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Since June 2020, a new H9N2 virus of the Y280 lineage has been epidemic in Korea. Initially, a Korean commercial vaccine against the Y280 and Y439 lineages of H9N2 was evaluated for use in SPF chickens. A single vaccination did not protect chickens against virus of the Y280 lineage, with no significant reduction in virus shedding and a 37.5% inhibition in virus recovery rate in cecal tonsil. rgHS314 was selected as a vaccine candidate, showing immunogenicity in SPF chickens, and was highly productive in eggs. Moreover, rgHS314 protected with high levels of protective immunity and significantly reduced virus shedding, with 100% and 83.3% inhibition of virus recovery in the cecal tonsil against homologous and heterologous challenge viruses, respectively. Taken together, these data suggest that a single vaccination with this recombinant vaccine candidate could elicit cross-reactive immune responses capable of protecting chickens against H9N2 viruses of the Y439 and Y280 lineages.

Background Nasopharyngeal (NP) colonization with Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) is common in children, and may evolve as the source of invasive infections. In Korea, the pneumococcal conjugate vaccines (PCVs) were introduced >10 years ago, enabling the authors to study the effect of the vaccine in preventing carriage. Methods NP swabs were taken and a household survey was conducted at daycare centres located in different regions of Korea in 2014 and 2019. Pneumococcal serotypes were identified using the Quellung method and sequencing. NTHi were identified based on pilA and bexA genes. Results In total, 1460 NP swabs were obtained with pneumococcal carriage rates of 36.4–42.1% and NTHi carriage rates of 36.5–26.7%. Among children carrying pneumococci, a significant increase was seen in serotype 23A between 2014 and 2019 (from 12.6% to 22.0%; P=0.005). Children who had received PCV were at lower risk of vaccine-type carriage (2.9% vs 0.8%; P=0.005). Conclusions Between 2014 and 2019, the proportion of children carrying serotype 23A increased significantly, while the carriage rate of NTHi decreased. Continuous surveillance is needed to assess the long-term effects of the PCVs on carriage dynamics of pneumococcus and NTHi.

The immunogenicity and protective efficacy of inactivated clade 2.3.2.1c (rgKA435) and clade 2.3.4.4c (rgES2) H5Nx vaccines, which are representatives of an avian influenza antigen bank in Korea, were examined in mice. Mice were vaccinated twice and then challenged with homologous virus. Hemagglutinin inhibition and serum neutralizing antibody titers in the rgES2-vaccinated group were higher (4.4 ± 1.7 and 10.8 ± 2.3 log2, respectively) than those in the rgKA435-vaccinated group (2.8 ± 1.1 and 2.5 ± 0.9 log2, respectively). rgES2 conferred 100% protection, with no morbidity, no severe body weight loss, and no virus replication in any of the tissues tested. By contrast, 80% of mice in the rgKA435 group survived. One mouse in this group died at 10 dpi. Virus titers in the lung and turbinate were 102.5–3.5 TCID50/0.1 ml at 3–7 dpi and 101.5 TCID50/0.1 ml at 3–5 dpi, respectively. In particular, the viral titer in the turbinate from the rgKA435 group at 3 dpi was significantly lower than that in the equivalent control group (p

The occurrence of severe outbreaks of highly pathogenic avian influenza in Korea led to establishment of a national antigen bank for emergency preparedness. Here, we developed five vaccines for this bank (clade 2.3.2.1C, clade 2.3.4.4A, B, C, and D) by reverse genetics, inactivated them with formalin, and evaluated the protective efficacy and potency of serial dilutions against lethal homologous challenge in specific-pathogen-free chickens. After vaccination with one dose, each vaccine resulted in 100% survival, with no clinical symptoms, or lack of detectable virus shedding, and high levels of pre-challenge protective immunity (8.4-10.2 log2). After vaccination with one-tenth of the full dose, protection was similar to that with the full dose. After vaccination with one-hundredth of the initial dose, survival was 20-80%, and all vaccines showed virus shedding. Four vaccines (excluding clade 2.3.2.1C) had satisfactory potency. In antibody-persistence tests, all vaccines maintained long-lasting protective immunity. Our results suggest that inactivated reverse-genetics vaccines genetically matched to outbreak viruses provide adequate protection after a single vaccination.

The spastin protein (SPAST) contains an ATPase with diverse cellular activities (AAA) domain and regulates microtubule dynamics. Missense mutations of the SPAST gene are frequently detected in patients with hereditary spastic paraplegias (HSPs) and represent the main reason of loss of SPAST function; however, the pathogenicity of mutant SPAST is heterogeneous. Here, SPAST variant with an I344K mutation (I344K-SPAST) was identified in a Korean family with autosomal dominant-type HSP. We investigated the role of the I344K-SPAST in HSP to provide a therapeutic mechanism. The I344K-SPAST mutation prolonged the half-life of the protein compared to wild-type SPAST (WT-SPAST) in cells by modulating post-translational modifications for proteasomal degradation. I344K-SPAST was localized in microtubule but defective in microtubule severing and ATPase activity compared to WT-SPAST in vitro and in cells. Mutant M87 isoform harboring the same mutation with I344K-M1 SPAST also increased protein stability and loss of MT severing activity, but the pathogenicity was not stronger than I344K-M1 SPAST in neurite outgrowth. Overexpression of I344K-SPAST resulted in microtubule accumulation following inhibited neurite growth in neuroblastoma, neural progenitor cells and mouse primary cortical neurons. Conversely, these pathogenic effects of I344K-SPAST were reduced by overexpression of WT-M1 SPAST in a dose dependent manner since WT-SPAST could interact with I344K-SPAST. Our data therefore provide proof-of-concept that gene transfer of WT-M1 SPAST may serve as a valid therapeutic option for HSPs.

Kidney disease is poorly understood because of the organ’s cellular diversity. We used single-cell RNA sequencing not only in resolving differences in injured kidney tissue cellular composition but also in cell-type-specific gene expression in mouse models of kidney disease. This analysis highlighted major changes in cellular diversity in kidney disease, which markedly impacted whole-kidney transcriptomics outputs. Cell-type-specific differential expression analysis identified proximal tubule (PT) cells as the key vulnerable cell type. Through unbiased cell trajectory analyses, we show that PT cell differentiation is altered in kidney disease. Metabolism (fatty acid oxidation and oxidative phosphorylation) in PT cells showed the strongest and most reproducible association with PT cell differentiation and disease. Coupling of cell differentiation and the metabolism was established by nuclear receptors (estrogen-related receptor alpha [ESRRA] and peroxisomal proliferation-activated receptor alpha [PPARA]) that directly control metabolic and PT-cell-specific gene expression in mice and patient samples while protecting from kidney disease in the mouse model.

SummaryThe kidney has a tremendous capacity to regenerate following injury, but factors that govern this response are still largely unknown. We isolated cells from mouse kidneys with high proliferative and multi-lineage differentiation capacity. These cells expressed a high level of Sox9. In regenerating kidneys, Sox9 expression was induced early, and 89% of proliferating cells were Sox9 positive. In vitro, Sox9-positive cells showed unlimited proliferation and multi-lineage differentiation capacity. Using an inducible Sox9 Cre line and lineage-tagging methods, we show that Sox9-positive cells can generate new daughter cells, contributing to the regeneration of proximal tubule, loop of Henle, and distal tubule segments but not to collecting duct and glomerular cells. Furthermore, inducible deletion of Sox9 resulted in reduced epithelial proliferation, more severe injury, and fibrosis development. In summary, we demonstrate that, in the kidney, Sox9-positive cells show progenitor-like properties in vitro and contribute to epithelial regeneration following injury in vivo.

Stable and reproducible kidney cellular models could accelerate disease understanding, help therapeutics development and improve nephrotoxicity screens. Generation of a reproducible in vitro kidney models have been challenging due to the cellular heterogeneity and structural complexity. Here, we established a renal cell line and developed a system to generate kidney spheroids containing multiple cell types that structurally and functionally recapitulates features of the kidney. First we generated immortalized cell lines from mouse and human kidneys that stably maintain their characteristics of expression of renal progenitor markers and its proliferative capacity. We show that these cells can be differentiated into kidney spheroids that contains multiple nephron segments; such as proximal tubule Loop of Henle, distal tubules, and podocytes. The cellular differentiation is enhanced by culturing these structures in an extracellular matrix. They expressed all apical and basolateral transporters that are important for drug metabolism. The spheroids recapitulated key functional aspects of the kidney including protein endocytosis, increased gamma-glutamyltransferase activity and cyclic AMP responded to external cues, such as parathyroid hormone. Following exposure, cells efflux and take up drugs via proximal tubule specific apical or basolateral transporters, display increased cell death and expression of renal injury marker. Here, we generated new mouse and human renal cell lines, developed an in vitro differentiation method to generate kidney spheroids that recapitulate the kidney both structurally and functionally, and can be used for drug toxicity and therapeutics development. Funding Statement: This research was supported by the KRIBB Research Initiative Program and the Midcareer Researcher Program (2016R1A2B4011124) through the National Research Foundation of Korea funded by the Ministry of Science and ICT. Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: All experimental protocol was approved by the Institutional Ethics Committee/IRB of the Korea Research Institute of Bioscience and Biotechnology (KRIBB).

The purpose of this study was to examine the relationship among the Self-esteem, Gratitude disposition and Happiness in Pre-service Early Childhood Teachers. The subjects in this study were 192 Pre-service Early Childhood Teachers in Busan in South Korea. The findings of the study were as follows: First, the early childhood teachers considered the level of their own Happiness, Self-esteem and Gratitude disposition to be above average. Second, there was a significant positive correlation among their total scores of Happiness, Self-esteem and Gratitude disposition. And there was a significant positive correlation among the subfactors of Happiness, Self-esteem and Gratitude disposition. Third, the independent variable that made the largest prediction of Happiness was Self-esteem, followed by Gratitude disposition.

In this study, the structural performance of prestressed composite girders with corrugated webs was evaluated by conducting experiments on a total of five specimens with the key test variables of prestress level, tendon layout patterns, welding methods, and shear connectors. The test results showed that flexural performances of the prestressed composite girders were superior to the non-prestressed specimen. Partial interaction analyses were also performed on the test specimens to investigate the horizontal shear transfer mechanisms between steel girder and concrete, and their results were discussed in detail.

Current influenza vaccines do not provide good protection against antigenically different influenza A viruses. As an approach to overcome strain specificity of protection, this study demonstrates significantly improved long-term cross protection by supplementing split vaccines with a conserved molecular target, a repeat of the influenza M2 ectodomain (M2e) expressed on virus-like particles (M2e5x VLPs) in a membrane-anchored form. Intramuscular immunization with H1N1 split vaccine (A/California/07/2009) supplemented with M2e5x VLPs induced M2e-specific humoral and cellular immune responses, and shaped the host responses to the vaccine in the direction of T-helper type 1 responses inducing dominant IgG2a isotype antibodies as well as interferon-γ (IFN-γ) producing cells in systemic and mucosal sites. Upon lethal challenge, M2e5x VLP-supplemented vaccination lowered lung viral loads and induced long-term cross protection against H3N2 or H5N1 subtype influenza viruses over 12 months. M2e antibodies, CD4 T cells, and CD8 T cells were found to contribute to improving heterosubtypic cross protection. In addition, improved cross protection by supplemented vaccination with M2e5x VLPs was mediated via Fc receptors. The results support evidence that supplementation with M2e5x VLPs is a promising approach for overcoming the limitation of strain-specific protection by current influenza vaccination.

Currently, there are limited ways to preserve or recover insulin secretory capacity in human pancreas. We evaluated the efficacy of cell therapy using insulin-secreting cells differentiated from human eyelid adipose tissue-derived stem cells (hEAs) into type 2 diabetes mice. After differentiating hEAs into insulin-secreting cells (hEA-ISCs) in vitro, cells were transplanted into a type 2 diabetes mouse model. Serum levels of glucose, insulin and c-peptide were measured, and changes of metabolism and inflammation were assessed in mice that received undifferentiated hEAs (UDC group), differentiated hEA-ISCs (DC group), or sham operation (sham group). Human gene expression and immunohistochemical analysis were done. DC group mice showed improved glucose level, and survival up to 60 days compared to those of UDC and sham group. Significantly increased levels of human insulin and c-peptide were detected in sera of DC mice. RT-PCR and immunohistochemical analysis showed human gene expression and the presence of human cells in kidneys of DC mice. When compared to sham mice, DC mice exhibited lower levels of IL-6, triglyceride and free fatty acids as the control mice. Transplantation of hEA-ISCs lowered blood glucose level in type 2 diabetes mice by increasing circulating insulin level, and ameliorating metabolic parameters including IL-6.

Influenza virus A (H5N1) clade 2.3.2.1 has recently caused widespread outbreaks of disease in domestic poultry and wild birds in Eastern Asia. In the current study, the antigenicity and pathogenicity of three clade 2.3.2.1 viruses (Ck/Kr/Gimje/08, Ws/Mongolia/1/09, and Ws/Mongolia/7/10) were investigated in domestic ducks and mice. The H5N1 influenza viruses in this study were antigenically similar to each other (r-values of 0.35-1.4). The three viruses replicated systemically in all tissues tested in domestic ducks, indicating high pathogenicity. However, the viruses produced different clinical signs and mortality rates: Ck/Kr/Gimje/08 and Ws/Mongolia/1/09 resulted in 100% mortality with severe neurological signs, whereas Ws/Mongolia/7/10 resulted in 50% mortality with relatively mild neurological signs. In mice, infection with Ck/Kr/Gimje/08 and Ws/Mongolia/7/10 resulted in weight loss that peaked at 4 days post-infection (22.3% and 20.8%, respectively), same MLD50 (2.2 Log10 EID50) and systemic replication. The three viruses had K deletion at the -2 position of the HA1-connecting peptide (PQRERRRK-R), which is associated with increased virulence in domestic ducks and harbored NA stalk deletion, NS1 deletion and mutation of P42S in NS1, and full length (90aa) in PB1-F2, which confer increased virulence in mice. Our study shows that clade 2.3.2.1 viruses from Korea and Mongolia are antigenically similar and highly pathogenic in both domestic ducks and mice. Moreover, we provide molecular determinants of the clade 2.3.2.1 viruses associated with the pathogenicity in domestic ducks and mice, respectively.

From the avian influenza virus (AIV) outbreaks and market surveillances in Vietnam during November 2011 and March 2012, a total of 196 AIV were isolated. Although H5N1 highly pathogenic avian influenza (HPAI) was the most prevalent subtype in Vietnam, 57 low pathogenic avian influenza (LPAI) viruses were identified from mainly domestic ducks and some chickens. Of note, various subtypes of LPAI viruses were isolated from domestic ducks in Vietnam: H3 (n = 16), H4 (n = 4), H6 (n = 24), H7 (n = 1), and H9 (n = 10). Geographically, the LPAI viruses were identified in different regions of Vietnam. Phylogenetic analysis of HA and NA genes in LPAIV in Vietnam showed that some H3 (group I) and H4 subtypes AIV clustered with the viruses of several Asian isolates from domestic poultry and wild birds. However, the H6, H9, and some H3 (group II and III) subtypes AIV were closely related to isolates from domestic poultry in Southern China. In addition, whereas the N2 and N6 subtypes AIV belonged to the Eurasian lineage, the N8 subtype AIV was classified to be both of Eurasian and American lineage. These findings revealed that the regional trade and wild birds play a key role transmission of LPAIV in domestic ducks in Vietnam. Further surveillance at the intercountry level is needed to understand the epidemiology of these viruses and to cope with emergence of novel AIV types.

Since 2003, the highly pathogenic avian influenza (HPAI) H5N1 has become a serious problem in animals and an increasing threat to public health. To develop effective vaccines for H5 HPAI in chickens, virus-like particles (VLP) were produced using a baculovirus expression system. The particles comprised hemagglutinin (HA) alone (HA-VLP) or HA in combination with a matrix protein (M1; HAM-VLP) derived from a recent clade 2.3.2.1 H5N1 HPAI virus. To compare the immunogenicity and protective efficacy of these VLPs, 10 μg HAM-VLP, the equivalent amounts of HA incorporated HA-VLP or whole inactivated virus (WIV), were emulsified with mineral oil and used to immunize chickens. The serum hemagglutination inhibition antibody levels induced by HA-VLP and HAM-VLP were comparable to WIV. Antibodies to nucleoprotein were detected only in the WIV group. Immunized chickens in each group survived and were protected against a lethal homologous virus challenge, showing no clinical signs of infection. The challenge virus was detected intermittently in some oropharyngeal swabs, but not in cloacal swabs or various organs, which means that VLPs and WIV provide protection against systemic but not local virus replication in chickens. After the challenge, the HA-VLP group showed significantly increased serum antibody levels compared to the HAM-VLP and WIV groups, and some chickens in the HA-VLP group seroconverted with respect to nucleoprotein. Taken together, these results suggest that VLPs may be an effective method for controlling HPAI in chickens. They could be applied to a differentiating infected from vaccinated animals (DIVA) strategy. In addition, it is likely that HAM-VLP is more efficacious than HA-VLP in chickens.

Migratory waterfowls are the most common reservoir for avian influenza virus (AIV), thus viral adaptation is required for efficient replication in land fowls. To date, low pathogenic (LP) H5 subtype AIVs have been isolated from migratory waterfowls, and the adaptation of these viruses to land fowls might lead to the generation of highly pathogenic AIVs. Thus, A/wild duck/Korea/50-5/2009 (H5N1) LPAIV was passaged 20 times through embryonated chicken eggs (ECEs), and the resulting genetic and phenotypic changes were investigated. The pathogenicities of the early (50-5-E2) and final passage (50-5-E20) strains to chicken embryos were similarly high, but the 50-5-E20 titer was 100 times higher than that of 50-5-E2. 50-5-E20 showed 8 amino acid changes in PA (1), HA (4), NA (1), M1 (1) and M2 (1), with different frequencies among influenza A viruses (0-99.6%). The relevance of these changes, except H103Y in HA, to viral replication remains unknown. To investigate the roles of internal genes and mutations in HA and NA in viral replication, four recombinant viruses possessing combinations of HA and NA genes of 50-5-E2 and 50-5-E20 with 6 internal genes of PR8 were generated through reverse genetics. The embryo pathogenicities of the H5N1 recombinant viruses carrying internal PR8 genes were reduced, and the titers of the recombinant viruses with 50-5-E20 HA were higher than those with 50-5-E2 HA. Therefore, the identified mutations might be useful as chicken adaptation markers for the generation of high growth H5N1 recombinant viruses in ECEs.

A total of 13 avian influenza viruses of the H10 subtype were isolated from wild birds in South Korea over the winter season between July 2008 and July 2011. The HA cleavage site of most of the isolated viruses, PEIMQGR↓G was similar to that of H10 viruses (A/turkey/England/384/79 and A/mandarin duck/Singapore/805/93), which are well known to be highly pathogenic in chickens. The exception was the A/mallard/Korea/1242/10(H10N6) virus, which had a PEMMQGR motif. Phylogenetic analysis showed that eight genes of the isolated H10 viruses belonged to the Eurasian lineage, and that the Korean H10 viruses could be divided four genotypes (genotypes A, B, C and D). Chicken challenge studies revealed that most of the H10 viruses did not replicate well through the natural infection route, but a genotype D virus was re-isolated from the brain of a chicken inoculated by the intravenous route. Although H10 viruses have not been isolated from poultry in South Korea, our results emphasize the continuing need to monitor the evolutionary genetics of the influenza virus in wild birds.

The present study was conducted to monitor wild birds based on the concern that they could disseminate avian influenza virus (AIV) between Mongolia and Korea, which shares the same migratory flyway. Of 1,528 fecal samples analyzed, 21 low-pathogenic AIV were isolated from 2007 to 2009. Nineteen AIV-positive fecal samples were identified as Anseriformes by DNA bar coding. The most frequently isolated subtype was H3 (61.9%), and the most prevalent hemagglutinin/neuraminidase combination was H3N8 (52.4%). Phylogenetic analysis was performed to assess their genetic relationships with those of domestic poultry and wild birds in Korea. The H3 and H7 surface genes belonged to the Eurasian lineage and clustered together in a group with Korean wild birds and poultry. Most N8 genes clustered phylogenetically with viruses isolated in Eurasia, whereas 1 of the Mongolian viruses and some Korean viruses belonged to the North American lineage. The polymerase acidic protein of the internal gene was not distinguishable from the H5N1 highly pathogenic AIV of the goose/Guangdong/1/1996 (Gs/Gd)-like virus. Our study suggests that Mongolian AIV isolates have evolved with genetically multiple genotypes and are closely related to those of AIV in poultry as well as in wild birds in Korea.

Active surveillance for avian influenza virus (AIV) has expanded from chicken to various poultry species including duck. To further effective antibody screening in laying breeder ducks, we validated the egg yolk antibody as alternative source to serum for AIV antibody. Sera and eggs were collected at weekly intervals after two types of AIV vaccination, H5N3 and H9N2. The antibody levels were determined by an agar gel immunodiffusion (AGID) test, haemagglutination inhibition (HI) test and the competitive enzyme-linked immunosorbent assay (C-ELISA). AGID test did not detect antibodies in egg yolk, and the agreement between AGID test and either HI test or C-ELISA in serum was slight and fair based on kappa statistics (kappa value (κ) ≤ 0.19 in H5N3 group and κ ≤ 0.37 in H9N2 groups). However, there was almost perfect agreement between HI test and C-ELISA (κ > 0.9 in all group). The C-ELISA was as sensitive and specific as the HI test, and could be used as a pre-screening test for the detection of type A avian influenza virus antibody. Comparison was made between egg yolk and serum antibody titers by a regression analysis. A high correlation was observed between serum and yolk antibody titers (r = 0.8762 for H5N3 and 0.8914 for H9N2 in HI test; r = 1 for H5N3 and 0.9686 for H9N2 in ELISA test), although egg yolk antibodies were detected later and remained lower levels than serum antibodies. In field trials involving 54 duck flocks, the positive rate of egg yolk and serum samples showed agreement for the detection of AIV antibody. We concluded that as an alternative to serum, antibody monitoring of laying breeder duck using egg yolk with C-ELISA is feasible and is recommended.

The prevalence and continuous evolution of H9N2 avian influenza viruses in poultry have necessitated the use of vaccines in veterinary medicine. Because of the inadequate growth properties of some strains, additional steps are needed for producing vaccine seed virus. In this study, we generated three H9N2/PR8 reassortant viruses using a total cDNA plasmid-transfection system, as an alternative strategy for developing an avian influenza vaccine for animals. We investigated the vaccine potency of the reassortant viruses compared with the existing vaccine strain which was adapted by the 20th serial passages in embryonated eggs with A/Ck/Kor/01310/01 (H9N2). The H9N2/PR8 reassortant viruses, containing the internal genes of the high-yielding PR8 strain and the surface gene of the A/Ck/Kor/01310/01 strain, could be propagated in eggs to the same extent as existing vaccine strain without additional processing. Similar to vaccine strain, the H9N2/PR8 reassortant viruses induced hemagglutination-inhibiting antibodies in chickens and prevented virus shedding and replication in multiple organs in response to homologous infection. However, due to the continuing evolution and increasing biologic diversity of H9N2 influenza in Korea, the vaccine provided only partial protection against currently isolates. Taken together, our results suggest that the H9N2/PR8 reassortant virus can be used as a seed virus for avian influenza vaccines in poultry farm. Considering the constant genetic changes in H9 strains isolated in Korea, this reverse genetic system may offer a prompt and simple way to change the vaccine seed virus and mitigate the impact of unexpected influenza outbreaks.

Background & Aims: Although genetic aspects of tumorigenesis in colorectal cancer (CRC) have been well studied, reliable biomarkers predicting prognosis are scarce. We aimed to identify recurrently altered genomic regions (RAR) in CRC with high resolution, to investigate their implications on survival and to explore novel cancer-related genes in prognosis-associated RARs. Methods: A 1-Mb resolution microarray-based comparative genomic hybridization (array CGH) was applied to 59 CRCs. RARs, defined as genomic alterations, detected in more than 10 cases were identified and analyzed for their association with survival. Expression levels of genes in prognosis-associated RARs were examined by real-time quantitative polymerase chain reaction. Results: Twenty-seven RARs were identified. Eleven high-level amplifications and 2 homozygous deletions also were detected, but they were not as common as RARs. Multivariate analysis revealed RAR-L1 (loss on 1p36; hazard ratio=8.15, P = .002) and RAR-L20 (loss on 21q22; hazard ratio=3.53, P = .034) are independent indicators of poor prognosis. Expression of CAMTA1 , located in RAR-L1, was reduced frequently in CRCs, and low CAMTA1 expression was associated significantly with poor prognosis, which indicates that CAMTA1 may play a role as a tumor suppressor in CRC. Five pairs of RARs were correlated significantly to each other and 3 pairs share genes involved in the same biological functions, suggesting possible collaborative roles in tumorigenesis. Conclusions: We identified recurrent genomic changes in 59 CRCs. RARs could be more important in sporadic tumors where the effect of genomic changes on tumorigenesis is relatively smaller than in familial cancer. Our results and analysis strategy will be helpful to elucidate pathogenesis of CRCs or to develop biomarkers for predicting prognosis.

The genetic mechanism for the development and progression of a lymphoma is unclear. This study investigated the alterations in the DNA copy number and the expression profiles of the genes located in the altered regions in mouse thymic lymphomas that were induced by two mutagens, gamma-irradiation and N-methyl-N-nitrosourea (MNU). Microarray-based comparative genomic hybridization was used to precisely delineate the boundaries of the altered region. The copy number gains of chromosomes 4 and 5 were observed only in the radiation-induced lymphomas, and gains of chromosomes 10 and 14 were observed only in the MNU-induced lymphomas. Regional copy number losses in chromosomes 11, 16, and 19 appeared frequently in the radiation-induced lymphomas. The cancer-related genes Pten, Ikaros/Znfn1a1, Ercc4, and Top3b were located in the minimal deletion regions. In particular, the expression levels of the Pten, Top3b, and Ikaros genes were downregulated in both lymphoma groups, but the expression level of Ercc4 was downregulated only in the MNU group. This study also examined the expression levels of Sparc, Cxcl1, and Myc (synonym: c-Myc), which are located in the copy number gained chromosomes. Sparc was upregulated specifically in the radiation group, and Cxcl1 in the MNU group. c-Myc was upregulated in both groups. There was limited correlation between the DNA copy number profiles and the expression of the cancer-related genes in mouse lymphomagenesis. The chromosome aberrations and novel expression profiles of the cancer-related genes within the altered regions may provide important clues to the genetic mechanism for the development of lymphoma.

The screening of natural products that preferentially inhibit growth of H-ras transformed rat2 cells vs. rat2 cells was performed to identify H-ras specific growth inhibitor. A lanostane-type triterpene acid, dehydrotrametenolic acid (3beta-hydroxylanosta-7,9(11),24-trien-21-oic acid), was isolated from the sclerotium of Poria cocos (Polyporaceae). Dehydrotrametenolic acid selectively inhibited the growth of H-ras transformed cells with a GI(50) value of 40 microM. FACS analysis indicated that the compound exerted its anti-proliferation effects through cell cycle arrest at G2/M phase and accumulation of sub-G1 population. Dehydrotrametenolic acid-induced apoptosis was further confirmed with chromosomal DNA fragmentation, caspase-3 activation, and degradation of PARP and Lamin A/C degradation. The compound also regulated the expression of H-ras, Akt and Erk, which are the downstream proteins of H-ras signaling pathways. The results suggest that dehydrotrametenolic acid can be a potential anticancer agent against H-ras transformed tumor.

Members of the Artemisia genus are important medicinal plants found throughout the world. Arteminolides A–D ( 1 – 4 ), isolated from the aerial parts of Artemisia, have an inhibitory activity on farnesyl-protein transferase (FPTase; EC 2.5.1.29) in in vitro assay. This study was carried out with the purpose of validating anti-tumor effects of the compounds in human tumor cells and mouse xenograft model. The arteminolides inhibited tumor cell growth in a dose-dependent manner. Furthermore, arteminolide C ( 3 ) blocked in vivo growth of human colon and lung tumor xenograft without the loss of body weight in nude mice.

Five sesquiterpene lactones, 8-acetylarteminolide ( 1 ), artanomaloide ( 2 ), arteminones ( 3 and 4 ), and dehydromatricarin ( 5 ), were isolated from the methanolic extract of the flower of Artemisia sylvatica and characterized on the basis of their spectral data. New sesquiterpene lactone 1 was identified as a configurational isomer of artanomaloide ( 2 ), and the new arteminones 3 and 4 are determined as stereoisomers. 8-Acetylarteminolide ( 1 ) strongly inhibited FPTase with an IC 50 of 1.8 μM, however, the other sesquiterpene lactones mildly inhibited the transferase with an IC 50 of 22–300 μM.