Mismatch Repair Status of Gastric Cancer and Its Association with the Local and Systemic Immune Response

Shin, Su&#x2010,Jin,Kim, Sang Yong,Choi, Yoon Young,Son, Taeil,Cheong, Jae&#x2010,Ho,Hyung, Woo Jin,Noh, Sung Hoon,Park, Chung&#x2010,Gyu,Kim, Hyoung&#x2010,Il AlphaMed Press 2019 The oncologist Vol.24 No.9

<P>This article reports on the relationship between microsatellite instability (MSI) status and the antitumor host immune response, focusing on the affect of these factors on prognosis in MSI‐high versus non MSI‐high gastric cancer.</P><P><B>Background.</B></P><P>Microsatellite instability (MSI)‐high (MSI‐H) colorectal cancer is known to be associated with increased tumor‐infiltrating lymphocytes (TILs), elevated host systemic immune response, and a favorable prognosis. In gastric cancer, however, MSI status has rarely been evaluated in the context of TILs and systemic immune response.</P><P><B>Materials and Methods.</B></P><P>We evaluated data for 345 patients with gastric cancer who underwent gastrectomy with MSI typing. The numbers of TILs were counted after immunohistochemical staining with anti‐CD3, CD4, CD8, forkhead box P3 (Foxp3), and granzyme B to quantify the subsets of TILs. To evaluate the systemic immune response, the differential white blood cell count and prognostic nutritional index (PNI) were obtained.</P><P><B>Results.</B></P><P>Of the 345 patients, 57 demonstrated MSI‐H tumors and 288 demonstrated non‐MSI‐H tumors. MSI‐H tumors carried significantly higher densities of CD8+ T cells, Foxp3+ T cells, and granzyme B+ T cells and a higher ratio of Foxp3/CD4 and granzyme B/CD8. The prognostic impact of TILs differed between patients with MSI‐H tumors and those with non‐MSI‐H tumors. The TIL subsets were not found to be significant prognostic factors for recurrence‐free survival (RFS) or overall survival (OS) in the MSI‐H tumor group. In the non‐MSI‐H tumor group, multivariate analysis showed that stage, PNI, and CD4+ T cells were independent prognostic factors for RFS, and stage, PNI, and the Foxp3/CD4 ratio were independent prognostic factors for OS.</P><P><B>Conclusions.</B></P><P>The association between systemic/local immune response and prognosis differed according to MSI status. Different tumor characteristics and prognoses according to MSI status could be associated with the immunogenicity caused by microsatellite instability and subsequent host immune response.</P><P><B>Implications for Practice.</B></P><P>This study demonstrates that the density of each subset of tumor‐infiltrating lymphocytes (TILs) differed between microsatellite instability (MSI)‐high and non‐MSI‐high tumors. Moreover, the prognostic effect of the preoperative systemic immune response status and TILs differed between the MSI‐high (MSI‐H) and non‐MSI‐H tumor groups. The present study may help to identify the mechanisms of cancer progression and develop treatment strategies for MSI‐high gastric cancer.</P>

Morphological abnormalities, impaired fetal development and decrease in myostatin expression following somatic cell nuclear transfer in dogs

Hong, Il‐,Hwa,Jeong, Yeon&#x2010,Woo,Shin, Taeyoung,Hyun, Sang&#x2010,Hwan,Park, Jin&#x2010,Kyu,Ki, Mi&#x2010,Ran,Han, Seon&#x2010,Young,Park, Se&#x2010,Il,Lee, Ji&#x2010,Hyun,Lee, Eun&#x2010,Mi Wiley Subscription Services, Inc., A Wiley Company 2011 Molecular reproduction and development Vol.78 No.5

<P><B>Abstract</B></P><P>Several mammals, including dogs, have been successfully cloned using somatic cell nuclear transfer (SCNT), but the efficiency of generating normal, live offspring is relatively low. Although the high failure rate has been attributed to incomplete reprogramming of the somatic nuclei during the cloning process, the exact cause is not fully known. To elucidate the cause of death in cloned offspring, 12 deceased offspring cloned by SCNT were necropsied. The clones were either stillborn just prior to delivery or died with dyspnea shortly after birth. On gross examination, defects in the anterior abdominal wall and increased heart and liver sizes were found. Notably, a significant increase in muscle mass and macroglossia lesions were observed in deceased SCNT‐cloned dogs. Interestingly, the expression of myostatin, a negative regulator of muscle growth during embryogenesis, was down‐regulated at the mRNA level in tongues and skeletal muscles of SCNT‐cloned dogs compared with a normal dog. Results of the present study suggest that decreased expression of myostatin in SCNT‐cloned dogs may be involved in morphological abnormalities such as increased muscle mass and macroglossia, which may contribute to impaired fetal development and poor survival rates. Mol. Reprod. Dev. 78:337–346, 2011. © 2011 Wiley‐Liss, Inc.</P>

Ascochlorin inhibits growth factor‐induced HIF‐1α activation and tumor‐angiogenesis through the suppression of EGFR/ERK/p70S6K signaling pathway in human cervical carcinoma cells

Jeong, Ji&#x2010,Hak,Jeong, Yun&#x2010,Jeong,Cho, Hyun&#x2010,Ji,Shin, Jae&#x2010,Moon,Kang, Jeong&#x2010,Han,Park, Kwan&#x2010,Kyu,Park, Yoon&#x2010,Yub,Chung, Il‐,Kyung,Chang, Hyeun&#x2010,Woo Wiley Subscription Services, Inc., A Wiley Company 2012 Journal of cellular biochemistry Vol.113 No.4

<P><B>Abstract</B></P><P>Ascochlorin, a non‐toxic prenylphenol compound derived from the fungus <I>Ascochyta viciae</I>, has been shown recently to have anti‐cancer effects on various human cancer cells. However, the precise molecular mechanism of this anti‐cancer activity remains to be elucidated. Here, we investigated the effects of ascochlorin on hypoxia‐inducible factor‐1α (HIF‐1α) and vascular endothelial growth factor (VEGF) expression in human epidermoid cervical carcinoma CaSki cells. Ascochlorin inhibited epidermal growth factor (EGF)‐induced HIF‐1α and VEGF expression through multiple potential mechanisms. First, ascochlorin selectively inhibited HIF‐1α expression in response to EGF stimulation, but not in response to hypoxia (1% O<SUB>2</SUB>) or treatment with a transition metal (CoCl<SUB>2</SUB>). Second, ascochlorin inhibited EGF‐induced ERK‐1/2 activation but not AKT activation, both of which play essential roles in EGF‐induced HIF‐1α protein synthesis. Targeted inhibition of epidermal growth factor receptor (EGFR) expression using an EGFR‐specific small interfering RNA (siRNA) diminished HIF‐1α expression, which suggested that ascochlorin inhibits HIF‐1α expression through suppression of EGFR activation. Finally, we showed that ascochlorin functionally abrogates in vivo tumor angiogenesis induced by EGF in a Matrigel plug assay. Our data suggest that ascochlorin inhibits EGF‐mediated induction of HIF‐1α expression in CaSki cells, providing a potentially new avenue of development of anti‐cancer drugs that target tumor angiogenesis. J. Cell. Biochem. 113: 1302–1313, 2012. © 2011 Wiley Periodicals, Inc.</P>

Characterization of age‐associated exhausted CD 8 ⁺ T cells defined by increased expression of Tim‐3 and PD ‐1

Lee, Kyoo&#x2010,A,Shin, Kwang&#x2010,Soo,Kim, Ga&#x2010,Young,Song, You Chan,Bae, Eun&#x2010,Ah,Kim, Il‐,Kyu,Koh, Choong&#x2010,Hyun,Kang, Chang&#x2010,Yuil John Wiley and Sons Inc. 2016 Aging Cell Vol.15 No.2

<P><B>Summary</B></P><P>Aging is accompanied by altered T‐cell responses that result in susceptibility to various diseases. Previous findings on the increased expression of inhibitory receptors, such as programmed cell death protein 1 (PD‐1), in the T cells of aged mice emphasize the importance of investigations into the relationship between T‐cell exhaustion and aging‐associated immune dysfunction. In this study, we demonstrate that T‐cell immunoglobulin mucin domain‐3 (Tim‐3), another exhaustion marker, is up‐regulated on aged T cells, especially CD8<SUP>+</SUP> T cells. Tim‐3‐expressing cells also produced PD‐1, but Tim‐3<SUP>+</SUP>PD‐1<SUP>+</SUP>CD8<SUP>+</SUP> T cells had a distinct phenotype that included the expression of CD44 and CD62L, from Tim‐3<SUP>−</SUP>PD‐1<SUP>+</SUP> cells. Tim‐3<SUP>+</SUP>PD‐1<SUP>+</SUP>CD8<SUP>+</SUP> T cells showed more evident properties associated with exhaustion than Tim‐3<SUP>−</SUP>PD‐1<SUP>+</SUP>CD8<SUP>+</SUP> T cells: an exhaustion‐related marker expression profile, proliferative defects following homeostatic or TCR stimulation, and altered production of cytokines. Interestingly, these cells produced a high level of IL‐10 and induced normal CD8<SUP>+</SUP> T cells to produce IL‐10, which might contribute to immune dysregulation in aged mice. The generation of Tim‐3‐expressing CD8<SUP>+</SUP> T cells in aged mice seems to be mediated by encounters with antigens but not by specific infection, based on their high expression of CD49d and their unbiased TCR Vβ usage. In conclusion, we found that a CD8<SUP>+</SUP> T‐cell population with age‐associated exhaustion was distinguishable by its expression of Tim‐3. These results provide clues for understanding the alterations that occur in T‐cell populations with age and for improving dysfunctions related to the aging of the immune system.</P>

Thin‐Wall Assembled SnO₂ Fibers Functionalized by Catalytic Pt Nanoparticles and their Superior Exhaled‐Breath‐Sensing Properties for the Diagnosis of Diabetes

Shin, Jungwoo,Choi, Seon&#x2010,Jin,Lee, Inkun,Youn, Doo&#x2010,Young,Park, Chong Ook,Lee, Jong&#x2010,Heun,Tuller, Harry L.,Kim, Il‐,Doo WILEY‐VCH Verlag 2013 Advanced functional materials Vol.23 No.19

<P><B>Abstract</B></P><P>Hierarchical SnO<SUB>2</SUB> fibers assembled from wrinkled thin tubes are synthesized by controlling the microphase separation between tin precursors and polymers, by varying flow rates during electrospinning and a subsequent heat treatment. The inner and outer SnO<SUB>2</SUB> tubes have a number of elongated open pores ranging from 10 nm to 500 nm in length along the fiber direction, enabling fast transport of gas molecules to the entire thin‐walled sensing layers. These features admit exhaled gases such as acetone and toluene, which are markers used for the diagnosis of diabetes and lung cancer. The open tubular structures facilitated the uniform coating of catalytic Pt nanoparticles onto the inner SnO<SUB>2</SUB> layers. Highly porous SnO<SUB>2</SUB> fibers synthesized at a high flow rate show five‐fold higher acetone responses than densely packed SnO<SUB>2</SUB> fibers synthesized at a low flow rate. Interestingly, thin‐wall assembled SnO<SUB>2</SUB> fibers functionalized by Pt particles exhibit a dramatically shortened gas response time compared to that of un‐doped SnO<SUB>2</SUB> fibers, even at low acetone concentrations. Moreover, Pt‐decorated SnO<SUB>2</SUB> fibers significantly enhance toluene response. These results demonstrate the novel and practical feasibility of thin‐wall assembled metal oxide based breath sensors for the accurate diagnosis of diabetes and potential detection of lung cancer.</P>

Copper Seed Layer Deposition by a New Liquid Precursor

Kang, Sang&#x2010,Woo,Shin, Yong&#x2010,Hyeon,Kim, Jin&#x2010,Tae,Yun, Ju&#x2010,Young,Chang, Yun&#x2010,Hee,Yang, Il‐,Doo WILEY‐VCH Verlag 2011 CHEMICAL VAPOR DEPOSITION -WEINHEIM- Vol.17 No.1

<P><B>Abstract</B></P><P>Cu(hfac)<SUB>2</SUB>(TEA) (hfac = 1,1,1,5,5,5‐hexafluoroacetylacetonate, TEA (triethylamine, N(C<SUB>2</SUB>H<SUB>5</SUB>)<SUB>3</SUB>)) is a new liquid Cu<SUP>II</SUP> precursor. Using Cu(hfac)<SUB>2</SUB>(TEA), we successfully deposit Cu thin films as a seed layer, even at the low deposition temperature of 373 K. To explain this behavior, the bonding status of Cu(hfac)<SUB>2</SUB> in the presence of TEA is determined by density‐functional theory. The theoretical bond length of Cu‐O in Cu(hfac)<SUB>2</SUB> is significantly greater (by 0.06 Å) than that without an adduct ligand.</P>

Liver X receptor mediates hepatitis B virus X protein–induced lipogenesis in hepatitis B virus–associated hepatocellular carcinoma

Na, Tae&#x2010,Young,Shin, Young Kee,Roh, Kyung Jin,Kang, Shin&#x2010,Ae,Hong, Il,Oh, Sae Jin,Seong, Je Kyung,Park, Cheol Keun,Choi, Yoon La,Lee, Mi&#x2010,Ock Wiley Subscription Services, Inc., A Wiley Company 2009 Hepatology Vol.49 No.4

<P><B>Abstract</B></P><P>Although hepatitis B virus X protein (HBx) has been implicated in abnormal lipid metabolism in hepatitis B virus (HBV)–associated hepatic steatosis, its underlying molecular mechanism remains unclear. Liver X receptor (LXR) plays an important role in regulating the expression of genes involved in hepatic lipogenesis. Here we demonstrate that LXRα and LXRβ mediate HBV‐associated hepatic steatosis. We have found that HBx induces the expression of LXR and its lipogenic target genes, such as sterol regulatory element binding protein‐1c (SREBP‐1c), fatty acid synthase (FAS), and peroxisome proliferator‐activated receptor, and this is accompanied by the accumulation of lipid droplets. RNA interference with LXR expression decreases the amount of lipid droplets as well as the expression of the lipogenic genes, and this indicates that HBx‐induced lipogenesis is LXR‐dependent. LXRα and HBx colocalize in the nucleus and are physically associated. HBx induces the transactivation function of LXRα by recruiting CREB binding protein to the promoter of the target gene. Furthermore, we have observed that expression of LXR is increased in the livers of HBx‐transgenic mice. Finally, there is a significant increase in the expression of LXRβ (<I>P</I> = 0.036), SREBP‐1c (<I>P</I> = 0.008), FAS, and stearoyl–coenyzme A desaturase‐1 (<I>P</I> = 0.001) in hepatocellular carcinoma (HCC) in comparison with adjacent nontumorous nodules in human HBV‐associated HCC specimens. <I>Conclusion:</I> Our results suggest a novel association between HBx and LXR that may represent an important mechanism explaining HBx‐induced hepatic lipogenesis during HBV‐associated hepatic carcinogenesis. (H<SMALL>EPATOLOGY</SMALL> 2009.)</P>

Synergistic associations of depression and apolipoprotein E genotype with incidence of dementia

Kim, Jae&#x2010,Min,Stewart, Robert,Kim, Seon&#x2010,Young,Kim, Sung&#x2010,Wan,Bae, Kyung&#x2010,Yeol,Yang, Su&#x2010,Jin,Shin, Il‐,Seon,Yoon, Jin&#x2010,Sang John Wiley Sons, Ltd. 2011 INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY Vol.26 No.9

<P><B>Abstract</B></P><P><B>Objectives</B></P><P>A cohort study of Japanese‐American men suggested interactive effects of depression and apolipoprotein E (APOE) e4 allele on risk of incident dementia. In another sample of East Asian origin, we sought to replicate the findings and to explore individual depressive symptoms where this interaction was most evident.</P><P><B>Methods</B></P><P>Of 625 Korean community elders without dementia at baseline, 518 (83%) were followed over a 2.4‐year period and were clinically assessed for incident dementia. Depression was identified by the Geriatric Mental State Schedule (GMS), and nine individual depressive symptoms relevant to DSM‐IV major depressive episode criteria were extracted. APOE genotype was ascertained. Covariates included age, gender, education, and disability.</P><P><B>Results</B></P><P>There were synergistic interactions between depression and APOE e4 on incident dementia independent of covariates. This interaction was particularly strong for four depressive symptoms: depressed mood, worthlessness, concentration difficulty, and suicidal ideation.</P><P><B>Conclusions</B></P><P>We were able to replicate the previous study, finding that, at least in East Asian origin populations, the APOE e4 allele is a stronger predictor of incident dementia in the presence of depressive syndrome, and particular depressive symptoms. Copyright © 2010 John Wiley & Sons, Ltd.</P>

Positive feedback regulation of Akt‐FMRP pathway protects neurons from cell death

Jeon, Se Jin,Han, Seol&#x2010,Heui,Yang, Sung&#x2010,Il,Choi, Ji woong,Kwon, Kyoung Ja,Park, Seung Hwa,Kim, Hahn Young,Cheong, Jae Hoon,Ryu, Jong Hoon,Ko, Kwang Ho,Wells, David G,Shin, Chan Young Blackwell Publishing Ltd 2012 Journal of Neurochemistry Vol.123 No.2

<P><I>J. Neurochem.</I> (2012) <B>123</B>, 226–238.</P><P><B>Abstract</B></P><P>Fragile X syndrome (FXS), the most common single genetic cause of mental retardation and autistic spectrum disease, occurs when <I>FMR1</I> gene is mutated. <I>FMR1</I> encodes fragile X mental retardation protein (FMRP) which regulates translation of mRNAs playing important roles in the development of neurons as well as formation and maintenance of synapses. To examine whether FMRP regulates cell viability, we induced apoptosis in rat primary cortical neurons with glutamate <I>in vitro</I> and with middle cerebral artery occlusion (MCAO) in striatal neurons <I>in vivo</I>. Both conditions elicited a rapid, but transient FMRP expression in neurons. This up‐regulated FMRP expression was abolished by pre‐treatment with PI3K and Protein Kinase B (Akt) inhibitors: LY294002, Akt inhibitor IV, and VIII. Reduced FMRP expression <I>in vitro</I> or <I>in vivo</I> using small hairpin <I>Fmr1</I> virus exacerbated cell death by glutamate or MCAO, presumably <I>via</I> hypophosphorylation of Akt and reduced expression of B‐cell lymphoma‐extra large (Bcl‐xL). However, over‐expression of FMRP using enhanced green fluorescent protein (eGFP)‐FMRP constructs alleviated cell death, increased Akt activity, and enhanced Bcl‐xL production. The pro‐survival role of Akt‐dependent up‐regulation of FMRP in glutamate‐stimulated cultured neuron as well as in ischemic brain may have a clinical importance in FXS as well as in neurodegenerative disorders and traumatic brain injury.</P>

Associations of serotonergic genes with poststroke emotional incontinence

Kim, Jae&#x2010,Min,Stewart, Robert,Kang, Hee&#x2010,Ju,Bae, Kyung&#x2010,Yeol,Kim, Sung&#x2010,Wan,Shin, Il‐,Seon,Kim, Joon&#x2010,Tae,Park, Man&#x2010,Seok,Cho, Ki&#x2010,Hyun,Yoon, Jin&#x2010 John Wiley Sons, Ltd 2012 INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY Vol.27 No.8

<P><B>Objectives</B></P><P>Poststroke emotional incontinence (PSEI) has been associated with serotonergic dysfunction. Polymorphisms of serotonin transporter (5‐HTT) and serotonin 2a receptor (5‐HTR2a) genes may regulate serotonergic signaling at brain synapses, and this study was to investigate associations with PSEI in an East Asian population.</P><P><B>Methods</B></P><P>In 276 stroke cases, PSEI was diagnosed by Kim's criteria. Covariates included age, gender, education, history of depression or stroke, current depression, and stroke severity and location. Genotypes were ascertained for 5‐HTT gene‐linked promoter region (5‐HTTLPR), serotonin transporter intron 2 variable number tandem repeat, 5‐HTR2a 1438A/G, and 5‐HTR2a 102 T/C. Associations with PSEI were estimated by using logistic regression models, and gene–gene interactions were investigated by using the generalized multifactor dimensionality reduction method.</P><P><B>Results</B></P><P>PSEI was present in 37 (13.4%) patients. The 5‐HTT gene‐linked promoter region <I>s</I>/<I>s</I> genotype was independently associated with PSEI. No associations with STin2 VNTR and 5‐HTR2a genes were found, and no significant gene–gene interactions were identified.</P><P><B>Conclusions</B></P><P>Stroke patients with 5‐HTTLPR <I>s</I> allele had higher susceptibility to PSEI, which underlines the potential role of serotonergic pathways in its etiology. Copyright © 2011 John Wiley & Sons, Ltd.</P>