tbuckley/cabot-search huggingface dataset:
The impact of antibody profile in thrombosis associated with primary antiphospholipid syndrome
Authors: Sabrina da Silva Saraiva, Bruna de Moraes Mazetto, Lais Quinteiro Tobaldine, Marina Pereira Colella, Erich Vinícius De Paula, Joyce Annichinno‐Bizzachi, Fernanda Andrade Orsi
Journal: American Journal of Hematology (2017)

Triple positivity (TP) for antiphospholipid antibodies(aPL) may identify aPL carriers with poorer prognosis. The clinical impact of TP in primary antiphospholipid syndrome(PAPS) remains unclear and further clinical evidences are needed to validate TP as a marker of severity. The aim of this study was to evaluate the impact of TP on the clinical course of PAPS with thrombosis(t-PAPS). We performed a retrospective analysis of a cohort of t-PAPS patients, comparing groups of patients with TP and non-TP profiles according to their demographic, clinical and laboratory features. We included 105 patients with t-PAPS, the median follow-up time of 3.7 years. Twenty-two patients(21%) had TP; the demographic distribution, the presence of cardiovascular risk factors and the site of thrombosis were similar between TP and non-TP patients. The frequency of thrombotic events did not differ between TP and non-TP patients during the study period. Pregnancy morbidities were more frequent in women with t-PAPS and TP than in those with non-TP profile (80% vs. 52.8%, P = 0.05). Patients with t-PAPS and TP presented, at diagnosis, higher dRVVT ratio (median R = 2.44 vs. 1.57, P < 0.0001), higher aCL titer (median = 50UI vs. 35 UI, P < 0.0001), lower C3 levels (median = 1.08 vs. 1.30 mg dL-1 , P = 0.001), lower C4 levels (median = 0.22 vs. 0.25 mg dL-1 , P = 0.05) and higher frequency of positive ANA test (50% vs. 20%, P = 0.008) than patients with t-PAPS and non-TP. Lower-than-normal levels of C3 was independently associated with TP (OR = 5.1, P = 0.02). The presence of TP in patients with t-PAPS was associated with immune derangement, with no effect on the clinical course of the disease.
Abstract 4771: The role of Hes1 in the normal and tumor stem cells of the intestine
Authors: Norihiro Goto, Akihisa Fukuda, Tsutomu Chiba, Hiroshi Seno
Journal: Cancer Research (2017)

Abstract Notch-Hes pathway plays a crucial role in the differentiation, proliferation, and tumorigenesis of the intestine. We previously reported that prenatal deletion of Hes1 reduces intestinal tumor proliferation; however, postnatal deletion of Hes1, which recapitulates Hes1-targeted tumor therapy, has not been thoroughly investigated. Here, we elucidated the novel role of Hes1 in normal stem cells (NSCs) and tumor stem cells (TSCs) of the adult intestine. First, we deleted Hes1 in Lgr5-expressing or Bmi1-expressing NSCs and performed lineage tracing using Lgr5CreERT2/+; Hes1flox/flox; Rosa26LacZ/+ and Bmi1CreER/+; Hes1flox/flox; Rosa26LacZ/+ mice. After Hes1 deletion, Lgr5-expressing or Bmi1-expressing NSCs gave rise to progeny cells, but could not self-renew. However, Hes1 deletion in NSCs did not disrupt intestinal homeostasis, because Hes1-positive NSCs were newly generated soon after Hes1-deleted NSCs were depleted. Next, we stabilized beta-catenin for intestinal tumor formation and deleted Hes1 in Lgr5-expressing cells using Lgr5CreERT2/+; Ctnnb1lox(ex3)/+; Hes1flox/flox mice. Tumor formation was dramatically suppressed, and the animal survival was significantly improved, suggesting that Hes1 is required for the initiation of intestinal tumor formation. Finally, we deleted Hes1 in Lgr5-expressing TSCs of established intestinal tumors using Lgr5CreERT2/+; Hes1flox/flox; ApcMin/+ mice. Of note, Hes1 deletion in TSCs of established intestinal tumors induced immediate apoptosis of TSCs and significantly reduced the number of tumors. qRT-PCR analysis of sorted Lgr5-expressing cells one day after Hes1 deletion revealed upregulation of pro-apoptotic genes and downregulation of anti-apoptotic genes in Hes1-deleted TSCs, but not in Hes1-deleted NSCs. We also deleted Hes1 in Dclk1-expressing TSCs of established intestinal tumors, and confirmed that, irrespective of stem cell markers analyzed, Hes1 deletion in TSCs leads to tumor regression by inducing immediate apoptosis in TSCs. Taken together, Hes1 is required in different ways for the maintenance of NSCs and TSCs: Hes1 deletion in NSCs does not perturb homeostasis, whereas Hes1 deletion in TSCs leads to tumor regression. Furthermore, Hes1 is necessary for the initiation of intestinal tumor formation. Therefore, we propose Hes1 is a novel tumor-specific therapeutic target. Citation Format: Norihiro Goto, Akihisa Fukuda, Tsutomu Chiba, Hiroshi Seno. The role of Hes1 in the normal and tumor stem cells of the intestine [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 4771. doi:10.1158/1538-7445.AM2017-4771
Abstract LB-191: Combination checkpoint inhibitor therapy: Anti-PD1 and Beta-alethine lead to complete responses of melanoma in a syngeneic mouse model
Authors: Floyd E. Taub, Suzin Wright, Amanda Guth
Journal: Cancer Research (2017)

Abstract Previously we reported that the combination of anti-PD1 and β-alethine completely stopped cancer growth in a syngeneic mouse melanoma model even under conditions when neither of the drugs had statistically significant effects as a single agent. In order to further examine this dramatic result, we extended the studies, evaluated immune parameters and tested if long-term immunity to re-challenge occurred. Surprisingly, three low doses of anti-PD1, spread over 9 days, were sufficient to allow concurrent and continuing weekly dosing of β-alethine to not only halt tumor growth, but to reverse it. The established melanoma regressed over the subsequent 4-6 weeks. Even more striking was that the short course of anti-PD1, which failed to reduce cancer growth as a single therapy, altered the immune system such that subsequent treatment with β-alethine was effective. β-alethine therapy, beginning eight days after the conclusion of anti-PD1 therapy, when tumors averaged 40 mm2, was sufficient to cause at least stabilization of cancer in all animals and complete response (no palpable tumor on repeated measurements) in the majority of animals. Statistical comparisons of all animals receiving combination therapy (either concurrently or sequentially) with controls resulted in significant differences using ANOVA for tumor size (p=0.005) or X2 tests for tumor presence (p &amp;lt;0.000). No toxicity was noted in treated animals. This is consistent with previous animal and GLP toxicity studies and the completed human Phase I/II trial. The human trial showed that β-alethine, as a single agent, caused no drug-related adverse events and lead shrinkage or stabilization in all patients with lymphoma who were not anergic to recall antigens pre-trial. The final result of re-challenging the mice with the original Cloudman melanoma at a higher dose than the initial cancer inoculation level will be presented. Citation Format: Floyd E. Taub, Suzin Wright, Amanda Guth. Combination checkpoint inhibitor therapy: Anti-PD1 and Beta-alethine lead to complete responses of melanoma in a syngeneic mouse model [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-191. doi:10.1158/1538-7445.AM2017-LB-191
Mutual transformation between adenocarcinoma and squamous carcinoma after EGFR tyrosine kinase inhibitors treatment in lung cancer.
Authors: Zheng ming Ying
Journal: Journal of Clinical Oncology (2017)

e20510 Background: Knowledge on the epidermal growth factor receptor (EGFR) has improved survival of non-small cell lung cancer (NSCLC). Several mechanisms underlying have been discovered, here we would report a rare resistant mechanism of histology mutual transformations. Methods: From July 2013 to June 2015, we retrospectively collected 135 NSCLC patients who were in resistance with TKI treatments. Patients’ clinical data including pathologic result, gene status, demographic information, clinical staging, and treatment were recorded. [YL1] Results: Among the 135 NSCLC patients, we found two cases of lung cancer with histological transformation from adenocarcinoma to squamous cell carcinoma, one case from squamous cell carcinoma to adenocarcima after TKI treatment. These cases still harbored sensitive epidermal growth factor gene mutations and developed acquired resistance T790M mutation. Conclusions: Histologic evolution may be a mechanism associated with TKI resistance .
Abstract 5750: USP15 inhibits HPV16 E6 degradation and catalytically inactive USP15 has reduced inhibitive activity
Authors: Aoi Tokuda, Masafumi Yoshimoto, Yuji Yaginuma
Journal: Cancer Research (2017)

Abstract HPVs can be classified as either high-risk or low-risk depending on the transforming potential of the virus. Most cervical cancers and a significant proportion of other anogenital cancers have been associated with infection by a small number of high-risk genital HPV types. Tumorigenesis induced by high-risk genital HPVs has been linked to the expression of two viral oncoproteins, E6 and E7, which cooperate in cellular immortalization and transformation processes. HPV16 E6 is an oncoprotein that causes the development of high-risk type human papilloma virus (HPV) and induces cancers, including oropharyngeal, anal, and cervical cancers. The stability of E6 is essential for its complete function as an oncoprotein. Using the yeast two-hybrid system, we identified ubiquitin-specific protease 15 (USP15) as an HPV16 E6-interacting protein. USP15 encodes a protein that consist of 952 amino acids and functions as a deubiquitinating enzyme. Deubiquitination is an essential process that releases ubiquitin chains from ubiquitin-protein conjugates. Aberrations in the ubiquitin-proteasome system have been recently connected to the pathogenesis of several human protein degradation disorders, including cancer and neurodegenerative diseases; as such, the proteasome is now considered to be important in the mechanism of carcinogenesis. USP15 cleaves polyubiquitin chains of HPV16 E6 and/or ubiquitin precursors. Immunohistochemical analysis showed that USP15 was highly expressed in normal cervical squamous cells, and cervical cancer cells. Our results indicated that USP15 can increase the level of HPV16 E6 by inhibiting E6 degradation. USP15 dose-dependently inhibited the degradation of HPV16 E6. In contrast, catalytically inactive mutants of USP15 had a reduced inhibitory effect on E6 degradation. In particular, USP15 mutants of all three cysteine boxes and the NHL mutant of the KRF box had a drastically reduced inhibitive effect on HPV16 E6 degradation. In addition, HPV16 E6 mRNA was not induced by USP15; therefore, HPV16 E6 appears to be post-translationally regulated. These results suggest that USP15 has the ability to stabilize E6 as a deubiquitinating enzyme, and HPV16 E6 can affect biological functions as an oncoprotein in infected human cells. Citation Format: Aoi Tokuda, Masafumi Yoshimoto, Yuji Yaginuma. USP15 inhibits HPV16 E6 degradation and catalytically inactive USP15 has reduced inhibitive 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 5750. doi:10.1158/1538-7445.AM2017-5750
Abstract 3171: Analysis of "drug addiction" mechanisms in the drug-resistant <i>ROS1</i>-rearranged cancer cells
Authors: Hayato Ogura, Jun Adachi, Takeshi Tomonaga, Naoya Fujita, Ryohei Katayama
Journal: Cancer Research (2017)

Abstract ROS1-rearranged non-small-cell lung cancer (NSCLC) is observed in approximately 1% of lung cancer patients. Crizotinib, ALK/ROS1/cMET tyrosine kinase inhibitor (TKI), showed high effect against ROS1-rearranged NSCLC in the clinical trials and is approved in US and EU. However, the cancers inevitably relapse due to the acquired resistance such as ROS1-G2032R mutation. We previously reported that cabozantinib could overcome those secondary mutations mediated crizotinib-resistance. Based on this finding, we tried to establish cabozantinib-resistant ROS1 mutant cells by ENU mutagenesis screening. Surprisingly, we found out a few CD74-ROS1 mutant clones that only grew in the presence of low-dose cabozantinib. Namely, these mutant clones were “addicted” to cabozantinib. When the fluorescent labeled cabozantinib addicted ROS1 mutant cells were co-cultured with non-addicted CD74-ROS1-WT-BaF3 cell in the presence or absence of low-dose cabozantinib, the drug-addicted cells became dominant in the low-dose cabozantinib, and CD74-ROS1-WT cells became dominant in the absence of it. To analyze the molecular mechanism of “drug-addiction” in the addicted CD74-ROS1 mutant cells, we performed comprehensive analysis such as inhibitor screening, cDNA microarray, and phosphoproteome analysis. As the result, we observed that the expression and phosphorylation of CD74-ROS1 in the addicted cells were excessively upregulated within 24 hours after removal of cabozantinib or other ROS1 inhibitors, such as crizotinib or lorlatinib. We also observed that the apoptosis was induced in these cells upon ROS1 inhibitor removal, whereas ROS1 mediated growth signaling were simultaneously activated. Consistent with this, cDNA microarray analysis revealed that the expression of both cell survival and cell death related genes were changed by ROS1 inhibitor removal. Furthermore, we identified that several proteins were highly phosphorylated by excessive ROS1 activation originated from ROS1 inhibitor removal. These observations suggest that these drug-addicted cells were died by excessive oncogenic signaling, and the appropriate oncogene signaling by low-dose TKI made them survive and grow without inducing apoptosis. Thus, the excessive oncogene signaling has “double-edged sword” characteristics for cancer cell viability and those characteristics could be a new therapeutic target. Citation Format: Hayato Ogura, Jun Adachi, Takeshi Tomonaga, Naoya Fujita, Ryohei Katayama. Analysis of "drug addiction" mechanisms in the drug-resistant ROS1-rearranged 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 3171. doi:10.1158/1538-7445.AM2017-3171
Abstract 244: Eicosapentaenoic acid reduces effects of some adipocyte derived factors on breast cancer cell inflammation and glucose metabolism
Authors: Arwa Aljawadi, Sara Alhaj, Suranganie Dharamawardhane, Shane Scoggin, Lauren Gollahon, Preethi Gunaratne, Naima Moustaid-Moussa
Journal: Cancer Research (2017)

Abstract Breast cancer is still the leading cause of death in women among all cancer types. Obesity, a chronic low grade inflammatory disease, is a key contributor to the progression of breast cancer especially in women, post-menopause. Given the current understanding of cancer-related inflammation and associated microvesicles in restructuring the microenvironment, we hypothesized that adipocyte-derived cytokines and exosomes negatively impact breast cancer progression. By contrast, eicosapentaenoic acid (EPA), a dietary omega 3 polyunsaturated fatty acid and a well-established anti-inflammatory compound will reduce adipocyte-secreted pro-inflammatory factors, thereby reducing breast cancer progression. To test these hypotheses, we investigated the effects of conditioned media or exosomes from 3T3-L1 adipocytes or human mesenchymal stem cells (HMSC), treated +/- 100uM EPA on MCF7 and MDA-MB231 breast cancer cells for 24 – 72 h. Following treatment, changes in breast cancer cell gene expression were measured using RT-qPCR and glycolytic rate was measured using XFe24 Seahorse extracellular flux analyze. We observed that conditioned medium from HMSC significantly increased the mRNA expression levels of oncogenic genes such as signal transducer and activator of transcription 3 (STAT3), baculoviral IAP repeat-containing protein3 (BIRC3) known as cIAP2, and the lipogenic fatty acids synthase (FASN). In contrast, conditioned media from EPA-treated human adipocytes reduced the expression levels of these genes. Similarly, exosomes isolated from EPA-treated adipocytes showed a significant reduction in mRNA expression levels of STAT3 and cIAP2 in both cancer cell lines. Furthermore, glycolysis was significantly reduced in MCF7 but not MDA-MB231 cells incubated with 3T3-L1 adipocyte-conditioned medium pretreated with EPA for 24 hrs. Taken together, our data suggest that adipocytes play a significant role in promoting breast cancer progression by providing a microenvironment that increases survival and inflammation. EPA is a promising anti-inflammatory nutrient that may help reduce breast cancer cell inflammation and survival, possibly by modulating adipocyte-derived cytokines and exosomes in obesity and thus warrants further investigations. Citation Format: Arwa Aljawadi, Sara Alhaj, Suranganie Dharamawardhane, Shane Scoggin, Lauren Gollahon, Preethi Gunaratne, Naima Moustaid-Moussa. Eicosapentaenoic acid reduces effects of some adipocyte derived factors on breast cancer cell inflammation and glucose metabolism [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 244. doi:10.1158/1538-7445.AM2017-244
Abstract 4997: Specialized microRNP and translation mechanisms in quiescent cancer cells
Authors: Syed I. Bukhari, Samuel S. Truesdell, Sooncheol Lee, Swapna Kollu, Anthony Classon, Myriam Boukhali, Esha Jain, Richard D. Mortensen, Akiko Yanagiya, Ruslan Sadreyev, Wilhelm Haas, Shobha Vasudevan
Journal: Cancer Research (2017)

Abstract Quiescence (G0) represents an assortment of reversible, cell cycle-arrested states that are resistant to unfavorable conditions and associated with cancer persistence. G0 involves regulated gene expression with selective mRNA expression and decreased canonical translation. Low mTOR activity in G0 activates the cap complex inhibitor, eIF4EBP, and impairs canonical translation. The alternative translation mechanisms in G0 remain to be uncovered. Our data show that microRNAs, regulatory, non-coding RNAs that target distinct mRNAs to alter gene expression, can associate with alternative complexes and translation factors to regulate specific mRNA translation in G0. One subset of transcripts expressed in G0 includes specific mRNAs recruited by an FXR1a-associated microRNP (microRNA-protein complex) for translation activation in G0 mammalian cells. MicroRNPs predominantly mediate repression and downregulation; however, FXR1a-microRNP lacks conventional microRNP repressors, and instead, contains a specific RNA binding protein isoform, FXR1a. FXR1a promotes translation and is overexpressed and associated with poor prognosis in several cancers. Our data reveal that microRNA-mediated activation requires target mRNAs with unadenylated/ shortened poly(A) tails to avoid the roles of PABP in enhancing microRNA-mediated downregulation and in canonical translation that is impaired in G0. Instead of canonical translation factors that are inhibited by eIF4EBP in G0, we find alternative translation factors—a non-canonical 5’cap binding factor and an eIF4G homolog that interacts with the ribosome—are recruited by the 3’-UTR binding FXR1a-microRNP, and promote specific mRNA translation. Our data show that G0 leukemic cells are chemoresistant and their translation profile is similar to surviving leukemic cells that are isolated after clinical therapy. We find expression of critical cytokines and immune regulators in G0. Significantly, inhibiting these immune regulators in resistant G0 cancer cells reduces their survival and chemoresistance. These data reveal a specialized translation mechanism in G0 cancer cells that promotes specific mRNA translation in these conditions of reduced canonical translation, and is important for chemoresistance. Citation Format: Syed I. Bukhari, Samuel S. Truesdell, Sooncheol Lee, Swapna Kollu, Anthony Classon, Myriam Boukhali, Esha Jain, Richard D. Mortensen, Akiko Yanagiya, Ruslan Sadreyev, Wilhelm Haas, Shobha Vasudevan. Specialized microRNP and translation mechanisms in quiescent 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 4997. doi:10.1158/1538-7445.AM2017-4997
Abstract 4517: A CRISPR approach to monitoring hypoxia-inducible proteins in real-time
Authors: Marie K. Schwinn, Thomas Machleidt, Brock F. Binkowski, Christopher T. Eggers, Keith V. Wood
Journal: Cancer Research (2017)

Abstract Hypoxia-inducible factor 1A (HIF1A) regulates expression of genes implicated in various aspects of oncogenesis, including angiogenesis, cell survival, metastasis, and glucose metabolism. Overexpression or hypoxia-induced stabilization of HIF1A has been associated with poor prognosis in cancer patients, making HIF1A and its associated pathway a high-profile target for anticancer therapies. We sought to develop a live-cell assay to monitor abundance of endogenous HIF1A and HIF1A-inducible proteins that could be used to identify potent and specific inhibitors of the hypoxia signaling pathway. To accomplish this goal, mammalian cell lines were edited by CRISPR using a Cas9:crRNA ribonucleoprotein complex with a single-stranded oligonucleotide donor DNA to introduce the HiBiT tag at the C-terminus of HIF1A and a number of known hypoxia-inducible proteins, including BNIP3, ANKRD37, HILDPA and KLF10. The 11 amino acid HiBiT peptide and its complementing 18 kDa polypeptide, known as LgBiT, spontaneously reconstitute into an active luciferase derived from the NanoLuc enzyme. Co-expression of LgBiT in edited cells, followed by addition of the cell-permeable luciferase substrate, leads to generation of a bright, steady luminescent signal that directly correlates with abundance of the HiBiT fusion. The edited cells were treated with several known modulators of the HIF1A signaling pathway, and changes in the abundance of the protein fusions were followed in real-time by monitoring luminescence. The HiBiT tag was also used to validate size and subcellular localization of the fusion proteins using bioluminescence imaging and antibody-free blotting. As expected, all tested compounds induced HIF1A accumulation. However, the downstream targets of HIF1A generated differing response to the chemical modulators, warranting further investigation into the modes by which these compounds act. By coupling the speed and efficiency of CRISPR-mediated editing with the small size and brightness of HiBiT, it was possible to generate a live-cell assay to monitor abundance of proteins along the HIF1A pathway. This assay could easily be adapted to screen for compound-induced effects on protein levels of HIF1A, as well as HIF1A- induced changes in expression patterns. Citation Format: Marie K. Schwinn, Thomas Machleidt, Brock F. Binkowski, Christopher T. Eggers, Keith V. Wood. A CRISPR approach to monitoring hypoxia-inducible proteins in real-time [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 4517. doi:10.1158/1538-7445.AM2017-4517