tbuckley/cabot-search huggingface dataset:
Stable liver-specific expression of human IDOL in humanized mice raises plasma cholesterol
Authors: Salam Ibrahim, Suryanarayan Somanathan, Jeffrey Billheimer, James M Wilson, Daniel J Rader
Journal: Cardiovascular Research (2016)

IDOL (inducible degrader of the low-density lipoprotein receptor, LDLR) is an E3 ubiquitin ligase that promotes the ubiquitination and degradation of the LDLR. IDOL is a potential therapeutic target for the development of a novel class of low-density lipoprotein cholesterol (LDL-C)-lowering therapies. In an attempt to develop a mouse model for testing IDOL inhibitors, we examined the effects of adeno-associated virus (AAV)-mediated stable expression of human IDOL in the livers of mice 'humanized' with regard to lipoprotein metabolism.Using a liver-specific AAV serotype 8 (AAV8)-mediated delivery, AAV-hIDOL produced a dose-dependent increase in LDL-C levels and a decrease in liver LDLR protein. Furthermore, we expressed hIDOL in a 'humanized' mouse model of heterozygous familial hypercholesterolaemia (LDLR(+/-)/Apobec1(-/-)/hApoB-Tg, LAhB). In this model, total cholesterol (TC) and LDL-C levels were increased by ∼60% starting from 1 week and were sustainable for at least 3 weeks post-injection. Finally, we demonstrate that the effects caused by hIDOL expression are LDLR- dependent given the unchanged plasma lipids in LAhB mice lacking LDLR.In conclusion, our study demonstrates a dose-dependent physiological effect of human IDOL on LDL metabolism in mice. This provides a potential model for preclinical testing of IDOL inhibitors for reduction of LDL-C levels.
Most ADHD diagnoses made in US children seem to follow guidelines
Authors: Michael McCarthy
Journal: BMJ (2015)

The majority of new cases of attention-deficit/hyperactivity disorder (ADHD) in children in the US are being diagnosed consistent with best practices, a new study has found. 

The percentage of children being diagnosed as having ADHD has risen steadily in the US in recent years, increasing 5% a year from 2003 to 2011. Currently about one in 10 school aged children, or about 6.4 million, is diagnosed as having ADHD.

Researchers …
Abstract 18328: Neurotrophin 3 Induces the Expression of Osteogenic Proteins in Human Aortic Valve Interstitial Cells via Trk Receptors
Authors: Qingzhou Yao, Rui Song, Qingchun Zeng, Lihua Ao, Xiyong Yu, David A Fullerton, Xianzhong Meng
Journal: Circulation (2013)

Calcific aortic valve disease affects a large number of elderly people, and progressive aortic valve leaflet calcification ultimately results in heart failure. However, the molecular mechanism that mediates valvular osteogenic responses is incompletely understood. Aortic valve interstitial cells (AVICs) express osteogenic proteins in response to stimulation of Toll-like receptor (TLR) 2 or 4. We recently found that soluble biglycan induces the expression of transforming growth factor-β1 (TGF-β1) and bone morphogenetic protein-2 (BMP-2) in human AVICs via TLR2. The objective of this study is to identify novel pro-osteogenic mediators and to elucidate the mechanisms underlying their action in human AVICs. Methods and results: We examined gene expression profile in AVICs isolated from 5 normal human aortic valves and 5 diseased human aortic valves using microarray analysis. Among a large group of genes analyzed, mRNA levels of neurotrophin 3 (NT3), a neural growth factor, were markedly up-regulated in AVIC isolates of diseased valves. Immunoblotting analysis confirmed higher levels of NT3 protein in AVICs of diseased valves. Surprisingly, normal human AVICs expressed greater levels of TGF-β1 and BMP-2 when exposed to recombinant human NT3 (0.05 or 0.10 μg/ml) for 3 days. Further, up-regulation of TGF-β1 and BMP-2 expression by NT3 was preceded by phosphorylation of Akt and glycogen synthase kinase 3 beta (GSK3β). The pro-osteogenic effect of NT3 was not affected by blocking antibodies against TLR2 and TLR4, indicating that NT3 is incapable of acting as a danger-associated molecular pattern in human AVICs. However, neural growth factor receptors (TrkA, TrkB, TrkC and p75 NTR ) were detectable in human AVICs. The pan Trk inhibitor K252a (0.2 μmol/L) suppressed Akt and GSK3β phosphorylation, and markedly reduced TGF-β1 and BMP-2 expression following NT3 stimulation. Conclusions: AVICs of diseased human aortic valves express higher levels of NT3. NT3 induces the expression of TGF-β1 and BMP-2 by human AVICs via Trk receptors. Thus, NT3 is a novel pro-osteogenic mediator in human aortic valve, and it may play a role in aortic valve leaflet calcification through up-regulation of the expression of osteogenic proteins by AVICs.
Clinical usefulness of PI3K/Akt/mTOR genotyping in companion with other clinical variables in metastatic renal cell carcinoma patients treated with everolimus in the second and subsequent lines
Authors: L. Bodnar, R. Stec, S. Cierniak, A. Synowiec, G. Wcisło, M. Jesiotr, R. Koktysz, W. Kozłowski, C. Szczylik
Journal: Annals of Oncology (2015)
Abstract 2118: A Population-based Comparison of the Cardiovascular Protective Effects of Hydrochlorothiazide and Chlorthalidone
Authors: Jeff Nagge, David N Juurlink
Journal: Circulation (2007)

Background Clinical practice guidelines for the treatment of hypertension recommend a thiazide diuretic as initial therapy for the majority of patients. Most clinicians consider chlorthalidone (CHL) and hydrochlorothiazide (HCTZ), the two most commonly prescribed thiazides, to be interchangeable, despite evidence suggesting these drugs are not equivalent. Methods We constructed a population-based retrospective cohort study by linking the health records of 1.4 million residents of Ontario, Canada aged 66 or older between July 1, 1993 and March 1, 2002. The index event for entry into the cohort was a new prescription for either HCTZ or CHL. The primary outcome was the time from the index event to a composite outcome of acute myocardial infarction (AMI), stroke, or all-cause mortality. Secondary analyses explored each outcome individually. Analysis was done using Cox proportional hazards regression with the HCTZ group as the reference. Results During 218,360 person-years of follow-up in the HCTZ group, there were 10 025 events (death, AMI or stroke), compared to 113 events during 4,214 person-years of follow-up in the CHL group. The unadjusted hazard ratio for the primary outcome was 0.73 (95% confidence interval 0.61 to 0.88), suggesting a substantially lower risk of events during CHL therapy. After adjustment for differences in baseline demographic and clinical characteristics, there was no statistically significant difference between the groups for the primary outcome (adjusted hazard ratio 0.85; 95% confidence interval 0.71 to 1.03). The hazard ratios for each component of the primary composite outcome all trended in the direction of a lower risk of events in users of CHL. Conclusion In a large cohort of older patients treated with thiazide diuretics, the use of CHL was not associated with a statistically significant reduction in the risk of AMI, stroke, or death. However, treatment effects favored CHL for every outcome, raising the hypothesis that CHL is superior to HCTZ. Further research is needed to confirm or refute this hypothesis.
Analysis of factors influencing outcome in patients with in transit malignant melanoma (MM) undergoing isolated limb perfusion (ILP) using standardized operative parameters with melphalan and biological agents
Authors: P. A. Soriano, S. K. Libutti, J. F. Pingpank, T. Beresenev, S. M. Steinberg, D. L. Bartlett, D. L. Fraker, C. Helsabeck, H. R. Alexander
Journal: Journal of Clinical Oncology (2006)

8006 Background: In transit disease afflicts about 10% of MM patients and no single systemic or regional treatment has been widely accepted as most effective or appropriate. Previously, the impact of ILP on the natural history of MM patients has been difficult to gauge. We report long-term outcomes in MM patients undergoing hyperthermic ILP in an era of increasingly accurate staging, uniform operative and treatment conditions, and regular follow-up. Methods: Between 5/1992 to 2/2005, 90 patients (median age: 57 y [range: 24–84]; F: 49, M: 41) with Stage IIIA or IIIAB MM underwent a 90 min hyperthermic (mean calf T: 39.3° C) ILP (melphalan: 10–13 mg/L limb volume, TNF: 3–6 mg [n=44], or IFN: 200 μg [n=38]) using uniform operative technique including intra-operative leak monitoring. There was 1 operative mortality (1/91, 1.1%). Patients were prospectively followed for response, in-field progression free (PFS), and overall survival (OS). Parameters associated with in-field PFS and OS were analyzed by the Kaplan-Meier method with log rank tests, as well as by Cox proportional hazards models. Results: There were 61 complete responses (68%) and 23 partial responses (26%). At a median follow-up of 47 months, median in-field PFS was 12.4 months, and median OS was 47.4 months; 5 and 10-year actuarial OS were 43 and 34%, respectively. Female gender and low tumor burden (&lt; 20 tumors) were associated with prolonged in-field PFS (M:F hazard ratio (HR): 2.07, CI:1.27–3.38; 21+ vs. ≤20 tumors HR: 2.29, CI: 1.21- 4.34; p&lt;0.011 for both) in a Cox model, whereas TNF, IFN, perfusion pressure, and tumor stage were not. Female gender was associated with improved OS (p=0.027, M:F HR=1.82, 95% CI 1.07–3.09) and Stage IIIA marginally so, in univariate analysis, (p=0.065). Conclusions: ILP for MM patients is associated with noteworthy in-field PFS and prolonged OS. Neither use of TNF nor tumor stage were significantly associated with in-field PFS in Cox models, while female gender was associated with better outcomes. In appropriately selected patients using standardized technique, ILP has clinical benefit in this setting. No significant financial relationships to disclose.
Effect of raloxifene on endometrial cancer risk in a population-based, case-control study
Authors: A. Demichele, A. Troxel, A. Weber, J. Berlin, G. Bunin, E. Turzo, D. Burgh, R. Schinnar, S. Rubin, T. Rebbeck, B. Strom
Journal: Journal of Clinical Oncology (2005)

5001 Background: Raloxifene, a selective estrogen receptor modulator, has been shown to reduce breast cancer risk in women with osteoporosis, and is currently being compared to tamoxifen for breast cancer chemoprevention in the “STAR” trial. In contrast to tamoxifen, raloxifene does not stimulate endometrial estrogen receptors, and may therefore be associated with a lower risk of endometrial cancer compared with tamoxifen. However, there are few data available on the absolute risk of endometrial cancer in users of raloxifene, or the relative risks of endometrial cancer among raloxifene and tamoxifen users in the general population. Methods: We performed a population-based, case-control study of breast and endometrial cancer. Cases had pathologically-confirmed endometrial cancer, and resided in a 9-county area surrounding Philadelphia. Controls with no history of endometrial cancer were obtained through random-digit dialing and matched to cases by age and race. Only African-American and Caucasian women were included in the study. Results: A total of 547 cases and 1412 controls were included in the current analysis. Among cases, 18 (3.3%) ever used raloxifene and 34 (6.2%) ever used tamoxifen. Among controls, 93 (6.6%) ever used raloxifene and 34 (2.2%) ever used tamoxifen. Compared to non-users, the odds ratio for development of endometrial cancer was 0.43 (95% CI 0.26 - 0.73) for raloxifene users, and 2.35 (95% CI 1.43 - 3.86) for tamoxifen users. After adjustment for other confounders, including BMI and previous history of breast cancer, the odds ratio associated with developing endometrial cancer among raloxifene users was 0.50 (95% CI 0.29 - 0.85), while the odds ratio among tamoxifen users was 1.50 (95% CI 0.77 - 2.92). The benefit of raloxifene on endometrial cancer risk remained even among those with short-term use (<3 years). Conclusions: Raloxifene use was associated with a 50% reduction in the odds of developing endometrial cancer in this population-based case-control study. These data suggest a possible protective effect of raloxifene on the endometrium, providing a further benefit to this drug in cancer chemoprevention. No significant financial relationships to disclose.
Correlates of clinically significant fatigue in women with newly diagnosed breast cancer
Authors: N. L. Gerber, G. Diao, N. Stout, P. Soballe, C. McGarvey, L. Pfalzer, B. Springer, C. Shieh
Journal: Journal of Clinical Oncology (2009)

e20517 Background: Cancer related fatigue (CRF) is common in cancer survivors. CRF has been reported to be one of the most distressing symptoms associated with cancer and its treatment. Activity and biological profiles of those who suffer from CRF, have been poorly characterized. This IRB approved prospective, natural history study reports fatigue and associated findings in women newly diagnosed with breast cancer (BrCa), receiving standard treatment. Methods: All women were evaluated pre-operatively and at &gt;9 months after diagnosis. Variables measured: Age, height, marital status, presence of children, menopausal status, tumor size, node status, estrogen receptor (ER+), hemoglobin, white blood cell count, fasting blood glucose, and BMI. Patient reported outcomes included visual analog scale (VAS) of fatigue (F), SF-36 version2, Physical Activity Questionnaire (PAQ, Harvard Alumni Health Study) and Sleep Questionnaire. Some variables were dichotomized to maximize the statistical power for the relatively small sample size. Bivariate correlations, and logistic regression analyses were performed using two fatigue conditions: presence of any F, or presence of clinically significant fatigue (CSF) defined as &gt;=4 on the VAS. Results: 61 women, mean age of 51y, 39% had BMI &gt;=25, 85% had &gt;= 1 child, 52% were post-menopause, 92% ER+. Increased F at follow-up was statistically significant when compared to baseline (p=&lt;0.0001, using paired t-test). Significant correlations (p&lt;0.1) are reported between CSF and the following: node+, BMI&gt;=25; inverse correlations with amount of vigorous activity (PAQ), physical function and vitality on SF-36. Physical function (SF-36) had significant inverse correlations with: age, menopause, and BMI. Low vitality was associated with: large tumor size, high WBC, longer time sleeping. Node+, BMI&gt;=25, low physical function and vitality levels retained statistically significant relationships to CSF in the regression analyses. Conclusions: Node+ BrCa, BMI&gt;=25, low level of physical activity and vitality (SF-36) are correlated with CSF. Except node status, each is treatable and may reduce CSF No significant financial relationships to disclose.
<i>Notes from the Field</i>: Outbreak of Locally Acquired Cases of Dengue Fever — Hawaii, 2015
Authors: David Johnston, Melissa Viray, Jenny Ushiroda, A. Christian Whelen, Rebecca Sciulli, Remedios Gose, Roland Lee, Eric Honda, Sarah Y. Park
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

On October 21, 2015, the Hawaii Department of Health (HDOH) was notified of a positive dengue immunoglobulin M (IgM) antibody result in a woman residing on Hawaii Island (also known as the Big Island). The patient had no history of travel off the island, and other family members reported having similar signs and symptoms, which consisted of fever, headache, myalgias and arthralgias, and a generalized erythematous rash. HDOH initiated an investigation to identify any additional cases and potential exposure sources. On October 24, HDOH received report of a group of mainland U.S. visitors who had traveled together on Hawaii Island, including several who had developed a febrile illness. Additionally, on October 27, HDOH was notified of an unrelated person, also on Hawaii Island, with a positive dengue IgM result. As of November 26, 2015, HDOH had identified 107 laboratory-confirmed cases of dengue fever, with dates of onset ranging from September 11 to November 18, 2015.
Rituximab in combination with CHOP regimen in angioimmunoblastic T-cell lymphoma: Results of the phase II RAIL trial—A prospective study of the Groupe d'Etude des Lymphomes de l'Adulte (GELA).
Authors: B. Joly, A. Plonquet, M. Grare, M. Delfau-Larue, R. Delarue, A. Delmer, O. Casasnovas, C. Gisselbrecht, P. Gaulard, C. Haioun
Journal: Journal of Clinical Oncology (2010)

8049 Background: Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive peripheral T-cell lymphoma with poor prognosis. The use of rituximab was based on the hallmark features of lymphoid B cell hyperstimulation in AITL and the presence of a variable content of CD20+ large B-blasts admixed within the neoplastic follicular helper T cells (TFH) in AITL. We postulated that AITL might benefit from a front line treatment with rituximab combined with CHOP. Methods: Between December 2005 and April 2008, 25 patients (pts) aged 59 to 79 years with newly diagnosed AITL were enrolled and treated in 11 centers with a combination of 8 cycles of Rituximab (375mg/m2 at day 1 of each cycle) and CHOP chemotherapy delivered every 3 weeks (R-CHOP21). The primary endpoint was the complete response rate. Results: Most of the pts had an advanced disease (stage IV: 92% and B symptoms: 68%). Median age was 67 years. All cases had histological and phenotypic features of AITL and 6 cases contained aggregates or sheets of large CD20+ B-blasts. The presence of EBERs- positive cells within the tumor correlated with detection of EBV genome in peripheral blood (PB) by Q- PCR (9/16 tested cases). Tumoral cells were detected in PB by flow cytometry in 7/15 pts. An oligoclonal or clonal T-cell population was detected in those 7 samples. 21 pts received 8 cycles of R-CHOP. 4 pts ended their treatment prematurely: 2 for toxicities and 2 for progression. The overall response rate was 80%, 44% achieving a complete response and 36% a partial response. Grade III-IV non hematological toxicities were low. With a median follow up of 24 months (m), the 2y-progression free survival was 42%. 11 pts had relapsed (range: 3-31 m). The 2y-overall survival was 62%. Conclusions: R-CHOP21 was well tolerated in this elderly population but did not improve the complete response rate from classical CHOP. This study led us to complete ancillary biological studies on tumoral samples of the enrolled patients of this rare entity. No significant financial relationships to disclose.
Effect of capecitabine (X) on quality of life (QoL) in patients (pts) with metastatic breast cancer (MBC)
Authors: J. G. M. Segalla, C. T. Oliveira, S. Lago, S. Cabral, R. Ribeiro, M. Perdicaris, E. Abdo, B. Garicochea, F. C. Moore, C. Fabiani
Journal: Journal of Clinical Oncology (2004)

8130 Background: X (Xeloda®) has proven efficacy and favorable safety as monotherapy in MBC and improves survival when added to docetaxel in first line. However, clinical outcomes need to be balanced with pt QoL. Pt preference for oral therapy is well documented. QoL data would add to understanding the potential pt benefits of X. Methods: We monitored QoL on X in women pretreated with anthracycline +/− taxanes. QoL was evaluated at baseline, before cycle 1, at weeks 7 and 13, and at treatment end using EORTC QLQ C-30 (v3.0) and BR-23 questionnaires. The proportion of pts with improvement, stabilization or worsening of QoL scores was determined from week 7 and analyzed using linear models with repeated measures (generalized estimating questions technique) and SAS (v8.2). Results: There were 529 evaluable pts: median age 53 years (22–88); median ECOG PS 1 (0–4); majority Caucasian (86%). We detected significant improvements (p<0.0001 unless stated) in: global health status, role and emotional functioning, pain, appetite loss, constipation, future perspective, systemic therapy, breast symptoms, hair loss, body image (p=0.00012), fatigue (p=0.0004), insomnia (p=0.0004), nausea/vomiting (p<0.001), arm symptoms (p=0.00114), diarrhea (p=0.00154), and financial problems (p=0.0086). The proportion of pts with stable or improved QoL was ≥70% for most scales (none <60%). At least 40% of pts reported improvements from week 7 onwards as follows: pain (49%), fatigue (47%), emotional functioning (45%), arm symptoms (45%), global health status (43%), role functioning (41%), and future perspective (41%). Pts with a poor PS at baseline (ECOG ≥3) had a greater improvement in QoL than those with a good PS. Conclusions: X measurably improves QoL (global score and individual domains) in pts with MBC. These findings highlight the importance of considering QoL and other measurable benefits of oral treatments alongside well-established measures of clinical evaluation in pts with metastatic disease. The QoL benefits, together with other proven clinical outcomes, suggest that earlier use of X in MBC would be of benefit to pts. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Fundação Hospital Amaral Carvalho
C-reactive protein (CRP) associated with higher risk patients with myelodysplastic syndromes (MDS)
Authors: N. Galili, S. Marionneaux, S. Lascher, A. Mazumder, D. Vesole, M. Mumtaz, M. Mehdi, S. Jagannath, A. Raza
Journal: Journal of Clinical Oncology (2008)

18009 Background: MDS and myeloma patients respond to many of the same therapeutic agents, suggesting a possible pathologic mechanism for both diseases. C-reactive protein (CRP) is an acute-phase protein produced by hepatocytes in response to tissue damage and inflammation under the transcriptional control of cytokines IL-6 and IL-1. Plasma CRP levels are a sensitive marker of inflammatory processes and are increased in patients with various cancers. CRP has been shown to bind and protect multiple myeloma cells from dexamethasone-induced apoptosis both in vitro and in vivo. CRP acts independently but in synergy with IL6, to promote survival and proliferation of myeloma. Increased expression of IL6 may be found in some patients with MDS suggesting that CRP may be a target of therapy in both diseases. We measured the serum concentrations of CRP in 94 MDS patients and 12 normal volunteers to see if levels correlated with clinical subtype as an initial step in exploring a common link between the two diseases. Methods: All patients and normal controls were consented according to IRB approved protocol. The standard immunochemical - turbidimetry method for CRP was used on the Ortho Vitros Fusion 5,1 instrument. The reference range for CRP measurements was 0.01-1.50 mg/dL. Results: Among 94 MDS patients, 36 had RA, 19 RARS, 27 RAEB, 9 RAEBt, 2 CMML and 1 AML. The IPSS score: 25 Low, 26 Int1, 24 Int2, 17 High and 2 unknown. Cytogenetics were normal in 47 and abnormal in 47. Higher than ULN CRP values were seen in 23 MDS cases (median 3.3 mg/dL, range 1.5–16.4 mg/dL) and 17/23 had either RAEB (6) or Int2/high risk disease. Normal controls had a median CRP of 0.27 mg/dL. Lower risk RA/RARS patients had 0.36 mg/dL and higher risk RAEB/RAEBt had 0.895mg/dL (p = 0.03). Similarly, according to IPSS, Low/Int1 had 0.395 mg/dL and Int2/High had 0.83 mg/dL (p = 0.05). Conclusion: We conclude that both sets of analyses indicate that higher CRP levels are associated with higher risk disease. The marrows of higher risk patients have decreasing numbers of apoptotic cells with increasing blast counts. The apoptotic protective role of CRP in these MDS remains to be elucidated. No significant financial relationships to disclose.