tbuckley/cabot-search huggingface dataset:
Retrospective analysis of two modes of lymphadenectomy (para-aortic + pelvic vs. pelvic alone) with regard to survival in endometrial cancer: A comparative study of two gynecologic units
Authors: Y. Handa, H. Kato, H. Hareyama, K. Hada, M. Kaneuchi, M. Oikawa, T. Mitamura, A. Aono, Y. Saitoh, K. Okuyama, K. Yamashita
Journal: Journal of Clinical Oncology (2007)

5599 Background: Patients with endometrial cancer are at high risk of severe post-operative complications because of obesity, diabetes mellitus, and hypertension. The purpose of this study is, for minimizing surgical injury, to determine whether para-aortic lymph nodes dissection is dispensable. Methods: 295 patients received hysterectomy and lymphadenectomy during 1995 - 2005 in two gynecologic units of hospitals, one of where para-aortic lymph nodes (to the level of renal vein) and pelvic lymph node (PAN+PLN) dissection were routinely performed and the other only pelvic lymph node (PLN) were dissected, were enrolled. Their overall survival was retrospectively compared between these units. Results: Mean lymph node count was 58.9±19.7 in 99 patients with PAN+PLN lymphadenectomy, and 36.8±14.6 in 196 patients with PLN alone. 5-year survival was 93.3% in PAN+PLN cases and 92.9% in PLN, with no significant difference. Cases who died of the disease (DD) were 6.1% in PAN+PLN and 9.2% in PLN (relative risk = 0.660). Distribution in each stage was ignorable between two units; however, specific histology types, such as serous, clear cell, and carcinosarcoma, were highly counted in DD of the PLN unit. 5-year survival of only endometrioid type, excluding specific histology types, was 92.9% in PAN+PLN and 95.1% in PLN, and DD were 6.6% in PAN+PLN and 6.0% in PLN (RR = 1.095). Lymph node metastases were found 13.1% in PAN+PLN and 4.1% in PLN. One case was observed PAN-alone metastsis, where histology was serous type. Conclusions: Overall survival in patients received PAN+PLN and PLN dissection is not significantly different in endometrial cancer. It is supposed that only PLN dissection is sufficient and PAN dissection is omittable especially in endometrioid type, however, PAN+PLN lymphadenectomy might be suggestive to reduce death in specific histology types. No significant financial relationships to disclose.
High-throughput screening of interacting proteins and their modulators in living cells
Authors: JianPing Lu, Laura Beatty, Jehonathan H Pinthus
Journal: Cancer Research (2008)

1539  One of the main limitations with genome-proteome based anti-cancer drug development is the lack of understanding of the complicated interaction networks between various proteins and the target. Accordingly, it is very difficult to predict the potential adverse effects of the drug under design. High throughput screening is required to confirm protein interactions as well as to identify molecules that can either promote or inhibit these interactions as early as at the pre-clinical phases of drug development. Unfortunately, the current methods used for the screening of protein interactions both in vitro (e.g. protein array) and in vivo (e.g. yeast two-hybrid) have many limitations. These include multiple costly and time-consuming complicated procedures, non-specific interactions, along with high rate of false positive/negative findings. We have developed a high throughput screening approach using a high efficiency recombinase-based expression plasmid vector library, each plasmid expressing two tagged-ORFs of interest. Consequently, high throughput screening and verification of novel protein interactions can be easily performed based on FRET (fluorescence resonance energy transfer), PFC (protein fragment complementation) or BiFC (bimolecular fluorescence complementation). This novel method overcomes the aforementioned limitations and presents a unique route for the investigation of protein functions of intact proteins in their native state in vivo. Using this method, we achieved increased transformation efficiency, higher stringency detection, decreased false positive results and high-throughput formats.  Our lab is currently applying the technology in screening and confirmation of  Novel protein interactions in living prokaryotic and eukaryotic cells.  Setting up high throughput protocols for the screening and verification of protein interactions.  Identification of potential drug candidates (small molecular chemicals, peptides etc.) that can modulate protein interactions towards the development of new anti-cancer agents.  For more information, contact: Sunita Asrani, Industrial Liaison Officer, Health Sciences, McMaster University Tel: (905) 525-9140 Ext. 28641 Fax: (905) 546-1372; Email: asranis@mcmaster.ca; JianPing Lu, Jehonathan Pinthus, Fax 001-905-575-6330 E-mail: jianping.lu@hrcc.on.ca; jehonathan.pinthus@hrcc.on.ca
Cardiac implantable electronic devices with a defibrillator component and all‐cause mortality in left ventricular assist device carriers: results from the PCHF‐VAD registry
Authors: Maja Cikes, Nina Jakus, Brian Claggett, Jasper J. Brugts, Philippe Timmermans, Anne‐Catherine Pouleur, Pawel Rubis, Emeline M. Van Craenenbroeck, Edvinas Gaizauskas, Sebastian Grundmann, Stefania Paolillo, Eduardo Barge‐Caballero, Domenico D'Amario, Aggeliki Gkouziouta, Ivo Planinc, Jesse F. Veenis, Luc‐Marie Jacquet, Laura Houard, Katarzyna Holcman, Arno Gigase, Filip Rega, Kestutis Rucinskas, Stamatios Adamopoulos, Piergiuseppe Agostoni, Bojan Biocina, Hrvoje Gasparovic, Lars H. Lund, Andreas J. Flammer, Marco Metra, Davor Milicic, Frank Ruschitzka
Journal: European Journal of Heart Failure (2019)
Can serial PET/CT imaging during and after chemoradiation treatment assist in individualizing therapy for patients with squamous cell cancer of the head and neck?
Authors: K. Greven
Journal: Journal of Clinical Oncology (2009)

e17022 Background: PET/CT imaging with FDG has the potential advantage over conventional imaging of demonstrating metabolic changes in tumors early in the course of chemoradiation which may aid in individualization of therapy for patients. Methods: Sixteen patients with stage III/IV head and neck cancer were prospectively entered on a study to evaluate the role of PET/CT between March 2006 and July 2007. Enrolled patients were treated with chemoradiation (CRT) and had a series of 5 PET/CT scans in the treatment position at the initiation of therapy, 2 and 4 weeks after initiation of chemoradiation and then 6 weeks and 3 months after completion of treatment. The max standard uptake values (SUV) were recorded in the primary tumors. In addition CT imaging was examined and the maximum dimensions of the primary tumor were recorded. Results: Three patients have recurred at the primary site and follow-up ranges from 15–30 months. Twelve patients had decreasing SUV 2 weeks after initiation of CRT, one stayed the same, and two increased. The change ranged from a 75% decrease to a 21% increase compared to the initial scan. All patients had stable or decreasing SUV 4 and 6 weeks after initiation of therapy (range: 0 to 100% decrease). The change in SUV at 2 weeks, 4 weeks, post RT 6 weeks and 3 months compared to baseline for the 3 patients with local recurrence and the 13 patients who remain disease free were -7%, -62%, -50%, and -16% compared to -34%, -62%, -77%, and -81%, respectively. Higher PET values were significantly associated with a higher risk of recurrence (p = 0.04). In contrast CT imaging demonstrated that tumor measurements at 2 weeks, 4 weeks, post RT 6 weeks, and 3 months steadily decreased in both groups with mean changes in the recurrence group and in the locally controlled group of -11%, -46%, -77%, and -100% and -47%, -57%, -73%, and -99%, respectively. CT measurements were not associated with the risk of recurrence (p = 0.72). Conclusions: Changes in SUV from PET/CT were significantly predictive of tumor recurrence compared to CT imaging alone. If this observation can be verified in a larger cohort of patients, individualization of treatment based on PET/CT changes may be possible in order to improve outcomes for these patients. No significant financial relationships to disclose.
Association of high amounts of physical activity with mortality risk: a systematic review and meta-analysis
Authors: Kim Blond, Cecilie Fau Brinkløv, Mathias Ried-Larsen, Alessio Crippa, Anders Grøntved
Journal: British Journal of Sports Medicine (2019)

Objectives To systematically review and analyse studies of high amounts of physical activity and mortality risk in the general population. Eligibility criteria Inclusion criteria related to follow-up (minimum 2 years), outcome (mortality from all causes, cancer, cardiovascular disease (CVD) or coronary heart disease), exposure (eg, a category of &gt;1000 metabolic equivalent of task (MET) min/week), study design (prospective cohort, nested case control or case-cohort) and reports of cases and person years of exposure categories. Information sources Systematic searches were conducted in Embase and Pubmed from database inception to 2 March 2019. Risk of bias The quality of the studies was assessed with the Newcastle–Ottawa scale. Included studies From 31 368 studies identified, 48 were included. Two authors independently extracted outcome estimates and assessed study quality. Synthesis of results We estimated hazard ratios (HRs) using random effect restricted cubic spline dose–response meta-analyses. Compared with the recommended level of physical activity (750 MET min/week), mortality risk was lower at physical activity levels exceeding the recommendations, at least until 5000 MET min/week for all cause mortality (HR=0.86, 95% CI 0.78 to 0.94) and for CVD mortality (HR=0.73, 95% CI 0.56 to 0.95). Strengths and limitations of evidence The strengths of this study include the detailed dose–response analyses, inclusion of 48 studies and examination of sources of heterogeneity. The limitations include the observational nature of the included studies and the inaccurate estimations of amount of physical activity. Interpretation Compared with the recommended level, mortality risk was lower at physical activity levels well above the recommended target range. Further, there was no threshold beyond which lifespan was compromised. Registration PROSPERO CRD42017055727.
Abstract 88: Pentraxin 3 in Coronary Artery Lesions in Kawasaki Disease
Authors: Toshiyuki Kitoh, Yoshiro Kitagawa, Reizo Baba, Atsushi Kaneko, Masaki Shimizu, Akihoro Yachie, Noriaki Kume, Takao Hamakubo
Journal: Circulation (2015)

Although vascular inflammation is an important feature of Kawasaki disease (KD), the usefulness of local inflammatory markers as biomarkers for KD is unknown. Pentraxin 3 (PTX3), soluble lectin-like oxidized low density lipoprotein receptor 1 (sLOX-1) and matrix metraloproteinase-9 (MMP-9) are biomarkers of inflammation of vascular components. Objective: We tested whether plasma concentrations of PTX3, sLOX-1 or MMP-9 would be a useful biomarker for detecting high risk patient of coronary artery aneurysm (CAA) in KD and compared with serum level of interleukin-6 (IL-6) and IL-18. The ability of the assays to identify KD patients at risk for CAA was analyzed. Methods: PTX3, sLOX-1, MMP-9, IL-6 and IL-18 concentrations of 50 KD patients at different four clinical points were analyzed. Point A represented on admission; B, pre-IVIG; A+B, before IVIG; C, after IVIG; D, after fever resolution. Each concentration was compared with the rate of occurrence of CAA and IVIG unresponsiveness. Results: Each value was evaluated in 50 KD patients (2 with CAA, 48 without CAA). Three patients were treated without IVIG, 17 with one course of IVIG, and six with two IVIGs, two with three IVIGs, respectively. At the points A+B, C, D means for PTX3 were; 33.4, 11.7, 9.00 ng/ml, mean for MMP-9; 34.6, 19.2, 24.2 ng/ml, mean for sLOX-1; 3.82, 2.33, 2.25 ng/ml, respectively. Levels of PTX3 (p&lt;0.001) and MMP-9 (p&lt;0.05) were significantly higher in before IVIG than after IVIG; whereas levels of sLOX-1, as well as those of IL-6 and IL-18 were comparable between before and after IVIG. PTX3 were well correlated with IL-6 level (R2=0.73). Both cases with extraordinary high PTX3 levels at admission of 91.8 and 65.3 ng/ml were complicated with coronary artery aneurysms, even though they were treated by three courses of IVIG. The level of plasma PTX3 was significant related with the course numbers of IVIG (p&lt;0.05). Conclusion: Levels of PTX3 and MMP-9 appear to be associated with clinical course of KD. Levels of PTX3 were correlated with the severity of disease; how many doses of IVIG enough to resolve fever. An extraordinary high PTX3 level might be suggestive of the existence of CAA. These data suggest that PTX3 can be a candidate biomarker for prediction of unresponsiveness and CAA formation in patients with KD.
Strategies to Adjust Positive End-Expiratory Pressure in Patients With ARDS
Authors: Michael C. Sklar, Ewan C. Goligher
Journal: JAMA (2019)

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The human IIIb-mRNA splice variant of FGFR1 is a functional transmembrane tyrosine kinase receptor and inhibits pancreatic cancer cell growth
Authors: Marko Kornmann, Zhangbing Liu, Susi Meier, Doris Henne-Bruns, Murray Korc
Journal: Cancer Research (2005)

4558  Introduction: Fibroblast growth factors (FGFs) and their high-affinity FGF receptors (FGFR) are involved in many biological processes including angiogenesis and mitogenesis. Several FGFs are overexpressed in human pancreatic cancer and high FGF expression correlates with poor prognosis. Several FGFR mRNA splice variants have been described which exhibit distinct ligand-binding properties. We have recently demonstrated that the IIIc variant of FGFR-1 has transforming capacities after expression in normal TAKA-1 pancreatic ductal cells which do not express endogenous FGFR-1. Nothing is presently known about the human IIIb variant which has been recently subcloned. The aim of this study was to characterize the effect of FGFR-1 IIIb expression in pancreatic ductal cells. Experimental procedures: A full-length human IIIb cDNA variant of FGFR-1 was constructed and expressed in TAKA-1 pancreatic ductal cells and PANC-1 human pancreatic cancer cells. Cell counting, MTT assays and soft agar were used to assess the effect of FGFR-1 IIIb expression on cell growth and colony formation. Immunoprecipitation, MAPK and p38 kinase assays were used to investigate the effect of FGFs on intracellular signaling. Results: The growth of TAKA-1 cells expressing IIIb was significantly enhanced by FGF-1, -2 and FGF-4 while no effect was seen in wild-type or control transfected TAKA-1 cells. FGF-1 and FGF-2 enhanced tyrosine phosphorylation of fibroblast growth factor receptor substrate-2 (FRS2), MAP and p38 kinase activity. In comparison to control transfected clones the basal growth of TAKA-1 and PANC-1 clones expressing FGFR-1 IIIb was inhibited. Additionally, the colony formation was significantly reduced after expression of IIIb in these cells. Conclusion: We demonstrated for the first time that the human IIIb variant of FGFR-1 is a functional fibroblast growth factor receptor. In contrast to the IIIc variant of FGFR-1 the IIIb variant inhibits the transforming ability of human pancreatic cancer cells.
Abstract #3748: Activation of NF-\#954;B is necessary for stimulation of apoptosis by antimitotic drugs in human LNCaP prostate cancer cells
Authors: Ricardo Parrondo, Alicia de las Pozas, Teresita Reiner, Carlos Perez-Stable
Journal: Cancer Research (2009)

One of the factors important in the progression of androgen-independent prostate cancer is the increased activity of NF-\#954;B, a transcription factor that promotes greater expression of inhibitors of apoptosis and of resistance to chemotherapy. It is commonly believed that inhibition of NF-\#954;B activity will decrease inhibitors of apoptosis and result in greater sensitivity to chemotherapy. However, there is also evidence to suggest that NF-\#954;B activation can sensitize cells to apoptosis and inhibition of NF-\#954;B can result in resistance to apoptosis. Our data indicates that the antimitotic drugs docetaxel (Doc) and 2-methoxyestradiol (2ME2) have diverse responses to NF-\#954;B activity, depending on the type of prostate cancer cell. In androgen-dependent LNCaP cells, which have a low basal NF-\#954;B activity, Doc and 2ME2 increases NF-\#954;B activity as determined by Western blot analysis of phospho-I\#954;B\#945;/p65, NF-\#954;B promoter reporter assays, and p65 nuclear localization. Inhibitors of NF-\#954;B purvalanol A, helenalin, or dominant-negative I\#954;B\#945; blocks apoptosis induced by Doc and 2ME2. In contrast, inhibition of the JNK and MAPK signaling pathways did not block Doc and 2ME2 apoptosis in LNCaP cells. In androgen-independent DU 145 and PC-3 cells, Doc and 2ME2 have little effect on the high basal NF-\#954;B activity and addition of purvalanol A or helenalin does not enhance apoptosis. These results suggest that combination of antimitotic drugs with inhibitors of NF-\#954;B may antagonize apoptosis in some types of prostate cancer cells. However, the combination of Doc or 2ME2 with betulinic acid, a natural pentacyclic triterpenoid proposed to activate NF-\#954;B, stimulates apoptosis in LNCaP and non-apoptotic cell death in DU 145 and PC-3 prostate cancer cells. Increase in sensitivity to cell death by the Doc or 2ME2 + betulinic acid combination may be due to lower X-linked inhibitor of apoptosis, higher death receptor 5, and higher nuclear localization of apoptosis-inducing factor. Overall, our data suggests that chemotherapy combinations of antimitotic drugs with activators of NF-\#954;B will stimulate cell death in all types of prostate cancer cells.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3748.
Degradation of proteins by PROTACs and other strategies
Authors: Yang Wang, Xueyang Jiang, Feng Feng, Wenyuan Liu, Haopeng Sun
Journal: Acta Pharmaceutica Sinica B (2019)

Blocking the biological functions of scaffold proteins and aggregated proteins is a challenging goal. PROTAC proteolysis-targeting chimaera (PROTAC) technology may be the solution, considering its ability to selectively degrade target proteins. Recent progress in the PROTAC strategy include identification of the structure of the first ternary eutectic complex, extra-terminal domain-4-PROTAC-Von-Hippel-Lindau (BRD4-PROTAC-VHL), and PROTAC ARV-110 has entered clinical trials for the treatment of prostate cancer in 2019. These discoveries strongly proved the value of the PROTAC strategy. In this perspective, we summarized recent meaningful research of PROTAC, including the types of degradation proteins, preliminary biological data in vitro and in vivo, and new E3 ubiquitin ligases. Importantly, the molecular design, optimization strategy and clinical application of candidate molecules are highlighted in detail. Future perspectives for development of advanced PROTAC in medical fields have also been discussed systematically.
Hepatitis C Virus Mediated Inhibition of miR‐181c Activates ATM Signaling and Promotes Hepatocyte Growth
Authors: Tapas Patra, Keith Meyer, Ratna B. Ray, Ranjit Ray
Journal: Hepatology (2019)

Background and Aims Hepatitis C virus (HCV) infection promotes hepatocyte growth and progress to hepatocellular carcinoma. We previously observed that HCV infection of hepatocytes transcriptionally down‐regulates miR‐181c expression through CCAAT/enhancer binding protein β (C/EBP‐β). Here, we examined the role of miR‐181c in the regulation of cell cycle progression in relation to HCV infection. In silico analysis suggested that ataxia‐telangiectasia mutated (ATM) protein, a protein kinase, is a direct target of miR‐181c. ATM is a central mediator of response for cellular DNA double‐strand break. Approach and Results Our results demonstrated that ATM expression is higher in HCV‐infected hepatocytes and chronic HCV‐infected liver biopsy specimens. We have shown a direct interaction of miR‐181c with the 3′ untranslated region of ATM, and the presence of ATM in miR‐181c‐associated RNA‐induced silencing complex. Exogenous expression of miR‐181c inhibited ATM expression and activation of its downstream molecules, Chk2 and Akt. On the other hand, introduction of anti‐miR‐181c restored ATM and phosphorylated Akt. Furthermore, introduction of miR‐181c significantly inhibited phospho–cyclin‐dependent kinase 2 (CDK2) and cyclin‐A expression, arresting cell cycle progression, whereas overexpression of miR‐181c promoted apoptosis of HCV‐infected hepatocytes and can be inhibited by overexpression of ATM from a clone lacking miR‐181c binding sites. In addition, miR‐181c significantly regressed tumor growth in the xenograft human hepatocellular carcinoma mouse model. Conclusions Together, our results suggest that HCV infection suppresses miR‐181c in hepatocytes, resulting in ATM activation and apoptosis inhibition for promotion of cell cycle progression. The results provide mechanistic insight into understanding the role of miR‐181c in HCV‐associated hepatocyte growth promotion, and may have the potential for therapeutic intervention.