tbuckley/cabot-search huggingface dataset:
Combination of olfactory test and substantia nigra transcranial sonopraphy in the differential diagnosis of Parkinson’s disease: a pilot study from China
Authors: Wei Chen, Yu-Yan Tan, Yun-Yun Hu, Wei-Wei Zhan, Li Wu, Yue Lou, Xi Wang, Yi Zhou, Pei Huang, Yuan Gao, Qin Xiao, Sheng-Di Chen
Journal: Translational Neurodegeneration (2012)

Both hyposmia and substania nigra (SN) hyperechogenicity on trascranial sonography (TCS) were risk markers for idiopathic Parkinson's disease (PD), which was beneficial to the differential diagnosis of the disease. However, each of their single diagnostic value is often limited. The purpose of present study was to explore whether the combination of olfactory test and TCS of SN could enhance the differential diagnostic power in Chinese patients with PD. Thirty-seven patients with PD and twenty-six patients with essential tremor (ET) were evaluated on 16-item odor identification test from extended version of sniffin' sticks and TCS of SN. The frequency of hyposmia and SN hyperechogenicity in each group was compared. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the two clinical biomarkers were analyzed. The frequency of hyposmia in patients with PD was significantly higher than in patients with ET (62.2% VS. 3.8%, P = 0.000). The frequency of SN hyperechogenicity in patients with PD was significantly higher than in ET subjects (48.6% VS. 15.4%, P = 0.006). The combination of hyposmia and SN hyperechogenicity (if either one or both present) discriminated patients with PD from ET with a sensitivity of 78.4% and 29.7%, specificity of 80.8% and 100%, PPV of 85.3% and 100%, and NPV of 72.4% and 50.0%, respectively. Our preliminary data suggested that the combination of hyposmia and SN hyperechogenicity could improve the diagnostic potential for discriminating Chinese patients with PD from ET.
Gonadotropin-Releasing Hormone Agonist for the Prevention of Chemotherapy-Induced Ovarian Failure in Patients With Lymphoma: 1-Year Follow-Up of a Prospective Randomized Trial
Authors: Isabelle Demeestere, Pauline Brice, Fedro A. Peccatori, Alain Kentos, Isabelle Gaillard, Pierre Zachee, Rene-Olivier Casasnovas, Eric Van Den Neste, Julie Dechene, Vivianne De Maertelaer, Dominique Bron, Yvon Englert
Journal: Journal of Clinical Oncology (2012)

To assess the efficacy of gonadotropin-releasing hormone agonist (GnRHa) in preventing chemotherapy-induced ovarian failure in patients treated for Hodgkin or non-Hodgkin lymphoma within the setting of a multicenter, randomized, prospective trial.Patients age 18 to 45 years were randomly assigned to receive either the GnRHa triptorelin plus norethisterone (GnRHa group) or norethisterone alone (control group) concomitantly with alkylating agents containing chemotherapy. The primary end point was the premature ovarian failure (POF) rate (follicle-stimulating hormone [FSH] ≥ 40 IU/L) after 1 year of follow-up.Eighty-four of 129 randomly assigned patients completed the 1-year follow-up. The mean FSH values were higher in the control group than in the GnRHa group during chemotherapy; however, this difference was no longer observed after 6 months of follow-up. After 1 year, 20% and 19% of patients in the GnRHa and control groups, respectively, exhibited POF (P = 1.00). More than half of patients in each group completely restored their ovarian function (FSH < 10 IU/L), but the anti-Müllerian hormone values were higher in the GnRHa group than in the control group (1.4 ± 0.35 v 0.5 ± 0.15 ng/mL, respectively; P = .040). The occurrence of adverse events was similar in both groups with the exception of metrorrhagia, which was more frequently observed in the control group than the GnRHa group (38.4% v 15.6%, respectively; P = .024).Approximately 20% of patients in both groups exhibited POF after 1 year of follow-up. Triptorelin was not associated with a significant decreased risk of POF in young patients treated for lymphoma but may provide protection of the ovarian reserve.
Beta agonists, inhaled steroids, and the risk of intensive care unit admission for asthma
Authors: M.D. Eisner, T.A. Lieu, F. Chi, A.M. Capra, G.R. Mendoza, J.V. Selby, P.D. Blanc
Journal: European Respiratory Journal (2001)

Although inhaled corticosteroid (ICS) use is associated with a decreased risk of hospitalization for asthma, the impact of ICS on the risk of life-threatening asthma exacerbation is less clear. The effect of ICS and inhaled beta agonist (IBA) dispensing on the risk of intensive care unit admission for asthma, a surrogate for life-threatening exacerbation, is evaluated. Using computerized International classification of diseases (ICD)-9 discharge diagnoses, a cohort of all 2,344 adult Northern California members of a health maintenance organization hospitalized for asthma over a 2-yr period were identified. Computerized pharmacy data was used to ascertain asthma medications dispensed during the 3-, 6-, and 12-month intervals preceding index hospitalization for asthma. During the 3-months preceding hospitalization, a minority of subjects had no IBA units dispensed (34%), with 14% receiving low level (1 unit), 20% medium level (2–3 units), and 32% high level (≥4 units) therapy. A substantial proportion received no ICS units (55%), whereas 13% had low, 16% medium, and 15% high level therapy. In multiple logistic regression analysis, high level IBA use was associated with a greater risk of intensive care unit (ICU) admission for asthma after controlling for asthma severity. There was no relationship, however, between low or medium level IBA use and ICU admission. Conversely, medium level and high level ICS use were associated with a reduced risk of ICU admission. Analysing 6- and 12-month medication dispensing data, similar risk patterns were observed. Inhaled corticosteroid dispensing was associated with reduced risk of intensive care unit admission among adults hospitalized for asthma, whereas the opposite applied for high dose beta agonist usage. This suggests that ICS prescription to adults with moderate-to-severe asthma could reduce the risk of life-threatening exacerbation.
Electrophysiological and Antiarrhythmic Effects of the Atrial Selective 5-HT <sub>4</sub> Receptor Antagonist RS-100302 in Experimental Atrial Flutter and Fibrillation
Authors: Marc M. Rahme, Bruno Cotter, Elisabeth Leistad, Manish K. Wadhwa, Rajendra Mohabir, Anthony P. D. W. Ford, Richard M. Eglen, Gregory K. Feld
Journal: Circulation (1999)

Background —Stimulation of 5-HT 4 receptors increases atrial chronotropic and inotropic responses. Whether other electrophysiological effects are produced is unknown. In humans and swine, 5-HT 4 receptors are present only in atrium. Therefore, the effects of a novel 5-HT 4 receptor antagonist, RS-100302, and the partial agonist cisapride on atrial flutter and fibrillation induced in swine were studied to delineate the role of the 5-HT 4 receptor in modulating atrial electrophysiological properties and the antiarrhythmic potential of RS-100302. Methods and Results —In 17 anesthetized, open-chest, juvenile pigs, atrial flutter or fibrillation was induced by rapid right atrial pacing with or without a right atrial free wall crush injury, respectively. Atrial effective refractory period (ERP), conduction velocity, wavelength, and dispersion of refractoriness were determined during programmed stimulation via a 56-electrode mapping plaque sutured to the right atrial free wall. Ventricular electrophysiological parameters were also measured. All electrophysiological parameters were measured at baseline and after infusion of RS-100302 and cisapride. In the atrium, RS-100302 prolonged mean ERP (115±8 versus 146±7 ms, P &lt;0.01) and wavelength (8.3±0.9 versus 9.9±0.8 cm, P &lt;0.01), reduced dispersion of ERP (15±5 versus 8±1 ms, P &lt;0.01), and minimally slowed conduction velocity (72±4 versus 67±5 cm/s, P &lt;0.01). These effects were all partially reversed by cisapride. RS-100302 produced no ventricular electrophysiological effects. RS-100302 terminated atrial flutter in 6 of 8 animals and atrial fibrillation in 8 of 9 animals and prevented reinduction of sustained tachycardia in all animals. Conclusions —The electrophysiological profile of RS-100302 suggests that it may have atrial antiarrhythmic potential without producing ventricular proarrhythmic effects.
Progenitors for Ly-1 B cells are distinct from progenitors for other B cells.
Authors: K Hayakawa, R R Hardy, L A Herzenberg, L A Herzenberg
Journal: The Journal of Experimental Medicine (1985)

Data from previous multiparameter fluorescence-activated cell sorter (FACS) analysis and sorting studies define a subset of murine B cells that expresses the Ly-1 surface determinant in conjunction with IgM, IgD, Ia, and other typical B cell markers. These Ly-1 B cells are physically and functionally distinct. They express more IgM and less IgD than most other B cells; they are not normally found in lymph node or bone marrow; they are always present at low frequencies (1-5%) in normal spleens, and, as we show here, they comprise about half of the B cells (10-20% of total cells) recovered from the peritoneal cavity in normal mice. Furthermore, most of the commonly studied IgM autoantibodies in normal and autoimmune mice are produced by these Ly-1 B cells, even though they seldom produce antibodies to exogenous antigens such as trinitrophenyl-Ficoll or trinitrophenyl-keyhole limpet hemocyanin. Cell transfer studies presented here demonstrate that the progenitors of Ly-1 B cells are different from the progenitors of the predominant B cell populations in spleen and lymph node. In these studies, we used FACS analysis and functional assays to characterize donor-derived (allotype-marked) B cells present in lethally irradiated recipients 1-2 mo after transfer. Surprisingly, adult bone marrow cells typically used to reconstitute B cells in irradiated recipients selectively failed to reconstitute the Ly-1 B subset. Liver, spleen, and bone marrow cells from young mice, in contrast, reconstituted all B cells (including Ly-1 B), and peritoneal "washout" cells (PerC) from adult mice uniquely reconstituted Ly-1 B. Bone marrow did not block Ly-1 B development, since PerC and newborn liver still gave rise to Ly-1 B when jointly transferred with marrow. These findings tentatively assign Ly-1 B to a distinct developmental lineage originating from progenitors that inhabit the same locations as other B cell progenitors in young animals, but move to unique location(s) in adults.
Expression of EBV Latent Antigens, Mammalian Target of Rapamycin, and Tumor Suppression Genes in EBV-Positive Smooth Muscle Tumors: Clinical and Therapeutic Implications
Authors: Kong Wee Ong, Marissa Teo, Victor Lee, Danny Ong, Ann Lee, Chieh Suai Tan, A. Vathsala, Han Chong Toh
Journal: Clinical Cancer Research (2009)

EBV-positive smooth muscle tumor (EBV+SMT) is a rare disease with no established therapy. We describe the largest single institution analysis in renal transplant recipients. It aims to define its clinical features and determine the expression of EBV latent genes as well as key molecular pathways.Patients with EBV+SMT were identified from the Singapore General Hospital Renal Transplant Registry database. These tumors were investigated for expression of EBV latent genes with Southern blots, EBV latent antigens, mammalian target of rapamycin (mTOR), Akt, p70 S6 kinase, and vascular endothelial growth factor using immunohistochemistry, as well as methylation status of cancer-related genes using methylation-specific PCR.Eight were found to be EBV+SMT in 1,123 transplant patients. All displayed indolent clinical courses and were unresponsive to immunosuppression reduction. Complete tumor regression was seen in one patient following administration of sirolimus. These tumors display the full range of known EBV latent genes. Immunohistochemistry with total and phosphorylated mTOR and Akt were positive for all patients, and vascular endothelial growth factor was positive in 25% of patients, suggesting activation of the mTOR/Akt pathway. Methylation of RASSF1A was found in all tissue samples, whereas promoter hypermethylation of RARbeta, GSTP1, DAPK, and p14 was observed in some samples.Our results suggest that these tumors display a EBV type III latency pattern. The mTOR pathway is also activated. EBV may play a role in silencing RASSF1A. EBV-specific immunotherapy, mTOR inhibitors, and demethylating agents are possible therapeutic options in this disease.
Life Expectancy in Patients Surviving More Than 5 Years After Hematopoietic Cell Transplantation
Authors: Paul J. Martin, George W. Counts, Frederick R. Appelbaum, Stephanie J. Lee, Jean E. Sanders, H. Joachim Deeg, Mary E.D. Flowers, Karen L. Syrjala, John A. Hansen, Rainer F. Storb, Barry E. Storer
Journal: Journal of Clinical Oncology (2010)

PURPOSE Hematopoietic cell transplantation can cure hematologic malignancies and other diseases, but this treatment can also cause late complications. Previous studies have evaluated the cumulative effects of late complications on survival, but longer-term effects on life expectancy after hematopoietic cell transplantation have not been assessed. PATIENTS AND METHODS We used standard methods to evaluate mortality, projected life expectancy, and causes of death in a cohort of 2,574 patients who survived without recurrence of the original disease for at least 5 years after allogeneic or autologous hematopoietic cell transplantation from 1970 through 2002. Sex- and age-specific comparisons were made with US population data. Results Estimated survival of the cohort at 20 years after transplantation was 80.4% (95% CI, 78.1% to 82.6%). During 22,923 person-years of follow-up, 357 deaths occurred. Mortality rates remained four- to nine-fold higher than the expected population rate for at least 30 years after transplantation, yielding an estimated 30% lower life expectancy compared with that in the general population, regardless of current age. In rank order, the leading causes of excess deaths were second malignancies and recurrent disease, followed by infections, chronic graft-versus-host disease, respiratory diseases, and cardiovascular diseases. CONCLUSION Patients who have survived for at least 5 years after hematopoietic cell transplantation without recurrence of the original disease have a high probability of surviving for an additional 15 years, but life expectancy is not fully restored. Further effort is needed to reduce the burden of disease and treatment-related complications in this population.
Vitamin D Deficiency and Secondary Hyperparathyroidism in the Elderly: Consequences for Bone Loss and Fractures and Therapeutic Implications
Authors: Paul Lips
Journal: Endocrine Reviews (2001)

Vitamin D deficiency is common in the elderly, especially in the housebound and in geriatric patients. The establishment of strict diagnostic criteria is hampered by differences in assay methods for 25-hydroxyvitamin D. The synthesis of vitamin D3 in the skin under influence of UV light decreases with aging due to insufficient sunlight exposure, and a decreased functional capacity of the skin. The diet contains a minor part of the vitamin D requirement. Vitamin D deficiency in the elderly is less common in the United States than elsewhere due to the fortification of milk and use of supplements. Deficiency in vitamin D causes secondary hyperparathyroidism, high bone turnover, bone loss, mineralization defects, and hip and other fractures. Less certain consequences include myopathy and falls. A diet low in calcium may cause an increased turnover of vitamin D metabolites and thereby aggravate vitamin D deficiency. Prevention is feasible by UV light exposure, food fortification, and supplements. Vitamin D3 supplementation causes a decrease of the serum PTH concentration, a decrease of bone turnover, and an increase of bone mineral density. Vitamin D3 and calcium may decrease the incidence of hip and other peripheral fractures in nursing home residents. Vitamin D3 is recommended in housebound elderly, and it may be cost-effective in hip fracture prevention in selected risk groups.
<i>Pten</i> Loss and RAS/MAPK Activation Cooperate to Promote EMT and Metastasis Initiated from Prostate Cancer Stem/Progenitor Cells
Authors: David J. Mulholland, Naoko Kobayashi, Marcus Ruscetti, Allen Zhi, Linh M. Tran, Jiaoti Huang, Martin Gleave, Hong Wu
Journal: Cancer Research (2012)

PTEN loss or PI3K/AKT signaling pathway activation correlates with human prostate cancer progression and metastasis. However, in preclinical murine models, deletion of Pten alone fails to mimic the significant metastatic burden that frequently accompanies the end stage of human disease. To identify additional pathway alterations that cooperate with PTEN loss in prostate cancer progression, we surveyed human prostate cancer tissue microarrays and found that the RAS/MAPK pathway is significantly elevated in both primary and metastatic lesions. In an attempt to model this event, we crossed conditional activatable K-ras(G12D/WT) mice with the prostate conditional Pten deletion model. Although RAS activation alone cannot initiate prostate cancer development, it significantly accelerated progression caused by PTEN loss, accompanied by epithelial-to-mesenchymal transition (EMT) and macrometastasis with 100% penetrance. A novel stem/progenitor subpopulation with mesenchymal characteristics was isolated from the compound mutant prostates, which was highly metastatic upon orthotopic transplantation. Importantly, inhibition of RAS/MAPK signaling by PD325901, a mitogen-activated protein (MAP)-extracellular signal-regulated (ER) kinase (MEK) inhibitor, significantly reduced the metastatic progression initiated from transplanted stem/progenitor cells. Collectively, our findings indicate that activation of RAS/MAPK signaling serves as a potentiating second hit to alteration of the PTEN/PI3K/AKT axis, and cotargeting both the pathways is highly effective in preventing the development of metastatic prostate cancers.
Will We Ever Be Ready for Blood Level–Guided Therapy?
Authors: Christine M. Walko, Howard L. McLeod
Journal: Journal of Clinical Oncology (2008)

We live in an amazing era of oncology practice. The molecular mechanisms driving many cancers are being deciphered, and with this information come new targeted treatment approaches. Indeed, we now have kinase inhibitors and growth factor antagonists to treat cancers for which many had given up hope of progress (such as renal cell carcinoma). Improvements in imaging technology and radiologic technique allow greater functional insights into the metabolism, blood flow, and cellular homogeneity of tumors. The use of genomic technology is now providing tools for the prediction of disease recurrence, drug sensitivity, or invasive potential. Yet, in the midst of all the excitement, we still find ourselves not able to apply some simple principles in daily practice. Therapeutic drug monitoring (TDM) is considered relatively
UPREGULATION OF HYPOXIA-INDUCIBLE FACTOR BY DI-METHYL OXALYL GLYCINE (DMOG) INCREASES NEOVASCULARIZATION WITHIN ISCHAEMIC MYOCARDIUM IN A PORCINE CORONARY OCCLUSION MODEL
Authors: Damian John Kelly, Jasmin Mecinovic, Nadine Arnold, Kim Suvarna, Christopher J. Schofield, Julian Gunn, Anthony H. Gershlick
Journal: Journal of the American College of Cardiology (2010)
High-Dose Oral Tamoxifen, a Potential Multidrug-Resistance-Reversal Agent: Phase I Trial in Combination With Vinblastine
Authors: D. L. Trump, D. C. Smith, P. G. Ellis, M. P. Rogers, S. C. Schold, E. P. Winer, T. J. Panella, V. C. Jordan, R. L. Fine
Journal: JNCI Journal of the National Cancer Institute (1992)

P-glycoprotein mediates resistance to natural-product anti-neoplastic agents like vinblastine through an active transport process resulting in reduced intracellular concentration of these agents. The triphenylethylene antiestrogen tamoxifen and its major metabolite N-desmethyltamoxifen at concentrations of 4-6 microM enhance the intracellular concentration of natural-product antineoplastics and augment the cytotoxicity of such drugs three-fold to 10-fold in a variety of human and murine cell lines.On the basis of these preclinical findings, we conducted a phase I clinical trial of high-dose, oral tamoxifen administered in conjunction with a 5-day continuous infusion of vinblastine.We studied 53 patients with advanced epithelial tumors. Tamoxifen was given orally as a loading dose on day 1, followed by two doses a day on days 2-13. Vinblastine was given as a 120-hour continuous infusion (1.5 mg/m2 per day) on days 9-13 of each tamoxifen course. The starting dose of tamoxifen was 40 mg/m2 administered twice a day following a loading dose of 150 mg/m2. The maximum dose was 260 mg/m2 twice a day following a loading dose of 680 mg/m2. Treatment cycles were repeated every 28 days.The dose-limiting toxic effects of tamoxifen were neurologic and began within 3-5 days after the start of treatment. They consisted of tremor, hyperreflexia, dysmetria, unsteady gait, and dizziness. One patient experienced a grand mal seizure 24 hours after the last tamoxifen dose. Toxic effects were rapidly reversible. Asymptomatic prolongation of the QT interval on electrocardiogram occurred at doses of tamoxifen of 80 mg/m2 or higher given twice a day. No coagulation or ophthalmologic abnormalities occurred. Tamoxifen did not enhance the toxicity of vinblastine. Mean plasma concentrations of tamoxifen or N-desmethyltamoxifen at 260 mg/m2 tamoxifen given twice a day for 13 days were 6.04 and 6.56 microM, respectively. There was no relationship between plasma antiestrogen content and the development of neurotoxic effects.Tamoxifen at 150 mg/m2 given twice a day following a loading dose of 400 mg/m2 results in plasma levels of tamoxifen and N-desmethyltamoxifen of 4 and 6 microM, respectively, without dose-limiting toxicity. We recommend this dose for phase II trials of tamoxifen to modulate P-glycoprotein-mediated drug resistance.Our study demonstrates that high-dose tamoxifen can be safely administered and that plasma concentrations that may inhibit P-glycoprotein function can be achieved.
The immune responses in CD40-deficient mice: Impaired immunoglobulin class switching and germinal center formation
Authors: Tsutomu Kawabe, Tetsuji Naka, Kanji Yoshida, Takashi Tanaka, Hiroshi Fujiwara, Sachiko Suematsu, Nobuaki Yoshida, Tadamitsu Kishimoto, Hitoshi Kikutani
Journal: Immunity (1994)
Unc119, a Novel Activator of Lck/Fyn, Is Essential for T Cell Activation
Authors: Magdalena M. Gorska, Susan J. Stafford, Osman Cen, Sanjiv Sur, Rafeul Alam
Journal: The Journal of Experimental Medicine (2004)

The first step in T cell receptor for antigen (TCR) signaling is the activation of the receptor-bound Src kinases, Lck and Fyn. The exact mechanism of this process is unknown. Here, we report that the novel Src homology (SH) 3/SH2 ligand–Uncoordinated 119 (Unc119) associates with CD3 and CD4, and activates Lck and Fyn. Unc119 overexpression increases Lck/Fyn activity in T cells. In Unc119-deficient T cells, Lck/Fyn activity is dramatically reduced with concomitant decrease in interleukin 2 production and cellular proliferation. Reconstitution of cells with Unc119 reverses the signaling and functional outcome. Thus, Unc119 is a receptor-associated activator of Src-type kinases. It provides a novel mechanism of signal generation in the TCR complex.