tbuckley/cabot-search huggingface dataset:
Abstract 18430: Conditional Deletion of Aryl Hydrocarbon Nuclear Translocator (Hypoxia Inducible Factor 1-Beta) in the Adult Heart Results in Cardiomyopathy Associated with Autophagy
Authors: Rongxue Wu, Kusum Chawla, Yoshihiko Ichikawa, Mohsen Ghanefar, Hossein Ardehali
Journal: Circulation (2010)

Background: Aryl hydrocarbon receptor nuclear translocator (ARNT) is a member of the basic helix-loop-helix Per/ARNT/Sim (bHLH-PAS) proteins and serves as a binding partner for a number of other family members. ARNT is also a required dimerization partner of HIF1alpha. Although HIF1alpha is essential for normal cardiac development, the role of ARNT in basal cardiac function in the adult heart is not known. We hypothesized that ARNT is necessary for normal cardiac physiology, and its deletion in adult heart results in cardiomyopathy.

Methods and Results: The deletion of ARNT gene in the hearts of 3 month old mice was achieved by crossing ARNTflox/flox mice with αMHC-MCM (tamoxifen-inducible heart specific Cre) transgenic mice followed by administration of tamoxifen by mouth. MHC-MCM/ARNT+/+ (WT) littermates were used as a control. The ARNT knock out (KO) mice exhibited enlarged left ventricle with a significant reduction in ejection fraction (KO vs. WT: 35.8 ± 3.6% vs. 61.2 ± 2.8%, n=12, p<0.01) and fractional shortening (KO vs. WT: 18.3 ± 1.5 % vs. 30.1 ± 1.1%, p<0.01), assessed by echocardiography. Closed-chest catheterization also demonstrated reduced +dP/dt (KO vs. WT: 4355 ± 538 vs. 9426 ± 180 mmHg, p<0.01) and increased left ventricular end diastolic pressure (KO vs. WT: 3.12 ± 1.1 vs. 8.47± 1.2 mmHg, P<0.05) in KO mice but not in WT mice. The worsened cardiac function in the KO mouse heart was associated with increases in ANF and BNP expression, interstitial fibrosis, and apoptosis as determined by TUNEL staining. Furthermore, electron microscopy revealed a variety of degenerative changes in the KO hearts. To determine the mechanism for cell death, we then assessed markers of autophagy in ARNT KO hearts. Beclin-1 expression was significantly higher in ARNT KO hearts than in WT hearts (p<0.01). Induction of autophagy in KO hearts was further confirmed by increased conversion of LC-3I to LC3-II.

Conclusion: ARNT is essential for the maintenance of structural and functional homeostasis in the adult heart, and its inactivation leads to cardiac contractile dysfunction. Our findings implicate a novel critical transcriptional requirement for ARNT in the maintenance of adult cardiac function.
Therapeutic affect reduction, emotion regulation, and emotional memory reconsolidation: A neuroscientific quandary
Authors: Kevin S. LaBar
Journal: Behavioral and Brain Sciences (2015)

Lane et al. emphasize the role of emotional arousal as a precipitating factor for successful psychotherapy. However, as therapy ensues, the arousal diminishes. How can the unfolding therapeutic process generate long-term memories for reconsolidated emotional material without the benefit of arousal? Studies investigating memory for emotionally regulated material provide some clues regarding the neural pathways that may underlie therapy-based memory reconsolidation.
Delivery of antigen to nasal-associated lymphoid tissue microfold cells through secretory IgA targeting local dendritic cells confers protective immunity
Authors: Nicolas Rochereau, Vincent Pavot, Bernard Verrier, Fabienne Jospin, Agathe Ensinas, Christian Genin, Blaise Corthésy, Stéphane Paul
Journal: Journal of Allergy and Clinical Immunology (2015)
Activating somatic mutations outside the SH2-domain of STAT3 in LGL leukemia
Authors: E Andersson, H Kuusanmäki, S Bortoluzzi, S Lagström, A Parsons, H Rajala, A van Adrichem, S Eldfors, T Olson, M J Clemente, A Laasonen, P Ellonen, C Heckman, T P Loughran, J P Maciejewski, S Mustjoki
Journal: Leukemia (2015)
Factors influencing prostate cancer specific mortality in patients receiving delayed androgen deprivation therapy for metastasis after biochemical recurrence following radical prostatectomy
Authors: D. V. Makarov, B. J. Trock, E. B. Humphreys, L. A. Mangold, M. A. Carducci, A. W. Partin, M. A. Eisenberger, P. C. Walsh
Journal: Journal of Clinical Oncology (2006)

4571 Background: For men developing PSA failure after radical prostatectomy (RP), administration of immediate androgen deprivation therapy (ADT) has not been shown to improve survival compared to delaying ADT until evidence of metastatic disease. We evaluated factors influencing prostate cancer (PCa) specific mortality (PCSM) in a cohort of PSA era patients developing metastases after RP treated with delayed ADT. Methods: 3,658 men had RP by a single surgeon at Johns Hopkins Hospital from 4/82 until 6/05. 553 had PSA failure. 216 developed radiographically evident distant metastasis. Of these, 91 men formed the study cohort: initially treated during the PSA era (1987–2005), received ADT only after documented metastasis, and having complete data. 41 of these men died. Median failure times were estimated with the Kaplan-Meier method. Prognostic impact was estimated as the hazard ratio (HR) derived from the Cox proportional hazards model. Results: Median followup from RP was 10 yrs (range 2–18). Actuarial median failure times are: 1 yr from RP to PSA failure (range 1–11), 32 mos from PSA failure to metastasis (range 0–129), 79 mos from metastasis to death (range 7–181), and 13 yrs from RP to death (range 2–18). The following variables were significant prognostic factors for PCSM in univariate analyses: Pain at diagnosis of metastases (p &lt; 0.01), time from RP to metastasis (p = 0.02), hematocrit at metastasis (p &lt; 0.01) and PSADT &lt;3 mos during the 2 years prior to metastasis (p &lt; 0.01). A multivariable Cox proportional hazards model demonstrated the following independent predictors of PCSM: pain (HR = 10.5 p &lt; 0.01), PSA at metastasis ≥100 ng/mL (HR = 5.3 p &lt; 0.01) and PSADT &lt; 3 months (HR = 7.1 p &lt; 0.01). PSADT determined in the two years immediately after PSA failure (HR = 1.0 p = 0.37) and time from RP to bone metastasis (HR = 1.0 p = 0.80) were not independent predictors of PCSM. Conclusion: Men receiving delayed ADT for development of metastasis after RP may have a prolonged survival time (13 yrs post RP - range 2–18). Optimizing the time for ADT in these patients requires well-designed, prospective randomized studies. Our data may facilitate the selection of patients and thresholds for implementation of ADT. No significant financial relationships to disclose.
Inhaled Technosphere Insulin Versus Inhaled Technosphere Placebo in Insulin-Naïve Subjects With Type 2 Diabetes Inadequately Controlled on Oral Antidiabetes Agents
Authors: Julio Rosenstock, Denise Franco, Vadym Korpachev, Brad Shumel, Yuhui Ma, Robert Baughman, Nikhil Amin, Janet B. McGill
Journal: Diabetes Care (2015)

To investigate the efficacy and safety of prandial Technosphere inhaled insulin (TI), an inhaled insulin with a distinct time action profile, in insulin-naïve type 2 diabetes (T2D) inadequately controlled on oral antidiabetes agents (OADs).Subjects with T2D with HbA1c levels ≥7.5% (58.5 mmol/mol) and ≤10.0% (86.0 mmol/mol) on metformin alone or two or more OADs were randomized to add-on prandial TI (n = 177) or prandial Technosphere inhaled placebo (TP) (n = 176) to their OAD regimen in this double-blind, placebo-controlled trial. Primary end point was change in HbA1c at 24 weeks.TI significantly reduced HbA1c by -0.8% (-9.0 mmol/mol) from a baseline of 8.3% (66.8 mmol/mol) compared with TP -0.4% (-4.6 mmol/mol) (treatment difference -0.4% [95% CI -0.57, -0.23]; P < 0.0001). More TI-treated subjects achieved an HbA1c ≤7.0% (53.0 mmol/mol) (38% vs. 19%; P = 0.0005). Mean fasting plasma glucose was similarly reduced in both groups. Postprandial hyperglycemia, based on 7-point glucose profiles, was effectively controlled by TI. Mean weight change was 0.5 kg for TI and -1.1 kg for the TP group (P < 0.0001). Mild, transient dry cough was the most common adverse event, occurring similarly in both groups (TI, 23.7%; TP, 19.9%) and led to discontinuation in only 1.1% of TI-treated and 3.4% of TP-treated subjects. There was a small decline in forced expiratory volume in 1 s in both groups, with a slightly larger decline in the group receiving TI (TI, -0.13 L; TP, -0.04 L). The difference resolved after treatment discontinuation.Prandial TI added to one or more OADs in inadequately controlled T2D is an effective treatment option. Mild, transient dry cough was the most common adverse event.
Mental illness, challenging behaviour, and psychotropic drug prescribing in people with intellectual disability: UK population based cohort study
Authors: Rory Sheehan, Angela Hassiotis, Kate Walters, David Osborn, André Strydom, Laura Horsfall
Journal: BMJ (2015)

<b>Objectives</b> To describe the incidence of recorded mental illness and challenging behaviour in people with intellectual disability in UK primary care and to explore the prescription of psychotropic drugs in this group. <b>Design</b> Cohort study. <b>Setting</b> 571 general practices contributing data to The Health Improvement Network clinical database. <b>Participants</b> 33 016 adults (58% male) with intellectual disability who contributed 211 793 person years’ data. <b>Main outcome measures</b> Existing and new records of mental illness, challenging behaviour, and psychotropic drug prescription. <b>Results</b> 21% (7065) of the cohort had a record of mental illness at study entry, 25% (8300) had a record of challenging behaviour, and 49% (16 242) had a record of prescription of psychotropic drugs. During follow-up, the rate of new cases of mental illness in people without a history at cohort entry was 262 (95% confidence interval 254 to 271) per 10 000 person years and the rate of challenging behaviour was 239 (231 to 247) per 10 000 person years. The rate of new psychotropic drug prescription in those without a previous history of psychotropic drug treatment was 518 (503 to 533) per 10 000 person years. Rates of new recording of severe mental illness declined by 5% (95% confidence interval 3% to 7%) per year (P&lt;0.001), and new prescriptions of antipsychotics declined by 4% (3% to 5%) per year P&lt;0.001) between 1999 and 2013. New prescriptions of mood stabilisers also decreased significantly. The rate of new antipsychotic prescribing was significantly higher in people with challenging behaviour (incidence rate ratio 2.08, 95% confidence interval 1.90 to 2.27; P&lt;0.001), autism (1.79, 1.56 to 2.04; P&lt;0.001), and dementia (1.42, 1.12 to 1.81; P&lt;0.003) and in those of older age, after control for other sociodemographic factors and comorbidity. <b>Conclusions</b> The proportion of people with intellectual disability who have been treated with psychotropic drugs far exceeds the proportion with recorded mental illness. Antipsychotics are often prescribed to people without recorded severe mental illness but who have a record of challenging behaviour. The findings suggest that changes are needed in the prescribing of psychotropics for people with intellectual disability. More evidence is needed of the efficacy and safety of psychotropic drugs in this group, particularly when they are used for challenging behaviour.
Comparison of five techniques of skin prick tests used routinely in Europe
Authors: M. S. Masse, A. Granger Vallée, A. Chiriac, H. Dhivert‐Donnadieu, L. Bousquet‐Rouanet, P.‐J. Bousquet, P. Demoly
Journal: Allergy (2011)

To cite this article : Masse MS, Granger Vallée A, Chiriac A, Dhivert‐Donnadieu H, Bousquet‐Rouanet L, Bousquet P‐J, Demoly P. Comparison of five techniques of skin prick tests used routinely in Europe. Allergy 2011; 66 : 1415–1419. Abstract Background: Skin prick tests represent indispensable tools in allergy, even more than 30 years after their introduction in clinical practice. Objectives: Few recent European studies have focused on this topic and we thus wanted to compare the instruments most often used today. Methods: Four instruments were investigated: the 23G intravenous (IV) needle, the ALK Lancet, the Stallergenes (STG) Prick Lancet and the Stallerpoint ® (using two different methods). Sensitivity, reproducibility, and acceptability were evaluated. In 22 subjects, we calculated the sensitivity and reproducibility (both intra‐ and interpatient) of these methods by testing the positive control five times. In 50 subjects, we tested the single‐blind acceptability of these same five techniques. Results: In terms of sensitivity, the IV needle (100%) and metal lancets (96% for the ALK Lancet and 98% for the STG Prick Lancet) were superior ( P &lt; 0.01) to the two Stallerpoint ® methods (20% and 57%). Intrapatient reproducibility was 16.2%, 14.6%, 15.0%, 97.1% and 18.1%, respectively. The instruments that were best tolerated by the patients were the IV needle and the two metal lancets. Conclusion: Metal needles and/or lancets are the tools of choice for skin prick testing.
Early transmission characteristics of influenza A(H1N1)v in Australia: Victorian state, 16 May – 3 June 2009
Authors: E S McBryde, I Bergeri, C van Gemert, J Rotty, E J Headley, K Simpson, R A Lester, M Hellard, J E Fielding
Journal: Eurosurveillance (2009)

Australia was one of the first countries of the southern hemisphere to experience influenza A(H1N1)v with community transmission apparent in Victoria, Australia, by 22 May 2009. With few identified imported cases, the epidemic spread through schools and communities leading to 897 confirmed cases by 3 June 2009. The estimated reproduction ratio up to 31 May 2009 was 2.4 (95% credible interval (CI): 2.1-2.6). Methods designed to account for undetected transmission reduce this estimate to 1.6 (95% CI: 1.5-1.8). Time varying reproduction ratio estimates show a steady decline in observed transmission over the first 14 days of the epidemic. This could be accounted for by ascertainment bias or a true impact of interventions including antiviral prophylaxis, treatment and school closure. Most cases (78%) in the first 19 days in Victoria were under the age of 20 years-old. Estimates suggest that the average youth primary case infected at least two other youths in the early growth phase, which was sufficient to drive the epidemic.
α-fetoprotein levels after interferon therapy and risk of hepatocarcinogenesis in chronic hepatitis C
Authors: Yasuhiro Asahina, Kaoru Tsuchiya, Takashi Nishimura, Masaru Muraoka, Yuichiro Suzuki, Nobuharu Tamaki, Yutaka Yasui, Takanori Hosokawa, Ken Ueda, Hiroyuki Nakanishi, Jun Itakura, Yuka Takahashi, Masayuki Kurosaki, Nobuyuki Enomoto, Mina Nakagawa, Sei Kakinuma, Mamoru Watanabe, Namiki Izumi
Journal: Hepatology (2013)

The effects of interferon (IFN) treatment and the post-IFN treatment α-fetoprotein (AFP) levels on risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CHC) are unknown. To determine the relationship between AFP and alanine transaminase (ALT) levels and HCC risk, a cohort consisting of 1,818 patients histologically proven to have CHC treated with IFN were studied. Cumulative incidence and HCC risk were analyzed over a mean follow-up period of 6.1 years using the Kaplan-Meier method and Cox proportional hazard analysis. HCC developed in 179 study subjects. According to multivariate analysis, older age, male gender, advanced fibrosis, severe steatosis, lower serum albumin levels, non sustained virological response (non-SVR), and higher post-IFN treatment ALT or AFP levels were identified as independent factors significantly associated with HCC development. Cutoff values for ALT and AFP for prediction of future HCC were determined as 40 IU/L and 6.0 ng/mL, respectively, and negative predictive values of these cutoffs were high at 0.960 in each value. The cumulative incidence of HCC was significantly lower in patients whose post-IFN treatment ALT and AFP levels were suppressed to less than the cutoff values even in non-SVR patients. This suppressive effect was also found in patients whose post-IFN treatment ALT and AFP levels were reduced to less than the cutoff values despite abnormal pretreatment levels.Post-IFN treatment ALT and AFP levels are significantly associated with hepatocarcinogenesis. Measurement of these values is useful for predicting future HCC risk after IFN treatment. Suppression of these values after IFN therapy reduces HCC risk even in patients without HCV eradication.
Mutation Analysis of IL2RG in Human X-Linked Severe Combined Immunodeficiency
Authors: Jennifer M. Puck, Amy E. Pepper, Paula S. Henthorn, Fabio Candotti, Judith Isakov, Todd Whitwam, Mary Ellen Conley, Roxanne E. Fischer, Howard M. Rosenblatt, Trudy N. Small, Rebecca H. Buckley
Journal: Blood (1997)
Preoperative systemic chemotherapy followed by adjuvant postoperative intraperitoneal therapy for gastric cancer: a University of Southern California pilot program.
Authors: L Leichman, H Silberman, C G Leichman, C P Spears, M Ray, F M Muggia, M Kiyabu, R Radin, L Laine, S Stain
Journal: Journal of Clinical Oncology (1992)

PURPOSE A clinical trial for patients with gastric cancer amenable to curative resection was undertaken to determine feasibility and response to preoperative systemic chemotherapy followed by postoperative intraperitoneal (IP) chemotherapy. METHODS AND MATERIALS Thirty-eight patients with resectable gastric tumor received two cycles of protracted intravenous (IV)-infusion fluorouracil (5FU), 200 mg/m2/d, for 3 weeks with weekly IV leucovorin 20 mg/m2 and IV cisplatin 100 mg/m2 days 1 and 29. Resection of the gastric tumor followed within 3 weeks of completion of systemic chemotherapy. Those who had all visible tumor removed with clear margins received two cycles of IP floxuridine 3,000 mg (total dose) per day for 3 days and IP cisplatin 200 mg/m2 with IV sodium thiosulfate on the fourth day of IP therapy. RESULTS Thirty-seven of 38 patients (97%) received two cycles of systemic chemotherapy. Thirty-five of 38 patients (92%) underwent laparotomy for gastric tumor resection. Thirty-three patients (87%) had gastric resections performed; 29 (76%) had all visible tumor removed with microscopically negative margins. No operative mortality was encountered. Twenty-six patients (68%) received IP treatment. IV neoadjuvant treatment was well tolerated and resulted in 68% of the patients reporting improvement in abdominal pain, 45% objective remissions by computed tomography (CT), 38% objective remissions by gastroscopy and biopsy, and 8% had complete surgical pathologic response. Neutropenic sepsis during the IP treatment phase contributed to the only treatment-related death. Four of 29 completely resected patients (14%) have had tumor recurrence. The median follow-up time of patients remaining alive is now 19 months. The median survival for 38 patients entered onto this protocol has not been reached at 17+ months. CONCLUSION This novel approach to the treatment of adenocarcinoma of the stomach is feasible. The neoadjuvant systemic therapy results in significant primary tumor regression. The determination of whether systemic or IP components of the program contribute to decreased recurrence or increased survival awaits a prospectively randomized clinical trial.
Weekly Docetaxel in the Treatment of Elderly Patients With Advanced Breast Cancer: A Minnie Pearl Cancer Research Network Phase II Trial
Authors: John D. Hainsworth, Howard A. Burris, Denise A. Yardley, James E. Bradof, Manuel Grimaldi, Leonard A. Kalman, Tim Sullivan, Margaret Baker, Joan B. Erland, F. Anthony Greco
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To evaluate the efficacy and toxicity of docetaxel administered weekly to elderly or poor-performance status patients with advanced breast cancer. PATIENTS AND METHODS: Forty-one patients with advanced breast cancer who were either over the age of 65 or considered to be poor candidates for combination chemotherapy received docetaxel 36 mg/m 2 weekly for 6 consecutive weeks, followed by 2 weeks without treatment. The median age of patients in this trial was 74 years, and 73% of patients had one or more visceral sites of metastases. Seventy-five percent of patients received weekly docetaxel as first-line treatment for metastatic breast cancer, and the other 25% received it as second-line treatment. Thirty-six patients were assessable for efficacy, and all patients were assessed for toxicity. RESULTS: A total of 448 doses of weekly docetaxel were administered to 41 patients. Thirteen patients (36%) had objective responses to treatment, and an additional 13 patients (36%) had stable disease or minor response. Median time to progression for responding and stable patients was 7 months (range, 3 to 27 months). Median survival for the entire group was 13 months, with 1- and 2-year actuarial survival rates of 61% and 29%, respectively. Severe neutropenia occurred in only 0.4% of courses, and no other hematologic toxicity was observed. Grade 3/4 fatigue was the most common toxicity, occurring in 20% of patients. CONCLUSION: Weekly docetaxel therapy is active and well tolerated by elderly and/or poor-performance status patients with advanced breast cancer. This treatment can be administered with minimal myelosuppression. Weekly docetaxel provides an additional option for treatment in this difficult subgroup of patients with metastatic breast cancer. Well-tolerated combination regimens containing weekly docetaxel merit evaluation for this patient population.
Abstract 16964: SCN5A Splice Variant Potentiates Dysfunction of a Novel LQT3 Mutation Associated with Life-threatening Arrhythmia in a 19 Week Fetus
Authors: Lisa Murphy, Anita Moon-Grady, Bettina Cuneo, Ronald Wakai, Suhong Yu, Jennifer Kunic, D W Benson, Alfred L George
Journal: Circulation (2011)

BACKGROUND: Inherited arrhythmia susceptibility such as the congenital long-QT syndrome (LQTS) can contribute to infant mortality, but the biological basis for LQTS presenting in utero is poorly understood. The purpose of this study was to elucidate the molecular genetic and pathophysiologic basis for LQTS and torsade de pointes in a fetus presenting at 19-weeks gestation, the earliest known presentation of this disease. METHODS: Molecular genetic studies of an affected fetus demonstrated a de novo SCN5A mutation. To elucidate the functional consequences of the mutation, in vitro electrophysiological studies were conducted on wild type (WT) and mutant human cardiac sodium channels in the canonical channel and in an alternatively spliced form expressed in fetal heart. RESULTS: A fetus presented at 19-6/7 weeks with episodes of ventricular ectopy that progressed to incessant ventricular tachycardia and hydrops fetalis. Family history did not suggest inherited arrhythmia susceptibility, but fetal magnetocardiography demonstrated torsade de pointes and a prolonged rate-corrected QT interval (604 ms). Genetic analysis following pregnancy termination disclosed a novel, de novo heterozygous SCN5A mutation (L409P) and homozygosity for the common SCN5A variant H558R. In vitro studies demonstrated that the mutation in combination with R558 causes significant depolarized shifts in voltage-dependence of steady-state inactivation and activation, accelerated recovery from inactivation and a 7-fold increase in persistent current (1.4% of peak current vs 0.2% for WT). However, when the mutation was expressed in the background of a fetal-expressed SCN5A transcript, channel dysfunction was potentiated with a marked increase in persistent current (11% of peak current) and greater shifts in voltage-dependence. Also, R558 alone in the fetal splice variant evoked a large increased persistent current (3.7% of peak current), hence both alleles were dysfunctional. CONCLUSION: Fetal LQTS may present as early as 19 weeks gestation. The functional effects of certain SCN5A mutations and variants may be magnified by alternative splicing events during fetal development helping to explain the unusual clinical severity of LQT3 in this setting.