tbuckley/cabot-search huggingface dataset:
Association of Cereal, Gluten, and Dietary Fiber Intake With Islet Autoimmunity and Type 1 Diabetes
Authors: Leena Hakola, Maija E. Miettinen, Essi Syrjälä, Mari Åkerlund, Hanna-Mari Takkinen, Tuuli E. Korhonen, Suvi Ahonen, Jorma Ilonen, Jorma Toppari, Riitta Veijola, Jaakko Nevalainen, Mikael Knip, Suvi M. Virtanen
Journal: JAMA Pediatrics (2019)

Dietary proteins, such as gluten, have been suggested as triggers of the disease process in type 1 diabetes (T1D).To study the associations of cereal, gluten, and dietary fiber intake with the development of islet autoimmunity (IA) and T1D.The prospective birth cohort Finnish Type 1 Diabetes Prediction and Prevention Study recruited children with genetic susceptibility to type 1 diabetes from September 1996 to September 2004 from 2 university hospitals in Finland and followed up every 3 to 12 months up to 6 years for diet, islet autoantibodies, and T1D. Altogether 6081 infants (78% of those invited) participated in the study. Dietary data were available for 5714 children (94.0%) and dietary and IA data were available for 5545 children (91.2%), of whom 3762 (68%) had data on islet autoantibodies up to age 6 years. Information on T1D was available for all children. Data were analyzed in 2018 and end point data were updated in 2015.Each child's intake of cereals, gluten, and dietary fiber was calculated from repeated 3-day food records up to 6 years.Islet autoimmunity was defined as repeated positivity for islet cell antibodies and at least 1 biochemical autoantibody of 3 analyzed, or T1D. Data on the diagnosis of T1D were obtained from Finnish Pediatric Diabetes Register.Of 5545 children (2950 boys [53.2%]), 246 (4.4%) developed IA and of 5714 children (3033 boys [53.1%]), 90 (1.6%) developed T1D during the 6-year follow-up. Based on joint models, the intake of oats (hazard ratio [HR], 1.08; 95% CI, 1.03-1.13), wheat (HR, 1.09; 95% CI, 1.03-1.15), rye (HR, 1.13; 95% CI, 1.03-1.23), gluten-containing cereals (HR, 1.07; 95% CI, 1.03-1.11), gluten without avenin from oats (HR, 2.23; 95% CI, 1.40-3.57), gluten with avenin (HR, 2.06; 95% CI, 1.45-2.92), and dietary fiber (HR, 1.41; 95% CI, 1.10-1.81) was associated with the risk of developing IA (HRs for 1 g/MJ increase in intake). The intake of oats (HR, 1.10; 95% CI, 1.00-1.21) and rye (HR, 1.20; 95% CI, 1.03-1.41) was associated with the risk of developing T1D. After multiple testing correction, the associations with IA remained statistically significant.A high intake of oats, gluten-containing cereals, gluten, and dietary fiber was associated with an increased risk of IA. Further studies are needed to confirm or rule out the findings and study potential mechanisms.
The novel optical reporter gene for study of tumor biology
Authors: Heidi Cho, Zhongxing Liang, Ke Liang, Younghyoun Yoon, Seunghee Kang, Matthew Goodman, Mark Goodman, Hyunsuk Shim
Journal: Cancer Research (2006)

997  For a tumor to constantly proliferate, malignant cells require nutrients, especially glucose and amino acids. There is abundant evidence that tumor growth depends heavily on glucose uptake. The L-type amino acid transporter 1 (LAT1) is a major nutrient transport system responsible for the transport of large neutral essential amino acids. In normal human tissue, LAT1 mRNA is highly expressed only in the brain, bone marrow and testis. In contrast, LAT1 mRNA levels are over-expressed in most cancer cell lines and patient tumor samples. CXCR4 has been shown to exhibit elevated levels in tumors. We hypothesize that CXCR4 may regulate LAT1 levels and upregulation of LAT1 is necessary for tumor cell growth and invasion that is induced by CXCR4. We found that CXCR4 levels correlated well with LAT1 mRNA levels in various cell lines and lowering CXCR4 levels by small interfering RNA (siRNA) lowered LAT1 mRNA levels. We investigated whether suppressing LAT1 levels would affect cell growth or invasion of CXCR4-positive tumors through the analysis of growth assays and Matrigel invasion assay after the knockdown of LAT1 using siRNA or specific inhibitors of LAT1. To further examine the control of gene expression of LAT1, we amplified the promoter sequence from genomic DNA using PCR methods and subcloned into pGL2-luciferase vector. We found that CXCR4 is required for LAT1 transcriptional activation. Finally, we will determine whether LAT1 overexpression can be a diagnostic marker for tumor detection by using non-invasive Positron Emission Tomography (PET) in preclinic animal models. Dr. Goodman has developed non-natural amino acid, anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid (FACBC) that is currently in clinical trial phase I at Emory Clinic. We injected luciferase-positive U87MG glioma cells into the nude mice subcutaneously, two spots each on their back and followed the tumor growth in vivo by non-invasive Bioluminescence imaging (BLI). When the average tumor size reached 1cc, the right-hand side tumors were treated with either 5 mM BCH (synthetic amino acid) while the left-hand side tumors were treated with saline solution by intratumoral injection. Then, animals were injected with FACBC intravenously and scanned in microPET 45 minutes post-injection. On the following day, animals were imaged for BLI. FACBC-PET images show that the right-hand side tumors were darker than the left-hand side tumors, indicating that the pretreatment of amino acids or their analog inhibited L-type amino acid transporter function, which results in much less uptake of FACBC by tumors. These results indicate that FACBC uptake critically depends on L-type amino acid transporter. Our study provides the rationale that FACBC uptake correlates to LAT1 activity and FACBC-PET can be a promising non-invasive diagnostic tool for malignant tumor detection.
Therapeutic inhibition of microRNA-34a ameliorates aortic valve calcification via modulation of Notch1-Runx2 signalling
Authors: Taku Toshima, Tetsu Watanabe, Taro Narumi, Yoichiro Otaki, Tetsuro Shishido, Tomonori Aono, Jun Goto, Ken Watanabe, Takayuki Sugai, Tetsuya Takahashi, Miyuki Yokoyama, Daisuke Kinoshita, Harutoshi Tamura, Shigehiko Kato, Satoshi Nishiyama, Takanori Arimoto, Hiroki Takahashi, Takuya Miyamoto, Mitsuaki Sadahiro, Masafumi Watanabe
Journal: Cardiovascular Research (2019)

Calcific aortic valve stenosis (CAVS) is the most common valvular heart disease and is increased with elderly population. However, effective drug therapy has not been established yet. This study aimed to investigate the role of microRNAs (miRs) in the development of CAVS.We measured the expression of 10 miRs, which were reportedly involved in calcification by using human aortic valve tissue from patients who underwent aortic valve replacement with CAVS or aortic regurgitation (AR) and porcine aortic valve interstitial cells (AVICs) after treatment with osteogenic induction medium. We investigated whether a specific miR-inhibitor can suppress aortic valve calcification in wire injury CAVS mice model. Expression of miR-23a, miR-34a, miR-34c, miR-133a, miR-146a, and miR-155 was increased, and expression of miR-27a and miR-204 was decreased in valve tissues from CAVS compared with those from AR. Expression of Notch1 was decreased, and expression of Runt-related transcription factor 2 (Runx2) was increased in patients with CAVS compared with those with AR. We selected miR-34a among increased miRs in porcine AVICs after osteogenic treatment, which was consistent with results from patients with CAVS. MiR-34a increased calcium deposition in AVICs compared with miR-control. Notch1 expression was decreased, and Runx2 expression was increased in miR-34a transfected AVICs compared with that in miR-control. Conversely, inhibition of miR-34a significantly attenuated these calcification signals in AVICs compared with miR-control. RNA pull-down assay revealed that miR-34a directly targeted Notch1 expression by binding to Notch1 mRNA 3' untranslated region. In wire injury CAVS mice, locked nucleic acid miR-34a inhibitor suppressed aortic velocity, calcium deposition of aortic valves, and cardiac hypertrophy, which were involved in decreased Runx2 and increased Notch1 expressions.miR-34a plays an important role in the development of CAVS via Notch1-Runx2 signalling pathway. Inhibition of miR-34a may be the therapeutic target for CAVS.
2-Amino-3-methylimidazo[4,5-f]quinoline metabolism by control and beta-naphthoflavone-treated mice.
Authors: Terry Zenser, Priscilla Jones, Jason Wickstra, Fong Fu Hsu, Vijaya Lakshmi
Journal: Cancer Research (2007)

1399  2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) is one of several heterocyclic amine carcinogens produced by high temperature cooking of red meat. These amines are thought to induce tumors in humans, i.e., colon and breast. Mouse models are being used to study the carcinogenicity of these amines. In contrast to rat, mouse metabolism of IQ has not been studied. In this study, we evaluated the metabolism of an oral 40 mg/kg dose of 14C-IQ in C57Bl/6 mice treated in the presence and absence of beta-naphthoflavone (B-NF), an inducer of phase 1 and 2 metabolism. Mice were treated with 40 mg/kg B-NF, i.p., for 3 days. Data in mice are compared to similarly treated F344 rats. Metabolism was assessed by HPLC with mouse urine and liver microsomes and slices. Metabolites were identified by ESI/MS and by their response to specific enzymatic and acid treatments. In the absence of B-NF, urinary N-acetyl-IQ (4.2 + 0.7 % of total radioactivity detected), IQ-N2-glucuronide (6.9 + 0.8 %), IQ-5-O-glucuronide (29.0 + 2.2 %), IQ-sulfamate (12.4 + 1.5 %), IQ-5-sulfate (2.4 + 0.2 %), Demethyl-IQ (23.8 + 0.6 %), and IQ (1.9 + 0.4 %) eluted at 10.5, 11.9, 17.0, 19.4, 25.9, 31.3, and 34.4 min, respectively. Following B-NF treatment, the urinary metabolites were mainly N-acetyl-IQ (18.6 + 3.4%) and IQ-5-O-glucuronide (43 + 4.2%) with the other individual metabolites not detected or less than 3%. The recovery of total administered radioactivity in urine for mice without and with B-NF was 67 + 6 and 47 + 2%, respectively. Liver slices were incubated with 0.06 mM 14C-IQ in supplemented DMEM and gassed with 5% CO2/95% O2 for 1 hour. The methanol soluble fraction was analyzed. Slice results reflected urinary elution patterns described for mice correspondingly treated either with or without B-NF. Ellipticine (0.5 mM), a selective P450 1A1 inhibitor, significantly inhibited slice metabolism of all metabolites except IQ-sulfamate while SKF-525A (0.5 mM), a general P450 inhibitor, was not very effective. Demethyl-IQ was the major metabolite of control mouse liver microsomes with formation inhibited by 0.02 mM ellipticine, but not by SKF-525A. There are notable differences between IQ metabolism in mice compared to rats. In the absence of B-NF, rats produced much less urinary N-acetyl-IQ (0.7 + 0.4) and Demethyl-IQ (1.6 + 0.2 %) and significantly more IQ-sulfamate (44.5 + 1.2) and IQ-5-sulfate (14.5 + 0.5%). The major rat urinary metabolite was IQ-sulfamate. Following B-NF treatment, IQ-5-O-glucuronide (54 + 4 %) and IQ-5-sulfate (31 + 2) were the major rat urinary metabolites. Previous studies have identified Demethyl-IQ (15%) as a major urinary metabolite of monkey. Thus, mouse metabolism of IQ is significantly different from rat and these differences may influence carcinogenicity.
Breast cancer: First results of an institutional cancer registry 2007-2011 in Colombia.
Authors: Andres Yepes, Luis Gonzalez, Isabel Cristina Durango, Beatriz Pineda, Juan D. Figueroa, Jaime Triana
Journal: Journal of Clinical Oncology (2013)

e12571 Background: The aim of this retrospective study was to describe the clinical characteristics of patients with breast cancer (BC) treated at the Oncology Unit of the Hospital Pablo Tobon Uribe in Medellin, Colombia, an institution's 10-year experience. Methods: All cases were Identified from our institution's cancer registry from 2007-2011. Results: During the study period 1224 BC were cases identified. Men: 12 (1%). Median age at diagnosis was 56 years (range 23-88). Stage at diagnosis was stage 0 (6.1%), stage I (30%), stage IIA (24.5%), stage IIB (10.8%), stage IIIA (6.8%), stage IIIB ( 6.1%), stage IIIC (9.5%), stage IV (3.4%) and unknown (2.8%). Primary right breast (50.2%). Most common histology was invasive ductal carcinoma (71%) and histologic grade 2 (34.6%). Estrogen and progesterone receptor status assessed at diagnosis was positive in 74,7% and 69% of cases tested respectively. HER2/neu status was positive in 14.2% (with hormone receptor positive 8,1% and hormone receptor negative 6.1%). Triple-negative BC 12.2%. Median tumor size was 2.3 cm (range 0.4-14.0 cm). Procedure performed was mastectomy in 59% and lumpectomy in 35%. Nodal staging was performed by axillary dissection (AD) (81%) and sentinel node biopsy (SN) alone (19%). Neoadjuvant chemotherapy was given to 39%, adjuvant chemotherapy to 69%, adjuvant hormonal therapy to 62% and adjuvant radiation therapy was used in 40,6%. The preferred adjuvant regimens was AC (doxorubicin / cyclophosphamide) followed by weekly paclitaxel in 51%. The average time from diagnosis to entry into consultation with specialist breast surgery 12 days. Time from diagnosis and staging complete and the beginning of the treatment: 16 days. Conclusions: The patient profile inquiry to our hospital with breast cancer is a woman of 56 years, with commitment right breast, invasive ductal carcinoma, grade 2, luminal A (estrogen receptor positive and / or progesterone receptor positive, HER2 negative), stage I and most commonly treated with mastectomy and chemotherapy with AC and paclitaxel.
Abstract 13745: Subclinical Hypothyroidism is Associated With Impaired Exercise Capacity and Adverse Prognosis in Heart Failure Patients
Authors: Yu Sato, Akiomi Yoshihisa, Takatoyo Kiko, Yusuke Kimishima, Shunsuke Watanabe, Yuki Kanno, Makiko Tatsumi, Satoshi Abe, Takamasa Sato, Satoshi Suzuki, Masayoshi Oikawa, Atsushi Kobayashi, Takayoshi Yamaki, Hiroyuki Kunii, Kazuhiko Nakazato, Shu-ichi Saitoh, Takafumi Ishida, Yasuchika Takeishi
Journal: Circulation (2017)

Backgrounds: It has been widely recognized that both overt hyper- and hypothyroidism can be a cause of heart failure (HF). On the other hand, it has been recently reported that subclinical hypothyr...
Excellent Response to Blinatumomab in Children and Young Adults with Refractory B Lineage Acute Lymphoblastic Leukaemia for Persistent MRD or after Debulking Chemotherapy for Higher Disease Burden
Authors: Vasudha Rao, Katherine Clesham, Jack Luke Bartram, Phil Ancliff, Sara Ghorashian, David O'Connor, Vesna Pavasovic, Anupama Rao, Sujith Samarasinghe, Carole Cairns, David Marks, David Taussig, Ajay Vora
Journal: Blood (2018)
A malignant human glioblastoma orthotopic mouse model with opportunities for non-invasive real time ultrasound imaging
Authors: Qian Xie, Ryan Thompson, Kim Hardy, Lisa DeCamp, Bree Berghuis, Sandra Cottingham, Ping Zhao, Brian Cao, James Resau, Rick Hay, George VandeWoude
Journal: Cancer Research (2008)

2905  Progress in understanding glioblastoma multiforme (GBM) pathobiology and developing novel therapies could be greatly accelerated with animal model systems that caricaturize human GBM and that enable tumor monitoring through noninvasive imaging in real time. We demonstrate that the invasive phenotype of GBM can be selected from established human GBM cell lines. Starting with the cell line DBTRG-05MG, we used an in vivo experimental metastasis selection method to obtain highly invasive DBM2 cells from lung metastases. Upon intracranial injection, DBM2 cells grow and invade both intra- and extra-cranially, with individual infiltrative tumor cells overexpressing the MET oncogene as visualized by immunohistochemistry. Intracranial tumor growth of DBM2 cells promotes osteolysis around the innoculum, providing a transcranial window for observing tumor growth and vascularization with high resolution micro-ultrasound (Vevo 770, VisualSonics, Inc). We also show that increased Area of the Opening (AO) of the skull is proportional to tumor growth. AO measurement by ultrasound provides an easy method to evaluate antitumor drug efficacy. We show that the geldanamycin derivative 17-AAG inhibits tumor growth and prolongs survival time in both orthotopic xenografts and lung metastases of DBM2 . We conclude that the DBM2 mouse model has invasive characteristics relevant to clinical GBM. This new model provides a valuable tool for investigating factors that modulate glioblastoma growth, assessing invasion and vascularity, and for testing novel therapeutic agents.
Novel Therapeutic Approaches Targeting the Renin-Angiotensin System and Associated Peptides in Hypertension and Heart Failure
Authors: Lauren B. Arendse, A. H. Jan Danser, Marko Poglitsch, Rhian M. Touyz, John C. Burnett, Catherine Llorens-Cortes, Mario R. Ehlers, Edward D. Sturrock
Journal: Pharmacological Reviews (2019)

Despite the success of renin-angiotensin system (RAS) blockade by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor (AT<sub>1</sub>R) blockers, current therapies for hypertension and related cardiovascular diseases are still inadequate. Identification of additional components of the RAS and associated vasoactive pathways, as well as new structural and functional insights into established targets, have led to novel therapeutic approaches with the potential to provide improved cardiovascular protection and better blood pressure control and/or reduced adverse side effects. The simultaneous modulation of several neurohumoral mediators in key interconnected blood pressure–regulating pathways has been an attractive approach to improve treatment efficacy, and several novel approaches involve combination therapy or dual-acting agents. In addition, increased understanding of the complexity of the RAS has led to novel approaches aimed at upregulating the ACE2/angiotensin-(1-7)/Mas axis to counter-regulate the harmful effects of the ACE/angiotensin II/angiotensin III/AT<sub>1</sub>R axis. These advances have opened new avenues for the development of novel drugs targeting the RAS to better treat hypertension and heart failure. Here we focus on new therapies in preclinical and early clinical stages of development, including novel small molecule inhibitors and receptor agonists/antagonists, less conventional strategies such as gene therapy to suppress angiotensinogen at the RNA level, recombinant ACE2 protein, and novel bispecific designer peptides.
Reply to Piquereau and Perros and to Pullamsetti and de Jesus Perez
Authors: Kondababu Kurakula, Olivier Boucherat, Diederik E. Van der Feen, Harm Jan Bogaard, Ewelina Kulikowski, Beatrijs Bartelds, Steeve Provencher, Rolf M. F. Berger, Sébastien Bonnet, Marie-José Goumans
Journal: American Journal of Respiratory and Critical Care Medicine (2019)
Response to Open Peer Commentaries on “‘Paid to Endure’: Paid Research Participation, Passivity, and the Goods of Work”
Authors: Erik Malmqvist
Journal: The American Journal of Bioethics (2019)

I thank my commentators for their insightful engagement with my article (Malmqvist 2019) and regret that I cannot here do justice to all the important issues they raise. In this response, I set asi...
Abstract #1411: Genome-wide scan identifies a copy number variable (CNV) region that regulates the expression of a candidate serine-threonine phosphatase in APC mutation-negative familial adenomatous polyposis (FAP) patients
Authors: Peh Yean Cheah, Lai Fun Thean, Carol Loi, Kok San Ho, Poh Koon Koh, Kong Weng Eu
Journal: Cancer Research (2009)

Background and aim: FAP is an autosomal dominantly inherited form of colorectal cancer caused by a germline mutation in the adenomatous polyposis coli (APC) gene. We search for new cancer gene in a subgroup of APC mutation-negative FAP variant patients with autosomal dominant inheritance, typical polyposis but accelerated disease progression. Methods: We performed Whole Genome Sampling Assay on both the lymphocyte and polyp DNA of two affected individuals of a FAP variant family and lymphocyte DNA of 2 other affected members, 4 unaffected members and 18 ethnicity-matched healthy controls using Affymetrix Genome-Wide Human single nucleotide polymorphism (SNP) Array 5.0. Results: A 111 kb region consisting 44 copy number (CN) probes, showed copy number loss in all 8 polyp DNAs (mean CN = 0.68) compared to the matched lymphocyte DNAs of two affected individuals. Fragments chosen randomly from this critical region for PCR analysis confirmed the copy number loss. Data mining reveal no known gene but only one putative 2.2 kb transcript in melanoma tissue. Extensive RT-PCR analysis indicated that this transcript is probably non-existent in lymphocyte and colonic mucosa tissues. A 2-Mb scan encompassing the deleted region identified a candidate serine-threonine phosphatase. Real-time PCR analyses indicate that expression of the 3\#8217;UTR of this gene is down-regulated in the polyps and tumors of the affected member compared to the mucosa. Conclusion: A 111 kb CNV region regulates the expression of a serine-threonine phosphatase in the TGF- \#946; signalling pathway that may contribute to colorectal tumorigenesis in FAP variant patients.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1411.
Inhibition of HER signaling induces growth arrest and apoptosis in ErbB2-driven non-small cell lung cancers
Authors: Guosheng Huang, Susumu Kobayashi, Cheng Jin, Jeffrey Kern, David Nethery, Daniel G. Tenen, Afshin Dowlati, Balazs Halmos
Journal: Cancer Research (2006)

3773  Mutations of the epidermal growth factor receptor (EGFR) and EGFR amplification occurs in approximately 10-20% of non-small cell lung cancers (NSCLC). Both genetic aberrations had been shown to correlate with responsiveness to small molecule EGFR inhibitors. This suggests a pivotal role for EGFR signaling in the maintenance of the proliferative state of these cells. The ErbB2 gene is amplified in 5-10% of non-small cell lung cancers and recently ErbB2 mutations similar to EGFR mutations had been described in another 2-5% of all non-small cell lung cancers. The biological role of ErbB2 mutations has not been fully defined and the therapeutic relevance of the ErbB2 pathway in the treatment of ErbB2-driven NSCLCs remains unclear. In the present study, we utilized an ErbB2-mutant (H1781) and an ErbB2-amplified (Calu-3) non small cell lung cancer cell line to model ErbB2-driven lung cancers. Stimulation of both H1781 as well as Calu-3 cells with EGF or neuregulin-1 led to a significant increase in ErbB2 phosphorylation (p-ErbB2) associated with a corresponding increase in p-ERK and p-AKT levels. Treatment of both cell lines with GW572016, a combined EGFR/ErbB2 inhibitor blocked p-ErbB2 as well as p-ERK and p-AKT activation. Blockade was accompanied by a dose-dependent growth inhibition in both cell lines, with an approximately 80% reduction in proliferation at a concentration of 1 μM following 72 hours of treatment. A marked increase in apoptosis was observed in the H1781 cell line (4% to 12% at 1 μM and 25% at 10 μM), while only a slight increase in apoptosis was seen in the Calu-3 cell line. BrDu proliferation assays showed a dramatic reduction in S-phase cells and an accumulation in the G1 phase explaining the growth arrest in Calu-3 cells. Further studies are being conducted to identify the contribution of EGFR versus ErbB2 signaling to the observed phenotype and downstream changes are also being explored to identify the effectors of proliferation arrest and apoptosis in these cell lines. Our studies demonstrate the therapeutic potential of HER inhibition in ErbB2-driven non-small cell lung cancers and also point to potential differences between ErbB2-mutant and ErbB2-amplified cancers with regards to their sensitivity to treatment with small molecule HER-inhibitors.