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ZMYM4 is a zinc finger protein, whose cancer-related functions are partially known (cell shape maintenance and cell death). In this study, we analyzed 4 sites of mononucleotide repeats in the coding sequence of ZMYM4 in gastric (GC) and colonic cancers (CC). Seven of the 32 high microsatellite instability (MSI-H) GCs (21.9%) and 23 of 113 MSI-H CCs (20.4%) harbored ZMYM4 frameshift mutations with no significant difference between the 2 organs (P>0.05). There was no ZMYM4 frameshift mutations in microsatellite-stable GCs and CCs. We also identified that 6 of 16 MSI-H CCs (37.5%) exhibited intratumoral heterogeneity of the ZMYM4 frameshift mutations. In both GC and CC with MSI-H, ZMYM4 expression in ZMYM4-mutated cases was significantly lower than that in ZMYM4-nonmutated cases. Our study indicates that ZMYM4 is altered at multiple levels (frameshift mutation, mutational intratumoral heterogeneity, and loss of expression), suggesting their relations with MSI-H GC and CC.

Tight junction and gap junction are major cell junctions that play important roles in cellular communication and structural integrity. Alterations of these junctions are known to be involved in cancer pathogenesis. Claudins and connexins are major tight and gap junction proteins, but genetic alterations of these genes have not been reported in gastric (GC) and colorectal cancers (CRC) with microsatellite instability (MSI). Claudin genes CLDN5 and CKDN6, and connexin genes GJB6 and GJB7 have mononucleotide repeats in the coding sequences that might be mutation targets in the cancers with MSI. We analyzed 79 GCs and 145 CRCs, and found CLDN5 frameshift mutations in 3 (3%) CRCs and 1 (2.9%) GC, CLDN6 frameshift mutations in 6 (6%) CRCs, GJB6 frameshift mutations in 5 (5%) CRCs and GJB7 frameshift mutation in one CRC (1%) with high MSI (MSI-H). We also analyzed intratumoral heterogeneity (ITH) of the frameshift mutations in 16 CRCs and found that CLDN6 and GJB6 frameshift mutations showed regional ITH in 2 (12.5%) and 2 (12.5%) cases, respectively. Our results show that CLDN5, CLDN6, GJB6 and GJB7 genes harbor not only frameshift mutations but also mutational ITH, which together may be features of GC and CRC with MSI-H. Based on the roles of cellular junctions in cancers, frameshift mutations of tight junction and gap junction genes might contribute to tumorigenesis by altering their functions in GC and CRC.

Microsatellite instability-high (MSI-H) colorectal cancer (CRC) is different from microsatellite stable (MSS) CRC concerning biological, and clinical features. In MSI-H CRCs, defects of mismatch repair genes produce increased mutation accumulation in repetitive DNA sequences. To see whether candidate tumor suppressor genes (TSGs) are altered in MSI-H CRC, we studied frameshift mutation and protein expression of candidate TSGs of RGS2, HNF1A, HNF1B, CAPN12, RCBTB2, ATE1, PKNOX1, and USP19. We found frameshift mutations of RGS2 in 5 (5%), HNF1A in 6 (6%), HNF1B in 2 (2%), CAPN12 in 3 (3%), RCBTB2 in 4 (4%), ATE1 in 2 (2%), PKNOX1 in 2 (2%), and USP19 in 2 (2%) MSI-H CRCs. However, we found no such mutations in MSS CRCs. RCBTB2, CAPN12, HNF1A, and HNF1B frameshift mutations revealed the regional difference in the same tumors. In addition, we identified loss of RGS2, HNF1A, and CAPN12 protein expression irrespective of MSI phenotype in 13-29% of CRCs. The results indicate that many TSGs harbor concurrent inactivating mutations and protein loss in MSI-H CRCs with intratumoral mutational heterogeneity, and that MSS CRCs are altered by protein losses. These alterations could contribute to CRC development and underlying mechanisms and consequences of the TSG alterations remain to be clarified.

The purpose of this study was to compare and analyze the effects of Crossfit training method on physical fitness in 30’s men. Subjects were divided into 2 groups: AMRAP(as many repetition as possible)group(n=50), TA(time attack)group(n=50). Measurement variables were physical fitness muscular strength, muscular endurance, flexibility, cardiovascular endurance, power. The two - way ANOVA was conducted to analyze the differences and interactions between group and time. In the case of interaction effect, Duncon test was conducted to Post hoc. All significance levels were verified at .05. The results were as follows; There were no significant statistically difference in the change of muscular strength, flexibility and power. but AMRAP group and TA group showed some differences in the amount of muscular strength according to the measurement time. and there were no significant effect of interaction between group and measurement time for muscular endurance, flexibility, cardiovascular endurance and power. Consequently, it showed that 8 weeks Crossfit training method made a similar effect on body composition and physical fitness in 30’s men.

Nucleotide-binding and leucine-rich repeat protein (NLRP) genes are involved in inflammasome formation that plays a role in inflammation/host defense and cell death. Both cell death and inflammation are crucial for cancer development, but the roles of NLRPs in cancer are partially known. In this study, we analyzed mononucleotide repeats in coding sequences of NLRP1, NLRP2, NLRP4 and NLRP9, and found 1, 1, 1 and 8 frameshift mutation (s) in gastric (GC) and colonic cancers (CRC), respectively. Five of the 32 high microsatellite instability (MSI-H) GCs (15.5%) and 6 of 113 MSI-H CRCs (5.5%) exhibited the frameshift mutations. There was no NLRP frameshift mutations in microsatellite stable (MSS) GCs and CRCs. We also discovered that 2 of 16 CRCs (12.5%) harbored intratumoral heterogeneity (ITH) of the NLRP9 frameshift mutations in one or more areas. In both GC and CRC with MSI-H, NLRP9 expression in NLRP9-mutated cases was significantly lower than that in NLRP9-non-mutated cases. Our data indicate that NLRP9 is altered at multiple levels (frameshift mutation, mutational ITH and loss of expression), which together could contribute to pathogenesis of MSI-H GC and CRC.

TRAF2 and TRAF3 genes of tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family are involved in diverse cell signaling, and function as both tumor suppressor gene and oncogene. Alterations of TRAF2 and TRAF3 in colon cancer (CC) along with their regional difference and microsatellite instability (MSI) are largely unknown. In the present study, we analyzed TRAF2 and TRAF3 frameshift mutations in 168 sporadic CCs (100 high MSI (MSI-H) and 68 microsatellite-stable (MSS) CCs). We identified TRAF2 and TRAF3 frameshift mutations in 4 (4%) and 3 CCs (3%) with MSI-H, respectively, but none in 68 cases of MSS CCs. Of the 168 CCs, we analyzed the mutations in multi-regions for 39 CCs (16 MSI-H and 23 MSS CCs), and discovered that 12.5% (2/16) and 6.3% (1/16) of MSI-H CCs exhibited regional difference in TRAF2 and TRAF3 mutations, respectively. In the multi-region samples of 23 MSS CCs, neither TRAF2 nor TRAF3 frameshift mutation was found. In 40% of CCs, both TRAF2 and TRAF3 expressions were increased compared to normal colon cells. Our data indicate that TRAF2 and TRAF3 frameshift mutations and their regional difference as well as altered expressions are present in MSI-H CCs, which could contribute to MSI-H cancer development.

Epigenetic dysregulation is a hallmark of cancers, and examples of its cancer-associated expression and mutation alterations are rapidly growing. Histone methylation, a process by which methyl groups are transferred to amino acids of histone proteins, is crucial for the epigenetic gene regulation. NSD2 (nuclear receptor-binding SET domain protein 2) and SETMAR are epigenetic regulators for histone methylation. KDM2B, also known as FBXL10, is a histone demethylase that targets histone methylation processes. They are known to be altered in many cancers, but somatic frameshift mutation and expression of these genes remain undetermined in many other subsets of cancers, including high microsatellite instability (MSI-H) colon cancer (CC). In this study, we analyzed mononucleotide repeats in coding sequences of NSD2, KDM2B and SETMAR genes, and found frameshift mutations in 10 %, 2 % and 1 % of CCs with MSI-H, respectively. Of note, there was no frameshift mutation of these genes in microsatellite stable (MSS) CCs. In addition, we discovered that 2 and 2 of 16 CRCs (12.5 % and 12.5 %) harbored intratumoral heterogeneity (ITH) of the NSD2 and KDM2B frameshift mutations, respectively. In the immunohistochemistry for NSD2, intensity of NSD2 immunostaining in MSI-H CC is decreased compared to that in MSS. These results suggest that NSD2 might be altered at multiple levels (frameshift mutation, mutational ITH and expression) in MSI-H CCs, and could be related to MSI-H cancer pathogenesis.

Nucleotide-binding and leucine-rich repeat protein (NLRP) genes are involved in inflammasome formation that plays a role in inflammation/host defense and cell death. Both cell death and inflammation are crucial for cancer development, but the roles of NLRPs in cancer are partially known. In this study, we analyzed mononucleotide repeats in coding sequences of NLRP1, NLRP2, NLRP4 and NLRP9, and found 1, 1, 1 and 8 frameshift mutation (s) in gastric (GC) and colonic cancers (CRC), respectively. Five of the 32 high microsatellite instability (MSI-H) GCs (15.5%) and 6 of 113 MSI-H CRCs (5.5%) exhibited the frameshift mutations. There was no NLRP frameshift mutations in microsatellite stable (MSS) GCs and CRCs. We also discovered that 2 of 16 CRCs (12.5%) harbored intratumoral heterogeneity (ITH) of the NLRP9 frameshift mutations in one or more areas. In both GC and CRC with MSI-H, NLRP9 expression in NLRP9-mutated cases was significantly lower than that in NLRP9-non-mutated cases. Our data indicate that NLRP9 is altered at multiple levels (frameshift mutation, mutational ITH and loss of expression), which together could contribute to pathogenesis of MSI-H GC and CRC.

Expression of MHC class II, which is important against cancer immunity, depends on the transcactivator CIITA. These data suggest a possibility that CIITA gene might be inactivated in cancers. In this study, we studied inactivating mutation status of CIITA gene in gastric (GC) and colorectal (CRC) cancers by analyzing the C7 repeat in the CIITA (exon 11) gene. We found frameshift mutations in 3 GCs and 6 CRCs in cancers with high microsatellite instability (MSI-H) (9/113), but not in those with microsatellite-stable (MSS) (0/90) (P = 0.004). They were all deletion or duplication of one base in the C7 repeat that would result in truncation of amino acid synthesis. Immune therapy is now a major option in cancer therapy and our results on the genetic alterations of MHC II-related CTIITA in MSH-H GC and CRC might provide useful information for the treatment of MSI-H cancers.

A scaffold protein DAB2 and its interaction partner DAB2IP have putative tumor suppressor gene (TSG) functions. Previous studies identified that both DAB2 and DAB2IP genes were inactivated by promoter hypermethylation in human cancers, but their mutational alterations in cancers remain largely unknown. The aim of our study was to find whether DAB2 and DAB2IP were mutated in gastric (GCs) and colorectal cancers (CRCs) by DNA sequencing. Both DAB2 and DAB2IP have mononucleotide repeats in their coding sequence that could be mutation targets in high microsatellite instability (MSI-H) cancers. We analyzed GC and CRC tissues and found that 8 of 34 GCs (23.5%) and 15 of 79 CRCs (20.0%) with MSI-H harbored DAB2IP frameshift mutations. DAB2 frameshift mutations were found in 2 of 79 CRCs (2.5%) with MSI-H. These mutations were not detected in microsatellite stable (MSS) cancers. We also found intratumoral heterogeneity (ITH) of DAB2IP frameshift mutations in 7 of 16 CRCs (43.8%). Loss of DAB2IP protein expression was found in approximately 20% of GCs and CRCs irrespective of MSI and DAB2IP frameshift mutation status. Our study shows that the TSG DAB2IP harbored frameshift mutations and ITH as well as expression loss. Together these tumor alterations might play a role in tumorigenesis of GC and CRC with MSI-H by down-regulating the tumor-inhibiting activities of DAB2IP.

PURPOSE The purpose of this study was to compare and analyze the effects of Taekwondo training including 8-week inspiratory muscle training on physical fitness, CRP, pulmonary function and isokinetic muscle function of middle-aged male smokers. METHODS 21 middle-aged male smokers were divided into 3 groups: inspiratory muscle training+Taekwondo training group (n=7), Taekwondo training group (n=7) and control group (n=7). Measurement variables were physical fitness (Body composition, muscular strength, muscular endurance, flexibility, cardiorespiratory function, balance), CRP, pulmonary function (FVC, FEV1, FEV1/FVC), and isokinetic muscle function (peak torque %BW, average power %BW). The repeated measure ANOVA was conducted to analyze the differences and interactions between groups and periods. In the case of any difference, t-test was conducted to perform post hoc test between pre and post treatment and the contrast was conducted to perform post hoc test between groups. One-way analysis of variance (ANOVA) was used between groups, and repeated measures t-test was used between groups. All significance levels were verified at .05. RESULTS As a result, the combined exercise group also showed statistically significant changes in the physical fitness (Body composition, muscular strength, muscular endurance, flexibility, cardiorespiratory function), pulmonary function (FEV1, FEV1/FVC), and isokinetic muscle function (peak torque %BW). CONCLUSIONS Consequently, it shows that 8 weeks Taekwondo training including inspiratory muscle training made a positive effect on fat content, muscular strength, muscular endurance, cardio respiratory fitness, R-extension in peak torque %BW in middle-aged male smokers.

Erythrocyte Membrane Protein Band 4.1 Like 3 (EPB41L3) is candidate tumor suppressor gene (TSG) in various cancers. EPB41L3 downregulation has been identified in many solid cancers including gastric (GC) and colorectal cancers (CRCs), but somatic inactivating mutation along with protein expression in cancers are largely unexplored. The aim of our study was to find whether EPB41L3 gene was mutated and expressionally altered in GC and CRC. EPB41L3 gene has a mononucleotide repeat in the coding sequence that could be mutated in cancers with high microsatellite instability (MSI-H). We analyzed 79 GCs and 124 CRCs, and found that only one CRC with MSI-H (1.3%) harbored the frameshift mutation within the repeat. In immunohistochemistry, loss of EPB41L3 expression was identified in 49% of GCs and 42% of CRCs. Our data may indicate EPB41L3 that loss of expression but not frameshift mutation may play a role in GC and CRC development by inhibiting TSG functions of EPB41L3.

Many genes act as both tumor suppressor gene (TSG) and proto-oncogene depending on cellular context and cancer type. Nemo-like kinase (NLK) encoding a serine/threonine kinase, Yin Yang 1 (YY1) encoding a zinc-finger transcription factor and PA2G4 encoding an ErbB3 binding protein have both of these two opposing functions. In the present study, we analyzed NLK, YY1 and PA2G4 frameshift mutations in sporadic GC and CRC with high microsatellite instability (MSI-H). Also, regional intratumoral heterogeneity (ITH) of frameshift mutations of these genes was analyzed in CRCs. We found frameshift mutations of NLK, YY1 and PA2G4 in CRC and GC with MSI-H (17/132: 12.9%), but not in those with MSS (0/90). Two (12.5%), one (6.3%) and one (6.3%) CRC (s) of the 16 CRCs exhibited ITH of NLK, YY1 and PA2G4 mutations among the 4–7 regions, suggesting that ITH of the frameshift mutations might be frequent in the CRCs. These results suggest that frameshift mutations of NLK, YY1 and PA2G4 along with the ITH might contribute to MSI-H cancer pathogenesis.

Approximately 60 approximately 80% of the elderly population report some degree of pain that interferes with life activities. As recipients of healthcare, the elderly are frequent recipients of medical and surgical treatments that result in acute pain and are at risk for inadequate pain management during hospitalization.