tbuckley/cabot-search huggingface dataset:
Abstract 297: Cardiac Transforming-growth-factor β-stimulated Clone 22 Gene Expression By Hypertrophic Stimuli
Authors: Annina Kelloniemi, Jani Aro, Elina Koivisto, Heikki Ruskoaho, Jaana Rysä
Journal: Circulation Research (2013)

Objectives: Transforming-growth-factor β-stimulated clone 22 (TSC-22) is a leucine zipper protein expressed in many tissues and possessing various transcription-modulating activities. However, its function in the heart remains largely unknown. The aim of the present study was to characterize the cardiac TSC-22 expression. Methods: Acute pressure overload was accomplished in conscious Sprague-Dawley (SD) rats by intravenous infusion of arginine 8 -vasopressin (AVP, 0.05 μg/kg/min) for 4 hours and subcutaneous infusion of angiotensin II (Ang II, 33 μg/kg/h) with and without Ang II receptor type 1 blocker losartan (400 μg/kg/h) by using osmotic minipumps for 2 weeks. Adenovirus-mediated intramyocardial gene transfer of TSC-22 was performed into left ventricle (LV) of SD rats. Experimental myocardial infarction (MI) was produced by ligation of the left anterior descending coronary artery. Cultured neonatal rat ventricular myocytes (NRVM) were treated with endothelin-1 (ET-1, 100 nM). Results: A significant 1.6-fold increase ( P &lt;0.05) in LV TSC-22 mRNA levels was noted already after 1 hour AVP infusion. Moreover, Ang II infusion markedly upregulated TSC-22 expression, LV mRNA levels being highest at 6 hours (11-fold, P &lt;0.001). Simultaneous infusion of losartan completely abolished Ang II-induced increase in TSC-22 mRNA levels. Adenovirus-mediated gene transfer of TSC-22 into LV resulted a 1.9-fold ( P &lt;0.001) increase in TSC-22 mRNA levels, accompanied by upregulated BNP mRNA levels (1.4-fold, P &lt;0.01). In response to experimental MI, TSC-22 mRNA levels were elevated 4.1-fold ( P &lt;0.001) at 1 day and 1.9-fold ( P &lt;0.05) at 4 weeks. In cultured NRVM, ET-1 treatment increased TSC-22 mRNA levels from 1 h to 24 h, the greatest increase being observed at 12 h (2.7-fold, P &lt;0.001). TSC-22 protein levels were upregulated from 4 h to 24 h with the highest increase at 24 h (4.7-fold, P &lt;0.01). Conclusion: These results indicate that TSC-22 expression is rapidly activated in response to pressure overload, MI and in ET-1 treated cultured NRVM. Moreover, adenovirus-mediated overexpression of TSC-22 mRNA was associated with elevated left ventricular BNP mRNA levels.
Prevalence of Celiac Disease in 52,721 Youth With Type 1 Diabetes: International Comparison Across Three Continents
Authors: Maria E. Craig, Nicole Prinz, Claire T. Boyle, Fiona M. Campbell, Timothy W. Jones, Sabine E. Hofer, Jill H. Simmons, Naomi Holman, Elaine Tham, Elke Fröhlich-Reiterer, Stephanie DuBose, Helen Thornton, Bruce King, David M. Maahs, Reinhard W. Holl, Justin T. Warner
Journal: Diabetes Care (2017)

Celiac disease (CD) has a recognized association with type 1 diabetes. We examined international differences in CD prevalence and clinical characteristics of youth with coexisting type 1 diabetes and CD versus type 1 diabetes only.Data sources were as follows: the Prospective Diabetes Follow-up Registry (DPV) (Germany/Austria); the T1D Exchange Clinic Network (T1DX) (U.S.); the National Paediatric Diabetes Audit (NPDA) (U.K. [England/Wales]); and the Australasian Diabetes Data Network (ADDN) (Australia). The analysis included 52,721 youths <18 years of age with a clinic visit between April 2013 and March 2014. Multivariable linear and logistic regression models were constructed to analyze the relationship between outcomes (HbA1c, height SD score [SDS], overweight/obesity) and type 1 diabetes/CD versus type 1 diabetes, adjusting for sex, age, and diabetes duration.Biopsy-confirmed CD was present in 1,835 youths (3.5%) and was diagnosed at a median age of 8.1 years (interquartile range 5.3-11.2 years). Diabetes duration at CD diagnosis was <1 year in 37% of youths, >1-2 years in 18% of youths, >3-5 years in 23% of youths, and >5 years in 17% of youths. CD prevalence ranged from 1.9% in the T1DX to 7.7% in the ADDN and was higher in girls than boys (4.3% vs. 2.7%, P < 0.001). Children with coexisting CD were younger at diabetes diagnosis compared with those with type 1 diabetes only (5.4 vs. 7.0 years of age, P < 0.001) and fewer were nonwhite (15 vs. 18%, P < 0.001). Height SDS was lower in those with CD (0.36 vs. 0.48, adjusted P < 0.001) and fewer were overweight/obese (34 vs. 37%, adjusted P < 0.001), whereas mean HbA1c values were comparable: 8.3 ± 1.5% (67 ± 17 mmol/mol) versus 8.4 ± 1.6% (68 ± 17 mmol/mol).CD is a common comorbidity in youth with type 1 diabetes. Differences in CD prevalence may reflect international variation in screening and diagnostic practices, and/or CD risk. Although glycemic control was not different, the lower height SDS supports close monitoring of growth and nutrition in this population.
Mechanisms of in vitro acquired resistance to vorinostat (suberoylanilide hydroxamic acid, SAHA)
Authors: Jennifer Roth, Susan Korenchuk, Theresa Zhang, Andrey Loboda, James Hardwick, Elizabeth Harrington, Victoria Richon, Valeria Fantin
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

694 

Vorinostat is a histone deacetylase (HDAC) inhibitor that induces differentiation, growth arrest and/or apoptosis of malignant cells both in vitro and in vivo . Vorinostat has demonstrated antitumor activity in both hematological malignancies and solid tumors, including an overall response rate of approximately 30% in cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease on or following 2 systemic therapies. As not all clinical responses are permanent, we developed model systems to investigate the mechanisms of acquired resistance to vorinostat and used these results to identify rational combination strategies to overcome this clinical issue. Using a dose escalation protocol vorinostat resistant clones were derived from sensitive HCT116 colon carcinoma cells and A549 non-small cell lung cancer (NSCLC) cells. This method established cell lines that can be maintained in media containing vorinostat at 2 μM (A549-VR2), 3μM (A549-VR3), 5 μM (A549-VR5) and 8 μM (HCT116-VR8) for a prolonged period of time (3 weeks) without signs of apoptosis. Gene expression profiling was performed on the parental HCT116 cells and vorinostat-resistant cells. In addition to an unbiased analysis of the data, the status of several pathways possibly related to vorinostat's mechanism of action were examined. Preliminary analyses revealed alterations in the expression of genes that participate in the apoptotic cascade (e.g. Bcl-2, survivin), protein acetylation (CBP/p300), redox homeostasis (SOD2, metallothionein) and Wnt/ β-catenin signaling pathway (frizzle, β-catenin and cyclin D1). The expression of candidate genes from this analysis was assessed across the panel of vorinostat-resistant A549 clones. The results indicate that acquired resistance to vorinostat appears to comprise mechanisms that inhibit the induction of apoptosis, including an increase in antioxidants and in anti-apoptotic Bcl-2 levels. In particular, upregulation of antioxidant enzymes and thiol modulating proteins including SOD2 and metallothioneins have been associated with clinical resistance to cytotoxic drugs and radiation therapy as well as poor prognosis. Future studies will help to address the clinical relevance of these findings. One prediction from this analysis is that compounds that inhibit the glutathione system like buthionine sulfoximine or agents that downregulate or block Bcl-2 could be used to revert these mechanisms of resistance. Combination strategies with emerging treatment modalities may help to increase vorinostat efficacy in specific genetic contexts.
MEDU-40. DETECTION OF NON-ENHANCING RECURRENT MEDULLOBLASTOMA ON DIFFUSION WEIGHTED IMAGING
Authors: Mariam Aboian, Cassie Kline, Yi Li, David Solomon, Anu Banerjee, Steve Braunstein, Sabine Mueller, William Dillon, Soonmee Cha
Journal: Neuro-Oncology (2017)

Medulloblastoma recurrence has historically been diagnosed based on identification of new contrast-enhancing lesions on surveillance imaging. We propose reduced diffusion is a more sensitive imaging marker than contrast-enhancement in identifying recurrent metastatic medulloblastoma. We identified 46 pediatric patients with medulloblastoma at our institution. Seventeen patients went on to develop definitive disease recurrence within the brain. In these patients, MR imaging at the time of diagnosis of recurrence and for 6 months prior to diagnosis was evaluated for presence of contrast enhanced lesions, size of contrast enhanced lesions, presence of lesions with reduced diffusion, and quantitative measurement of ADC within the recurrent lesions. All patients with recurrent medulloblastoma demonstrated reduced diffusion within recurrent lesions. ADC measurements were 0.658 ± 0.072 for recurrent lesions as compared to 0.923 ± 0.146 for contralateral normal white matter region of interest (ROI) measurements (p = 0.00001). Eleven patients (65%) with disease recurrence demonstrated contrast enhancement within the recurrent lesions. All six patients with non-enhancing recurrence demonstrated reduced diffusion with mean ADC of 0.680 ± 0.097, which was statistically significantly lower compared to contralateral normal brain with ADC values 0.894 ± 0.089 (p = 0.003). Non-enhancing recurrent disease was found equally within the tumor resection bed and mixed distal and tumor resection bed. In our cohort of patients with recurrent medulloblastoma, recurrent lesions did not uniformly demonstrate contrast enhancement on MR imaging but all recurrent lesions demonstrated reduced diffusion. Our findings support diffusion weighted imaging (DWI) is more sensitive than contrast enhancement for detection of medulloblastoma recurrence. As such, DWI should be considered part of standard of care imaging for medulloblastoma surveillance.
Modifications to vancomycin raise hope for combating antibiotic resistance
Authors: Nigel Hawkes
Journal: BMJ (2017)

Chemists in California have modified the molecule of the antibiotic vancomycin to make it harder for bacteria to avoid destruction.1

The result could provide one answer to the growing problem of antibiotic resistance, said Dale Boger and colleagues, from the Scripps Research Institute in La Jolla. “Doctors could use this modified form of vancomycin without fear of resistance emerging,” claimed Boger, who has been working on enhancing vancomycin for some years.

The drug was discovered in 1956 and first used in 1958. The fact that it is still highly effective attests to the …
<i>VHL</i> Inactivation in Precancerous Kidney Cells Induces an Inflammatory Response via ER Stress–Activated IRE1<b>α</b> Signaling
Authors: Chan-Yen Kuo, Chih-Hung Lin, Tien Hsu
Journal: Cancer Research (2017)

Abstract Mutations and epigenetic inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) are major causes of clear-cell renal cell carcinoma (ccRCC) that may originate from chronic inflammation. However, the role of VHL loss of function in the development of ccRCC via inflammation remains poorly understood. VHL-mutant cells exhibit metabolic abnormalities that can cause chronic endoplasmic reticulum (ER) stress and unfolded protein response. We hypothesize that unresolved ER stress induces the inflammatory responses observed in ccRCC. ER stress markers including BiP and XBP1s were significantly increased in cultured and primary VHL loss-of-function kidney cells. In epithelial cells, the kinase activity of IRE1α was required for the induction of NF-κB and JNK and for the recruitment of macrophages. IRE1α kinase activity was also important for the development of fibrotic phenotype in conditional Vhlh knockout mice. Our results offer insights into the therapeutic potential against ccRCC development by relieving metabolic stress. Such cancer prevention strategy may be critical for high-risk cohorts such as the familial VHL disease patients. Cancer Res; 77(13); 3406–16. ©2017 AACR.
Optical imaging for monitoring tumor oxygenation response after initiation of single-agent bevacizumab followed by neoadjuvant chemotherapy in breast cancer patients.
Authors: Shigeto Ueda, Toshiaki Saeki
Journal: Journal of Clinical Oncology (2014)

e13503 Background: Diffuse optical imaging techniques for measuring tissue hemoglobin concentration have been recently accepted as a way to assess tumor vascularity and oxygenation. We investigated the correlation between early optical response to single-agent bevacizumab and treatment outcome. Methods: Seven patients with advanced or metastatic breast cancer were treated with single-agent bevacizumab followed by addition of weekly paclitaxel. Optical imaging of patient’s breasts was performed to measure tumor total hemoglobin concentration (tHb) and oxygen saturation (stO2) at baseline and on days 1, 3, 6, 8, and 13 after the first infusion of bevacizumab. To assess early metabolic response, 2-deoxy-2-(18F)-fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT), 18F-fluoromisonidazole (FMISO)-PET/CT, and magnetic resonance imaging were performed at baseline and after two cycles of the regimen. Results: Seven patients were grouped as responders (n = 4) and nonresponders (n = 3) on the basis of metabolic response measured by FDG-PET/CT. The responders showed remarkable tumor shrinkage and low accumulations of FMISO tracer relative to those of the nonresponders at the completion of two cycles of chemotherapy. Tumors of both groups showed remarkable attenuation of mean tHb as early as day 1 after therapy initiation. The nonresponders had lower baseline stO2 levels compared with adjacent breast tissue stO2 levels along with a pattern of steadily low stO2 levels during the observation window. On the other hand, the responders appeared to sustain high stO2 levels with temporal fluctuation. Conclusions: Low tumor stO2 level after single-agent bevacizumab treatment was characteristic of the nonresponders. Tumor stO2 level could be a predictor of an additional benefit of bevacizumab over that provided by paclitaxel.
Role of Fibulin 3 in Aging‐Related Joint Changes and Osteoarthritis Pathogenesis in Human and Mouse Knee Cartilage
Authors: Akihiko Hasegawa, Tomo Yonezawa, Noboru Taniguchi, Koji Otabe, Yukio Akasaki, Tetsuya Matsukawa, Masahiko Saito, Masashi Neo, Lihua Y. Marmorstein, Martin K. Lotz
Journal: Arthritis & Rheumatology (2016)

The EFEMP1 gene encoding fibulin 3 is specifically expressed in the superficial zone (SZ) of articular cartilage. The aims of this study were to examine the expression patterns of fibulin 3 in the knee joints during aging and during osteoarthritis (OA) and to determine the role of fibulin 3 in the pathogenesis of OA.Immunohistochemical analysis was performed on normal and OA knee cartilage samples from humans and mice. Experimental OA was induced in wild-type and fibulin 3-/- mice, and the severity of OA was evaluated by histologic scoring. To examine fibulin 3 function, human chondrocyte monolayer cultures were transfected with small interfering RNA (siRNA), followed by quantitative polymerase chain reaction and Western blot analyses. Human bone marrow-derived mesenchymal stem cells (BM-MSCs) were transduced with an EFEMP1 lentivirus and analyzed for markers of chondrogenesis.Fibulin 3 was specifically expressed in the SZ of normal knee joint cartilage from humans and mice, and the expression levels declined with aging. Both aging-related OA and experimental OA were significantly more severe in fibulin 3-/- mice compared with wild-type mice. Fibulin 3 expression was high in undifferentiated human BM-MSCs and decreased during chondrogenesis. Suppression of fibulin 3 by siRNA significantly increased the expression of SOX9, type II collagen, and aggrecan in human articular chondrocytes, while overexpression of fibulin 3 inhibited chondrogenesis in BM-MSCs.Fibulin 3 is specifically expressed in the SZ of articular cartilage and its expression is reduced in aging and OA. Fibulin 3 regulates differentiation of adult progenitor cells, and its aging-related decline is an early event in the pathogenesis of OA. Preventing aging-associated loss of fibulin 3 or restoring it to normal levels in SZ chondrocytes has the potential to delay or prevent the onset of OA.
Delivering safer immunotherapies for cancer
Authors: Lauren Milling, Yuan Zhang, Darrell J. Irvine
Journal: Advanced Drug Delivery Reviews (2017)

Cancer immunotherapy is now a powerful clinical reality, with a steady progression of new drug approvals and a massive pipeline of additional treatments in clinical and preclinical development. However, modulation of the immune system can be a double-edged sword: Drugs that activate immune effectors are prone to serious non-specific systemic inflammation and autoimmune side effects. Drug delivery technologies have an important role to play in harnessing the power of immune therapeutics while avoiding on-target/off-tumor toxicities. Here we review mechanisms of toxicity for clinically-relevant immunotherapeutics, and discuss approaches based in drug delivery technology to enhance the safety and potency of these treatments. These include strategies to merge drug delivery with adoptive cellular therapies, targeting immunotherapies to tumors or select immune cells, and localizing therapeutics intratumorally. Rational design employing lessons learned from the drug delivery and nanomedicine fields has the potential to facilitate immunotherapy reaching its full potential.
Abstract 140: Effect of Acute β-Adrenergic Receptor Stimulation on Cardiac Function in Gravin Knockout Mice
Authors: Ashley N Guillory, Cori S Wijaya, Xing Yin, Andrea Diaz Diaz, Abeer Rababa'h, Bradley K McConnell
Journal: Circulation Research (2012)

Gravin, an A kinase anchoring protein expressed in the myocardium, localizes protein kinase A (PKA), protein kinase C and other signaling molecules to the β2-adrenergic receptor (β2-AR). PKA modulates cardiac function by phosphorylating key substrates of the excitation-contraction coupling mechanism such as troponin I, phospholamban, L-type Ca2+ channels and the ryanodine receptor. PKA is activated upon agonist stimulation of β-ARs, thus, the purpose of this study was to determine whether disruption of the PKA/Gravin interaction would alter cardiac function upon β-AR stimulation. WT and gravin-knockout (KO) mice were given an acute challenge with isoproterenol (ISO; 0.25μg/g) injected intraperitoneally, then cardiac function was measured via echocardiography. Control animals were injected with an equal volume of 0.002% ascorbic acid. All experiments were performed with n≥6. Baseline electrocardiography revealed no differences between the WT and KO mice prior to treatment. Additionally, there were no significant differences in body weight or left ventricular (LV) mass between the WT and gravin-KO mice. As expected, heart rate was equally increased in both ISO treated groups when compared to their respective controls (WT vehicle: 489±28.9; KO vehicle: 447.8±20.1; WT ISO: 596.4±8.1; KO ISO: 570.7±16.4; BPM; p&lt;0.0001). However, cardiac output was significantly increased in the gravin-KO vehicle mice as well as in the gravin-KO mice acutely challenged with ISO compared to their WT counterparts (WT vehicle: 19.82±1.18; KO vehicle: 24.78±1.00; WT ISO: 26.97±1.35; KO ISO: 32.84±1.39; ml/min; p&lt;0.0001). Similarly, stroke volume was also much greater in both the vehicle and ISO treated gravin-KO mice than the respective WT group (WT vehicle: 43.94±4.01; KO vehicle: 51.30±2.36; WT ISO: 54.47±4.16; KO ISO: 68.03±2.67; µl; p=0.0056). Finally, LV fractional shortening was also significantly enhanced in both gravin-KO groups when compared with WT mice (WT vehicle: 33.89±2.47; KO vehicle: 43.00±3.25; WT ISO: 54.47±4.16; KO ISO: 68.03±2.67; %; p&lt;0.0001). This data indicates that disruption of gravin’s scaffold mediated signaling is able to increase baseline contractility as well as augment contractility in response to acute β-AR stimulation.
Adolescent and young adult oncology (AYAO) patient enrollments onto National Cancer Institute (NCI)-supported trials from 2000 to 2010.
Authors: Nita Seibel, Sally Hunsberger, Ann M. O'Mara, Troy Budd, Steven H. Friedman, Shanda Finnigan, Denise R. Lewis, David Robert Freyer
Journal: Journal of Clinical Oncology (2014)

10058 Background: Lack of participation in clinical trials has been proposed as a key explanation for the survival deficit of AYAO patients. We compared the proportion of newly diagnosed AYAO patients (out of all patients) enrolled on NCI-sponsored cooperative group therapeutic trials from 2000 to 2010 to the proportion that would be expected based on SEER incidence data. Location of care was also assessed. Methods: We studied AYAO accrual to all open trials by evaluating two age groups (15-19 and 20-39 years) and two time periods (2000-2005 and 2006-2010). For each cancer type, the observed proportion of AYAO patients was calculated by dividing the total number of AYAO participants accrued by the total number of trial participants. This was compared to SEER 17 data by calculating the same proportion using the cancer specific incidence for the same age and year groupings. The proportion of community based (CCOP) accrual to non-CCOP accrual was compared for the AYAO patients. Results: Of 116,665 patients enrolled from 294 NCI-sponsored studies with eighteen cancer types, 12,392 were aged 15-39 years. For both time periods, the observed proportion of 15 - 19 year olds was greater than the SEER data for ALL, AML, CNS, Hodgkins, and bone cancers while the clinical trial proportion of 20-39 year olds exceeded the SEER data for AML, colon, NHL, and breast cancer. Among CCOPs, the proportion of AYAO accrual was greater for younger than older patients in ALL, bone cancer, Hodgkin, and STS. Conclusions: For many cancer types, both adolescent and young adult patient enrollments onto NCI studies exceed what would be expected based on SEER incidence data. Although AYAO patients are represented on clinical trials, recruiting and ensuring trials are available for this age group should remain a priority.
Pilot study of knowledge and management of concussion in emergency department doctors in singapore
Authors: Joanne Probert, Dinesh Sirisena, Joy Walter
Journal: British Journal of Sports Medicine (2017)

Objective 1. To gain an understanding of Singapore Emergency Physicians (EPs) knowledge and practice habits when assessing concussions in the Emergency Department (ED). 2. To determine what knowledge exists regarding current international concussion management and return-to-play guidelines Design A 21 item anonymous internet survey was developed and disseminated to EPs in Singapore. A limited time period for completion was given. Because of anonymity, non-responders could not be specifically targeted. Participation was voluntary and no incentives were offered. Results 26 responses which included 9 Associate Consultants or above, 4 Registrars, 14 junior doctors. 63% were Singapore trained. 88.9% were aware of the concussion diagnosis but only 50% could document the salient points required to diagnose concussion. The highest percentage (33.3%) reported seeing cases of concussion monthly, 18.5% fortnightly, 29.6% weekly and 14.8% daily. 33.3% of EPs were aware of Internationally Recognised guidelines but only 11% use them. 70.4% refer concussions for follow up (47.4% to Neurosurgery and 21.1% to Sports Medicine). Only 14.8% of EPs have had specific training in sports concussion management. Conclusions 1. It is likely that concussion is under diagnosed; many EPs only report seeing cases monthly and are unaware of the salient features to diagnose concussion. 2. International guidelines regarding return-to-play and standardised assessment have not reached the majority of EPs. 3. A small proportion of concussion cases are referred to Sports Clinics for follow up. 4. Further training in sports concussion management in Singapore EDs is needed. 5. Further studies in this area are required. Competing interests Joanne Probert – Trainer for World Rugby.