tbuckley/cabot-search huggingface dataset:
Abstract 1891: Annexin A2-binding S100 proteins promote proliferation and cell cycle progression of EGFR positive cancer cells
Authors: Naoko Ogama, Ryuuichi Nagashima, Nobuyuki Tanaka
Journal: Cancer Research (2017)

Abstract (a) Aim: The purpose of this study is to clarify an unknown function of Annexin A2-binding S100A proteins in tumor growth, cell cycle progression and invasion. Annexin A2 is a membrane bound protein originally identified as v-Src substrate, and often found to be overexpressed in many types of cancers. As a multicompartmental protein that orchestrates a spectrum of dynamic membrane-related events, it is associated with actin cytoskeleton control, vesicle formation and intercellular interaction. (b) Methods and Results: During our proteomics analysis using solid tumor cell lines, we identified both Annexin A2 and S100A proteins in cancer stem cell-rich population. We next examined S100A proteins expression in several Head and Neck cancer PDX samples. Immunohistochemical data from in vivo specimens as well as western blots showed that S100A expression abundance was well associated with poor prognosis. Annexin A2 has been indicated to be involved in malignant phenotypes such as invasion and metastasis, and Annexin A2 and S100A form (S100-Annexin A2)x2 dimers, we next examined roles of S100A proteins in cancer, by using shRNA-mediated depletion experiments. (c) New Findings: Depletion of S100A from PDX-derived cancer cells resulted in loss of both in vivo tumor formation and invasion. Furthermore, cell cycle progression was inhibited by the depletion, suggesting its potential role in proliferation controls. Similar to the mutant Ras-driven tumors, EGFR-overexpression increased S100A gene expresssion. (d) Conclusion: These results strongly suggest that increases in S100A plays significant roles in cancer cell proliferation and invasion. Note: This abstract was not presented at the meeting. Citation Format: Naoko Ogama, Ryuuichi Nagashima, Nobuyuki Tanaka. Annexin A2-binding S100 proteins promote proliferation and cell cycle progression of EGFR positive cancer cells [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 1891. doi:10.1158/1538-7445.AM2017-1891
The Significance of Hormones in the Origin of Cancer&lt;xref ref-type="fn" rid="fn1"&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/xref&gt;
Authors: Leo Loeb
Journal: JNCI Journal of the National Cancer Institute (1940)

The Significance of Hormones in the Origin of Cancer Get access Leo Loeb Leo Loeb professor emeritus of pathology Laboratory of Research Pathology, Oscar Johnson Institute, Washington University School of Medicine Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 1, Issue 2, October 1940, Pages 169–195, https://doi.org/10.1093/jnci/1.2.169 Published: 01 October 1940
Unmet need in mental health provision
Authors: Nick Mann
Journal: BMJ (2017)

The rise in out of area placements is the result of having cut 72% of England’s mental health beds since 1987 and is emblematic of increasing unmet need in mental health provision.1 Thousands more patients are being denied any bed, as admission thresholds inevitably rise. Who is monitoring harms in these patients, in terms of avoidable deterioration, injurious behaviour, and suicide?

The Department of Health, NHS Improvement and NHS England, and the …
Abstract 2706:KRT16germline mutation associated with familial syndrome of tylosis with esophageal cancer (TOC)
Authors: Erin L. Young, Lance Pflieger, Luke Maese, Trent Fowler, Kinley Garfield, N. Jewel Samadder, Bella Johnson, Clinton C. Mason, Barry Moore, Shawn Ryanearson, Mark Yandell, Wendy Kohlmann, Joshua D. Schiffman
Journal: Cancer Research (2017)

Abstract Tylosis (palmoplantar keratoderma) with esophageal cancer (TOC) also known as Howel-Evans syndrome has been associated with pathogenic mutations in RHBDF2. A potential TOC family was referred for clinical evaluation at the Family Cancer Assessment Clinic (FCAC) at Huntsman Cancer Institute, Salt Lake City, Utah. Multiple relatives of the proband had hyperkeratosis on the areas of skin associated with pressure and friction, especially the feet, as well as oral leukoplakia. The proband’s father, paternal aunt, paternal grandfather, and paternal great grandfather had been diagnosed with esophageal cancer. Clinical testing was unable to identify a germline mutation in RHBDFR2 that explained the observed phenotype and inheritance pattern. As part of Heritage 1K Project (University of Utah), Pediatric &amp; Adult Cancer Section, we performed whole genome sequencing (WGS) on 5 family members, 4 that were affected with the hyperkeratosis, and 1 unaffected family member, to identify other potential genetic causes for the observed TOC phenotype. We prioritized variants via VAAST (Variant Annotation, Analysis and Search Tool). Reducing our genes of interest to those involved in palmoplantar keratoderma with PHEVOR (Phenotype Driven Variant Ontological Re-ranking Tool), we identified a pathogenic mutation: KRT16 c.379C&amp;gt;T p.Arg127Cys. This mutation is reported in a large palmoplantar keratoderma family (without esophageal cancer) and is listed as pathogenic in Clinvar (www.ncbi.nlm.nih.gov/clinvar). KRT16 c.379C&amp;gt;T p.Arg127Cys was present in each of the affected family members, but not in the unaffected relative. Our analysis is the first of its kind to suggest carriers of pathogenic variants in KRT16 are at-risk for esophageal cancer, and may benefit from esophageal surveillance. Additionally, patients presenting with a family history of esophageal cancer should be considered for germline testing for KRT16 mutations along with RHBDF2 mutations. Citation Format: Erin L. Young, Lance Pflieger, Luke Maese, Trent Fowler, Kinley Garfield, N. Jewel Samadder, Bella Johnson, Clinton C. Mason, Barry Moore, Shawn Ryanearson, Mark Yandell, Wendy Kohlmann, Joshua D. Schiffman. KRT16 germline mutation associated with familial syndrome of tylosis with esophageal cancer (TOC) [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 2706. doi:10.1158/1538-7445.AM2017-2706
Abstract 79: Trastuzumab and C6.5 diabody armed with deBouganin overcome drug resistance to ADCs comprised of anti-microtubule agents
Authors: Shilpa Chooniedass, Rachelle L. Dillon, Arjune Premsukh, Gregory P. Adams, Glen C. MacDonald, Jeannick Cizeau
Journal: Cancer Research (2017)

Abstract DeBouganin (deB) is a de-immunized form of bouganin, a Ribosome Inactivating Protein (RIP) that when internalized blocks protein synthesis thereby leading to cell death. When conjugated to trastuzumab (T-deB) or genetically attached to the C6.5 diabody, deBouganin was more potent than DM1 and unaffected by mechanisms of resistance to which DM1 is susceptible. To further highlight the differentiating mechanism of action of deBouganin, HCC1419 and BT-474 tumor cells that survived T-DM1 or trastuzumab-MMAE (T-MMAE) treatment in vitro were re-exposed to T-DM1, T-MMAE, or treated with T-deB or an anti-HER2 C6.5 diabody-deBouganin fusion protein. C6.5 diabody-deBouganin and T-deB were potent against HCC1419 and BT-474 cells surviving T-DM1 or T-MMAE treatment. However, the surviving cell populations were resistant to T-DM1, T-MMAE, DM1, MMAE and taxol treatment. In addition, cross-resistance was seen against trastuzumab-duocarmycin which contains a payload with a cell cycle independent mechanism of action. The contribution of multi-drug resistance, Bcl-2 family members and other survival pathways accounting for the resistant phenotype will be discussed. Overall, the data suggest that treatment with chemotherapeutics or ADCs comprised of small molecule compounds such as anti-microtubule agents, can lead to the outgrowth of tumor cells resistant to similar agents. In contrast, antibodies and antibody fragments armed with deBouganin can overcome these mechanisms of resistance and may therefore represent a more effective treatment option. Citation Format: Shilpa Chooniedass, Rachelle L. Dillon, Arjune Premsukh, Gregory P. Adams, Glen C. MacDonald, Jeannick Cizeau. Trastuzumab and C6.5 diabody armed with deBouganin overcome drug resistance to ADCs comprised of anti-microtubule agents [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 79. doi:10.1158/1538-7445.AM2017-79
Abstract 2797: MiR-137 and MiR-496 target Del-1 and affect triple negative breast cancer progression
Authors: Jeeyeon Lee, Yee Soo Chae, Soo Jung Lee, Jin Hyang Jung, Ho Yong Park, Moon-Chang Baek
Journal: Cancer Research (2017)

Abstract Background: Although Del-1 was recently proposed as a new biomarker for early breast cancer in our previous studies, the mechanisms of Del-1 expression are barely understood. In the current study, we selected two microRNAs (miR-137 and - 496), potentially affecting Del-1 expression in breast cancer and examined their impact on Del-1 expression in a variety of breast cancer cell lines to identify their potential role in Del-1 expression and thereby breast cancer development or progression. Methods: Del-1 mRNA and miR-137/- 496 levels were measured by qRT-PCR among breast epithelial (MCF10A) and cancer cells (MDA-MB-231, MCF7, SK-BR3 and T-47D). The effects of miR-137/- 496 on cell proliferation and invasion were detected using MTT, wound healing and Transwell assays. Furthermore, luciferase reporter assay was used to identify the direct regulation of Del-1 by miR-137 or - 496 in MDA-MB-231 cells. Plus, we analyzed the expressions of miR-137 or - 496 and Del-1 mRNA from 20 patients with triple negative early breast cancer. Results: miR-137 and - 496 levels were low in all breast cancer cell lines. As Del-1 mRNA expression was remarkably higher in MDA-MB-231 compared to the other breast cancer cell lines, further functional analyses were done with MDA-MB-231 representing triple negative breast cancer subtype. Both miR-137 and miR-496 were revealed to directly bind at the 3’-UTR of Del-1. Del-1 by Luciferase reporter assay and Del-1 expression was upregulated by inhibitors and reversed by both mimics of both miR-137 and miR-496. Furthermore, both miR-137 and miR-496 were also demonstrated to inhibit cell proliferation, migration and invasion of MDA-MB-231, suggesting that these miRNAs affect cancer progression via Del-1. MiR-137 and miR-496 were remarkably down-regulated in 7 out of 12 triple negative breast cancer tissues, in particular with high Ki67 and high histologic grade. Conclusion: Although Del-1 was recently introduced as a new biomarker for triple negative breast cancer, the mechanisms of Del-1 expression were barely identified. The current study firstly demonstrated that microRNA 137 and 496 are involved in Del-1 regulation by binding at Del-1 gene, affecting cancer progression by altering Del-1 expression. Citation Format: Jeeyeon Lee, Yee Soo Chae, Soo Jung Lee, Jin Hyang Jung, Ho Yong Park, Moon-Chang Baek. MiR-137 and MiR-496 target Del-1 and affect triple negative breast cancer progression [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 2797. doi:10.1158/1538-7445.AM2017-2797
Abstract 5725: Search for a combination of risk stratification markers for recurrence after curative resection of gastric cancer
Authors: Takashi Oshima, Yohei Miyagi, Yayoi Kimura, Kentaro Sakamaki, Shoji Yamanaka, Naohide Oue, Toru Aoyama, Tsutomu Sato, Haruhiko Cho, Manabu Shiozawa, Takaki Yoshikawa, Yasushi Rino, Wataru Yasui, Toshio Imada, Munetaka Masuda
Journal: Cancer Research (2017)

Abstract Objective: Adjuvant chemotherapy after curative resection is standard treatment for stage II/III gastric cancer. Personalized therapy based on biomarker analysis is expected to further improve outcomes. We analyzed frozen specimens of gastric cancer to investigate markers for stratification of recurrence risk and report our findings. Methods: We studied 778 patients with stage II/III gastric cancer in whom ≥5 years had elapsed since curative resection. We first measured the expression levels of 127 genes in gastric cancer tissue by quantitative polymerase-chain-reaction (PCR) assay in 255 patients (training set, 145; validation set, 110) to identify poor prognostic factors. Next, we studied patients who received 1 year of adjuvant chemotherapy after curative resection of T4a, Nx, M0, stage III gastric cancer and performed an exploratory proteomic analysis to compare the expressions of 1756 proteins between 12 patients who died of recurrence within 3 years and 12 patients who survived with no recurrence for at least 5 years. Proteins with a max fold change of &amp;gt;2 and significant differences (P&amp;lt;0.001) were identified. Immunostaining of tissue microarray sections from another cohort of 499 patients was performed to confirm our results and to identify combinations of markers for risk stratification. Results: On quantitative PCR assay, SPARC, HER2, CXCR4, INHBA, VSNL1, MMP11, CCR7, MRP1, CEACAM7, p53, EZH2, PDGFRB, and VCAM1 were identified as candidate markers. On exploratory proteomic analysis, SPARC, CLC, PRG2, and PRG3 were identified. A tissue microarray was constructed for the 16 candidate markers to evaluate combinations of markers. The combination of SPARC, EZH2, HER2, and p53 could be used for risk stratification (5-year survival rate, 68% vs. 33%; P=0.0111). Conclusions: The combination of SPARC, EZH2, HER2, and p53 can be used as a marker to stratify the risk of recurrence after curative resection of stage II/III gastric cancer. Citation Format: Takashi Oshima, Yohei Miyagi, Yayoi Kimura, Kentaro Sakamaki, Shoji Yamanaka, Naohide Oue, Toru Aoyama, Tsutomu Sato, Haruhiko Cho, Manabu Shiozawa, Takaki Yoshikawa, Yasushi Rino, Wataru Yasui, Toshio Imada, Munetaka Masuda. Search for a combination of risk stratification markers for recurrence after curative resection of gastric 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 5725. doi:10.1158/1538-7445.AM2017-5725
Abstract 2553: High-density array-CGH with targeted NGS unmask multiple non-contiguous minute deletions on chromosome 3p21 in mesothelioma
Authors: Michele Carbone, Yoshie Yoshikawa, Mitsuru Emi, Tomoko Hashimoto-Tamaoki, Masaki Ohmuraya, Ayuko Sato, Tohru Tsujimura, Seiki Hasegawa, Takashi Nakano, Masaki Nasu, Sandra Pastorino, Agata Szymiczek, Angela Bononi, Harvey I. Pass, Haining Yang
Journal: Cancer Research (2017)

Abstract We used a custom-made comparative genomic hybridization-array (aCGH; average probe interval 254 bp) to screen 33 malignant mesothelioma (MM) biopsies for somatic copy number loss throughout the 3p21 region (10.7 Mb) that harbors 251 genes, including BRCA1-associated protein 1 (BAP1), the most commonly mutated gene in MM. We identified frequent minute biallelic deletions (&amp;lt;3 Kb) in 46/251 genes: four were cancer associated genes: SETD2 (7/33), BAP1 (8/33), PBRM1 (3/33) and SMARCC1 (2/33). These four genes were further investigated by targeted Next Generation Sequencing (tNGS), which revealed sequence-level mutations causing biallelic inactivation. Combined high-density aCGH and tNGS revealed biallelic gene inactivation in SETD2 (9/33, 27%), BAP1 (16/33, 48%), PBRM1 (5/33, 15%) and SMARCC1 (2/33, 6%). The incidence of genetic alterations detected is much higher than reported in the literature because minute deletions are not detected by NGS or commercial aCGH. Many of these minute deletions were not contiguous but rather they alternated with segments showing oscillating copy number changes along the 3p21 region. Functional assays revealed that SETD2, PBRM1 and SMARCC1 act as tumor suppressor in MM. In summary, we found that in MM: 1) multiple minute simultaneous biallelic deletions are frequent in chromosome 3p21, where they occur as distinct events involving multiple genes; 2) in addition to BAP1, mutations of SETD2, PBRM1 and SMARCC1 are frequent in MM; 3) our results suggest that high-density aCGH combined with tNGS provide a more precise estimate of the frequency and types of genes inactivated in human cancer, than approaches based exclusively on NGS strategy. Citation Format: Michele Carbone, Yoshie Yoshikawa, Mitsuru Emi, Tomoko Hashimoto-Tamaoki, Masaki Ohmuraya, Ayuko Sato, Tohru Tsujimura, Seiki Hasegawa, Takashi Nakano, Masaki Nasu, Sandra Pastorino, Agata Szymiczek, Angela Bononi, Harvey I. Pass, Haining Yang. High-density array-CGH with targeted NGS unmask multiple non-contiguous minute deletions on chromosome 3p21 in mesothelioma [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 2553. doi:10.1158/1538-7445.AM2017-2553
Abstract 5646: Germline activating mutations in the proto-oncogeneGCM2in primary hyperparathyroidism
Authors: Bin Guan, James M. Welch, Julie C. Sapp, Hua Ling, Meghana Vemulapalli, Yulong Li, Jennifer J. Johnston, Electron Kebebew, Leslie G. Biesecker, William F. Simonds, Stephen J. Marx, Sunita K. Agarwal
Journal: Cancer Research (2017)

Abstract Primary hyperparathyroidism (PHPT) is a common endocrine disease caused by parathyroid tumors (adenoma or hyperplasia). The hypersecreting parathyroid tumor elevates serum parathyroid hormone level, which causes hypercalcemia and the classical symptoms of PHPT, including kidney stones, osteoporosis, and neuromuscular symptoms associated with hypercalcemia, such as muscle weakness, drowsiness, and depression. Familial PHPT occurs in an isolated nonsyndromal form, termed familial isolated hyperparathyroidism (FIHP), or as part of a syndrome, such as multiple endocrine neoplasia type 1 or hyperparathyroidism-jaw tumor syndrome. We performed exome sequencing on germline DNA of eight index cases from eight unrelated kindreds with FIHP. Rare variants were identified (minor allele frequency &amp;lt;1%), and selected variants were assessed for co-segregation in affected family members by Sanger sequencing. Candidate genes were then screened in an additional 32 kindreds with FIHP. The functional consequence of variants in one FIHP candidate gene (GCM2, a parathyroid tissue-specific transcription factor) was analyzed in a cell culture model. In eight kindreds with FIHP, we identified three rare GCM2 missense variants. Functional characterization of GCM2 variants and deletion-analyses revealed a small C-terminal Conserved Inhibitory Domain (CCID). Two of the three rare variants were recurrent, located in the CCID that enhanced the transcriptional activity of GCM2, and found in seven of 40 (18%) kindreds with FIHP. Functional assays for transcriptional activity demonstrated that these two rare variants acted as gain-of-function mutations, suggesting that GCM2 is a parathyroid proto-oncogene. We further investigated the ethnicity of individuals with GCM2 CCID activating variants in PHPT patient samples and in genome survey datasets. Our results demonstrate that germline activating mutations in the GCM2 CCID can cause FIHP, and specific activating mutations expose a large population at risk for PHPT. Our findings of the first gene with mutations specific for FIHP are expected to have an important impact on clinical practice, including treatment decisions and genetic testing of individuals with PHPT and family members. Citation Format: Bin Guan, James M. Welch, Julie C. Sapp, Hua Ling, Meghana Vemulapalli, Yulong Li, Jennifer J. Johnston, Electron Kebebew, Leslie G. Biesecker, William F. Simonds, Stephen J. Marx, Sunita K. Agarwal. Germline activating mutations in the proto-oncogene GCM2 in primary hyperparathyroidism [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 5646. doi:10.1158/1538-7445.AM2017-5646
Quantitative Antisense Screening and Optimization for Exon 51 Skipping in Duchenne Muscular Dystrophy
Authors: Yusuke Echigoya, Kenji Rowel Q. Lim, Nhu Trieu, Bo Bao, Bailey Miskew Nichols, Maria Candida Vila, James S. Novak, Yuko Hara, Joshua Lee, Aleksander Touznik, Kamel Mamchaoui, Yoshitsugu Aoki, Shin’ichi Takeda, Kanneboyina Nagaraju, Vincent Mouly, Rika Maruyama, William Duddy, Toshifumi Yokota
Journal: Molecular Therapy (2017)
Abstract 4042: N-121, a novel polypeptide conjugate of SN-38, demonstrated enhanced intratumoral accumulation and sustained release of free SN-38 with potent antitumor activity
Authors: Haojun Wang, Wei Li, Xiaojian Zhou, Liuyi Wan, Guanghui Wen
Journal: Cancer Research (2017)

Abstract Introduction: SN-38 is a critical chemotherapeutic agent active against a variety of solid tumors including advanced colorectal cancer. Clinical use of SN-38 is hampered by its poor solubility in pharmaceutically acceptable solvents. Although irinotecan, the only approved prodrug of SN-38, is widely used, its efficacy is limited by low conversion to the active SN-38 as well as hematologic and gastrointestinal dose-limiting toxicities. In an attempt to improve the water solubility, antitumor activity and safety profiles of SN-38, we synthesized a water soluble polypeptide-SN-38 conjugate (N-121) and examined its antitumor activity and pharmacokinetics (PK) in mouse models. Methods: Antitumor activity and PK of SN-38, administered as N-121 or irinotecan, was evaluated following tail vein injection in male nude mice with subcutaneous orthotopic xenografts of the HCT116 human colon cancer. Mice received N-121 400 mgk (mg/kg) (32 mkg of eq. SN-38) or irinotecan 80 mgk once a week for 2 weeks and were followed for up to 46 days. Results: N-121 drastically improved by over 1000 fold the water solubility of SN-38. At a SN-38 equivalent dose of less than half of that of irinotecan, N-121 resulted in a much longer tumor growth delay (36 days) than irinotecan (14 days). The more durable tumor growth inhibition with N-121 was consistent with its enhanced intratumoral accumulation: intratumoral trough levels of SN-38 were about 250-fold higher than those observed in plasma, compared with only 15-fold with irinotecan. With N-121, Intratumoral levels of SN-38 remained stable over the PK observation period (48 h), contrasting to a marked decline in SN-38 levels with irinotecan; intratumoral trough levels of SN-38 from N-121 were about 50-fold higher than those achieved with irinotecan. N-121 was well tolerated with a slight weight loss of 7.2%. Conclusion: N-121, a novel water soluble polypeptide-SN-38 conjugate, exhibited enhanced and sustained intratumoral exposure of SN-38 with high antitumor activity in a mouse xenograft tumor model. These promising results warrant further evaluation of N-121. Note: This abstract was not presented at the meeting. Citation Format: Haojun Wang, Wei Li, Xiaojian Zhou, Liuyi Wan, Guanghui Wen. N-121, a novel polypeptide conjugate of SN-38, demonstrated enhanced intratumoral accumulation and sustained release of free SN-38 with potent antitumor activity [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 4042. doi:10.1158/1538-7445.AM2017-4042