tbuckley/cabot-search huggingface dataset:
Genetic and Environmental Interactions Modify the Risk of Diabetes-Related Autoimmunity by 6 Years of Age: The TEDDY Study
Authors: Jeffrey P. Krischer, Kristian F. Lynch, Åke Lernmark, William A. Hagopian, Marian J. Rewers, Jin-Xiong She, Jorma Toppari, Anette-G. Ziegler, Beena Akolkar
Journal: Diabetes Care (2017)

We tested the associations between genetic background and selected environmental exposures with respect to islet autoantibodies and type 1 diabetes.
Patient-derived Interstitial Fluids and Predisposition to Aggressive Sporadic Breast Cancer through Collagen Remodeling and Inactivation of p53
Authors: Timothy C. Kenny, Hank Schmidt, Kerin Adelson, Yujin Hoshida, Anna P. Koh, Nagma Shah, John Mandeli, Jess Ting, Doris Germain
Journal: Clinical Cancer Research (2017)

Purpose: Despite the fact that interstitial fluid (IF) represents a third of our body fluid, it is the most poorly understood body fluid in medicine. Increased IF pressure is thought to result from the increased deposition of extracellular matrix in the affected tissue preventing its reabsorption. In the cancer field, increased rigidity surrounding a cancerous mass remains the main reason that palpation and radiologic examination, such as mammography, are used for cancer detection. While the pressure produced by IF has been considered, the biochemical composition of IF has not been considered in its effect on tumors.Experimental Design: We classified 135 IF samples from bilateral mastectomy patients based on their ability to promote the invasion of breast cancer cells.Results: We observed a wide range of invasion scores. Patients with high-grade primary tumors at diagnosis had higher IF invasion scores. In mice, injections of high-score IF (IFHigh) in a normal mammary gland promotes ductal hyperplasia, increased collagen deposition, and local invasion. In a mouse model of residual disease, IFHigh increased disease progression and promoted aggressive visceral metastases. Mechanistically, we found that IFHigh induces myofibroblast differentiation and collagen production through activation of CLIC4. IFHigh also downregulates RYBP, leading to degradation of p53. Furthermore, in mammary glands of heterozygous p53-mutant knock-in mice, IFHigh promotes spontaneous tumor formation.Conclusions: Our study indicates that IF can increase the deposition of extracellular matrix and raises the provocative possibility that they play an active role in the predisposition, development, and clinical course of sporadic breast cancers. Clin Cancer Res; 23(18); 5446-59. ©2017 AACR.
Abstract 175: Pro-survival Function of Mef2 in Cardiomyocytes is Enhanced by β-blockers
Authors: Sara Hashemi, Jahan Salma, Stephanie Wales, John C McDermott
Journal: Circulation Research (2015)

β1-adrenergic receptor (β1-AR) stimulation increases apoptosis in cardiomyocytes via activation of cAMP/ protein kinase A (PKA) signaling. β-adrenergic receptor antagonists, or β-blockers, oppose the action of PKA signaling by blocking the β1-receptor and effectively inhibit apoptosis and heart failure. The Myocyte Enhancer Factor 2 (MEF2) proteins have been implicated as nuclear targets for signaling cascades involved in muscle-gene expression and have important roles in proliferation, apoptosis and survival in multiple cell types. We previously reported that PKA signaling represses MEF2 activity. Here, we assessed whether β-blockers can inhibit neonatal cardiac myocyte apoptosis by interfering with PKA dependent MEF2 repression. We show that siRNA mediated MEF2 loss of function induced cardiomyocyte apoptosis. β1AR activation by isoproterenol treatment represses MEF2 transcriptional activity and promotes apoptosis in neonatal cardiomyocytes and, importantly, this effect was reversed in cells expressing a PKA resistant form of MEF2D (S121/190A), as indicated by FACS analysis. We also report that a β-blocker, Atenolol, antagonizes isoproterenol induced apoptosis and also acutely enhanced MEF2 transcriptional activity. We observed that β-adrenergic stimulation modulated MEF2 cellular localization in neonatal cardiomyocytes and this was reversed by atenolol treatment. In addition, we also document that Kru[[Unable to Display Character: &amp;#776;]]ppel-like factor 6 (KLF6) is an important MEF2 target gene and loss of function analysis using siRNA-mediated knockdown of KLF6 expression resulted in cardiomyocyte apoptosis. Collectively, these observations, establish that MEF2 plays an important pro-survival role in cardiomyocytes which can be modulated by β-adrenergic signaling. These observations have important clinical implications and may contribute to novel strategies for preventing cardiomyocyte apoptosis associated with heart pathology.
Abstract 084: Dkk1 Knock out Leads To Augmentation Of Cardiac Hypertrophy Following Aortic Banding
Authors: Johannes H Riffel, Elmar Bernhold, Marco Hagenmueller, Min Zhang, Christof Niehrs, Hugo A Katus, Stefan E Hardt
Journal: Circulation Research (2013)

Background: Myocardial hypertrophy is an important risk factor for cardiac morbidity and mortality. In the normal adult heart, Wnt signaling remains quiescent. However, recent studies have demonstrated reactivation of Wnt signaling in hypertrophic growth of cardiomyocytes. Under such conditions Wnt signaling may be beneficial or maladaptive depending on the context. The Wnt coreceptors LRP5 and LRP6 are important for signal transmission via the β-catenin pathway and are negatively regulated by Dkk1, a member of a small family of secretory proteins. Dkk1 binds to LRP6 and thereby acts as a Wnt antagonist. In our study we investigated the cardiovascular phenotype of Dkk1 knock-out mice following aortic banding. Study Design and Results: Dkk1 (+/-) knock-out mice were subjected to aortic banding (AB) or sham operation. After 4 weeks echocardiographic and invasive measurements were performed. After that the mice were euthanized, heart weight was measured and myocardial samples were snap frozen for biochemical measurements or fixed in formalin for further histological evaluation. Under baseline conditions there were no differences in cardiomyocyte size, heart weight and cardiac function in Dkk1 knock-out animals compared to wild type animals. 4 weeks after aortic banding we observed a significant increase in heart weight/body weight ratio in Dkk1 knock out animals compared to the control group (7.3 ± 0.3 mg/g vs. 6.4 ± 0.3 mg/g, p &lt; 0.05). Furthermore cardiomyocyte size was highly elevated in Dkk1 knock out mice compared to control animals, suggesting an augmentation in cardiac hypertrophy. Transcription levels of the pro-hypertrophic markers atrial natriuretic factor (ANF) and beta-MHC were increased in Dkk1 knock out animals. Interestingly echocardiographic data revealed an aggravation of cardiac function in Dkk1 knock out mice following aortic banding (Ejection fraction (EF): 62 ± 3 % vs. 74 ± 1 %, p &lt; 0.05). Summary: Our findings suggest that Dkk1 knock out aggravates cardiac hypertrophy following aortic banding. The underlying molecular mechanisms remain to be further explored.
Association of immune-inflammation index with outcome of high-risk acral melanoma patients treated with adjuvant high-dose interferon.
Authors: Jiayi Yu, Si Ming Li, Yan Kong, Lu Si, Xinan Sheng, Zhihong Chi, Chuanliang Cui, Jun Guo
Journal: Journal of Clinical Oncology (2016)

e21070 Background: High-dose interferon alfa-2b(IFN-α-2b) improves the survival of high-risk melanoma patients, especially acral melanoma patient. However, there is a significant number of patients fails to benefit from treatment because of the toxicities. In this study, we aimed to identify baseline peripheral blood biomarkers to predict the outcome of acral melanoma patients with adjuvant high-dose interferon treatment. Methods: Pretreatment full blood counts, CD4+CD25+ regulatory T cells (CD4+Tregs),CD8+CD28-regulatory T cells(CD8+Tregs), CD8+CD28+cytotoxic T lymphocyte(CTL),serum lactate dehydrogenase (LDH), and clinical date were assessed in 113acral melanoma patients. 76 patients treated with 4-week IFN-α-2b (15*106 U/m2d1–5/w*4w) and 37 patients treated with1-year IFN-α-2b (15*106 U/m2 d1–5/w*4w + 9*106 U tiw*48w). Relapse free survival (RFS) and overall survival (OS) were assessed using the Kaplan–Meier method, and multivariate Cox regression analysis were applied, adjusting for other prognostic factors: LDH, stage, ulceration. Results: The univariate analysis showed that Neutrophil-to-lymphocyte ratio (NLR) ≥ 2.35, platelet-to-lymphocyte ratio (PLR) ≥ 129, systemic immune-inflammation index (SII) ≥ 615 × 109/L, elevated LDH were significantly associated with poor RFS and OS. The SII is calculated as follows: platelet count × neutrophil count/lymphocyte count. In the multivariate analysis, the immune-inflammation index (SII) were associated with RFS(HR = 2.042; 95% CI: 1.269-3.284; P = 0.003) and OS (HR = 2.537; 95% CI: 1.495-4.305; P = 0.001).Interestingly, higher CD4+Treg frequencies were significantly associated with better survival. We will collect more data to verify the results. Conclusions: This study demonstrated that the combination of platelet count and neutrophil-lymphocyte ratio could serve to predict the prognosis in high-risk acral melanoma patients treated with adjuvant high-dose interferon, which is easily assessable in clinical practice.
Screening for Syphilis and Other Sexually Transmitted Infections in Pregnant Women — Guam, 2014
Authors: Susan Cha, Tasneem Malik, Winston E. Abara, Mia S. DeSimone, Bernadette Schumann, Esther Mallada, Michael Klemme, Vince Aguon, Anne Marie Santos, Thomas A. Peterman, Gail Bolan, Mary L. Kamb
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Prenatal screening and treatment for sexually transmitted infections (STIs) can prevent adverse perinatal outcomes. In Guam, the largest of the three U.S. territories in the Pacific, primary and secondary syphilis rates among women increased 473%, from 1.1 to 6.3 per 100,000 during 2009-2013 (1). In 2013, the first congenital syphilis case after no cases since 2008 was reported (1,2). Little is known about STI screening coverage and factors associated with inadequate screening among pregnant women in Guam. This study evaluated the prevalence of screening for syphilis, human immunodeficiency virus (HIV), chlamydia, and gonorrhea, and examined correlates of inadequate screening among pregnant women in Guam. Data came from the medical records of a randomly selected sample of mothers with live births in 2014 at a large public hospital. Bivariate analyses and multivariable models using Poisson regression were conducted to determine factors associated with inadequate screening for syphilis and other STIs. Although most (93.5%) women received syphilis screening during pregnancy, 26.8% were not screened sufficiently early to prevent adverse pregnancy outcomes. Many women were not screened for HIV infection (31.1%), chlamydia (25.3%), or gonorrhea (25.7%). Prenatal care and insurance were important factors affecting STI screening during pregnancy. Prenatal care providers play an important role in preventing congenital infections. Policies and programs increasing STI and HIV services for pregnant women and improved access to and use of prenatal care are essential for promoting healthy mothers and infants.
A phase I study of veliparib (ABT-888) in combination with carboplatin and paclitaxel in advanced solid malignancies.
Authors: Leonard Joseph Appleman, Jan Hendrik Beumer, Yixing Jiang, Shannon Puhalla, Yan Lin, Taofeek Kunle Owonikoko, R Donald Harvey, Ronald Stoller, Daniel P. Petro, Hussein Abdul-Hassan Tawbi, Athanassios Argiris, Sandra Strychor, Brian Kiesel, Edward Chu, Stacie Peacock Shepherd, Vincent L. Giranda, Alice P. Chen, Chandra Prakash Belani, Suresh S. Ramalingam
Journal: Journal of Clinical Oncology (2012)

3049 Background: Veliparib (ABT-888, NSC 737664) is an orally available inhibitor of poly(ADP-ribose) polymerase (PARP)-1 and -2: enzymes that recruit base excision repair machinery to single-stranded DNA breaks. Expression of PARP-1 may be increased in cancer cells and confer resistance to DNA-damaging agents. The objectives of this phase I study included determination of the recommended phase 2 dose (RP2D), maximum tolerated dose (MTD), dose limiting toxicity (DLT) and pharmacokinetics (PK) of veliparib in combination with paclitaxel (P) and carboplatin (C). Methods: Eligibility criteria included advanced solid tumors, ≤ 3 prior chemotherapy regimens for advanced disease, ECOG performance status 0-2. Veliparib was given PO BID on days 1-7 of each 21 day cycle, and P and C were administered on day 3. In dose levels 1-7, veliparib was not given during cycle 1 to serve as intra-patient control for toxicity and PK assessment, and DLT was evaluated during cycle 2. A standard “3+3” dose escalation was utilized starting at veliparib 20 mg BID, P 150 mg/m2, C AUC 5. Plasma concentrations of veliparib, P and C were determined by LC-MS/MS and AAS during cycle 1 and 2. Results: To date, 68 patients have been enrolled. Tumor types included lung (15), breast (14), melanoma (10), squamous cell of head/neck (7), and urothelial (5). Toxicities observed were expected with C plus P chemotherapy, including neutropenia, thrombocytopenia, peripheral neuropathy. DLTs were seen in 2 out of 7 evaluable patients at the maximum administered dose: veliparib 120 mg BID, P 200 mg/m 2 , C AUC 6, (febrile neutropenia, hyponatremia). Veliparib 80 mg, P 200 mg/m 2 , C AUC 6 was well tolerated with 1 out of 9 DLT (febrile neutropenia). Median number of cycles was 5 (1-17). Partial response was seen in 11 (Lung-2, breast-2, melanoma-2, urothelial-2, head and neck, gastric, unknown primary) and complete response in 1 patient with breast cancer and 1 patient with urothelial cancer. Stable disease was observed in 35 patients. Veliparib did not affect the PK disposition of P or C. Conclusions: Veliparib in combination with P and C was well-tolerated with a safety profile similar to P and C alone. Promising anti-tumor activity was observed in several tumor types.
Abstract 1186: Overexpression Of Endothelial Lipase In The Liver Promotes The Clearance Of Plasma Lipids But Accelerates Liver Steatosis In A Mouse Model Of Metabolic Syndrome
Authors: Tomoyuki Yasuda, Tatsuro Ishida, Yoko Kojima, Hanayo Tanaka, Takeaki Okada, Akira Fukuda, Tetsuya Hara, Michihiko Inoue, Kenichi Hirata
Journal: Circulation (2007)

The metabolic syndrome includes high triglyceride (TG) and low HDL-cholesterol (HDL-C) levels in the plasma, and often accompanies steatosis in the liver. Endothelial lipase (EL) is a phospholipase that regulates HDL metabolism. EL is expressed by hepatocytes, while the function of EL in the liver has not been identified. Here, we examined the role of EL in the liver using a mouse model of metabolic syndrome. The EL expression in the liver was analyzed by real-time PCR. It revealed that liver EL expression was significantly increased in obese and diabetic db/db mice compared to that of control mice. To examine the significance of the EL upregulation in the liver, we injected the recombinant adenovirus encoding human EL into mice. The EL overexpression in the liver resulted in a significant decrease in plasma HDL-C, TG, and free fatty acid levels. Interestingly, the EL overexpression in the liver increased liver weight and liver TG content both in wild-type and db/db mice. In db/db mice, particularly, EL overexression accelerated the formation of steatosis by increasing the mRNA level of fatty acid synthase. These findings indicate that EL expression is increased in the liver in the metabolic syndrome. The upregulation of EL promotes the uptake of plasma lipids by hepatocytes, and accelerates the progression of steatosis in db/db mice. Thus EL may play a role in the genesis of steatosis as well as dyslipidemia in the metabolic syndrome.
Phase I study of sapacitabine and seliciclib in patients with advanced solid tumors.
Authors: Sara M. Tolaney, John Frederick Hilton, James M. Cleary, Leena Gandhi, Eunice Lee Kwak, Jeffrey W. Clark, Andrew Wolanski, Tracy Demeo Bell, Scott J. Rodig, Judy H. Chiao, David Blake, Geoffrey Shapiro
Journal: Journal of Clinical Oncology (2016)

2503 Background: Sapacitabine is an oral nucleoside analogue; the active metabolite CNDAC generates ssDNA breaks that are converted to dsDNA breaks (DSB) during subsequent replication, resulting in cell death. CNDAC-induced DSB repair is dependent on homologous recombination (HR). Seliciclib is an oral CDK2, 7 and 9 inhibitor, and sensitizes cells to CNDAC by decreasing DSB repair via compromise of HR protein activation. This phase I study evaluates sequential and concomitant sapacitabine and seliciclib treatment. Methods: Dose escalation was conducted in patients with incurable solid tumors with sapacitabine b.i.d. x 7 consecutive days (d 1-7) followed by seliciclib b.i.d. x 3 consecutive days (d 8-10) or sapacitabine q.d. concomitantly with seliciclib q.d. x 5 days per week x 2 weeks (d 1-5, 8-12). MTD was the highest dose level at which less than one-third of at least 6 patients experienced cycle 1 DLT. Skin biopsies were obtained to assess DNA damage following sapacitabine and seliciclib treatment. Results: 67 patients were treated including 45 BRCA mutation carriers (BRCA +ves). MTDs are sapacitabine 50 mg b.i.d./seliciclib 1200 mg b.i.d. and sapacitabine 250 mg q.d./seliciclib 200 mg q.d. respectively. DLTs were reversible elevations in transaminase and bilirubin, neutropenia/febrile neutropenia and pneumonia. The most frequent grade 3/4 adverse events included elevations in ALT (10%), AST (13%), bilirubin (6%) and alkaline phosphatase (7%), neutropenia (21%), febrile neutropenia (6%), hyperglycemia (6%), hypokalemia (6%), and abdominal pain (7%). Skin biopsies showed a 2.3-fold increase in gH2AX staining post-sapacitabine (n = 16; p = 0.007) and a further 0.58-fold increase post-seliciclib (n = 12; p = 0.069). Six confirmed PRs occurred in BRCA +ves with pancreatic, ovarian and breast cancer. Response durations range from 49 to > 224 weeks in 4 ovarian and breast patients. SD was observed in 10 additional BRCA +ves with durations ranging from 26 to 81 weeks in 5 ovarian and breast cancer patients. Conclusions: Sequential and concomitant sapacitabine and seliciclib is safe with preliminary antitumor activity (35% PR + SD) in BRCA +ves, the status of which may be a potential biomarker for response across multiple tumor types. Clinical trial information: NCT00999401.
Efficient Generation of Dopamine Neurons by Synthetic Transcription Factor mRNAs
Authors: Sang-Mi Kim, Mi-Sun Lim, Eun-Hye Lee, Sung Jun Jung, Hee Yong Chung, Chun-Hyung Kim, Chang-Hwan Park
Journal: Molecular Therapy (2017)

Generation of functional dopamine (DA) neurons is an essential step for the development of effective cell therapy for Parkinson's disease (PD). The generation of DA neurons can be accomplished by overexpression of DA-inducible genes using virus- or DNA-based gene delivery methods. However, these gene delivery methods often cause chromosomal anomalies. In contrast, mRNA-based gene delivery avoids this problem and therefore is considered safe to use in the development of cell-based therapy. Thus, we used mRNA-based gene delivery method to generate safe DA neurons. In this study, we generated transformation-free DA neurons by transfection of mRNA encoding DA-inducible genes Nurr1 and FoxA2. The delivery of mRNA encoding dopaminergic fate inducing genes proved sufficient to induce naive rat forebrain precursor cells to differentiate into neurons exhibiting the biochemical, electrophysiological, and functional properties of DA neurons in vitro. Additionally, the generation efficiency of DA neurons was improved by the addition of small molecules, db-cAMP, and the adjustment of transfection timing. The successful generation of DA neurons using an mRNA-based method offers the possibility of developing clinical-grade cell sources for neuronal cell replacement treatment for PD. Generation of functional dopamine (DA) neurons is an essential step for the development of effective cell therapy for Parkinson's disease (PD). The generation of DA neurons can be accomplished by overexpression of DA-inducible genes using virus- or DNA-based gene delivery methods. However, these gene delivery methods often cause chromosomal anomalies. In contrast, mRNA-based gene delivery avoids this problem and therefore is considered safe to use in the development of cell-based therapy. Thus, we used mRNA-based gene delivery method to generate safe DA neurons. In this study, we generated transformation-free DA neurons by transfection of mRNA encoding DA-inducible genes Nurr1 and FoxA2. The delivery of mRNA encoding dopaminergic fate inducing genes proved sufficient to induce naive rat forebrain precursor cells to differentiate into neurons exhibiting the biochemical, electrophysiological, and functional properties of DA neurons in vitro. Additionally, the generation efficiency of DA neurons was improved by the addition of small molecules, db-cAMP, and the adjustment of transfection timing. The successful generation of DA neurons using an mRNA-based method offers the possibility of developing clinical-grade cell sources for neuronal cell replacement treatment for PD.
A novel single domain antibody (sdAb) SBT-100 to target intracellular STAT3 to affect growth and regression of human triple negative breast cancer (TNBC) cells.
Authors: Sunanda Singh, Genoveva Murillo, Rajendra Mehta, Dong Chen, Avani Singh, Samara Singh, Anjali Singh, Ashutosh S Parihar
Journal: Journal of Clinical Oncology (2016)

1083 Background: TNBC has limited response to chemotherapy, and poor prognosis when it metastasizes. Activated STAT3 has been shown to play an important role in the pathogenesis of TNBC. We evaluated the hypothesis that inhibition of STAT3 by a sdAb would inhibit growth of TNBC cells in vitro and in mouse xenograft studies. Methods: Human TNBC cell lines MDA-MB-231, MDA-MB-468, and MDA-MB-453 were grown in culture and treated with varying doses of SBT-100, which specifically binds human STAT3. On day 3 MTT assay were performed to assess growth inhibition. In mouse xenograft studies, human MDA-MB-231 cells were grown as tumors (size range: 77±7.17 - 104.71±14.64 mm3) in athymic mice and treated with varying doses of SBT-100 or with vehicle intraperitoneally for 14 days and observed for 7 days post treatment. Immunoprecipitation (IP) and western blot studies were performed to assess binding of STAT3 by SBT-100. Results: After 3 days of SBT-100 treatment in vitro growth suppression was as observed follows: MDA-MB-231, 90% inhibition (p < 0.001); MDA-MB-468, 85% inhibition (p < 0.001), and MDA-MB-453, 64% inhibition (p < 0.001). In the mouse xenograft experiment using MDA-MB-231 tumors, the control group received vehicle only, Group 1 received 1mg/kg/BID, Group 2 received 2mg/kg/BID, and Group 3 received 2mg/kg/day. All treatment groups showed significant tumor size growth suppression and, Groups 1 & 2 showed regression during the 14 day treatment period, which was maintained during the 1 week observation period. No toxicity was observed in the treated mice. IP studies showed that SBT-100 binds both unphosphorylated and phosphorylated STAT3. Conclusions: The single domain antibody SBT-100 binds human STAT3, and significantly suppresses the growth of TNBC cells in vitro and in vivo.