tbuckley/cabot-search huggingface dataset:
Metastasis Stage, Adjuvant Treatment, and Residual Tumor Are Prognostic Factors for Medulloblastoma in Children: Conclusions From the Children's Cancer Group 921 Randomized Phase III Study
Authors: Paul M. Zeltzer, James M. Boyett, Jonathan L. Finlay, A. Lel Albright, Lucy B. Rorke, Jerrold M. Milstein, Jeffrey C. Allen, Kenneth R. Stevens, Philip Stanley, Hao Li, Jeffrey H. Wisoff, J. Russell Geyer, Patsy McGuire-Cullen, James A. Stehbens, Susan B. Shurin, Roger J. Packer
Journal: Journal of Clinical Oncology (1999)

PURPOSE: From 1986 to 1992, “eight-drugs-in-one-day” (8-in-1) chemotherapy both before and after radiation therapy (XRT) (54 Gy tumor/36 Gy neuraxis) was compared with vincristine, lomustine (CCNU), and prednisone (VCP) after XRT in children with untreated, high-stage medulloblastoma (MB). PATIENTS AND METHODS: Two hundred three eligible patients with an institutional diagnosis of MB were stratified by local invasion and metastatic stage (Chang T/M) and randomized to therapy. Median time at risk from study entry was 7.0 years. RESULTS: Survival and progression-free survival (PFS) ± SE at 7 years were 55% ± 5% and 54% ± 5%, respectively. VCP was superior to 8-in-1 chemotherapy, with 5-year PFS rates of 63% ± 5% versus 45% ± 5%, respectively (P = .006). Upon central neuropathology review, 188 patients were confirmed as having MB and were the subjects for analyses of prognostic factors. Children aged 1.5 to younger than 3 years had inferior 5-year estimates of PFS, compared with children 3 years old or older (P = .0014; 32% ± 10% v 58% ± 4%, respectively). For MB patients 3 years of age or older, the prognostic effect of tumor spread (M0 v M1 v M2+) on PFS was powerful (P = .0006); 5-year PFS rates were 70% ± 5%, 57% ± 10%, and 40% ± 8%, respectively. PFS distributions at 5 years for patients with M0 tumors with less than 1.5 cm 2 of residual tumor, versus ≥ 1.5 cm 2 of residual tumor by scan, were significantly different (P = .023; 78% ± 6% v 54% ± 11%, respectively). CONCLUSION: VCP plus XRT is a superior adjuvant combination compared with 8-in-1 chemotherapy plus XRT. For patients with M0 tumors, residual tumor bulk (not extent of resection) is a predictor for PFS. Patients with M0 tumors, ≥ 3 years with ≤ 1.5 cm 2 residual tumor, had a 78% ± 6% 5-year PFS rate. Children younger than 3 years old who received a reduced XRT dosage had the lowest survival rate.
Toward a Neuropsychological Theory of Antidepressant Drug Action: Increase in Positive Emotional Bias After Potentiation of Norepinephrine Activity
Authors: Catherine J. Harmer, Simon A. Hill, Matthew J. Taylor, Philip J. Cowen, Guy M. Goodwin
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: Antidepressants that increase serotonin or norepinephrine in the brain are effective in treating depression, but there is no neuropsychological account of how these changes relieve depressive states. Cognitive theories suggest that biases in information processing lead depressed patients to make unrealistically negative judgments about themselves and the world. METHOD: A single dose of the noradrenergic antidepressant reboxetine or placebo was administered to 24 healthy volunteers. Effects on emotional processing were assessed through facial expression recognition, emotional categorization, and emotional memory. RESULTS: On the three measures, reboxetine biased perception toward positive, rather than negative, information in the absence of changes in nonemotional performance or mood. CONCLUSIONS: These results suggest that a single dose of an antidepressant can increase the processing of positively valenced material in nondepressed volunteers. Antidepressants may therefore work in a manner similar to that of psychological treatments that aim to redress negative biases in information processing.
Immunomodulation of FOXP3+ Regulatory T Cells by the Aromatase Inhibitor Letrozole in Breast Cancer Patients
Authors: Daniele Generali, Gaynor Bates, Alfredo Berruti, Maria P. Brizzi, Leticia Campo, Simone Bonardi, Alessandra Bersiga, Giovanni Allevi, Manuela Milani, Sergio Aguggini, Luigi Dogliotti, Alison H. Banham, Adrian L. Harris, Alberto Bottini, Stephen B. Fox
Journal: Clinical Cancer Research (2009)

Abstract Purpose: We have shown previously that tumor infiltration by FOXP3+ regulatory T cells (Treg) is associated with increased relapse and shorter survival of patients with both in situ and invasive breast cancer. Because estrogen regulates Treg numbers in mice and promotes the proliferation of human Tregs, we hypothesized that blocking estrogen receptor-α signaling would abrogate Tregs and be associated with response to hormonal therapy and increased survival. Experimental Design: FOXP3+ Tregs were quantified in tumor samples collected at baseline by incisional biopsy and after 6 months at definitive surgery in 83 elderly breast cancer patients (T2-4 N0-1) enrolled in a randomized phase II trial based on 6 months of primary letrozole (2.5 mg/d) or 6 months of letrozole plus oral “metronomic” cyclophosphamide (50 mg/d). Results: Treg number ranged from 0 to 380 (median, 30) before treatment and from 0 to 300 (median, 8) after treatment. There was a significant reduction in Tregs in letrozole and letrozole-cyclophosphamide patients (P &amp;lt; 0.0001 and P &amp;lt; 0.002, respectively) after treatment. Treg number at residual histology was inversely related with response (P &amp;lt; 0.03 and P = 0.50, respectively) and a greater Treg reduction was observed in responding patients (P &amp;lt; 0.03). Conclusion: This study suggests that aromatase inhibitors may have an indirect antitumor mechanism of action through reducing Tregs in breast tumors and may be of use in estrogen receptor-α-negative tumors in combination with immunotherapy approaches.
Effect of 1-hyoscyamine on gastric secretion of acid and intrinsic factor in man.
Authors: G Dotevall, A Walan, A Weinfeld
Journal: Gut (1967)

EDITORIAL COMMENT It has been suggested that intrinsic factor, like pepsin, is stored in the mucosa and that histamine and some cholinergic agents produce an increased secretion by an early 'wash-out' mechanism.This study provides further evidence in support of this concept.
Inhibition of Ron Kinase Blocks Conversion of Micrometastases to Overt Metastases by Boosting Antitumor Immunity
Authors: Henok Eyob, Huseyin Atakan Ekiz, Yoko S. DeRose, Susan E. Waltz, Matthew A. Williams, Alana L. Welm
Journal: Cancer Discovery (2013)

Abstract Many “nonmetastatic” cancers have spawned undetectable metastases before diagnosis. Eventual outgrowth of these microscopic lesions causes metastatic relapse and death, yet the events that dictate when and how micrometastases convert to overt metastases are largely unknown. We report that macrophage-stimulating protein and its receptor, Ron, are key mediators in conversion of micrometastases to bona fide metastatic lesions through immune suppression. Genetic deletion of Ron tyrosine kinase activity specifically in the host profoundly blocked metastasis. Our data show that loss of Ron function promotes an effective antitumor CD8+ T-cell response, which specifically inhibits outgrowth of seeded metastatic colonies. Treatment of mice with a Ron-selective kinase inhibitor prevented outgrowth of lung metastasis, even when administered after micrometastatic colonies had already been established. Our findings indicate that Ron inhibitors may hold potential to specifically prevent outgrowth of micrometastases in patients with cancer in the adjuvant setting. Significance: Our data shed new light on an understudied, yet critically important aspect of metastasis: the conversion of clinically undetectable micrometastatic tumor cells to overt metastases that eventually cause death of the patient. Our work shows that Ron inhibition can significantly reduce metastatic outgrowth, even when administered after metastatic colonies are established. Cancer Discov; 3(7); 751–60. ©2013 AACR. This article is highlighted in the In This Issue feature, p. 705
A multiply redundant genetic switch 'locks in' the transcriptional signature of regulatory T cells
Authors: Wenxian Fu, Ayla Ergun, Ting Lu, Jonathan A Hill, Sokol Haxhinasto, Marlys S Fassett, Roi Gazit, Stanley Adoro, Laurie Glimcher, Susan Chan, Philippe Kastner, Derrick Rossi, James J Collins, Diane Mathis, Christophe Benoist
Journal: Nature Immunology (2012)
Lead Time and Overdiagnosis in Prostate-Specific Antigen Screening: Importance of Methods and Context
Authors: G. Draisma, R. Etzioni, A. Tsodikov, A. Mariotto, E. Wever, R. Gulati, E. Feuer, H. de Koning
Journal: JNCI Journal of the National Cancer Institute (2009)

The time by which prostate-specific antigen (PSA) screening advances prostate cancer diagnosis, called the lead time, has been reported by several studies, but results have varied widely, with mean lead times ranging from 3 to 12 years. A quantity that is closely linked with the lead time is the overdiagnosis frequency, which is the fraction of screen-detected cancers that would not have been diagnosed in the absence of screening. Reported overdiagnosis estimates have also been variable, ranging from 25% to greater than 80% of screen-detected cancers. We used three independently developed mathematical models of prostate cancer progression and detection that were calibrated to incidence data from the Surveillance, Epidemiology, and End Results program to estimate lead times and the fraction of overdiagnosed cancers due to PSA screening among US men aged 54–80 years in 1985–2000. Lead times were estimated by use of three definitions. We also compared US and earlier estimates from the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) that were calculated by use of a microsimulation screening analysis (MISCAN) model. The models yielded similar estimates for each definition of lead time, but estimates differed across definitions. Among screen-detected cancers that would have been diagnosed in the patients' lifetimes, the estimated mean lead time ranged from 5.4 to 6.9 years across models, and overdiagnosis ranged from 23% to 42% of all screen-detected cancers. The original MISCAN model fitted to ERSPC Rotterdam data predicted a mean lead time of 7.9 years and an overdiagnosis estimate of 66%; in the model that was calibrated to the US data, these were 6.9 years and 42%, respectively. The precise definition and the population used to estimate lead time and overdiagnosis can be important drivers of study results and should be clearly specified.
Phase I Trial of Overlapping Long Peptides from a Tumor Self-Antigen and Poly-ICLC Shows Rapid Induction of Integrated Immune Response in Ovarian Cancer Patients
Authors: Paul Sabbatini, Takemasa Tsuji, Luis Ferran, Erika Ritter, Christine Sedrak, Kevin Tuballes, Achim A. Jungbluth, Gerd Ritter, Carol Aghajanian, Katherine Bell-McGuinn, Martee L. Hensley, Jason Konner, William Tew, David R. Spriggs, Eric W. Hoffman, Ralph Venhaus, Linda Pan, Andres M. Salazar, Catherine Magid Diefenbach, Lloyd J. Old, Sacha Gnjatic
Journal: Clinical Cancer Research (2012)

Long peptides are efficiently presented to both CD4(+) and CD8(+) T cells after intracellular processing by antigen-presenting cells. To investigate the safety and in vivo immunogenicity of synthetic overlapping long peptides (OLP) from a human tumor self-antigen, we conducted a phase I clinical trial with OLP from cancer-testis antigen NY-ESO-1 in various adjuvant combinations.Twenty-eight patients with advanced ovarian cancer in second or third remission were enrolled sequentially in three cohorts and received at least one vaccination. Patients in Cohort 1 (n = 4) received 1.0 mg OLP, Cohort 2 (n = 13) received OLP in Montanide-ISA-51, and Cohort 3 (n = 11) received OLP + 1.4 mg Poly-ICLC in Montanide-ISA-51 on weeks 1, 4, 7, 10, and 13. Humoral and cellular responses were evaluated by standardized immunomonitoring techniques (ELISA, ELISPOT assay, intracellular cytokine staining, and tetramer staining).The vaccine was generally well tolerated with injection site reactions and fatigue that resolved. NY-ESO-1-specific antibody and CD8(+) T cells were undetectable after vaccination with OLP alone, but were found in 6 of 13 (46%) and 8 of 13 (62%) patients, respectively, after vaccination with OLP+Montanide, and in 10 of 11 (91%) and 10 of 11 (91%) patients, respectively, after vaccination with OLP+Montanide+Poly-ICLC. NY-ESO-1-specific CD4(+) T cells were detected in all patients with greater frequency and polyclonality when Montanide-ISA-51 was used for vaccination. Inclusion of Poly-ICLC as an adjuvant further accelerated the induction of NY-ESO-1-specific immune responses.The current study shows that NY-ESO-1 OLP vaccine is safe and rapidly induces consistent integrated immune responses (antibody, CD8(+) and CD4(+)) in nearly all vaccinated patients when given with appropriate adjuvants.
TR-03 * PHARMACOLOGICAL MODULATION OF BLOOD-BRAIN BARRIER: A NOVEL THERAPEUTIC APPROACH TO REFRACTORY CNS TUMORS
Authors: S. Becciani, M. Da Ros, A. Lisa Iorio, L. Giunti, A. Stival, M. Lucchesi, M. Massimino, M. de Martino, I. Sardi
Journal: Neuro-Oncology (2015)

A key condition for the efficacy of chemotherapy is that it reaches the tumor mass at a therapeutic concentration. In CNS tumors this process is hampered by the blood brain barrier (BBB). Lately emerged that Multi Drug Resistance (MDR) phenomenon is explained through the cooperation of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), two “gatekeeper” efflux pumps working in tandem on the BBB, also present on plasma-membrane of certain brain tumors. Recently, we have demonstrated that morphine, ondansetron and dexamethasone can interfere with the permeability of BBB allowing doxorubicine accumulation within the rat brain, detected by LC-MS/MS mass spectrometry. All these drugs are substrates of P-gp and BCRP transporters. The aim of the current proposal is to understand the action mechanism of BBB “permeabilization” induced by morphine or other drugs and to exploit this method for the “treatment” of brain tumor in an animal model; i) Quantifying the level drugs that do not usually cross the BBB (mitoxantrone or melphalan) after morphine pre-treatment in a preclinical model. Verifying the cytotoxic effect of morphine plus doxorubicin (and other chemotherapeutic agents) treatment by using MTT and TUNEL analysis in glioblastoma cell lines; ii) Quantifying the level of drugs that do not usually cross the BBB after morphine pre-treatment in an artificial BBB through a monolayer of MDCKII cells over-expressing the human P-gp or BCRP; iii) Investigating the regulatory role of certain microRNA in MDR mechanism by RT-PCR and western blot analysis of P-gp, BCRP, miR-21, miR-27a and miR-451. Our preliminary results suggest that blocking efflux transporters by pretreatment with morphine, ondansetron or desamethasone is able to allow doxorubicin penetration inside the brain. These data will enable us to novel therapeutic approaches to refractory or recurrent CNS tumors in which molecules usually stopped by the BBB may have a therapeutic impact.
Oesophageal manometry during eating in the investigation of patients with chest pain or dysphagia.
Authors: P J Howard, A Pryde, R C Heading
Journal: Gut (1989)

Dysphagia is a frequent cause of referral for oesophageal manometry although the motor response to eating is not routinely studied. We examined symptoms and oesophageal motor patterns in response to eating bread in 30 patients with either gastro-oesophageal reflux (n = 20), or normal oesophageal function tests (n = 10). No patient experienced symptoms while swallowing water but one complained of heartburn and one developed symptomatic oesophageal 'spasm' during eating. In eight further patients, pain or dysphagia which occurred with swallowing bread was associated with aperistalsis. Comparing asymptomatic and symptomatic periods, there was a slight increase in mean swallow frequency from 7.5 (0.79) (SEM) to 9.0 (1.17) swallows per minute (NS; n = 10). The mean number of aperistalsis swallows increased from 4.5 (0.96) per minute to 6.2 (1.30) (p less than 0.01; n = 10). Aperistalsis during symptoms was mainly caused by non-conducted swallows rather than synchronous contractions (mean 5.8 (1.45) per minute compared with 1.2 (0.44]. Aperistalsis can be produced by rapid swallowing in the normal oesophagus through 'deglutitive inhibition'. These results suggest that some patients experience dysphagia associated with aperistalsis perhaps as a response to increased frequency of swallowing. Functional abnormalities of this nature will not be detected by conventional oesophageal manometry.
Chronic Ingestion of Flavan-3-ols and Isoflavones Improves Insulin Sensitivity and Lipoprotein Status and Attenuates Estimated 10-Year CVD Risk in Medicated Postmenopausal Women With Type 2 Diabetes
Authors: Peter J. Curtis, Mike Sampson, John Potter, Ketan Dhatariya, Paul A. Kroon, Aedín Cassidy
Journal: Diabetes Care (2012)

OBJECTIVE To assess the effect of dietary flavonoids on cardiovascular disease (CVD) risk in postmenopausal women with type 2 diabetes on established statin and hypoglycemic therapy. RESEARCH DESIGN AND METHODS Despite being medicated, patients with type 2 diabetes have elevated CVD risk, particularly postmenopausal women. Although dietary flavonoids have been shown to reduce CVD risk factors in healthy participants, no long-term trials have examined the additional benefits of flavonoids to CVD risk in medicated postmenopausal women with type 2 diabetes. We conducted a parallel-design, placebo-controlled trial with type 2 diabetic patients randomized to consume 27 g/day (split dose) flavonoid-enriched chocolate (containing 850 mg flavan-3-ols [90 mg epicatechin] and 100 mg isoflavones [aglycone equivalents)]/day) or matched placebo for 1 year. RESULTS Ninety-three patients completed the trial, and adherence was high (flavonoid 91.3%; placebo 91.6%). Compared with the placebo group, the combined flavonoid intervention resulted in a significant reduction in estimated peripheral insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR] −0.3 ± 0.2; P = 0.004) and improvement in insulin sensitivity (quantitative insulin sensitivity index [QUICKI] 0.003 ± 0.00; P = 0.04) as a result of a significant decrease in insulin levels (−0.8 ± 0.5 mU/L; P = 0.02). Significant reductions in total cholesterol:HDL-cholesterol (HDL-C) ratio (−0.2 ± 0.1; P = 0.01) and LDL-cholesterol (LDL-C) (−0.1 ± 0.1 mmol/L; P = 0.04) were also observed. Estimated 10-year total coronary heart disease risk (derived from UK Prospective Diabetes Study algorithm) was attenuated after flavonoid intervention (flavonoid +0.1 ± 0.3 vs. placebo 1.1 ± 0.3; P = 0.02). No effect on blood pressure, HbA1c, or glucose was observed. CONCLUSIONS One-year intervention with flavan-3-ols and isoflavones improved biomarkers of CVD risk, highlighting the additional benefit of flavonoids to standard drug therapy in managing CVD risk in postmenopausal type 2 diabetic patients.
Human airway smooth muscle is structurally and mechanically similar to that of other species
Authors: L.Y.M. Chin, Y. Bossé, Y. Jiao, D. Solomon, T.L. Hackett, P.D. Paré, C.Y. Seow
Journal: European Respiratory Journal (2009)

Airway smooth muscle (ASM) plays a vital role in the exaggerated airway narrowing seen in asthma. However, whether asthmatic ASM is mechanically different from nonasthmatic ASM is unclear. Much of our current understanding about ASM mechanics comes from measurements made in other species. Limited data on human ASM mechanics prevents proper comparisons between healthy and asthmatic tissues, as well as human and animal tissues. In the current study, we sought to define the mechanical properties of healthy human ASM using tissue from intact lungs and compare these properties to measurements in other species. The mechanical properties measured included: maximal stress generation, force–length properties, the ability of the muscle to undergo length adaptation, the ability of the muscle to recover from an oscillatory strain, shortening velocity and maximal shortening. The ultrastructure of the cells was also examined. Healthy human ASM was found to be mechanically and ultrastructurally similar to that of other species. It is capable of undergoing length adaptation and responds to mechanical perturbation like ASM from other species. Force generation, shortening capacity and velocity were all similar to other mammalian ASM. These results suggest that human ASM shares similar contractile mechanisms with other animal species and provides an important dataset for comparisons with animal models of disease and asthmatic ASM.
Advances in targeted therapies XI
Authors: F C Breedveld, J R Kalden, J S Smolen
Journal: Annals of the Rheumatic Diseases (2009)

The papers brought together in this supplement of the Annals of the Rheumatic Diseases constitute summaries of presentations at the XIth International Symposium on Advances in Targeted Therapies, which was held from 22 to 26 April 2009. These presentations represent the state of the art on the biology of mechanisms of action and pathophysiology of tumour necrosis factor (TNF) as well as other important mediators of inflammation. Current knowledge on the means and consequences of blocking TNF or other molecules or cellular mechanisms is also presented.

We are grateful to Drs Crofford, Feldmann, Furst, Klareskog, Lipsky, …
Expression patterns of the glial cell line–derived neurotrophic factor, neurturin, their cognate receptors GFRα-1, GFRα-2, and a common signal transduction element c-Ret in the human skin hair follicles
Authors: Mohamed A. Adly, Hanan A. Assaf, Paolo Pertile, Mahmoud R. Hussein, Ralf Paus
Journal: Journal of the American Academy of Dermatology (2008)
Vibratory ventilation decreases filtration of fluid in the lungs of newborn lambs.
Authors: J U Raj, R B Goldberg, R D Bland
Journal: Circulation Research (1983)

To compare effects of vibratory and mechanical ventilation on fluid balance in the newborn lung, we measured pulmonary arterial and left atrial pressures, pleural and airway pressures, lung blood flow and lymph flow, and concentrations of protein in lymph and plasma of 19 healthy lambs, 2-4 weeks old, during a 2- to 4-hour period of spontaneous breathing, followed by 4-8 hours of mechanical ventilation at 30 breaths/min and 4-8 hours of vibratory ventilation, in which the lambs received 1650 whiffs of air/min. In 8 of 22 studies, we increased lung microvascular pressure by filling a balloon catheter in the left atrium with saline. There was no significant difference in mean airway pressure during the two types of ventilation. Despite higher lung vascular pressures, lymph flow was less and lymph protein concentration was greater during vibratory than during mechanical ventilation. These findings are consistent with reduced lung fluid filtration, possibly from reduced pulmonary blood flow and increased perimicrovascular pressure, during vibratory ventilation. In eight lambs killed after 8 hours of vibratory ventilation, extravascular lung water was normal and microscopy showed no edema. We conclude that vibratory ventilation has no adverse effect on lung fluid balance and may benefit lambs by decreasing net filtration of fluid into their lungs.