tbuckley/cabot-search huggingface dataset:
Abstract 4344: Low mitochondrial copy number induces resistance to chemotherapy in esophageal cancer
Authors: Moyuru Yamada, Koji Tanaka, Yasunori Masuike, Tomoki Makino, Tsuyoshi takahashi, Yukinori Kurokawa, Makoto Yamasaki, Kiyokazu Nakajima, Masaki Mori, Yuichiro Doki, Kabuki Odagiri
Journal: Cancer Research (2018)

Abstract Introduction: Esophageal squamous cell carcinoma (ESCC) is the one of the deadliest gastrointestinal cancers. The important problem in treating ESCC is resistance to chemotherapy. A few previous reports showed that mitochondrial DNA (mtDNA) copy number was decreased in esophageal squamous cell carcinoma (ESCC). However, it is unclear whether alteration of mtDNA copy number affects the effect of chemotherapy for ESCC. In the present study, we investigated the relationship between mtDNA copy number and the effect of chemotherapy in ESCC. Methods: To analyze the mtDNA copy number of surgically resected primary tumors from ESCC patients, qPCR for Cytochrome Oxidase I was performed. Human ESCC cells (TE8 and TE11) with decreased mtDNA copy number were established by knockdown of mitochondrial transcription factor A (TFAM). Those cells were treated with 5FU, cisplatin and docetaxel. The response of chemotherapy was accessed by cell viability assay (WST assay) and apoptosis assay (flow cytometry). To investigate the mechanism of resistance of chemotherapy, expression of EMT-related genes such as CDH1, CDH2, vimentin and zeb1 was measured by qPCR. Wound healing assay and invasion assay were performed to access the cell migration and invasion. Results: Patients were categorized into higher and lower subgroups according to the median value of the mtDNA copy number. Lower mtDNA copy number group was significantly correlated with tumor depth and pathologic response of chemotherapy. ESCC patients with lower mtDNA copy number had significantly poorer 5-year recurrence-free and overall survival than higher group. By shRNA knockdown of TFAM gene expression, mtDNA copy number decreased to 40% in TE8 and 60% in TE11 compared with non-target control cells. Viability of mtDNA-depleted TE8 and TE11 treated with chemotherapy was higher than that of control cells. Apoptosis assay showed the percentages of apoptosis induced by chemotherapy in mtDNA-depleted TE8 and TE11 were lower than those of control cells. Invasion assay and wound healing migration assay showed that mtDNA-depleted TE8 and TE11 were significantly more invaded and migrated than the control-sh cells. Conclusions: These results suggest that low mitochondrial copy number induces resistance to chemotherapy in esophageal cancer. Citation Format: Moyuru Yamada, Koji Tanaka, Yasunori Masuike, Tomoki Makino, Tsuyoshi takahashi, Yukinori Kurokawa, Makoto Yamasaki, Kiyokazu Nakajima, Masaki Mori, Yuichiro Doki, Kabuki Odagiri. Low mitochondrial copy number induces resistance to chemotherapy in esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4344.
Abstract 18939: Haplotype-Dependent Differential Regulation of the Human AT1R Gene is Exacerbated by Age: Effects on Tissue Inflammatory and Redox Milieu
Authors: Anita Rana, Sudhir Jain, Nitin Puri, Meenakshi Kaw, Ashok Kumar
Journal: Circulation (2014)

Age-associated inflammation and redox imbalance underlie etiopathogenesis of cardiovascular-renal diseases, including hypertension and end organ damage. Angiotensin II (Ang II), via activation of t...
Tracking Chromatid Segregation to Identify Human Cardiac Stem Cells That Regenerate Extensively the Infarcted Myocardium
Authors: JanKajstura, YingnanBai, DonatoCappetta, JunghyunKim, ChristianArranto, FumihiroSanada, DomenicoD'Amario, AlexMatsuda, SilvanaBardelli, JoãoFerreira-Martins, ToruHosoda, AnnarosaLeri, MarcelloRota, JosephLoscalzo, PieroAnversa
Journal: Circulation Research (2012)

Rationale:According to the immortal DNA strand hypothesis, dividing stem cells selectively segregate chromosomes carrying the old template DNA, opposing accumulation of mutations resulting from nonrepaired replication errors and attenuating telomere shortening. Objective:Based on the premise of the immortal DNA strand hypothesis, we propose that stem cells retaining the old DNA would represent the most powerful cells for myocardial regeneration. Methods and Results:Division of human cardiac stem cells (hCSCs) by nonrandom and random segregation of chromatids was documented by clonal assay of bromodeoxyuridine-tagged hCSCs. Additionally, their growth properties were determined by a series of in vitro and in vivo studies. We report that a small class of hCSCs retain during replication the mother DNA and generate 2 daughter cells, which carry the old and new DNA, respectively. hCSCs with immortal DNA form a pool of nonsenescent cells with longer telomeres and higher proliferative capacity. The self-renewal a...
TRIM44 promotes quiescent multiple myeloma cell occupancy and survival in the osteoblastic niche via HIF-1α stabilization
Authors: Zheng Chen, Tsung-Chin Lin, Xiaohong Bi, Guijin Lu, Brian C. Dawson, Roberto Miranda, L. Jeffrey Medeiros, Ian McNiece, Nami McCarty
Journal: Leukemia (2018)

Despite progress in the treatment of MM, including the use of high-dose chemotherapy and autologous stem cell transplantation, a considerable proportion of patients are refractory to all therapies. This resistance is related to the molecular genetic heterogeneity in MM cells as well as to the contributions from the BM, which is one of the key determinants of treatment outcome. Our previous studies using fluorescent tracers revealed that MM heterogeneity is correlated with the presence of quiescent stem-like cancer cells, which prefer to reside within the osteoblastic niche of the BM. In this report, we identified a novel protein, tripartite motif containing 44 (TRIM44), which is overexpressed in the osteoblastic niche of the BM, enabling MM cells to compete with HSCs for niche support. TRIM44 expression in MM cells promoted cell quiescence but increased bone destruction in xenograft mice, similar to what is observed in MM patients. TRIM44 functions as a deubiquitinase for hypoxia inducible factor-1α (HIF-1α), which stabilizes HIF-1α expression during hypoxia and normoxia. Stabilized HIF-1α stimulates MM cell growth and survival during hypoxia. Our work is the first report to reveal signaling in quiescent MM cells and the functions of TRIM44.
Abstract 2893: Balancing the efficacy and toxicity of anti-CD47 antibodies by direct screening in humanized mouse models
Authors: Yanan Guo, Chaoshe Guo, Yuelei Shen, Benny Yang
Journal: Cancer Research (2018)

Abstract CD47 is a transmembrane protein found on the surface of many cells in the body. Its expression is often up-regulated in many cancer cells. The receptor of CD47 was identified as SIRPa, which is expressed on phagocytic cells. Engagement of SIRPa by CD47 serves as “do not eat me” signal, thus inhibiting the phagocytic activity of macrophages. Cancer cells often hijack this pathway by boosting CD47 expression on their surface, in order to prevent innate cell-mediated phagocytosis. Molecules blocking the CD47-SIRPa interaction will unleash such inhibition and promote tumor destruction. Accordingly, anti-CD47 antibodies offer new hope to successful cancer treatment. Despite people are enthusiastic about CD47 as a potential target, the side effects associated with CD47 blockade have emerged as a major concern. For example, treatment with anti-CD47 antibody greatly reduced the number of circulating red blood cells and platelets that also express CD47. Thus, the class of CD47 antibodies that stimulate tumor cell killing while sparing normal cells in vivois desirable for the cancer patients. We are interested in understanding whether humanized mouse models could aid the evaluation of a variety of monoclonal CD47 antibodies we generated. We first screened them using the CDX platformestablished at Biocytogen. Indeed, most antibodies were able to clear human tumor cells in B-NDG mice. However, when we screened the toxicity of these antibodies using humanized CD47 mice (B-hCD47), many antibodies caused rapid death of animals upon the first administration. Interestingly, we found two clonal antibodies bearing the least toxicity since the treated animals exhibited minimal weight loss. Thus, we concluded that humanized mice could expedite the development of safer CD47 antibodies that can be advanced to human clinical trials. Citation Format: Yanan Guo, Chaoshe Guo, Yuelei Shen, Benny Yang. Balancing the efficacy and toxicity of anti-CD47 antibodies by direct screening in humanized mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2893.
Abstract 5896: Downregulation of calcium-sensing receptor enhances MET-mediated prostate cancer chemosensitivity
Authors: Luying Huang, Fuhao Wang, Haibo Tong, Atsushi Mizokami, Evan T. Keller, Yi Lu, Jian Zhang
Journal: Cancer Research (2018)

Abstract Chemoresistance, in various types of cancer including prostate cancer (PCa), is one of the major challenges in cancer therapy. Others and our lab have reported that the epithelial-to-mesenchymal transition (EMT) plays critical roles in development of chemoresistance and metastasis. The calcium-sensing receptor (CaSR) plays important roles in maintenance of calcium homeostasis and altered CaSR expression, and functional changes are involved in certain diseases, including tumorigenesis and its development. However, the mechanism of CaSR in PCa chemoresistance remains unclear. In current study, the CaSR expression level was detected in parental PC3 and DU145 cells and their chemoresistant PC3-TxR and DU145-TxR cells. We found the CaSR was highly expressed in chemoresistant PC3-TxR and DU145-TxR cells. Then by using siRNA technique, CaSR expression was transiently knocked down in chemoresistant cells. The tumor cell migration, invasion, and colony formation were evaluated by wound healing, transwell, and colony formation assays, respectively. The drug sensitivity was evaluated using MTS assay. We observed that the abilities of tumor cell migration and invasion were significantly diminished in CaSR knockdown PC3-TxR and DU145-TxR cells. The ability of colony formation was also reduced. Interestingly, the sensitivity to paclitaxel was reactivated in CaSR knockdown PC3-TxR and DU145-TxR cells. We finally observed that E-cadherin expression was increased in CaSR knockdown chemoresistant cells, and Snail, Vimentin and β-catenin were decreased; these results are consistent with EMT phenotypic alterations. Taken together, we conclude that downregulation of CaSR enhances MET-mediated prostate cancer chemosensitivity. Supported by NSFC Key Project 81130046; NSFC projects 81773146,81272415; JCYJ20170412152943794, JCYJ20170412154619484, JCYJ20170307105128101, JCYJ2017030711041760; Guangxi Key Projects 2013GXNSFEA053004. Citation Format: Luying Huang, Fuhao Wang, Haibo Tong, Atsushi Mizokami, Evan T. Keller, Yi Lu, Jian Zhang. Downregulation of calcium-sensing receptor enhances MET-mediated prostate cancer chemosensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5896.
Atorvastatin, Etidronate, or Both in Patients at High Risk for Atherosclerotic Aortic Plaques
Authors: TetsuyaKawahara, MasakoNishikawa, ChieKawahara, TetsuyaInazu, KunioSakai, GenSuzuki
Journal: Circulation (2013)

Background—Statins are not effective in reducing atherosclerotic plaques of the abdominal aorta, and accumulating evidence suggests that bisphosphonates have the potential to induce the regression of atherosclerotic plaques of the abdominal aorta. Methods and Results—A prospective, randomized, open-label, blinded-end-point trial involving 108 participants with hypercholesterolemia was conducted. Participants received 20 mg atorvastatin daily, 400 mg etidronate daily, or both drugs daily. The primary end point was the percent change in maximal vessel wall thickness of atherosclerotic plaques in the thoracic and abdominal aortas as measured by magnetic resonance imaging after 12 months of treatment. In both the combination therapy and atorvastatin groups, maximal vessel wall thickness of the thoracic aorta was reduced by 13.8% (95% confidence interval, −16.4 to −11.3) and 12.3% (95% confidence interval, −14.9 to −9.7), respectively. These reduction rates were comparable between groups (P=0.61). Meanwhile, i...
Abstract A06: BRCA-like phenotype as a hallmark of osteosarcoma's converging evolution
Authors: Michal Kovac, Sebastian Ribi, Claudia Blattmann, Michaela Nathrath, Daniel Baumhoer
Journal: Clinical Cancer Research (2018)

Abstract Background: Osteosarcomas are aggressive bone tumors with a high degree of genetic heterogeneity, which has historically limited treatment options in patients who do not respond to standard chemotherapy. Methods: We sequenced exomes and genomes of 32 pretherapeutic osteosarcomas, 6 time-series consisting of chemotherapy-naïve biopsies, resection specimens, recurring tumors and/or metastases, and 15 unpaired metastases from (mainly) poor responders. We then interrogated signatures of mutation processes in cancer genomes and reconciled clonal maps with phylogenetic trees, thus building an evolutionary history of each tumor. Where possible, we searched for evidence of selection acting on the tumors and hallmarks that could be therapeutically exploited. Results: We identified pathogenic mutations in at least 14 cancer drivers, some of which were formerly unknown in the context of osteosarcoma. However, there was no single cancer driver gene that could explain the majority of cases. Instead, &amp;gt;80% of osteosarcomas exhibited a specific combination of single-base substitutions, LOH, or large-scale genome instability characteristic of BRCA1/2-deficient tumors. The BRCA-like phenotype developed through parallel evolution by deleterious mutations affecting the BRCA1/2 genes and their binding partners such as PALB2 or CHEK2. We therefore investigated the sensitivity of a panel of osteosarcoma cell lines to the poly(ADP)-ribose polymerase inhibitor talazoparib alone and in combination with chemotherapeutic drugs. We identified an association between homologous recombination repair deficiency and the response of osteosarcoma cell lines to talazoparib. In combination with temozolomide, talazoparib led to the activation of BAX and BAK, loss of mitochondrial membrane potential, DNA fragmentation, and caspase-dependent cell death. Conclusion: The acquisition of a BRCA-like phenotype through converging evolution has important implications for the development of novel treatment strategies in osteosarcoma using PARP inhibitors alone or together with standard chemotherapy. Citation Format: Michal Kovac, Sebastian Ribi, Claudia Blattmann, Michaela Nathrath, Daniel Baumhoer. BRCA-like phenotype as a hallmark of osteosarcoma's converging evolution [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr A06.
Abstract 3509: The glutaminase inhibitor CB-839 synergizes with CDK4/6 and PARP inhibitors in pre-clinical tumor models
Authors: Ethan D. Emberley, Mark Bennett, Jason Chen, Matthew Gross, Tony Huang, Amani Makkouk, Gisele Marguier, Alison Pan, Sandra M. Spurlock, Susanne Steggerda, Francesco Parlati
Journal: Cancer Research (2018)

Abstract Many tumor cells utilize the amino acid glutamine to meet the elevated bioenergetic and biosynthetic demands of rapid cell growth. The enzyme glutaminase converts glutamine to glutamate, which is used to fuel the TCA cycle, synthesize amino acids and nucleotides, and balance cellular oxidative stress. We developed CB-839, a potent and orally bioavailable small molecule inhibitor of glutaminase, that blocks production of glutamate and generation of downstream metabolites glutathione, malate and aspartate. Mice treated with CB-839 had decreased levels of nucleotides in their tumors, likely due to glutamine-derived aspartate being required for nucleotide biosynthesis. Consistent with our finding that CB-839 decreases nucleotide pools, CB-839 treatment delayed cancer cells from either entry into S-phase or progression through S-phase. Based on this observation, the ability of CB-839 to synergize with therapies that block cell cycle progression was tested. CB-839 synergized with the CDK4/6 inhibitor palbociclib in colorectal carcinoma (CRC), triple negative breast cancer (TNBC) and ER+ breast cancer cell lines resulting in anti-proliferative activity. The combination of CB-839 with palbociclib also led to decreased cell cycle progression through S-phase and caused an accumulation of cells in G1 as measured by an EdU DNA incorporation assay. In vivo, the combination of CB-839 with palbociclib resulted in enhanced anti-tumor activity in both an ER+ breast cancer and CRC xenograft tumor model. We next investigated whether CB-839 treatment would enhance the anti-tumor effects of DNA repair inhibitors, given the ability of CB-839 treatment to decrease nucleotide pools. CB-839 treatment in combination with the PARP inhibitors niraparib and talazoparib led to synergistic anti-proliferative activity in TNBC, CRC, non-small cell lung carcinoma, ovarian and prostate cancer cells. In vivo, the combination of CB-839 with PARP inhibitors showed enhanced anti-tumor activity compared to single agent treatment in a CRC tumor xenograft model. CB-839 is currently undergoing evaluation for efficacy in the treatment of cancer in several phase I/II clinical trials. These encouraging pre-clinical results support the testing of CB-839 with CDK4/6 or PARP inhibitors in cancer patients. Citation Format: Ethan D. Emberley, Mark Bennett, Jason Chen, Matthew Gross, Tony Huang, Amani Makkouk, Gisele Marguier, Alison Pan, Sandra M. Spurlock, Susanne Steggerda, Francesco Parlati. The glutaminase inhibitor CB-839 synergizes with CDK4/6 and PARP inhibitors in pre-clinical tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3509.
Diabetes and Dyslipidemia
Authors: KhanhHoang, Y.-D. IdaChen, GeraldReaven, LunanZhang, HeatherRoss, MargaretBillingham, HannahValantine
Journal: Circulation (1998)

Background—Clinical observations suggest that transplant coronary artery disease (TxCAD) is immunologically mediated but may be accelerated by metabolic derangements. We developed a rat model of heterotopic heart transplantation in the presence of diabetes and dyslipidemia to further study their role in TxCAD development. Methods and Results—Major histocompatibility complex–mismatched strains of inbred rats underwent heterotopic heart transplantation (ACI-to-Lewis allografts). Diabetes (DM) was induced by streptozotocin injection (80 mg/kg) after transplantation; dyslipidemia was worsened by feeding of a 60% high-fructose diet (+F). Allograft transplants were divided into four groups: (1) +DM/+F; (2) +DM/−F; (3) −DM/+F; and (4) −DM/−F. Isograft transplants (Lewis to Lewis, +DM/±F) were controls. All animals received daily cyclosporine (5 mg/kg). Grafts surviving >30 days were evaluated for TxCAD on histological sections and graded 0 to 5 for intimal thickness. All streptozotocin-treated animals were diabe...
Letter by Abdellaoui et al Regarding Article, “Intracoronary Compared With Intravenous Bolus Abciximab Application in Patients With ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention”
Authors: MohamedAbdellaoui, GillesRioufol, GérardFinet
Journal: Circulation (2009)
Near-Infrared-II (NIR-II) Bioimaging <i>via</i> Off-Peak NIR-I Fluorescence Emission
Authors: Shoujun Zhu, Bryant C. Yung, Swati Chandra, Gang Niu, Alexander L. Antaris, Xiaoyuan Chen
Journal: Theranostics (2018)

Significantly reduced photon scattering and minimal tissue autofluorescence levels in the second biological transparency window (NIR-II; 1000-1700 nm) facilitate higher resolution in vivo biological imaging compared to tradition NIR fluorophores (~700-900 nm).However, the existing palette of NIR-II fluorescent agents including semiconducting inorganic nanomaterials and recently introduced small-molecule organic dyes face significant technical and regulatory hurdles prior to clinical translation.Fortunately, recent spectroscopic characterization of NIR-I dyes (e.g., indocyanine green (ICG), IRDye800CW and IR-12N3) revealed long non-negligible emission tails reaching past 1500 nm.Repurposing the most widely used NIR dye in medicine, in addition to those in the midst of clinical trials creates an accelerated pathway for NIR-II clinical translation.This review focuses on the significant advantage of imaging past 1000 nm with NIR-I fluorophores from both a basic and clinical viewpoint.We further discuss optimizing NIR-I dyes around their NIR-II/shortwave infrared (SWIR) emission, NIR-II emission tail characteristics and prospects of NIR-II imaging with clinically available and commercially available dyes.
Abstract 1204: Incidences of malignant primary soft-tissue sarcomas regardless of primary site: A nationwide population-based study in Taiwan
Authors: Giun-Yi Hung, Jiun-Lin Horng, Chueh-Chuan Yen
Journal: Cancer Research (2018)

Abstract Population-based studies on soft tissue sarcomas (STS) incidence beyond extremities and trunk wall are lacking in Asia. In this study, we aimed to report the incidences of STS arise in any part of the body. The data of primary STS registered in the population-based Taiwan Cancer Registry during 2007 and 2013 was acquired via the Health and Welfare Data Science Center, Taiwan. Histologic subtype-, age-, and gender-specific STS incidence rates of all sites were analyzed. A total of 11393 subjects were identified, with an age-standardized incidence rate of 5.62 (95% CI, 5.51-5.73) per 100,000 person-years. Approximately 30% of STS occurred in soft tissues (ICD-O-3 topography codes of C47, C49), and 70% occurred in all other primary sites (ICD-O-3 topography codes of C00-C80 except C47, C49, C40 and C41). The three most common primary sites other than soft tissues were stomach (15.9%), skin (14.3%) and small intestine (10.5%). Gastrointestinal stromal tumor (GIST) was the most common subtype, accounting for 29.2% of STS, followed by liposarcoma (11.5%) and leiomyosarcoma (9.7%). For overall STS, no significant incidence trend was identified during 2007-2013. However, a significant declining trend in incidence rate of undifferentiated pleomorphic sarcoma was found (annual percentage change, APC, -7.8%). By contrast, a significant upward trend was identified in other specified sarcomas (APC, 7.3%). For the first time, this analysis demonstrated that STS incidence varied by histologic subtype, gender, age, and primary site in Asians. In the future, more population-based studies should be performed in Asians for comparison with the results from Western countries to better clarification if racial variation exists in any subtype-specific incidence rates of STS. Citation Format: Giun-Yi Hung, Jiun-Lin Horng, Chueh-Chuan Yen. Incidences of malignant primary soft-tissue sarcomas regardless of primary site: A nationwide population-based study in Taiwan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1204.