The safety and efficacy of systemic delivery of a new liver-de-targeted TGFβ signaling inhibiting adenovirus in an immunocompetent triple negative mouse mammary tumor model

Aberrant TGFβ signaling is linked to metastasis and tumor immune escape of many cancers including metastatic triple negative breast cancer (mTNBC). Previously, we have found that oncolytic adenoviruses expressing a TGFβ signaling inhibitory protein (sTGFβRIIFc) induced immune activation in a mouse TNBC (4T1) immunocompetent subcutaneous model with intratumoral injection. Systemic administration of adenoviruses can be a superior route to treat mTNBC but faces the challenges of increased toxicity and viral clearance. Thus, we created a liver-de-targeted sTGFβRIIFc- and LyP-1 peptide-expressing adenovirus (mHAdLyp.sT) with enhanced breast cancer cell tropism. Its safety and immune response features were profiled in the 4T1 model. Our data showed that the systemic administration of mHAdLyp.sT resulted in reduced hepatic and systemic toxicity. mHAdLyp.sT was also effective in increasing Th1 cytokines and anti-tumor cell populations by cytokine analysis, spleen/tumor qRT-PCR, and flow cytometry. We further tested the therapeutic effects of mHAdLyp.sT alone and in combination with immune checkpoint inhibitors (ICIs). mHAdLyp.sT alone and with all ICI combinations elicited significant inhibition of lung metastasis by histological analysis. When mHAdLyp.sT was combined with both anti-PD-1 and anti-CTLA-4 antibodies, primary 4T1 tumor growth was also significantly inhibited. We are confident in advancing this new treatment option for mTNBC

Granulocyte colony-stimulating factor blockade enables dexamethasone to inhibit lipopolysaccharide-induced murine lung neutrophils

Glucocorticoids promote neutrophilic inflammation, the mechanisms of which are poorly characterized. Using a lipopolysaccharide (LPS)-induced acute murine lung injury model, we determined the role of granulocyte colony-stimulating factor (G-CSF) in mouse lung neutrophil numbers in the absence and presence of dexamethasone, a potent glucocorticoid. G-CSF was blocked using a neutralizing antibody. Airway neutrophil numbers, cytokine levels, and lung injury parameters were measured. Glucocorticoid treatment maintained LPS-induced airway G-CSF while suppressing TNF and IL-6. The addition of anti-G-CSF antibodies enabled dexamethasone to decrease airway G-CSF, neutrophils, and lung injury scores. In LPS-challenged murine lungs, structural cells and infiltrating leukocytes produced G-CSF. In vitro using BEAS 2B bronchial epithelial cells, A549 lung epithelial cells, human monocyte-derived macrophages, and human neutrophils, we found that dexamethasone and proinflammatory cytokines synergistically induced G-CSF. Blocking G-CSF production in BEAS 2B cells using shRNAs diminished the ability of BEAS 2B cells to protect neutrophils from undergoing spontaneous apoptosis. These data support that G-CSF plays a role in upregulation of airway neutrophil numbers by dexamethasone in the LPS-induced acute lung injury model

Occupational Neurologic Disorders in Korea

This article presents a schematic review of the clinical manifestations of occupational neurologic disorders in Korea and discusses the toxicologic implications of these conditions. Vascular encephalopathy, parkinsonism, chronic toxic encephalopathy, cerebellar dysfunction, peripheral neuropathy, and neurodegenerative diseases are common presentations of occupational neurotoxic syndromes in Korea. Few neurotoxins cause patients to present with pathognomic neurologic syndrome. Detailed neurologic examinations and categorization of the clinical manifestations of neurologic disorders will improve the clinical management of occupational neurologic diseases. Physicians must be aware of the typical signs and symptoms of possible exposure to neurotoxins, and they should also pay attention to less-typical, rather-vague symptoms and signs in workers because the toxicologic characteristics of occupational neurologic diseases in Korea have changed from typical patterns to less-typical or equivocal patterns. This shift is likely to be due to several years of low-dose exposure, perhaps combined with the effects of aging, and new types of possibly toxicant-related neurodegenerative diseases. Close collaboration between neurologists and occupational physicians is needed to determine whether neurologic disorders are work-related

Bone Mineral Density According to Age, Bone Age, and Pubertal Stages in Korean Children and Adolescents

To determine whether bone age (BA)-based bone mineral density (BMD) reference values are more accurate than chronological age-based BMD values in predicting the BMD of children who have a discrepancy between their chronological age and BA; we calculated BMD reference values for 514 healthy Korean children (262 girls and 252 boys) aged 5-20 yr by dual-energy X-ray absorptiometry. We found that children with BA chronological age discrepancy fitted better to the BA BMD reference curve than to the chronological age BMD reference curve. In contrast, most children without BA-chronological age discrepancy fitted well to both BA and chronological age BMD reference curves, because the 2 reference curves are very similar. In the linear regression analysis, BA-based equations for BMD had a higher R 2 value and lower standard error of estimate than chronological age-based equations. These results indicate that BA-based BMD values are more accurate in predicting BMD in children who have a discrepancy between their BA and chronological age.Gordon CM, 2008, J CLIN DENSITOM, V11, P43, DOI 10.1016/j.jocd.2007.12.005MOON JS, 2008, KOREAN J PEDIAT, V51, P1Baim S, 2008, J CLIN DENSITOM, V11, P6, DOI 10.1016/j.jocd.2007.12.002Buken B, 2007, FORENSIC SCI INT, V173, P146, DOI 10.1016/j.forsciint.2007.02.023Savaridas SL, 2007, J PEDIATR ORTHOPED, V27, P952, DOI 10.1097/bpo.0b013e31815b12f4Cui LH, 2007, J BONE MINER METAB, V25, P165, DOI 10.1007/s00774-006-0747-3Sheth RD, 2006, EPILEPSY BEHAV, V9, P601, DOI 10.1016/j.yebeh.2006.08.003Clark EM, 2006, J BONE MINER RES, V21, P1489, DOI 10.1359/JBMR.060601Ferrari SL, 2006, J BONE MINER RES, V21, P501, DOI 10.1359/JBMR.051215Cooper C, 2006, OSTEOPOROSIS INT, V17, P337, DOI 10.1007/s00198-005-2039-5Bachrach LK, 2005, ENDOCRIN METAB CLIN, V34, P521, DOI 10.1016/j.ecl.2005.04.001Pludowski P, 2005, J CLIN DENSITOM, V8, P48Jones G, 2005, BONE, V36, P352, DOI 10.1016/j.bone.2004.11.001Arabi A, 2004, BONE, V35, P1169, DOI 10.1016/j.bone.2004.06.015Freedman DS, 2002, PEDIATRICS, V110van der Sluis IM, 2002, ARCH DIS CHILD, V87, P341van der Sluis IM, 2002, J PEDIATR, V141, P204, DOI 10.1067/mpd.2002.125728Goulding A, 2001, J PEDIATR, V139, P509, DOI 10.1067/mpd.2001.116297Henderson CJ, 2000, ARTHRITIS RHEUM, V43, P531Bachrach LK, 1999, J CLIN ENDOCR METAB, V84, P4702, DOI 10.1210/jc.84.12.4702Semeao EJ, 1999, J PEDIATR, V135, P593, DOI 10.1016/S0022-3476(99)70058-2Bass S, 1999, J CLIN INVEST, V104, P795Ilich JZ, 1996, SKELETAL RADIOL, V25, P431BEUNEN GP, 1994, INT J OBESITY, V18, P542ALLEN DB, 1994, J ALLERGY CLIN IMMUN, V93, P967RECKER RR, 1992, JAMA-J AM MED ASSOC, V268, P2403KROGER H, 1992, BONE MINER, V17, P75TROUERBACH WT, 1991, BONE MINER, V13, P55GLASTRE C, 1990, J CLIN ENDOCR METAB, V70, P1330GREULICH WW, 1950, RADIOGRAPHIC ATLAS S

Safety and efficacy of acupuncture for mild cognitive impairment: a study protocol for clinical study

BackgroundMild cognitive impairment (MCI) is an intermediary condition between typical cognitive decline that occurs owing to aging and dementia. It is necessary to implement an intervention to slow the progression from MCI to Alzheimer’s disease. This manuscript reports the protocol for a clinical trial on the effect of acupuncture in patients with MCI.MethodsThe trial will be a randomized, prospective, parallel-arm, active-controlled trial. Sixty-four patients with MCI will be randomized to the Rehacom or acupuncture group (n = 32 each). The participants in the acupuncture group will receive electroacupuncture at GV24 (Shenting) and GV20 (Baihui) and acupuncture at EX-HN1 (Sishencong) once (30 min) a day, twice per week for 12 weeks. The patients in the Rehacom group will receive computerized cognitive rehabilitation using RehaCom software once (30 min) daily, twice weekly for 12 weeks. The primary outcome measure is the change in the Montreal Cognitive Assessment Scale score. The secondary outcome measures are the Geriatric Depression Scale, Alzheimer’s Disease Assessment Scale-Korean version-cognitive subscale-3 scores, and European Quality of Life Five Dimensions Five Level Scale. The safety outcomes will include the incidence of adverse events, blood pressure, blood chemistry parameters, and pulse rate. The efficacy outcome will be assessed at baseline and at six weeks, 13 weeks, and 24 weeks after baseline.DiscussionThe findings of this protocol will provide information regarding the effects of acupuncture on MCI.Clinical trial registrationhttps://cris.nih.go.kr/cris/search/detailSearch.do?search_lang=E&focus=reset_12&search_page=M&pageSize=10&page=undefined&seq=25579&status=5&seq_group=25579, KCT0008861

Data_Sheet_2_Safety and efficacy of acupuncture for mild cognitive impairment: a study protocol for clinical study.pdf

BackgroundMild cognitive impairment (MCI) is an intermediary condition between typical cognitive decline that occurs owing to aging and dementia. It is necessary to implement an intervention to slow the progression from MCI to Alzheimer’s disease. This manuscript reports the protocol for a clinical trial on the effect of acupuncture in patients with MCI.MethodsThe trial will be a randomized, prospective, parallel-arm, active-controlled trial. Sixty-four patients with MCI will be randomized to the Rehacom or acupuncture group (n = 32 each). The participants in the acupuncture group will receive electroacupuncture at GV24 (Shenting) and GV20 (Baihui) and acupuncture at EX-HN1 (Sishencong) once (30 min) a day, twice per week for 12 weeks. The patients in the Rehacom group will receive computerized cognitive rehabilitation using RehaCom software once (30 min) daily, twice weekly for 12 weeks. The primary outcome measure is the change in the Montreal Cognitive Assessment Scale score. The secondary outcome measures are the Geriatric Depression Scale, Alzheimer’s Disease Assessment Scale-Korean version-cognitive subscale-3 scores, and European Quality of Life Five Dimensions Five Level Scale. The safety outcomes will include the incidence of adverse events, blood pressure, blood chemistry parameters, and pulse rate. The efficacy outcome will be assessed at baseline and at six weeks, 13 weeks, and 24 weeks after baseline.DiscussionThe findings of this protocol will provide information regarding the effects of acupuncture on MCI.Clinical trial registrationhttps://cris.nih.go.kr/cris/search/detailSearch.do?search_lang=E&focus=reset_12&search_page=M&pageSize=10&page=undefined&seq=25579&status=5&seq_group=25579, KCT0008861.</p

Data_Sheet_1_Safety and efficacy of acupuncture for mild cognitive impairment: a study protocol for clinical study.PDF

BackgroundMild cognitive impairment (MCI) is an intermediary condition between typical cognitive decline that occurs owing to aging and dementia. It is necessary to implement an intervention to slow the progression from MCI to Alzheimer’s disease. This manuscript reports the protocol for a clinical trial on the effect of acupuncture in patients with MCI.MethodsThe trial will be a randomized, prospective, parallel-arm, active-controlled trial. Sixty-four patients with MCI will be randomized to the Rehacom or acupuncture group (n = 32 each). The participants in the acupuncture group will receive electroacupuncture at GV24 (Shenting) and GV20 (Baihui) and acupuncture at EX-HN1 (Sishencong) once (30 min) a day, twice per week for 12 weeks. The patients in the Rehacom group will receive computerized cognitive rehabilitation using RehaCom software once (30 min) daily, twice weekly for 12 weeks. The primary outcome measure is the change in the Montreal Cognitive Assessment Scale score. The secondary outcome measures are the Geriatric Depression Scale, Alzheimer’s Disease Assessment Scale-Korean version-cognitive subscale-3 scores, and European Quality of Life Five Dimensions Five Level Scale. The safety outcomes will include the incidence of adverse events, blood pressure, blood chemistry parameters, and pulse rate. The efficacy outcome will be assessed at baseline and at six weeks, 13 weeks, and 24 weeks after baseline.DiscussionThe findings of this protocol will provide information regarding the effects of acupuncture on MCI.Clinical trial registrationhttps://cris.nih.go.kr/cris/search/detailSearch.do?search_lang=E&focus=reset_12&search_page=M&pageSize=10&page=undefined&seq=25579&status=5&seq_group=25579, KCT0008861.</p

Identification of Grain Size-Related QTLs in Korean japonica Rice Using Genome Resequencing and High-Throughput Image Analysis

Grain size is a key factor influencing the grain yield in rice. To identify the as-yet-unknown genes regulating grain size in Korean japonica rice, we developed a recombinant inbred line population (n = 162) from a cross between Odae (large-grain) and Joun (small-grain), and measured six traits including the thousand-grain weights of unhulled and hulled seeds, grain area, grain length, grain width and grain length-to-width ratio using high-throughput image analysis at the F8 and F9 generations. A genetic map was constructed using 248 kompetitive allele-specific PCR (KASP) markers that were polymorphic between the parental genotypes, and 29 QTLs affecting the six traits were identified, of which 15 were stable in both F8 and F9 generations. Notably, three QTL clusters affecting multiple traits were detected on chromosomes 6, 7 and 11. We analyzed whole-genome resequencing data of Odae and Joun, and selected candidate genes for the stable QTLs in the identified clusters that have high- or moderate-impact variations between Odae and Joun and encode proteins the families of which have been reported to be related to grain size regulation. These results will facilitate the identification of genes underlying the QTLs and promote molecular breeding of high-yielding Korean japonica rice varieties