tbuckley/cabot-search huggingface dataset:
Genomic imbalances in precancerous tissues signal oral cancer risk
Authors: Cathie Garnis, Raj Chari, Timon PH Buys, Lewei Zhang, Raymond T Ng, Miriam P Rosin, Wan L Lam
Journal: Molecular Cancer (2009)

Oral cancer develops through a series of histopathological stages: through mild (low grade), moderate, and severe (high grade) dysplasia to carcinoma in situ and then invasive disease. Early detection of those oral premalignant lesions (OPLs) that will develop into invasive tumors is necessary to improve the poor prognosis of oral cancer. Because no tools exist for delineating progression risk in low grade oral lesions, we cannot determine which of these cases require aggressive intervention. We undertook whole genome analysis by tiling-path array comparative genomic hybridization for a rare panel of early and late stage OPLs (n = 62), all of which had extensive longitudinal follow up (>10 years). Genome profiles for oral squamous cell carcinomas (n = 24) were generated for comparison. Parallel analysis of genome alterations and clinical parameters was performed to identify features associated with disease progression. Genome alterations in low grade dysplasias progressing to invasive disease more closely resembled those observed for later stage disease than they did those observed for non-progressing low grade dysplasias. This was despite the histopathological similarity between progressing and non-progressing cases. Strikingly, unbiased computational analysis of genomic alteration data correctly classified nearly all progressing low grade dysplasia cases. Our data demonstrate that high resolution genomic analysis can be used to evaluate progression risk in low grade OPLs, a marked improvement over present histopathological approaches which cannot delineate progression risk. Taken together, our data suggest that whole genome technologies could be used in management strategies for patients presenting with precancerous oral lesions.
Impact of Active Versus Usual Algorithmic Titration of Basal Insulin and Point-of-Care Versus Laboratory Measurement of HbA1c on Glycemic Control in Patients With Type 2 Diabetes
Authors: Laurence Kennedy, William H. Herman, Poul Strange, Anthony Harris
Journal: Diabetes Care (2006)

OBJECTIVE—The objective of this study was to assess the impact of active versus usual monitoring of algorithmic insulin titration and point-of-care (POC) versus laboratory HbA1c (A1C) measurement on glycemic control in primary care. RESEARCH DESIGN AND METHODS—The Glycemic Optimization with Algorithms and Labs at Point of Care (GOAL A1C) study was a 24-week, randomized, parallel-group, four-arm, open-label study of 7,893 adults with type 2 diabetes uncontrolled by oral antidiabetic agents and requiring insulin. Patients were randomly assigned by investigators from 2,164 sites in the U.S. to insulin glargine with either 1) usual (no unsolicited contact between visits) insulin titration using a simple algorithm with laboratory A1C testing, 2) usual titration with POC A1C testing, 3) active (weekly monitored) titration with laboratory A1C testing, or 4) active titration with POC A1C testing. Outcome measures included a change in A1C and fasting self-monitoring of blood glucose (SMBG) levels, percentage of patients achieving A1C &amp;lt;7.0%, and hypoglycemia frequency. RESULTS—Significant A1C and SMBG reductions were observed in all arms (P &amp;lt; 0.0001). Compared with usual insulin titration, active titration achieved greater A1C reduction (1.5 vs. 1.3%; P &amp;lt; 0.0001), SMBG reduction (88 vs. 79 mg/dl; P &amp;lt; 0.0001), and proportion of patients achieving A1C &amp;lt;7.0% (38 vs. 30%; P &amp;lt; 0.0001). Among patients receiving active titration, POC A1C testing was associated with an increase in the proportion achieving an A1C &amp;lt;7.0% (41% for POC vs. 36% for laboratory; P &amp;lt; 0.0001). Hypoglycemia rates were low (usual vs. active groups: 3.7 vs. 6.0 all confirmed episodes/patient-year [P &amp;lt; 0.001]; 0.09 vs. 0.14 severe episodes/patient-year [NS]). CONCLUSIONS—In a predominantly primary care setting, addition of insulin glargine using a simple algorithm achieved significant improvements in glycemic control in patients with type 2 diabetes in all four study arms. Active titration resulted in significant incremental improvements in glycemic control, and, among patients receiving active titration, POC A1C testing resulted in a greater portion achieving A1C &amp;lt;7.0%.
Synchronization and integration of multiple hypertrophic pathways in the heart
Authors: K SCHLUTER
Journal: Cardiovascular Research (2004)

Nine years ago, Cardiovascular Research (vol.30(4), 1995) published a Spotlight Issue on signal transduction summarizing important cellular signaling events in cardiovascular cells.At that time, a main focus of research was centered on intracellular cascades modifying cellular responses in multiple cardiovascular cells, including vascular smooth muscle cells, cardiac fibroblasts, and cardiomyocytes.The present Spotlight Issue is intended to give the readership of Cardiovascular Research an update on the aforementioned signaling cascades involved in myocardial hypertrophy and to point out what has become increasingly evident during the last decade: multiple hypertrophic pathways work together in a complex scenario by integration and synchronization of a multitude of signals generated by distinct mechanisms.This editorial briefly introduces the topics covered in this Spotlight Issue.
Contractile Reserve and Intracellular Calcium Regulation in Mouse Myocytes From Normal and Hypertrophied Failing Hearts
Authors: Kenta Ito, Xinhua Yan, Minori Tajima, Zhi Su, William H. Barry, Beverly H. Lorell
Journal: Circulation Research (2000)

Abstract —Mouse myocyte contractility and the changes induced by pressure overload are not fully understood. We studied contractile reserve in isolated left ventricular myocytes from mice with ascending aortic stenosis (AS) during compensatory hypertrophy (4-week AS) and the later stage of early failure (7-week AS) and from control mice. Myocyte contraction and [Ca 2+ ] i transients with fluo-3 were measured simultaneously. At baseline (0.5 Hz, 1.5 mmol/L [Ca 2+ ] o , 25°C), the amplitude of myocyte shortening and peak-systolic [Ca 2+ ] i in 7-week AS were not different from those of controls, whereas contraction, relaxation, and the decline of [Ca 2+ ] i transients were slower. In response to the challenge of high [Ca 2+ ] o , fractional cell shortening was severely depressed with reduced peak-systolic [Ca 2+ ] i in 7-week AS compared with controls. In response to rapid pacing stimulation, cell shortening and peak-systolic [Ca 2+ ] i increased in controls, but this response was depressed in 7-week AS. In contrast, the responses to both challenge with high [Ca 2+ ] o and rapid pacing in 4-week AS were similar to those of controls. Although protein levels of Na + -Ca 2+ exchanger were increased in both 4-week and 7-week AS, the ratio of SR Ca 2+ -ATPase to phospholamban protein levels was depressed in 7-week AS compared with controls but not in 4-week AS. This was associated with an impaired capacity to increase sarcoplasmic reticulum Ca 2+ load during high work states in 7-week AS myocytes. In hypertrophied failing mouse myocytes, depressed contractile reserve is related to an impaired augmentation of systolic [Ca 2+ ] i and SR Ca 2+ load and simulates findings in human failing myocytes.
Screening for Distress and Unmet Needs in Patients With Cancer: Review and Recommendations
Authors: Linda E. Carlson, Amy Waller, Alex J. Mitchell
Journal: Journal of Clinical Oncology (2012)

This review summarizes the need for and process of screening for distress and assessing unmet needs of patients with cancer as well as the possible benefits of implementing screening.Three areas of the relevant literature were reviewed and summarized using structured literature searches: psychometric properties of commonly used distress screening tools, psychometric properties of relevant unmet needs assessment tools, and implementation of distress screening programs that assessed patient-reported outcomes (PROs).Distress and unmet needs are common problems in cancer settings, and programs that routinely screen for and treat distress are feasible, particularly when staff are supported and links with specialist psychosocial services exist. Many distress screening and unmet need tools have been subject to preliminary validation, but few have been compared head to head in independent centers and in different stages of cancer. Research investigating the overall effectiveness of screening for distress in terms of improved recognition and treatment of distress and associated problems is not yet conclusive, but screening seems to improve communication between patients and clinicians and may enhance psychosocial referrals. Direct effects on quality of life are uncertain, but screening may help improve discussion of quality-of-life issues.Involving all stakeholders and frontline clinicians when planning screening for distress programs is recommended. Training frontline staff to deliver screening programs is crucial, and continuing to rigorously evaluate outcomes, including PROs, process of care, referrals, and economic costs and benefits is essential.
Treatment of lateral epicondylitis using skin-derived tenocyte-like cells
Authors: D Connell, A Datir, F Alyas, M Curtis
Journal: British Journal of Sports Medicine (2009)

Objectives: To culture collagen-producing cells derived from skin fibroblasts and o evaluate prospectively the safety and potential use of this cell preparation for treatment of refractory lateral epicondylitis in a pilot study. Design: Prospective clinical pilot study. Setting: Institution-based clinical research. Patients: A total of 12 patients (5 men and 7 women; mean age 39.1 years) with clinical diagnosis of refractory lateral epicondylitis. Interventions: Laboratory-prepared collagen-producing cells derived from dermal fibroblasts were injected into the sites of intrasubstance tears and fibrillar discontinuity of the common extensor origin under ultrasonography guidance. Main outcome measures: The outcome assessment was performed over 6 months. The Patient-Rated Tennis Elbow Evaluation (PRTEE) scale was used to assess pain severity and functional disability. Tendon healing response was measured using four criteria on ultrasonography: tendon thickness, hypoechogenicity, intrasubstance tears and neovascularity. Results: Cell cultures rich in collagen-producing cells was successfully prepared. After injection, the median PRTEE score decreased from 78 before the procedure to 47 at 6 weeks, 35 at 3 months and 12 at 6 months after the procedure (p&lt;0.05). The healing response on ultrasonography showed median decrease in: (1) number of tears, from 5 to 2; (2) number of new vessels, from 3 to 1; and (3) tendon thickness, from 4.35 to 4.2 (p&lt;0.05). Of the 12 patients, 11 had a satisfactory outcome, and only one patient proceeded to surgery after failure of treatment at the end of 3 months. Conclusions: Skin-derived tenocyte-like cells can be cultured in the laboratory to yield a rich preparation of collagen-producing cells. Our pilot study suggests that these collagen-producing cells can be injected safely into patients and may have therapeutic value in patients with refractory lateral epicondylitis.
CXCR3 Enhances a T-Cell–Dependent Epidermal Proliferative Response and Promotes Skin Tumorigenesis
Authors: Ashley E. Winkler, Joshua J. Brotman, Meredith E. Pittman, Nancy P. Judd, James S. Lewis, Robert D. Schreiber, Ravindra Uppaluri
Journal: Cancer Research (2011)

Abstract The chemokine receptor CXCR3 has been proposed to play a critical role in host antitumor responses. In this study, we defined CXCR3-expressing immune cell infiltration in human skin squamous cell carcinomas and then used CXCR3-deficient mice to assess the contribution of CXCR3 to skin tumorigenesis. Our studies employed two established protocols for chemical skin carcinogenesis [methylcholanthrene (MCA) or 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) models]. CXCR3 deletion did not affect tumor development in the MCA model; however, CXCR3 was important in the DMBA/TPA model where gene deletion reduced the incidence of skin tumors. This decreased incidence of skin tumors did not reflect differences in epidermal development but rather was associated with reduced epidermal thickness and proliferation in CXCR3−/− mice, implicating the CXCR3 pathway in DMBA/TPA-induced epidermal inflammation and proliferation. Notably, CXCR3 expressed in CD4+ and CD8+ T cells was found to be important for enhanced epidermal proliferation. Specifically, CXCR3-deficient mice reconstituted with T cells isolated from wild-type mice treated with DMBA/TPA restored wild-type levels of epidermal proliferation in the mutant mice. Taken together, our findings establish that CXCR3 promotes epidermal tumorigenesis likely through a T-cell–dependent induction of keratinocyte proliferation. Cancer Res; 71(17); 5707–16. ©2011 AACR.
Onfield assessment of concussion in the adult athlete
Authors: Margot Putukian, Martin Raftery, Kevin Guskiewicz, Stanley Herring, Mark Aubry, Robert C Cantu, Mick Molloy
Journal: British Journal of Sports Medicine (2013)

Background The onfield assessment of concussion in the adult athlete is challenging, given the elusiveness of injury, the sensitivity and specificity of the sideline assessment tools and the evolving nature of concussive injury. This paper reviews the evidence related to the onfield assessment and considers questions related to same day return to play, what to do when no physician is available onsite, as well as the benefit of remote notification of potential concussive events. Objective To review the evidence regarding the onfield assessment of concussion in the adult athlete. Additional key issues to consider include same day return to play for the adult athlete with concussion, what to do in a community setting when no doctor is present and whether there is any benefit with remote notification of potential concussive events that occur on the playing field. Data Sources Systematic literature review of concussion assessment and management. PubMed, MEDLINE, Psych Info and Cochrane Library databases were reviewed using the MeSH key words concussion and mild traumatic brain injury combined with athletic injuries. Each was refined by adding the key words ‘adult’, ‘sideline assessment’, ‘onfield assessment’ and ‘return to play’. Results For the MEDLINE search, using ‘concussion’ and ‘athletic injuries’ as key words, there were 880 results, and refining by ‘adult’ there were 292 results. When ‘traumatic brain injury’ and ‘athletic injuries’ were combined, there were 210 results. When refining by ‘adult’, there were 89 results. Many of these results overlapped. Following an initial review, these articles form the basis of the discussion. Conclusions The onfield evaluation of sport-related concussion is often a challenge, given the elusiveness and variability of presentation, difficulty in making a timely diagnosis, specificity and sensitivity of the sideline assessment tools and the reliance on symptoms. Despite these challenges, the sideline evaluation is based on recognition of injury, assessment of symptoms, cognitive and cranial nerve function and balance. Serial assessments are often necessary and, since signs and symptoms may be delayed, erring on the side of caution (keeping an athlete out of participation when there is any suspicion for injury) is important. A standardised assessment of concussion is useful in the assessment of the athlete with suspected concussion but should not take the place of the clinician's judgement.
Breathing–Swallowing Interaction in Neuromuscular Patients
Authors: Nicolas Terzi, David Orlikowski, Philippe Aegerter, Michèle Lejaille, Maria Ruquet, Gérard Zalcman, Christophe Fermanian, Jean-Claude Raphael, Frédéric Lofaso
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Malnutrition and aspiration are major problems in patients with neuromuscular disease. Because impaired swallowing contributes to malnutrition, means of improving swallowing are needed.To investigate interactions between breathing and swallowing in neuromuscular disorders and to evaluate the impact of mechanical ventilation (MV) on swallowing in tracheostomized patients.We studied 10 healthy individuals and 29 patients with neuromuscular disease and chronic respiratory failure (including 19 with tracheostomy). The tracheostomized patients who could breathe spontaneously were recorded during spontaneous breathing (SB) and with MV, in random order.Breathing-swallowing interactions were investigated by chin electromyography and inductive respiratory plethysmography, using three water-bolus sizes (5, 10, and 15 ml) in random order. In contrast to healthy individuals, neuromuscular patients showed piecemeal deglutition with several swallows over several breathing cycles for each bolus. The percentage of swallows followed by expiration was about 50% in the patients compared with nearly 100% in the control subjects. The number of swallows and total swallowing time per bolus correlated significantly to maximal inspiratory pressure. In the 10 tracheostomized patients who were recorded both in SB and MV, the number of swallows and total swallowing time per bolus were significantly reduced during MV compared with SB.Neuromuscular patients showed abnormal breathing-swallowing interactions, which correlated to maximal inspiratory pressure. Moreover, MV improved the swallowing parameters in tracheostomized patients who were able to breathe spontaneously.
Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial
Authors: J Wolter
Journal: Thorax (2002)

Background: Relentless chronic pulmonary inflammation is the major contributor to morbidity and mortality in patients with cystic fibrosis (CF). While immunomodulating therapies such as prednisolone and ibuprofen may be beneficial, their use is limited by side effects. Macrolides have immunomodulatory properties and long term use dramatically improves prognosis in diffuse panbronchiolitis, a condition with features in common with the lung disease of CF. Methods: To determine if azithromycin (AZM) improves clinical parameters and reduces inflammation in patients with CF, a 3 month prospective randomised double blind, placebo controlled study of AZM (250 mg/day) was undertaken in adults with CF. Monthly assessment included lung function, weight, and quality of life (QOL). Blood and sputum collection assessed systemic inflammation and changes in bacterial flora. Respiratory exacerbations were treated according to the policy of the CF Unit. Results: Sixty patients were recruited (29 men) of mean (SD) age 27.9 (6.5) years and initial forced expiratory volume in 1 second (FEV<sub>1</sub>) 56.6 (22.3)% predicted. FEV<sub>1</sub>% and forced vital capacity (FVC)% predicted were maintained in the AZM group while in the placebo group there was a mean (SE) decline of –3.62 (1.78)% (p=0.047) and –5.73 (1.66)% (p=0.001), respectively. Fewer courses of intravenous antibiotics were used in patients on AZM (0.37 <i>v</i> 1.13, p=0.016). Median C reactive protein (CRP) levels declined in the AZM group from 10 to 5.4 mg/ml but remained constant in the placebo group (p&lt;0.001). QOL improved over time in patients on AZM and remained unchanged in those on placebo (p=0.035). Conclusion: AZM in adults with CF significantly improved QOL, reduced CRP levels and the number of respiratory exacerbations, and reduced the rate of decline in lung function. Long term AZM may have a significant impact on morbidity and mortality in patients with CF. Further studies are required to define frequency of dosing and duration of benefit.
Deferiprone versus deferoxamine in thalassemia intermedia: Results from a 5-year long-term Italian multicenter randomized clinical trial
Authors: Giuseppina Calvaruso, Angela Vitrano, Rosario Di Maggio, Eliana Lai, Grazia Colletta, Alessandra Quota, Calogera Gerardi, Luciana Concetta Rigoli, Massimiliano Sacco, Lorella Pitrolo, Aurelio Maggio
Journal: American Journal of Hematology (2015)

In patients with thalassemia intermedia (TI), such as beta-TI, alpha-thalassemia (mainly HbH disease and mild/moderate forms of HbE/beta-thalassemia), iron overload is an important challenge in terms of diagnosis, monitoring, and treatment. Moreover, to date, the only possible chelators available are deferoxamine, deferasirox, and deferiprone. Here, we report the first 5-year long-term randomized clinical trial comparing the effectiveness of deferiprone versus deferoxamine in patients with TI. Body iron burden, which was determined by measuring serum ferritin levels in the same patient over 5 years and analyzed according to the generalized linear mixed model (GLMM), showed a linear decrease over time in the mean serum ferritin levels in both treatment groups (P-value = 0.035). The overall period of observation was 235.2 person-years for the deferiprone patients compared with 214.3 person-years for the deferoxamine patients. The results of the log-rank test suggested that the deferiprone treatment did not affect survival compared with the deferoxamine treatment (P-value = 0.360). The major adverse events observed included gastrointestinal symptoms and joint pain or arthralgia. Neutropenia and agranulocytosis were also detected, suggesting needing of strict hematological control. In conclusion, long-term iron chelation therapy with deferiprone is associated with an efficacy and safety similar to that of deferoxamine, suggesting that this drug is an alternative option in cases in which deferoxamine and deferasirox are contraindicated.
Progesterone Receptor Status Significantly Improves Outcome Prediction Over Estrogen Receptor Status Alone for Adjuvant Endocrine Therapy in Two Large Breast Cancer Databases
Authors: Valerie-Jeanne Bardou, Grazia Arpino, Richard M. Elledge, C. Kent Osborne, Gary M. Clark
Journal: Journal of Clinical Oncology (2003)

Purpose: To determine whether progesterone receptor (PgR) status provides additional value to estrogen receptor (ER) status and improves prediction of benefit from endocrine treatment among patients with primary breast cancer. Patients and Methods: Clinical outcomes of patients in two large databases were analyzed as a function of steroid receptor status. The first database (PP), contained 3,739 patients who did not receive any systemic adjuvant therapy and 1,688 patients who received adjuvant endocrine therapy but no chemotherapy. The second database (SPORE), contained 10,444 patients who received adjuvant endocrine therapy but no chemotherapy. Biochemical ER and PgR assays were identically performed in two different central laboratories. Results: In univariate and multivariate analyses, the prognostic significance of PgR status among systemically untreated patients is modest. Among endocrine-treated patients, however, multivariate analyses, including lymph-node involvement, tumor size, and age, demonstrate that PgR status is independently associated with disease-free and overall survival. For recurrence, the reduction in relative risk (RR) was 25% for ER-positive/PgR-negative patients and 53% for ER-positive/PgR-positive patients, compared with ER-negative/PgR-negative patients (P &lt; .0001, PP patients). Patients with ER-positive/PgR-negative tumors have a reduction in RR of death of 30% (SPORE patients) and 38% (PP patients), compared with patients with ER-negative/PgR-negative tumors (P &lt; .0001). For ER-positive/PgR-positive tumors, the reduction of the risk of death was greater than 46% in SPORE patients and 58% in PP patients, indicating that ER-positive/PgR-positive patients derive more benefit from endocrine therapy (P &lt; .0001). Conclusion: When accurately measured, PgR status is an independent predictive factor for benefit from adjuvant endocrine therapy. Therefore, PgR status should be taken into account when discussing RR reductions expected from endocrine treatment with individual patients.