tbuckley/cabot-search huggingface dataset:
Functional Profiling of Receptor Tyrosine Kinases and Downstream Signaling in Human Chondrosarcomas Identifies Pathways for Rational Targeted Therapy
Authors: Yi-Xiang Zhang, Jolieke G. van Oosterwijk, Ewa Sicinska, Samuel Moss, Stephen P. Remillard, Tom van Wezel, Claudia Bühnemann, Andrew B. Hassan, George D. Demetri, Judith V.M.G. Bovée, Andrew J. Wagner
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Chondrosarcomas are notoriously resistant to cytotoxic chemotherapeutic agents. We sought to identify critical signaling pathways that contribute to their survival and proliferation, and which may provide potential targets for rational therapeutic interventions. Experimental Design: Activation of receptor tyrosine kinases (RTK) was surveyed using phospho-RTK arrays. S6 phosphorylation and NRAS mutational status were examined in chondrosarcoma primary tumor tissues. siRNA or small-molecule inhibitors against RTKs or downstream signaling proteins were applied to chondrosarcoma cells and changes in biochemical signaling, cell cycle, and cell viability were determined. In vivo antitumor activity of BEZ235, a phosphoinositide 3-kinase (PI3K)/mTOR inhibitor, was evaluated in a chondrosarcoma xenograft model. Results: Several RTKs were identified as critical mediators of cell growth, but the RTK dependencies varied among cell lines. In exploration of downstream signaling pathways, strong S6 phosphorylation was found in 69% of conventional chondrosarcomas and 44% of dedifferentiated chondrosarcomas. Treatment with BEZ235 resulted in dramatic reduction in the growth of all chondrosarcoma cell lines. Tumor growth was similarly inhibited in a xenograft model of chondrosarcoma. In addition, chondrosarcoma cells with an NRAS mutation were sensitive to treatment with a mitogen-activated protein kinase/extracellular signal–regulated kinase kinase (MEK) inhibitor. Functional NRAS mutations were found in 12% of conventional central chondrosarcomas. Conclusions: RTKs are commonly activated in chondrosarcoma, but because of their considerable heterogeneity, targeted inhibition of the PI3K/mTOR pathway represents a rational therapeutic strategy. Chondrosarcomas with NRAS mutations may benefit from treatment with MEK inhibitors. Clin Cancer Res; 19(14); 3796–807. ©2013 AACR.
Association Between Higher Serum Fetuin-A Concentrations and Abnormal Albuminuria in Middle-Aged and Elderly Chinese With Normal Glucose Tolerance
Authors: Mian Li, Min Xu, Yufang Bi, Aiyun Song, Yu Liu, Xiaoying Li, Guang Ning
Journal: Diabetes Care (2010)

OBJECTIVE To study the association of serum fetuin-A as a potential risk factor with abnormal albuminuria in Chinese individuals with normal glucose tolerance (NGT). RESEARCH DESIGN AND METHODS The cross-sectional analysis included 607 men and 1,042 women aged 40 or older with NGT. RESULTS Women with combined microalbuminuria and macroalbuminuria (n = 68) had significantly higher serum fetuin-A concentrations than those with normal albumin excretion (n = 974) (314.3 vs. 280.4 mg/l, P = 0.007). Compared with the lowest quartile, the highest quartile of serum fetuin-A had 40% increased risk of abnormal albuminuria after the multiple adjustments in women (Pfor trend = 0.02). However, the associations were not detected in men. CONCLUSIONS Higher serum fetuin-A was associated with abnormal albuminuria independent of BMI, waist circumference, homeostasis model assessment of insulin resistance, blood pressure, and other determinants of albuminuria in middle-aged and elderly Chinese women with NGT.
tPA Protects Renal Interstitial Fibroblasts and Myofibroblasts from Apoptosis
Authors: Kebin Hu, Ling Lin, Xiaoyue Tan, Junwei Yang, Guojun Bu, Wendy M. Mars, Youhua Liu
Journal: Journal of the American Society of Nephrology (2008)

Activation and expansion of interstitial fibroblasts and myofibroblasts play an essential role in the evolution of renal fibrosis. After obstructive injury, mice lacking tissue-type plasminogen activator (tPA) have fewer myofibroblasts and less interstitial fibrosis than wild-type controls. This suggests that tPA controls the size of the fibroblast/myofibroblast population in vivo, and this study sought to determine the underlying mechanism. In vitro, tPA inhibited staurosporine or H(2)O(2)-induced caspase-3 activation, prevented cellular DNA fragmentation, and suppressed the release of cytochrome C from mitochondria into the cytosol in a rat interstitial fibroblast cell line (NRK-49F). tPA also protected TGF-beta1-activated myofibroblasts from apoptosis. This antiapoptotic effect of tPA was independent of its protease activity but required its membrane receptor, the LDL receptor-related protein 1 (LRP-1). Deletion or knockdown of LRP-1 abolished tPA-mediated cell survival, whereas re-introduction of an LRP-1 minigene in a mouse LRP-1-deficient fibroblast cell line (PEA-13) restored the cytoprotective ability of tPA. tPA triggered a cascade of survival signaling involving extracellular signal-regulated kinase 1/2 (Erk1/2), p90RSK, and phosphorylation of Bad. Blockade of Erk1/2 activation abrogated the antiapoptotic effect of tPA, whereas expression of constitutively active MEK1 promoted cell survival similar to tPA. In vivo, compared with wild-type controls, apoptosis of interstitial myofibroblasts was increased in tPA(-/-) mice after obstructive injury, and myofibroblasts were completely depleted 4 wk after relief of the obstruction. Together, these findings illustrate that tPA is a survival factor that prevents apoptosis of renal interstitial fibroblasts and myofibroblasts through an LRP-1-, Erk1/2-, p90RSK-, and Bad-dependent mechanism.
Thalamocortical dysfunction and complex visual hallucinations in brain disease – Are the primary disturbances in the cerebral cortex?
Authors: Daniel Collerton, Elaine Perry
Journal: Behavioral and Brain Sciences (2004)

Applying Behrendt &amp; Young's (B&amp;Y's) model of thalamocortical synchrony to complex visual hallucinations in neurodegenerative disorders, such as dementia with Lewy bodies and progressive supranuclear palsy, leads us to propose that the primary pathology may be cortical rather than thalamic. Additionally, the extinction of active hallucinations by eye closure challenges their conception of the role of reduced sensory input.
CN-19 * HISTOLOGICAL EXAMINATION OF ENHANCING LESION ADJACENT TO THE IMPLANTED BCNU- WAFERS SUGGESTS VASCULAR DAMAGE AS THE MAJOR UNDERLYING MECHANISM
Authors: K. Ueki, H. Matsuda, F. Higuchi, T. Udzuka, P. Kim
Journal: Neuro-Oncology (2014)

BCNU wafer (BW) is known to increase risk of edema, frequently accompanied by enhancing lesions. The underlying mechanism is not clarified. We performed close histological examination including electron microscopy of the mass-effect-causing enhancing lesion resected from 4 patients (3 glioblastomas and 1 anaplastic oligodendroglioma) 2-33 months after the BW implantation. There noticed were two types of tissue damage in the resected lesions: 1) necrosis in immediate contact with the wafer or its remnant, and 2) necrosis with marked vasculopathy affecting arterial branches and venules. The former contained phagocyted or non-phagocyted crystalline structured polymer, and translucent spherical bodies with calcified core that were not surrounded by viable cells. In the latter, marked degeneration of arterioles were observed, suggesting relatively prolonged exposure to toxic substances such as the released BCNU, degraded polymer and cytokines. Similar type of vasculopathy had been observed in monkey brains implanted with the BCNU-free polymer. Our data suggest that the edema and neecrotic response induced by the BW implantation are results of not only the direct effect of the released drug, but also of inflammatory vasculopathy caused by the degraded polymer itself that occur even in later phase.
Agenesis of the right pulmonary artery in a young asymptomatic girl
Authors: P Morales, L Miravet, V Marco
Journal: European Respiratory Journal (1991)

We report the case of a 13 yr old, asymptomatic girl with agenesis of the right pulmonary artery. In the context of a tuberculosis survey in her school, an X-ray examination disclosed a decreased volume of the right lung. Ventilation and perfusion scans and digital substraction angiography established the diagnosis.
Pattern of CD14+ Follicular Dendritic Cells and PD1+ T Cells Independently Predicts Time to Transformation in Follicular Lymphoma
Authors: Jacob P. Smeltzer, Jason M. Jones, Steven C. Ziesmer, Deanna M. Grote, Bing Xiu, Kay M. Ristow, Zhi Zhang Yang, Grzegorz S. Nowakowski, Andrew L. Feldman, James R. Cerhan, Anne J. Novak, Stephen M. Ansell
Journal: Clinical Cancer Research (2014)

Transformation of follicular lymphoma is a critical event associated with a poor prognosis. The role of the tumor microenvironment in previous transformation studies has yielded conflicting results.To define cell subtypes associated with transformation, we examined tissue specimens at diagnosis from patients with follicular lymphoma that later transformed and, using immunohistochemistry (IHC), stained for CD68, CD11c, CD21, CXCL13, FOXP3, PD1, and CD14. Cell content and the pattern of expression were evaluated. Those identified as significantly associated with time to transformation (TTT) and overall survival (OS) were further characterized by flow cytometry and multicolor IHC.Of note, 58 patients were analyzed with median TTT of 4.7 years. The pattern of PD1(+) and CD14(+) cells rather than the quantity of cells was predictive of clinical outcomes. On multivariate analysis, including the follicular lymphoma international prognostic index score, CD14(+) cells localized in the follicle were associated with a shorter TTT (HR, 3.0; P = 0.004). PD1(+) cells with diffuse staining were associated with a shorter TTT (HR, 1.9; P = 0.045) and inferior OS (HR, 2.5; P = 0.012). Multicolor IHC and flow cytometry identified CD14(+) cells as follicular dendritic cells (FDC), whereas PD1(+) cells represented two separate populations, TFH and exhausted T cells.These results identify the presence of PD1(+) T cells and CD14(+) FDC as independent predictors of transformation in follicular lymphoma. Clin Cancer Res; 20(11); 2862-72. ©2014 AACR.
The human atrial strength-interval relation. Influence of cycle length and procainamide.
Authors: A E Buxton, F E Marchlinski, J M Miller, D F Morrison, L H Frame, M E Josephson
Journal: Circulation (1989)

We defined the atrial strength-interval relation in 23 patients at cycle lengths of 600, 450, and 300 msec before and after procainamide. The atrial diastolic threshold was similar at cycle lengths of 600 and 450 msec, but the threshold at 300 msec was significantly higher than that determined at 600 and 450 msec both before and after procainamide. Procainamide significantly increased the diastolic threshold only at a cycle length of 300 msec. The strength-interval relation was nonlinear, showing progressively decreasing decrements in the measured refractory period as the stimulating current was increased. Progressive decreases in the drive cycle length from 600 to 450 to 300 msec caused similar decreases in refractory periods. The shape of the curves was similar at cycle lengths of 600 and 450 msex. However, at low current strengths, the slope of the curve determined at 300 msex was significantly more vertical than the slopes of the curves at the longer drive cycle lengths. Procainamide caused similar increases in apparent refractory periods at each paced cycle length. Procainamide did not alter the shape of the curves at any paced cycle length. These observations confirm the importance of stimulation frequency on atrial excitability. They suggest that the effects of procainamide on the effective refractory period of the atrium are not cycle length dependent, although the drug effects on threshold are dependent on the drive cycle length.
Lung dendritic cells imprint T cell lung homing and promote lung immunity through the chemokine receptor CCR4
Authors: Zamaneh Mikhak, James P. Strassner, Andrew D. Luster
Journal: The Journal of Experimental Medicine (2013)

T cell trafficking into the lung is critical for lung immunity, but the mechanisms that mediate T cell lung homing are not well understood. Here, we show that lung dendritic cells (DCs) imprint T cell lung homing, as lung DC–activated T cells traffic more efficiently into the lung in response to inhaled antigen and at homeostasis compared with T cells activated by DCs from other tissues. Consequently, lung DC–imprinted T cells protect against influenza more effectively than do gut and skin DC–imprinted T cells. Lung DCs imprint the expression of CCR4 on T cells, and CCR4 contributes to T cell lung imprinting. Lung DC–activated, CCR4-deficient T cells fail to traffic into the lung as efficiently and to protect against influenza as effectively as lung DC–activated, CCR4-sufficient T cells. Thus, lung DCs imprint T cell lung homing and promote lung immunity in part through CCR4.
Manual Therapy, Physical Therapy, or Continued Care by a General Practitioner for Patients with Neck Pain
Authors: Jan Lucas Hoving, Bart W. Koes, Henrica C.W. de Vet, Danielle A.W.M. van der Windt, Willem J.J. Assendelft, Henk van Mameren, Walter L.J.M. Devillé, Jan J.M. Pool, Rob J.P.M Scholten, Lex M. Bouter
Journal: Annals of Internal Medicine (2002)

Neck pain is a common problem, but the effectiveness of frequently applied conservative therapies has never been directly compared.To determine the effectiveness of manual therapy, physical therapy, and continued care by a general practitioner.Randomized, controlled trial.Outpatient care setting in the Netherlands.183 patients, 18 to 70 years of age, who had had nonspecific neck pain for at least 2 weeks.6 weeks of manual therapy (specific mobilization techniques) once per week, physical therapy (exercise therapy) twice per week, or continued care by a general practitioner (analgesics, counseling, and education).Treatment was considered successful if the patient reported being "completely recovered" or "much improved" on an ordinal six-point scale. Physical dysfunction, pain intensity, and disability were also measured.At 7 weeks, the success rates were 68.3% for manual therapy, 50.8% for physical therapy, and 35.9% for continued care. Statistically significant differences in pain intensity with manual therapy compared with continued care or physical therapy ranged from 0.9 to 1.5 on a scale of 0 to 10. Disability scores also favored manual therapy, but the differences among groups were small. Manual therapy scored consistently better than the other two interventions on most outcome measures. Physical therapy scored better than continued care on some outcome measures, but the differences were not statistically significant.In daily practice, manual therapy is a favorable treatment option for patients with neck pain compared with physical therapy or continued care by a general practitioner.
Origins of Western diseases
Authors: MJ Quinn
Journal: Journal of the Royal Society of Medicine (2011)

Recent gynaecological studies show that childbirth, constipation, trauma and surgery cause injuries to autonomic nerves at different anatomical sites in the female pelvis resulting in endometriosis, adenomyosis and fibroids. Re-growth of abnormal nerves causes allodynic symptoms (‘light touch causing pain or discomfort’) some years later including vulvodynia, dyspareunia, dysmenorrhea, irritative bladder and bowel symptoms. Further consequences of autonomic denervation include tissue hypoplasia and hyperplasia, visceral dysfunction, susceptibility to infection, alcohol, tobacco and drugs, as well as pain with sensitization of the central nervous system. The ‘autonomic denervation’ view extrapolates these observations from the female pelvis to the varied anatomy of branches of the cardiac and coeliac plexi to provide primary mechanisms for many forms of Western disease. This account sets out the autonomic denervation view, identifies features of autonomic denervation in extrapelvic organs, and, contrasts it with prior accounts of chronic Western diseases including those of DP Burkitt, PRJ Burch and DP Barker.
Does controlling movement require intelligence?
Authors: Mark L. Latash, J. Greg Anson
Journal: Behavioral and Brain Sciences (1997)

Motor control schemes should have an element of control and an element of coordination. The former is a source of initiative and a zroduct of the brain's work (mind, intelligence, or “homunculus”) while the latter can be viewed as a process with constraints emerging at a hierarchically lower, autonomous level. Limiting scientific analysis to an object smaller than the universe necessarily leads to a hierarchical (cybernetic) approach.
Impact of Patient-Reported Outcomes in Oncology: A Longitudinal Analysis of Patient-Physician Communication
Authors: Elena E. Takeuchi, Ada Keding, Noha Awad, Ursula Hofmann, Lyndsay J. Campbell, Peter J. Selby, Julia M. Brown, Galina Velikova
Journal: Journal of Clinical Oncology (2011)

Purpose Regularly collecting patient-reported outcomes (PROs) of health-related quality of life with feedback to oncologists may assist in eliciting and monitoring patients' problems during cancer treatment. This study examined how PRO feedback had an impact on patient-physician communication over time to gain a better understanding of how it may influence patient care. Patients and Methods Exploratory analyses were performed on a data set from a previous study. Patients were randomly assigned to intervention (regular completion of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 and Hospital Anxiety and Depression Scale with feedback to oncologists), attention-control (completion of same questionnaires without feedback), and control (standard care) arms. The content of consultation audio recordings between 28 oncologists and 198 patients over four consecutive visits (792 consultations) was analyzed. Mixed-effects models and multivariate regressions were used to examine the longitudinal impact of the intervention on patient-physician communication, dynamics of patient-physician interaction, and the association between PROs and the content of clinic discussion. Results Patients in the intervention arm discussed more symptoms over time compared with patients in the attention-control (P = .008) and control (P = .04) arms. No study arm effect was observed for function discussions. Discussion topics were predominantly raised by patients/relatives, regardless of arm allocation. Clinic discussions were associated with severity of patient-reported symptoms but not with patient-reported functional concerns. Conclusion A positive longitudinal impact of the intervention on symptom discussion was observed, but not for function discussion, suggesting that potentially serious problems may remain unaddressed. Training oncologists in responding to patient-reported functional concerns may increase the impact of this intervention.
Hidden Morbidity in Cancer: Spouse Caregivers
Authors: Michal Braun, Mario Mikulincer, Anne Rydall, Andrew Walsh, Gary Rodin
Journal: Journal of Clinical Oncology (2007)

This study assesses psychological distress among advanced cancer patients and their spouse caregivers, while examining the relative contribution of caregiving burden and relational variables (attachment orientation and marital satisfaction) to depressive symptoms in the spouse caregivers.A total of 101 patients with advanced GI or lung cancer and their spouse caregivers were recruited for the study. Measures included Beck Depression Inventory-II (BDI-II), Caregiving Burden scale, Experiences in Close Relationships scale, and ENRICH Marital Satisfaction scale.A total of 38.9% of the caregivers reported significant symptoms of depression (BDI-II > or = 15) compared with 23.0% of their ill spouses (P < .0001). In a hierarchical regression predicting caregiver's depression, spouse caregiver's age and patient's cancer site were entered in the first step, objective caregiving burden was entered in the second step, subjective caregiving burden was entered in the third step, caregiver's attachment scores were entered in the fourth step, and caregiver's marital satisfaction score was entered in the fifth step. The final model accounted for 37% of the variance of caregiver depression, with subjective caregiving burden (beta = .38; P < .01), caregiver's anxious attachment (beta = .21; P < .05), caregiver's avoidant attachment (beta = .20; P < .05), and caregiver's marital satisfaction (beta = -.18; P < .05) making significant contributions to the model.Spouse caregivers of patients with advanced cancer are a high-risk population for depression. Subjective caregiving burden and relational variables, such as caregivers' attachment orientations and marital dissatisfaction, are important predictors of caregiver depression.
Respiratory heat/water loss alone does not determine the severity of exercise-induced asthma
Authors: N Noviski, E Bar-Yishay, I Gur, S Godfrey
Journal: European Respiratory Journal (1988)

Respiratory heat loss (RHL) or water loss (RWL) have been proposed as possible triggering factors in exercise and hyperventilation-induced asthma (EIA and HIA). It has recently been demonstrated that exercise intensity and climatic factors are both important in determining the severity of EIA. Eight young asthmatics performed both exercise and isocapnic hyperventilation (IHV) manoeuvres under identical climatic conditions, as part of our investigation of these interactive factors which determine the severity of the asthmatic response. It was found that, when challenged at low ventilatory levels, exercise produced a significantly attenuated asthmatic response compared to IHV. The fall in forced expired volume in 1 sec (delta FEV1) following exercise was 15 +/- 4% as compared with 27 +/- 3% after IHV (p less than 0.002). It is concluded that while the hypernoea in exercise may serve as a trigger, exercise per se introduces an additional factor which serves to limit the full response seen with IHV. This attenuated response is revealed at low ventilatory levels but is masked at high levels.