tbuckley/cabot-search huggingface dataset:
609. Systemic Delivery of Dysferlin Overlap Vectors Mediates Functional Recovery of Dysferlin Deficiency
Authors: Patricia C. Sondergaard, Danielle A. Griffin, Eric R. Pozsgai, Ryan Johnson, Kim Shontz, Jerry R. Mendell, Louise R. Rodmo-Klapac
Journal: Molecular Therapy (2015)

Dysferlinopathies comprise a family of disorders caused by mutations in the dysferlin (DYSF) gene leading to absent or mutant protein. Dysferlin protein has been implicated in multiple functional roles specifically in membrane stabilization/repair, t-tubule formation and vesicle trafficking. The loss of dysferlin causes a progressive dystrophy characterized by chronic muscle fiber loss, fat replacements and fibrosis resulting in deteriorating muscle weakness. Efforts made in the gene therapy arena with dysferlin or surrogate gene replacement have shown some efficacy in restoring membrane repair, however, only delivery of full-length DYSF has been able to correct the underlying histopathology. Therefore, there is a strong rationale to develop therapies that deliver the entire DYSF cDNA. A potential issue with this is the size of the DYSF gene (6.5 kb) which is too large for canonical AAV packaging. To circumvent this, we have developed and previously shown efficacy with a unique dual vector system using AAV to deliver and express DYSF specifically in muscle cells. This two vector system (AAV.DYSF.DV) packaged in the rh. 74 serotype is defined by a 1 kb region of homology between the two vectors. Following delivery to muscle, this overlap serves as a substrate for recombination/repair to generate the full-length gene. Our previous work studied the efficacy of this treatment strategy through intramuscular and regional vascular delivery routes. However, as generalized muscle weakness is common in dysferlinopathies, therapies targeting all muscle groups are warranted to maximize clinical efficacy. In this update, we have treated dysferlin-deficient mice systemically by intravenous injection to target all muscles through the vasculature for efficacy and safety studies. Mice were evaluated at 3 and 6 months post-treatment for dysferlin expression, restoration of membrane repair capability, diaphragm specific force measurements and muscle histology. Additional animals are awaiting MRI analysis following 1 year of treatment. A single systemic dose of 6×1012 vector genomes (3×1012 vg of each vector) resulted in widespread gene expression exceeding 30% of muscle fibers. Treated muscles showed a significant decrease in central nucleation and collagen deposition. Membrane repair ability was improved toward wild-type and force deficits in the diaphragm were restored to wildtype levels. The mice showed no evidence of local or systemic toxicity, further confirming previous safety data. This study, in conjunction with our previous work, lays the foundation for clinical trial.
A single fluorescent probe enables clearly discriminating and simultaneously imaging liquid-ordered and liquid-disordered microdomains in plasma membrane of living cells
Authors: Minggang Tian, Yong Liu, Yuming Sun, Ruoyao Zhang, Ruiqing Feng, Ge Zhang, Lifang Guo, Xuechen Li, Xiaoqiang Yu, Jing Zhi Sun, Xiuquan He
Journal: Biomaterials (2016)
625. Arming a Tumor Targeted Oncolytic Herpes Simplex Virus Type 1 With Matrix Metalloproteinase 9 for Enhanced Vector Distribution and Killing Activity
Authors: Paola Sette, Marco Marzulli, Daniela Leronni, Mingdi Zhang, William Goins, Balveen Kaur, Bolyard Chelsea, Timothy Cripe, Antonio Chiocca, Joseph Glorioso, Nduka Amankulor, Paola Grandi
Journal: Molecular Therapy (2015)

Early phase human clinical trials using several versions of oncolytic herpes simplex virus type 1 (oHSV) have shown promise in the treatment of GBM, but efficacy has been limited. Impediments to oHSV therapy include poor virus spread due in part to the tumor extracellular matrix, and insufficient replication in tumor cells as a result of attenuating mutations. Thus, the central goal of this project is to improve oncolytic vector delivery, replication and spread while maintaining safety and tumor specificity. We have already developed a new class of two stage tumor targeted oHSV combining (i) selective infection through tumor-specific receptors and (ii) selective replication based on differential expression of microRNAs (miRs) in tumor and normal cells. We further modify our vector by arming with the matrix metalloproteinase 9 (MMP9) as a means to reduce vector trapping in the tumor extracellular matrix. Here we show that MMP9 expression (i) enhances Oncolytic vector spreading in GBM neruospheres in vitro and (ii) improves tumor killing in a xenogeneic model of primary human GBM with significant long-term survival (≥50%) comparable to the control.
An autopsy case of AFP producing carcinoma of the rectum with multiple liver metastases treated by cetuximab + mFOLFOX6
Authors: Shinichi Takemura, Takashi Doi, Takahiro Kamiga, Kyohei Ariake, Taiki Kajiwara, Takashi Aizawa, Norikazu Takagi, Fusakuni Kuroda
Journal: Annals of Oncology (2015)
EARLY IDENTIFICATION OF LEFT VENTRICULAR DYSFUNCTION WITH SPECKLE TRACKING ECHOCARDIOGRAPHY IN ANTINEOPLASTIC THERAPY-INDUCED CARDIOTOXICITY
Authors: N. Maurea, C. Coppola, C.G. Tocchetti, G. Ragone, E. Di Pietro, G. Esposito, A. Rapacciuolo, C. Arra, R.V. Iaffaioli, C. De Lorenzo
Journal: Annals of Oncology (2010)
Abstract 4967: The BAP1 deubiquitinase promotes triple-negative breast cancer partially by stabilizing the KLF5 transcription factor
Authors: Ceshi Chen, Junying Qin, Zhongmei Zhou
Journal: Cancer Research (2015)

Abstract The transcription factor KLF5 is highly expressed in basal triple-negative breast cancer (TNBC) and promotes breast cancer cell proliferation, survival and tumor growth. However, the mechanism by which KLF5 is regulated in breast cancer remains unclear. In this study, we performed a genome-wide siRNA library screening against deubiquitinases (DUBs) and identified BAP1 as a bona fide KLF5 DUB. BAP1 interacts with KLF5 directly and stabilizes KLF5 via deubiquitination. KLF5 is in the BAP1/HCF-1 complex, and this newly identified complex promotes cell cycle progression partially by inhibiting p27 gene expression. Furthermore, BAP1 knockdown inhibits tumorigenicity and lung metastasis, which can be partially rescued by ectopic KLF5 expression. Collectively, our findings not only identified BAP1 as the first DUB for KLF5 but also revealed a critical mechanism for KLF5 expression regulation in TNBC. BAP1 could be a potential therapeutic target for TNBC and other cancers. Citation Format: Ceshi Chen, Junying Qin, Zhongmei Zhou. The BAP1 deubiquitinase promotes triple-negative breast cancer partially by stabilizing the KLF5 transcription factor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4967. doi:10.1158/1538-7445.AM2015-4967
The <i>KRAS</i> Variant as a Predictive Biomarker of Cetuximab Response in Head and Neck Cancer
Authors: Jeffrey P. Bruce, Wei Xu, Fei-Fei Liu
Journal: JAMA Oncology (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Abstract LB-107: Targeting ATR using a novel ATR inhibitor AZD6738 in human gastric cancer cells
Authors: Ahrum Min, Seock-Ah Im, Hyemin Jang, Seongyeong Kim, Miso Lee, Jungeun Kim, Kyung-Hun Lee, Sae-Won Han, Tae-Young Kim, Do-Youn Oh, Tae-You Kim, Woo-Ho Kim, Yung-Jue Bang
Journal: Cancer Research (2015)

Abstract Introduction: The DNA repair system is critical for maintaining genomic integrity. In particular, the homologous recombination (HR) repair pathway, on that repairs DNA double-strand breaks (DSBs), is directly associated with cancer development. Many cancer cells could contain mutations in genes involved in the HR pathway including BRCA1/2, ATM, ATR, and RAD51. ATR can be activated by various types of DNA damage and it initiates DNA damage-induces signaling cascade. As a result, ATR pathway components are considered promising therapeutic targets because ATR inhibition is likely to have greater deleterious effect on cancer cells. Materials and Methods: The antiproliferative activity of AZD6738 was examined in vitro using a cytotoxic assay, cell cycle analysis, and western blotting. To figure out the action mechanism of AZD6738 in gastric cancer cells, the expression of proteins which participate in DNA repair were investigated. The accumulation of DNA damage was also assessed with a DNA comet assay. These in vitro data were validated in vivo using a human gastric cancer xenograft model. Results: Human gastric cancer cell lines showed heterogeneous response to AZD6738. In AZD6738 sensitive cells, ATR inhibition leads to the accumulation of unrepaired DSBs due to dysfunctional RAD51 foci formation along with increased caspase 3-dependent cell death and S phase cell cycle arrest. Compared with sensitive cells, the activation of ATM-chk2 signaling pathway under the ATR inhibition was observed in the AZD6738 insensitive cells. It suggests that the activation of ATM-chk2 signal leads to attenuation of AZD6738 sensitivity. Furthermore, AZD6738 significantly suppressed tumor growth with increased apoptosis in vivo. Conclusion: We evaluated the anti-tumor activity of AZD6738 in gastric cancer in vitro and in vivo model. This is the first study to show that AZD6738 interferes with RAD51-mediated homologous recombination, as well as promotes cell death by inducing S cell cycle arrest and apoptosis in gastric cancer cells. Our findings can help to promote novel treatment strategies using AZD6738 in gastric cancer. Citation Format: Ahrum Min, Seock-Ah Im, Hyemin Jang, Seongyeong Kim, Miso Lee, Jungeun Kim, Kyung-Hun Lee, Sae-Won Han, Tae-Young Kim, Do-Youn Oh, Tae-You Kim, Woo-Ho Kim, Yung-Jue Bang. Targeting ATR using a novel ATR inhibitor AZD6738 in human gastric cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-107. doi:10.1158/1538-7445.AM2015-LB-107
Abstract 4113: Characterization of a novel TIMP-2 deficient mouse model of experimental lung metastasis
Authors: Sarvesh Kumar
Journal: Cancer Research (2015)

Abstract It is well known that the balance between matrix metalloproteinases (MMPs) and their endogenous inhibitors, the tissue inhibitors of metalloproteases (TIMPs) impacts tumor progression, thereby providing a novel avenue for cancer therapies. We have previously shown that forced TIMP-2 expression inhibits lung tumor growth independent of MMP inhibition via direct effects on tumor cells and modulation of the tumor microenvironment. The current study was undertaken to examine how reduced TIMP-2 expression impacts lung tumor growth using a novel TIMP-2 deficient (T2D) mouse model in a clean C57BL6 background. This is first time we fully developed and characterized TIMP2 deficient mice, validated by genotyping, histologic staining, protein and mRNA expression. The deletion of TIMP2 gene down regulated the expression TIMP2 mRNA and protein as demonstrated by quantitative RT-PCR and immunoblot experiments, respectively. Further, we investigated the impact of TIMP2 deletion on Lewis lung carcinoma model of metastasis. Lewis lung carcinoma cells transfected with luciferase (LL/2-Luc-M38, Caliper) were intratracheally instilled in the lungs into group's have heterozygous (T2D+/−), homozygous (T2D−/−), and wild type (WT) littermates. Tumor progression was monitored by IVIS imaging after 2nd week of intratracheal instillation and continued till 4th week, mice were sacrificed and lungs were perfused and harvested for further analysis. The IVIS analysis showed higher tumor burden in TIMP2 deficient and heterozygous mice as compared to wild type littermate, suggested that TIMP2 deficiency aggravates tumor development in deficient mice. The effects of recombinant TIMP2 on tumor microenvironment and microarray experiments are currently in progress. The molecular mechanism underlying the observed activities will be investigated. Collectively, these preliminary findings suggest that TIMP2 may be a novel target for lung cancer therapy. Citation Format: Sarvesh Kumar. Characterization of a novel TIMP-2 deficient mouse model of experimental lung metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4113. doi:10.1158/1538-7445.AM2015-4113
Achievement of personalized pain goal (PPG) in cancer patients referred to a supportive care clinic.
Authors: S. Dalal, D. Hui, L. M. T. Nguyen, R. Chacko, E. Bruera
Journal: Journal of Clinical Oncology (2011)

9060 Background: Cancer pain quality improvement initiatives recommend tailoring pain treatments to patient’s (pt’s) individual goals for comfort/functioning. The pt’s PPG for pain relief (0-10 pain-intensity that pt considers to be comfortable, in physical, functional, and psychosocial domains) is a simple measure of such goals. Pain and PPG are routinely assessed at our institution. Study was conducted to determine the proportion of cancer pts treated for pain, who achieve a pain response, as determined by their PPG, and identify factors associated with its non-achievement. Methods: Records of consecutive cancer pts seen in the Supportive-Care Clinic in consultation, who had follow-up visits within 1-5 weeks (n=348) were reviewed. All pts were treated by palliative-medicine specialists. Pain-response was defined as (1) Clinical-response (30% or ≥2 point pain reduction), and (2) PPG-response (if pain ≤ PPG). Logistic-regression model was used to estimate the effect of various factors on PPG-response. Results: Males 51%, median age 58 years, and survival 188 (IQR 92-412) days. At baseline, 239 pts (69%) had pain ≥4. Median pain was 7 (IQR 5-8) and PPG 3 (2-3). At follow-up (median 14-days), pain significantly decreased (7 vs 5, p < 0.001), while PPG remained stable (p=0.9). Initial PPG remained the same (51%) or changed by <2-points (31%) in 195 pts (82%). 122 pts (51%) achieved a clinical-response, but only 66 (28%) achieved their PPG (Table). Using PPG as gold-standard, sensitivity of clinical-response was 89%, and specificity 65%. Baseline factors associated with non-achievement of PPG were higher Memorial Delirium Assessment Scale scores (odds-ratio 1.43 per point, p= 0.002), positive alcoholism screening (CAGE ≥ 2) (2.79, 0.04) and insomnia (1.13, 0.04). Conclusions: PPG is a simple pt reported outcome for pain goals. Our preliminary findings suggest that PPG is stable over time, and that traditional definitions of clinical-response have a large percentage of false-positives. Predictors of lack of PPG-response include delirium, alcoholism history, and insomnia. Clinical-response by PPG-response. Achieved PPG Yes No Total Clinical Response Yes 59 60 119 No 7 111 118 Total 66 171 237 2 pts missing
Bisphosphonates and acute kidney injury in cancer patients: A RADAR report.
Authors: B. J. Edwards, S. Usmani, A. T. Samaras, J. M. McKoy, J. S. Holbrook, S. M. Belknap, S. T. Rosen, D. P. West
Journal: Journal of Clinical Oncology (2011)

e16576 Background: Bisphosphonates, in particular zoledronic acid (ZA), have been associated with renal toxicity manifested as deterioration in renal function and potential renal failure. Preclinical data indicate that ZA is cytostatic and pro-apoptotic in cancer cell lines, and exerts a synergistic effect with other chemotherapeutic agents. In clinical trials, the risk for renal function deterioration was significantly increased in patients receiving ZA infusion over 5 minutes compared with those receiving the same dose over 15 minutes. Methods: We reviewed Medline and PubMed databases for information related to identification, diagnosis, and treatment of bisphosphonate–associated renal injury (search period: 1970-2009; search terms: renal, renal failure, kidney injury, renal impairment, kidney disease, osteoporosis, neoplasias, and bisphosphonates. Searches of websites and safety databases maintained by the Food and Drug Administration (FDA), European Medicines Agency (EMEA), Canada Health, and Australia’s Adverse Drug Reactions Advisory Committee (ADRAC) and Advisory Committee on the Safety of Medicines (ACSOM) were completed. The FDA Adverse Event Reporting System (AERS) database was searched using 76 terms relating to renal problems combined with all drug names for bisphosphonates (search period: January 1998-June 2009). Results: In FDA AERS, we identified 480 cases of bisphosphonate-associated acute kidney injury in cancer patients. Patients were mostly female 298 (56%), mean age 66 ± 10 yrs; the malignancies identified were multiple myeloma (n=220, 46%), breast cancer (n=98, 20%), prostate cancer (n=24, 5%) and undefined (n=139, 29%). Associated agents included ZA (n=411, 87.5%), pamidronate (n=8, 17%), and alendronate (n=36, 2%). Outcomes included hospitalization (n=304, 63.3%), death (n=68, 14%), and “other” (n=71, 15%). Conclusions: Bisphosphonates are associated with acute kidney injury in patients with cancer, and lead to significant morbidity and mortality. Underlying kidney disease cannot be overlooked as a predisposing factor for acute kidney injury with bisphosphonate therapy.
Abstract 5076: Tumor cell-derived exosomes educate bone marrow mesenchymal stromal cells toward a protumorigenic function
Authors: Rie Nakata, Lucia Borriello, Muller Fabbri, Hiroyuki Shimada, Yves A. Declerck
Journal: Cancer Research (2015)

Abstract The bone marrow constitutes a microenvironment for tumor cells that promotes their survival, dormancy and therapeutic resistance. Central to this sanctuary function are mesenchymal stromal cells (MSC) which, like tumor-associated macrophages, can have an anti- or a pro-tumorigenic function in cancer progression. Here, using neuroblastoma, the second most common cancer in children that is highly metastatic to the bone marrow as a model of tumor cell - MSC communication - we have explored the mechanism by which tumor cells “educate” MSC toward a pro-tumorigenic function. We demonstrate that neuroblastoma cells release 30-100 nm size extracellular vesicles rich in tetraspanins (CD63) and chaperone proteins (HSP70), and therefore with characteristics of exosomes, and that they are captured by MSC. As a result, MSC increase their expression of several pro-tumorigenic cytokines and chemokines like interleukin (IL)-4, IL-6, IL-8, vascular endothelial cell growth factor (VEGF) and monocyte-chemotactic protein-1 (MCP-1). Capture of tumor-derived exosomes by MSC activates MEK/ERK1/2 and Akt (but not NF-κB), and whereas MEK/ERK1/2 activation is critical for the production of pro-tumorigenic cytokines/chemokines, Akt activation is not. In addition to the presence of structural, metabolic and chaperone proteins and the absence of inflammatory cytokines, a proteomic analysis of the cargo of these neuroblastoma-derived exosomes revealed an abundance of Galectin-3 binding protein (Gal-3BP), a protein that we had previously reported to increase the transcriptional expression of IL-6 in MSC. Further supporting the role of exosomes in educating MSC, we found that inhibition of exosome release in neuroblastoma cells by knock-down of Rab-27B, a GTPase involved in exosome secretion, was associated with a suppression of cytokine/chemokine production by MSC. We then demonstrated that “educated” MSC stimulate neuroblastoma cell proliferation both in vitro and in vivo and their resistance to chemotherapy in a signal transduction and activation (STAT)3 and MEK-ERK1/2- dependent manner. These data thus indicate that the production of exosomes by tumor cells induces the production of cytokines and chemokines in bone marrow-derived MSC, contributing to the protective microenvironment of the bone marrow niche. Citation Format: Rie Nakata, Lucia Borriello, Muller Fabbri, Hiroyuki Shimada, Yves A. Declerck. Tumor cell-derived exosomes educate bone marrow mesenchymal stromal cells toward a protumorigenic function. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5076. doi:10.1158/1538-7445.AM2015-5076