tbuckley/cabot-search huggingface dataset:
First estimates of the global and regional incidence of neonatal herpes infection
Authors: Katharine J Looker, Amalia S Magaret, Margaret T May, Katherine M E Turner, Peter Vickerman, Lori M Newman, Sami L Gottlieb
Journal: The Lancet Global Health (2017)

BackgroundNeonatal herpes is a rare but potentially devastating condition with an estimated 60% fatality rate without treatment. Transmission usually occurs during delivery from mothers with herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) genital infection. However, the global burden has never been quantified to our knowledge. We developed a novel methodology for burden estimation and present first WHO global and regional estimates of the annual number of neonatal herpes cases during 2010–15.MethodsWe applied previous estimates of HSV-1 and HSV-2 prevalence and incidence in women aged 15–49 years to 2010–15 birth rates to estimate infections during pregnancy. We then applied published risks of neonatal HSV transmission according to whether maternal infection was incident or prevalent with HSV-1 or HSV-2 to generate annual numbers of incident neonatal infections. We estimated the number of incident neonatal infections by maternal age, and we generated separate estimates for each WHO region, which were then summed to obtain global estimates of the number of neonatal herpes infections.FindingsGlobally the overall rate of neonatal herpes was estimated to be about ten cases per 100 000 livebirths, equivalent to a best-estimate of 14 000 cases annually roughly (4000 for HSV-1; 10 000 for HSV-2). We estimated that the most neonatal herpes cases occurred in Africa, due to high maternal HSV-2 infection and high birth rates. HSV-1 contributed more cases than HSV-2 in the Americas, Europe, and Western Pacific. High rates of genital HSV-1 infection and moderate HSV-2 prevalence meant the Americas had the highest overall rate. However, our estimates are highly sensitive to the core assumptions, and considerable uncertainty exists for many settings given sparse underlying data.InterpretationThese neonatal herpes estimates mark the first attempt to quantify the global burden of this rare but serious condition. Better collection of primary data for neonatal herpes is crucially needed to reduce uncertainty and refine future estimates. These data are particularly important in resource-poor settings where we may have underestimated cases. Nevertheless, these first estimates suggest development of new HSV prevention measures such as vaccines could have additional benefits beyond reducing genital ulcer disease and HSV-associated HIV transmission, through prevention of neonatal herpes.FundingWorld Health Organization.
Abstract 3328: Mitigating long-term cardiac adverse effects of radiation exposure: Emerging opportunities in protein oxidation and autophagy modulation
Authors: Elliot T. Rosen, Dmitry Kryndushkin, Yanira Gonzalez, Baikuntha Aryal, Leena Chehab, Jennifer Dickey, Ashutosh Rao
Journal: Cancer Research (2015)

Abstract Radiation-induced heart disease (RIHD) presents a significant challenge in the oncology setting. Patients who receive acute doses of irradiation to the thoracic cavity for Hodgkin's Lymphoma and breast cancer are subject to an elevated risk of RIHD. The ability to mitigate the long-term cardiac effects of radiation exposure in these populations by modulating protein oxidation and the process of autophagy in the heart has the potential to lead to improved health outcomes. We utilized the spontaneously hypertensive rat (SHR), which has proven a good model for drug-induced cardiotoxicity, to evaluate radiation-induced heart disease. SHRs were exposed to low, medium, or high doses of full-body irradiation. Necropsy was performed to collect serum and tissue samples at various time points up to one year. Echocardiography and electrocardiography were performed to evaluate functional changes in cardiac performance. Four weeks following ionizing radiation, both males and females showed decreased heart mass and decreased whole body mass in the groups exposed to medium and high doses of radiation. A marked difference in both heart and whole body mass was observed in the high dose group after one year. Anemic conditions were noted by low red blood cell counts observed in both males and females at all three time points in the animals receiving the highest dose of irradiation. Cardiac troponin T analysis revealed cardiotoxicity in both the medium and high dose groups at early time points. Echocardiography revealed that left ventricular volume at diastole was increased in males following high dose irradiation, and that left ventricular mass decreased following high irradiation exposures. Finally, it should also be noted that after one year, multiple animals receiving radiation developed spontaneous tumors. We are currently exploring the oxidative stress-mediated molecular mechanisms behind the radiation-induced cardiac damage and the subsequent, protective autophagic response. Citation Format: Elliot T. Rosen, Dmitry Kryndushkin, Yanira Gonzalez, Baikuntha Aryal, Leena Chehab, Jennifer Dickey, Ashutosh Rao. Mitigating long-term cardiac adverse effects of radiation exposure: Emerging opportunities in protein oxidation and autophagy modulation. [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 3328. doi:10.1158/1538-7445.AM2015-3328
Abstract 3770: The spindle assembly checkpoint requires phosphatase activity
Authors: Kristen Foss, Liguo Zhang, Alexander C. Robeson, Sally Kornbluth
Journal: Cancer Research (2015)

Abstract The spindle assembly checkpoint (SAC) prevents activation of the anaphase-promoting complex (APC/C) until all chromosomes are correctly attached to the mitotic spindle. A defective SAC contributes to errors in chromosome segregation, which promotes aneuploidy and may eventually lead to cancer. Early in mitosis, the mitotic checkpoint complex (MCC) inactivates the APC/C by binding the APC/C activating protein cdc20 until the chromosomes are properly aligned, at which point the MCC dissociates and releases cdc20 to activate the APC/C. Once the APC/C is activated, it targets many substrates for degradation, including cyclin B and securin, and the cell progresses into anaphase. The precise molecular mechanisms regulating SAC inactivation are still poorly understood. We sought to determine the role of mitotic phosphatases in the SAC. To address this question, we treated mitotic cells with various phosphatase inhibitors to examine their effect on APC/C activation. Using this approach we identified two inhibitors, calyculin A and okadaic acid (1uM), that cause MCC dissociation and APC/C activation leading to cyclin A and cyclin B degradation in nocodazole-arrested cells. Although the cells are able to degrade cyclin B, they do not exit mitosis as evidenced by high levels of cdk1 substrate phosphorylation and chromosome condensation. Our results demonstrate that a calyculin A and okadaic acid (1uM) sensitive phosphatase is required for SAC activation. Citation Format: Kristen Foss, Liguo Zhang, Alexander C. Robeson, Sally Kornbluth. The spindle assembly checkpoint requires phosphatase activity. [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 3770. doi:10.1158/1538-7445.AM2015-3770
Abstract 1655: Targeting RFX-1 as a novel therapeutic strategy in hepatocellular carcinoma
Authors: Jung-Chen Su
Journal: Cancer Research (2015)

Abstract Regulatory factor X (RFX) 1 is a transcription factor that has been linked to negative regulation of tumor progression; however, its biological function and signaling cascades are unknown. In this study, we identify RFX-1 is a negative regulator of cell proliferation in human HCC. We demonstrated that ectopic expression of RFX-1 suppressed the colony forming ability of HCC cell lines through activating SHP-1 expression. In addition, nude mice bearing RFX-1-overexpressing tumors showed a repression of growth rate compared to the control group. Notably, we demonstrated that mRNA and protein level of RFX-1 is highly correlated with SHP-1 in 101 clinical HCC patients, indicating that RFX-1 might be a tumor suppressor of human HCC. To identify the RFX-1 activator for HCC therapy, we screened in-house small molecule library and found that one of small molecules, SC-2001, targeted RFX-1 and exhibited potent anti-tumor effect on HCC cells. In addition, we proved that SHP-1 activation and STAT3 dephosphorylation induced by SC-2001-activated RFX-1. Furthermore, genetic knockdown of RFX-1 reversed SC-2001-induced cell growth inhibition. Importantly, by a mouse xenograft model, silencing of RFX-1 could rescue the anti-HCC tumor effect caused by SC-2001 in vivo, implying that RFX-1 is a promising target for HCC therapy. Taken together, our results indicated that RFX-1/SHP-1/STAT3 signaling might a potential strategy for HCC therapy, and SC-2001 is a promising lead compound for drug development of HCC target therapy. Citation Format: Jung-Chen Su. Targeting RFX-1 as a novel therapeutic strategy in hepatocellular 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 1655. doi:10.1158/1538-7445.AM2015-1655
532. Foamy Viral Vector Integration Sites in SCID-Repopulating Cells After MGMTP140K-Mediated In Vivo Selection
Authors: Miles E. Olszko, Jennifer E. Adair, Ian Linde, Dustin T. Rae, Patty Trobridge, Jonah D. Hocum, David J. Rawlings, Hans-Peter Kiem, Grant D. Trobridge
Journal: Molecular Therapy (2015)

Foamy virus (FV) vectors are promising for hematopoietic stem cell (HSC) gene therapy but preclinical data on the clonal composition of FV vector transduced human repopulating cells is needed. Human CD34+ human cord blood cells were transduced with an FV vector encoding a methylguanine methyltransferase (MGMT) P140K transgene, transplanted into immunodeficient NOD/SCID IL2Rgnull (NSG) mice, and selected in vivo for gene-modified cells. The retroviral insertion site (RIS) profile of repopulating clones was examined using modified genomic sequencing PCR (MGS-PCR). We observed polyclonal repopulation with no evidence of clonal dominance even with the use of a strong internal spleen focus forming virus (SFFV) promoter known to be genotoxic. However we did observe that highly captured sites were found more often near proto-oncogenes than less frequently captured sites (Figure 1). Our data supports the use of FV vectors with MGMTP140K for HSC gene therapy, but also suggests additional safety features should be developed and evaluated.
Cell-Based Immunotherapy with Different Subsets of Tolerogenic Dendritic Cell in Idiopathic Thrombocytopenic Purpura.
Authors: Xiao-Lin Zhang, Jun Peng, Shu-Qian Xu, Xin-Guang Liu, Yuan Yu, Ping Qin, Yan Shi, Lin Wang, Ming Hou
Journal: Blood (2008)
Molecular Mechanisms of Bortezomib Resistance in Acute Lymphoblastic Leukemia Cells in Comparison with Multiple Myeloma Cells.
Authors: Niels E. Franke, Ruud Oerlemans, Sonja Zweegman, Ina van Zantwijk, Gertjan J. Kaspers, Gerrit Jansen, Jacqueline Cloos
Journal: Blood (2007)
Autobiographical episodic memory-based training for the treatment of mood, anxiety and stress-related disorders: A systematic review and meta-analysis
Authors: Caitlin Hitchcock, Aliza Werner-Seidler, Simon E. Blackwell, Tim Dalgleish
Journal: Clinical Psychology Review (2016)

We review evidence for training programmes that manipulate autobiographical processing in order to treat mood, anxiety, and stress-related disorders, using the GRADE criteria to judge evidence quality. We also position the current status of this research within the UK Medical Research Council's (2000, 2008) framework for the development of novel interventions. A literature search according to PRISMA guidelines identified 15 studies that compared an autobiographical episodic memory-based training (AET) programme to a control condition, in samples with a clinician-derived diagnosis. Identified AET programmes included Memory Specificity Training (Raes, Williams, & Hermans, 2009), concreteness training (Watkins, Baeyens, & Read, 2009), Competitive Memory Training (Korrelboom, van der Weele, Gjaltema, & Hoogstraten, 2009), imagery-based training of future autobiographical episodes (Blackwell & Holmes, 2010), and life review/reminiscence therapy (Arean et al., 1993). Cohen's d was calculated for between-group differences in symptom change from pre- to post-intervention and to follow-up. We also completed meta-analyses for programmes evaluated across multiple studies, and for the overall effect of AET as a treatment approach. Results demonstrated promising evidence for AET in the treatment of depression (d=0.32), however effect sizes varied substantially (from -0.18 to 1.91) across the different training protocols. Currently, research on AET for the treatment of anxiety and stress-related disorders is not yet at a stage to draw firm conclusions regarding efficacy as there were only a very small number of studies which met inclusion criteria. AET offers a potential avenue through which low-intensity treatment for affective disturbance might be offered.
Feasibility and pharmacokinetic study of potential ABCG2 inihibitor, gefitinib (GB), in combination with irinotecan (IRN) for adolescents and young adults (AYA).
Authors: H. Kawamoto, Y. Tabei, T. Kimura, K. Hishima, A. Makimoto
Journal: Journal of Clinical Oncology (2011)

9564 Background: The combination of GB and IRN is expected synergy because GB inhibits ABCG2, which pumps IRN out of the tumor cells. The most common single IRN therapy in pediatric oncology is a protracted regimen for 10-day or 5-day. We adopted 5-day regimen with respect to safety and patient convenience to develop multi-agent regimens. We conducted a pilot phase I trial of the combination of GB and IRN for AYA cancer patients to estimate dose-limiting toxicity (DLT) and pharmacokinetics (PK). Expression of ABCG2 and EGFR on pathology samples was also investigated. Methods: Patients (pts) under 40 and with recurrent bone or CNS tumor were eligible. GB 112.5mg/m2 was administered orally once a day for 12 days, concurrently with IRN 35mg/m2 for 5 consecutive days. Antibiotics (cefixime or cefpodoxime) were used to reduce IRN induced diarrhea. Courses were repeated every 3 weeks. PK analysis was performed during the first course. Results: Four pts with a median of 17.5 prior treatment courses were enrolled and received 15 courses (Table). DLT occurred in the only one pt who has UGT1A1 *28/*6 variants and had a intrathoracic hemorrhage episode just before registered this study. No grade4 non-hematologic toxicity occurred in 15 courses, while G2-3 diarrhea caused more than three days earlier discontinuation of GB in every courses and more than 10% weight loss in all pts. The median SN-38 lactone AUC at this dose was 101 ng*hr/ml, almost same to that reported with single IRN 5days regimen. Conclusions: A certain clinical benefit was observed in a patient with metastatic osteosarcoma. However, toxicities including grade 2-3 diarrhea were not always tolerable in heavily-pretreated AYA pts. Especially the exacerbation of gastrointestinal toxicity by GB seemed to be difficult to maximize anti-tumor effect of IRN by dosing up. This pilot phase I trial resulted in early termination. 35y M 13y M 21y F 25y M Histology Ganglioglioma Osteosarcoma Glioblastoma Ewing’s sarcoma EGFR expression + + + – ABCG2 expression – – + + DLT – Thrombocytopenia anemia – – Treatment courses 2 7 (30mg/m2/day after 2nd course) 3 3
Maximally Tolerated Busulfan Area Under the Concentration-Time Curve (AUC) In Combination with Fludarabine as Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation.
Authors: Janelle Perkins, Teresa Field, Jongphil Kim, Hugo F. Fernandez, Lia Perez, Ernesto Ayala, Mohamed Kharfan-Dabaja, Marcie Tomblyn, Daniel Sullivan, Claudio Anasetti
Journal: Blood (2010)
Daratumumab, a Human CD38 Antibody Induces Apoptosis of Myeloma Tumor Cells Via Fc Receptor-Mediated Crosslinking.
Authors: J. H. Marco Jansen, Peter Boross, Marije B. Overdijk, Jeroen J. Lammerts van Bueren, Paul W.H.I. Parren, Jeanette H. W. Leusen
Journal: Blood (2012)
The Prognostic Impact of Blast Cell Immunophenotyping in Intermediate Risk AML Patients at Diagnosis.
Authors: Marianne H. Hoffmann, Eva B. Leinoe, Tobias W. Klausen, Ronnie C. Danielsen, Erik Kjaersgaard, Kjeld Schmiegelow, Henrik Hasle, Nina Hastrup, Jorgen S. Kristensen, Inge H. Dufva, Niels E. Hansen, Olav J. Bergmann, Hans E. Johnsen
Journal: Blood (2004)
330. Using CRISPR/Cas9 to Edit Hematopoietic Stem and Progenitor Cells
Authors: Eduardo Seclen, Hsu-Yu Chen, George N. Llewellyn, Su J. Yang, Morgan Chateau, Cathy X. Wang, Paula M. Cannon
Journal: Molecular Therapy (2016)

Engineered nucleases such as zinc finger nucleases (ZFNs) and CRISPR/Cas9 have the potential to improve the precision of gene therapies based on hematopoietic stem and progenitor cells (HSPC). ZFNs were the first of this class of reagents to be approved for the clinic, through the disruption of the CCR5 gene as an anti-HIV therapy. Since ZFNs only need to be expressed transiently to permanently disrupt a gene, ZFN mRNA electroporation has proved to be an effective method to deliver CCR5 ZFNs to HSCPs. Optimizing the delivery of CRISPR/Cas9 to HSPC requires, in addition, consideration of how to deliver multiple components - the Cas9 nuclease and one or more single guide RNAs (sgRNAs) - in a transient but coincidental window of expression. This is further complicated if a DNA homology template is also to be delivered, in order to direct site-specific gene editing or insertion. Some of the difficulties of working with HSPC include their sensitivity to DNA or viral vectors that can result in unacceptable levels of cytotoxicity, the possibility for only limited in vitro culturing, and the complexity of the studies needed to evaluate any impact of the treatment on HSPC biology. In addition, the relatively large size (4.1kb) of the standard S. pyogenes Cas9 (spCas9) makes it a challenge for certain delivery systems, although a smaller variant from S. aureus (saCas9, 3.2 kb) is also available. In this work, we evaluated several approaches for the delivery of both Cas9 and sgRNAs to HSPC, including AAV vectors, in vitro transcribed Cas9 mRNA, and synthesized sgRNAs. The use of the smaller saCas9 allowed us to evaluate AAV vectors for Cas9 delivery, as well as in combination with sgRNA, using AAV serotype 6 that we identified as having good tropism for human HSPC. Various combinations of the different platforms, and time between deliveries, were optimized to maximize nuclease activity without overt toxicity. Using in vitro synthesized Cas9 mRNA and sgRNAs, we found that a single co-electroporation step was preferable to reduce the toxicity of sequential electroporations, and that chemical modification of the sgRNA was necessary to stabilize it and allow its function when co-delivered in this way. For AAV vectors, although the smaller size of saCas9 allowed it to be co-packaged together with a sgRNA in a single AAV6 vector that worked in cell lines, this combination did not effectively function in HSC. However, the sgRNA component alone was effectively delivered by AAV6 vectors, and could be combined with a later delivery of saCas9 mRNA by electroporation. With this latter approach, we were able to disrupt the CCR5 locus at similar levels to those we achieve using the clinically optimized protocol for CCR5 ZFNs.
Abstract 4758: Genomic profiling of prostate cancer in Korean population
Authors: Ha Young Park, Jong-il Kim, Weon Seo Park, Kang Hyun Lee
Journal: Cancer Research (2015)

Abstract Prostate cancer is one of the most common cancers for male population in the world. The search for accurate biomarkers in prostate cancer is critical for evolution of accurate management of prostate cancer. Previous studies have identified that several genomic alterations in prostate cancer including TMPRSS2-ERG fusion, PTEN deletion and SPOP single nucleotide variants (SNVs), the majority of which are from western population. To characterize the somatic mutations of prostate cancer in Korean, we sequenced the whole exome of 49 prostate cancer patient tissues and matched normal tissues. A total of 738 somatic non-silent variants affecting 692 distinct genes were identified. In addition to already known genes (SPOP, FOXA1 and PTEN), we also found previously uncharacterized genes such as GRIN2A, LRP1, LRP1B and KRT1. Of the 40 mutated genes across multiple cases, missense SNVs of SPOP (5/49 cases, 10.2%) were the most frequent, followed by missense and splice-site SNVs of GRIN2A (4/49 cases, 8.2%). Mutations in low density lipoprotein-related protein encoded by LRP1 and LRP1B affected considerable portion of all cases (7/49, 14.3%), describe the probable relation between lipid metabolism and prostate cancer. As a results, we suggested the distinct patterns of genetic variations involved in prostate cancer of Korean population. Note: This abstract was not presented at the meeting. Citation Format: Ha Young Park, Jong-il Kim, Weon Seo Park, Kang Hyun Lee. Genomic profiling of prostate cancer in Korean population. [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 4758. doi:10.1158/1538-7445.AM2015-4758