localized at cellular endomembranes, the specific endomembrane compartment(s) where this activity occurs have not been identified. The peroxisome is an autonomously replicating membrane-bound organelle that participates in energy metabolism via beta-oxidation of fatty acids. In silico analysis identified both type 1 and type 2 peroxisomal targeting sequences (PTS) in TSC2 and TSC1, respectively, predicting that TSC2 and its interaction partner, TSC1 localize to the peroxisome. This prediction was confirmed by confocal microscopy and subcellular fractionation: exogenous myc- or flag-tagged TSC1 and TSC2 co-localized with peroxisomal markers to discrete punctate structures within cells and endogenous TSC1 and TSC2 were present in peroxisome fractions purified from cells. Mutation of the PTS in either TSC1 or TSC2 abrogated localization to the peroxisome, with loss of the distinctive punctate staining pattern and co-localization with peroxisomal markers. Repression of mTOR signaling by TSC2 is due to its GAP (GTPase activating protein) activity, which maintains the mTOR activator Rheb in an inactive, GDP-bound state. Consistent with the peroxisome being the endomembrane compartment for TSC2 function, both Rheb and mTOR were present in peroxisome fractions containing TSC2. A cell-based functional assay performed by co-transfection of TSC2, TSC1, Rheb and S6K demonstrated that whereas wild-type TSC2 was proficient at repressing basal mTOR signaling, the TSC2 PTS1 mutant that cannot not localize to the peroxisome could not repress mTOR signaling and functioned as a dominant negative. Furthermore, cells lacking peroxisomes isolated from the peroxisomal biogenesis disorder Zellweger Syndome displayed high levels of mTOR activity and were deficient in TSC2-mediated repression of mTOR signaling. These data indicate that in addition to its well-known ability to participate in energy metabolism, the peroxisome plays a unique role within the cell in TSC2 tumor suppressor function and regulation of mTOR signaling.
Pilot study of unsupervised use of laparoscopic box trainers in a cohort of core surgical trainees
Authors: J. Bennett, J. Carter, H. Davies, S. Higgs, C. Rodd, R. Longman
Journal: International Journal of Surgery (2015)

s / International Journal of Surgery 23 (2015) S15eS134 S17 open hernia repair G3 or control G4 (surgical text on open hernia repair). The outcomemeasures were cognitive knowledge and overall global rating assessed by a checklist interview. Results: No differences in the baseline characteristics in trainees randomised to G1, G3 or G4 with mean similar ages, naivety for procedure and pre-intervention multiple-choice questionnaire. G1 trainees achieved significantly higher cognitive analysis performance scores for step-by-step knowledge of an open inguinal hernia mesh repair comparedwith trainees in G3 (p < 0.05) and G4 (p < 0.05). A similar significant finding was found for the general performance scores compared with trainees in G3 (p < 0.05) and G4 (p < 0.05). Conclusion: The interactive simulator of the open hernia facilitates clear thought processes and improves surgical trainees' knowledge of the hernia procedure step-by-step compared to other more traditional ways methods. 0154: REVIEW OF SHAPE OF TRAINING (GREENAWAY) REPORT: THE WEST OF SCOTLAND SURGICAL TRAINEES' VIEWPOINT A. Di Carlo , G. Nicholson , J.R. McGregor . University of Glasgow, UK; West of Scotland Surgical Association, UK; University Hospital
Therapy of melanoma lesions by intratumoral electroporation of IL-2 plasmid
Authors: Holly M. Horton, Rodrick Planchon, Michael Sawdey, Larry Smith, David Kaslow
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

5997 

In several earlier studies, we demonstrated that intratumoral injection of plasmid DNA (pDNA) encoding IL-2 can result in tumor regression and the generation of tumor-specific T cells (Saffran et al ., Cancer Gene Ther ., 1998 5:321 and Horton et al, J. Immunol . 1999 163:6378). In the present study, we expand upon the previous work to evaluate whether intratumoral delivery of IL-2 pDNA enhanced by electroporation (EP) can improve its antitumor efficacy. Mice bearing s.c. Cloudman melanoma were treated by intratumoral injection of murine IL-2 pDNA followed by EP beginning on day 9 or 10 (tumors were approximately 20-80 mm3). Tumors were injected with 30 μg of IL-2 pDNA or control pDNA followed by EP with caliper electrodes at a setting of 800 V/cm, 8 pulses and 1 msec/pulse. IL-2 pDNA + EP significantly inhibited the growth of the melanoma lesions (p<0.05) compared to tumors treated with control pDNA + EP. In addition, 60% of the mice treated with the IL-2 pDNA + EP became tumor-free. In contrast, only 20% of the mice treated with IL-2 pDNA without EP became tumor-free and up to 10% of the mice treated with control pDNA +/− EP became tumor-free. These data suggest that intralesional injection of IL-2 pDNA + EP can promote tumor regression. In a pharmacokinetic mouse study, the level of murine IL-2 protein in the tumor mass and serum was determined. Therapy with IL-2 pDNA + EP resulted in 2-3 fold higher levels of IL-2 over several days in the tumor compared to the levels found with non-electroporated IL-2 pDNA. These results suggest that EP can enhance the level of expression of IL-2 pDNA in the tumor tissue. In addition, IL-2 levels were 20-200 fold higher in the tumor than in the serum suggesting that intralesional IL-2 pDNA therapy primarily results in localized secretion, which may reduce the severe systemic toxicity associated with IL-2. The overall findings suggest that melanoma may respond favorably to IL-2 pDNA + EP therapy, and support further development of this approach.
Non-Hodgkin's lymphoma and skin cancer
Authors: P. Sasieni, V. Bataille
Journal: BMJ (1995)

PrimiparaDied who are at high risk of developing matemal tetanus.This is because women (especially teen- agers) with unwanted pregnancies often do not attend for antenatal care and may resort to unsafe abortion.On the basis of our personal experience we support the authors' proposal to include adolescent girls as a target for vaccination for tetanus toxoid.This strategy would substantially reduce the rates of maternal mortality in young women from maternal tetanus secondary to induced abortion.
Effects of Medical Therapies on Retinopathy Progression in Type 2 Diabetes
Journal: New England Journal of Medicine (2010)

We investigated whether intensive glycemic control, combination therapy for dyslipidemia, and intensive blood-pressure control would limit the progression of diabetic retinopathy in persons with type 2 diabetes. Previous data suggest that these systemic factors may be important in the development and progression of diabetic retinopathy.
Left Atrial Thrombus Formation After Successful Left Atrial Appendage Ligation
Authors: Dhanunjaya Lakkireddy, Ajay Vallakati, Arun Kanmanthareddy, Ted Feldman, Douglas Gibson, Matthew Price, David S. Rubenson, Jie Cheng, Miguel Valderrábano, Rajeev R. Fernando, Susan T. Laing, Eugene Chung, Sudharani Bommana, Donita Atkins, Jayasree Pillarisetti, Bradley P. Knight, Rudolph Evonich, Abdi Rasekh, James Gray, Arun Raghav Mahankali Sridhar, Mathew Earnest, Ryan Ferrell, Jayant Nath, Yeruva Madhu Reddy
Journal: Journal of the American College of Cardiology (2015)
ACC expert consensus document on coronary artery stents
Authors: DavidR Holmes, John Hirshfeld, David Faxon, RonaldE Vlietstra, Alice Jacobs, SpencerB King, ThomasM Bashore, NancyD Bridges, CharlesB Higgins, LorenF Hiratzka, WilliamC Little, RaymondD Magorien, MichaelA Nocero, Stephen Oesterle, RobertA Vogel, JamesS Forrester, PamelaS Douglas, DavidP Faxon, JohnD Fisher, RaymondJ Gibbons, JonathanL Halperin, AdolphM Hutter, JudithS Hochman, Sanjiv Kaul, WilliamS Weintraub, WilliamL Winters, MichaelJ Wolk
Journal: Journal of the American College of Cardiology (1998)
A Randomized Comparison of Sirolimus- Versus Paclitaxel-Eluting Stent Implantation in Patients With Diabetes Mellitus
Authors: Seung-Whan Lee, Seong-Wook Park, Young-Hak Kim, Sung-Cheol Yun, Duk-Woo Park, Cheol Whan Lee, Myeong-Ki Hong, Kyoung-Suk Rhee, Jei Keon Chae, Jae-Ki Ko, Jae-Hyeong Park, Jae-Hwan Lee, Si Wan Choi, Jin-Ok Jeong, In-Whan Seong, Yoon Haeng Cho, Nae-Hee Lee, June Hong Kim, Kook-Jin Chun, Hyun-Sook Kim, Seung-Jung Park
Journal: Journal of the American College of Cardiology (2009)
Resistance to the BH3 peptidomimetic obatoclax in non-small cell lung cancer associated with a block in BCL-2 family post-translational regulation
Authors: Francis McCoy, Jane Hurwitz, Alex D Chacko, Ian Paul, Fabio Liberante, Barry O'Hagan, George McKerr, Patrick Johnston, Dean A Fennell
Journal: Journal of Thoracic Oncology (2009)
Appreciating methodological complexity and integrating neurobiological perspectives to advance the science of resilience
Authors: Birgit Kleim, Isaac R. Galatzer-Levy
Journal: Behavioral and Brain Sciences (2015)

Abstract Kalisch and colleagues identify several routes to a better understanding of mechanisms underlying resilience and highlight the need to integrate findings from neuroscience and animal learning. We argue that appreciating methodological complexity and integrating neurobiological perspectives will advance the science of resilience and ultimately help improve the lives of those exposed to stress and adversity.
Lymph node retrieval for colorectal cancer: Estimation of the minimum resection length to achieve at least 12 lymph nodes for the pathological analysis
Authors: Gianpiero Gravante, Rupert Parker, Mohamed Elshaer, Adimabua Christopher Mogekwu, Nada Humayun, Katie Thomas, Rachael Thomson, Sarah Hudson, Roberto Sorge, Katy Gardiner, Salem Al-Hamali, Mohamed Rashed, Ashish Kelkar, Saleem El-Rabaa
Journal: International Journal of Surgery (2015)
Xenotransplantation
Authors: D. K C Cooper
Journal: BMJ (2000)

This new form of treatment might benefit millionsEditor-Fano has written a response in the eBMJ (and published here, the third letter) commenting on Vanderpool's article on xenotransplantation. 1 2 He advocates a ban on xenotransplantation, largely on the grounds of the risk of the transfer of infection.Cells taken from carefully screened pigs have been used in the treatment of patients with diabetes, certain neurological diseases, and liver failure.There has been no definite evidence of the transfer of a porcine infection to human recipients.Nevertheless, as with almost every medical or scientific advance, it will be impossible to exclude all risk, even if this is related only to hitherto unknown pig bacteria or viruses.The ultimate decision whether to use any new therapeutic agent or procedure rests on an assessment of the risk to benefit ratio.As the potential benefits to individuals or society increase, the acceptance of slightly increased risk becomes warranted.We must not reduce our obligation to take all possible steps to minimise any perceived risk to society, but we have a moral obligation to accept a small risk to the community if the new treatment leads to great benefit to many individuals in that community.The potential benefits of xenotransplantation are immense.Many millions of people with such diverse conditions as diabetes and degenerative brain disease may have the quality of their lives vastly improved, and in those with advanced organ failure xenotransplantation will be lifesaving.In the United States over 60 000 people currently await a human donor organ but only 20 000 organs will become available this year.At least 10 people die every day while waiting.Similar figures could be quoted for other regions of the developed world.This new form of treatment may ultimately benefit millions of patients.Rather than calling for a ban on it we suggest that support should be given to the great efforts being made to ensure that it will be not only successful but also safe.
Sorafenib and SC-1 Exhibit Anti-fibrotic Effects Through Signal Transducer and Activator of Transcription 3 Inhibition
Authors: Tung-Hung Su, Chung-Wai Shiau, Ping Jao, Chen-Hua Liu, Chun-Jen Liu, Wei-Tien Tai, Yung-Ming Jeng, Hung-Chih Yang, Tai-Chung Tseng, Hsiang-Po Huang, Huei-Ru Cheng, Pei-Jer Chen, Kuen-Feng Chen, Jia-Horng Kao, Ding-Shinn Chen
Journal: Clinical Gastroenterology and Hepatology (2015)
Dose finding trial of Yttrium 90 ibritumomab tiuxetan (<sup>90</sup>YIT) with autologous stem cell transplantation (ASCT) in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL)
Authors: I. W. Flinn, B. S. Kahl, E. C. Frey, J. A. Bianco, R. J. Hammes, J. Webb, L. J. Swinnen, G. Sgouros, R. L. Wahl
Journal: Journal of Clinical Oncology (2006)

7535 Background: 90 YIT is an effective agent for patients with lymphoma. Unfortunately, dose escalation is limited by hematopoetic toxicity. In order to determine the non-hematopoetic maximum tolerated dose, we are conducting a dose finding study of 90 YITwith ASCT. Methods: Eligible patients had relapsed or refractory NHL, rituximab sensitive disease, age ≥18 years, platelet count ≥75,000/mm 3 , WBC &gt;3,000/mm 3 , bone marrow involvement ≤35%, and acceptable renal and hepatic function. Patients receive weekly rituximab (375 mg/m 2 ) for 4 consecutive weeks followed by a single dose of cyclophosphamide (2.5 g/m 2 ). Filgrastim 10 mcg/kg is administered post cyclophosphamide until stem cell collection. Following successful collection of at least 2 X 10 6 CD34/kg, patients receive a dosimetric dose of indium 111 ( 111 In) ibritumomab tiuxetan (5 mCi) on day 1, quantitative planar and SPECT/CT scans followed by cohort specific dose of 90 Y IT on day 15. Stem cell infusion occurs when estimated marrow dose rate is &lt; 1 cGy/hour. Results: 22 patients (12M:10F) (median age 55, 44–70) with a median of 2 prior regimens (range, 1–8) have been entered onto study. 5 patients failed to mobilize stem cells and did not receive 90 YIT. 16 patients have been treated with 90 Y IT to the following dose cohorts based on dosimetry-predicted maximal organ radiation absorbed dose: 0.4 mCi/kg = 3; 14–18 Gy = 5; 24 Gy = 6, 28 Gy = 2. The range of administered 90 Y IT activities was 20.2–143.1 mCi. All patients engrafted rapidly. One patient died from treatment-related causes: pneumonia day 27 post-transplant. At 60 days post-transplant, 10 patients achieved a CR, 3 patients had a PR, and 2 had progressive disease. The most common treatment-related toxicities were hematologic, as expected. This therapy was delivered completely in the outpatient setting. 4 patients required admission post 90 YIT for febrile neutropenia. No significant hepatotoxicity has been seen to date despite the fact that the liver is the organ that receives the highest absorbed dose of radiation. Conclusions: Significant dose escalation with 90 YIT can be achieved with ASCT. Dose escalation continues and the MTD has yet to be determined. [Table: see text]
Efficacy of a Gluten-Free Diet in Subjects With Irritable Bowel Syndrome-Diarrhea Unaware of Their HLA-DQ2/8 Genotype
Authors: Imran Aziz, Nick Trott, Rebecca Briggs, John R. North, Marios Hadjivassiliou, David S. Sanders
Journal: Clinical Gastroenterology and Hepatology (2015)
Heterogeneity, consistency and model fit should be assessed in Bayesian network meta-analysis
Authors: Jie Wei, Chao Zeng, Guang-hua Lei
Journal: Annals of the Rheumatic Diseases (2015)

Heterogeneity, consistency and model fit should be assessed in Bayesian network meta-analysisWe read with deep interest the article by Wang et al 1 aimed to compare the efficacy of 20 non-steroidal anti-inflammatory drugs (NSAIDs) in the short-term treatment of ankylosing spondylitis (AS).This Bayesian network meta-analysis indicated that etoricoxib was more effective in reducing pain in AS than some other NSAIDs.The result was very useful in the decisionmaking process, especially for pain relief in treating patients with AS.However, there are some worthwhile issues that need to be explored.First, it is commonly agreed that meta-analysis, including network meta-analysis, should assess heterogeneity, which may be defined as the presence of variation in true effect sizes underlying the different studies.Unfortunately, however, heterogeneity was not assessed in this network meta-analysis.Between-study heterogeneity indicates the presence of effect modifiers, and variability in relative treatment effects has a bad impact on the external validity of trial evidence, and limits the ability to generalise from the results. 2 There may exist some potential covariates, especially for the various drug doses and treatment durations of the same NSAID, meaning that it is highly likely that there was heterogeneity.In addition, some extremely important covariates, such as drug dose, for the same NSAID should be considered in this network meta-analysis.The authors should consider the relative contribution of true variability and random variation due to biases.Perhaps Bayesian meta-regression should be conducted to consider the covariates.Second, unlike classical meta-analysis, Bayesian network meta-analysis combines all available direct and indirect evidences on the relative treatment effects. 3Inconsistency can also be caused by the effect modifiers and specifically by an imbalance in the distribution of effect modifiers in the direct and indirect evidence. 4Consistency assessing is also worthy of expectation.Third, a better model fit can reduce the inconsistency between direct and indirect evidences. 5Thus, model fit should be assessed to assure the reliability of the results as well.In order to provide reliable evidence, a checklist, 6 which is intended for those who review evidence syntheses and those submitting syntheses, should be recommended.Above all, perhaps, heterogeneity, consistency and model fit should be assessed in this Bayesian network meta-analysis to make the results more reliable for guiding clinical practice.We respect the great contributions of the authors, and we also very much look forward to seeing authors' response to these issues.
Combination of EP4 antagonist and checkpoint inhibitors promotes anti-tumor effector T cells in preclinical tumor models
Authors: Xingfeng Bao, Diana Albu, Kuan-Chun Huang, Jiayi Wu, Natalie Twine, Kenichi Nomoto, Mary Woodall-Jappe
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Immunotherapies targeting the immune checkpoint receptors have shown great promise for a subset of cancer patients. However, robust and safe combination therapies are still needed to increase the benefit of cancer immunotherapy and bring it to broader patient populations. We have
Measuring to Improve: Peer and Crowd-sourced Assessments of Technical Skill with Robot-assisted Radical Prostatectomy
Authors: Khurshid R. Ghani, David C. Miller, Susan Linsell, Andrew Brachulis, Brian Lane, Richard Sarle, Deepansh Dalela, Mani Menon, Bryan Comstock, Thomas S. Lendvay, James Montie, James O. Peabody
Journal: European Urology (2016)
TAVR-Associated Prosthetic Valve Infective Endocarditis
Authors: Azeem Latib, Charbel Naim, Michele De Bonis, Jan Malte Sinning, Francesco Maisano, Marco Barbanti, Alessandro Parolari, Roberto Lorusso, Luca Testa, Guglielmo Mario Actis Dato, Antonio Miceli, Sandro Sponga, Francesco Rosato, Carlo De Vincentiis, Nikos Werner, Claudia Fiorina, Antonio Bartorelli, Omar Di Gregorio, Francesco Casilli, Manuela Muratori, Francesco Alamanni, Mattia Glauber, Ugolino Livi, Georg Nickenig, Corrado Tamburino, Ottavio Alfieri, Antonio Colombo
Journal: Journal of the American College of Cardiology (2014)
Abstract 16420: Impact of Potent Oral P2Y12 Inhibiting Therapies on Multiple Platelet Signaling Pathways: Results of a Prospective Ex vivo Pharmacodynamic Investigation
Authors: Francesco Franchi, Jung Rae Cho, Fabiana Rollini, Mona Bhatti, Christopher DeGroat, Ana Muniz-Lozano, Mohamad Taha, Ronakkumar Patel, Elizabeth C Dunn, Elisabetta Ferrante, Martin M Zenni, Luis A Guzman, Theodore A Bass, Dominick J Angiolillo
Journal: Circulation (2014)

Background:  Although pharmacodynamic (PD) studies have compared the effects of the P2Y 12  receptor inhibitors prasugrel and ticagrelor on adenosine (ADP) mediated platelet aggregation showing enhanced effects compared with clopidogrel, to date there are no studies assessing how these agents affect other platelet signaling pathways. The aim of this study was to assess the PD effects on multiple platelet signaling pathways after switching clopidogrel treated patients to prasugrel or ticagrelor.   Methods:  In this prospective PD study, clopidogrel (75mg/qd) treated patients (n=110) with coronary artery disease (CAD) were randomized to switch to prasugrel (60mg loading dose/10mg maintenance dose qd) or ticagrelor (180mg loading dose /90mg maintenance dose bid) for 1 week. PD assessments were performed to evaluate the acute (baseline and 30 min, 2 hrs, 24 hrs after LD) and chronic (1 week) effects of therapy using Multiple Electrode Aggregometry following stimuli with multiple agonists: arachidonic acid (AA), ADP (with and without PGE 1 ), collagen and TRAP.   Results:  There were no differences in baseline (on-clopidogrel) platelet reactivity. Switching to prasugrel and ticagrelor led to a reduction in platelet reactivity stimulated by ADP (with and without PGE 1 ) as early as 30 min and sustained up to 1 week (p 12  inhibition. No PD differences were found between prasugrel and ticagrelor with all agonists.   Conclusions:  In CAD patients on maintenance clopidogrel therapy, in addition to exerting prompt and enhanced inhibition of ADP mediated platelet aggregation, switching to either prasugrel or ticagrelor is also associated with diminished thrombin-induced platelet aggregation. These  ex vivo  results support an interplay between the ADP P2Y 12  and the thrombin platelet signaling pathways previously reported in  in vitro  experimental models.
Detection of pulmonary scarring by chest radiography and lung cancer risk
Authors: S Adejumo
Journal: Thorax (2009)

The relationship between lung scarring and lung cancer is uncertain, although it has been postulated that inflammation induces genetic damage leading to DNA mutations with a resultant increase in the risk of scar cancers.

In this study, using analysis of data from the prostate, lung, colorectal and ovarian cancer screening trial, the authors tried …