tbuckley/cabot-search huggingface dataset:
Abstract 3015: Selective inhibition of mutant KRAS cell and tumor growth by PHT-7.3, an inhibitor of the KRas signaling nanocluster protein Cnk1
Authors: Roisin Delaney, Marco Maruggi, Martin Indarte, Robert Lemos, Geoff Grandjean, Lynn Kirkpatrick, Garth Powis
Journal: Cancer Research (2017)

Abstract Activating mutations of KRas is the most common proto-oncogenic event in human cancer but there remains no effective therapy for patients harboring mutated KRas (mut-KRas). Despite intense efforts, tight nucleotide binding, few defined pockets, and redundant localization signals have impeded the development of compounds that bind or inhibit KRas. We have identified connector enhancer of kinase suppressor of Ras 1 (Cnk1) as a critical mediator for growth driven by mut-KRas in human cancer cells. Cnk1 co-localizes with mutant KRas at the membrane and deletion of Cnk1 abrogates KRas activation and the activation of the Ras effectors Ral and Rho. Cnk1 deletion caused cells with mutant KRas to accumulate at the G1 checkpoint similar to selective deletion of mutant KRas itself. Following a screen and initial structural optimization a small molecule probe compound PHT-7.3 was identified and shown to bind selectively to the pleckstrin homology PH domain of Cnk1 preventing Cnk1 and mut-KRas co-localization. PHT-7.3 inhibited mut-KRas but not wt-KRas non small cell lung cancer (nsclc) cell growth, and selectively blocks mut-KRas downstream signaling in cells. PHT-7.3 exhibited cytostatic antitumor activity in the mut-KRas(G12S) A549 and mut-KRas(G12V) H441 nsclc xenografts, but not in the wt-KRas H1975 nsclc xenograft. Mut-KRas downstream signaling was inhibited by PHT-7.3 in the xenografts with downregulation of activated Rho and Ral signaling. PHT-7.3 showed further increased antitumor activity in A549 xenografts in combination with erlotinib or trametinib. Thus, the work identifies the PH domain of Cnk1 as a druggable target whose inhibition selectively blocks mutant-KRas activation, and PHT-7.3 as a lead agent in the development of therapies for KRas tumors. Citation Format: Roisin Delaney, Marco Maruggi, Martin Indarte, Robert Lemos, Geoff Grandjean, Lynn Kirkpatrick, Garth Powis. Selective inhibition of mutant KRAS cell and tumor growth by PHT-7.3, an inhibitor of the KRas signaling nanocluster protein Cnk1 [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 3015. doi:10.1158/1538-7445.AM2017-3015
Abstract 1531: Therapeutic strategies for osteosarcoma stem cells by regulating adipocyte differentiation based on actin dynamics
Authors: Hiroyuki Nobusue, Nobuhiro Takahashi, Nobuyuki Onishi, Takatsune Shimizu, Eiji Sugihara, Yoshinao Oki, Koichi Akashi, Koichiro Kano, Hideyuki Saya
Journal: Cancer Research (2017)

Abstract We generated induced cancer stem cells that initiate osteosarcoma (OS) by overexpression of c-MYC and loss of Ink4a/Arf in bone marrow-derived stromal cells, and found that the loss of adipogenic potential is an essential event for OS tumorigenesis. Therefore, our understanding of regulatory mechanisms of adipocyte differentiateon would greatly contribute to control OS tumorigenesis. Here, we show that regulation of the transcriptional coactivator MKL1 (megakaryoblastic leukemia 1) by actin cytoskeleton dynamics drives adipocyte differentiation mediated by PPARγ. Exposure of preadipocytes to an adipogenic cocktail results in the rapid disruption of actin stress fibres as a consequence of downregulation of RhoA-ROCK signaling, which regulates the formation of actin stress fibers and focal adhesions, and the consequent increase in monomeric G-actin levels. The resulting increase in the amount of G-actin leads to the interaction of G-actin with MKL1, which prevents nuclear translocation of MKL1 and allows expression of PPARγ followed by adipogenic differentiation. We further found that depletion of MKL1 can drive adipocyte differentiation in preadipocytes and even in nonadipogenic fibroblasts in the absence of an adipogenic cocktail, and these data revealed that MKL1 functions as a gatekeeper that controls adipocyte differentiation. In addition, we found that treatment with ROCK inhibitors induced terminal adipocyte differentiateon even in OS stem cells through regulation of MKL1 by actin cytoskeleton dynamics, which resulted in a significant suppression of tumorigenesis. Our findings provide new insight into the regulatory mechanism of adipogenesis, and trans-differentiation approach by controlling actin cytoskeleton dynamics may provide a novel therapeutic strategy for targeting cancer stem cells. Citation Format: Hiroyuki Nobusue, Nobuhiro Takahashi, Nobuyuki Onishi, Takatsune Shimizu, Eiji Sugihara, Yoshinao Oki, Koichi Akashi, Koichiro Kano, Hideyuki Saya. Therapeutic strategies for osteosarcoma stem cells by regulating adipocyte differentiation based on actin dynamics [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 1531. doi:10.1158/1538-7445.AM2017-1531
Abstract 4520: Hepatitis B virus X protein regulates hypoxia-inducible factor-1alpha (HIF-1 alpha) and lysyl oxidase like 2 (LOXL2) pathway in hepatocellular carcinoma
Authors: Cerise Yuen-Ki Chan, Aki Pui-Wah Tse, Elley Yong-Tuen Chiu, Karen Man-Fong Sze, Hui-Yu Koh, Irene Oi-Lin Ng, Carmen Chak-Lui Wong
Journal: Cancer Research (2017)

Abstract Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a fatal malignancy and is prevalent in HBV-endemic geographical areas. Hepatitis B virus (HBV) infection is a major etiologic factor of HCC. HBV is a double-stranded DNA virus and encodes for a viral onco-protein called transactivator protein X (HBx) which interacts with the host proteins to enhance proliferative potential of the host cells. Here, using Tet-ON and Tet-OFF HBx inducible systems in HBV-negative HCC cell lines, we showed that induced expression of HBx stabilizes hypoxia-inducible factor-1α (HIF-1α) protein under hypoxia. Reversely, knockdown of HBx in HBV-positive HCC cell lines reduced HIF-1α protein stabilization under hypoxia. More intriguingly, we found that induced HBx expression up-regulated the mRNA and protein expression a known HIF-1α transcriptional target, lysyl oxidase like 2 (LOXL2) in HCC. Our previous study showed that LOXL2 cross-linked collagen in the extracellular matrix to promote HCC metastasis. Scanning electron microscopy demonstrated that knockdown of HBx in HCC cell lines markedly reduced formation of collagen fibers in vitro. Transwell invasion assay showed that knockdown of HBx reduced HCC invasive ability. Picrosirius red staining further showed that knockdown of HBx reduced collagen cross-linking in vivo and repressed HCC growth and metastasis. Taken together, our study unprecedentedly show the HBx remodels the ECM through HIF-1α/LOXL2 pathway to promote HCC metastasis. Citation Format: Cerise Yuen-Ki Chan, Aki Pui-Wah Tse, Elley Yong-Tuen Chiu, Karen Man-Fong Sze, Hui-Yu Koh, Irene Oi-Lin Ng, Carmen Chak-Lui Wong. Hepatitis B virus X protein regulates hypoxia-inducible factor-1alpha (HIF-1 alpha) and lysyl oxidase like 2 (LOXL2) pathway in hepatocellular 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 4520. doi:10.1158/1538-7445.AM2017-4520
Abstract 2975: Collagen type XI alpha 1 confers cisplatin chemoresistance in ovarian cancer through inhibitor of apoptosis proteins (IAPs)
Authors: Miran Rada, Jennifer Cha, Jessica Sage, Sandra Orsulic, Dong-Joo Cheon
Journal: Cancer Research (2017)

Abstract Ovarian cancer is the most lethal gynecological cancer, which affects one in 70 females in the United States during their lifetime. While cisplatin is the frontline treatment for ovarian cancer, chemoresistance severely limits the treatment success. The goal of this study is to identify novel therapeutic targets to overcome cisplatin resistance. We recently identified Collagen type XI alpha 1 (COL11A1) as a novel biomarker associated with cisplatin resistance in ovarian cancer. COL11A1 is a component of the tumor stroma and its expression is restricted to cancer-associated fibroblasts (CAFs) adjacent to tumor cells. We further showed that COL11A1 protects ovarian cancer cells from cisplatin-induced apoptosis, yet the underlying mechanism is largely unknown. To understand the molecular mechanism by which COL11A1 protects cancer cells from cisplatin-induced apoptosis, we overexpressed COL11A1 in ovarian cancer cells and performed RNA-Seq. Our RNA-Seq data revealed that COL11A1 did not change the levels of genes involved in cisplatin transport, inactivation, and DNA repair pathways in cancer cells, which are well-established mechanisms to confer cisplatin resistance. Rather, COL11A1 enhances the expression of the Inhibitors of Apoptosis Proteins (IAPs), including XIAP, BIRC2 (c-IAP1) and BIRC3 (c-IAP2). Using a full-length COL11A1 protein, genetic manipulation, and co-culture method, we confirmed that COL11A1 significantly increases the expression of IAPs upon cisplatin treatment. The inhibition of XIAP, BIRC2 and BIRC3 with an IAP antagonist BV6 attenuated the ability of COL11A1 to inhibit cisplatin-mediated apoptosis. Our data indicates that COL11A1 activates Akt, and Akt is known to phosphorylate XIAP at serine-87, which protects it from ubiquitination and degradation in response to cisplatin. Collectively, our data identify IAP as a mediator of COL11A1’s action in blocking cisplatin-induced apoptosis. Note: This abstract was not presented at the meeting. Citation Format: Miran Rada, Jennifer Cha, Jessica Sage, Sandra Orsulic, Dong-Joo Cheon. Collagen type XI alpha 1 confers cisplatin chemoresistance in ovarian cancer through inhibitor of apoptosis proteins (IAPs) [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 2975. doi:10.1158/1538-7445.AM2017-2975
Ultrasonography of major salivary glands compared with parotid and labial gland biopsy and classification criteria in patients with clinically suspected primary Sjögren’s syndrome
Authors: Esther Mossel, Konstantina Delli, Jolien F van Nimwegen, Alja J Stel, Frans G M Kroese, Fred K L Spijkervet, Arjan Vissink, Suzanne Arends, Hendrika Bootsma
Journal: Annals of the Rheumatic Diseases (2017)

Objective To assess the validity of ultrasound of major salivary glands (sUS) compared with parotid and labial gland biopsies, sialometry, anti-SSA/Ro antibody status and classification criteria in patients clinically suspected with primary Sjögren’s syndrome (pSS). Methods 103 consecutive outpatients with clinically suspected pSS underwent sUS. Parenchymal echogenicity, homogeneity, hypoechogenic areas, hyperechogenic reflections and clearness of salivary gland border were scored according to the Hocevar scoring system. Total ultrasound score was calculated as the sum of these domains (range 0–48). Results Absolute agreement between sUS and parotid (83%) and labial (79%) gland biopsy outcome was good. Negative sUS predicts negative parotid gland biopsy, and positive sUS predicts positive labial gland biopsy. Compared with the American European Consensus Group (AECG) classification, sUS showed an absolute agreement of 82%, sensitivity of 71% and specificity of 92%. Compared with the American College of Rheumatology (ACR) classification, absolute agreement was 86%, sensitivity was 77% and specificity was 92%. Compared with the ACR-European League Against Rheumatism (EULAR) classification, absolute agreement was 80%, sensitivity was 67% and specificity was 94%. Positive sUS predicts classification, but negative sUS does not exclude classification. The combination of positive sUS with presence of anti-SSA/Ro antibodies or negative sUS with absence of anti-SSA/Ro antibodies showed a high predictive value for classification as pSS or non-pSS. Conclusion In our prospective inception cohort study derived from daily clinical practice, absolute agreement between sUS and salivary gland biopsies was slightly higher for parotid compared with labial gland biopsies. The combination of positive sUS and presence of anti-SSA/Ro antibodies highly predicts classification according to the AECG, ACR and ACR-EULAR classification criteria.
Abstract 5366: Detection of low-frequency somatic variants using single-molecule, real-time sequencing
Authors: Primo Baybayan, Laura Nolden
Journal: Cancer Research (2017)

Abstract Detection of somatic mutations, especially in heterogeneous tumor samples where variants may be present at a low level, is challenging. Single Molecule, Real-Time (SMRT®) Sequencing is ideal for minor variant detection because of its ability to sequence single molecules with very high accuracy (&amp;gt;QV40) using the circular consensus sequencing (CCS) approach. Here, we characterize the Sequel System for the detection of low-frequency somatic variants using constructs containing mutations in coding regions in EGFR, NPM1, AKT1 and JAK2 representing deletion, insertion, substitution and homopolymer variants. Wild type and mutant amplicons, provided by SeraCare, were mixed and serially diluted from 10% down to 0.1% allelic frequency. Independent SMRTbell libraries were constructed for each dilution point, sequenced and analyzed using SMRT Sequencing to identify the variants and determine the observed frequency. The random error profile and high-accuracy CCS reads make it possible to accurately detect low-frequency somatic variants. We will demonstrate sensitivity of the PacBio Systems to detect mutations down to 0.1%. Citation Format: Primo Baybayan, Laura Nolden. Detection of low-frequency somatic variants using single-molecule, real-time sequencing [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 5366. doi:10.1158/1538-7445.AM2017-5366
Abstract 3757: Ewing Sarcoma regression by Allo-MHC/Chm1 specific T cells without GVHD
Authors: Uwe Thiel, Sebastian Schober, ingo Einspieler, Andreas Kirschner, David Schirmer, Thomas Grünewald, Irene Teichert-von Lüttichau, Guenther Richter, Poul Sorensen, Stefan Burdach
Journal: Cancer Research (2017)

Abstract Background: Chondromodulin-I (CHM1) sustains malignancy in Ewing sarcoma (ES). Refractory ES carries a dismal prognosis and patients with bone marrow (BM) metastases do not survive irrespective of therapy. We assessed HLA-A*02:01/ CHM1 specific allorestricted T cell receptor (TCR) wildtype and transgenic cytotoxic (CD8+) T cells against ES. Patients and Methods: Three refractory HLA-A2+ ES patients were treated with HLA-A*02:01/peptide specific allorepertoire-derived (i.e. allorestricted) CD8+ T cells. Patient #1 received up to 4.8x105/kg body weight HLA-A*02:01- allorestricted donor derived wild type CD8+ T cells. Patient #2 received up to 8.2x106/kg HLA-A*02:01- donor derived and patient #3 up to 6x106/kg autologous allorestricted TCR transgenic CD8+ T cells. All patients were treated with the same TCR complementary determining region 3 allorecognition sequence for CHM1319. Results: HLA-A*02:01/CHM1319 specific allorestricted CD8+ T cells showed specific in vitro lysis of all patient-derived ES cell lines. Therapy was well tolerated and did not cause graft versus host disease (GVHD). Patients #1 and #3 showed slow progression, whereas patient #2, while having BM involvement, showed partial metastatic regression associated with T cell homing to involved lesions. CHM1319 TCR transgenic T cells could be tracked in his BM for weeks. Conclusions: CHM1319-TCR transgenic T cells home to affected BM and may cause partial disease regression. HLA-A*02:01/antigen specific allorestricted T cells proliferate in vivo without causing GVHD. Citation Format: Uwe Thiel, Sebastian Schober, ingo Einspieler, Andreas Kirschner, David Schirmer, Thomas Grünewald, Irene Teichert-von Lüttichau, Guenther Richter, Poul Sorensen, Stefan Burdach. Ewing Sarcoma regression by Allo-MHC/Chm1 specific T cells without GVHD [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 3757. doi:10.1158/1538-7445.AM2017-3757
Abstract 5003: Serum parathyroid hormone and risks of colorectal adenoma, adenoma recurrence and colorectal cancer, results from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial
Authors: Xiangzhu Zhu, Martha J. Shrubsole, Edward Giovannucci, Todd L. Edwards, Qi Dai
Journal: Cancer Research (2017)

Abstract Background: Serum parathyroid hormone (PTH) may be related to risk of incident colorectal cancer. However, no study has prospectively examined whether serum PTH is differentially related to risks of different stages of colorectal carcinogenesis (incident adenoma and metachronous adenoma). Further, it is unclear if PTH is associated with risk of incident colorectal neoplasia in individuals receiving endoscopic screenings. To address these important scientific inquiries, we have conducted three nested case-control studies within the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial. Methods: The PLCO is a large, multicenter, population-based randomized trial designed to determine the effects of screening on cancer-related mortality with a median of 12.5 years of follow up. We evaluated the associations between serum PTH and the risks of incident colorectal adenoma (755 cases and 514 controls), metachronous adenoma (755 cases and 755 controls) and incident colorectal cancer (755 cases and 514 controls) within PLCO participants aged 55 to 74 years. Odds ratios (OR) and 95% confidence intervals (95%CIs) were estimated using unconditional logistic regression models after adjusting for potential confounding factors. Results: Compared to low serum PTH (&amp;lt;30 ng/L), higher concentrations of serum PTH were associated with significantly reduced risk of incident colorectal cancer with the ORs (95% CIs) being 0.65(0.48-0.88) and 0.52(0.35-0.76) for PTH ≥30 ng/L and PTH≥65 ng/L (p for trend, 0.001). The inverse associations appeared significant for both women and men. However, overall, serum PTH was not related to risk of incident adenoma and metachronous adenoma. Conclusion: In conclusion, compared to the lowest PTH levels, higher serum PTH were related to reduced risks of incident colorectal cancer among an US population who received endoscopy, but not incident colorectal adenoma and metachronous adenoma. Citation Format: Xiangzhu Zhu, Martha J. Shrubsole, Edward Giovannucci, Todd L. Edwards, Qi Dai. Serum parathyroid hormone and risks of colorectal adenoma, adenoma recurrence and colorectal cancer, results from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [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 5003. doi:10.1158/1538-7445.AM2017-5003
Abstract 1959: MTA1 promotes tumor progression and bone metastasis in prostate cancer via positive regulation of MUC1 and CTSB
Authors: Avinash Kumar, Swati Dhar, Gisella Campanelli, Nasir A. Butt, Christian R. Gomez, Jason M. Schallheim, Anait S. Levenson
Journal: Cancer Research (2017)

Abstract About 80% of the time that prostate cancer cells metastasize, they spread to the bones. Metastasis involves activation of invasive programs through genetic and epigenetic alterations, including changes in expression of chromatin remodeler proteins. We have previously identified metastasis-associated protein 1 (MTA1), a chromatin remodeler, as a component of vicious cycle of bone metastasis and confirmed significantly higher expression of MTA1 in bone metastatic samples from patients. In an attempt to dissect molecular mechanisms of MTA1 action, we performed integrative analysis of our bone metastasis signature data along with MTA1 ChIP-Seq data, which revealed mucin 1 (MUC1) and cathepsin B (CTSB) as strong potential candidates responsible for MTA1-driven invasiveness.Here, we show that loss of function studies with MTA1 in PC3M cells exhibit reduced expression for MUC1 and CTSB. We also demonstrate that depletion of MTA1 in PC3M aggressive prostate cancer cellsdoes not affect cell proliferation but leads to decrease in colony forming ability, invasive and migratory property of these cells. When PC3M cells silenced for MTA1 and tagged with luciferase are used to generate subcutaneous or intracardiac xenografts, it leads to reduced tumor progression or decreased metastasis to bone, respectively as evident by bioluminescent measurements and histology of tumors. Ongoing experiments aim to validate the role of MUC1 and CTSB in MTA1-driven invasiveness and metastasis in prostate cancer. Citation Format: Avinash Kumar, Swati Dhar, Gisella Campanelli, Nasir A. Butt, Christian R. Gomez, Jason M. Schallheim, Anait S. Levenson. MTA1 promotes tumor progression and bone metastasis in prostate cancer via positive regulation of MUC1 and CTSB [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 1959. doi:10.1158/1538-7445.AM2017-1959
Measuring Patient-Reported Outcomes: Key Metrics in Reconstructive Surgery
Authors: Sophocles H. Voineskos, Jonas A. Nelson, Anne F. Klassen, Andrea L. Pusic
Journal: Annual Review of Medicine (2018)

Satisfaction and improved quality of life are among the most important outcomes for patients undergoing plastic and reconstructive surgery for a variety of diseases and conditions. Patient-reported outcome measures (PROMs) are essential tools for evaluating the benefits of newly developed surgical techniques. Modern PROMs are being developed with new psychometric approaches, such as Rasch Measurement Theory, and their measurement properties (validity, reliability, responsiveness) are rigorously tested. These advances have resulted in the availability of PROMs that provide clinically meaningful data and effectively measure functional as well as psychosocial outcomes. This article guides the reader through the steps of creating a PROM and highlights the potential research and clinical uses of such instruments. Limitations of PROMs and anticipated future directions in this field are discussed.