tbuckley/cabot-search huggingface dataset:
Abstract 3527: Clarification of the molecular mechanism for cancer development in Xp11.2 translocation renal cell carcinoma
Authors: Masaya Baba, Ying Huang, Takanobu Motoshima, Hisashi Hasumi, Yukiko Hasumi, Mitsuko Furuya, Yoji Nagashima, Masahiro Yao, Yuichi Oike, Tomomi Kamba, Laura S. Schmidt, W. Marston Linehan
Journal: Cancer Research (2017)

Abstract Xp11.2 translocation renal cell carcinoma (Xp11.2 tRCC) is a newly defined subset of RCC, which have chromosomal translocations involving the TFE3 transcription factor at Xp11.2. All translocations seen in Xp11.2 tRCC, including PRCC-TFE3, PSF-TFE3, ASPL-TFE3, CTLC-TFE3 and NONO-TFE3 produce chimeric TFE3 genes, which encode fusion TFE3 proteins retaining the basic helix-loop-helix leucine zipper (bHLH-Zip) structure for DNA binding, suggesting that these fusion TFE3 proteins function as oncogenic transcription factors. To clarify the molecular mechanism for Xp11.2 tRCC development, we have established cell lines, which express fusion TFE3 proteins (NONO-TFE3, PRCC-TFE3, PSF-TFE3) in a doxycycline dependent manner. Genes upregulated universally in all fusion TFE3 cell lines upon doxycycline addition were identified. In addition, we have generated an Xp11.2 translocation RCC mouse model, in which a floxed Neomycin cassette followed by a PRCC-TFE3 cDNA is inserted in the Rosa26 locus. By crossing these mice with cadherin 16-Cre transgenic mice, we can induce kidney specific PRCC-TFE3 expression resulting in RCC development. We will report and discuss the role of fusion TFE3 target genes in our mouse model and in clinical samples of Xp11.2 tRCC. Funded in part by FNLCR Contract HHSN261200800001E to LSS. Citation Format: Masaya Baba, Ying Huang, Takanobu Motoshima, Hisashi Hasumi, Yukiko Hasumi, Mitsuko Furuya, Yoji Nagashima, Masahiro Yao, Yuichi Oike, Tomomi Kamba, Laura S. Schmidt, W. Marston Linehan. Clarification of the molecular mechanism for cancer development in Xp11.2 translocation renal cell carcinoma [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 3527. doi:10.1158/1538-7445.AM2017-3527
Abstract 2212: Protein engineering of the decapping enzyme NudT16 enhances its ability to hydrolyze protein-conjugated ADP-ribose for post-translational site identification via mass spectrometry
Authors: Puchong Thirawatananond, Robert L. McPherson, Jasmine K. Malhi, Anthony K. Leung, Sandra B. Gabelli
Journal: Cancer Research (2017)

Abstract During nonhomologous end joining of DNA follow double-stranded breaks, one common signaling response is the adenosine diphosphate ribosylation (ADP-ribosylation) of recruiter scaffold proteins. ADP-ribosylation is a post-translational modification (PTM) that occurs on aspartate, glutamate, lysine, arginine and cysteine on proteins and is mediated chiefly by polyadenosine ribose polymerases (PARP). Using NAD+ as its substrate, PARP transfers an ADP-ribose onto another protein, releasing a nicotinamide ring in the process; this modification presents as a mono-ADP-ribosylation (MARylation) or poly-ADP-ribosylation (PARylation). While site identification of MARylated protein can be achieved through tandem MS/MS and searching for peptides whose spectra have been shifted by 541.0611 Da, a similar approach for PARylated protein is confounded by the variable length and branching of its PTM. To this end, ADP-ribosylated protein is normally incubated with a snake venom phosphodiesterase (SVP) to leave a standardized phosphoribose tag of 212.0086 Da. It has been shown that a recombinantly-expressed Nudix protein NudT16 provides a cost-effective alternative to SVP to process ADP-ribosylated protein. NudT16 in the cell normally decaps small nucleolar RNA. Our studies here sought to utilize the x-ray crystallographic structure of NudT16 in complex with ADP-ribose in guiding rational design mutations to enhance binding of our desired ADP-ribose substrate and to widen the hydrolase’s active site to better accommodate a protein-conjugated ADP-ribose. Mutants have demonstrated improved catalytic efficiency for ADP-ribose hydrolysis. Radiolabeled immunoassays of PARylated protein concur with these kinetic experiments by showing a reduction of radiolabeled PARP. Rational design of a ADP-ribose-hydrolyzing NudT16 with comparable catalytic efficiency to SVP eases lead discovery of biological mechanisms that are mediated through ADP-ribosylation such as DNA repair. Citation Format: Puchong Thirawatananond, Robert L. McPherson, Jasmine K. Malhi, Anthony K. Leung, Sandra B. Gabelli. Protein engineering of the decapping enzyme NudT16 enhances its ability to hydrolyze protein-conjugated ADP-ribose for post-translational site identification via mass spectrometry [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 2212. doi:10.1158/1538-7445.AM2017-2212
Low-Dose Naltrexone Treatment of Familial Benign Pemphigus (Hailey-Hailey Disease)
Authors: Omer Ibrahim, Sara R. Hogan, Alok Vij, Anthony P. Fernandez
Journal: JAMA Dermatology (2017)

<h3>Importance</h3> Familial benign pemphigus, or Hailey-Hailey disease (HHD), is a rare and debilitating genetic dermatosis characterized by chronic, recurrent vesicles, erosions, and maceration in flexural areas. Despite the reported therapeutic modalities, such as topical and systemic corticosteroids, systemic immunomodulators, topical and systemic retinoids, and laser, HHD can still be markedly difficult to control. <h3>Objective</h3> To assess low-dose naltrexone hydrochloride in the treatment of recalcitrant HHD. <h3>Design, Setting, and Participants</h3> In this case series, 3 patients with biopsy-proven recalcitrant HHD were evaluated in the outpatient dermatology clinic at the Cleveland Clinic. Each patient was treated with low-dose naltrexone hydrochloride at a dosage of 1.5 to 3.0 mg per day. No laboratory monitoring was necessary. Clinical response (healing of erosions, improvement in erythema, and alleviation of pain), adverse effects, and subjective quality of life were monitored throughout the treatment. The study dates were January 2016 to January 2017. <h3>Main Outcomes and Measures</h3> Objective clinical response as assessed by the treating dermatologist, subjective quality of life as reported by the patient, and recorded adverse effects were monitored throughout the treatment at intervals of 2 to 3 months. <h3>Results</h3> The 3 patients included a woman in her 40s and 2 men in their 60s. Each patient exhibited at least an 80% improvement in extent of disease, with one patient demonstrating 90% clearance. All 3 patients had substantial improvement in quality of life, with one patient reporting improvement in his depression. No adverse effects were recorded. <h3>Conclusions and Relevance</h3> Low-dose naltrexone may represent a low-cost and low-risk alternative or adjunct in the treatment of HHD.
Abstract 1370: EGFR-mediated Spred1 phosphorylation inhibits NF1 to sustain constitutive Ras/MAPK signaling
Authors: Evan Markegard, Ellen L. Mercado, Jillian M. Silva, Jacqueline Galeas, Marena I. Trinidad, Anatoly Urisman, Frank McCormick
Journal: Cancer Research (2017)

Abstract Spred proteins negatively regulate Ras/MAPK signaling following growth factor stimulation. Inhibition of Ras primary occurs through Spreds ability to bind and localize NF1, a RasGAP and major tumor suppressor, to the plasma membrane. Spred1 and NF1 loss-of-function mutations occur across multiple cancer types including non-small cell lung carcinoma, glioblastoma, melanoma, stomach carcinoma, and uterine carcinosarcoma. Here we demonstrate that EGFR signaling disrupts Spred1-NF1 binding. Mass spectrometry was performed on cells overexpressing EGFRL858R to identify potential phosphorylation sites on Spred1 and NF1 that could disrupt Spred1-NF1 binding by steric hindrance. A serine phosphorylation site on Spred1 was identified in which a phosphomimetic and phosphodeficient mutant decreased or increased Spred1-NF1 binding, respectively. Phosphomimetic Spred1 is unable to suppress Ras-GTP following EGF stimulation. Therefore, phosphorylation of Spred1 at this site by a serine kinase downstream of EGFR may disrupt Spred1-NF1 binding. To identify the Spred1 kinase we are performing an in vitro kinase assay and an unbiased CRISPRa screen. Our findings provide one potential mechanism by which EGFR signaling disrupts negative feedback to sustain constitutive Ras signaling. Furthermore, this work may elucidate a novel therapeutic target for restoring NF1-mediated inhibition of Ras. Citation Format: Evan Markegard, Ellen L. Mercado, Jillian M. Silva, Jacqueline Galeas, Marena I. Trinidad, Anatoly Urisman, Frank McCormick. EGFR-mediated Spred1 phosphorylation inhibits NF1 to sustain constitutive Ras/MAPK signaling [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 1370. doi:10.1158/1538-7445.AM2017-1370
Abstract 4775: PTHrP regulate CSC and promote EMT in the PyMT model of breast cancer progression
Authors: Rui Zhang, Jiarong Li, Andrew C. Karaplis, Richard Kremer
Journal: Cancer Research (2017)

Abstract PTH-related peptide (PTHrP) was first discovered in cancer patients as the primary cause of humoral hypercalcemia of malignancy (HHM). We previously showed that PTHrP ablation in the MMTV-PyMT murine model of breast cancer progression can dramatically prolongs tumor latency, slows tumor growth &amp; metastases suggesting that PTHrP may regulate cancer stem cells (CSCs). CSCs &amp; epithelial-mesenchymal transition (EMT) have been recognized as driving forces in tumor initiation &amp; progression, &amp; have been characterized previously using ALDH &amp; CD49/EpCAM markers. Here, we aim to determine the role of PTHrP in CSCs &amp; EMT regulation. For this purpose, we analyzed tumor cells derived from Pthrpflox/flox;Cre- (Control) &amp; Pthrpflox/flox;Cre+ (KO) tumors. Cells were incubated with ALDH reagent followed by CD49f/EpCAM antibody labelling &amp; subjected to FACS analysis. Using CD49f/EpCAM labelling, cells separated into two distinct populations, luminal progenitor cells (CD49f+EpCAM+) &amp; EMT cells (CD49f+EpCAM-). In control tumors, ~85% of cells were characterized as luminal progenitor and ~15% as EMT. In contrast, in KO tumors, ~97% of cells were characterized as luminal progenitor whereas only ~2% were EMT. Using ALDH staining alone, ~8% &amp; ~10% of the cells from the control &amp; KO tumor were ALDH+, respectively. Furthermore, the majority of the ALDH+ cells were predominately contained within the luminal progenitor population in both the control &amp; KO tumors cells. Next, we confirmed the dividing capacity of the two cell populations using a lipophilic fluorescent dye, PKH26. As expected, luminal progenitor cells exhibited a fast-dividing phenotype, whereas EMT cells displayed a slow dividing phenotype. However, using mammosphere assay, we did not see any significant difference in mammosphere forming efficiency between control &amp; KO tumor. In summary, PTHrP ablation significantly diminishes the EMT population in KO compared to the control tumor. In conclusion, PTHrP may shift the tumor cell phenotype towards EMT, which suggests a mechanism underlying PTHrP - driven metastases. Citation Format: Rui Zhang, Jiarong Li, Andrew C. Karaplis, Richard Kremer. PTHrP regulate CSC and promote EMT in the PyMT model of 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 4775. doi:10.1158/1538-7445.AM2017-4775
Abstract 3257: Molecular characterization of the human stomach microbiota in gastric cancer patients
Authors: Guoqin Yu, Javier Torres, Nan Hu, Rafael Medrano-Guzman, Roberto Herrera-Goepfert, Michael S. Humphrys, Lemin Wang, Chaoyu Wang, Ti Ding, Jacques Ravel, Philip R. Taylor, Christian Abnet, Alisa Goldstein
Journal: Cancer Research (2017)

Abstract Background Helicobacter pylori (Hp) is the primary cause of gastric cancer but we know little of its relative abundance and other microbes in the stomach, especially at the time of gastric cancer diagnosis. Here we characterized the taxonomic and derived functional profiles of gastric microbiota in 157 non-malignant gastric tissue samples from two different sets of gastric cancer patients, and compared them with microbial profiles of oral, stool, nasal, vagina and skin samples from Human Microbiome Project. Results We show that Hp is the most abundant member of gastric microbiota in both Chinese and Mexican samples (51% and 24% respectively), followed by the genera commonly seen in the oral microbiota. Taxonomic (phylum) profiles of stomach microbiota largely resembled oral microbiota when the Helicobacter reads were removed. The functional profiles of stomach microbiota, however, were distinct from those found in other body sites and had higher inter-subject dissimilarity. Gastric microbiota composition did not differ by Hp colonization status or stomach anatomic site, but did differ between paired non-malignant and tumor tissues in either Chinese or Mexican samples. Conclusions Our study is the first to show that Hp is the dominant member of the gastric microbiota in many gastric cancer patients rather than diminished or depleted as traditionally believed. Our results provide insights on the gastric microbiota composition and function in gastric cancer patients, which may have important clinical implications. Citation Format: Guoqin Yu, Javier Torres, Nan Hu, Rafael Medrano-Guzman, Roberto Herrera-Goepfert, Michael S. Humphrys, Lemin Wang, Chaoyu Wang, Ti Ding, Jacques Ravel, Philip R. Taylor, Christian Abnet, Alisa Goldstein. Molecular characterization of the human stomach microbiota in gastric cancer patients [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 3257. doi:10.1158/1538-7445.AM2017-3257
Abstract 331: SIRPB1 promotes prostate cancer cell proliferation & migration
Authors: Qiong Song, Siyuan Qin, Chunlin Zou, Wenchu Wang, Lihui Wang, Haibo Tong, William J. Catalona, Jian Zhang, Yi Lu, Zhou Wang
Journal: Cancer Research (2017)

Abstract Signal-regulatory-protein beta 1(SIRPB1) is a member of the signal-regulatory-protein (SIRP) family that belongs to the immunoglobulin superfamily and is capable of modulating receptor tyrosine kinase-coupled signaling. The copy-number variations (CNV) at the SIRPB1 locus were associated with aggressiveness of prostate cancer in patients. To test if SIRPB1 could affect prostate cancer development and progression, we investigated the potential role and mechanisms of SIRPB1 action in prostate cancer cell lines in vitro and in xenograft tumors. Knockdown of SIRPRB1 by RNA interference resulted in significant suppression of cell colony formation, cell mobility, cell migration, and invasion. The knockdown also induced cell cycle arrest during the G0/G1 phase and a remarkable enhancement of apoptosis in PC3 prostate cancer cells. In contrast, overexpression of SIPRB1 significantly induced cell migration, invasion, colony formation and cell cycle in C4-2 prostate cancer cells. Furthermore, overexpression of SIRPB1 in C4-2 cell model enhanced its tumor take rate in nude mice. Also, SIRPB1 mRNA expression was increased in up to 39% of the prostate cancer specimens based on in silico analysis of several public databases. These results suggest that SIRPB1 is a potential oncogene in the prostate and could be used as a biomarker to identify patients at risk of developing aggressive prostate cancer. Citation Format: Qiong Song, Siyuan Qin, Chunlin Zou, Wenchu Wang, Lihui Wang, Haibo Tong, William J. Catalona, Jian Zhang, Yi Lu, Zhou Wang. SIRPB1 promotes prostate cancer cell proliferation &amp; migration [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 331. doi:10.1158/1538-7445.AM2017-331
Abstract 5385: Colorectal cancer methylome and laterality
Authors: Sho Hirabayashi, Masamichi Hayashi, Goro Nakayama, Keisuke Kurimoto, Hiroshi Tanabe, Mitsuro Kanda, Hideki Takami, Yukiko Niwa, Naoki Iwata, Daisuke Kobayashi, Chie Tanaka, Suguru Yamada, Hiroyuki Sugimoto, Masahiko Koike, Tsutomu Fujii, Michitaka Fujiwara, Yasuhiro Kodera
Journal: Cancer Research (2017)

Abstract Background: Colorectal cancers are anatomically derived from Midgut area (from cecum to mid transverse colon) and Hindgut area (from mid transverse to anal canal). The laterality of colorectal cancers was reported as one of the prognosis markers of these cancers. Midgut originated cancers had statistically poorer overall survivals than Hind gut (Yahagi et al, J Gastrointest Surg, 2016). In addition to clinical reasons, for example its symptomless nature of the bowel obstruction on the right side, the difference of genetic and/or epigenetic profiles between both side colorectal cancers may exists. Methods: Surgically resected 30 colorectal cancers (Midgut n=9, Hidgut n=21) were included. Any clinicopathological factors except for tumor site was not statistically different between 2 groups. We decided to focus on colon cancer methylome and laterality in this study. Two novel methylation markers of colon cancers (PAX5 and VGF) which were extracted from microarray analysis were used, and quantitative methylation-specific PCR (QMSP) assay was performed for each marker.Results: Both PAX5 and VGF methylations were extremely tumor-specific markers (P&amp;lt;0.001 and P=0.011). Interestingly, Both markers tended to have high methylation frequency in Midgut derived cancers. High frequency of PAX5 promoter methylation was found in 9/9 cases (100%) of Midgut and 15/21 cases (71%) of Hindgut (P=0.141), while that of VGF was found in 6/9 cases (67%) of Midgut and 4/21 cases (19%) of Hindgut (P=0.030). In addition, three multiple colon cancers were found in the cohort. All of them were derived from Midgut area (T1/T1, T3/Tis and T3/Tis), and had high frequency of both PAX5 (2/3, 67%) and VGF (3/3, 100%) methylation. Conclusion: Cancer methylome between Midgut and Hindgut seemed to be different, and it may affect tumor malignancy, plurality and chemotherapy sensitivity. Now we are in progress of increased colorectal cancer cases (over 100) and methylation markers. Citation Format: Sho Hirabayashi, Masamichi Hayashi, Goro Nakayama, Keisuke Kurimoto, Hiroshi Tanabe, Mitsuro Kanda, Hideki Takami, Yukiko Niwa, Naoki Iwata, Daisuke Kobayashi, Chie Tanaka, Suguru Yamada, Hiroyuki Sugimoto, Masahiko Koike, Tsutomu Fujii, Michitaka Fujiwara, Yasuhiro Kodera. Colorectal cancer methylome and laterality [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 5385. doi:10.1158/1538-7445.AM2017-5385
Direct Macromolecular Drug Delivery to Cerebral Ischemia Area using Neutrophil-Mediated Nanoparticles
Authors: Chun Zhang, Cheng-li Ling, Liang Pang, Qi Wang, Jing-xin Liu, Bing-shan Wang, Jian-ming Liang, Yi-zhen Guo, Jing Qin, Jian-xin Wang
Journal: Theranostics (2017)

Delivery of macromolecular drugs to the brain is impeded by the blood brain barrier. The recruitment of leukocytes to lesions in the brain, a typical feature of neuroinflammation response which occurs in cerebral ischemia, offers a unique opportunity to deliver drugs to inflammation sites in the brain. In the present study, cross-linked dendrigraft poly-L-lysine (DGL) nanoparticles containing cis-aconitic anhydride-modified catalase and modified with PGP, an endogenous tripeptide that acts as a ligand with high affinity to neutrophils, were developed to form the cl PGP-PEG-DGL/CAT-Aco system. Significant binding efficiency to neutrophils, efficient protection of catalase enzymatic activity from degradation and effective transport to receiver cells were revealed in the delivery system. Delivery of catalase to ischemic subregions and cerebral neurocytes in MCAO mice was significantly enhanced, which obviously reducing infarct volume in MCAO mice. Thus, the therapeutic outcome of cerebral ischemia was greatly improved. The underlying mechanism was found to be related to the inhibition of ROS-mediated apoptosis. Considering that neuroinflammation occurs in many neurological disorders, the strategy developed here is not only promising for treatment of cerebral ischemia but also an effective approach for various CNS diseases related to inflammation.
Abstract 5301: Cancer causation: rethinking the role of analogy
Authors: Douglas L. Weed
Journal: Cancer Research (2017)

Abstract Introduction. Fifty years has passed since the publication of Austin Bradford Hill’s classic paper on causal inference. Much has changed in the biomedical and public health sciences regarding cancer causation during that half century, but Hill’s considerations (often called “criteria”) remain durable. That said, there is a curious phenomenon involving Hill’s seminal work that has escaped the attention of the scientific community. His consideration of analogy—the last on his list just after experimentation—has all but disappeared. The purpose of this paper is to rethink and resurrect analogy as an important consideration in causal inference in environmental epidemiology. Methods. Given that this is a conceptual—non-quantitative—project, the methods used are the informal logic of scientific thinking, methods of systematic reviews, and judgment. Results. In contemporary epidemiology, analogy is either completely ignored (e.g. in many textbooks), equated with biologic plausibility or coherence, or aligned with the scientist’s imagination. None of these examples, however, capture Hill’s description of analogy which emphasizes the contrast of two bodies of evidence. Coupled with developments in the methods of systematic assessments of evidence—including but not limited to meta-analysis—analogy can be restructured as a key component of causal inference. For theoretical support see similar methods in biomedical ethics and artificial intelligence. Practical examples will be discussed. Conclusions. Analogical reasoning—an updated version of analogy—can emerge assuming the following developments: (1) a collection—a library—of known cases of causal inference (i.e. bodies of evidence involving established causal relationships), including, for example, the assessments of the International Agency for Research on Cancer (IARC) and the National Toxicology Program (NTP), (2) a systematic process for describing the key features of a causal relationship creating paradigm cases, and (3) an objective comparison of a “new” body of evidence for a putative causal relationship with a relevant paradigm case. Citation Format: Douglas L. Weed. Cancer causation: rethinking the role of analogy [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 5301. doi:10.1158/1538-7445.AM2017-5301