tbuckley/cabot-search huggingface dataset:
Neural Tumor-Initiating Cells Have Distinct Telomere Maintenance and Can be Safely Targeted for Telomerase Inhibition
Authors: Pedro Castelo-Branco, Cindy Zhang, Tatiana Lipman, Mayumi Fujitani, Loen Hansford, Ian Clarke, Calvin B. Harley, Robert Tressler, David Malkin, Erin Walker, David R. Kaplan, Peter Dirks, Uri Tabori
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Cancer recurrence is one of the major setbacks in oncology. Maintaining telomeres is essential for sustaining the limitless replicative potential of such cancers. Because telomerase is thought to be active in all tumor cells and normal stem cells, telomerase inhibition may be nonspecific and have detrimental effects on tissue maintenance and development by affecting normal stem cell self-renewal. Methods: We examined telomerase activity, telomere maintenance, and stem cell maturation in tumor subpopulations from freshly resected gliomas, long-term, primary, neural tumor-initiating cells (TIC) and corresponding normal stem cell lines. We then tested the efficacy of the telomerase inhibitor Imetelstat on propagation and self-renewal capacity of TIC and normal stem cells in vitro and in vivo. Results: Telomerase was undetectable in the majority of tumor cells and specific to the TIC subpopulation that possessed critically short telomeres. In contrast, normal tissue stem cells had longer telomeres and undetectable telomerase activity and were insensitive to telomerase inhibition, which results in proliferation arrest, cell maturation, and DNA damage in neural TIC. Significant survival benefit and late tumor growth arrest of neuroblastoma TIC were observed in a xenograft model (P = 0.02). Furthermore, neural TIC exhibited irreversible loss of self-renewal and stem cell capabilities even after cessation of treatment in vitro and in vivo. Conclusions: TIC exhaustion with telomerase inhibition and lack of telomerase dependency in normal stem cells add new dimensions to the telomere hypothesis and suggest that targeting TIC with telomerase inhibitors may represent a specific and safe therapeutic approach for tumors of neural origin. Clin Cancer Res; 17(1); 111–21. ©2011 AACR.
Dose-Limiting Toxicity After Hypofractionated Dose-Escalated Radiotherapy in Non–Small-Cell Lung Cancer
Authors: Donald M. Cannon, Minesh P. Mehta, Jarrod B. Adkison, Deepak Khuntia, Anne M. Traynor, Wolfgang A. Tomé, Richard J. Chappell, Ranjini Tolakanahalli, Pranshu Mohindra, Søren M. Bentzen, George M. Cannon
Journal: Journal of Clinical Oncology (2013)

Purpose Local failure rates after radiation therapy (RT) for locally advanced non–small-cell lung cancer (NSCLC) remain high. Consequently, RT dose intensification strategies continue to be explored, including hypofractionation, which allows for RT acceleration that could potentially improve outcomes. The maximum-tolerated dose (MTD) with dose-escalated hypofractionation has not been adequately defined. Patients and Methods Seventy-nine patients with NSCLC were enrolled on a prospective single-institution phase I trial of dose-escalated hypofractionated RT without concurrent chemotherapy. Escalation of dose per fraction was performed according to patients' stratified risk for radiation pneumonitis with total RT doses ranging from 57 to 85.5 Gy in 25 daily fractions over 5 weeks using intensity-modulated radiotherapy. The MTD was defined as the maximum dose with ≤ 20% risk of severe toxicity. Results No grade 3 pneumonitis was observed and an MTD for acute toxicity was not identified during patient accrual. However, with a longer follow-up period, grade 4 to 5 toxicity occurred in six patients and was correlated with total dose (P = .004). An MTD was identified at 63.25 Gy in 25 fractions. Late grade 4 to 5 toxicities were attributable to damage to central and perihilar structures and correlated with dose to the proximal bronchial tree. Conclusion Although this dose-escalation model limited the rates of clinically significant pneumonitis, dose-limiting toxicity occurred and was dominated by late radiation toxicity involving central and perihilar structures. The identified dose-response for damage to the proximal bronchial tree warrants caution in future dose-intensification protocols, especially when using hypofractionation.
Inhibition of Hepatocellular Carcinomas <b> <i>in vitro</i> </b> and Hepatic Metastases <b> <i>in vivo</i> </b> in Mice by the Histone Deacetylase Inhibitor HA-But
Authors: Danila Coradini, Sonia Zorzet, Raffaella Rossin, Ignazio Scarlata, Cinzia Pellizzaro, Claudia Turrin, Michele Bello, Silvia Cantoni, Annalisa Speranza, Gianni Sava, Ulderico Mazzi, Alberto Perbellini
Journal: Clinical Cancer Research (2004)

The purpose is to evaluate the CD44-mediated cellular targeting of HA-But, a hyaluronic acid esterified with butyric acid (But) residues, to hepatocellular carcinoma cell lines in vitro and to hepatic tumor metastases in vivo.In vitro, the CD44-dependent cytotoxicity in two human hepatocellular carcinoma cell lines (HepB3 and HepG2) with high and low CD44 expression was investigated; in vivo, the effect on liver metastases originating from intrasplenic implants of Lewis lung carcinoma (LL3) or B16-F10 melanoma in mice was compared with the pharmacokinetics of organ and tissue distribution using different routes of administration.HepB3 and HepG2 cell lines showed different expression of CD44 (78 and 18%, respectively), which resulted in a CD44-dependent HA-But inhibitory effect as demonstrated also by the uptake analysis performed using radiolabeled HA-But ((99m)Tc-HA-But). Pharmacokinetic studies showed different rates of (99m)Tc-HA-But distribution according to the route of administration (i.v., i.p., or s.c.): very fast (a few minutes) after i.v. treatment, with substantial accumulation in the liver and spleen; relatively slow after i.p. or s.c. treatment, with marked persistence of the drug at the site of injection. The effect of s.c. and i.p. treatment with HA-But on liver metastases originating from intrasplenic implants of LL3 carcinoma or B16-F10 melanoma (both CD44-positive: 68 and 87%, respectively), resulted in 87 and 100% metastases-free animals, respectively (regardless of the route of administration), and a significant prolongation of the life expectancy compared with control groups.HA-But tends to concentrate in the liver and spleen and appears to be a promising new drug for the treatment of intrahepatic tumor lesions.
Bayesian Analysis of Posttest Predictive Value of Screening Instruments for the Psychosis High-Risk State
Authors: Christopher Gale, Paul Glue, Sarah Gallagher
Journal: JAMA Psychiatry (2013)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Psychiatry journal
A randomized controlled trial of laser treatment among hirsute women with polycystic ovary syndrome
Authors: W.J. Clayton, M. Lipton, J. Elford, M. Rustin, L. Sherr
Journal: British Journal of Dermatology (2005)

Background Facial hirsutism is one of the characteristic features of polycystic ovary syndrome (PCOS), and this can lead to high levels of depression and anxiety. Objectives To evaluate the impact of laser treatment on the severity of facial hirsutism and on psychological morbidity in women with PCOS. Methods A randomized controlled trial of five high‐fluence treatments (intervention) vs. five low‐fluence treatments (control) was performed over 6 months in a National Health Service teaching hospital. Subjects were 88 women with facial hirsutism due to PCOS recruited from hospital outpatient clinics and a patient support group in 2001–2002. The main outcomes were self‐reported severity of facial hair (measured on a scale of 1–10), depression, anxiety (measured on the Hospital Anxiety and Depression Scale) and quality of life (measured on the WHOQOL‐BREF). Results Self‐reported severity of facial hair in the intervention group (n = 51) fell from 7·3 to 3·6 over the 6‐month study period; for the control group (n = 37) the corresponding scores were 7·1 and 6·1. The change was significantly greater in the intervention group [ancova F(1,83) = 24·5, P < 0·05]. Self‐reported time spent on hair removal declined from 112 to 21 min per week in the intervention group and from 92 to 56 min in the control group [F(1,80) = 10·2, P ≤ 0·05]. Mean depression scores fell from 6·7 to 3·6 in the intervention group, compared with 6·1 to 5·4 in the control group [F(1,83) = 14·7, P < 0·05]. A similar change was seen for mean anxiety scores: intervention 11·1 to 8·2, control 9·6 to 9·3 [F(1,84) = 17·8, P < 0·05]. Psychological quality of life also improved more in the intervention group, from 49·6 to 61·2 vs. 50·1 to 51·5 in the control group [F(1,84) = 10·9, P < 0·05]. Conclusions Laser treatment appeared to reduce the severity of facial hair and time spent on hair removal as well as alleviating depression and anxiety in women with PCOS. These findings suggest that ways of making this method of hair removal more widely available to women with facial hirsutism should be considered.
Acute serum amyloid A the NOTCH signaling pathway and cytoskeletal dynamics in rheumatoid arthritis
Authors: P. Rooney, M. Connolly, W. Gao, D. J. Veale, U. Fearon
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background</h3> Acute serum amyloid A (A-SAA) is strongly expressed in rheumatoid arthritis (RA) synovial tissue (ST) and is critically involved in regulating cell migration and angiogenesis. Cell migration and endothelial cell (EC) morphology is dependent on complex signalling interactions which link cytoskeletal rearrangement to extracellular matrix. These processes are also dependent on NOTCH signalling pathways which regulate cell survival and cell shape. <h3>Methods</h3> NOTCH1-IC and downstream signaling components HRT1, HRT2 were quantified in synovial tissue/cells by immunohistology and realtime PCR. RAST explants and human microvascular endothelial cells (HDEC) were stimulated with A-SAA (10 and 50 μg/ml) or TNFα (10 ng/ml) for (3–24 h), NOTCH-1C, its ligand DLL-4 and downstream signaling components HRT1, HRT2 were quantified by real-time PCR. NOTCH-1IC, and growth factors (<i>vascular endothelial growth factor</i> (VEGF), angiopoietin-2) were assessed by western blot and ELISA. A-SAA modulation of filamentous actin (F-actin) and focal adhesions (vinculin) was examined by dual immunofluorescence. A-SAA induced angiogenesis and migration were assessed by Matrigel tube formation assays and scratch assays. To examine if A-SAA induced angiogenesis, altered cell shape and migration were mediated by NOTCH signaling, functional assays were performed with A-SAA in the presence of siRNA against NOTCH-1IC. <h3>Results</h3> NOTCH 1IC, HRT1, HRT2 were expressed in the lining layer and perivascular regions of RA synovial tissue. A-SAA (10 μg/ml) increased NOTCH1IC and VEGF mRNA and protein expression. A-SAA induced HRT-1 mRNA with no effect on HRT2 mRNA. A-SAA inhibited DLL-4 mRNA, which is consistent with a negative feedback loop that controls the interactions between NOTCH-1IC and DLL-4 in the regulation of EC tip versus stalk cells. No effect was observed for angiopoietin 2. A-SAA induced disassembly of EC F-actin cytoskeleton and loss of focal adhesions as demonstrated by a reduction in vinculin staining. Alterations in cytoskeletal dynamics in response to A-SAA was observed as early as 15 min with maximal effect at 24 h, where dramatic formation of filopodia protrusions were demonstrated. Finally, A-SAA induced angiogenesis and cell migration were inhibited when cells were transfected with NOTCH1IC siRNA. <h3>Conclusion</h3> A-SAA induces the NOTCH signalling pathway, VEGF and cytoskeletal rearrangement which allows temporal and spatial reorganisation of cells during cell migratory events and EC morphology. Together these results suggest a critical role for A-SAA in driving cell shape, migration and invasion in the inflamed joint.
What about gr/gr deletions and male infertility? Systematic review and meta-analysis
Authors: Katrien Stouffs, Willy Lissens, Herman Tournaye, Patrick Haentjens
Journal: Human Reproduction Update (2010)

BACKGROUNDThe impact of gr/gr deletions on male fertility is unclear. These partial deletions of the AZFc region of the Y chromosome have been detected more frequently in infertile patients. However, few individual studies have demonstrated a statistically significant association. This study aims to quantify the strength of association between gr/gr deletions and male infertility, and to explore potential sources of heterogeneity, including ethnicity and geographical location.
Increasing COPD awareness
Authors: J. Zielinski
Journal: European Respiratory Journal (2006)

Early diagnosis and smoking cessation are the only available methods to stop the progression of chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate the effects of early detection of airflow limitation (AL) in a population with high risk for COPD, using spirometric screening. Smokers aged 40 yrs with a smoking history of 10 pack-yrs were invited to visit a local outpatient chest clinic for simple spirometry (forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)). Smoking history was recorded, followed by smoking cessation advice relating the results of spirometry to the smoking behaviour. Subjects who did not fulfil the above criteria (younger and/or nonsmokers) were also screened. A total 110,355 subjects were investigated; they were aged 53.5+/-11.5 yrs and 58.2% were males. Of the total amount of subjects, 64% were current smokers, 25.1% were former smokers and 10.9% were lifelong nonsmokers. Spirometry tests were within normal values for 70.3%, and 20.3% showed signs of AL: this was mild in 7.6%, moderate in 6.7% and severe in 5.9%. The remaining 8.3% of subjects presented with a restrictive pattern of ventilatory impairment. Airflow limitation was found in 23% of smokers aged 40 yrs with a history of 10 pack-yrs. This study concluded that large-scale voluntary spirometry screening of the population with high risk for COPD detects a large number of subjects with AL.
Generation of Antitumor Responses by Genetic Modification of Primary Human T Cells with a Chimeric NKG2D Receptor
Authors: Tong Zhang, Amorette Barber, Charles L. Sentman
Journal: Cancer Research (2006)

Abstract To create more effective T cells against human tumors, we have designed a strategy to allow T cells to recognize tumor cells using natural killer (NK) cell receptors but retain the effector responses of T lymphocytes. NKG2D is an activating cell surface receptor expressed on NK cells and on some T-cell subsets. Its ligands are primarily expressed on tumor cells. We have shown that by linking mouse NKG2D to the CD3ζ chain, it was possible to generate a chimeric NKG2D (chNKG2D) receptor that allowed activation of murine T cells on engagement with NKG2D ligand-positive tumor cells leading to antitumor responses in mice. In this study, a human version of the chNKG2D receptor was expressed on primary human T cells, and antitumor responses were determined. Human peripheral blood mononuclear cell–derived T cells were retrovirally transduced with a human chNKG2D receptor gene. These chNKG2D-bearing human T cells responded to NKG2D ligand-positive tumor cells by producing T-helper 1 cytokines, proinflammatory chemokines, and significant cellular cytotoxicity. This response could be blocked by anti-NKG2D antibodies, and it was dependent on NKG2D ligand expression on the target cells but not on expression of MHC molecules. In addition, the activity of chNKG2D-bearing T cells remained unimpaired after exposure to a soluble NKG2D ligand, soluble MICA, at concentrations as high as 1.5 μg/mL. These data indicate the feasibility of using chNKG2D receptors in primary human T cells and suggest that this approach may be a promising means for cancer immunotherapy. (Cancer Res 2006; 66(11): 5927-33)
Inhaled insulin does not trigger lung inflammation and airway remodelling
Authors: M. Papagianni, A. Hatziefthimiou, G. Chachami, K. Gourgoulianis, P-A. Molyvdas, E. Paraskeva
Journal: European Respiratory Journal (2009)

end of the study, the treatment has efficacy even if 1 or 2 yrs have elapsed since the patient stops treatment.To date, there is no convincing evidence to support such an assumption.Unknown usual care treatment for withdrawals including ICS could further bias the results.Thus, for short-term secondary outcomes (e.g.exacerbations) the intention-to-treat analysis might not produce robust and meaningful results.Estimating and correcting for regression towards the mean could help in achieving clinically more reliable results.In addition, AARON et al. [6] argue elsewhere that premature termination of a drug, for whatever reason (including withdrawal of informed consent), might indicate both impaired tolerance and lack of efficacy.Thus, regarding the end-point withdrawal as just another measure of effectiveness.Effectiveness, however, is not the efficacy of a drug in a randomised controlled trial, but in the real life medical care situation, which may be quite different.
Significance and Management of Proteinuria in Kidney Transplant Recipients
Authors: Hatem Amer, Fernando G. Cosio
Journal: Journal of the American Society of Nephrology (2009)

Proteinuria is common after kidney transplantation and typically urine protein levels are below 500 mg/d. However, even these low levels are associated with reduced graft survival. Most allografts with proteinuria >1500 mg/d have new glomerular pathology. In contrast, lower levels of proteinuria are generally associated with nonglomerular, nonspecific histologic changes. The relationship between proteinuria and graft survival is independent of other variables, including graft function and graft histology. Thus, proteinuria allows stratification of risk in patients with or without glomerular pathology. Proteinuria should be monitored periodically posttransplant and investigation of the cause should be pursued vigorously.
Underuse of Hospice Care by Medicaid-Insured Patients With Stage IV Lung Cancer in New York and California
Authors: Jennifer W. Mack, Kun Chen, Francis P. Boscoe, Foster C. Gesten, Patrick J. Roohan, Jane C. Weeks, Maria J. Schymura, Deborah Schrag
Journal: Journal of Clinical Oncology (2013)

Medicare patients with advanced cancer have low rates of hospice use. We sought to evaluate hospice use among patients in Medicaid, which insures younger and indigent patients, relative to those in Medicare.Using linked patient-level data from California (CA) and New York (NY) state cancer registries, state Medicaid programs, NY Medicare, and CA Surveillance, Epidemiology, and End Results-Medicare data, we identified 4,797 CA Medicaid patients and 4,001 NY Medicaid patients ages 21 to 64 years, as well as 27,416 CA Medicare patients and 16,496 NY Medicare patients ages ≥ 65 years who were diagnosed with stage IV lung cancer between 2002 and 2006. We evaluated hospice use, timing of enrollment, and location of death (inpatient hospice; long-term care facility or skilled nursing facility; acute care facility; home with hospice; or home without hospice). We used multiple logistic regressions to evaluate clinical and sociodemographic factors associated with hospice use.Although 53% (CA) and 44% (NY) of Medicare patients ages ≥ 65 years used hospice, fewer than one third of Medicaid-insured patients ages 21 to 64 years enrolled in hospice after a diagnosis of stage IV lung cancer (CA, 32%; NY, 24%). A minority of Medicaid patient deaths (CA, 19%; NY, 14%) occurred at home with hospice. Most Medicaid patient deaths were either in acute-care facilities (CA, 28%; NY, 36%) or at home without hospice (CA, 39%; NY, 41%). Patient race/ethnicity was not associated with hospice use among Medicaid patients.Given low rates of hospice use among Medicaid enrollees and considerable evidence of suffering at the end of life, opportunities to improve palliative care delivery should be prioritized.
Prognostic value of blood gas analyses in patients with idiopathic pulmonary arterial hypertension
Authors: M. M. Hoeper, M. W. Pletz, H. Golpon, T. Welte
Journal: European Respiratory Journal (2007)

Blood gas abnormalities in patients with idiopathic pulmonary arterial hypertension (IPAH) may be related to disease severity and prognosis. The present authors performed a 12-yr retrospective analysis assessing arterialised capillary blood gases, haemodynamics, exercise variables and survival in 101 patients with IPAH. At baseline, arterial oxygen tension (P(a,O(2))) and carbon dioxide arterial tension (P(a,CO(2))) were 9.17+/-1.86 and 4.25+/-0.532 kPa, respectively. While P(a,O(2) )was not associated with survival, a low P(a,CO(2 ))was a strong and independent prognostic marker. When patients were divided according to a baseline P(a,CO(2 ))value above or below 4.25 kPa, a cut-off value determined by receiver operating characteristics analysis, survival rates were 98 and 86% at 1 yr, 82 and 69% at 2 years, 80 and 51% at 3 yrs, 77 and 41% at 5 yrs, and 65 and 12% at 8 yrs, respectively. P(a,CO(2 ))after 3 months of medical therapy was strongly associated with survival. Hypocapnia at rest and during exercise correlated with low cardiac output, low peak oxygen uptake and reduced ventilatory efficacy. Multiple regression analysis revealed that 6-min walking distance, right atrial pressure and P(a,CO(2 ))were independently associated with survival. In patients with idiopathic pulmonary arterial hypertension, hypocapnia (carbon dioxide arterial tension <4.25 kPa) is an independent marker of mortality.