tbuckley/cabot-search huggingface dataset:
383. Clinico-Pathological Correlation in the Earliest Stages of Muscular Dystrophy Suggests Sensitive Physiological Parameters as Novel Primary Endpoints for Systemic Gene Therapy
Authors: Benjamin W. Kozyak, Andy Mead, Yafeng Song, Leon Morales, Joe Kornegay, Hansell H. Stedman
Journal: Molecular Therapy (2016)

The clinical progression of Duchenne Muscular Dystrophy (DMD) begins with locomotive symptoms in childhood but eventually includes symptoms of severe cardiorespiratory failure. Our studies in mdx mice and GRMD dogs have reavealed surprisingly large early deficits in physiological reserve, attributable to the deficiency of dystrophin. In young GRMD dogs, the findings of diaphragmatic fibrosis and myofiber shortening correlated strongly with non-invasively measured abnormalities in respiratory muscle recruitment. In juvenile GRMD dogs without clinical signs of heart failure, detailed studies of cardiac mechanics revealed profoundly abnormal Frank-Starling and inotropic responses. Thus, submaximal exercise loading has the capactiy to reveal very early, otherwise subclinical deficits in physiological reserve. We have utilized several non-invasive systems to measure integrative cardiopulmonary mechanics in animals trained to undertake submaximal volitional exercise. Our findings demonstrate the possibility of continuous non-invasive monitoring of cardiac output, stroke volume, systemic vascular resistance, and several ventilatory parameters in young dogs and children during treadmill exercise, as well as upright and recumbent bicycling at work outputs appropriate for low risk serial testing in the earliest stages of DMD. As the field contemplates primary endpoints for use in trials of systemic gene therapy, these metrics hold promise as the most sensitive measurements of the earliest functional deficits in organ systems eventually responsible for the lethality of DMD.
Decision Zone at the Margins of Life and Good Health: The Role of Medical Staff Guidelines for the Care of Extremely Early Gestation Pregnancies and Premature Infants
Authors: Kevin M. Dirksen, Joseph W. Kaempf, Mark W. Tomlinson, Nicole M. Schmidt
Journal: The American Journal of Bioethics (2016)

Some physicians would offer or recommend comfort care in periviability situations where others routinely provide fetal resuscitation and neonatal intensive care unit (NICU) care (Peerzada, Richards...
LEF1 Gene Mutations In Childhood T-Cell Acute Lymphoblastic Leukemia and T Cell Non-Hodgkin's Lymphoma
Authors: Myoung-ja Park, Nobutaka Kiyokawa, Motohiro Kato, Nobuhiro Suzuki, Megumi Oda, Junichi Hara, Ryoji Kobayashi, Keizo Horibe, Seiji Ogawa, Yasuhide Hayashi
Journal: Blood (2010)
Abstract 208: Novel intracellular Doppler imaging predicts therapeutic efficacy for personalized medicine
Authors: John J. Turek, Dan Merrill, Michelle Custead, Michael Childress, David D. Nolte, Bakhtiyor Yakubov, Ran An, Daniela Matei
Journal: Cancer Research (2015)

Abstract This study reports first application of biodynamic imaging (BDI), a novel Doppler imaging technology, in studies of ovarian cancer xenografts and preclinical trials of canine multicentric lymphoma responding to doxorubicin. In a study of A2780 human ovarian cell lines implanted in mice, an unexpected and large difference was discovered between mouse tumor explants versus A2780 cells grown as 3D tumor spheroids. The biopsied explants from mice were three times more sensitive to platinum, applied in vitro, than were multicellular tumor spheroids. A preclinical trial has been completed for canine non-Hodgkins lymphoma using BDI to predict patient outcome under doxorubicin therapy. The 3D imaging capability of BDI enabled the measurement of tumor heterogeneity in response to the therapy. The biodynamic assay took only 24 hours to complete, while the clinical outcome was often unknown for one to several months. The therapeutic efficacy of doxorubicin was predicted by BDI with 90% accuracy. Based on this success, biodynamic imaging is entering human pilot trials in ovarian, pancreatic, and esophageal cancer. Biodynamic imaging is a radically different approach to the prediction of therapeutic efficacy for personalized medicine with higher accuracy and more biological relevance than standard cell-based assays. Supported in part by NIH NIBIB 1R01EB016582-01. Citation Format: John J. Turek, Dan Merrill, Michelle Custead, Michael Childress, David D. Nolte, Bakhtiyor Yakubov, Ran An, Daniela Matei. Novel intracellular Doppler imaging predicts therapeutic efficacy for personalized medicine. [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 208. doi:10.1158/1538-7445.AM2015-208
Group-Wide, Prospective Study of Ototoxicity Assessment in Children Receiving Cisplatin Chemotherapy (ACCL05C1): A Report From the Children’s Oncology Group
Authors: Kristin R. Knight, Lu Chen, David Freyer, Richard Aplenc, Mary Bancroft, Bonnie Bliss, Ha Dang, Biljana Gillmeister, Eleanor Hendershot, Dale F. Kraemer, Lanie Lindenfeld, Jane Meza, Edward A. Neuwelt, Brad H. Pollock, Lillian Sung
Journal: Journal of Clinical Oncology (2017)

Purpose Optimal assessment methods and criteria for reporting hearing outcomes in children who receive treatment with cisplatin are uncertain. The objectives of our study were to compare different ototoxicity classification systems, to evaluate the feasibility of including otoacoustic emissions and extended high frequency audiometry, and to evaluate a central review mechanism for audiologic results for cisplatin-treated children in the cooperative group setting. Patients and Methods Eligible participants were 1 to 30 years, with planned cisplatin-containing treatment. Hearing evaluations were conducted at baseline, before each cisplatin cycle, and at the end of therapy. Audiologic results were assessed and graded by the testing audiologist and by two central review audiologists using the American Speech-Language-Hearing Association Ototoxicity Criteria (ASHA), Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE), and Brock Ototoxicity Grades (Brock). One central reviewer also used the International Society of Pediatric Oncology Ototoxicity Scale (SIOP). Results At the end of treatment, the prevalence of any degree of ototoxicity ranged from 40% to 56%, and severe ototoxicity ranged from 7% to 22%. Compared with CTCAE, SIOP detected significantly more ototoxicity ( P = .004), whereas Brock criteria detected significantly fewer patients with any or severe ototoxicity ( P &lt; .001 for both). SIOP detected ototoxicity earlier than did the other scales. Agreement between the central reviewers and the institutional audiologist was almost perfect for ASHA and Brock, whereas the poorest agreement occurred with CTCAE. Conclusion The SIOP scale may be superior to ASHA, Brock, and CTCAE scales for classifying ototoxicity in pediatric patients who were treated with cisplatin. Future studies should evaluate inter-rater reliability of the SIOP scale.
Differential Impact of Transcriptional vs. Post-Transcriptional Control Mechanisms in the Regulation of Transferrin Receptor-1 and -2 in Human Myeloid Cells.
Authors: Maria Samara, Ioanna Chiotoglou, Christos Chassanidis, Sophia Likousi, Kostas Stamatopoulos, Panagoula Kollia
Journal: Blood (2006)
Adjuvant therapy with imatinib in gastrointestinal stromal tumor (GIST) patients with intermediate or high risk: Analysis from a single-center contrast study
Authors: J. Li, F. J. Gong, J. Li, W. A. Wu, L. Shen
Journal: Journal of Clinical Oncology (2009)

10556 Background: Imatinib benefits the patients with metastatic GIST but whether it is effective in the adjuvant setting after complete tumor resection of primary GIST is questionable. Methods: Patients who had undergone complete tumor resection with intermediate or high risk of recurrence (define) were enrolled in a single-center non-randomized open contrast study. Patients had adjuvant therapy with imatinib (400mg once a day) for 3 years commencing within 12 weeks of tumor resection, or had follow-up alone. We performed c-kit and PDGFRA mutation analysis for patients with archival tumor samples. The primary objective was recurrence-free survival (RFS) and the second objective was correlation of gene mutation profile with efficacy of adjuvant therapy. Results: One hundred and five patients were enrolled: 56 patients in adjuvant therapy group and 49 patients in control group. Median follow-up was 30 months (range 12–62); Median treatment duration in adjuvant therapy group were 20 months (range 12–36); There was relatively higher 1-year and 2-year RFS in the adjuvant therapy group compared with the control group (100% vs 89.8%,94.4% vs 60.0%) (Log-RankP&lt; 0.001). Hazard risk was 0.13 (95% CI 0.039–0.438, P= 0.001) in Cox proportional hazard regression model. For further sub-group analysis, Log-rank and Cox regression analysis showed that adjuvant therapy could significantly decrease recurrence risk in patients with high risk disease (define)(2-year RFS: 91.5% vs 46,2%, Log-Rank: P&lt;0.001, HR:0.107 (95%CI 0.031–0.370), P&lt;0.001). c-kit and PDGFRA mutation were analyzed in forty-nine patients. There was a better survival benefit from adjuvant therapy for patients with c-kit exon 11 mutation. Conclusions: Adjuvant therapy with imatinib can improve 1-year and 2-year recurrence-free survival for patients with an intermediate or high risk of recurrence after complete tumor resection. No significant financial relationships to disclose.
604. TALE-VP64 Targeting the Frataxin Promoter Increase the Expression of That Gene in Friedreich Fibroblasts
Authors: Jacques P. Tremblay, Joël Rousseau, Pierre Chapdelaine
Journal: Molecular Therapy (2015)

Friedreich's ataxia (FRDA) is due to a reduced frataxin expression due to a trinucleotide repeat. It is 30% in patients with 200 GAA repeats and only 5% in patients with 900 GAA repeats 33. However, carriers of this disease produce about only 50% of the normal level of frataxin but do not develop symptoms. We have engineered 12 genes coding for TALE proteins targeting different nucleotide sequences present in the frataxin promoter. Each expression plasmid contains a TALEFrat gene fused with a transcription activator, VP64 under the EF1α promoter, a 2A peptide and an EGFP. When one of these plasmids was transfected alone in human cells, only green fluorescence was detected by FACS indirectly confirming the expression of the TALEFrat/VP64 protein. To identify which of our 12 different TALEFrat/VP64 proteins were able to better induce the expression of the frataxin gene, we have constructed a reporter plasmid containing the proximal region of the frataxin promoter, followed by a minimal CMV promoter and a mCherry reporter gene (pCR3.1 proximal-promoter-frataxin-miniCMV-mCherry). This reporter plasmid was initially transfected in human cells alone. Very few cells expressed the red fluorescence because the promoter was not effective without transactivation by binding factors. When the reporter plasmid was co-transfected in human cells with one of the pCR3.1-TALEFrat/VP64-2A-EGFP plasmids, a much higher number of cells expressed the red fluorescence because the TALEFrat/VP64 attached to the proximal frataxin promoter and induced the transcription of mCherry. The 3 TALEFrat/VP64, which induced the strongest expression of mCherry, were targeting promoter sequences close to each other. A plasmid coding for TALEFrat#8/VP64 was nucleofected in normal fibroblasts. Using quantitative RT-PCR, we have confirmed in 3 independent experiments that the expression of the frataxin mRNA (relative to GAPDH mRNA) in human cells was doubled or triple by TALEFrat#8/VP64 when results were normalized with cells transfected with EGFP or non-transfected cells. We have also shown that this TALE also increased by 2 folds the frataxin protein in fibroblasts from a FRDA patient. In a recent preliminary result, we have shown that the transfection of TALEFrat#8/VP64 plasmid in YG8R fibroblasts also increases frataxin mRNA (by about 1.4 to 1.9 fold) and protein (by about 1.4 fold). Such increases would be in the therapeutic range (i. e., 50% of normal frataxin level) for many patients. However, for patients that have less than 25% of the normal level of frataxin expression, a further increase of frataxin would be required and this project may permit to obtain higher frataxin increases and thus this would lead to an increased number of FRDA patients who would benefit from our therapy.
Serologic Screening for Genital Herpes
Authors: Cynthia Feltner, Catherine Grodensky, Charles Ebel, Jennifer C. Middleton, Russell P. Harris, Mahima Ashok, Daniel E. Jonas
Journal: JAMA (2016)

Genital herpes simplex virus (HSV) infection is a prevalent sexually transmitted infection. Vertical transmission of HSV can lead to fetal morbidity and mortality.To assess the evidence on serologic screening and preventive interventions for genital HSV infection in asymptomatic adults and adolescents to support the US Preventive Services Task Force for an updated recommendation statement.MEDLINE, Cochrane Library, EMBASE, and trial registries through March 31, 2016. Surveillance for new evidence in targeted publications was conducted through October 31, 2016.English-language randomized clinical trials (RCTs) comparing screening with no screening in persons without past or current symptoms of genital herpes; studies evaluating accuracy and harms of serologic screening tests for HSV-2; RCTs assessing preventive interventions in asymptomatic persons seropositive for HSV-2.Dual review of abstracts, full-text articles, and study quality; pooled sensitivities and specificities of screening tests using a hierarchical summary receiver operating characteristic curve analysis when at least 3 similar studies were available.Accuracy of screening tests, benefits of screening, harms of screening, reduction in genital herpes outbreaks.A total of 17 studies (n = 9736 participants; range, 24-3290) in 19 publications were included. No RCTs compared screening with no screening. Most studies of the accuracy of screening tests were from populations with high HSV-2 prevalence (greater than 40% based on Western blot). Pooled estimates of sensitivity and specificity of the most commonly used test at the manufacturer's cutpoint were 99% (95% CI, 97%-100%) and 81% (95% CI, 68%-90%), respectively (10 studies; n = 6537). At higher cutpoints, pooled estimates were 95% (95% CI, 91%-97%) and 89% (95% CI, 82%-93%), respectively (7 studies; n = 5516). Use of this test at the manufacturer's cutpoint in a population of 100 000 with a prevalence of HSV-2 of 16% (the seroprevalence in US adults with unknown symptom status) would result in 15 840 true-positive results and 15 960 false-positive results (positive predictive value, 50%). Serologic screening for genital herpes was associated with psychosocial harms, including distress and anxiety related to positive test results. Four RCTs compared preventive medications with placebo, 2 in nonpregnant asymptomatic adults who were HSV-2 seropositive and 2 in HSV-2-serodiscordant couples. Results in both populations were heterogeneous and inconsistent.Serologic screening for genital herpes is associated with a high rate of false-positive test results and potential psychosocial harms. Evidence from RCTs does not establish whether preventive antiviral medication for asymptomatic HSV-2 infection has benefit.
Abstract 170: Survival prediction model with long non-coding RNA profile in lung adenocarcinoma cancer
Authors: Wei-An Wang, Liang-Chuan Lai, Mong-Hsun Tsai, Tzu-Pin Liu, Eric Y. Chuang
Journal: Cancer Research (2015)

Abstract Long non-coding RNAs (LncRNA) are over 200 nucleotides bases non-protein-transcript RNA. Recently, there is a rapid growing literature about LncRNA. LncRNAs are considered as regulator of mRNA, structure components and precursor to small RNAs. However, the mechanism of LncRNA in tumor progression is still not clear yet. Previous studies has validated several LncRNA are associated with prostate cancer and breast cancer (e.g. MATAT-1, PCA3). Here, we investigate the LncRNA expression profile in lung adenocarcinoma cancer and predict patient survival with cox regression model. We download the dataset GSE30219 on Gene Expression Omnibus, microarray data on Affymetrix U133-plus2 platform. With the LncRNA probes selection pipeline on U133-plus2 investigated by Du et al., total 2,427 probes are associated with LncRNA, and every LncRNA is targeted by at least four probes. It is believed that LncRNAs are subtype specific due to previous studies, so we first defined the differential expression LncRNA probes between Adenocarcinoma and Squamous cancer with student t-test, and selected the top 50 p-value probes. Next, with the profile of these 50 probes and the clinical data, we focus on survival analysis of Adenocarcinoma and cox regression was used to identify the survival related probes in the 50 probes, P-value &amp;lt; 0.05. Finally, the expression profiles of survival related probes were trained with cox regression again to build up a prediction model. With score given by the prediction model, samples are divided into two groups: high-risk and low-risk when score higher than 0 or score under 0, respectively. The Kaplan-Meier curve was used to illustrate the relationship between two groups. By using GSE30219 as training model set, GSE30219 was used as internal-validation and GSE8894 was used as external validation. The result of internal-validation shows significantly different. The difference of two groups on external- validation shows, although not greatly as internal- validation, there is still exists a slightly differences. To sum up, LncRNA profiles in Lung Adenocarcinoma might play a role in survival rate. However, further improvement of prediction model is needed since the risk ratio of each sample should be reported, not only the cox scores. Also the Adenocarcinoma specific LncRNA probes should be investigated to enhance the confidence of prediction model. Citation Format: Wei-An Wang, Liang-Chuan Lai, Mong-Hsun Tsai, Tzu-Pin Liu, Eric Y. Chuang. Survival prediction model with long non-coding RNA profile in lung adenocarcinoma cancer. [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 170. doi:10.1158/1538-7445.AM2015-170
Celecoxib Similar to 2 NSAIDs for Cardiovascular Safety
Authors: Anita Slomski
Journal: JAMA (2016)

The selective cyclooxygenase 2 (COX-2) inhibitor celecoxib is no more likely than 2 nonsteroidal anti-inflammatory drugs (NSAIDs) to cause cardiovascular death, nonfatal myocardial infarction, or stroke in patients with coronary disease or other cardiovascular risks.
Abstract 4583: Computational analysis predicts unbalanced IDH1/IDH2 expression associate with 2-HG-inactivating beta-oxygenation pathway in colorectal cancer
Authors: Jun Koseki, Hugh Colvin, Takahito Fukusumi, Naohiro Nishida, Masamitsu Konno, Koichi Kawamoto, Kenta Tsunekuni, Yuichiro Doki, Masaki Mori, Hideshi Ishii
Journal: Cancer Research (2015)

Abstract Bioinformatics and computational modeling offer innovative approaches to investigate cancer metabolism and predict the secondary and tertiary cellular responses. Dysregulation of metabolism has also been implicated in the pathophysiology of cancer. A significant proportion of patients with glioblastoma and hematological malignancies harbor the mutated forms of the oxidative phosphorylation (OxPhos) enzymes, isocitrate dehydrogenase (IDH) 1 or 2. The mutated forms of IDH1 and IDH2 produce an oncogenic metabolite, D-2-hydroxyglutarate (D2HG). A recent study of breast cancer patients showed that D2HG can also be produced in the absence of mutated IDH, through an alternative route involving over-activated MYC signaling. We developed a novel methodology to computationally analyze gene expression in colorectal cancer, and identified novel sets of genes that are associated with patient survival. The study of OxPhos-related genes revealed that an imbalance between the expression of IDH1 and IDH2, defined as overexpression of one isoform in relation to the other, was associated with worse prognosis in colorectal cancer patients. This effect was further accentuated by reduced expression of the beta-oxygenation enzyme, 3-D-hydroxyacyl-CoA dehydratase (HCDH) 4, which has been reported to contribute to metabolism of intracellular D2HG. The present computational analysis revealed a novel and potential mechanism of colorectal cancer development, through over-production of D2HG when there is an imbalance between IDH1 and IDH2 expression, resulting in decreased clearance of D2HG when the beta-oxidization pathway is diminished. Additional validation analysis with other gene expression dataset has resulted in that IDH1/2 imbalanced expression had a shorter DFS compared with balanced expression. Altogether, these findings provide a strong rationale for studying this mechanism further in order to discover novel therapeutic targets for the treatment of colorectal cancer. Citation Format: Jun Koseki, Hugh Colvin, Takahito Fukusumi, Naohiro Nishida, Masamitsu Konno, Koichi Kawamoto, Kenta Tsunekuni, Yuichiro Doki, Masaki Mori, Hideshi Ishii. Computational analysis predicts unbalanced IDH1/IDH2 expression associate with 2-HG-inactivating beta-oxygenation pathway in colorectal cancer. [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 4583. doi:10.1158/1538-7445.AM2015-4583
Abstract 3370: Incorporation of mesenchymal stem cells into areas of lung metastasis in an osteosarcoma model
Authors: Luciana M. Gutierrez, Mariana A. Amoros, Gustavo Sevlever, Osvaldo Podahjcer, Graciela Cremaschi, Eugenie S. Kleinerman, Marcela F. Bolontrade
Journal: Cancer Research (2015)

Abstract Lung is the most common metastatic site in osteosarcoma patients with a majority presenting lung micrometastasis at diagnosis time. MSCs compose a heterogeneous cell population with the ability to migrate and home into remodeling tissues, including tumors. To evaluate the participation of MSCs in lung metastasis formation, we intravenously injected LM7 osteosarcoma cells into immunosuppressed mice. Pre-labelled MSCs (DiR+/CMDiI+, at a dose of 0.5-1×10e6 cells) were intravenously administered 10 weeks after tumor cells injection, when microscopic metastasis become apparent. MSCs biodistribution was evaluated both through real time (DiR+) and microscopic (CMDiI+) analysis. MSCs levels in the lungs of tumor-bearing mice as compared to mice with no tumor burden was 1.15×10E5±0.07 p2/sec/cm2/sr vs. 5.44×10E4±0.5p2/sec/cm2/sr (one week post-inoculation, infrared signal, p&amp;lt;0.01). This indicates a high homing ability of the stromal cells into the metastatic tumor microenvironment. Microscopic analysis corroborated infrared signal with MSCs presence and incorporation within the metastatic sites. In addition, MSCs displayed heterogeneous distribution within lungs with LM7 metastasis as opposed to the homogeneous MSCs distribution observed in lungs without metastasis. This suggests that MSCs are chemoattracted and retained in preferential areas within the lungs with LM7 osteosarcoma metastases. The setup of an experimental osteosarcoma metastatic model which incorporates administered MSCs as tumor stromal cells will be useful to analyze MSCs function in tumor metastasis formation. Note: This abstract was not presented at the meeting. Citation Format: Luciana M. Gutierrez, Mariana A. Amoros, Gustavo Sevlever, Osvaldo Podahjcer, Graciela Cremaschi, Eugenie S. Kleinerman, Marcela F. Bolontrade. Incorporation of mesenchymal stem cells into areas of lung metastasis in an osteosarcoma model. [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 3370. doi:10.1158/1538-7445.AM2015-3370