tbuckley/cabot-search huggingface dataset:
71. Chimeric lentiviral vectors derived from HIV-1 and HIV-2
Authors: Suresh K. Arya, Jenice D'Costa, Geetanjali Sachdeva, Jean Cho, Kritika Kachapati
Journal: Molecular Therapy (2004)

While a source of great misery, lentiviruses can be modified and channeled toward the useful purpose of developing vectors for gene transfer in gene therapy, functional genomics, and animal transgenesis. Being retroviruses and by virtue of their integration into the target cell genome, they provide for long term transgene expression. The added advantage of lentiviral vectors is their ability to affect gene transfer in non-dividing as well as dividing cells, without any anticipated immune reaction. To make a compelling case for their use, specially in gene therapy, three interrelated issues need to be addressed - targeting, regulation and safety. To enhance their safety or to minimize the chance of recombination, we are creating chimeric vectors derived from HIV-1 and HIV-2. This is being done both for transfer vectors and packaging constructs. It is based on the premise that there is sufficient sequence diversity between HIV-1 and HIV-2 to curtail recombination. Vectors were produced by transient transfection of human embryo kidney 293T cells, using matching sets of transfer vector and packaging construct DNAs, and pseudotyped with VSV-G. For ease of detection, the transfer vectors carried indicator GFP gene. The resulting supernatants were titrated on 293T cells and their content of the core antigen (p24 or p27) determined by Eliza assays. Preliminary results show that the titer for the homologously packaged HIV-1 vector [HIV-1 × HIV-1p] was about 2.7 × 10e3 TU/ng and that of the homologously packaged HIV-2 vector [HIV-2 × HIV-2p] was about 0.2 × 10e3 TU/ng. The cross-packaged transfer vectors, HIV-1 × HIV-2p and HIV-2 × HIV-1p, had titer of about 0.12 × 10e3 TU/ug and 0.16 × l0e3 TU/ug, respectively. For the chimeric transfer vectors, the titer of the HIV-1 vector with the replacement of the HIV-1 leader-gag segment with that of the HIV-2 leader-gag segment was roughly the same as for the wild type vector, both in homologous and hetrologous packaging reaction. Initial experiments with the reverse transfer vector chimera gave titers lower than that for the corresponding wild type vector. Two of the packaging construct chimeras also have been tested. These chimeras consist of the exchanges of 5′ halves ('gag-pol') and 3′ halves ('tat-rev-nef') genes. When tested with HIV-2 transfer vectors, 3′ half chimeras appeared to be more like the wild type constructs than the 5′ half chimeras. This may reflect specificity of interaction between the leader sequence and the gag protein. Additional chimeric vectors are being created to test this hypothesis. The results show that the creation of chimeric vectors between HIV-1 and HIV-2 is feasible and suggest that an optimal combination of chimeric transfer vectors and packaging constructs with enhanced safety and minimal loss of efficiency can be designed.
Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing
Authors: Gillian S. Ashcroft, Kejian Lei, Wenwen Jin, Glenn Longenecker, Ashok B. Kulkarni, Teresa Greenwell-Wild, Hollie Hale-Donze, George McGrady, Xiao-Yu Song, Sharon M. Wahl
Journal: Nature Medicine (2000)
Abstract 2476: Intraventricular Septal Intramural Asynchrony in Patients with Hypertrophic Cardiomyopathy Using Tissue Velocity Imaging Correlates with the Severity of Myocardial Fibrosis
Authors: Jun Tanaka, Satoshi Nakatani, Makoto Amaki, Hideaki Kanzaki, Shuji Hashimoto, Hatsue Ishibashi-Ueda, Masafumi Kitakaze, Kazumasa Harada, Iwao Kuwajima
Journal: Circulation (2007)

Background: Hypertrophic cardiomyopathy (HCM) is histologically characterized by myocardial fibrosis and disarray. These myocardial changes may affect timing of regional peak contractions. We inves...
Hereditary angio-oedema: treatment with danazol.
Authors: GERHARD TAPPEINER, HELMUT HINTNER, JOSEF GLATZL, KLAUS WOLFF
Journal: British Journal of Dermatology (1979)

An 8-year-old boy with hereditary angio-oedema was treated with danazol under close endocrinological supervision. The boy's C1 esterase inhibitor (Clinh) and C4 levels increased rapidly to near normal values under a daily doses of 400 mg and were maintained at about 50% of the normal by maintenance doses of 200 mg danazol every other day. Throughout the entire treatment period (11 months) the boy has been maintained free from attacks of angio-oedema. No hormonal imbalance was detected in the follow-up period. Our results indicate that danazol should be suitable for the treatment of HAE not only in adults but also in prepubescent children.
Ramucirumab, another anti-angiogenic agent for metastatic colorectal cancer in second-line setting—its impact on clinical practice
Authors: Gaurav Goel, Weijing Sun
Journal: Journal of Hematology & Oncology (2015)

The recent FDA approval of ramucirumab (RAISE trial) has added a third agent to our existing armamentarium of angiogenesis inhibitors (bevacizumab and ziv-aflibercept) for the second-line treatment of metastatic colorectal cancer, which may have some impacts in the current clinic practice.
Abstract 4020: Exploring target gene(s) within chromosome 19-amplification detected in a subclone from metastatic tumors in mouse transplantable OSCC
Authors: Tomoki Muramatsu, Ken-ichi Kozaki, Seiya Imoto, Rui Yamaguchi, Hitoshi Tsuda, Tatsuyuki Kawano, Satoru Miyano, Johji Inazawa
Journal: Cancer Research (2014)

Abstract Cancer metastasis is caused by a highly complex molecular and cellular mechanism. Although this mechanism has been gradually revealed, there are few genes found as useful diagnostic markers or molecular targets for clinical application so far. In this study, we attempted to establish highly metastatic cells by in vivo selection for identifying metastasis-related genes with an oral squamous cell carcinoma cell line (HOC313-parent). As a result, we established a highly metastatic subline (HOC313-LM) derived from a metastatic site of axillary lymph node. To explore metastasis-related genes and signaling pathways, we performed integrative omics including several genomic and epigenomic approaches combined with systems biology. Since the amplification of chromosome 19 was identified in HOC313-LM by array CGH, we focused on this amplicon containing 44 genes. Among them, one gene, which was essential for the posttranslational modification, was associated with tumor formation and metastasis in vivo via the Rho signaling pathway. Indeed, activation of the Rho signaling pathway emerged in HOC313-LM by our systems biology approach using the gene expression data sets. In addition, the expression pattern of this gene correlated with poor disease-free survival and distant metastasis in patients with esophageal squamous cell carcinoma. Then, we performed therapeutic experiments using a known inhibitor of this gene, and found that tumor growth was inhibited by this compound. Taken together, our findings suggested that this gene might serve as a novel molecular target for anti-cancer therapy. Citation Format: Tomoki Muramatsu, Ken-ichi Kozaki, Seiya Imoto, Rui Yamaguchi, Hitoshi Tsuda, Tatsuyuki Kawano, Satoru Miyano, Johji Inazawa. Exploring target gene(s) within chromosome 19-amplification detected in a subclone from metastatic tumors in mouse transplantable OSCC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4020. doi:10.1158/1538-7445.AM2014-4020
Abstract 3636: Anti-CD20 therapy prevents protumor regulatory T-cell expansion and triggers a memory Th1 response in tumor-bearing mice
Authors: Claire Deligne, Sophie Siberil, Jean-Luc Teillaud
Journal: Cancer Research (2014)

Abstract The long-lasting clinical response by lymphoma patients to anti-CD20 treatment has been attributed to a ‘vaccinal’-type effect through the induction of an anti-tumor adaptive immunity. Using a model where C57Bl/6 mice were injected intravenously with EL4 tumor cells expressing human CD20, we previously showed that CD4 cells are central to the host protection induced by anti-CD20 therapy. Here, we have first shown that the transfer of highly purified CD4+ T cells induces a long-term protection, demonstrating that this T-cell subset plays indeed a key role in the induction of an adaptive memory response. In addition, CD4+ effector memory T cells were detected in surviving animals. We have then analyzed the changes occurring in various T cell subsets in tumor-bearing animals receiving anti-CD20 treatment. On the one hand, untreated animals exhibited a large expansion of CD4+FoxP3+ regulatory T cells (Tregs), with reduced survival. Depletion of these cells using anti-CD25 injection led to long-term survival, indicating that a Treg-dependent immuno-suppressive environment is established after tumor injection in this model. On the other hand, anti-CD20 therapy, that induces a long-lasting protection, reversed the initial expansion of Tregs one week after the end of anti-CD20 treatment, and was accompanied by a marked increase in the number of Th1 cells. Concomitantly, an increase in the serum levels of interleukin-12 was observed, as well as an increased in the number of activated myeloid dendritic cells producing this cytokine. Moreover, a strong decrease in the survival was observed when Natural Killer cells were depleted using anti-asialo GM1 antibodies or following neutralization of interferon-γ. Thus, the host protection elicited by anti-CD20 treatment involves a network of cells from both innate and adaptive immunity that both are needed for long-term protection. In conclusion, our work demonstrates that anti-CD20 therapy promotes a strong anti-tumor adaptive immunity, opposes Treg expansion, and that a pro-tumor immune contexture shaped by the presence of growing tumor cells can be reversed by antibody treatment. Citation Format: Claire Deligne, Sophie Siberil, Jean-Luc Teillaud. Anti-CD20 therapy prevents protumor regulatory T-cell expansion and triggers a memory Th1 response in tumor-bearing mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3636. doi:10.1158/1538-7445.AM2014-3636
Excised melanocytic lesions in children and adolescents - a 10-year survey
Authors: E. Moscarella, I. Zalaudek, L. Cerroni, I. Sperduti, C. Catricalà, J. Smolle, R. Hofmann-Wellenhof, A. Sgambato, G. Pellacani, G. Argenziano
Journal: British Journal of Dermatology (2012)

Background Early recognition and prompt excision is to date the only available strategy for reducing mortality from melanoma. Little is known about the accuracy of melanoma detection in children and adolescents. Objectives To assess the accuracy of melanoma detection in a paediatric population. Methods From the Department of Dermatology, Medical University of Graz, Austria, we reviewed the dermatopathology reports of naevi and melanomas excised in patients younger than 20 years over a 10-year period (1998–2007). Patients were subdivided into four age groups: 0–4, 5–9, 10–14 and 15–19 years. Results Accuracy in melanoma detection was tested using the number needed to excise (NNE) value that is obtained by dividing the total number of excised lesions by the number of melanomas. A total of 22 564 lesions were reviewed, disclosing 22 526 naevi and 38 melanomas, for an overall NNE value of 593·8. Five melanomas were excised in children aged 10–14 years (NNE 1141) and 33 in children aged 15–19 years (NNE 479·8), whereas no melanomas were found among 1026 lesions excised in children younger than 10 years. In children aged 0–4 years, congenital and Spitz/Reed naevi accounted for 34·5% and 20% of lesions, respectively. These percentages decreased progressively when moving to older age groups (P < 0·0001). In contrast, the percentage of dermal and compound naevi rose in direct proportion with age, being 3·4% and 20·7%, respectively, in the youngest age group, and 36·7% and 31·9%, respectively, among the oldest patients (P < 0·0001). Conclusions The overall NNE value in paediatric patients over the 10-year study period was 593·8, meaning that about 594 lesions were excised to find one melanoma. This value is 20 times higher than the rates found in adult patients.
Abstract MP56: Epigenome-wide association study of lipid and inflammatory marker to response fenofibrate in the Genetics of Lipid Lowering Drugs and Diet Network Study
Authors: Bertha Hidalgo, Ryan Irvin, Stella Aslibekyan, Jin Sha, Degui Zhi, Devin Absher, Jose Ordovas, Hemant Tiwari, Donna Arnett
Journal: Circulation (2014)

Introduction: There is considerable inter-individual variation in response to lipid-lowering drug therapies. This study aimed to discover the epigenetic factors associated with response to fenofibrate, which may be used to facilitate initiatives in personalized medicine. Methods: We conducted an epigenome-wide association study for lipid and inflammatory marker response to 3 weeks of daily treatment with 160 mg of fenofibrate among 749 participants in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study. For both lipids and inflammatory markers, we analyzed the ratio of the post-3 week lipid or inflammatory marker concentration divided by the baseline concentration. We fit mixed models with methylation status of each CpG as the dependent variable and lipid or inflammatory ratio as the variable of interest adjusting for age, sex, study site, and T-cell purity (fixed effects) and family structure (random effect). A Bonferroni corrected P-value of 1.1x10^-7 was considered significant. Results: Methylation of a CpG site in CPT1A on chromosome 11 was significantly associated with LDL cholesterol response to fenofibrate (P=4.18x10 -8 ). In addition, a CpG site in NEU2 on chromosome 2, was significantly associated with IL2 response (P=7.80x10 -7 ). CPT1A plays an important role in fatty acid metabolism, whereas NEU2 is a type of salidase known to be involved in the development of atherosclerosis. Conclusions: Our findings suggest that methylation of CpG sites within CPT1A and NEU2 are associated with LDL cholesterol and IL2 response to fenofibrate, respectively, and could prove useful for identifying patients who benefit from fenofibrate therapy.
Abstract 12526: AKAP150-Mobilized PKC Activation Mediates Myocardial Dysfunction in Diabetes
Authors: Zeng Chao, Jinyi Wang, Na Li, Mingzhi Shen, Haichang Wang, Qiujun Yu
Journal: Circulation (2014)

Background: Chronic activation of conventional PKC (cPKC) is a key signaling that directs the cardiac toxicity of hyperglycemia. AKAP150, a scaffold protein of the A-kinase anchoring proteins (AKAPs) family, is less defined regarding its capability to anchor and regulate cPKC signaling in cardiomyocytes. This study was aimed to investigate the role of AKAP150 in cPKC-mediated cardiac injury in diabetes. Methods and Results: In cardiac tissues from streptozotocin-induced diabetic rats and high-glucose treated neonatal rat cardiomyocytes, expression of AKAP150 increased significantly at both mRNA and protein levels, with a marked elevation in expression and activity of cPKC and phosphorylation levels of p65NF-κB and p47phox. AKAP150 knockdown was established via intramyocardial injection in vivo and transfection in vitro of adenovirus carrying AKAP150 targeted shRNA. Downregulation of AKAP150 reversed diabetes-induced diastolic dysfunction, as evidenced by decreased left ventricular end-diastolic diameter and early/late mitral diastolic wave ratio. AKAP150 inhibition also abrogated high-glucose induced cardiomyocyte apoptosis (TUNEL staining and annexin V/PI flow cytometry) and oxidative stress (ROS production, NADPH oxidase activity and lipid peroxidation). More importantly, reduced AKAP150 expression significantly reversed high-glucose induced membrane translocation and activation of cPKC, and inhibited phosphorylation of p65NF-κB and p47phox. Immunofluorescent co-expression and immunoprecipitation analysis indicated enhanced anchoring of AKAP150 with cPKC within the plasma membrane in both diabetic myocardium and high-glucose treated cardiomyocytes. Further studies using antibodies and specific inhibitors against different cPKC isoforms revealed that AKAP150 preferentially co-localized and functionally bound with PKC α and β, which are the major isoforms responsible for cardiac glucotoxicity. Conclusions: Cardiac AKAP150 positively responds to hyperglycemic stimuli and functions to enhance the efficiency of glucotoxicity signaling through a cPKC/p47phox/ROS pathway that induces myocardial dysfunction, cardiomyocyte apoptosis and oxidative stress.
Extrafacial lentigo maligna melanoma: analysis of 71 cases and comparison with lentigo maligna melanoma of the head and neck
Authors: None Cox, None Aitchison, None Mackie
Journal: British Journal of Dermatology (1998)

We report a retrospective analysis of extrafacial lentigo maligna melanoma (LMM), and a comparison with patients with LMM of the head and neck. Seventy-one patients (22 men, 49 women) with extrafacial LMM were identified from the Scottish Melanoma Group database for January 1979-March 1996. Their mean age (63 years) was significantly less than that of 335 patients with head and neck LMM (mean 72 years, P < 0.001), with a significantly greater difference among women than men. Extrafacial sites comprised 17.5% of LMMs. There was a marked body site distribution difference between the sexes (P = 0. 001): 68% of extrafacial LMMs in men were on the trunk while 80% in women were on the limbs, particularly the lower leg. Extrafacial LMMs were thinner at presentation than head and neck LMMs (P < 0.05) in both sexes, but this was not simply explained by the younger age of these patients as there was no significant correlation between age and tumour thickness at either extrafacial or at head and neck sites. Although the female lower leg is a site of chronic solar exposure in older women, the other extrafacial sites are habitually covered in the temperate Scottish climate. The significantly younger age group of patients with LMM at extrafacial compared with head and neck sites therefore suggests that the relationship between LMM and sunlight is not simply related to cumulative solar exposure. The demonstration that head and neck LMMs were thicker at presentation compared with extrafacial sites, despite being at a more routinely visible part of the body, suggests that there are still opportunities for targeted pigmented lesion public education.
Re: Yves Allorya, Willemien Beukers, Ana Sagrera, et al. Telomerase Reverse Transcriptase Promoter Mutations in Bladder Cancer: High Frequency Across Stages, Detection in Urine, and Lack of Association with Outcome. Eur Urol 2014;65:360–6
Authors: Jayant K. Rane, Matthew S. Simms, Norman J. Maitland
Journal: European Urology (2014)
Abstract 285: The Relationship Between Time Interval From Collapse to Return of Spontaneous Circulation and Neurologically Intact Survival for Patients Treated With Hypothermia After Non-Ventricular Fibrillation Arrest Out of Hospital. J-PULSE-Hypo Registry
Authors: Taketomo Soga, Ken Nagao, Masakazu Matsuzaki, Asuka Kasai, Naohiro Yonemoto, Hiroyuki Yokoyama, Hiroshi Nonogi
Journal: Circulation (2010)

Background:  Clinical evidence strongly supports mild therapeutic hypothermia for unconscious patients with out-of-hospital cardiac arrest due to ventricular fibrillation (VF), but there are insufficient data that hypothermia had neurological benefit for those with non-VF arrest.   Methods:  We did a multicenter observational study of therapeutic hypothermia for unconscious adult patients with return of spontaneous circulation (ROSC) after out-of-hospital cardiac arrest. The J-PULSE Hypothermia committee entrusted each hospital with timing of cooling, cooling methods, target temperature, duration, and rewarming rate. The primary endpoint was a favorable neurological outcome at hospital discharge.   Results:  Of the 452 unconscious adult patients treated with therapeutic hypothermia, 435 who were cooled to 32 °C to 34 °C were included; 94 were non-VF arrest (non-VF group) and 341 were VF arrest (VF group). The non-VF group had a lower frequency of favorable neurological outcome than the VF group (27.7% vs. 63.7%, p   Conclusion:  Therapeutic hypothermia for non-VF patients has neurological benefits when the ROSC was achieved within 25 minutes after cardiac arrest.
Evaluation of PI3K-pathway–activation status in matched primary (P) and metastatic (M) ER+/HER2- breast cancer (BC) lesions according to PIK3CA-mutation status.
Authors: Debora Fumagalli, Vinu Jose, Roberto Salgado, Stefan Michiels, Timothy R. Wilson, Carol O'Brien, Ling Huw, Ghizlane Rouas, Carmen Criscitiello, Lina Pugliano, Martine J. Piccart-Gebhart, Mark R. Lackner, Sherene Loi, Christos Sotiriou
Journal: Journal of Clinical Oncology (2014)

11060 Background: Despite the high frequency of PIK3CA mutations (mut) in BC, their role in tumor progression is uncertain. We have previously shown that PIK3CA mut status was highly concordant between Ps and matched Ms in ER+/HER2- BCs (89%). We sought to evaluate the levels of PI3K pathway activation concordance in Ps and matched Ms. Methods: For a series of 119 P ER+/HER2- BCs and 31 matched Ms with known PIK3CA mut status, the expression of 400 genes was obtained with the Nanostring technology. The expression of a PI3K pathway activation gene signature (PIK3CA-GS by Loi S PNAS 2010) and of single genes (ESR1 and AURKA) was derived. For 97 of the Ps and 27 of the Ms, the copy number data of 40 genes was obtained with an EvaGreen qPCR assay. Results: 43% of all samples had a PIK3CA mut. The PIK3CA-GS was able to predict moderately samples’ mut status (AUC 0.641, p 0.004). When considering only the Ps, 65% (36/55) of PIK3CA mut and 42% (27/64) of wild type (WT) samples had an expression of PIK3CA-GS higher than the median value, indicating PI3K activation status. The proportion of CCND1 amplified cases was moderately higher in WT compared to mut samples (p 0.06) while the proportion of FGFR1 (p 0.001) and ZNF703 (p<0.001) amplified cases was higher in GS low compared to GS high samples. When considering the 31 pairs, we observed a moderate correlation between PIK3CA-GS values in Ps and matched Ms (Spearman rho=0.50, p<0.01). In each pair, the expression level of the GS could change substantially: in 6 (19%) cases it went up, in 6 (19%) it went down and in 19 (61%) it remained the same. Compared to matched Ps, Ms looked biologically more aggressive with significantly higher levels of proliferation as measure by AURKA (p 0.04) and lower levels of ESR1 (p 0.01) despite maintaining an ER+ status at IHC. Conclusions: Despite the high concordance of PIK3CA genotype between Ps and matched Ms, activation of downstream signaling seems to vary. This suggests that, beside genotyping, additional investigations should be performed in each lesion to assess the level of pathway activation. Evaluation of downstream effectors using phosphorylated antibodies at IHC is ongoing (pAKT, pMTOR, pERK1/2, pS6).