tbuckley/cabot-search huggingface dataset:
Abstract 925: IL-4 / IL-13 mediated cell-to-cell fusion in prostate cancer progress
Authors: Berna Uygur, Evgenia Leikina, Leonid Chernomordik
Journal: Cancer Research (2016)

Abstract Poorly understood interactions between prostate cancer (PCa) cells and their microenvironment direct the epithelial to mesenchymal transition (EMT) during disease progression. Cell-to-cell fusion, such as cell fusion in muscles and placenta, is one of the ways in which cells can drastically change their properties. Cell fusion has been proposed to promote tumor cell diversity and the ability to metastasize. Metastatic disease has been also suggested to depend on the interleukin 4 (IL-4) signaling. Patients with hormone-refractory PCa have elevated levels of IL-4 and it has been proposed that targeting IL4 -receptor interactions limits metastatic disease. Here, to mimic conditions at the interphase between rhabdosphincter myofibers and apical anterior regions of prostatic gland we explored interactions of PC3 cells (human PCa cell line) with skeletal muscle cells. Co-culturing of these cells resulted in an elevated concentration of related cytokines IL-4 and/or IL-13 in the tissue culture medium from the co-cultured cells but not from muscle cells cultured on their own. The co-culturing (i); the application of the conditioned medium from the co-cultured cells (ii); and treating PC3 cells with recombinant IL-4 (iii) resulted in a robust fusion between PC3 cells, in a significant increase in the percentage of PC3 cells expressing stem cell marker CD133, in the drug resistance, in an increase of the expression of mesenchymal-characteristic markers pAKT, MMP9, desmin, and in the loss of E-cadherin that is another marker for EMT. The described effects required co-culturing of the PC3 cells and muscle cells. Moreover, the co-culturing and recombinant IL-4 application also upregulated the expression of the two proteins - annexin A5 and syncytin that play important role in several cell-cell fusion processes. Significantly, application of either (i) IL-4-neutralizing antibodies or (ii) peptide inhibitors of syncytin; and (iii) lowering annexin A5 expression suppressed cell proliferation and fusion. Our findings substantiate a hypothesis that IL-4 and IL-13 in the microenvironment of PCa cells promote the EMT and raise metastatic potential of PCa cells by their fusion mediated by upregulated syncytin- and annexin A5. Citation Format: Berna Uygur, Evgenia Leikina, Leonid Chernomordik. IL-4 / IL-13 mediated cell-to-cell fusion in prostate cancer progress. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 925.
Abstract 71: Cas9 protein engineering for cell cycle-specific genome editing to enhance homology directed repair
Authors: Tony Gutschner, Monika Hämmerle, Giannicola Genovese, Giulio F. Draetta, Lynda Chin
Journal: Cancer Research (2016)

Abstract The comprehensive and coordinated efforts of The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) identified the somatic genomic alterations occurring in a broad panel of human cancers. The challenge ahead is to understand the functions of these somatically altered genes.Genome editing tools like the CRISPR/Cas9 system represent a transformative technology that allows the precise engineering of cells harboring specific (point) mutations found in specific tumor subtypes, enabling the investigation of the role of a candidate cancer gene in a stringently defined genetic context. Once recruited to its DNA target sequence in cells, Cas9 induces a DNA double strand break (DSB), which is either repaired by the non-homologous end-joining pathway (NHEJ), or by homology-directed repair (HDR). The HDR pathway allows for a precise site-specific knock-in and thus functional analysis of cancer-associated sequence variants. However, HDR activity is restricted to the late S and G2 phases of the cell cycle, while the NHEJ pathway dominates DNA repair throughout the cell cycle. Thus, the error-prone NHEJ pathway out-competes the HDR pathway, which reduces the likelihood for precise insertions, deletions or base substitutions at the DSB. Here, we devised a strategy to increase HDR by directly synchronizing the expression of Cas9 with cell cycle progression. Fusion of Cas9 to the N-terminal region of human Geminin converted this gene-editing protein into a substrate for the E3 ubiquitin ligase complex APC/Cdh1 resulting in a cell cycle tailored expression with low levels in G1, but high expression in S/G2/M. Importantly, Cas9-hGem(1/110) increased the relative rate of HDR by up to 87% at a single-copy reporter locus, and up to 42% at the endogenous MALAT1 locus compared to wild-type Cas9. In summary, our regulatory concept takes advantage of cell-autonomous pathways to enable fluctuation of Cas9 protein levels coupled to cell cycle dynamics. This resulted in higher site-specific integration events without sophisticated manipulation of cells by small molecules or additional gene targeting reagents. Future methodological developments may enable high-resolution expression of Cas9 and alternative genome engineering proteins like Cpf1 by combining cell cycle phase-specific transcriptional and post-translational regulatory elements. This might enhance HDR efficiencies even further, and will help to make sense of cancer genomic data. Citation Format: Tony Gutschner, Monika Hämmerle, Giannicola Genovese, Giulio F. Draetta, Lynda Chin. Cas9 protein engineering for cell cycle-specific genome editing to enhance homology directed repair. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 71.
Abstract 4122: Ceramide is a key factor that regulates the crosstalk between TGF-ß and sonic hedgehog signaling at the basal cilia to control cell migration and tumor metastasis
Authors: Salih Gencer, Natalia Oleinik, Mohammed Dany, Besim Ogretmen
Journal: Cancer Research (2016)

Abstract Recent studies indicate that ceramide species with different fatty-acid chain lengths play diverse biological functions in various cellular processes, highlighting the importance of ceramide synthases (CerS) in these processes. Migration and cell mobility, a part of these processes, also are effected by ceramide metabolism. However, the molecular mechanism of CerS/and ceramide involved is unknown. Here, we investigated the effect of CerS/and ceramide on migration and its related signal pathways in situ and in vivo model. Interestingly, our data show that among CerS only CerS4/ceramide is involved to cell migration and tumor metastasis. Here, we also have generated CerS4-/- mice for in vivo studies. Interestingly, we observed that genetically loss of CerS4 resulted in severe irreversible alopecia, which was associated with hyper-proliferation and migration of keratinocytes. Mechanistically, we show here that genetic loss or shRNA-mediated knockdown of CerS4 enhances cell migration by which ligand-independent signaling of TGF-beta receptors I and II in various cell types, including keratinocytes, mouse embryonic fibroblasts and cancer cells. Moreover, we found that ceramide directly interact with Smad7 and this interaction was decreased by shRNA-mediated knockdown of CerS4. Thus, ceramide-Smad7 binding modulates plasma membrane association of TGF-ßR1 at primary basal cilia, and inhibits its signaling through Sonic-Hedgehog (Shh) for migration. Furthermore, Ceramide accumulation at the primary basal cilia was decreased by knockdown of CerS4. Thus, these data revealed that CerS4/ceramide signaling plays key roles in the regulation of cell migration and metastasis via controlling the TGF-ßR and Shh axis at primary basal cilia. Citation Format: Salih Gencer, Natalia Oleinik, Mohammed Dany, Besim Ogretmen. Ceramide is a key factor that regulates the crosstalk between TGF-ß and sonic hedgehog signaling at the basal cilia to control cell migration and tumor metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4122.
Abstract 2601: Gingerol aspirinate derivatives as novel chemopreventive agents for colon cancer
Authors: Yingdong Zhu, Fang Wang, Yantao Zhao, Pei Wang, Shengmin Sang
Journal: Cancer Research (2016)

Abstract Regular aspirin use has been convincingly shown to reduce the risk of colorectal cancer. However, long-term use of aspirin leads to gastrotoxicity. Herein, we designed and synthesized a novel class of gingerol- and shogaol-based aspirin prodrugs to simultaneously release aspirin and gingerol or shogaol to attenuate the side effects caused by aspirin. Prodrug GAS exerted enhanced anticancer activities, which are better than a physical mixture of aspirin and 6-gingerol as well as each individual. In addition, GAS eliminated the gastric toxicity induced by aspirin in mice. Metabolism of GAS in mice showed that the majority of GAS is decomposed to release 6-gingerol and aspirin or salicylic acid either in the intestine or after absorption. Mechanistic studies demonstrate GAS could dose-dependently inhibit COX pathway. These findings highlighted the improved anticancer properties of gingerol-based aspirin prodrugs. GAS may represent novel and safe alternatives of aspirin for the purpose of daily use in the future. Citation Format: Yingdong Zhu, Fang Wang, Yantao Zhao, Pei Wang, Shengmin Sang. Gingerol aspirinate derivatives as novel chemopreventive agents for colon cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2601.
An Enriched Multigen Low-Density Array To Predict Outcome in Advanced Hodgkin Lymphoma Paraffin-Embedded Samples.
Authors: Beatriz Sanchez-Espiridion, Abel Sanchez-Aguilera, Carlos Montalban, Monica Garcia-Cosio, Carmen Bellas, Vicente Romagosa, Javier Menarguez, Manuel F. Fresno, Jose F. Tomas, Manuel M. Morente, Miguel A. Piris, Juan F. Garcia
Journal: Blood (2007)
High Expression of LAG3, LPL and ZAP-70 Genes in B-CLL Strongly Correlates with Unmutated IgVH and Early Therapy Requirement.
Authors: Jana Kotaskova, Marek Mraz, Boris Tichy, Jitka Kabathova, Jitka Malcikova, Martin Trbusek, Hana Francova, Michael Doubek, Yvona Brychtova, Jiri Mayer, Sarka Pospisilova
Journal: Blood (2008)
Chemotherapy With CMF for Triple-Negative Breast Cancer With Carcinoma Erysipelatoides
Authors: Chi-Feng Yen, Hung-Bun Lam
Journal: JAMA Dermatology (2016)

create and maintain such an effective dressing, and that if more lesions were present, the task would be more problematic, we suggest that compression bandaging may be an effective therapy for dissecting cellulitis in select, motivated patients.
Feline Leukemia Virus: Current Status and Future Trends1
Authors: Padman S. Sarma, Jack Gruber
Journal: JNCI Journal of the National Cancer Institute (1986)

Journal Article Feline Leukemia Virus: Current Status and Future Trends Get access Padman S. Sarma, Padman S. Sarma Search for other works by this author on: Oxford Academic PubMed Google Scholar Jack Gruber Jack Gruber Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 76, Issue 4, April 1986, Pages 774–777, https://doi.org/10.1093/jnci/76.4.774 Published: 01 April 1986
Seattle Regimen RIC-HSCT in Early-Phase Multiple Myeloma: A Multi-Centre Experience Demonstrating Very Low Treatment-Related Mortality and Rapid Graft-Versus-Myeloma Effect Associated with Graft-Versus-Host Disease
Authors: Michael J Shipton, David JM Routledge, Neil Bodagh, James Cavet, Eleni Tholouli, Samar Kulkarni, Simon DJ Gibbs
Journal: Blood (2015)
Sickle Cell Disease
Authors: Lydia H. Pecker, Sophie Lanzkron
Journal: Annals of Internal Medicine (2021)

Sickle cell disease is an umbrella term for a group of hemoglobinopathies characterized by the presence of 2 β-globin gene mutations or deletions, at least 1 of which is the point mutation that leads to the production of hemoglobin S. Sickle cell disease is associated with hemolytic anemia, significant chronic end-organ damage, and early death. In high-income countries, at least 95% of children with the disease survive into adulthood, resulting in a growing population of affected adults with significant comorbidities, complex medical issues, and not enough specialists to provide care. Hydroxyurea is the primary therapy, and recent advances in understanding disease pathophysiology have led to new therapies; progress in bone marrow transplant and gene editing has resulted in cure in some patients. The purpose of this review is to provide an overview of the diagnosis, common acute and chronic clinical manifestations, and best practices for management of sickle cell disease.
Abstract 4602: A83-01 inhibits TGF-β/Smad3 and Wnt/β-catenin-mediated EMT and tumor metastasis in HER2-overexpressing breast cancer cells
Authors: Yanyuan Wu, Tran Trinh, Marianna Sarkissyan, Sami Dwabe, Juri Kim, Robin Farias-Eisner, Jay Vadgama
Journal: Cancer Research (2016)

Abstract Interactions between Wnt and TGF-β (Transforming growth factor-β) signaling pathways play a critical role in promoting EMT (Epithelial to Mesenchymal Transition) and tumor metastasis. We previously demonstrated that activation of Wnt3/β-catenin signaling pathway promoting EMT is an important mechanism leading to HER2-cells becoming resistant to trastuzumab. In this study, we used HER2-overexpressing breast cancer cells to investigate the interactions between TGF-β and Wnt/β-catenin pathways in regulation of EMT and promoting breast cancer cells invasion. Our data showed that phosphorylation of Smad3 at ser423/425 by TGF-β led to nuclear localization of Smad3 and upregulation of Twist protein expression in HER2-overexpressing breast cancer cells. Cells treated with TGF-β showed poor response to trastuzumab and exhibited EMT-like phenotype; decreased E-cadherin and increased N-cadherin expression. A small molecule inhibitor, A83-01 which inhibits phosphorylation of Smad3 repressed TGF-β-induced nuclear accumulation of Smad3 and Twist expression. The A83-01 also inhibited TGF-β-induced cell migration and invasion and enhanced anti-tumor activity of trastuzumab. The TGF-β/Smad3 induced EMT in HER2-cells was found to be concordant with activation of Wnt3/β-catenin pathway. Following TGF-β treatment, Chromatin immunoprecipitation identified occupancy of Twist at promoter region of Wnt3. This data suggests that Twist in response to TGF-β activated Wnt3 gene transcription in HER2-overexpressing breast cancer cells. Knock-down of Twist by shRNA down-regulated Wnt3 expression and inhibited TGF-β-induced nuclear accumulation of β-catenin. Subsequently, TGF-β-induced matrix metalloproteinases, MMP1, MMP7, MMP9, VEGF (Vascular endothelial growth factors) and activation of Wnt/β-catenin signaling were repressed by the shRNA treatment. In summary, our data demonstrated for the first time that the TGF-β/Smad3 mediated Twist results in transcriptional upregulation of Wnt3/β-catenin pathway and promotes EMT and cell invasion. The data suggests that therapeutic targeting of Twist by A83-01 and similar small molecules could inhibit the interaction between TGF-β and Wnt pathways and prevent breast cancer progressing to EMT and metastases. Citation Format: Yanyuan Wu, Tran Trinh, Marianna Sarkissyan, Sami Dwabe, Juri Kim, Robin Farias-Eisner, Jay Vadgama. A83-01 inhibits TGF-β/Smad3 and Wnt/β-catenin-mediated EMT and tumor metastasis in HER2-overexpressing breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4602.
Reducing Uncertainties About the Effects of Chemoradiotherapy for Cervical Cancer: A Systematic Review and Meta-Analysis of Individual Patient Data From 18 Randomized Trials
Journal: Journal of Clinical Oncology (2008)

Background After a 1999 National Cancer Institute (NCI) clinical alert was issued, chemoradiotherapy has become widely used in treating women with cervical cancer. Two subsequent systematic reviews found that interpretation of the benefits was complicated, and some important clinical questions were unanswered. Patients and Methods We initiated a meta-analysis seeking updated individual patient data from all randomized trials to assess the effect of chemoradiotherapy on all outcomes. We prespecified analyses to investigate whether the effect of chemoradiotherapy differed by trial or patient characteristics. Results On the basis of 13 trials that compared chemoradiotherapy versus the same radiotherapy, there was a 6% improvement in 5-year survival with chemoradiotherapy (hazard ratio [HR] = 0.81, P &lt; .001). A larger survival benefit was seen for the two trials in which chemotherapy was administered after chemoradiotherapy. There was a significant survival benefit for both the group of trials that used platinum-based (HR = 0.83, P = .017) and non–platinum-based (HR = 0.77, P = .009) chemoradiotherapy, but no evidence of a difference in the size of the benefit by radiotherapy or chemotherapy dose or scheduling was seen. Chemoradiotherapy also reduced local and distant recurrence and progression and improved disease-free survival. There was a suggestion of a difference in the size of the survival benefit with tumor stage, but not across other patient subgroups. Acute hematologic and GI toxicity was increased with chemoradiotherapy, but data were too sparse for an analysis of late toxicity. Conclusion These results endorse the recommendations of the NCI alert, but also demonstrate their applicability to all women and a benefit of non–platinum-based chemoradiotherapy. Furthermore, although these results suggest an additional benefit from adjuvant chemotherapy, this requires testing in randomized trials.
Updated analysis of NCIC CTG MA.17 (letrozole vs. placebo to letrozole vs placebo) post unblinding
Authors: N. J. Robert, P. E. Goss, J. N. Ingle, D. Tu, L. Shepherd, M. Palmer, J. Pater
Journal: Journal of Clinical Oncology (2006)

550 Background: 5187 postmenopausal women were originally randomized to NCIC CTG MA.17 to receive letrozole (LET) or placebo (PLAC) after 5 years of tamoxifen. The hazard ratio (HR) for disease-free survival (DFS) was 0.58 (0.450.76, p=0.00004) after a median follow-up of 30 months (mo). The trial was unblinded in October 2003 after the first interim analysis. Women randomized to PLAC were offered LET at the time of unblinding. The goal of this analysis was to determine whether women switching from PLAC to LET benefit in terms of disease outcome and to evaluate treatment related toxicities. Methods: LET and PLAC-LET have been compared to PLAC, based on the hazard ratio and adjusting for baseline patient and disease variables including, among others, tumor size, nodal status and prior adjuvant chemotherapy. Results: Information about their follow-up treatment after unblinding was available on 2268 women originally assigned to PLAC and who were free of recurrence and alive at the time of unblinding. Among them, 1655 crossed over from PLAC to LET while 613 elected no treatment. With 54 mo f/up the HR for DFS was 0.31 (0.18, 0.55: p&lt;0.0001) favoring patients who crossed over to LET compared to those who stayed on no treatment. The treatment switch was well tolerated with no significant difference in bone fractures or cardiovascular events. An updated analysis of DFS, DDFS and OS by nodal and tumor receptor status, prior chemotherapy, menopausal status at the start of tamoxifen, and duration of prior tamoxifen therapy will be presented at the meeting. Conclusion: Women with hormone dependent breast cancer prescribed LET after a prolonged delay from completing tamoxifen experienced a significant improvement in outcome (DFS, DDFS, OS) and should be considered for this therapy. [Table: see text]
A Distinct Immunophenotypic Profile Of Del(5q) MDS Allows For Fast Monitoring Of Response To Treatment With Lenalidomide Or Azacitidine
Authors: Uta Oelschlaegel, Brigitte Mohr, Michael Kramer, Stefani Parmentier, Katja Sockel, Christian Thiede, Martin Bornhäuser, Gerhard Ehninger, Uwe Platzbecker
Journal: Blood (2013)
Phase 2 study of aldoxorubicin in relapsed glioblastoma.
Authors: Morris D. Groves, Jana Portnow, Brian C. Boulmay, Sant P. Chawla, Hillary Dinh, Shanta Chawla, Scott Wieland, Daniel J. Levitt
Journal: Journal of Clinical Oncology (2016)

2027 Background: Glioblastoma (GBM) is the most common primary brain tumor with a median survival of ~14 months after initial therapy. Relapsed patients usually receive bevacizumab with an ORR of~20%, and OS of ~31 weeks. Recently Prakash et al demonstrated in an orthotopic mouse model of GBM that IV aldoxorubicin (A) but not doxorubicin (D) significantly delayed tumor growth and prolonged survival by over 100%. D does not pnetrate the blood-brain barrier. A is a prodrug of D that is attached to a pH sensitive linker that binds covalently to albumin and is released preferentially within tumors. We assessed the preliminary efficacy and safety of A administered to GBM patients who progressed after first line therapy. Methods: Patients > 18 yrs with 1st relapse GBM received either 250 mg/m2 (21) or 350 mg/m2(7) every 21 days until tumor progression, unacceptable toxicity or withdrawal. Tumors were assessed every 6 weeks by MRI and in some instances Dynamic Susceptibility Contrast (DSC) MRI. Safety monitoring included serum chemistries and CBC prior to each infusion and echocardiograms every 2 molnths. Results: Median age was 56 yrs (28-73); 19 females and 9 males. Subjects received 1-20 cycles of treatment. Median drug exposure for the 250 mg/m2 dose is 1042 mg/m2 D equivalents (Deq) (range 371-5768 mg/m2 Deq) and for the 350 mg/m2 dose is 1912 mg/m2 Deq (range 472-3647 mg/m2Deq). Best responses in 21 subjects according to MRI were 3 PR, 7 SD and 11 PD. Median overall survival has not been reached (range is 0.5-17.3+ months) with median f/u of 7 months (1-17+ months). Major grade 3 or 4 AEs include neutropenia (6 subjects) febrile neutropenia (2 subjects) mucositis (2 subjects), thrombocytopenia (2 subjects) and anemia (2 subjects). 2 subjects experienced treatment-related SAEs. No subjects had a decrease in their LVEF below 50% of expected values.Two subjects with apparent PD by scan underwent tumor debulking and had no microscopic evidence of disease. Another subject demonstrated no active malignancy upon DSC MRI scanning. Conclusions: Unlike doxorubicin, Aldoxorubicin appears to penetrate the blood-brain barrier in humans and is associated with objective tumor responses, stable disease and prolonged survival. Pseudoprogression occurs and may confuse responsiveness to A. Clinical trial information: NCT02014844.
Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming
Authors: Young Chan Chae, Valentina Vaira, M. Cecilia Caino, Hsin-Yao Tang, Jae Ho Seo, Andrew V. Kossenkov, Luisa Ottobrini, Cristina Martelli, Giovanni Lucignani, Irene Bertolini, Marco Locatelli, Kelly G. Bryant, Jagadish C. Ghosh, Sofia Lisanti, Bonsu Ku, Silvano Bosari, Lucia R. Languino, David W. Speicher, Dario C. Altieri
Journal: Cancer Cell (2016)