tbuckley/cabot-search huggingface dataset:
Activation of Signal Transducer and Activator of Transcription 5 in Human Prostate Cancer Is Associated with High Histological Grade
Authors: Hongzhen Li, Tommi J. Ahonen, Kalle Alanen, Jianwu Xie, Matthew J. LeBaron, Thomas G. Pretlow, Erica L. Ealley, Ying Zhang, Martti Nurmi, Baljit Singh, Paula M. Martikainen, Marja T. Nevalainen
Journal: Cancer Research (2004)

Abstract We have recently identified signal transducer and activator of transcription 5 (Stat5) as a critical survival factor for prostate cancer cells. We now report that activation of Stat5 is associated with high histological grade of human prostate cancer. Specifically, immunohistochemical analysis demonstrated a strong positive correlation with activation of Stat5 and high Gleason score in 114 human prostate cancers. To investigate the mechanisms underlying constitutive activation of Stat5 in prostate cancer, a dominant-negative mutant of Janus kinase 2 (Jak2) was delivered by adenovirus to CWR22Rv cells. Dominant-negative-Jak2 effectively blocked the activation of Stat5 whereas wild-type Jak2 enhanced activation, indicating that Jak2 is the main kinase that phosphorylates Stat5 in human prostate cancer cells. A ligand-induced mechanism for activation of Stat5 in prostate cancer was suggested by the ability of prolactin (Prl) to stimulate activation of both Jak2 and Stat5 in CWR22Rv human prostate cancer cells and in CWR22Rv xenograft tumors. In addition, Prl restored constitutive activation of Stat5 in five of six human prostate cancer specimens in ex vivo long-term organ cultures. Finally, Prl protein was locally expressed in the epithelium of 54% of 80 human prostate cancer specimens with positive correlation with high Gleason scores and activation of Stat5. In conclusion, our data indicate that increased activation of Stat5 was associated with more biologically aggressive behavior of prostate cancer. The results further suggest that Jak2 is the principal Stat5 tyrosine kinase in human prostate cancer, possibly activated by autocrine/paracrine Prl.
A Dual PI3K/mTOR Inhibitor, PI-103, Cooperates with Stem Cell–Delivered TRAIL in Experimental Glioma Models
Authors: Tugba Bagci-Onder, Hiroaki Wakimoto, Maarten Anderegg, Cody Cameron, Khalid Shah
Journal: Cancer Research (2010)

The resistance of glioma cells to a number of antitumor agents and the highly invasive nature of glioma cells that escape the primary tumor mass are key impediments to the eradication of tumors in glioma patients. In this study, we evaluated the therapeutic efficacy of a novel PI3-kinase/mTOR inhibitor, PI-103, in established glioma lines and primary CD133(+) glioma-initiating cells and explored the potential of combining PI-103 with stem cell-delivered secretable tumor necrosis factor apoptosis-inducing ligand (S-TRAIL) both in vitro and in orthotopic mouse models of gliomas. We show that PI-103 inhibits proliferation and invasion, causes G(0)-G(1) arrest in cell cycle, and results in significant attenuation of orthotopic tumor growth in vivo. Establishing cocultures of neural stem cells (NSC) and glioma cells, we show that PI-103 augments the response of glioma cells to stem cell-delivered S-TRAIL. Using bimodal optical imaging, we show that when different regimens of systemic PI-103 delivery are combined with NSC-derived S-TRAIL, a significant reduction in tumor volumes is observed compared with PI-103 treatment alone. To our knowledge, this is the first study that reveals the antitumor effect of PI-103 in intracranial gliomas. Our findings offer a preclinical rationale for application of mechanism-based systemically delivered antiproliferative agents and novel stem cell-based proapoptotic therapies to improve treatment of malignant gliomas.
Sarcoplasmic Reticulum Ca <sup>2+</sup> Refilling Controls Recovery From Ca <sup>2+</sup> -Induced Ca <sup>2+</sup> Release Refractoriness in Heart Muscle
Authors: Peter Szentesi, Christophe Pignier, Marcel Egger, Evangelia G. Kranias, Ernst Niggli
Journal: Circulation Research (2004)

In cardiac muscle Ca 2+ -induced Ca 2+ release (CICR) from the sarcoplasmic reticulum (SR) is initiated by Ca 2+ influx via L-type Ca 2+ channels. At present, the mechanisms underlying termination of SR Ca 2+ release, which are required to ensure stable excitation-contraction coupling cycles, are not precisely known. However, the same mechanism leading to refractoriness of SR Ca 2+ release could also be responsible for the termination of CICR. To examine the refractoriness of SR Ca 2+ release, we analyzed Na + -Ca 2+ exchange currents reflecting cytosolic Ca 2+ signals induced by UV-laser flash-photolysis of caged Ca 2+ . Pairs of UV flashes were applied at various intervals to examine the time course of recovery from CICR refractoriness. In cardiomyocytes isolated from guinea-pigs and mice, β-adrenergic stimulation with isoproterenol-accelerated recovery from refractoriness by ≈2-fold. Application of cyclopiazonic acid at moderate concentrations (&lt;10 μmol/L) slowed down recovery from refractoriness in a dose-dependent manner. Compared with cells from wild-type littermates, those from phospholamban knockout (PLB-KO) mice exhibited almost 5-fold accelerated recovery from refractoriness. Our results suggest that SR Ca 2+ refilling mediated by the SR Ca 2+ -pump corresponds to the rate-limiting step for recovery from CICR refractoriness. Thus, the Ca 2+ sensitivity of CICR appears to be regulated by SR Ca 2+ content, possibly resulting from a change in the steady-state Ca 2+ sensitivity and in the gating kinetics of the SR Ca 2+ release channels (ryanodine receptors). During Ca 2+ release, the concomitant reduction in Ca 2+ sensitivity of the ryanodine receptors might also underlie Ca 2+ spark termination by deactivation.
Induction of potent antitumor immunity by in situ targeting of intratumoral DCs
Authors: Katsuyoshi Furumoto, Luis Soares, Edgar G. Engleman, Miriam Merad
Journal: Journal of Clinical Investigation (2004)

Recent reports of tumor regression following delivery of autologous tumor antigen-pulsed DCs suggest that defective antigen presentation may play a key role in tumor escape. Here we show in two different murine tumor models, CT26 (colon adenocarcinoma) and B16 (melanoma), that the number and activation state of intratumoral DCs are critical factors in the host response to tumors. We used CCL20/macrophage inflammatory protein-3alpha (MIP-3alpha) chemokine to increase the number of tumoral DCs and intratumoral injections of CG-rich motifs (CpGs) to activate such cells. Expression of CCL20 in the tumor site attracted large numbers of circulating DCs into the tumor mass and, in the case of CT26 tumors, led to complete tumor regression. Intratumoral CpG injections, in addition to CCL20, were required to induce therapeutic immunity against B16 tumors. In this model CpG overcame tumor-mediated inhibition of DC activation and enabled tumoral DCs to cross-present tumor antigens to naive CD8 T cells. CpG activation of tumoral DCs alone was not sufficient to induce tumor regression in either tumor model, nor was systemic delivery of the DC growth factor, Flt3 ligand, which dramatically increased the number of circulating DCs but not the number of tumoral DCs. These results indicate that the number of tumoral DCs as well as the tumor milieu determines the ability of tumor-bearing hosts to mount an effective antitumor immune response. Our results also suggest that DCs can be manipulated in vivo without delivery of defined tumor antigens to induce a specific T cell-mediated antitumor response and provide the basis for the use of chemokines in DC-targeted clinical strategies.
Clinical Studies of Cyclazocine in the Treatment of Narcotic Addiction
Authors: ALFRED M. FREEDMAN, MAX FINK, ROBERT SHAROFF, ARTHUR ZAKS
Journal: American Journal of Psychiatry (1968)

Cyclazocine, a long-acting narcotic antagonist, was found to be safe and useful in the treatment of narcotic addicts in a voluntary municipal hospital. Treatment induction in 15 days to a daily maintenance dose of 4.0 mg. was well tolerated. That dosage effectively blocked clinical and EEG effects of challenges with 15 mg. of intravenous heroin, administered in two minutes, for periods greater than 24 hours. Cyclazocine treatment permits "engagement" and continuity of rehabilitation and resocialization efforts, and provides a useful alternative to the methadone maintenance treatment model.
Tailored Education May Reduce Health Literacy Disparities in Asthma Self-Management
Authors: Michael K. Paasche-Orlow, Kristin A. Riekert, Andrew Bilderback, Arjun Chanmugam, Peter Hill, Cynthia S. Rand, Fred L. Brancati, Jerry A. Krishnan
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Although inadequate health literacy has been associated with lower asthma medication knowledge and worse metered-dose inhaler (MDI) technique, the relationship between health literacy and the capacity to learn asthma self-management skills is unknown.In this prospective cohort study of adults hospitalized for severe asthma exacerbations at two inner-city hospitals, we examined the relationship between inadequate health literacy and difficulties learning and retaining instructions about discharge medications and appropriate MDI technique.At hospital discharge, participants received one-on-one, 30-min, guideline-based, written and oral instruction about their asthma discharge regimen as well as appropriate MDI technique.Seventy-three patients were enrolled. Inadequate health literacy was identified in 16 (22%) participants. Before instruction, inadequate health literacy was associated with lower asthma medication knowledge (5.2/10 vs. 7.2/10, p < 0.001) and worse MDI technique (3.2/6 vs. 3.9/6, p = 0.03). However, inadequate health literacy was not associated with difficulty learning (p = 0.33) or retaining (p = 0.35) instructions about the discharge regimen. Similarly, inadequate health literacy was not associated with difficulty learning (p = 0.26) or retaining (p = 0.97) appropriate MDI technique. Results were similar in multivariable models adjusted for demographic characteristics and asthma severity indicators.These findings suggest that inadequate health literacy is a surmountable barrier to learning and remembering key asthma self-management skills.
Virally delivered Channelrhodopsin-2 Safely and Effectively Restores Visual Function in Multiple Mouse Models of Blindness
Authors: M Mehdi Doroudchi, Kenneth P Greenberg, Jianwen Liu, Kimberly A Silka, Edward S Boyden, Jennifer A Lockridge, A Cyrus Arman, Ramesh Janani, Shannon E Boye, Sanford L Boye, Gabriel M Gordon, Benjamin C Matteo, Alapakkam P Sampath, William W Hauswirth, Alan Horsager
Journal: Molecular Therapy (2011)

Previous work established retinal expression of channelrhodopsin-2 (ChR2), an algal cation channel gated by light, restored physiological and behavioral visual responses in otherwise blind rd1 mice. However, a viable ChR2-based human therapy must meet several key criteria: (i) ChR2 expression must be targeted, robust, and long-term, (ii) ChR2 must provide long-term and continuous therapeutic efficacy, and (iii) both viral vector delivery and ChR2 expression must be safe. Here, we demonstrate the development of a clinically relevant therapy for late stage retinal degeneration using ChR2. We achieved specific and stable expression of ChR2 in ON bipolar cells using a recombinant adeno-associated viral vector (rAAV) packaged in a tyrosine-mutated capsid. Targeted expression led to ChR2-driven electrophysiological ON responses in postsynaptic retinal ganglion cells and significant improvement in visually guided behavior for multiple models of blindness up to 10 months postinjection. Light levels to elicit visually guided behavioral responses were within the physiological range of cone photoreceptors. Finally, chronic ChR2 expression was nontoxic, with transgene biodistribution limited to the eye. No measurable immune or inflammatory response was observed following intraocular vector administration. Together, these data indicate that virally delivered ChR2 can provide a viable and efficacious clinical therapy for photoreceptor disease-related blindness.
Experimental obesity in man: cellular character of the adipose tissue
Authors: Lester B. Salans, Edward S. Horton, Ethan A. H. Sims
Journal: Journal of Clinical Investigation (1971)

Studies of adipose tissue cellularity were carried out in a group of nonobese adult male volunteers who gained 15-25% of their body weight as the result of prolonged high caloric intake. Adipose cell size (lipid content per cell) was determined in tissue obtained from three subcutaneous sites (gluteal, anterior abdominal wall, and triceps) and total adipose cell number estimated from measurement of total body fat.
Oestrogen receptor co-activator AIB1 is a marker of tamoxifen benefit in postmenopausal breast cancer
Authors: M. Weiner, L. Skoog, T. Fornander, B. Nordenskjöld, D.C. Sgroi, O. Stål
Journal: Annals of Oncology (2013)

The oestrogen receptor (ER) co-activator amplified in breast cancer 1 (AIB1) has been suggested as a treatment predictive and prognostic marker in breast cancer. Studies have however not been unanimous.AIB1 protein expression was analysed by immunohistochemistry on tissue micro-arrays with tumour samples from 910 postmenopausal women randomised to tamoxifen treatment or no adjuvant treatment. Associations between AIB1 expression, clinical outcome in the two arms and other clinicopathological variables were examined.In patients with ER-positive breast cancer expressing low tumour levels of AIB1 (<75%), we found no significant difference in recurrence-free survival (RFS) or breast cancer-specific survival (BCS) between tamoxifen treated and untreated patients. In patients with high AIB1 expression (>75%), there was a significant decrease in recurrence rate (HR 0.40, 95% CI 0.26-0.61, P < 0.001) and breast cancer mortality rate (HR 0.38, 95% CI 0.21-0.69, P = 0.0015) with tamoxifen treatment. In the untreated arm, we found high expression of AIB1 to be significantly associated with lower RFS (HR 1.74, 95% CI 1.20-2.53, P = 0.0038).Our results suggest that high AIB1 is a predictive marker of good response to tamoxifen treatment in postmenopausal women and a prognostic marker of decreased RFS in systemically untreated patients.
Risk of Embolism and Death in Infective Endocarditis: Prognostic Value of Echocardiography
Authors: Franck Thuny, Giovanni Disalvo, Olivier Belliard, Jean-François Avierinos, Valeria Pergola, Valerie Rosenberg, Jean-Paul Casalta, Joanny Gouvernet, Geneviève Derumeaux, Diana Iarussi, Pierre Ambrosi, Raffaello Calabro, Alberto Riberi, Frédéric Collart, Dominique Metras, Hubert Lepidi, Didier Raoult, Jean-Robert Harle, Pierre-Jean Weiller, Ariel Cohen, Gilbert Habib
Journal: Circulation (2005)

The incidence of embolic events (EE) and death is still high in patients with infective endocarditis (IE), and data about predictors of these 2 major complications are conflicting. Moreover, the exact role of echocardiography in risk stratification is not well defined. In a multicenter prospective European study, including 384 consecutive patients (aged 57+/-17 years) with definite IE according to Duke University criteria, we tested clinical, microbiological, and echocardiographic data as potential predictors of EE and 1-year mortality. Transesophageal echocardiography was performed in all patients. Embolism occurred before or after IE diagnosis (total-EE) in 131 patients (34.1%) and after initiation of antibiotic therapy (new-EE) in 28 patients (7.3%). Staphylococcus aureus and Streptococcus bovis were independently associated with total-EE, whereas vegetation length >10 mm and severe vegetation mobility were predictors of new-EE, even after adjustment for S aureus and S bovis. One-year mortality was 20.6%. In multivariable analysis, independently of the other predictors of death (age, female sex, creatinine serum >2 mg/L, moderate or severe congestive heart failure, and S aureus) and comorbidity, vegetation length >15 mm was a predictor of 1-year mortality (adjusted relative risk=1.8; 95% CI, 1.10 to 2.82; P=0.02). In IE, vegetation length is a strong predictor of new-EE and mortality. In combination with clinical and microbiological findings, echocardiography may identify high-risk patients who will need a more aggressive therapeutic strategy.
Weekly Dosing With the Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor SU9518 Significantly Inhibits Arterial Stenosis
Authors: Yasundo Yamasaki, Kazuhisa Miyoshi, Nobuyuki Oda, Motomu Watanabe, Hidekazu Miyake, Julie Chan, Xueyan Wang, Li Sun, Cho Tang, Gerald McMahon, Kenneth E. Lipson
Journal: Circulation Research (2001)

Abstract —The platelet-derived growth factor (PDGF) ligands and their receptors have been implicated as critical regulators of the formation of arterial lesions after tissue injury. SU9518 (3[5-{5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl}-2,4-dimethyl-1 H -pyrrol-3-yl]propionic acid) is a novel synthetic indolinone that potently and selectively inhibits the cellular PDGF receptor kinase and PDGF receptor–induced cell proliferation. Inhibition of PDGF receptor phosphorylation in cell-based assays occurs within 5 minutes after drug exposure and persists for &gt;6 hours after drug removal. The pharmacokinetics indicate plasma levels that exceeded the effective concentration required to inhibit the PDGF receptor in cells for up to 8 hours or 7 days after a single oral or subcutaneous administration, respectively. In the rat balloon arterial injury–induced stenosis model, once-daily oral or once-weekly subcutaneous administration of SU9518 reduced intimal thickening of the carotid artery (ratio of neointimal to medial area, 1.94±0.38 versus 1.03±0.29 [ P &lt;0.01] 2.21±0.32 versus 1.34±0.45 [ P &lt;0.01], respectively). These studies provide the rationale to evaluate PDGF receptor tyrosine kinase inhibitors, including inhibitors related to the indolinone, SU9518, for the treatment of arterial restenosis.
Association Between Popliteal Artery Wall Thickness and Knee Structure in Adults Without Clinical Disease of the Knee: A Prospective Cohort Study
Authors: Yuanyuan Wang, Diaz Novera, Anita E. Wluka, Jessica Fairley, Graham G. Giles, Richard O'Sullivan, Flavia M. Cicuttini
Journal: Arthritis & Rheumatology (2014)

There is evidence of a vascular contribution to the pathogenesis of osteoarthritis (OA). The aim of this study was to examine the association between popliteal artery wall thickness, which was previously shown to be associated with the risk of OA, and structural changes in the knee in an asymptomatic cohort. A total of 297 adults with no significant knee pain, injury, or history of clinical knee disease were recruited. Participants underwent magnetic resonance imaging of the knee at baseline and 2 years later. Popliteal artery wall thickness, knee cartilage volume, and bone marrow lesions (BMLs) were assessed. Of 278 participants with valid popliteal artery wall thickness measurements, 254 (91.4%) completed the 2-year followup assessment. After adjusting for age, sex, body mass index, and tibial bone area, increased popliteal artery wall thickness was found to be associated with a reduced medial tibial cartilage volume (B = -6.7 [95% confidence interval (95% CI) -12.9, -0.6], P = 0.03) and an increased rate of medial tibial cartilage volume loss (B = 0.06 [95% CI 0.01, 0.12], P = 0.03). There was a trend toward worsening of medial tibiofemoral BMLs in relation to increased popliteal artery wall thickness (odds ratio 1.07 [95% CI 0.99, 1.15]; P = 0.07). No significant associations with the lateral tibiofemoral compartment were observed. Increased popliteal artery wall thickness was associated with adverse changes in knee structure, as evidenced by reduced medial tibial cartilage volume, increased rate of cartilage volume loss, and a trend toward worsening of BMLs over 2 years. These findings suggest an association between vascular pathology and early structural changes in the knee, which supports the hypothesis that vascular health may play a role in the development of knee OA.
Birth weight of offspring and insulin resistance in late adulthood: cross sectional survey
Authors: D. A Lawlor
Journal: BMJ (2002)

<h3>Abstract</h3> <b>Objective:</b> To investigate the association between birth weight of offspring and mothers9 insulin resistance in late adulthood. <b>Design:</b> Cross sectional survey. <b>Setting:</b> General practitioner9s surgeries in 23 towns in Great Britain. <b>Participants:</b> 4286 women aged 60-79 years <b>Main outcome measures:</b> Maternal insulin resistance <b>Results:</b> Birth weight of offspring was inversely related to maternal insulin resistance in late adulthood. For each 1 kg higher birth weight of offspring, women had a 15% reduction in the odds of being in the fourth with highest insulin resistance, compared to other fourths (odds ratio 0.85; 95% confidence interval 0.71 to 1.00). This increased to 27% (0.73; 0.60 to 0.90) after adjusting data for potential confounders. A U shaped relation between birth weight of offspring and diabetes in older age was found; women with the lightest and heaviest offspring had the highest prevalence of diabetes <b>Conclusions:</b> Birth weight of offspring is inversely related to the mother9s insulin resistance in late adulthood, despite the association of glucose intolerance during pregnancy with heavier offspring at birth. Common genetic factors contribute to the relation between birth weight and risk of cardiovascular disease and diabetes in adults
Relationship of Insulin Resistance and Related Metabolic Variables to Coronary Artery Disease: A Mathematical Analysis
Authors: David Eddy, Len Schlessinger, Richard Kahn, Barbara Peskin, Rick Schiebinger
Journal: Diabetes Care (2008)

People with diabetes have an increased risk of coronary artery disease (CAD). An unanswered question is what portion of CAD can be attributed to insulin resistance, related metabolic variables, and other known CAD risk factors.
Respiratory Responses to Experimental Unilobar Pulmonary Edema
Authors: FRANK D. GRAY, DONALD P. SHEDD, EIICHI KATO
Journal: Circulation Research (1958)

The effect of unilobar engorgement and edema in a dog's lung on the effort of breathing was studied by expressing the latter as the velocity of air-flow attained per unit of pressure change across the lung, and as static compliance. Edema of the left lower lobe, produced by shunting blood from the femoral into the pulmonary artery, affected the effort of breathing only at high infusion rates and volumes, otherwise changes in resting (mid) position and respiratory rate kept the effort of breathing constant. Static compliance decreased with infusion, possibly because the infused blood encroached on the air space.