Current Advances in Retroviral Gene Therapy

There have been major changes since the incidents of leukemia development in X-SCID patients after the treatments using retroviral gene therapy. Due to the risk of oncogenesis caused by retroviral insertional activation of host genes, most of the efforts focused on the lentiviral therapies. However, a relative clonal dominance was detected in a patient with β-thalassemia Major, two years after the subject received genetically modified hematopoietic stem cells using lentiviral vectors. This disappointing result of the recent clinical trial using lentiviral vector tells us that the current and most advanced vector systems does not have enough safety. In this review, various safety features that have been tried for the retroviral gene therapy are introduced and the possible new ways of improvements are discussed. Additional feature of chromatin insulators, co-transduction of a suicidal gene under the control of an inducible promoter, conditional expression of the transgene only in appropriate target cells, targeted transduction, cell type-specific expression, targeted local administration, splitting of the viral genome, and site specific insertion of retroviral vector are discussed here

Limitations of Conventional Contrast-enhanced MRI in Selecting Sentinel Node Biopsy Candidates among DCIS Patients

Purpose: A better predictive model for occult invasive disease in ductal carcinoma in situ (DCIS) patients is essential to guide the tailored use of sentinel node biopsies. We hypothesized that recent improvement of contrast-enhanced breast magnetic resonance imaging (MRI) could provide more accurate information on the presence of occult invasion in DCIS patients. Methods: From a prospectively maintained database, we identified 143 DCIS patients diagnosed with needle biopsies in whom MRI images were available. Results: Sixty-five patients (45.5%) were upstaged to invasive carcinoma after curative surgery. Ultrasonographic lesion size, mass-appearance on mammography, type of needle used, and the presence of suspicious microinvasive foci were associated with increased likelihood of upstaging. Among the features of MRI, only mass-appearance was significantly associated with the presence of invasive disease (p=0.002). However, up to 50% of masses in MRI cases had mass-appearance on mammography as well. Other morphologic and pharmacokinetic features of MRI, such as shape, margin, and patterns of enhancement and washout, did not have a significant association. Conclusion: Among various morphologic and pharmacokinetic parameters of contrast-enhanced MRI, only mass-appearance was associated with occult invasive disease. Our results show the limitations of current contrast-enhanced MRI in predicting invasive disease in patients with preoperative diagnoses of DCIS.Moon HG, 2009, ANN ONCOL, V20, P636, DOI 10.1093/annonc/mdn683Kuerer HM, 2009, J CLIN ONCOL, V27, P279, DOI 10.1200/JCO.2008.18.3103HU M, 2009, P NATL ACAD SCI USA, V106, P3372Gadre SA, 2008, HISTOPATHOLOGY, V53, P545, DOI 10.1111/j.1365-2559.2008.03152.xOkumura Y, 2008, BMC CANCER, V8, DOI 10.1186/1471-2407-8-287Sakorafas GH, 2008, CANCER TREAT REV, V34, P483, DOI 10.1016/j.ctrv.2008.03.001Morrow M, 2008, ANN SURG ONCOL, V15, P2641, DOI 10.1245/s10434-008-0083-zPorembka MR, 2008, ANN SURG ONCOL, V15, P2709, DOI 10.1245/s10434-008-9947-5Lee JW, 2008, J SURG ONCOL, V98, P15, DOI 10.1002/jso.21077Hu M, 2008, CANCER CELL, V13, P394, DOI 10.1016/j.ccr.2008.03.007Ansari B, 2008, BRIT J SURG, V95, P547, DOI 10.1002/bjs.6162Orel S, 2008, J CLIN ONCOL, V26, P703, DOI 10.1200/JCO.2007.14.3594Facius M, 2007, CLIN IMAG, V31, P394, DOI 10.1016/j.clinimag.2007.04.030Kuhl CK, 2007, LANCET, V370, P485Jung EJ, 2007, INT J CANCER, V120, P2331, DOI 10.1002/ijc.22434Nielsen BS, 2007, INT J CANCER, V120, P2086, DOI 10.1002/ijc.22340van der Velden APS, 2006, AM J SURG, V192, P172, DOI 10.1016/j.amjsurg.2006.02.026Goyal A, 2006, BREAST CANCER RES TR, V98, P311, DOI 10.1007/s10549-006-9167-2Mansel RE, 2006, J NATL CANCER I, V98, P599, DOI 10.1093/jnci/djj158Lyman GH, 2005, J CLIN ONCOL, V23, P7703, DOI 10.1200/JCO.2005.08.001Wilkie C, 2005, AM J SURG, V190, P563, DOI 10.1016/j.amjsurg.2005.06.011Groves AM, 2005, MAGN RESON IMAGING, V23, P733, DOI 10.1016/j.mri.2005.06.003Hylton N, 2005, J CLIN ONCOL, V23, P1678, DOI 10.1200/JCO.2005.12.002Leonard GD, 2004, J NATL CANCER I, V96, P906, DOI 10.1093/jnci/djh164Hata T, 2004, J AM COLL SURGEONS, V198, P190, DOI 10.1016/j.jamcollsurg.2003.10.008Hwang EW, 2003, ANN SURG ONCOL, V10, P381, DOI 10.1245/ASO.2003.03.085*AM COLL RAD, 2003, ACR BI RADS BREAST IMorrow M, 2002, CA-CANCER J CLIN, V52, P277Jackman RJ, 2001, RADIOLOGY, V218, P497Brown LF, 1999, CLIN CANCER RES, V5, P1041

Early gastric cancer arising from heterotopic gastric mucosa in the gastric submucosa

The incidence of heterotopic gastric mucosa located in the submucosa in resected stomach specimens has been reported to be 3.0 to 20.1%. Heterotopic gastric mucosa is thought to be a benign disease, which rarely becomes malignant. Heterotopic gastric mucosa exists in the gastric submucosa, and gastric cancer rarely occurs in heterotopic gastric mucosa. Since tumors are located in the normal submucosa, they appear as submucosal tumors during endoscopy, and are diagnosed through endoscopic biopsies with some difficulty. For such reasons, heterotopic gastric mucosa is mistaken as gastric submucosal tumor. Recently, two cases of early gastric cancer arising from heterotopic gastric mucosa in the gastric submucosa were treated. Both cases were diagnosed as submucosal tumors based on upper gastrointestinal endoscopy, endoscopic ultrasound, and computed tomography findings, and in both cases, laparoscopic wedge resections were performed, the surgical findings of which also suggested submucosal tumors. However, pathologic assessment of the surgical specimens led to the diagnosis of well-differentiated intramucosal adenocarcinoma arising from heterotopic gastric mucosa in the gastric submucosa

An integrative approach for exploring the nature of fibroepithelial neoplasms.

BACKGROUND: Malignant phyllodes tumour (MPT) is a rare breast malignancy with epithelial and mesenchymal features. Currently, there are no appropriate research models or effective targeted therapeutic approaches for MPT. METHODS: We collected fresh frozen tissues from nine patients with MPT and performed whole-exome and RNA sequencing. Additionally, we established patient-derived xenograft (PDX) models from patients with MPT and tested the efficacy of targeting dysregulated pathways in MPT using the PDX model from one MPT. RESULTS: MPT has unique molecular characteristics when compared to breast cancers of epithelial origin and can be classified into two groups. The PDX model derived from one patient with MPT showed that the mouse epithelial component increased during tumour growth. Moreover, targeted inhibition of platelet-derived growth factor receptor (PDGFR) and phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) by imatinib mesylate and PKI-587 showed in vivo tumour suppression effects. CONCLUSIONS: This study revealed the molecular profiles of MPT that can lead to molecular classification and potential targeted therapy, and suggested that the MPT PDX model can be a useful tool for studying the pathogenesis of fibroepithelial neoplasms and for preclinical drug screening to find new therapeutic strategies for MPT

Molecular characterization of two glutathione peroxidase genes of Panax ginseng and their expression analysis against environmental stresses

Glutathione peroxidases (GPXs) are a group of enzymes that protect cells against oxidative damage generated by reactive oxygen species (ROS). GPX catalyzes the reduction of hydrogen peroxide (H2O2) or organic hydroperoxides to water or alcohols by reduced glutathione. The presence of GPXs in plants has been reported by several groups, but the roles of individual members of this family in a single plant species have not been studied. Two GPX cDNAs were isolated and characterized from the embryogenic callus of Panax ginseng. The two cDNAs had an open reading frame (ORF) of 723 and 681 bp with a deduced amino acid sequence of 240 and 226 residues, respectively. The calculated molecular mass of the matured proteins are approximately 26.4 kDa or 25.7 kDa with a predicated isoelectric point of 9.16 or 6.11, respectively. The two PgGPXs were elevated strongly by salt stress and chilling stress in a ginseng seedling. In addition, the two PgGPXs showed different responses against biotic stress. The positive responses of PgGPX to the environmental stimuli suggested that ginseng GPX may help to protect against environmental stresses

Characteristics of Hospitalized Children with 2009 Pandemic Influenza A (H1N1): A Multicenter Study in Korea

The majority of Korean patients with pandemic influenza A (H1N1) during the 2009 epidemic were under 20 yr of age. The limited data on the clinical characteristics of these children led us to conduct a case note-based investigation of children admitted to 6 university hospitals with 2009 H1N1 influenza. A total of 804 children was enrolled. The median age was 5 yr; 63.8% were males; and 22.4% had at least one chronic underlying disease. Ninety-five of the patients (11.8%) were critically ill and they suffered more from shortness of breath, dyspnea and lymphopenia than the other patients. Among all the patients, 98.8% were treated with antivirals and 73% received treatment within 48 hr of illness onset. All the enrolled patients are alive and appear to have had good outcomes, probably due to the early intervention and antiviral treatment. This study deals with hospitalized children whose diagnoses of influenza A (H1N1) were confirmed, and therefore provides important new information about the clinical patterns of children with influenza A (H1N1) in Korea

Droplet-like Fermi surfaces in the anti-ferromagnetic phase of EuFe2_2As2_2, an Fe-pnictide superconductor parent compound

Using angle resolved photoemission it is shown that the low lying electronic states of the iron pnictide parent compound EuFe$_2$As$_2$ are strongly modified in the magnetically ordered, low temperature, orthorhombic state compared to the tetragonal, paramagnetic case above the spin density wave transition temperature. Back-folded bands, reflected in the orthorhombic/ anti-ferromagnetic Brillouin zone boundary hybridize strongly with the non-folded states, leading to the opening of energy gaps. As a direct consequence, the large Fermi surfaces of the tetragonal phase fragment, the low temperature Fermi surface being comprised of small droplets, built up of electron and hole-like sections. These high resolution ARPES data are therefore in keeping with quantum oscillation and optical data from other undoped pnictide parent compounds.Comment: 4 figures, 6 page

A multi-institutional study of the prevalence of BRCA1 and BRCA2 large genomic rearrangements in familial breast cancer patients

Background: Large genomic rearrangements (LGRs) in the BRCA1/2 genes are frequently observed in breast cancer patients who are negative for BRCA1/2 small mutations. Here, we examined 221 familial breast cancer patients from 37 hospitals to estimate the contribution of LGRs, in a nationwide context, to the development of breast cancer. Methods: Direct sequencing or mutation scanning followed by direct sequencing was performed to screen small mutations. BRCA1/2 small mutation-negative patients were screened for the presence of LGRs using a multiple ligation-dependent probe amplification (MLPA) assay. Results: Using a combined strategy to detect the presence of small mutations and LGRs, we identified BRCA1/2 small mutations in 78 (35.3%) out of 221 familial breast cancer patients and BRCA1 LGRs in 3 (2.1%) out of 143 BRCA1/2 small mutation-negative patients: the deletion of exons 11–13, the deletion of exons 13–15, and whole gene deletion of exons 1-24. The novel deletion of exons 11–13 is thought to result from a non-homologous recombination event mediated by a microhomology sequence comprised of 3 or 4 base pairs: c.3416_4357 + 1863delins187 (NG_005905.2: g.33369_44944delins187). Conclusions: In this study, we showed that LGRs were found in 3.7% (3/81) of the patients who had mutations in BRCA1 or BRCA2, and 7.5% (3/40) of patients with mutations in BRCA1. This suggests that the contribution of LGRs to familial breast cancer in this population might be comparable to that in other ethnic populations. Given these findings, an MLPA to screen for mutations in the BRCA1 gene is recommended as an initial screening test in highly selective settings.Peer Reviewe