tbuckley/cabot-search huggingface dataset:
Abstract 3383: Exome sequencing in dedifferentiated ovarian mucinous carcinoma
Authors: Kaori Sanuki, Kentaro Nakayama, Kohei Nakamura, Masako Ishikawa, Tomoka Ishibashi, Hitomi Yamashita, Ruriko Ono, Toshiko Minamoto, Kosuke Yoshihara, Satoru Kyo
Journal: Cancer Research (2017)

Abstract Mucinous ovarian tumor represent a distinct histotype of epithelial ovarian cancer and is thought to begin as a mucinous adenoma that progresses in a slow stepwise fashion. Dedifferentiated mucinous ovarian carcinoma is a rare type of carcinoma with a few reports and a progressive and poor prognosis. While the molecular genetic features of ovarian mucinous carcinoma is now well known, the pathogenesis of dedifferentiated mucinous carcinoma is largely unknown. In order to comprehensively analyse somatic mutations in dedifferentiated mucinous carcinoma, we applied exome sequencing to the DNA of a sample of affinity-purified, dedifferentiated mucinous carcinoma. Through comparative analyses of normal cells from the same patient, we identified several genes that were mutated in this tumor. P53, which encodes a well-known tumor suppressor protein, and KRAS, which encodes a well-known oncoprotein, had previously been implicated in ovarian mucinous carcinoma. The other mutated genes were previously unknown to be involved in mucinous carcinoma. CEP170 encodes a microtubule-binding protein that controls the targeting of the kinesin-13 depolymerase protein to the mitotic spindle, and kinesin-13 family influence the dynamics of microtubule growth and shrinkage. CEP170 gene mutation may be related to inability of a cell division properly. CEP170 mutations were identified with a prevalence of 33.3% in dedifferentiated mucinous ovarian carcinoma. Currently, CEP170 gene knock down assay and engineered expression of CEP170 assay in ovarian mucinous carcinoma is being performed whether morphologic change is observed. In summary, CEP170 may be one of the responsible gene in carcinogenesis of differentiated mucinous carcinoma. Citation Format: Kaori Sanuki, Kentaro Nakayama, Kohei Nakamura, Masako Ishikawa, Tomoka Ishibashi, Hitomi Yamashita, Ruriko Ono, Toshiko Minamoto, Kosuke Yoshihara, Satoru Kyo. Exome sequencing in dedifferentiated ovarian mucinous 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 3383. doi:10.1158/1538-7445.AM2017-3383
Abstract 2180: Triphenylmethanol conjugates of leuprorelin asanti-cancer prodrugs
Authors: Yousef Ahmadibeni, Kaleh Karim, William Boadi
Journal: Cancer Research (2017)

Abstract Leuprorelin (LEP) is a synthetic analogue of gonadotropin-releasing hormone (GnRH), first was approved by the FDA for treatment of advanced prostate cancer and endometriosis in 1985. The initial effect of administration LEP is to stimulate the pituitary secretion of FSH and LH. After a prolonged stimulation (constant concentration of LEP in the blood) pituitary becomes insensitive to the action of GnRH. This reduces the level of gonadotropin in the blood, resulting in decreased levels of sex hormones to postcastration or menopausal levels. In addition to the usual side effects of this agonist analogs of LH-RH, other reported adverse effects include transient hypertension, dry mouth, excessive salivation, paraesthesia and increased dysuria. Improving the biological activity of LEP by increasing the cellular uptake and retention is a remedy to this end. In this study, a prodrug strategy has been introduced to optimize the hydrophobicity of LEP by using an appropriate hydrophobic linker attached to tris(4-methoxyphenyl)methanol (TPM) derivatives with the expectation to improve the cellular uptake. In this regard, several LEP conjugates of TPM derivatives with optimized hydrophobicity were synthesized by the reaction of methoxy benzenes (e.g. anisole, 2-fluoroanisole, 2-methylanisole 1,2-dimethoxybenzene or methyl 2-methoxybenzoate and 1,3,5-trioxane, followed by the conjugation with LEP and dodecanedioic acid in the presence of HBTU/DIPEA/DIC in moderate yields. Comparative antiproliferative assays between TPM-LEP conjugates and the corresponding non-covalent physical mixtures of the TPM derivatives and LEP were performed against human Caucasian prostate adenocarcinoma (PC3), human breast cancer cell line (BT549) and mouse pre-adipocytes (3T3-L1) cells and indicated moderare to high inhibition of the cell proliferation at a concentration of 5-100 µM after 24-72 h of incubation. These data suggest that TPM-LEP derivatives with optimized hydrophobicity can be used to improve the biological activity of LEP. Citation Format: Yousef Ahmadibeni, Kaleh Karim, William Boadi. Triphenylmethanol conjugates of leuprorelin asanti-cancer prodrugs [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 2180. doi:10.1158/1538-7445.AM2017-2180
Abstract 3720: Biological and clinical relevance of PD-L1 expression in tumor and inflammatory cells in NSCLC
Authors: Carlos Bais, Chris Morehouse, Brandon W. Higgs, Rebelatto Marlon, Keith Steele, Xiaoping Jin, Li Shi, Susana Korolevich, Ashok Gupta, Koustubh Ranade
Journal: Cancer Research (2017)

Abstract Background: High PD-L1 expression has been shown to be associated with improved clinical outcomes to anti-PD-1/L1 therapies in NSCLC and other indications. However, only a fraction of the PD-L1 high patients (pts) respond. PD-L1 can be induced by IFNG and expressed in tumor cells (TC) and inflammatory cells (IC). Improving our ability to predict patient benefit from anti-PD-1/L1 therapies requires a better understanding of associations between PD-L1 expression in TC and/or IC and outcome. Here we explore the relationship between patterns of IHC PD-L1 expression in TC and IC, gene expression, and clinical outcome. Methods: CP1108/NCT01693562 was a nonrandomized phase 1/2 trial evaluating durvalumab in pts with advanced NSCLC or other solid tumors. As of 29 APR 2016, 368 previously treated NSCLC pts received durvalumab ≤12 months with a median 18.8 months follow up. Pts with ≥25% TC or IC were scored TC+ and/or IC+, respectively. Results: TC+ PD-L1 pts (includes IC+ and IC- PD-L1 pts) had improved survival compared to TC- PD-L1 pts. TC+ and IC+ PD-L1 pts had: improved survival compared to TC+/IC-, TC-/IC+, or TC-/IC- PD-L1 pts. However, prevalence of TC+/IC+ was lower than TC+. Twenty-one genes significantly differed between TC+/IC+, TC+/IC-, TC-/IC+, and TC-/IC- PD-L1 patient subsets, the vast majority being well-known IFNG-inducible genes and mostly over-expressed in the TC+/IC+ subset. Conclusions: TC+ and IC+ PD-L1 pts had the highest levels of IFNG-inducible gene expression, a key biological feature that distinguishes PD-L1 IHC positive from negative pts. Thus, in addition to PD-L1 IHC, the predictive value of IFNG should be investigated in additional relevant studies Selection CriteriaPrevalence of Biomarker Positive BiomarkerPositive/negative median OSlog-rank pHRcox pTC+158/276 (57%)15.67/7.730.00910.690.046TC+/IC+70/276 (25%)25.63/8.377.46E-060.345.24E-05TC+/IC-88/276 (32%)10.5/13.970.0941.50.032TC-/IC+50/276 (18%)9.07/13.230.830.960.84TC-/IC-68/276 (25%)5.77/14.030.000841.660.012 All comers: median OS: 11.2 months (N=304) Citation Format: Carlos Bais, Chris Morehouse, Brandon W. Higgs, Rebelatto Marlon, Keith Steele, Xiaoping Jin, Li Shi, Susana Korolevich, Ashok Gupta, Koustubh Ranade. Biological and clinical relevance of PD-L1 expression in tumor and inflammatory cells in NSCLC [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 3720. doi:10.1158/1538-7445.AM2017-3720
Abstract 5191: A combination of Stat3 inhibitor and radiation for the treatment of malignant pleural mesothelioma
Authors: Seiji Matsumoto, Hiroshi Doi, Akihiro Fukuda, Tohoru Nakamichi, Ayumi Kuroda, Masaki Hashimoto, Teruhisa Takuwa, Nobuyuki Kondo, Seiki Hasegawa
Journal: Cancer Research (2017)

Abstract Background: Trimodality therapy, including surgery, is the treatment for patients with malignant pleural mesothelioma (MPM). However, the 5-year survival rate remains less than 40%. To improve the survival rate, we investigated Stat3 as a potential therapeutic target for MPM. Methods:Cell viability was assessed using Cell Counting Kit-8 (CCK-8: WST-8 Dojindo). MPM cells (NCI-H28, NCI-H226, NCI-H2052, NCI-H2452, MSTO-211H) were seeded into 96-well plates. After treatment with a Stat3 inhibitor (BBI-608 : napabucasin), Cell Counting Kit-8 solution was added to each well and absorbance was measured using a microplate reader. The level of phosphorylated Stat3 (p-Stat3) in cell lysates was measured by ELISA. ROS level in cells was measured by FACS analysis. In the in vivo study, H226 cells were injected subcutaneously in the flank region of nude mice randomly assigned to four treatment groups (5 mice/group)—(1) treatment with vehicle control, (2) treatment with Stat3 inhibitor, (3) radiation therapy (RT), and (4) Stat3 inhibitor and RT. Tumor size was measured twice/week. Results: Napabucasin decreased the viability of MPM cells (epithelioid, sarcoma, biphasic) in a dose-dependent manner. p-Stat3 levels decreased by 90% after treatment with 10 μM napabucasin in H226 cells. Napabucasin treatment induced more ROS production in MPM cells than did Pemetrexed. Moreover, combinatorial treatment with napabucasin and radiation (2 Gy, 5 Gy) induced more ROS production than did RT alone. In the mouse model, treatment with napabucasin alone significantly suppressed tumor growth (p &amp;lt; 0.05), but napabucasin and RT completely suppressed tumor growth. Conclusion:We showed that napabucasin inhibited proliferation of the MPM cells (epithelial, biphasic, sarcomatoid) and demonstrated that combination therapy with napabucasin and radiation completely suppressed tumor growth in a mouse model. Treatment with the napabucasin alone and the combination of napabucasin and RT induced high ROS production in MPM cells. Collectively, the combination of Stat3 inhibitor with Radiation Therapy (START) is a promising approach for the treatment of MPM.TheA combination of of Stat3 inhibitor and radiation with for the treatment of malignant pleural mesothelioma Citation Format: Seiji Matsumoto, Hiroshi Doi, Akihiro Fukuda, Tohoru Nakamichi, Ayumi Kuroda, Masaki Hashimoto, Teruhisa Takuwa, Nobuyuki Kondo, Seiki Hasegawa. A combination of Stat3 inhibitor and radiation for the treatment of malignant pleural 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 5191. doi:10.1158/1538-7445.AM2017-5191
The first-in-class alkylating HDAC inhibitor EDO-S101 is highly synergistic with proteasome inhibition against multiple myeloma through activation of multiple pathways
Authors: L Besse, M Kraus, A Besse, J Bader, T Silzle, T Mehrling, C Driessen
Journal: Blood Cancer Journal (2017)

The first-in-class alkylating HDAC inhibitor EDO-S101 is highly synergistic with proteasome inhibition against multiple myeloma through activation of multiple pathways
Abstract LB-149: ITGA1 marks pre-malignant pancreatic lesions and drives stem-like cell survival and TGFβ/collagen-induced therapy resistance and metastasis in pancreatic cancer
Authors: Sa La Kim, Armen Gharibi, Justin Molnar, Daniel Brambilla, Yvess Adamian, Malachia Hoover, Joy Lin, Julie Hong, Jonathan A. Kelber
Journal: Cancer Research (2017)

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of few malignancies to have single-digit 5-year survival rates at &amp;lt;7%. This dismal prognosis is due in part to the limited ability of clinicians to make pre-metastatic diagnoses and effectively treat localized pancreatic tumors. Thus, there is a dire need to improve early detection methods and identify new therapeutic targets for abrogating PDAC progression. To this end, we mined our previously published pseudopodium-enriched (PDE) protein/phosphoprotein datasets to identify novel PDAC-specific biomarkers and/or therapeutic targets. We discovered that 37 of the top 100 PDE proteins are frequently upregulated in human pancreatic cancer and other tumor types. Integrin alpha 1 (ITGA1) was of primary interest because its high expression in pancreatic cancer precursor lesions may provide a path toward earlier diagnoses, while targeting its cell surface function may abrogate tumor-stroma interactions known to exacerbate PDAC. In this regard, the expression of ITGA1-specific collagens within the pancreatic cancer microenvironment significantly correlates with indicators of poor patient prognosis such as high tumor grade, p53/SMAD4 mutation status and erlotinib resistance. Depleting ITGA1 from PDAC cells revealed that it is required for collagen-induced migration and survival. We further demonstrate that collagen induces PDAC cell attachment and spreading in an ITGA1-dependent manner. Notably, collagen/ITGA1 signaling promotes the survival of ALDH1-positive stem-like cells and cooperates with TGFβ to drive gemcitabine resistance. Finally, we report that increased ITGA1 expression in PDAC tissue indicates the presence of epithelial-mesenchymal transition (EMT) and that ITGA1 is required for TGFβ/collagen-induced EMT and hepatotropic metastasis. Our data suggest that ITGA1 is a new biomarker for PDAC initiation and, when targeted, can sensitize tumors to available chemotherapies to suppress the growth of pancreatic tumors at primary and metastatic sites. Citation Format: Sa La Kim, Armen Gharibi, Justin Molnar, Daniel Brambilla, Yvess Adamian, Malachia Hoover, Joy Lin, Julie Hong, Jonathan A. Kelber. ITGA1 marks pre-malignant pancreatic lesions and drives stem-like cell survival and TGFβ/collagen-induced therapy resistance and metastasis in pancreatic 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 LB-149. doi:10.1158/1538-7445.AM2017-LB-149
Abstract 1762: Keratin 17 identifies prognostic subtypes of pancreatic ductal adenocarcinoma
Authors: Luisa F. Escobar-Hoyos, Cindy Leiton, Elizabeth Vanner, Lucia Roa-Pena, Jinyu Li, Scott Powers, Ali Akalin, Jela Bandovic, Peter Bailey, David Chang, Richard Moffitt, Jen Jen Yeh, Andrew Biankin, Kenneth Shroyer
Journal: Cancer Research (2017)

Abstract Recent RNA sequencing (RNASeq) studies from Bailey et al., 2016, Moffitt et al., 2015 and Collisson et al., 2011 reported that mRNA expression from bulk tumor defines molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) that are highly correlated with patient survival. These studies independently identified Keratin 17 (K17) mRNA overexpression as one of over 20 upregulated transcripts that define the RNA signature of the most lethal PDACs. Studies in our lab determined that neither K17 gene missense mutations nor copy-number alterations explain the upregulation of K17 mRNA expression by malignant cells. In addition, we found that K17 expression, measured at the protein level by immunohistochemistry or at the level of mRNA by RNASeq, is sufficient to stratify patients by short- vs long- term survival at baseline after resection. These retrospective survival analyses were performed in four independent patient cohorts using a uniform threshold to define low- vs high- K17 patients (total n= 558). High-K17 cases were twice as likely to die from this disease compared to stage-matched low-K17 cases (P values &amp;lt; 0.05). Furthermore, we determined that K17 expression is associated with outcome after Gemcitabine treatment using the Bailey et al., 2016 patient cohort (n= 94). This is the first study to show that the expression of a single gene, K17, can accurately subtype PDAC at initial diagnosis. In conclusion, K17 was identified as a robust and independent, clinically relevant, prognostic and predictive biomarker to stratify clinical outcome at the time of initial diagnosis and to potentially inform clinical decisions regarding chemotherapeutic intervention. Citation Format: Luisa F. Escobar-Hoyos, Cindy Leiton, Elizabeth Vanner, Lucia Roa-Pena, Jinyu Li, Scott Powers, Ali Akalin, Jela Bandovic, Peter Bailey, David Chang, Richard Moffitt, Jen Jen Yeh, Andrew Biankin, Kenneth Shroyer. Keratin 17 identifies prognostic subtypes of pancreatic ductal adenocarcinoma [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 1762. doi:10.1158/1538-7445.AM2017-1762
Prevalence of elevated blood pressure in children and adolescents in Africa: a systematic review and meta-analysis
Authors: Jean Jacques Noubiap, Mickael Essouma, Jean Joel Bigna, Ahmadou M Jingi, Leopold N Aminde, Jobert Richie Nansseu
Journal: The Lancet Public Health (2017)

Despite substantial attention paid to the threat of elevated blood pressure in children and adolescents in high-income countries and the epidemic of hypertension in African adult populations, data on the burden of elevated blood pressure in African children and adolescents have not yet been synthesised. We did a systematic review and meta-analysis to provide estimates of the prevalence of elevated blood pressure and assess associated factors among children and adolescents in Africa.We searched Embase, PubMed, African Journals Online, and African Index Medicus to identify articles published from Jan 1, 1996, to Feb 2, 2017, and searched the reference list of retrieved articles. Each study was independently reviewed for methodological quality. We used a random-effects model to estimate the prevalence of elevated blood pressure across studies and heterogeneity (I2) was assessed via the χ2 test on Cochran's Q statistic. This review is registered with PROSPERO, number CRD42015019029.We included 51 studies in qualitative synthesis and 25 in the meta-analysis reporting data of a pooled sample of 54 196 participants aged 2-19 years. Study quality was high with only four medium-quality studies and no low-quality studies. Prevalence of elevated blood pressure varied widely across studies (range 0·2-24·8%). The pooled prevalence of elevated blood pressure (systolic or diastolic blood pressure ≥95th percentile) was 5·5% (95% CI 4·2-6·9), whereas that of slightly elevated blood pressure (systolic or diastolic blood pressure ≥90th percentile and <95th percentile) was 12·7% (2·1-30·4). The prevalence of elevated blood pressure was largely associated with body-mass index (BMI), with a prevalence of elevated blood pressure six times higher in obese (30·8%, 95% CI 20·1-42·6) versus normal-weight children (5·5%, 3·1-8·4; p<0·0001).This study suggests a high prevalence of elevated blood pressure among children and adolescents in Africa, with overweight and obesity being an important risk factor. Efforts to address this burden of elevated blood pressure in children and adolescents should mainly focus on primary prevention at the community level, by promoting healthy lifestyles and avoiding other cardiovascular risk factors, especially overweight and obesity. This study also stresses the need for more elaborate studies using uniform and reliable diagnostic methods to reliably map the burden of elevated blood pressure in children and adolescents in Africa.None.
Abstract 3764: Targeting GPR64 in pediatric sarcomas with CAR transgenic T cells
Authors: David Schirmer, Isabel Storz, Karin Wisskirchen, Regina Feederle, Oxana Schmidt, Hinrich Abken, Crystall Mackall, Ulrike Protzer, Stefan Burdach, Günther H. Richter
Journal: Cancer Research (2017)

Abstract Introduction: Ewing Sarcoma (ES) is the second most common bone malignancy in children and young adolescents with a high potential of dissemination into lung and bones. Patients with disseminated disease into the bone have an approximate long-term survival rate of only 10%, compelling the search for new therapeutic treatment modalities like engineered T cell therapy. Here the therapeutic potential of chimeric antigen receptor (CAR) transgenic T cells directed against G-protein coupled receptor 64 (GPR64) was examined. Experimental procedure: Two different monoclonal antibodies (mAb) directed against the extracellular region of GPR64 were generated and characterized. Subsequently, retroviral constructs containing second generation CARs together with the scFv fragments of the respective mAbs were designed. Constructs consisting of different spacers and co-stimulatory elements were compared (dIgG1-CD28-CD3z vs. CD8a-4-1BB-CD3z). Primary lymphocytes were transduced and tested in vitro via flow cytometry, ELISpot and xCelligence assay as well as in immunodeficient xenograft mice. Results: Antibodies specifically stained ES cells as determined by flow cytometry and immune histology. The signal intensity was reduced after RNAi mediated down-regulation of GPR64 in ES cell lines confirming specificity of the isolated mAbs. Following sequence determination of those mAbs two different CAR constructs were designed. Retroviruses containing such CARs transduced primary lymphocytes with high efficiency. The CAR transgenic T cells were enriched for CD8+CAR+ cells via microbead isolation and demonstrated strong proliferative capacities in vitro. Furthermore, target structures were specifically recognized as determined by ELISpot and xCelligence assays but dIgG1-CD28 CAR T cells derived from one hybridoma revealed hints of early exhaustion via auto-activation. Conclusion: CAR transgenic T cells targeting GPR64 show a promising approach to transfer the success of CARs in hematological malignancies to solid tumors. The cells generated in this study show strong specificity towards GPR64 and are able to control tumor cell growth. Since GPR64 expression is not restricted to ES but also up-regulated in a number of carcinomas derived from prostate, kidney or lung, GPR64-specific CARs may also be a future treatment option for other tumor entities. Citation Format: David Schirmer, Isabel Storz, Karin Wisskirchen, Regina Feederle, Oxana Schmidt, Hinrich Abken, Crystall Mackall, Ulrike Protzer, Stefan Burdach, Günther H. Richter. Targeting GPR64 in pediatric sarcomas with CAR transgenic T 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 3764. doi:10.1158/1538-7445.AM2017-3764