tbuckley/cabot-search huggingface dataset:
Abstract 2278: The hypusine cascade promotes cancer progression and metastasis through the regulation of RhoA in squamous cell carcinoma
Authors: Tomoki Muramatsu, Ken-ichi Kozaki, Seiya Imoto, Rui Yamaguchi, Hitoshi Tsuda, Tatsuyuki Kawano, Maki Morishita, Satoru Miyano, Johji Inazawa
Journal: Cancer Research (2015)

Abstract Metastasis is one of the critical factors contributing to poor prognosis in cancer, but the mechanisms are poorly understood. We established a highly metastatic subline (HOC313-LM) derived from an oral squamous cell carcinoma cell line (HOC313) for uncovering the metastatic mechanisms. We identified deoxyhypusine synthase (DHPS) as a metastasis-related gene through the specific amplification at 19p13.2-p13.13 in the HOC313-LM. Overexpression of DHPS promoted cell motility, invasion and metastasis through activation of the RhoA signaling pathway, and increased the tumor formation in vivo. We also demonstrated that eukaryotic translation factor 5A (eIF5A) bound to RhoA mRNA and regulated its translation. Moreover, GC7, a DHPS inhibitor, showed significant decrease in the tumor formation in vivo. In patients with esophageal squamous cell carcinoma (ESCC), overexpression of DHPS in ESCC tumors was significantly associated with worse recurrence-free survival, and correlated with distant metastasis. Our elucidation of these molecular mechanisms within the hypusine cascade suggests opportunities for novel therapeutic targets in SCC. Citation Format: Tomoki Muramatsu, Ken-ichi Kozaki, Seiya Imoto, Rui Yamaguchi, Hitoshi Tsuda, Tatsuyuki Kawano, Maki Morishita, Satoru Miyano, Johji Inazawa. The hypusine cascade promotes cancer progression and metastasis through the regulation of RhoA in squamous cell carcinoma. [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 2278. doi:10.1158/1538-7445.AM2015-2278
Abstract 3438: Whole pelvis versus prostate-only radiotherapy with or without short course androgen deprivation therapy and mortality risk
Authors: Lior Z. Braunstein, Ming-Hui Chen, Daniel E. Dosoretz, Sharon Salenius, Michael Katin, Akash Nanda, Anthony V. D'Amico
Journal: Cancer Research (2015)

Abstract Purpose: To determine whether extent of prostate radiotherapy (i.e. whole-pelvic radiotherapy (WPRT) versus prostate/seminal-vesicle radiotherapy [PSVRT]) is associated with all-cause mortality (ACM) in men treated with or without androgen deprivation therapy (ADT). Methods: A multi-institutional cohort of 3,709 prostate cancer patients was prospectively assembled from 1991-2006. Median age was 72 years and all patients had T1c-T3N0M0 adenocarcinoma of the prostate. Patients were treated with WPRT or PSVRT followed by a brachytherapy boost, with or without neoadjuvant ADT (median duration 4.2months). 70% of patients had unfavorable-risk disease (Gleason ≥7; PSA ≥10ng/mL; or stage ≥T2b). Cox regression was applied to determine whether the radiation treatment volume affected the risk of ACM. A test for interaction between radiation volume and ADT use was conducted. Results: After a median follow-up of 3.3 years, 561 deaths were observed. A decreased risk of ACM was noted with the use of WPRT versus PSVRT (adjusted hazard ratio [AHR] 0.58; 95% confidence interval [CI] 0.38-0.89; p = 0.01), or with ADT (AHR 0.71; 95%CI 0.58-0.90; p = 0.004). However, combining WPRT and ADT did not further improve ACM in comparison to either WPRT alone or PSVRT with ADT. Moreover, there was a significant interaction between the RT treatment volume and ADT (AHR 1.61; 95%CI 1.004-2.58; p = 0.048). Conclusions: Treatment with WPRT or short-course ADT is associated with a decreased risk of ACM, though combining the two does not yield greater benefit. This observation suggests a shared mechanism for this risk-reduction which we hypothesize to be sterilization of micrometastatic disease within the pelvic lymph nodes. Citation Format: Lior Z. Braunstein, Ming-Hui Chen, Daniel E. Dosoretz, Sharon Salenius, Michael Katin, Akash Nanda, Anthony V. D'Amico. Whole pelvis versus prostate-only radiotherapy with or without short course androgen deprivation therapy and mortality risk. [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 3438. doi:10.1158/1538-7445.AM2015-3438
Pertussis Response to Tdap (8 mcg/dose of the Pertussis Toxoid (PT) In Recipients of Allogeneic Hematopoietic Stem Cell Transplants (Allo HSCT).
Authors: Esperanza Papadopoulos, Christine Scurra Iovino, Molly Knowles, Juliet Barker, Andromachi Scaradavou, Nancy A Kernan, Trudy N Small
Journal: Blood (2010)
Weighing Risk of Cardiovascular Mortality Against Potential Benefit of Hormonal Therapy in Intermediate-Risk Prostate Cancer
Authors: Nataniel H. Lester-Coll, Skyler Johnson, William J. Magnuson, Samuel Z. Goldhaber, David J. Sher, Anthony V. D’Amico, James B. Yu
Journal: JNCI Journal of the National Cancer Institute (2016)

The purpose of this study is to determine the optimal strategy for men with newly diagnosed intermediate-risk prostate cancer by age and cardiac risk.A Markov model was calibrated to the EORTC 22991 trial, which randomly assigned men with intermediate-risk prostate cancer to radiation therapy (RT) with or without six months of hormonal therapy (HT). We compared quality-adjusted life-years (QALYs) in men age 50, 60, and 70 years by age decile and cardiac risk group. Competing risks of cardiovascular mortality were estimated from the published literature. Sensitivity analyses were used to assess the impact of varying model assumptions.HT was associated with a net decrease of 0.3 to 0.4 QALYs in men with a history of myocardial infarction. However, for all other men, HT improved QALYs (range = 0.4-2.6 QALYs). Younger men with fewer cardiac risk factors experienced the largest benefit from HT. In sensitivity analyses, the model was only found to be sensitive to the probability of biochemical failure. Men at low risk for biochemical failure (≤8.7% at five years) did not benefit from HT. Further, the benefits of HT did not begin to manifest until after 7.3 years of follow-up.The optimal choice of therapy depends upon age, cardiac risk, and disease recurrence risk. Young men with intermediate-risk prostate cancer with no cardiac risk factors benefit most from HT. Men with a history of myocardial infarction who are at very low risk for biochemical failure may be negatively impacted by the addition of HT.
348. Correction of CNS and Somatic Pathology by Intra-Cerebrospinal Fluid Gene Therapy for Mucopolysaccharidosis Type II
Authors: Virginia A. Haurigot, Sandra Motas, Sara Marcó, Albert Ribera, Carles Roca, Xavier Sánchez, Miquel García, Maria Molas, Victor Sánchez, Xavier León, Jesús Ruberte, Fatima Bosch
Journal: Molecular Therapy (2016)

Mucopolysaccharidosis type II (MPSII), or Hunter Syndrome, is a X-linked recessive Lysosomal Storage Disease (LSD) caused by deficiency in Iduronate-2-sulfatase (IDS), an enzyme involved in the stepwise degradation of the glycosaminoglycans (GAGs) heparan sulfate (HS) and dermatan sulfate (DS). GAG storage builds up in the CNS and peripheral tissues causing severe neurologic and multisystemic somatic disease. Patients usually die during the second decade of life. Periodic intravenous enzyme replacement therapy (ERT) currently constitutes the only approved therapeutic option for MPSII. However, the inability of recombinant IDS to efficiently cross the blood-brain barrier limits the efficacy of the approach in treating neurological symptoms. Alternatively, the periodic infusion of ERT to the cerebrospinal fluid is under clinical testing, but serious adverse events associated with the use of intrathecal drug delivery devices have been reported. Here we report a gene therapy approach directly addressing the CNS pathology of MPSII. Through a minimally invasive procedure we delivered adeno-associated virus vectors of serotype 9 encoding IDS (AAV9-Ids) to the CSF of MPSII mice with already established disease. Four months after vector administration, treated mice showed a significant increase in IDS activity throughout the encephalon, with full resolution of lysosomal storage lesions, reversal of lysosomal dysfunction, normalization of the brain transcriptomic signature and disappearance of neuroinflammation. Moreover, our approach not only resulted in widespread distribution of vector in the CNS but also in liver transduction, providing a peripheral source of therapeutic protein that corrected the storage disease in visceral organs, with evidence of cross-correction of non-transduced organs by circulating enzyme. Importantly, MPSII mice treated with AAV9-Ids also showed normalization of behavioural deficits. These results provide a strong proof of concept for the clinical translation of our approach for the treatment of Hunter patients with cognitive impairment.
Abstract 4112: Mechanisms of transendothelial migration by invasive breast carcinoma cells from patients
Authors: Jeanine Pignatelli, Joan Jones, Xiaoming Chen, Bryan Smith, Daniel Flynn, John Condeelis, Maja Oktay
Journal: Cancer Research (2015)

Abstract The majority of breast cancer related deaths are not due to the primary tumor, but rather to the dissemination of metastatic tumor cells from it to distant sites. Our lab has previously identified the tumor microenvironment of metastasis (TMEM) in mouse and human mammary tumors, sites where transendothelial migration, intravasation and dissemination occur. The constituent cells of TMEM are an endothelial cell, a perivascular TIE2-expressing macrophage (TEM) and an invasive Mena-over expressing tumor cell in direct contact. TMEM are present in human invasive breast tumors and the density of TMEM is positively associated with the risk of developing metastases. Using invasive ductal carcinoma cells of the breast obtained from patients by fine needle aspiration (FNA), we demonstrated that intravasation-directed transendothelial migration (iTEM) of these cancer cells requires macrophages and, depending on clinical subtype, involves either paracrine (macrophage CSF1-R; tumor cell EGFR), or both paracrine and autocrine (tumor cell EGFR + CSF1-R) signaling. Compared to the total population of primary breast cancer cells assayed, cells capable of transendothelial migration expressed relatively high MenaINV and low Mena11a levels, independently of clinical subtype. MenaINV and Mena11a are functionally distinct isoforms of Mena, a key regulator of motility and invasion. Depletion of MenaINV using siRNA showed that MenaINV is required for efficient macrophage-dependent iTEM of tumor cells. Furthermore, relative MenaINV expression correlated with the density of TMEM, which were previously shown to correlate with risk of metastasis in patients. From these observations we have identified the signaling pathways involved in macrophage-dependent tumor cell iTEM. Two novel small molecule inhibitors, Rebastinib (Tie2 inhibitor) and Altiratinib (c-MET inhibitor), have been identified that show great promise in preventing key steps in iTEM. Our data reveal targetable signaling events required for transendothelial migration of human breast cancer cells, and indicate that relative MenaINV levels and TMEM frequency are correlated prognostic markers of metastasis and therapeutic targets for most human breast cancers. Citation Format: Jeanine Pignatelli, Joan Jones, Xiaoming Chen, Bryan Smith, Daniel Flynn, John Condeelis, Maja Oktay. Mechanisms of transendothelial migration by invasive breast carcinoma cells from patients. [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 4112. doi:10.1158/1538-7445.AM2015-4112
104. Development of Mitotically Stable Third Generation Adenoviral Vectors for Applications in Rapidly Dividing Cells
Authors: Philip Boehme, Erik Schulz, Wenli Zhang, Martin Mueck-Haeusl, Anja Ehrhardt
Journal: Molecular Therapy (2015)

Since the ex vivo strategies using lentiviral vectors have shown great success, vectors need to be explored aiming at long-term transgene expression in vivo in dividing cells. In order to attain this objective, we are developing two independent viral vector systems. Both hybrid systems are based on third generation high-capacity adenoviral vectors (HCAdV), which mainly have three advantages: Highest transgene capacity of all viral vectors (36kb), low toxicity (no viral genes encoded), and tissue specificity (several serotypes are available). Since adenoviral vectors are predominantly episomally maintained we combined them either with a S/MAR (scaffold/matrix attachment region) system for episomal persistence or SB100X, a transposase based integration machinery. HCAdV-SB100X is the latest version of a series of HCAdV-SB hybrid vectors developed from our group. The gene of interest (GOI) is flanked by inverted repeat sequences and after FLP mediated circularization it is mobilized and integrated in a "copy and paste" manner into one out of ~2,000,000 AT dinucleotides present in the human genome. After performing colony forming assays we could show that our latest vector HCAdV-SB100 is more than a 100-fold more active compared to the negative control HCAdV-mSB and it shows nearly 10-fold increased activity compared to the precursor version HCAdV-HSB5 in forming blasticidin resistant colonies. We performed experiments in U-87 glioblastoma and A549 adenocarcinoma cells. HCAdV-SB100X showed for all conditions an increased number of copiess per cell of the GOI compared to HCAdV-HSB5. We observed a strong "overproduction inhibition effect" for SB100X also described in the literature, which means that by increasing the ratio between SB and the GOI less integration events leading to resistant colonies occur. This is why we are currently testing optimal ratios between transposon and transposase to achieve a maximum amount of resistant colonies. The second vector system (HCAdV-SMAR) carrying the identical transgene as for the SB100X system is thought to function via sequence-moderated binding to matrix proteins mediating extrachromosomal retention and replication. Using an improved molecular design we could show that HCAdV-SMAR is forming a significantly higher number of mitotically active balsticidin resistant colonies in various cell lines compared to a negative control without SMAR. For both vector systems results from qPCR studies revealed significantly higher transgene copy numbers per cell for the SB100X system (up to 20 copies per cell) and for the S/MAR system (up to 10 copies per cell). By combining both vectors with newest adenoviral targeting technologies and strategies for adenoviral immune escape we are now able to evaluate both vectors carrying the same transgene under different in vivo conditions in a direct manner for different disease models.
635. Effects of Mechanical Strain on Zmpste24-Deficient Prematurely Aged Muscle-Derived Stem Cells
Authors: Andrea Liebowitz, Elizabeth Morris, Alex Scibetta, Xiaodong Mu, Johnny Huard
Journal: Molecular Therapy (2016)

Mice deficient in Zmpste24, a metalloproteinase involved with formation of lamin A, are a model for aging and for Hutchinson-Gilford Progeria Syndrome, a human disorder caused by a similar defect. Z24-/- muscle-derived stem cells (MDSCs) are defective in proliferation and differentiation potential. Stretching stem cells prior to implantation has been shown to improve outcomes. Based on these results, stretching may be able to rejuvenate aged stem cells. Therefore, examining the response of stretched and non-stretched Z24-/- MDSCs to stress can show if stretching rescues some of the negative processes involved with aging. Z24-/- MDSCs were seeded on BioFlex plates (Flexcell Inc) at a density of 50,000 cells per well. Cells were stretched for 24 hours with 10% uniaxial elongation and a 0.5Hz frequency. Z24-/- mice had increased cell senescence and muscle stem cell depletion in the skeletal muscle. Muscle stem cells isolated from Z24-/- mice have increased activation of ROS (reactive oxygen species). Cells mechanically strained for 24 hours appeared to be more resistant to oxidative stress and express higher levels of RhoA, which is a mediator of cell stress: more senescent cells were observed in the non-flexed vs. flexed groups under standard conditions and under oxidative stress. The flexed cells also had a better survival rate following oxidative stress for 24h. These results indicate that flexing compensates for some of the progeria phenotype. Flexing appears to prime the cells so they are more resistant to stressors like H2O2. The lower number of senescent flexed vs. non-flexed cells seems to indicate that the flexing protects the cells from entering senescence. Mechanical strain also appears to give the cells greater resistance to reactive oxidative species. PCR results of TNE-α showed that non-flexed cells expressed the pro-inflammatory cytokine 1.33-fold compared to flexed cells. This indicates that mechanical stimulation may improve the cells' response to stressors and reduce inflammation. These preliminary results indicate that mechanical strain may rejuvenate and rescue the cells from defects in cell proliferation and differentiation. Based on these results, flexing cells in vitro may improve the quality and outcome of stem cells implanted into patients, especially in older donors whose cells may behave similar to the Z24-/- cells.
Adult Philadelphia-Positive Acute Lymphoblastic Leukemia (Ph + ALL) Treated at Diagnosis with Imatinib Followed by 2nd Line TKI (Imatinib or Dasatinib) and Stem Cell Transplantation.
Authors: A. M. Carella, G. Catania, G. Pica, G. Beltrami, S. Nati, R. Vimercati, A. Congiu, E. Rossi, M. Spriano
Journal: Blood (2009)
Infantile Paralysis: Anterior Poliomyelitis
Journal: JAMA (1941)

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Abstract 163: Genetic Basis of Isoproterenol-Induced Cardiac Fibrosis
Authors: Christoph D Rau, Rozeta Avetisyan, Dorit Stein, Milagros Romay, Jessica Wang, Yibin Wang, Aldons J Lusis
Journal: Circulation Research (2014)

Background: Cardiac fibrosis is a common pathology in the diseased heart, which can cause a loss of elasticity and contractile dysfunction. Cardiac fibrosis is a complex process driven by many pathological triggers which involve numerous genes, pathways and cell types. Despite its importance, the genetic basis for the development of cardiac fibrosis has not been systematically explored. Methods and Results: We have developed a resource, the Hybrid Mouse Diversity Panel (HMDP) for high resolution GWAS and systems genetics study of quantitative traits in mice. Eight week old female mice from 80 unique inbred strains of the HMDP were given 30 ug/g/day of isoproterenol (ISO) for three weeks and cardiac fibrosis was assessed by Masson Trichrome staining which revealed a wide spectrum in the degree of fibrosis among the HMDP strains both before and after treatment. Using the Efficient Mixed Model Algorithm, we identified 13 significant or suggestive loci contributing to cardiac fibrosis, many containing numerous gene candidates. Within one of these loci, Abcc6, an orphan ABC transporter linked to the human disease pseudoxanthoma elasticum, was identified as a possible candidate for ISO-induced cardiac fibrosis. A splice-site mutation present in 19 strains of the HMDP was significantly linked to a higher degree of ISO-induced cardiac fibrosis(P=1E-4) but was not linked to increased fibrosis in untreated animals(P=0.25). Targeted genetic knockout of Abcc6 promoted ISO-induced cardiac fibrosis while reintroducing the wildtype Abcc6 allele to an genetic strain homozygous for the Abcc6 splice site mutation significantly alleviated ISO-induced cardiac fibrosis. Conclusion: A GWAS performed on levels of cardiac fibrosis observed in ISO treated animals using HMDP mice as model system uncovered significant genetic contributions to stress-induced cardiac fibrosis. Abcc6 is a novel gene contributing to ISO-induced cardiac fibrosis in the heart.