tbuckley/cabot-search huggingface dataset:
Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva
Authors: Kyosuke Hino, Kazuhiko Horigome, Megumi Nishio, Shingo Komura, Sanae Nagata, Chengzhu Zhao, Yonghui Jin, Koichi Kawakami, Yasuhiro Yamada, Akira Ohta, Junya Toguchida, Makoto Ikeya
Journal: Journal of Clinical Investigation (2017)

Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling. Although Activin-A evokes enhanced chondrogenesis in vitro and heterotopic ossification (HO) in vivo, the underlying mechanisms have yet to be revealed. To this end, we developed a high-throughput screening (HTS) system using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to identify pivotal pathways in enhanced chondrogenesis that are initiated by Activin-A. In a screen of 6,809 small-molecule compounds, we identified mTOR signaling as a critical pathway for the aberrant chondrogenesis of mesenchymal stromal cells derived from FOP-iPSCs (FOP-iMSCs). Two different HO mouse models, an FOP model mouse expressing FOP-ACVR1 and an FOP-iPSC-based HO model mouse, revealed critical roles for mTOR signaling in vivo. Moreover, we identified ENPP2, an enzyme that generates lysophosphatidic acid, as a linker of FOP-ACVR1 and mTOR signaling in chondrogenesis. These results uncovered the crucial role of the Activin-A/FOP-ACVR1/ENPP2/mTOR axis in FOP pathogenesis.
Abstract 5487: Identification of super-enhancer-associated cancer genes provides novel therapeutic targets in adult T-cell leukemia/lymphoma
Authors: Takaomi Sanda, Regina WJ Wong, Phuong TN Cao, Wei Zhong Leong, Alice WY Yam, Tinghu Zhang, Shinsuke Iida, Takashi Okamoto, Ryuzo Ueda, Nathanael S. Gray, Takashi Ishida
Journal: Cancer Research (2017)

Abstract Super-enhancers are often enriched at cancer genes in various malignancies. Identification of such enhancers would pinpoint critical factors that directly contribute to pathogenesis. Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive lymphoproliferative disorder that arises from CD4+ mature T-lymphocytes. A recent genome-wide sequencing study revealed a large number of genetic and chromosomal abnormalities. However, there is still a lack of functional evidence for these genetic abnormalities in ATL pathogenesis due to the large mutational burden and the considerable genetic heterogeneity. Here, we performed super-enhancer profiling combined with gene expression analysis in primary ATL samples and cell lines. Super-enhancers are frequently enriched at genes involved in T-cell activation and T-cell receptor signaling pathway in both ATL and normal CD4+ T-cells, reflecting the origin of leukemia cells. Super-enhancers at the CCR4 gene, a known therapeutic target in ATL, were observed in all ATL cases. Additionally, we identified previously-uncharacterized genes that were highly activated in ATL cells and required for cell growth. A small-molecule inhibitor of CDK7 efficiently downregulated the expression of these genes and inhibited cell growth. Our study provides a novel strategy to identify critical cancer genes in cancer. Note: This abstract was not presented at the meeting. Citation Format: Takaomi Sanda, Regina WJ Wong, Phuong TN Cao, Wei Zhong Leong, Alice WY Yam, Tinghu Zhang, Shinsuke Iida, Takashi Okamoto, Ryuzo Ueda, Nathanael S. Gray, Takashi Ishida. Identification of super-enhancer-associated cancer genes provides novel therapeutic targets in adult T-cell leukemia/lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5487. doi:10.1158/1538-7445.AM2017-5487
US plan gives greater role to electronic cigarettes in tobacco harm reduction
Authors: Michael McCarthy
Journal: BMJ (2017)

The US Food and Drug Administration (FDA) will seek to reduce nicotine levels in combustible cigarettes to non-addictive levels while exploring giving electronic cigarettes and other nicotine delivery products a greater role in reducing the harm caused by tobacco.

In a 28 July speech announcing the plan, FDA commissioner Scott Gottlieb said that the recent development of new electronic nicotine delivery devices makes it possible to reduce cigarette use driven by nicotine addiction.

Gottlieb said that, although nicotine was “by no means completely safe and benign,” products that deliver the drug present a “continuum of risk” in which the …
Abstract 5674: Cancer immunogenomics for the development of personalized ovarian cancer vaccine
Authors: Muzamil Y. Want, Takemasa Tsuji, Richard Koya, Sebastiano Battaglia
Journal: Cancer Research (2017)

Abstract Ovarian cancer (OC) is the fifth leading cause of cancer death in the United States with approximately 20,000 women being diagnosed every year. Since OC development is mainly asymptomatic, patients are often diagnosed at late stage and present local and distal metastases. This offers a clinical challenge, as roughly 70% of the patients develop chemoresistant disease. With the advent of cancer immunogenomics it is now possible to identify tumor specific mutations, or neoantigens/neoepitopes, that can be exploited for the development of personalized T cell therapies via DC vaccines or adoptive cell therapy (ACT). We therefore hypothesize that tumor cells isolated from malignant ascites reflect the genomic landscape of the primary tumor, offering a unique opportunity to identify clinically actionable tumor neoantigens. We utilized primary tumor, tumor cells isolated from malignant ascites and metastatic samples to create patient-derived xenografts (PDX) mice and to interrogate the tumor mutational landscape. Somatic mutations were identified by whole exome sequencing (WES) and RNASeq analysis in tumor samples, using PBMCs as germline control. In parallel 20 PDX of ovarian cancer were established in NSG mice by injecting 2×106 cells/mouse subcutaneously (SQ, n=10) and intraperitoneally (IP, n=10). Tumor growth was monitored weekly via caliper measurement for mice injected SQ and via abdominal circumference for mice injected IP. Mutational analysis and prediction of high affinity peptides was done using bioinformatics approach. We have utilized different algorithms that are based on Artificial Neural Networks or published motifs for predicting binding of 8-11 mer peptides to number of Human MHC alleles (HLA) and out of 168 mutated peptides identified, 30 were found to have high affinity for different HLAs compared to wild type peptide. Mutated and wild type peptides were pulsed into dendritic cells and co-cultured with CD8+ T cells for 20 days. Validation of stimulated CD8+ T cells by these mutated peptides using ELISPOT is underway. TCR specific for neoantigen from CD8+T cells will be identified and cloned using retroviral vectors. Transfected CD8+ T cells with neoantigen specific TCR will be confirmed by co-culturing them with dendritic cells pulsed with wild type and mutated peptides. Further engineered CD8+ T cells specific for neoantigens will be tested for adoptive cell therapy in the established PDX models of ovarian cancer. Citation Format: Muzamil Y. Want, Takemasa Tsuji, Richard Koya, Sebastiano Battaglia. Cancer immunogenomics for the development of personalized ovarian cancer vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5674. doi:10.1158/1538-7445.AM2017-5674
Abstract 4363: Bisulfite DNA sequencing analyses to detect methylation patterns in the p73 gene promoter in prostate cancer cell lines
Authors: Nicholas E. Braganca, L. Michael Carastro, Johannes J. Schabort, Jong Y. Park
Journal: Cancer Research (2017)

Abstract Transcription is regulated through a variety of different mechanisms. One facet of transcriptional regulation is epigenetics, which is the regulation of gene expression without altering the nucleotide sequence of the genome, but rather reversible modifications, e.g. CpG methylation. The CpG islands in tumor suppressor gene promoters are often hypermethylated, thus down regulating their expression. The p73 gene is a member of the p53 tumor suppressor family of proteins, and like p53, has a bifurcated promoter. The p73 P1 promoter transcribes a full-length mRNA, which then translates into the transcriptionally active p73. The p73 P2 promoter transcribes a truncated mRNA, which translated into transcriptionally inactive ΔNp73. The ΔNp73 product lacks the N-terminal trans-activation domain that TAp73 possesses. This study sought to analyze the extent of DNA methylation in the CpG islands in the p73 P1 promoter of three prostate cancer (PCa) cell lines (LNCaP, PC-3, and DU145), and primary prostate cells. We hypothesized that the p73 P1 promoter would be hypermethylated in prostate cancer cell lines and hypomethylated in primary prostate cells. The methylation status of the p73 P1 promoter in all four prostate cell lines was analyzed by using bisulfite sequencing PCR (BSP). Our analyses revealed that a CpG island in the p73 P1 was hypermethylated in LNCaP, PC-3, and DU145 cells compared to primary prostate cells. Furthermore, among the three PCa cell lines evaluated, the p73 P1 promoter was the most methylated in DU145 cells, and the least methylated in LNCaP cells. The P1 region sequenced contained 28 CpG islands, and among them, only five were methylated in the primary prostate cells (18% methylated), 23 were methylated in LNCaP cells (82% methylated), 26 in PC-3 cells (93% methylated), and 28 in DU145 cells (100% methylated). Furthermore, of the 28 CpG sites, 14 of them were differentially methylated in the primary prostate cell line versus the three PCa cell lines evaluated in this study. These data are consistent with the PCa tumor-derived cell lines (LNCaP, PC-3, and DU145) having hypermethylated CpG sites in the p73 P1 promoter compared to the primary prostate cell line. Citation Format: Nicholas E. Braganca, L. Michael Carastro, Johannes J. Schabort, Jong Y. Park. Bisulfite DNA sequencing analyses to detect methylation patterns in the p73 gene promoter in prostate cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4363. doi:10.1158/1538-7445.AM2017-4363
Abstract 5869: Resistance mechanism against trastuzumab in HER2-positive cancer cells and its negation by Src inhibition
Authors: Meihua Jin, Ah Rong Nam, Ji Eun Park, Ju Hee Bang, Yung Jue Bang, Do Youn Oh
Journal: Cancer Research (2017)

Abstract Background: Trastuzumab in combination with chemotherapy is a standard of care for patients with HER2-positive breast and gastric cancer. Resistance mechanism to trastuzumab, anti-HER2 therapy, includes multiple pathways. Among them, Src is not well known especially in HER2-positive gastric and biliary tract cancers. We investigated the role of Src involved in trastuzumab resistance and explored the potential of Src inhibition as a trastuzumab resistance overcoming strategy. Methods: Four trastuzumab-resistant (HR) cells (SNU216HR, N87HR, SNU2670HR, SNU2773HR) were established from 2 HER2-amplified gastric cancer cells (SNU216, NCI-N87) and 2 HER2-amplified biliary tract cancer cells (SNU2670, SNU2773). For Src inhibition, bosutinib was used. MTT assay, colony formation assay, cell cycle analysis by FACS Calibur flow cytometer, and cell migration assay were done. Animal experiments were conducted to test anti-tumor effect of bosutinib using SNU2670 and SNU2670HR xenograft models. Results: SNU2670HR/NCI-N87HR cells showed pSrc activation, in contrast, SNU216HR/SNU2773HR cells exhibited decreased pSrc expression. In these pSrc decreased HR cells, pFAK was elevated. Bosutinib downregulated Src-FAK signaling more obviously in Src activated HR cells than parental cells. In pSrc decreased HR cells, bosutinib reduced Src-dependent FAK phosphorylation to affect cell fate. Bosutinib inhibited the growth of both parental cells and HR cells, and induced apoptosis and G1 arrest in HR cells. Bosutinib suppressed HR cell migration more effectively compared with parental cells. Bosutinib exhibited potent tumor growth inhibition in both SNU2670 and SNU2670HR xenograft models and more significantly suppressed tumor growth in HR models. Conclusion: Src activation may contribute to trastuzumab resistance in part in HER2-positive gastric and biliary tract cancer cells. Targeting Src might be a candidate strategy to overcome trastuzumab resistance in HER2-positive cancers. Citation Format: Meihua Jin, Ah Rong Nam, Ji Eun Park, Ju Hee Bang, Yung Jue Bang, Do Youn Oh. Resistance mechanism against trastuzumab in HER2-positive cancer cells and its negation by Src inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5869. doi:10.1158/1538-7445.AM2017-5869
Abstract 1311: Germline variation at 8q24 and prostate cancer risk
Authors: Kan Wang, Ali Amin Al Olama, Rosalind Eeles, David Conti, Zsofia Kote-Jarai, Christopher A. Haiman
Journal: Cancer Research (2017)

Abstract The 8q24 region harbors multiple risk variants for distinct cancers including 7 for prostate cancer, the majority of which lie in separate linkage disequilbrium blocks. It is not known whether a common biological mechanism underlies the association of genetic variation with cancer risk at 8q24, or whether there are site-specific functions of regulatory elements that are affected in this region. Given the proximity, the MYC oncogene is a likely candidate as are multiple long non-coding RNAs in the region. To further understand the contribution of germline variation to prostate cancer risk we performed a comprehensive fine-mapping analysis of the region in men of European ancestry from the PRACTICAL/ELLIPSE Consortium. More specifically, we tested 1,731 genotype tag SNPs and 12,221 imputed variants spanning the risk region (127.3-129.0Mb) in 56,363 prostate cancer cases and 37,386 controls of European ancestry that were genotyped with the Illumina OncoArray. We performed stepwise logistic regression and identified 13 variants with risk allele frequencies between 0.006 and 0.998 that surpassed genome-wide statistical significance (p-values between 3.2x10-8 and 8.0 x10-78) and with per allele odds ratios ranging from 1.11(rs5013678) to 2.68(rs183373024). Ongoing analyses that will be presented include incorporating existing GWAS and fine-mapping data (iCOGs) for men of European and African ancestry (35,000 cases and 35,000 controls) using JAM, a Bayesian approach that investigates multi-SNP models using marginal meta-analysis statistics. Leveraging the power from the overall multiethnic meta-analysis (&amp;gt;93,000 cases and &amp;gt;72,000 controls) will provide further insight into the number of independent signals in the region and their contribution to prostate cancer risk in these populations. Citation Format: Kan Wang, Ali Amin Al Olama, Rosalind Eeles, David Conti, Zsofia Kote-Jarai, Christopher A. Haiman. Germline variation at 8q24 and prostate cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1311. doi:10.1158/1538-7445.AM2017-1311
Abstract LB-176: Extracts ofPsidium guajava(guava) andSyzygium samarangense(wax apple) leaves and teas with Nrf2 induction activity protect mouse AML12 hepatocytes from tumor-initiating acetaminophen-induced damage
Authors: Zheng-Yuan Su, Yen-Fan Chan, Pei-Chun Chen, Ping-Hua Sung, Zi-Han Lin
Journal: Cancer Research (2017)

Abstract The liver is the primary organ responsible for the major detoxifications and metabolic functions in the human body; however, liver carcinogenesis can be triggered by acetaminophen (paracetamol, APAP), a tumor-initiator. Nrf2 is a master regulator to induce the expression of phase II detoxification/antioxidant enzymes. Some of fruit plant leaves in Taiwan have hepatoprotective potential, including Psidium guajava (guava) leaves (GL) and Syzygium samarangense (wax apple) leaves (WAL) as well as the processing guava tea (GT) and wax apple tea (WAT). In this study, we found that water extracts (WE), including GL-WE (250 μg/mL), WAL (250 μg/mL), GT (500 μg/mL), and WAT (500 μg/mL) without cytotoxicity can active Nrf2 pathway at 24 hrs in HepG2-C8 cells which are stably transfected with an antioxidant response element (ARE)-luciferase construct. These extracts also effectively recovered the cell viability of mouse liver AML12 cells with APAP-induced injury when the cells were pretreated with the extracts for 24 hrs and then co-treated with extracts and APAP for another 48 hrs. A better understanding of the mechanisms how these extracts inhibit oxidative stress/inflammation related to APAP-induced liver carcinogenesis in the future would open new avenues of approaches for the prevention of liver cancer in human. Citation Format: Zheng-Yuan Su, Yen-Fan Chan, Pei-Chun Chen, Ping-Hua Sung, Zi-Han Lin. Extracts of Psidium guajava (guava) and Syzygium samarangense (wax apple) leaves and teas with Nrf2 induction activity protect mouse AML12 hepatocytes from tumor-initiating acetaminophen-induced damage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-176. doi:10.1158/1538-7445.AM2017-LB-176
Abstract 4454: MED12 is recurrently mutated in Middle Eastern colorectal cancer
Authors: Abdul K. Siraj, Tariq Masoodi, Rong Bu, Fouad Al-Dayel, Khawla S. Al-Kuraya
Journal: Cancer Research (2017)

Abstract Colorectal cancer (CRC) is a common cancer and a leading cause of cancer deaths. Previous studies have identified a number of key steps in the evolution of CRC but our knowledge of driver mutations in CRC remains incomplete. Recognizing the potential of studying different human populations to reveal novel insights in disease pathogenesis, we conducted genomic analysis of CRC in Saudi patients. In the discovery phase of the study, we conducted whole-genome sequencing of tumor and corresponding germline DNA in 27 CRC patients. In addition to known driver mutations, we identified three MED12 somatic mutations. In the replication phase, we employed a next-generation sequencing approach to capture and sequence MED12 and other candidate genes in a larger sample of 400 CRC patients and confirmed the enrichment for recurrent MED12 mutations. In order to gain insight into a plausible biological mechanism for the potential role of MED12 mutations in CRC, we studied CRC cell lines that differ substantially in the expression level of MED12, and found the latter to be correlated inversely with TGF-beta signaling and directly with apoptosis in response to chemotherapeutic agents. Importantly, these correlations were replicated when MED12 expression was experimentally manipulated. Our data expand the recently described role of MED12 as a tumor suppressor in other cancers to include CRC, and suggest TGF-beta signaling as a potential mediator of this effect. Citation Format: Abdul K. Siraj, Tariq Masoodi, Rong Bu, Fouad Al-Dayel, Khawla S. Al-Kuraya. MED12 is recurrently mutated in Middle Eastern colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4454. doi:10.1158/1538-7445.AM2017-4454
The assembly competence domain is essential for inv(16)-associated acute myeloid leukemia
Authors: H-G Kim, J LeGrand, C S Swindle, H J Nick, R A Oster, D Chen, S Purohit-Ghelani, C V Cotta, R Ko, L Gartland, V Reddy, S W Hiebert, A D Friedman, C A Klug
Journal: Leukemia (2017)
Some mental healthcare is “rooted in the past”
Authors: Jacqui Wise
Journal: BMJ (2017)

Some patients in England with mental health disorders still receive care that is over-restrictive and institutional in nature, leaving people feeling “powerless and helpless,” according to a report from the Care Quality Commission (CQC).1

Over a three year period the regulator inspected and rated services provided by 54 NHS trusts and 221 independent mental health providers in England.

It found there are about 3500 beds in locked mental health rehabilitation wards, with about two thirds of these managed in the independent sector. The report says that some of these wards are long stay wards that risk institutionalising patients. The wards are often a long way from the patient’s home so patients risk becoming isolated from their friends and families. The CQC said that this model of care does not have a place …