EFFECT OF LOW DOSE RADIATION ON DIFFERENTIATION OF BONE MARROW CELLS INTO DENDRITIC CELLS

Low dose radiation has been shown to be beneficial to living organisms using several biological systems, including immune and hematopoietic systems. Chronic low dose radiation was shown to stimulate immune systems, resulting in controlling the proliferation of cancer cells, maintain immune balance and induce hematopoietic hormesis. Since dendritic cells are differentiated from bone marrow cells and are key players in maintaining the balance between immune activation and tolerance, it may be important to further characterize whether low dose radiation can influence the capacity of bone marrow cells to differentiate into dendritic cells. We have shown that bone marrow cells from low dose- irradiated (γ-radiation, 0.2Gy, 15.44mGy/h) mice can differentiate into dendritic cells that have several different characteristics, such as expression of surface molecules, cytokine secretion and antigen uptake capacity, when compared to dentritic cells differentiated from the control bone marrow cells. These differences observed in the low dose radiation group can be beneficial to living organisms either by activation of immune responses to foreign antigens or tumors, or maintenance of self-tolerance. To the best of our knowledge, this is the first report showing that total-body low dose radiation can modulate the capacity of bone marrow cells to differentiate into dendritic cells

Scale-up study for ex-vivo expansion of allogeneic natural killer cells in stirred-tank bioreactor

Natural killer (NK) cells are a type of lymphocyte in the blood that are responsible for innate and adaptive immune response, and they mature in the liver and bone marrow. Being a key role in host defense system with direct and indirect killing of virus-infected cells or cancer cells, NK cell has been considered an attractive candidate for cancer therapy. Peripheral blood shows the low frequency of NK cells, so ex vivo expansion method is important to obtain sufficient NK cells for therapeutic use. Currently, we successfully developed bioreactor process for NK cell expansion on lab-scale. Stirred-tank bioreactor could be considered as optimal alternative system for large-scale NK cell expansion compared with other ones because it is automated, less labor intensive, scalable, well-controlled and cost-effective. In bioreactor process, agitation is one of important parameters for NK cell expansion because it is necessary to provide homogenous culture conditions. So we defined effects of agitation in bioreactor and figured out an optimum condition. After that scale-up studies were carried out with manufacturing-scale bioreactor based on these results. The results in terms of growth rate, viability cytotoxicity and purity, were comparable with lab-scale

Cerebellar Hypoperfusion during Transient Global Amnesia: An MRI and Oculographic Study

Background and Purpose Transient global amnesia (TGA) is characterized by sudden anterograde and retrograde amnesia lasting for LIP to 24 hours. Diffusion-weighted magnetic resonance imaging (DWI) in cases of TGA and ischemia demonstrates a high frequency of high signal intensities restricted to the hippocampus, and this has been proposed as an etiology of TGA. The aims of this study were to characterize the DWI and single-photon-emission computed tomography (SPECT) findings during the acute and recovered phases of TGA and to correlate the findings with oculomotor abnormalities. Methods Five consecutive patients with a clinical diagnosis of TGA underwent DWI and SPECT of the brain within 24 hours after symptom onset and again 3 days later. Eye movements were also recorded using three-dimensional video-oculography. Results In all patients, DWI disclosed small punctuate (1-3 mm), high-signal lesions in the lateral portion of the hippocampus. The initial SPECT also revealed hypoperfusion in the cerebellar vermis, which had recovered by the follow-up examination. Three patients showed saccadic hypermetria or impaired smooth pursuit only during the acute phase. Conclusions Our patients with TGA showed cerebellar vermian hypoperfusion in addition to ischemic insults to the lateral hippocampus. The oculomotor abnormalities observed in our patients support the Occurrence of cerebellar dysfunction during the TGA attack. J Clin Neurol 2009;5:74-80This study was supported by a grant of the Korean Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (no. A050079).Yang Y, 2008, J CLIN NEUROL, V4, P59Sander K, 2005, LANCET NEUROL, V4, P437Lampl Y, 2004, ACTA NEUROL SCAND, V110, P75Tong DC, 2004, NEUROLOGY, V62, P2154Takeuchi R, 2004, EUR J NUCL MED MOL I, V31, P578, DOI 10.1007/s00259-003-1406-8Teicher MH, 2003, NEUROSCI BIOBEHAV R, V27, P33, DOI 10.1016/S0149-7634(03)00007-1Anderson CM, 2002, PSYCHONEUROENDOCRINO, V27, P231Asada T, 2000, PSYCHIAT CLIN NEUROS, V54, P691Pantoni L, 2000, ACTA NEUROL SCAND, V102, P275Jovin TG, 2000, J NEUROIMAGING, V10, P238Warren JD, 2000, J CLIN NEUROSCI, V7, P57Levitt JJ, 1999, AM J PSYCHIAT, V156, P1105Loeber RT, 1999, SCHIZOPHR RES, V37, P81Giedd JN, 1999, PROG NEURO-PSYCHOPH, V23, P571SCHMAHMANN JD, 1999, MOVEMENT DISORDERSBerquin PC, 1998, NEUROLOGY, V50, P1087Schmidtke K, 1998, J NUCL MED, V39, P155Ghelarducci B, 1997, ARCH ITAL BIOL, V135, P369HODGES JR, 1994, J NEUROL NEUROSUR PS, V57, P605HODGES JR, 1990, J NEUROL NEUROSUR PS, V53, P834HODGES JR, 1990, BRAIN, V113, P639HEATH RG, 1976, J NEUROL NEUROSUR PS, V39, P1037

Reduced Dose Intensity FOLFOX-4 as First Line Palliative Chemotherapy in Elderly Patients with Advanced Colorectal Cancer

To evaluate the toxicity and efficacy of a reduced dose intensity (mini-) FOLFOX-4 regimen as a first-line palliative chemotherapy in elderly patients (≥70 yr of age) with advanced colorectal cancer, data from prospective databases at Seoul National University Bundang Hospital and Seoul Municipal Boramae Hospital were analyzed. A total of 20 patients were enrolled between January 2001 and August 2004, and were treated with oxaliplatin 65 mg/m2 on day 1, and with 2-hr infusions of leucovorin 150 mg/m2 followed by a 5-FU bolus (300 mg/m2) and 22-hr continuous infusions (450 mg/m2) for 2 consecutive days every 2 weeks until progression, unacceptable toxicity or patient refusal. Sixteen patients were evaluable for response with an overall response rate of 43.8%. Median progression-free survival was 4.8 months (95% CI: 3.0-6.7) and overall survival was 13.5 months (95% CI: 11.1-16.0). The main side effects were anemia and neutropenia, which were observed in 20.8% and 17.7%, respectively, of the total cycles administered. There were no grade 4 toxicities and only one patient suffered from febrile neutropenia. No grade 3 toxicities occurred except for anemia (5.2%) and vomiting (1.0%). In conclusion, the mini-FOLFOX-4 regimen was found to be well tolerated with acceptable toxicity, and to provide a benefit for elderly patients with colorectal cancer

ZMYND10 stabilizes intermediate chain proteins in the cytoplasmic pre-assembly of dynein arms

Zinc finger MYND-type-containing 10 (ZMYND10), a cytoplasmic protein expressed in ciliated cells, causes primary ciliary dyskinesia (PCD) when mutated; however, its function is poorly understood. Therefore, in this study, we examined the roles of ZMYND10 using Zmynd10–/–mice exhibiting typical PCD phenotypes, including hydrocephalus and laterality defects. In these mutants, morphology, the number of motile cilia, and the 9+2 axoneme structure were normal; however, inner and outer dynein arms (IDA and ODA, respectively) were absent. ZMYND10 interacted with ODA components and proteins, including LRRC6, DYX1C1, and C21ORF59, implicated in the cytoplasmic pre-assembly of DAs, whose levels were significantly reduced in Zmynd10–/–mice. LRRC6 and DNAI1 were more stable when co-expressed with ZYMND10 than when expressed alone. DNAI2, which did not interact with ZMYND10, was not stabilized by co-expression with ZMYND10 alone, but was stabilized by co-expression with DNAI1 and ZMYND10, suggesting that ZMYND10 stabilized DNAI1, which subsequently stabilized DNAI2. Together, these results demonstrated that ZMYND10 regulated the early stage of DA cytoplasmic pre-assembly by stabilizing DNAI1

Chemically treated plasma Aβ is a potential blood-based biomarker for screening cerebral amyloid deposition

Background Plasma β-amyloid (Aβ) is a potential candidate for an Alzheimers disease (AD) biomarker because blood is an easily accessible bio-fluid, which can be collected routinely, and Aβ is one of the major hallmarks of AD pathogenesis in the brain. However, the association between plasma Aβ levels and AD diagnosis is still unclear due to the instability and inaccurate measurements of plasma Aβ levels in the blood of patients with AD. If a consistent value of plasma Aβ from the blood can be obtained, this might help determine whether plasma Aβ is a potential biomarker for AD diagnosis. Methods We predicted the brain amyloid deposit by measuring the plasma Aβ levels. This cross-sectional study included 353 participants (215 cognitively normal, 79 with mild cognitive impairment, and 59 with AD dementia) who underwent Pittsburgh-compound B positron emission tomography (PiB-PET) scans. We treated a mixture of protease inhibitors and phosphatase inhibitors (MPP) and detected plasma Aβ42 and Aβ40 (MPP-Aβ42 and MPP-Aβ40) in a stable manner using xMAP technology. Results MPP-Aβ40 and MPP-Aβ42/40 (MPP-Aβs) were significantly different between subjects with positive amyloid deposition (PiB+) and those with negative amyloid deposition (PiB–) (P < 0.0001). Furthermore, MPP-Aβ40 (P < 0.0001, r = 0.23) and MPP-Aβ42/40 ratio (P < 0.0001, r = –0.23) showed significant correlation with global PiB deposition (standardized uptake value ratio). In addition, our integrated multivariable (MPP-Aβ42/40, gender, age, and apolipoprotein E genotypes) logistic regression model proposes a new standard for the prediction of cerebral amyloid deposition. Conclusions MPP-Aβ might be one of the potential blood biomarkers for the prediction of PiB-PET positivity in the brain

Neuronal Apoptosis Inhibitory Protein is Overexpressed in Patients with Unfavorable Prognostic Factors in Breast Cancer

Neuronal apoptosis inhibitory protein (NAIP) is a recently identified inhibitor of apoptosis protein. However, the clinical relevance of NAIP expression is not completely understood. In an attempt to determine the clinical relevance of NAIP expression in breast cancer, the levels of NAIP and survivin expression were measured in 117 breast cancer samples and 10 normal breast tissues using quantitative reverse-transcriptase-polymerase chain reaction. While there was no evidence of NAIP expression in the normal breast tissue, NAIP was expressed in all breast cancer samples. The level of NAIP expression in breast cancer was significantly higher (257 times) than in the universal tumor control. There was a strong correlation between the level of NAIP expression and the level of survivin expression (p=0.001). The level of NAIP expression in patients with a large tumor (≥T2) and patients with an unfavorable histology (nuclear grade III) was significantly higher than in those patients with a small tumor (T1) and patients with a favorable histology (nuclear grade I, II) (p=0.026 and p=0.050, respectively). Although the level of NAIP expression was higher in patients with other unfavorable prognostic factors, it was not significant. The three-year relapse-free survival rate was not significantly the patients showing high NAIP expression and patients showing low NAIP expression (86.47±4.79% vs. 78.74±6.57%). Further studies should include the expressions of NAIP in a larger number of patients and for a longer period of follow-up to evaluate correlation with metastasis and treatment outcome. In conclusion, NAIP is overexpressed in breast cancer patients with unfavorable clinical features such as stage and tumor size, suggesting that NAIP would play a role in the disease manifestation

Genetic associations of in vivo pathology influence Alzheimers disease susceptibility

Introduction Although the heritability of sporadic Alzheimers disease (AD) is estimated to be 60–80%, addressing the genetic contribution to AD risk still remains elusive. More specifically, it remains unclear whether genetic variants are able to affect neurodegenerative brain features that can be addressed by in vivo imaging techniques. Methods Targeted sequencing analysis of the coding and UTR regions of 132 AD susceptibility genes was performed. Neuroimaging data using 11C-Pittsburgh Compound B positron emission tomography (PET), 18F-fluorodeoxyglucose PET, and MRI that are available from the KBASE (Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimers disease) cohort were acquired. A total of 557 participants consisted of 336 cognitively normal (CN) adults, 137 mild cognitive impairment (MCI), and 84 AD dementia (ADD) groups. Results We called 5391 high-quality single nucleotide variants (SNVs) on AD susceptibility genes and selected significant associations between variants and five in vivo AD pathologies: (1) amyloid β (Aβ) deposition, (2) AD-signature region cerebral glucose metabolism (AD-Cm), (3) posterior cingulate cortex (PCC) cerebral glucose metabolism (PCC-Cm), (4) AD-signature region cortical thickness (AD-Ct), and (5) hippocampal volume (Hv). The association analysis for common variants (allele frequency (AF) > 0.05) yielded several novel loci associated with Aβ deposition (PIWIL1-rs10848087), AD-Cm (NME8-rs2722372 and PSEN2-rs75733498), AD-Ct (PSEN1-rs7523) and, Hv (CASS4-rs3746625). Meanwhile, in a gene-based analysis for rare variants (AF < 0.05), cases carrying rare variants in LPL, FERMT2, NFAT5, DSG2, and ITPR1 displayed associations with the neuroimaging features. Exploratory voxel-based brain morphometry between the variant carriers and non-carriers was performed subsequently. Finally, we document a strong association of previously reported APOE variants with the in vivo AD pathologies and demonstrate that the variants exert a causal effect on AD susceptibility via neuroimaging features. Conclusions This study provides novel associations of genetic factors to Aβ accumulation and AD-related neurodegeneration to influence AD susceptibility.The study was supported by grants from the National Research Foundation of Korea (2014M3C7A1046049 and 2018M3C9A5064708 for Choi M and 2014M3C7A1046042 for Lee DY) and grants from the Ministry of Health and Welfare of Korea (HI18C0630 for Mook-Jung IH and Lee DY, and HI19C0149 for Lee DY)

Observation of an enhancement in e+e- to Upsilon(1S)pi+pi-, Upsilon(2S)pi+pi-, and Upsilon(3S)pi+pi- production near sqrt{s}=10.89 GeV at Belle

We measure the production cross sections for e+e- -> Upsilon(1S)pi+pi-, Upsilon(2S)pi+pi-, and Upsilon(3S)pi+pi- as a function of sqrt{s} between 10.83 GeV and 11.02 GeV. The data consists of 8.1 fb^-1 collected with the Belle detector at the KEKB e+e- collider. We observe enhanced production in all three final states that does not agree well with the conventional Upsilon(10860) lineshape. A fit using a Breit-Wigner resonance shape yields a peak mass of [10888.4 +2.7/-2.6 (stat) +- 1.2 (syst)] MeV/c^2 and a width of [30.7 +8.3/-7.0 (stat) +- 3.1 (syst)] MeV/c^2.Comment: 6 pages, 3 figures, Contributed to the 34th International Conference on High Energy Physics, Philadelphia, USA, July 2008; Submit to PRD(RC