BACKGROUNDS/AIMS: In hepatocellular carcinoma (HCC), bile duct invasion occurs far more rarely than vascular invasion and is not well characterized. In addition, the pathologic finding of bile duct invasion is not considered an independent prognostic factor for HCC following surgery. In this study, we determined the characteristics of HCC with bile duct invasion, and assessed the clinical significance of bile duct invasion. METHODS: We retrospectively reviewed the medical records of 363 patients who underwent hepatic resection for HCC at Seoul National University Hospital (SNUH) from January 2009 to December 2011. Preoperative, operative, and pathological data were collected. The risk factors for recurrence and survival were analyzed. Subsequently, the patients were divided into 2 groups according to disease stage (American Joint Committee on Cancer/International Union Against Cancer 7th edition): early stage (T1 and 2) and advanced stage (T3 and 4) group; and risk factors in the sub-groups were analyzed. RESULTS: Among 363 patients, 13 showed bile duct invasion on pathology. Patients with bile duct invasion had higher preoperative total bilirubin levels, greater microvascular invasion, and a higher death rate than those without bile duct invasion. In multivariate analysis, bile duct invasion was not an independent prognostic factor for survival for the entire cohort, but, was an independent prognostic factor for early stage. CONCLUSIONS: Bile duct invasion accompanied microvascular invasion in most cases, and could be used as an independent prognostic factor for survival especially in early stage HCC (T1 and T2).
Bile Ducts* ; Bile* ; Bilirubin ; Carcinoma, Hepatocellular* ; Cohort Studies ; Humans ; Joints ; Medical Records ; Mortality ; Multivariate Analysis ; Pathology ; Recurrence ; Retrospective Studies ; Risk Factors ; Seoul

Adipocyte differentiation is a very complex process in which whole-cell changes are accompanied. Among them, type I procollagen gene has been shown to specifically decrease during adipocyte differentiation; however, little is known about the molecular mechanism. To examine how type I procollagen gene expression is regulated at the level of transcription during adipocyte differentiation, 3T3-L1 preadipocyte cell line was used as an in vitro model. Northern blot analysis demonstrated that mRNA expression of type I procollagen gene was dramatically reduced during adipocyte differentiation. Time-course analysis indicated that decrease in mRNA expression occurred at early stage of differentiation. Studies on several stable cell lines showed that transcriptional activities of both alpha1 and alpha2 promoters decreased significantly during adipocyte differentiation. Despite extensive deletion-promoter analyses, however, we could not identify the cis-element responsible for the switch-off of type I procollagen gene during adipocyte differentiation, suggesting that the transcriptional repression of this gene occur through general transcription machinery rather than a specific cis-element. In conclusion, down-regulation of type I procollagen mRNA expression during adipocyte differentiation is due to repression of its promoter activity through general transcription machinery.
3T3 Cells ; Adipocytes/cytology/*metabolism ; Animal ; Cell Differentiation/*genetics ; Cell Line ; Collagen Type I/*genetics/metabolism ; Down-Regulation/genetics ; Gene Expression Regulation ; Genes, Reporter ; Kinetics ; Mice ; Mutation ; Procollagen/*genetics/metabolism ; Promoter Regions (Genetics) ; RNA, Messenger/metabolism ; Repressor Proteins/genetics/metabolism ; Transcription, Genetic

Adipocyte differentiation is a very complex process in which whole-cell changes are accompanied. Among them, type I procollagen gene has been shown to specifically decrease during adipocyte differentiation; however, little is known about the molecular mechanism. To examine how type I procollagen gene expression is regulated at the level of transcription during adipocyte differentiation, 3T3-L1 preadipocyte cell line was used as an in vitro model. Northern blot analysis demonstrated that mRNA expression of type I procollagen gene was dramatically reduced during adipocyte differentiation. Time-course analysis indicated that decrease in mRNA expression occurred at early stage of differentiation. Studies on several stable cell lines showed that transcriptional activities of both alpha1 and alpha2 promoters decreased significantly during adipocyte differentiation. Despite extensive deletion-promoter analyses, however, we could not identify the cis-element responsible for the switch-off of type I procollagen gene during adipocyte differentiation, suggesting that the transcriptional repression of this gene occur through general transcription machinery rather than a specific cis-element. In conclusion, down-regulation of type I procollagen mRNA expression during adipocyte differentiation is due to repression of its promoter activity through general transcription machinery.
3T3 Cells ; Adipocytes/cytology/*metabolism ; Animal ; Cell Differentiation/*genetics ; Cell Line ; Collagen Type I/*genetics/metabolism ; Down-Regulation/genetics ; Gene Expression Regulation ; Genes, Reporter ; Kinetics ; Mice ; Mutation ; Procollagen/*genetics/metabolism ; Promoter Regions (Genetics) ; RNA, Messenger/metabolism ; Repressor Proteins/genetics/metabolism ; Transcription, Genetic

OBJECTIVE: To evaluate the correlation between serum levels of anti-Mullerian hormone (AMH) and ovarian response to mild stimulation in normoovulatory women and anovulatory women with polycystic ovary syndrome (PCOS). METHODS: Seventy-four cycles of mild stimulation (clomiphene citrate+gonadotropin followed by timed intercourse or intrauterine insemination) performed in normoovulatory women (57 cycles) and anovulatory women with PCOS (17 cycles). Ovarian sensitivity was defined by the number of mature follicles (> or =14 mm) on triggering day per 100 IU of gonadotropin. A correlation between ovarian sensitivity and the baseline serum AMH level (absolute or multiples of the median [MoM] value for each corresponding age) was calculated. Correlation between ovarian response and serum AMH level was evaluated. RESULTS: Ovarian sensitivity to mild stimulation was positively correlated with absolute serum AMH (r=0.535, p<0.001) or AMH-MoM value (r=0.390, p=0.003) in normoovulatory women, but this correlation was not observed in anovulatory women with PCOS (r=0.105, p>0.05, r=-0.265, p>0.05, respectively). CONCLUSION: Ovarian response to mild stimulation is possibly predicted by the serum AMH level in normoovulatory women, but not in anovulatory women with PCOS.
Anti-Mullerian Hormone ; Female ; Gonadotropins ; Humans ; Ovulation Induction ; Polycystic Ovary Syndrome

Nocardiosis is uncommon in healthy people but occurs as an opportunistic infection in patients after hematopoietic stem cell transplantation, solid organ transplantation, malignancy, or acquired immune deficiency syndrome. Involvement of Nocardia in the spinal cord is rare; to our knowledge, only six cases have been reported. We report here the case of a 54-year-old man with a spinal cord abscess and epidural and paraspinal abscesses in the thoracic and lumbar spinal cord, causing paraplegia, voiding and defecation difficulties, and combined lung involvement, which developed 5 months after allogeneic hematopoietic stem cell transplantation. Nocardia grew in a fungus culture obtained by percutaneous lung biospy and CT-guided aspiration of the spinal abscess. A double combination regimen of antibiotic therapy (imipenem/cilastatin sodium, amikacin) was given. His paraplegia and his voiding and defecation difficulties improved considerably. To our knowledge, this is the first reported case of spinal cord Nocardiosis observed after allogeneic hematopoietic stem cell transplantation.
Abscess ; Acquired Immunodeficiency Syndrome ; Defecation ; Fungi ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells ; Humans ; Lung ; Middle Aged ; Nocardia ; Nocardia Infections ; Opportunistic Infections ; Organ Transplantation ; Paraplegia ; Sodium ; Spinal Cord ; Transplants

Nocardiosis is uncommon in healthy people but occurs as an opportunistic infection in patients after hematopoietic stem cell transplantation, solid organ transplantation, malignancy, or acquired immune deficiency syndrome. Involvement of Nocardia in the spinal cord is rare; to our knowledge, only six cases have been reported. We report here the case of a 54-year-old man with a spinal cord abscess and epidural and paraspinal abscesses in the thoracic and lumbar spinal cord, causing paraplegia, voiding and defecation difficulties, and combined lung involvement, which developed 5 months after allogeneic hematopoietic stem cell transplantation. Nocardia grew in a fungus culture obtained by percutaneous lung biospy and CT-guided aspiration of the spinal abscess. A double combination regimen of antibiotic therapy (imipenem/cilastatin sodium, amikacin) was given. His paraplegia and his voiding and defecation difficulties improved considerably. To our knowledge, this is the first reported case of spinal cord Nocardiosis observed after allogeneic hematopoietic stem cell transplantation.
Abscess ; Acquired Immunodeficiency Syndrome ; Defecation ; Fungi ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells ; Humans ; Lung ; Middle Aged ; Nocardia ; Nocardia Infections ; Opportunistic Infections ; Organ Transplantation ; Paraplegia ; Sodium ; Spinal Cord ; Transplants

BACKGROUND: Adipose-derived stem cells (ADSCs) exert immunomodulatory effects in the treatment of transplant rejection. This study aimed to evaluate the effects of ADSCs on the skin graft survival in a human-to-rat xenograft transplantation model and to compare single and multiple injections of ADSCs. METHODS: Full-thickness human skin xenografts were transplanted into the backs of Sprague–Dawley rats. The rats were injected subcutaneously on postoperative days 0, 3, and 5. The injections were as follows: triple injections of phosphate-buffered saline (PBS group), a single injection of ADSCs and double injections of PBS (ADSC 9 1 group), and triple injections of ADSCs (ADSC 9 3 group). The immunomodulatory effects of ADSCs on human skin xenografts were assessed. RESULTS: Triple injections of ADSCs considerably delayed cell-mediated xenograft rejection compared with the PBS and ADSC 9 1 groups. The vascularization and collagen type 1–3 ratios in the ADSC 9 3 group were significantly higher than those in the other groups. In addition, intragraft infiltration of CD3-, CD4-, CD8-, and CD68-positive cells was reduced in the ADSC 9 3 group. Furthermore, in the ADSC 9 3 group, the expression levels of proinflammatory cytokine interferon-gamma (IFN-c) were decreased and immunosuppressive prostaglandin E synthase (PGES) was increased in the xenograft and lymph node samples. CONCLUSION This study presented that triple injections of ADSCs appeared to be superior to a single injection in suppressing cell-mediated xenograft rejection. The immunomodulatory effects of ADSCs are associated with the downregulation of IFN-c and upregulation of PGES in skin xenografts and lymph nodes.

Colorectal injury related to anorectal manometry is very rare and is mostly associated with previous rectal surgery. We experienced two cases of colorectal injury related to anorectal manometry in patients without a history of surgery. The anorectal manometry finding of the first patient suggested rectal hyposensitivity, and the maximum tolerable volume was measured as 350 mL. After anorectal manometry, she complained of hematochezia. Sigmoidoscopy showed a deep 5 cm ulcer with vessel exposure at the rectum. She recovered after conservative treatment. In the second case, rectal bleeding occurred while measuring the maximal tolerable rectal volume. A 2.5 cm mural defect and 4 cm mucosal defect were detected in the rectosigmoid area at sigmoidoscopy. Computed tomography showed intraperitoneal free air around the distal sigmoid colon. She improved after conservative management. We suggest that anorectal manometry be performed with great caution, even in patients without a history of surgery.
Colon, Sigmoid ; Gastrointestinal Hemorrhage ; Glycosaminoglycans ; Hemorrhage ; Humans ; Intestinal Perforation ; Manometry ; Rectum ; Sigmoidoscopy ; Ulcer

SINE-VNTR-Alu (SVA) elements are present in hominoid primates and are divided into 6 subfamilies (SVA-A to SVA-F) and active in the human population. Using a bioinformatic tool, 22 SVA element-associated genes are identified in the human genome. In an analysis of genomic structure, SVA elements are detected in the 5' untranslated region (UTR) of HGSNAT (SVA-B), MRGPRX3 (SVA-D), HYAL1 (SVA-F), TCHH (SVA-F), and ATXN2L (SVA-F) genes, while some elements are observed in the 3'UTR of SPICE1 (SVA-B), TDRKH (SVA-C), GOSR1 (SVA-D), BBS5 (SVA-D), NEK5 (SVA-D), ABHD2 (SVA-F), C1QTNF7 (SVA-F), ORC6L (SVA-F), TMEM69 (SVA-F), and CCDC137 (SVA-F) genes. They could contribute to exon extension or supplying poly A signals. LEPR (SVA-C), ALOX5 (SVA-D), PDS5B (SVA-D), and ABCA10 (SVA-F) genes also showed alternative transcripts by SVA exonization events. Dominant expression of HYAL1_SVA appeared in lung tissues, while HYAL1_noSVA showed ubiquitous expression in various human tissues. Expression of both transcripts (TDRKH_SVA and TDRKH_noSVA) of the TDRKH gene appeared to be ubiquitous. Taken together, these data suggest that SVA elements cause transcript isoforms that contribute to modulation of gene regulation in various human tissues.
3' Untranslated Regions ; 5' Untranslated Regions ; Exons ; Gene Expression Profiling ; Genome, Human ; Genomics ; Humans ; Lung ; Organ Specificity ; Poly A ; Primates ; Protein Isoforms

Fasiglifam (TAK-875) a G-protein coupled receptor 40 (GPR40) agonist, significantly improves hyperglycemia without hypoglycemia and weight gain, the major side effects of conventional anti-diabetics. Unfortunately, during multi-center Phase 3 clinical trials, unexpected liver toxicity resulted in premature termination of its development. Here, we investigated whether TAK-875 directly inflicts toxicity on hepatocytes and explored its underlying mechanism of toxicity. TAK-875 decreased viability of 2D and 3D cultures of HepG2, a human hepatocarcinoma cell line, in concentration- (>50 μM) and time-dependent manners, both of which corresponded with ROS generation. An antioxidant, N-acetylcysteine, attenuated TAK-875-mediated hepatotoxicity, which confirmed the role of ROS generation. Of note, knockdown of GPR40 using siRNA abolished the hepatotoxicity of TAK-875 and attenuated ROS generation. In contrast, TAK-875 induced no cytotoxicity in fibroblasts up to 500 μM. Supporting the hepatotoxic potential of TAK-875, exposure to TAK-875 resulted in increased mortality of zebrafish larvae at 25 μM. Histopathological examination of zebrafish exposed to TAK-875 revealed severe hepatotoxicity as manifested by degenerated hypertrophic hepatocytes with cytoplasmic vacuolation and acentric nuclei, confirming that TAK-875 may induce direct hepatotoxicity and that ROS generation may be involved in a GPR40-dependent manner.
Acetylcysteine ; Cell Line ; Cytoplasm ; Fibroblasts ; GTP-Binding Proteins ; Hepatocytes ; Humans ; Hyperglycemia ; Hypoglycemia ; Larva ; Liver ; Mortality ; Reactive Oxygen Species* ; RNA, Small Interfering ; Weight Gain ; Zebrafish