tbuckley/cabot-search huggingface dataset:
IGFBP2 and IGFBP3 Protein Expressions in Human Breast Cancer: Association with Hormonal Factors and Obesity
Authors: Nicole M. Probst-Hensch, Julia H.B. Steiner, Peter Schraml, Zsuzsanna Varga, Ursina Zürrer-Härdi, Martina Storz, Dimitri Korol, Mathias K. Fehr, Daniel Fink, Bernhard C. Pestalozzi, Urs M. Lütolf, Jean-Philippe Theurillat, Holger Moch
Journal: Clinical Cancer Research (2010)

The insulin-like growth factor (IGF) signaling system is involved in breast cancer initiation and progression. The prognostic relevance of tumor expression patterns of IGFI-related proteins remains poorly understood. This study associates the expression of selected IGF proteins with breast tumor and patient characteristics.IGFI, IGFI receptor, IGF-binding protein (IGFBP)2, and IGFBP3 expression was measured in 855 primary breast carcinomas by immunohistochemistry using tissue microarrays. We investigated the association of tumor and nodal stage, grade, hormone receptor status, HER2 gene amplification, menopausal status, body mass index, and survival with IGF protein expression.In contrast to IGFI, the expression of IGFI receptor, IGFBP2, and IGFBP3 was associated with estrogen receptor status. In addition, IGFBP3 was positively correlated with body mass index and premenopausal status. Importantly, IGFBP2 was an independent and positive predictor of overall survival (hazard ratio, 0.48; 95% confidence interval, 0.24-0.95; P = 0.04). There was a weak suggestion for IGFBP2 and overweight to modify each other's effect on survival.According to these results, which need confirmation in larger patient series, the prognostic relevance of IGFBP2 and IGFBP3 protein expressions in breast cancer may depend on the hormonal context and body weight.
Severe Congenital Pulmonic Stenosis without Marked Right Ventricular Hypertension
Authors: JOHN M. VEROSKY, E. S. CROSSETT
Journal: Circulation (1960)

Obligatory relations exist between orifice size, flow, and pressure gradient across a stenotic pulmonary valve. If the cardiac output is reduced, the patient may have severe stenosis and present only moderate right ventricular hypertension. This situation may be an acute one, which will produce progressive symptomatology, or a chronic one, which, in the growing child, will produce poor physical growth. Catheterization should be done if any of the following is present: severe symptoms, severe right ventricular hypertrophy electrocardiographically, or evidence of reduced cardiac output (such as otherwise unexplainable poor physical growth). Operation is urgently indicated if catheterization reveals either right ventricular systolic hypertension greater than 90 to 100 mm. of mercury or if there is evidence of a very small pulmonary orifice.
Sensitivity of Remediastinoscopy: Influence of Adhesions, Multilevel N2 Involvement, or Surgical Technique?
Authors: Paul Van Schil, Georgios Stamatis
Journal: Journal of Clinical Oncology (2006)

cancer end points such as survival and breast cancer relapse, not fertility end points such as pregnancies and live births, which would require much longer follow-up.In fact, several of the trials allow oophorectomy or irradiation to be used for ovarian suppression, emphasizing that these trials should not be perceived as fertility preservation studies.Only two trials (Southwest Oncology Group trial S0230 and Ovarian Protection Trial in Oestrogen Non-Responsive Premenopausal Breast Cancer Patients Receiving Adjuvant or Neo-Adjuvant Chemotherapy [OPTION]) were designed specifically to test whether ovarian suppression during chemotherapy prevents premature ovarian failure.Nevertheless, we thank Wildiers et al for reiterating that the risks and benefits of ovarian suppression for both fertility preservation and breast cancer outcomes are unclear in premenopausal women and deserve further study.Second, the Panel recommends that patients enroll onto clinical trials specifically designed to evaluate the effectiveness of various fertility preservation methods, rather than receive treatment off-study, so that better data will be available in the future.This is particularly true for hormone-sensitive tumors where fertility preservation interventions may impact cancer outcomes, but also applies to all cancer patients interested in fertility preservation.
Relation Between Acanthosis Nigricans and Insulin Sensitivity in Overweight Hispanic Children at Risk for Type 2 Diabetes
Authors: Hassan A. Kobaissi, Marc J. Weigensberg, Geoff D.C. Ball, Martha L. Cruz, Gabriel Q. Shaibi, Michael I. Goran
Journal: Diabetes Care (2004)

OBJECTIVE—To investigate in a population of Hispanic children if 1) the presence of acanthosis nigricans (AN) is related to insulin sensitivity (Si) independent of adiposity and 2) scale scoring AN severity adds to the clinical estimation of insulin sensitivity, above and beyond the presence or absence AN alone. RESEARCH DESIGN AND METHODS—The study population, 131 Hispanic overweight children (mean BMI percentile 97.0 ± 3.1, 72 boys, 59 girls, ages 8–13 years, mean Tanner stage 2.4 ± 1.5) with a family history of type 2 diabetes, underwent a physical examination of the neck to determine AN absence or presence (0–1), AN extent score (0–4 scale), AN texture score (0–3 scale), and an AN combined score (extent + texture; 0–7 scale). Si was measured by the frequently sampled intravenous glucose tolerance test and minimal modeling. Multivariate linear regression analysis was used to determine the role of BMI and AN in predicting Si. RESULTS—BMI was the main predictor of Si, explaining ∼41% of the variance. The presence of AN explained an additional 4% of the variability in Si; scale scoring of AN extent or texture did not significantly improve the prediction. CONCLUSIONS—Although AN is an independent risk factor for insulin resistance in overweight Hispanic children at risk for type 2 diabetes, body adiposity is the primary determinant of insulin sensitivity. In addition, scale scoring AN seems of minimal usefulness in clinically estimating the severity of insulin resistance over and above assessing the presence or absence of AN and calculating BMI.
When You Look Matters: The Effect of Assessment Schedule on Progression-Free Survival
Authors: K. S. Panageas, L. Ben-Porat, M. N. Dickler, P. B. Chapman, D. Schrag
Journal: JNCI Journal of the National Cancer Institute (2007)

Progression-free survival (PFS) is increasingly used as an endpoint for cancer clinical trials. Disease progression is typically assessed on the basis of radiologic testing at scheduled time points or after a fixed number of treatment cycles. The date of the radiologic evaluation at which progression is first evident is used as a proxy for the true progression time. The true progression time actually lies somewhere within the time interval between two assessments, a situation that results in interval-censored data. An analysis that ignores this interval censoring and uses the detection date as the date of progression unavoidably results in an overestimation of median PFS. This overestimation can erroneously result in a result being described as clinically significant when in fact a longer median PFS may just be a consequence of the length of the surveillance interval. Furthermore, if surveillance intervals are heterogenous within a disease group, comparisons of median PFS across studies may not be meaningful. The decision to use PFS as a primary endpoint should be made carefully when designing clinical trials, and investigators focused on a particular disease should develop consensus standards and strive for consistent surveillance intervals.
Cardiac-Specific Overexpression of Fibroblast Growth Factor-2 Protects Against Myocardial Dysfunction and Infarction in a Murine Model of Low-Flow Ischemia
Authors: Stacey L. House, Craig Bolte, Ming Zhou, Thomas Doetschman, Raisa Klevitsky, Gilbert Newman, Jo El J. Schultz
Journal: Circulation (2003)

Preconditioning the heart before an ischemic insult has been shown to protect against contractile dysfunction, arrhythmias, and infarction. Pharmacological studies have suggested that fibroblast growth factor-2 (FGF2) is involved in cardioprotection. However, because of the number of FGFs expressed in the heart and the promiscuity of FGF ligand-receptor interactions, the specific role of FGF2 during ischemia-reperfusion injury remains unclear.FGF2-deficient (Fgf2 knockout) mice and mice with a cardiac-specific overexpression of all 4 isoforms of human FGF2 (FGF2 transgenic [Tg]) were compared with wild-type mice to test whether endogenous FGF2 elicits cardioprotection. An ex vivo work-performing heart model of ischemia was developed in which murine hearts were subjected to 60 minutes of low-flow ischemia and 120 minutes of reperfusion. Preischemic contractile function was similar among the 3 groups. After ischemia-reperfusion, contractile function of Fgf2 knockout hearts recovered to 27% of its baseline value compared with a 63% recovery in wild-type hearts (P<0.05). In FGF2 Tg hearts, an 88% recovery of postischemic function occurred (P<0.05). Myocardial infarct size was also reduced in FGF2 Tg hearts compared with wild-type hearts (13% versus 30%, P<0.05). There was a 2-fold increase in FGF2 release from Tg hearts compared with wild-type hearts (P<0.05). No significant alterations in coronary flow or capillary density were detected in any of the groups, implying that the protective effect of FGF2 is not mediated by coronary perfusion changes.These results provide evidence that endogenous FGF2 plays a significant role in the cardioprotective effect against ischemia-reperfusion injury.
Renal Interstitial Fluid Angiotensin I and Angiotensin II Concentrations during Local Angiotensin-Converting Enzyme Inhibition
Authors: Akira Nishiyama, Dale M. Seth, L. Gabriel Navar
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. It was recently demonstrated that angiotensin II (AngII) concentrations in the renal interstitial fluid (RIF) of anesthetized rats were in the nanomolar range and were not reduced by intra-arterial infusion of an angiotensin-converting enzyme (ACE) inhibitor (enalaprilat). This study was performed to determine changes in RIF AngI and AngII concentrations during interstitial administration of ACE inhibitors (enalaprilat and perindoprilat). Studies were also performed to determine the effects of enalaprilat on the de novo formation of RIF AngII elicited by interstitial infusion of AngI. Microdialysis probes (cut-off point, 30,000 D) were implanted in the renal cortex of anesthetized rats and were perfused at 2 μl/min. The effluent dialysate concentrations of AngI and AngII were measured by RIA, and reported values were corrected for the equilibrium rates at this perfusion rate. Basal RIF AngI (0.74 ± 0.05 nM) and AngII (3.30 ± 0.17 nM) concentrations were much higher than plasma AngI and AngII concentrations (0.15 ± 0.01 and 0.14 ± 0.01 nM, respectively; n = 27). Interstitial infusion of enalaprilat through the microdialysis probe (1 or 10 mM in the perfusate; n = 5 and 8, respectively) significantly increased RIF AngI concentrations but did not significantly alter AngII concentrations. However, perindoprilat (10 mM in the perfusate, n = 7) significantly decreased RIF AngII concentrations by 22 ± 4% and increased RIF AngI concentrations. Interstitial infusion of AngI (100 nM in the perfusate, n = 7) significantly increased the RIF AngII concentration to 8.26 ± 0.75 nM, whereas plasma AngI and AngII levels were not affected (0.15 ± 0.02 and 0.14 ± 0.02 nM, respectively). Addition of enalaprilat to the perfusate (10 mM) prevented the conversion of exogenously added AngI. These results indicate that addition of AngI in the interstitial compartment leads to low but significant conversion to AngII via ACE activity (blocked by enalaprilat). However, the addition of ACE inhibitors directly into the renal interstitium, via the microdialysis probe, either did not reduce RIF AngII levels or reduced levels by a small fraction of the total basal level, suggesting that much of the RIF AngII is formed at sites not readily accessible to ACE inhibition or is formed via non-ACE-dependent pathways.
Loss of the calcium-sensing receptor (CaSR) decreases slowly-adapting receptor responsiveness to mechanical stretch independent of oxygenation status
Authors: Nicolle Domnik, Sandra Vincent, John MacLeod, Ernest Cutz, John Fisher
Journal: European Respiratory Journal (2014)

The CaSR plays an integral role in the regulation of parathyroid hormone (Pth) and is widely expressed in the epithelium of the developing lung ( J Physiol  586:2008). Recently, Lambrecht et al. reported CaSR is expressed on the cells of neuroepithelial bodies (NEB) in the post-natal lung (J  Cell Sci  126:2013). NEB are proposed to act as both hypoxia sensors and mechanosensors; however, while  in vitro  and morphological evidence supports both roles, neither hypothesis has been functionally addressed  in vivo . We employed a double-knockout (CaSR  -/-  , Pth  -/-  ; KO) mouse model to examine the impact of loss of CaSR on pulmonary mechano- and chemo- sensation, as assessed via action potential discharge in single, vagal, slowly-adapting receptors (SAR) during quasi-static inflation in hyperoxic (40% O 2 -, 60% N 2 ) and hypoxic (10% O 2 , 90%N 2 ) conditions. Hypoxia did not alter the discharge frequency ( f ) vs tracheal pressure (Ptr) relationship in wildtype (WT; n = 7) or CaSR- KO (n= 7) mice (P g 0.05). In normoxia, KO mice exhibited decreased  f  compared with WT mice (P = 0.001, 2-way ANOVA; mean + SEM: Ptr=5cmH 2 O: WT, 86+9.3 vs KO, 74+7.1; 10cmH 2 O: 148+10.7 vs 111+8.2; 15cmH 2 O: 191+18.8 vs 124+9.1; 20cmH 2 O:150+40.7 vs 116+8.6). During hypoxia, KO mice showed a similarly reduced  f  vs Ptr relationship vs the WT (Pl0.001). We conclude that hypoxia does not alter murine SAR mechanosensitivity whereas, loss of CaSR function reduces SAR mechanosensitivity. We identify a novel mechanism involved in SAR mechanosensitivity to lung inflation relevant to the physiology of pulmonary sensation and respiratory phenotypes of individuals exhibiting CaSR mutations.
Spatial Inference of Admixture Proportions and Secondary Contact Zones
Authors: E. Durand, F. Jay, O. E. Gaggiotti, O. Francois
Journal: Molecular Biology and Evolution (2009)

Genetic admixture of distinct gene pools is the consequence of complex spatiotemporal processes that could have involved massive migration and local mating during the history of a species. However, current methods for estimating individual admixture proportions lack the incorporation of such a piece of information. Here, we extend Bayesian clustering algorithms by including global trend surfaces and spatial autocorrelation in the prior distribution on individual admixture coefficients. We test our algorithm by using spatially explicit and realistic coalescent simulations of colonization followed by secondary contact. By coupling our multiscale spatial analyses with a Bayesian evaluation of model complexity and fit, we show that the algorithm provides a correct description of smooth clinal variation, while still detecting zones of sharp variation when they are present in the data. We also apply our approach to understand the population structure of the killifish, Fundulus heteroclitus, for which the algorithm uncovers a presumed contact zone in the Atlantic coast of North America.
The Prognostic Value of FoxP3+ Tumor-Infiltrating Lymphocytes in Cancer: A Critical Review of the Literature
Authors: Ronald J. deLeeuw, Sara E. Kost, Juzer A. Kakal, Brad H. Nelson
Journal: Clinical Cancer Research (2012)

Abstract CD8+ tumor-infiltrating lymphocytes (TIL) are associated with survival in a variety of cancers. A second subpopulation of TIL, defined by forkhead box protein P3 (FoxP3) expression, has been reported to inhibit tumor immunity, resulting in decreased patient survival. On the basis of this premise, several groups are attempting to deplete FoxP3+ T cells to enhance tumor immunity. However, recent studies have challenged this paradigm by showing that FoxP3+ T cells exhibit heterogeneous phenotypes and, in some cohorts, are associated with favorable prognosis. These discrepant results could arise from differences in study methodologies or the biologic properties of specific cancer types. Here, we conduct the first systematic review of the prognostic significance of FoxP3+ T cells across nonlymphoid cancers (58 studies from 16 cancers). We assessed antibody specificity, cell-scoring strategy, multivariate modeling, use of single compared with multiple markers, and tumor site. Two factors proved important. First, when FoxP3 was combined with one additional marker, double-positive T cells were generally associated with poor prognosis. Second, tumor site had a major influence. FoxP3+ T cells were associated with poor prognosis in hepatocellular cancer and generally good prognosis in colorectal cancer, whereas other cancer types were inconsistent or understudied. We conclude that FoxP3+ T cells have heterogeneous properties that can be discerned by the use of additional markers. Furthermore, the net biologic effects of FoxP3+ T cells seem to depend on the tumor site, perhaps reflecting microenvironmental differences. Thus, depletion of FoxP3+ T cells might enhance tumor immunity in some patient groups but be detrimental in others. Clin Cancer Res; 18(11); 3022–9. ©2012 AACR.
A Phase I Study of Veliparib in Combination with Metronomic Cyclophosphamide in Adults with Refractory Solid Tumors and Lymphomas
Authors: Shivaani Kummar, Jiuping Ji, Robert Morgan, Heinz-Josef Lenz, Shannon L. Puhalla, Chandra P. Belani, David R. Gandara, Deborah Allen, Brian Kiesel, Jan H. Beumer, Edward M. Newman, Larry Rubinstein, Alice Chen, Yiping Zhang, Lihua Wang, Robert J. Kinders, Ralph E. Parchment, Joseph E. Tomaszewski, James H. Doroshow
Journal: Clinical Cancer Research (2012)

Oral administration of the alkylating agent cyclophosphamide at low doses, metronomic dosing, is well tolerated, with efficacy in multiple tumor types. PARP inhibition potentiates effects of cyclophosphamide in preclinical models. We conducted a phase I trial of the PARP inhibitor veliparib and metronomic cyclophosphamide in patients with refractory solid tumors and lymphoid malignancies.
Mechanisms of Immune Sensitization of Human Bronchus
Authors: KLAUS F. RABE
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Section:ChooseTop of pageAbstract <<EARLY STUDIES IN THE CANI...FORCE AND VELOCITY CHANGE...MYOGENIC RESPONSES IN HUM...INDUCED HYPERRESPONSIVENE...POTENTIAL ROLE OF ANTI-Ig...PERSPECTIVESReferencesCITING ARTICLES
Molecular Pathways: Turning Proteasomal Protein Degradation into a Unique Treatment Approach
Authors: Sebastian Stintzing, Heinz-Josef Lenz
Journal: Clinical Cancer Research (2014)

Abstract Cancer treatment regimens have evolved from single cytotoxic substances affecting all proliferative tissues toward antibodies and kinase inhibitors targeting tumor-specific pathways. Treatment efficacy and cancer survival have improved overall, and side effects have become less frequent. The ubiquitin-proteasome system–mediated proteasomal protein degradation is the most critical pathway to regulate the quantity of signal proteins involved in carcinogenesis and tumor progression. These processes are, as well as protein recycling, highly regulated and offer targets for biomarker and drug development. Unspecific proteasome inhibitors such as bortezomib and carfilzomib have shown clinical efficacy and are approved for clinical use. Inhibitors of more substrate-specific enzymes of degradation processes are being developed and are now in early clinical trials. The novel compounds focus on the degradation of key regulatory proteins such as p53, p27Kip1, and ß-catenin, and inhibitors specific for growth factor receptor kinase turnover are in preclinical testing. Clin Cancer Res; 20(12); 3064–70. ©2014 AACR.
Effects of flutter and PEP mask physiotherapy on symptoms and lung function in children with cystic fibrosis
Authors: CM van Winden, A Visser, W Hop, PJ Sterk, S Beckers, JC de Jongste
Journal: European Respiratory Journal (1998)

Recently, the flutter was introduced as a new device to improve sputum expectoration. Preliminary data suggested a significant improvement in expectoration and lung function during flutter treatment in patients with cystic fibrosis (CF). The aim of the present study was to compare the effects of the flutter and the positive expiratory pressure (PEP) mask on symptoms and lung function in children with CF. In a crossover randomized study 22 patients with CF (mean age 12 yrs, range 7-17 yrs) performed physiotherapy using either the flutter or the PEP mask twice a day during two treatment periods of 2 weeks, separated by a one week wash-out period, in a random sequence. Lung function parameters (peak expiratory flow, forced vital capacity (FVC), forced expiratory volume in one second, maximal midexpiratory flow, maximal expiratory flow at 25% of FVC, thoracic gas volume, total lung capacity, residual volume/total lung capacity, airway resistance and specific airway conductance) and changes in transcutaneous oxygen haemoglobin saturation were assessed before and after the first supervised session and at the end of each treatment period. Throughout the study peak flow was measured and symptoms were scored daily. No significant changes in any lung function parameter occurred after a single session or after 2 weeks of physiotherapy with either method. There was no difference in acceptability and subjective efficacy. In conclusion, any superiority of the flutter over the positive expiratory pressure mask technique for expectoration could not be confirmed during 2 weeks of daily treatment in children with cystic fibrosis. Both methods are well accepted by children and do not change lung function. Long-term comparison of both methods, including expectoration measurements, seems to be required for further evaluation of the potential success of physiotherapy in cystic fibrosis.