tbuckley/cabot-search huggingface dataset:
Ionizing Radiation Up-regulates Telomerase Activity in Cancer Cell Lines by Post-translational Mechanism via Ras/Phosphatidylinositol 3-Kinase/Akt Pathway
Authors: Ron Ram, Orit Uziel, Orit Eldan, Eyal Fenig, Einat Beery, Shelly Lichtenberg, Yardena Nordenberg, Meir Lahav
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Telomerase is considered currently as a hallmark of cancer, and its inhibition is expected to become an important anticancer modality. In contrast to abundant data concerning the effect of cytotoxic drugs on telomerase activity (TA), there is scant information on the effect of radiation on telomerase. The mechanism of telomerase regulation by irradiation has never been evaluated in detail. In the present study, we investigated the effect of radiation on TA and its regulation in cancer cells. Experimental Design: The effect of various radiation doses on TA in several malignant and nonmalignant cell lines was evaluated. All malignant cells exhibited similar telomerase response to radiation and its regulation was assessed at transcriptional and post-translational levels in K562 cells. Next step was the evaluation of the upstream signaling pathways leading to changes in TA using kinetics and specific inhibitors. Results: Radiation up-regulated TA in dose-dependent manner only in cancer cells. Telomerase was activated by phosphorylation by Akt and by cytoplasmic-nuclear shift. Transcriptional processes were not involved in TA. This telomerase regulation is mediated by Ras/phosphatidylinositol 3-kinase/Akt pathway. The canonical membrane effectors of irradiation (epidermal growth factor receptor, insulin-like growth factor-I receptor, and Ca2+ influx) were not involved in this process. Conclusions: Radiation up-regulates telomerase activity specifically in cancer cells. This study adds to accumulating evidence pointing to post-translational level as important mode of telomerase regulation. Telomerase activation due to radiation may be detrimental in treatment of cancer. Data described in this study may add to future interventions aiming at inhibition of telomerase activation during irradiation.
Polypharmacy: Geriatric Oncology Evaluation Should Become Mainstream
Authors: Stuart M. Lichtman
Journal: Journal of Clinical Oncology (2015)

All adult oncologists are now geriatric oncologists. This is no longer a nichefield with only a few dedicated researchers. The demographic shift brought on by the baby boomer generation has already happened and is creating a rapid increase in the population of adults older than 65 years of age. In the United States, 10,000 baby boomers reach the age of 65 years each day, and those older than age 80 are the fastest growing segment of the population. This demographic change and aging as an established risk factor for the development of cancer will result in a marked increase in the number of older patients with cancer. The dramatic increase in the number of these patients will further strain our health care system, not only monetarily but also by the increased manpower needed to adequately care for them. Older patients with cancer, particularly those older than age 70 years, have specific needs that are not present in younger patients. It is well established that the traditional oncology evaluation is not adequate andwillfailtouncovermanyspecificproblems. 1 Geriatricassessment will no longer be the purview of the geriatrician but will need to be incorporatedintodailypracticeinalloncologyfields.Therefore,weall need to become well-educated geriatric oncologists. 2
Repeated adenoviral administration into the biliary tract can induce repeated expression of the original gene construct in rat livers without immunosuppressive strategies
Authors: K Tominaga
Journal: Gut (2004)

<b>Background:</b> Systemic adenoviral readministration appears to be limited by immunogenicity. <b>Aims:</b> We examined the feasibility of repeated adenovirus mediated gene transfer into the liver via the biliary tract. <b>Methods:</b> Recombinant adenoviruses carrying a reporter <i>lacZ</i> gene were infused retrogradely into the common bile duct of rats. Transduction efficiency of the <i>lacZ</i> gene was estimated histochemically and quantitatively. <b>Results:</b> Retrograde administration of recombinant adenoviruses into the common bile duct of rats resulted in efficient transgene expression in the liver, specifically in hepatocytes, but not in biliary epithelia. Transduction efficiency induced by intrabiliary adenoviral administration was not substantially different from that induced by intraportal adenoviral infusion. Transgene expression in the liver was however transient, and development of neutralising antibodies against adenovirus was observed in serum but not in bile. When adenoviruses were readministered into the common bile duct, successful re-expression of the transgene in the liver was achieved despite the existence of neutralising antibodies in serum. Interestingly, although proliferation of adenovirus specific T cells in response to adenoviral readministration was suppressed significantly by immunosuppressive FK506 treatment, levels of transgene expression in the liver achieved by intrabiliary adenoviral readministration were not significantly different between animals treated with and without FK506. Furthermore, third adenoviral administration into the common bile duct also induced successful transgene expression in the liver. <b>Conclusions:</b> These results suggest that adenovirus mediated gene transfer into the liver may be repeatable without immunosuppressive strategies in clinical settings by means of endoscopic retrograde cholangiography.
Thrombin-activatable Fibrinolysis Inhibitor and Protein C Inhibitor in Interstitial Lung Disease
Authors: Hajime Fujimoto, Esteban Cesar Gabazza, Osamu Hataji, Hisamichi Yuda, Corina Nayade D'Alessandro-Gabazza, Mariko Nakano, Omar Enrique Franco, Tatsuya Hayashi, Koji Suzuki, Yukihiko Adachi, Osamu Taguchi
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Intraalveolar activation of the coagulation system due to reduced fibrinolytic function plays a critical role in the pathogenesis of interstitial lung disease. Recently, a new potent inhibitor of fibrinolysis, thrombin-activatable fibrinolysis inhibitor, has been isolated and characterized from human plasma. This study evaluated the levels of thrombin-activatable fibrinolysis inhibitor and protein C inhibitor, another suppressor of fibrinolysis, in the bronchoalveolar lavage fluid from patients with interstitial lung disease. There were 82 patients with interstitial lung disease and 8 normal subjects. The bronchoalveolar lavage fluid levels of thrombin-activatable fibrinolysis inhibitor and protein C inhibitor were significantly higher in all patients with interstitial lung disease than in normal subjects. Both inhibitors of fibrinolysis were significantly and inversely correlated with fibrinolytic activity in all patients. The levels of thrombin-activatable fibrinolysis inhibitor were significantly correlated with those of protein C inhibitor, thrombin–antithrombin complex, and monocyte chemoattractant protein-1. Reverse transcriptase-polymerase chain reaction showed that alveolar macrophages isolated from patients with interstitial lung disease as well as immortalized lung epithelial cell lines express thrombin-activatable fibrinolysis inhibitor antigen. Overall, these findings suggest that thrombin-activatable fibrinolysis inhibitor and protein C inhibitor may play important roles in the mechanism of intraalveolar hypofibrinolysis associated with interstitial lung diseases.
Sunbed use in children aged 11-17 in England: face to face quota sampling surveys in the National Prevalence Study and Six Cities Study
Authors: C. S Thomson, S. Woolnough, M. Wickenden, S. Hiom, C. J Twelves
Journal: BMJ (2010)

<b>Objectives</b> To quantify the use of sunbeds in young people across England, identify geographical variation, and explore patterns of use, including supervision. <b>Design</b> Two random location sampling surveys. <b>Setting</b> National Prevalence Study in England; Six Cities Study in Liverpool, Stoke/Stafford, Sunderland, Bath/Gloucester, Oxford/Cambridge, and Southampton. <b>Participants</b> 3101 children aged 11-17 in the National Prevalence study and 6209 in the Six Cities study. <b>Results</b> In the National Prevalence Study 6.0% (95% confidence interval 5.1% to 6.8%) of those aged 11-17 had used a sunbed. Use was higher in girls than in boys (8.6% (7.2% to 10.0%) <i>v</i> 3.5% (2.6% to 4.4%), respectively), in those aged 15-17 compared with those aged 11-14 (11.2% (9.5% to 12.9%) <i>v</i> 1.8% (1.2% to 2.4%), respectively), and in those from lower rather than higher social grades (7.6% (5.7% to 9.5%) <i>v</i> 5.4% (4.5% to 6.3%), respectively). Sunbed use was higher in the "north" (11.0%, 8.9% to 13.0%) than in the "midlands" (4.2%, 2.5% to 5.8%) and the "south" (4.2%, 3.3% to 5.2%). In the Six Cities Study, sunbed use was highest in Liverpool and Sunderland (20.0% (17.5% to 22.4%) and 18.0% (15.6% to 20.3%), respectively), with rates especially high in girls, those aged 15-17, or from lower social grades. Mean age of first use was 14, and 38.4% (34.7% to 42.1%) of children used a sunbed at least once a week. Nearly a quarter (23.0%, 19.8% to 26.1%) of children had used a sunbed at home (including home of friends/relatives), and 24.7% (21.0% to 28.4%) said they had used sunbeds unsupervised in a tanning/beauty salon or gym/leisure centre. <b>Conclusions</b> Sunbed use by children is widespread in England, is often inadequately supervised, and is a health risk. National legislation is needed to control sunbed outlets.
The Development and Characterization of a Human Midgut Carcinoid Cell Line
Authors: George Van Buren, Asif Rashid, Anthony D. Yang, Eddie K. Abdalla, Michael J. Gray, Wenbiao Liu, Ray Somcio, Fan Fan, E. Ramsay Camp, James C. Yao, Lee M. Ellis
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Gastrointestinal neuroendocrine tumors (NET) are rare heterogeneous tumors that hypersecrete neuropeptides. The scarcity of good gastrointestinal NET models has limited the ability to study potential therapeutic agents. We describe and characterize the establishment of a human midgut carcinoid tumor cell line carcinoid tumor 2 (CNDT2). Experimental Design: Tumor cells (CNDT2) were isolated from a liver metastasis from a patient with a primary ileal carcinoid. After 9 weeks in culture, the cells were plated in soft agar, and cells from a single colony were put back in culture (CNDT2.1). Those CNDT2.1 cells were injected s.c. into nude mice. Cells were isolated from a single resultant tumor (CNDT2.5), cultured, and characterized by electron microscopy, reverse transcription-PCR, serotonin enzyme immunoassay, Western blotting, and immunohistochemical analysis for NET markers and potential therapeutic targets. Results: CNDT2 cells grew in monolayers in vitro, formed colonies in soft agar, and formed tumors in mice. Electron microscopy revealed round, pleomorphic, electron-dense neurosecretory granules characteristic of NETs. Tumor xenografts exhibited the appearance of NETs with small “salt-and-pepper” nuclei on H&amp;E staining and chromogranin A, synaptophysin, and CD56 on immunohistochemical staining. CNDT2.5 cells produced serotonin and expressed insulin-like growth factor receptor-I, platelet-derived growth factor receptor-β, vascular endothelial growth factor receptor-1, cMET, epidermal growth factor receptor, neuropilin-1, and somatostatin receptors 1 to 5. Cytogenetic analysis revealed the presence of deletions at 2p and 6q and numerous translocations. Conclusion: The establishment of this human midgut carcinoid tumor cell line may serve as a useful model system for studying cell biology and novel targeted agents in preclinical models.
Relevance of Monocytic Features for Neovascularization Capacity of Circulating Endothelial Progenitor Cells
Authors: Carmen Urbich, Christopher Heeschen, Alexandra Aicher, Elisabeth Dernbach, Andreas M. Zeiher, Stefanie Dimmeler
Journal: Circulation (2003)

Background— Transplantation of ex vivo expanded circulating endothelial progenitor cells (EPCs) from peripheral blood mononuclear cells improves the neovascularization after critical ischemia. However, the origin of the endothelial progenitor lineage and its characteristics have not yet been clearly defined. Therefore, we investigated whether the phenotype and functional capacity of EPCs to improve neovascularization depend on their monocytic origin. Methods and Results— Monocytic CD14 + cells were isolated from mononuclear cells and incubated on fibronectin-coated dishes in endothelial medium in the presence of vascular endothelial growth factor. After 4 days of cultivation, adherent cells deriving from CD14 + or CD14 − mononuclear cells showed equal expression of endothelial marker proteins and capacity for clonal expansion as determined by measuring endothelial colony-forming units. In addition, transplanted EPCs (5×10 5 cells) deriving from CD14 + or CD14 − cells were incorporated into vascular structures of nude mice after hind-limb ischemia and significantly improved neovascularization from 0.27±0.12 (no cells) to 0.66±0.12 and 0.65±0.17, respectively ( P &lt;0.001; laser Doppler-derived relative blood flow). In contrast, no functional improvement of neovascularization was detected when freshly isolated CD14 + mononuclear cells without ex vivo expansion were used (0.33±0.17). Moreover, macrophages or dendritic cells differentiated from isolated CD14 + cells were significantly less effective in improving neovascularization than EPCs cultivated from the same starting population ( P &lt;0.01). Conclusions— These data demonstrate that EPCs can be generated from nonmonocytic CD14 − peripheral blood mononuclear cells and exhibit a unique functional activity to improve neovascularization after hind-limb ischemia.
Second Round Results of the Finnish Population-Based Prostate Cancer Screening Trial
Authors: Tuukka Mäkinen, Teuvo L. J. Tammela, Ulf-Håkan Stenman, Liisa Määttänen, Jussi Aro, Harri Juusela, Paula Martikainen, Matti Hakama, Anssi Auvinen
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Large randomized trials provide the only valid means of quantifying the benefits and drawbacks of prostate-specific antigen (PSA) screening, but the follow-up of ongoing studies is still too short to allow evaluation of mortality. We report here the intermediate indicators of screening efficacy from the second round of the Finnish trial. Experimental Design: The Finnish trial, with ∼80,000 men in the target population, is the largest component in the European Randomized Study of Screening for Prostate Cancer. The first round was completed in 1996–1999. Each year 8,000 men 55–67 years of age were randomly assigned to the screening arm, and the rest formed the control arm. Men randomized to the screening arm in 1996 were reinvited 4 years later, in 2000, and PSA was determined. Results: Of the eligible 6415 men, 4407 (69%) eventually participated in the second round of screening. Of the first-round participants, up to 84% (3833 of 4556) attended rescreening. A total of 461 screenees (10.5%) had PSA levels of ≥4 μg/liter. Altogether, 97 cancers were found, yielding an overall detection rate of 2.2% (97 of 4407). Seventy-nine cases were found among the 3833 second-time screenees (detection rate 2.1%) and 18 in those 574 men (3.1%) who had not participated previously. A PSA of ≥4 μg/liter, but negative biopsy in the first screening round was associated with an up to 9-fold risk of cancer in rescreening relative to those with lower PSA levels at baseline. Ninety-one (94%) of all of the detected cancers were clinically localized. Conclusions: As surrogate measures of an effective screening program, both compliance as well as the overall and advanced prostate cancer detection rates remained acceptable. Men defined as screen-positive but with a negative confirmation of cancer at prevalence screen formed a high-risk group at rescreening.
Echocardiographic, Histopathologic, and Surgical Findings in <i>Staphylococcus lugdunensis</i> Mitral Valve Endocarditis After Prostate Biopsy
Authors: Faisal A. Arain, Brandie D. Williams, Scott D. Lick, Nahal Boroumand, Masood Ahmad
Journal: Circulation (2013)
HER2 Signaling and Resistance to the Anti-EGFR Monoclonal Antibody Cetuximab: A Further Step toward Personalized Medicine for Patients with Colorectal Cancer
Authors: Fortunato Ciardiello, Nicola Normanno
Journal: Cancer Discovery (2011)

Abstract Primary and acquired resistance to anti-epidermal growth factor receptor (EGFR) drugs are clinically relevant problems in patients with metastatic colorectal carcinoma. A complex network of molecular alterations is involved in this phenomenon. Bertotti et al. report the development of serially transplantable groups of tumor xenografts in immune-deficient mice from patient-derived, genetically characterized metastatic colorectal carcinoma samples. These experimental models (“xenopatients”) might represent a novel approach to discover and characterize the mechanisms of resistance to anti-EGFR therapy and other molecularly targeted therapies in metastatic colorectal carcinoma. In this respect, Bertotti et al. were able to identify HER2 gene amplification as one such mechanism of resistance to anti-EGFR therapy. Cancer Discovery; 1(6); 472–74. ©2011 AACR. Commentary on Bertotti et al., p. 508.
Prognostic Value of Gated Myocardial Perfusion Imaging for Asymptomatic Patients With Type 2 Diabetes
Authors: Yoshimitsu Yamasaki, Kenichi Nakajima, Hideo Kusuoka, Tohru Izumi, Atsunori Kashiwagi, Ryuzo Kawamori, Kazuaki Shimamoto, Nobuhiro Yamada, Tsunehiko Nishimura
Journal: Diabetes Care (2010)

OBJECTIVE Individuals with type 2 diabetes are at high risk for cardiovascular events. We evaluated the prognostic value of gated myocardial perfusion single-photon computed tomography (SPECT) for asymptomatic diabetic patients in a Japanese population. RESEARCH DESIGN AND METHODS Asymptomatic patients (n = 485) aged ≥50 years with either a maximal carotid artery intima-media thickness of ≥1.1 mm, or a urinary albumin ≥30 mg/g creatinine or who had at least two of the following, abdominal obesity, low HDL cholesterol, high triglyceride levels, and hypertension, were enrolled at 50 institutions. The patients were evaluated using gated SPECT with the stress-rest protocol and followed up for 3 years. RESULTS During the follow-up period, 62 (13%) events occurred, including 5 cardiac deaths and 57 cardiovascular events. Patients with summed stress scores (SSS) of ≥9 had a significantly higher incidence (of either death or cardiovascular events) than those with SSS scores of &amp;lt;9 (23 vs. 12%; P = 0.009). Multivariate Cox regression analysis showed that significant variables were SSS ≥9, a low estimated glomerular filtration rate, and being a current smoker. Univariate Cox regression analysis showed that ticlopidine and insulin use are potent medical modulators of cardiovascular events. CONCLUSIONS The incidences of cardiovascular events and death were significantly high in a select population of type 2 diabetic patients with SPECT abnormalities. A targeted treatment strategy is required for asymptomatic but potentially high-risk patients with type 2 diabetes.
Infectious diseases expert sentenced to prison and fined
Authors: Janice Hopkins Tanne
Journal: BMJ (2004)

Dr Thomas Butler, an expert on plague who was convicted on 47 of 69 charges involving missing vials of plague bacteria, was sentenced last week in Texas to two years in federal prison. He was fined $15 000 (£8300; €12 200) and must pay restitution of $38 675 to Texas Tech University in Lubbock, where he was formerly professor of medicine and head of the infectious diseases division.

The case began in January 2003, when Dr Butler told his laboratory safety officer that 30 …
Associations of Increases in Serum Creatinine with Mortality and Length of Hospital Stay after Coronary Angiography
Authors: Steven D. Weisbord, Huanyu Chen, Roslyn A. Stone, Kevin E. Kip, Michael J. Fine, Melissa I. Saul, Paul M. Palevsky
Journal: Journal of the American Society of Nephrology (2006)

The absence of a universally accepted definition of radiocontrast nephropathy (RCN) has hampered efforts to characterize effectively the incidence and the clinical significance of this condition. The objective of this study was to identify a clinically relevant definition of RCN by assessment of the relationships between increases in serum creatinine (Scr) of varying magnitude after coronary angiography and clinical outcomes. An electronic medical database was used to identify all patients who underwent coronary angiography at the University of Pittsburgh Medical Center during a 12-yr period and abstract Scr levels before and after angiography, as well as demographic characteristics and comorbid conditions. Changes in Scr after angiography were categorized into mutually exclusive categories on the basis of absolute and relative changes from baseline levels, with a separate category denoting "unknown" change. Discrete proportional odds models were used to examine the association between increases in Scr and 30-d in-hospital mortality and length of stay. A total of 27,608 patients who underwent coronary angiography were evaluated. Small absolute (0.25 to 0.5 mg/dl) and relative (25 to 50%) increases in Scr were associated with risk-adjusted odds ratios for in-hospital mortality of 1.83 and 1.39, respectively. Larger increases in Scr generally were associated with greater risks for these clinical outcomes. Small increases in Scr after the administration of intravascular radiocontrast are associated with adverse patient outcomes. This observation will help guide the post-procedure care of patients who undergo coronary angiography and has important implications for future studies that investigate RCN.
Long term safety of methotrexate in routine clinical care: discontinuation is unusual and rarely the result of laboratory abnormalities
Authors: Y Yazici
Journal: Annals of the Rheumatic Diseases (2004)

To analyse patients with rheumatoid arthritis, treated with methotrexate in a weekly academic rheumatology clinic over 13 years, for continuation of courses and reasons for discontinuation.All 248 patients with an analysable longitudinal course who took methotrexate in standard care between 1990 and 2003 were studied. Continuation of courses was analysed using life tables. All abnormal and severely abnormal values for aspartate aminotransferase (AST) >40 U/l, >80 U/l, albumin <35 g/l, <30 g/l, white blood cell (WBC) count <4.0 x 10(9)/l, <3.0 x 10(9)/l, and platelet count <150 x 10(9)/l, <100 x 10(9)/l, were identified. Responses of the clinician and subsequent laboratory values were reviewed.Over 1007 person-years, the probability of continuing methotrexate over five years was 79% (95% confidence interval, 72% to 84%). Severe laboratory abnormalities occurred in 2.9 per 100 person-years, specifically 0.9 for AST >80 U/l, 1.1 for albumin <30 g/l, 0.7 for WBC <3.0 x 10(9)/l, and 0.3 for platelets <100 x 10(9)/l. No severe laboratory abnormality progressed to further severity or clinical disease. Permanent discontinuations of methotrexate occurred in 46 patients (19%), 26 (10% of all patients) for adverse effects, 15 (32.6%) for inefficacy; only two discontinuations resulted from laboratory abnormalities, both of WBC, possibly from other sources.Methotrexate was associated with a high rate of continuation, and few clinically significant laboratory abnormalities. Discontinuation primarily reflected clinical rather than laboratory findings. Vigilance for methotrexate toxicity is required but methotrexate appears among the safest treatments for rheumatoid arthritis.
Piperacillin–tazobactam as an initial empirical therapy of bacteremia caused by extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae
Authors: Cheol-In Kang, So Yeon Park, Doo Ryeon Chung, Kyong Ran Peck, Jae-Hoon Song
Journal: Journal of Infection (2012)