Ablation of Dual-Specificity Phosphatase 6 Protects against Nonalcoholic Fatty Liver Disease via Cytochrome P450 4A and Mitogen-Activated Protein Kinase.

Dual-specificity phosphatase 6 (DUSP6) is a specific phosphatase for mitogen-activated protein kinase (MAPK). This study used a high-fat diet (HFD)-induced murine nonalcoholic fatty liver disease model to investigate the role of DUSP6 in this disease. Wild-type (WT) and Dusp6-haploinsufficiency mice developed severe obesity and liver pathology consistent with nonalcoholic fatty liver disease when exposed to HFD. In contrast, Dusp6-knockout (KO) mice completely eliminated these phenotypes. Furthermore, primary hepatocytes isolated from WT mice exposed to palmitic and oleic acids exhibited abundant intracellular lipid accumulation, whereas hepatocytes from Dusp6-KO mice showed minimal lipid accumulation. Transcriptome analysis revealed significant down-regulation of genes encoding cytochrome P450 4A (CYP4A), known to promote ω-hydroxylation of fatty acids and hepatic steatosis, in Dusp6-KO hepatocytes compared with that in WT hepatocytes. Diminished CYP4A expression was observed in the liver of Dusp6-KO mice compared with WT and Dusp6-haploinsufficiency mice. Knockdown of DUSP6 in HepG2, a human liver-lineage cell line, also promoted a reduction of lipid accumulation, down-regulation of CYP4A, and up-regulation of phosphorylated/activated MAPK. Furthermore, inhibition of MAPK activity promoted lipid accumulation in DUSP6-knockdown HepG2 cells without affecting CYP4A expression, indicating that CYP4A expression is independent of MAPK activation. These findings highlight the significant role of DUSP6 in HFD-induced steatohepatitis through two distinct pathways involving CYP4A and MAPK.

Expression of Periostin in Benign Salivary Gland Tumors.

Parotid tumors present a wide range of histological features, from benign to malignant. Periostin, an extracellular matrix protein specifically expressed in the periosteum and periodontal ligament, is isolated from osteoblast cell lines. It regulates fibrosis and collagen deposition and plays an important role in myocardial repair after myocardial infarction. It is also known to be involved in otorhinolaryngological-diseases. This study included 36 patients [38 specimens; 16 men and 20 women, mean age 59.2 (range 26-82) years] who underwent parotid tumor resection at the Division of Otorhinolaryngology, Tohoku Medical and Pharmaceutical University, between April 2017 and March 2022 and were clinically and pathologically diagnosed as having benign parotid tumors. Formalin-fixed, paraffin-embedded sections from the surgical specimens were autoclaved and immunostained with anti-periostin antibodies to evaluate the expression and distribution of periostin. Histologically, the tumors were diagnosed as pleomorphic adenomas in 15 cases (15 specimens), Warthin's tumors in 13 cases (15 specimens), basal cell adenomas in 2 cases (2 specimens), oncocytomas in 4 cases (4 specimens), and myoepitheliomas in 2 cases (2 specimens). An increased expression of periostin was found in 32 of 38 samples (84.2%) in the stroma of benign parotid tumors. Four distinct patterns of periostin expression were observed in benign parotid gland tumors: negative, superficial, infiltrative, and diffuse. Statistically significant differences were found between periostin expression patterns and histological classification of the tumors. Our results suggest that periostin may be involved in the pathogenesis of benign parotid tumors and could serve as a new biomarker for these tumors.

Collagen XVII regulates tumor growth in pancreatic cancer through interaction with the tumor microenvironment.

Expression of the gene for collagen XVII (COL17A1) in tumor tissue is positively or negatively associated with patient survival depending on cancer type. High COL17A1 expression is thus a favorable prognostic marker for breast cancer but unfavorable for pancreatic cancer. This study explored the effects of COL17A1 expression on pancreatic tumor growth and their underlying mechanisms. Analysis of published single-cell RNA-sequencing data for human pancreatic cancer tissue revealed that COL17A1 was expressed predominantly in cancer cells rather than surrounding stromal cells. Forced expression of COL17A1 did not substantially affect the proliferation rate of the mouse pancreatic cancer cell lines KPC and AK4.4 in vitro. However, in mouse homograft tumor models in which KPC or AK4.4 cells were injected into syngeneic C57BL/6 or FVB mice, respectively, COL17A1 expression promoted or suppressed tumor growth, respectively, suggesting that the effect of COL17A1 on tumor growth was influenced by the tumor microenvironment. RNA-sequencing analysis of tumor tissue revealed effects of COL17A1 on gene expression profiles (including the expression of genes related to cell proliferation, the immune response, Wnt signaling, and Hippo signaling) that differed between C57BL/6-KPC and FVB-AK4.4 tumors. Our data thus suggest that COL17A1 promotes or suppresses cancer progression in a manner dependent on the interaction of tumor cells with the tumor microenvironment.

Suspected Immune Thrombocytopenic Purpura Induced by Lenalidomide for the Treatment of Myelodysplastic Syndrome with Deletion of Chromosome 5q: A Case Report.

Lenalidomide (LEN), one of the key drugs in the treatment of myelodysplastic syndromes (MDS) with 5q deletion, as well as multiple myeloma (MM), has various immunomodulatory effects and has been associated with autoimmune diseases, including immune thrombocytopenic purpura (ITP). A 78-year-old man presented with pancytopenia and was diagnosed with MDS with 5q deletion and other chromosomal abnormalities. Two cycles of LEN therapy (one cycle: 10 mg/day for 21 days) resulted in a transient improvement in anemia, followed by MDS progression with severe thrombocytopenia (4 × 109/L) refractory to platelet transfusions. As other non-immune and alloimmune causes of transfusion-refractory thrombocytopenia were excluded, and the level of platelet-associated immunoglobulin G was extremely high compared with the level before treatment with LEN, the diagnosis of ITP was highly suspected. Despite treatment with prednisolone (PSL), eltrombopag, and repeated platelet transfusions, his platelet count did not increase, and he died of a gastrointestinal hemorrhage. Several cases of ITP induced by LEN used to treat MM had been reported, but the platelet count recovered after administration of PSL in these previous cases. However, we should be mindful of using LEN for patients with MDS because its treatment may become extremely difficult if ITP develops.

Immunohistochemical Localization of D-ß-Aspartic Acid and Periostin in Vocal Fold Polyps.

Long-term voice abuse or sudden vocal fold microvascular disruption may lead to injury and subsequent repair/remodeling in the vocal fold mucosa. Periostin is known to be involved in airway remodeling and also in various otolaryngological diseases. D-ß-aspartic acid is the major isomer of D-aspartic acid found in elderly tissue. In this study we investigated the expression and the role of D-ß-aspartic acid and periostin in the formation of vocal fold polyps. The expression patterns of D-ß-aspartic acid and periostin in 36 surgical specimens of vocal fold polyps from 36 patients were investigated immunohistochemically. In the epithelium of vocal polyps, D-ß-aspartic acid was expressed in all cases. Expression of D-ß-aspartic acid was detected in 25 samples obtained from patients with vocal fold polyps stroma. Expression of periostin was detected in 28 samples obtained from patients with vocal fold polyps. Two patterns of D-ß-aspartic acid expression were observed in vocal fold polyps stroma: positive type and negative type. The following four patterns of periostin expression were observed in vocal fold polyps: negative type, superficial type, infiltrative type, and diffuse type. An association was observed between D-ß-aspartic acid expression patterns and periostin expression patterns. From these findings we speculate that periostin and D-ß-aspartic acid participate in certain pathological changes in vocal fold polyps, such as extracellular matrix accumulation, local fibrosis, and the formation and development of vocal fold polyps.

Tumor-to-Tumor Metastasis of Medullary Thyroid Carcinoma to Paraganglioma in a Multiple Endocrine Neoplasia Type 2B Patient: A Case Report and Literature Review.

Tumor-to-tumor metastasis is a rare phenomenon in which primary tumor cells metastasize to other tumors. Herein, we report an extremely rare case of tumor-to-tumor metastasis of medullary thyroid carcinoma to a paraganglioma in a patient with multiple endocrine neoplasia type 2B. Based on genetic examination, a 36-year-old woman was diagnosed with multiple endocrine neoplasia type 2B when she was 24 years old. She had a history of total thyroidectomy for medullary thyroid carcinoma and bilateral adrenalectomy for pheochromocytomas, which were performed when she was 15 years and 29 years old, respectively. Follow-up computed tomography demonstrated a retroperitoneal tumor of 30 mm in diameter beside the left kidney and a liver tumor of 16 mm in diameter located in segment 6. The retroperitoneal and liver tumors were surgically resected and examined by a pathologist. Histological examination revealed the classic Zellballen pattern in the retroperitoneal tumor, rendering the diagnosis of a paraganglioma recurrence. Inside the tumor, a white nodule positive for carcinoembryonic antigen, weakly positive for calcitonin, and negative for tyrosine hydroxylase, was identified and diagnosed as a metastatic medullary thyroid carcinoma with high malignant potential. The liver lesion was diagnosed as a metastasis of the medullary thyroid carcinoma. This is the first report of tumor-to-tumor metastasis of medullary thyroid carcinoma to paraganglioma in a patient with multiple endocrine neoplasia type 2B twenty years after total thyroidectomy.

Small Intestinal Adenocarcinoma Arising at the Anastomotic Site after Kasai Operation for Biliary Atresia: A Case Report and Literature Review.

Biliary atresia is an obliterative cholangiopathy of unknown etiology. Hepatic portoenterostomy, in which obliterated extrahepatic bile ducts are resected and bile flow is restored, known as Kasai operation, is performed within 3 months after birth. While this operation enhances long-term survival of patients, the occurrence of primary malignant hepatic tumors has been increasing. We report a case of small intestinal adenocarcinoma arising at the anastomotic site after Kasai operation. A 49-year-old man, who underwent Kasai operation for biliary atresia when he was 2 months old, experienced rapidly progressive jaundice and liver dysfunction. Deceased-donor liver transplantation was performed for liver failure. Macroscopically, there was a white-yellow tumor located at the anastomotic site of hepatic portoenterostomy of the resected liver. Pathological examination revealed a well-differentiated adenocarcinoma with some Paneth cells in the neoplastic lesion. Immunohistochemically, the tumor cells were negative for cytokeratin 7 (CK7) but positive for cytokeratin 20 (CK20) and a homeobox domain-containing transcription factor (CDX2). Mucin expression in tumor cells was negative for mucin 1 (MUC1) and mucin 6 (MUC6) and positive for mucin 2 (MUC2) and mucin 5AC (MUC5AC). The pathological diagnosis was small intestinal adenocarcinoma originating from the jejunum. The patient was discharged 48 days after the operation. The patient had not experienced recurrence at 10 months after the operation. This is the first report of small intestinal adenocarcinoma arising at the anastomotic site after Kasai operation for biliary atresia. Special care should be taken for the patients after Kasai operation with acute progressive jaundice and liver dysfunction because there is a possibility of malignancy in their native liver.

Periostin is an aggravating factor and predictive biomarker of eosinophilic chronic rhinosinusitis.

BACKGROUND: Patients with eosinophilic chronic rhinosinusitis (ECRS) respond poorly to many treatment modalities. Overproduction of periostin in the nasal mucosa is reported to contribute to polyp formation. This study examined periostin levels in patients with ECRS in comparison with levels in patients with non-ECRS. METHODS: Fifty-nine patients with chronic rhinosinusitis were grouped into those with ECRS and those with non-ECRS. We compared the relationships between peripheral blood eosinophil level, serum periostin level, histopathological findings, clinical and laboratory findings, nose findings, diagnostic score of the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis Study, and postoperative recurrence of nasal polyps in each group. RESULTS: In the ECRS group, a positive correlation was found between peripheral blood eosinophil level and serum periostin level (rs = 0.49, P < 0.01: Spearman's rank correlation coefficient). ROC curve analysis was used to evaluate the serum periostin level that could predict postoperative recurrence of nasal polyps in the ECRS group: the area under the curve (AUC) was 0.95, sensitivity was 92%, and specificity was 100%; the serum periostin cutoff value for postoperative recurrence of nasal polyps was 130 ng/ml. In ROC curve analysis to evaluate peripheral blood eosinophil level, the AUC was 0.73, sensitivity was 69.2%, and specificity was 85.0%; the cutoff value was 8.8%. CONCLUSIONS: periostin was implicated in the pathophysiology of ECRS. Periostin shown to be a more useful biomarker than eosinophils in ECRS. Periostin was shown to likely be an important biomarker for pathological severity of ECRS and postoperative recurrence of nasal polyps.

Expression of Periostin in Vocal Fold Polyps.

Long-term voice abuse or sudden vocal fold microvascular disruption may lead to injury and subsequent repair/remodeling in the vocal fold mucosa. Periostin is known to be involved in airway remodeling and also in various otolaryngological diseases. The aim of this article was to investigate the expression and the role of periostin in the formation of vocal fold polyps. The expression patterns of periostin in 59 surgical specimens of vocal fold polyps from 54 patients were investigated immunohistochemically. Normal vocal fold mucosa specimens from 5 patients who had undergone total laryngectomy were used as the control group. Retrospective study with planned data collection was conducted at Tohoku Medical and Pharmaceutical University. Expression of periostin was detected in 43 (72.9%) samples and four patterns of periostin expression were observed in vocal fold polyps: negative type, superficial type, infiltrative type, and diffuse type. An association was observed between periostin expression patterns and the histological subtypes of vocal fold polyps. The infiltrative pattern of periostin expression was significantly dominant in vascular-hyaline types. Expression of transforming growth factor-ß (TGF-ß) was also detected in the vocal fold polyps. Our results confirmed that periostin might be involved in certain pathological changes in vocal fold polyps, such as extracellular matrix accumulation, local fibrosis, and formation and development of vocal fold polyps.

Selective association of desmin intermediate filaments with a phospholipid layer in droplets.

Desmin, an intermediate filament protein expressed in muscle cells, plays a key role in the integrity and regulation of the contractile system. Furthermore, the distribution of desmin in cells and its interplay with plasma and organelle membranes are crucial for cell functions; however, the fundamental properties of lipid-desmin interactions remain unknown. Using a water-in-oil method for a limited space system in vitro, we examined the distribution of desmin in three types of phospholipid droplets: 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), and 1,2-dioleoyl-sn-glycero-3-phosphoserine (DOPS). When fluorescent-labeled desmin was observed for 60 min after desmin assembly was initiated by adding 25 mM KCl, desmin accumulated on both the DOPE and DOPS layers; however, it did not accumulate on the DOPC layer of droplets. An increase in salt concentration did not moderate the accumulation. The initial form of either oligomer or mature filament affected the accumulation on each lipid layer. When liposomes were included in the droplets, desmin was associated with DOPE but not on DOPC liposomes. These results suggest that desmin has the potential for association with phospholipids concerning desmin form and lipid shape. The behavior and composition of living membranes may affect the distribution of desmin networks.

The prognostic significance of neuroendocrine markers and somatostatin receptor 2 in hepatocellular carcinoma.

Prostatic and colon carcinomas with neuroendocrine differentiation are reported to behave more aggressively than those without such differentiation. In hepatocellular carcinomas (HCCs), however, only a few studies have reported the expression status of neuroendocrine markers and somatostatin receptor 2, the main target of a somatostatin analog. Furthermore, the prognostic significance of the markers in HCCs has not been fully explored. We evaluated the expression of the neuroendocrine makers (chromogranin A, synaptophysin, and CD56) and somatostatin receptor 2 (SSTR2) in 95 HCCs, and investigated the correlation between the expression of these markers and clinicopathological findings. Chromogranin A was immunolocalized in 2 cases, synaptophysin in 15 cases, CD56 in 11 cases, and SSTR2 in 19 cases. Immunoreactivity of synaptophysin and CD56 were the significant unfavorable prognostic factors in terms of 2-year disease-free survival (DFS) and the overall survival (OS) along with a high nuclear mitosis level (>10/10 high-power field), a larger tumor size (>5 cm), the presence of vascular and/or biliary invasion, and high TNM stage (III/IV). Multivariate Cox proportional hazards analysis identified synaptophysin as an independent prognostic factor for 2-year DFS and OS. Synaptophysin expression can be used to predict an unfavorable prognosis in patients with HCC.

Copper-Mediated Conversion of Alkynes into Nitriles via Iodotriazoles.

We disclose our studies on a copper-mediated reaction of alkynes with trimethylsilyl azide to afford nitriles, and proposed a reaction mechanism, which involves an iodoalkyne and an iodotriazole as intermediates.

Intestinal necrosis related to administration of cation exchange resin without sorbitol: A retrospective analysis of 61 patients with end-stage renal diseases.

Intestinal necrosis associated with cation exchange resin (CER) is considered related to sorbitol, but it has been reported even in patients receiving CER alone. This study was performed to identify the risk factors of CER-related intestinal necrosis. The pathological database of 61 end-stage renal disease patients with surgical intervention for intestinal perforation was reviewed. The correlations between CER treatment and clinicopathological factors were studied among three groups: (i) patients administered CER and with CER at the perforation site (n = 23), (ii) patients administered CER with undetected CER at the perforation site (n = 12) and (iii) patients not administered CER (n = 26). The majority of the perforation site in group 1 was in the sigmoid colon (82.6%) with significantly higher average age and more frequent CER adhesion rates to the mucosa around the perforation site than group 2. The laxative administration rate in group 1 was significantly higher than group 3 and tended to be higher than group 2. The incidence of CER-related intestinal necrosis was estimated at 0.57%. CER should be used with extreme caution in elderly patients with passage disturbance.

Total Synthesis of Tetrodotoxin.

A total synthesis of tetrodotoxin was accomplished. A Diels-Alder reaction between a known enone and a siloxy diene gave a tricyclic product, the steric bias of which was used to construct the remaining stereogenic centers. A nitrogen atom was introduced either by a four-step sequence involving a Curtius rearrangement, or a three-step sequence featuring a newly developed transformation of a terminal alkyne into a nitrile. Introduction of the guanidine moiety followed by the formation of the heterocyclic system by cascade reactions led to tetrodotoxin.

Activation of the Hypoxia Inducible Factor 1α Subunit Pathway in Steatotic Liver Contributes to Formation of Cholesterol Gallstones.

BACKGROUND & AIMS: Hypoxia-inducible factor 1α subunit (HIF1A) is a transcription factor that controls the cellular response to hypoxia and is activated in hepatocytes of patients with nonalcoholic fatty liver disease (NAFLD). NAFLD increases the risk for cholesterol gallstone disease by unclear mechanisms. We studied the relationship between HIF1A and gallstone formation associated with liver steatosis. METHODS: We performed studies with mice with inducible disruption of Hif1a in hepatocytes via a Cre adenoviral vector (inducible hepatocyte-selective HIF1A knockout [iH-HIFKO] mice), and mice without disruption of Hif1a (control mice). Mice were fed a diet rich in cholesterol and cholate for 1 or 2 weeks; gallbladders were collected and the number of gallstones was determined. Livers and biliary tissues were analyzed by histology, quantitative reverse-transcription polymerase chain reaction, immunohistochemistry, and immunoblots. We measured concentrations of bile acid, cholesterol, and phospholipid in bile and rates of bile flow. Primary hepatocytes and cholangiocytes were isolated and analyzed. HIF1A was knocked down in Hepa1-6 cells with small interfering RNAs. Liver biopsy samples from patients with NAFLD, with or without gallstones, were analyzed by quantitative reverse-transcription polymerase chain reaction. RESULTS: Control mice fed a diet rich in cholesterol and cholate developed liver steatosis with hypoxia; levels of HIF1A protein were increased in hepatocytes around central veins and 90% of mice developed cholesterol gallstones. Only 20% of the iH-HIFKO mice developed cholesterol gallstones. In iH-HIFKO mice, the biliary lipid concentration was reduced by 36%, compared with control mice, and bile flow was increased by 35%. We observed increased water secretion from hepatocytes into bile canaliculi to mediate these effects, resulting in suppression of cholelithogenesis. Hepatic expression of aquaporin 8 (AQP8) protein was 1.5-fold higher in iH-HIFKO mice than in control mice. Under hypoxic conditions, cultured hepatocytes increased expression of Hif1a, Hmox1, and Vegfa messenger RNAs (mRNAs), and down-regulated expression of AQP8 mRNA and protein; AQP8 down-regulation was not observed in cells with knockdown of HIF1A. iH-HIFKO mice had reduced inflammation and mucin deposition in the gallbladder compared with control mice. Liver tissues from patients with NAFLD with gallstones had increased levels of HIF1A, HMOX1, and VEGFA mRNAs, compared with livers from patients with NAFLD without gallstones. CONCLUSIONS: In steatotic livers of mice, hypoxia up-regulates expression of HIF1A, which reduces expression of AQP8 and concentrates biliary lipids via suppression of water secretion from hepatocytes. This promotes cholesterol gallstone formation. Livers from patients with NAFLD and gallstones express higher levels of HIF1A than livers from patients with NAFLD without gallstones.

Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers.

BACKGROUND/OBJECTIVE: Insulin signals, via the regulation of key enzyme expression, both suppress gluconeogenesis and enhance lipid synthesis in the liver. Animal studies have revealed insulin signaling favoring gluconeogenesis suppression to be selectively impaired in steatotic livers. However, whether, and if so how, such selective insulin resistance occurs in human steatotic livers remains unknown. Our aim was to investigate selective insulin resistance in human livers with non-alcoholic fatty liver disease (NAFLD). SUBJECTS/METHODS: We examined mRNA expressions of key molecules for insulin signaling, gluconeogenesis and lipogenesis in human liver biopsy samples obtained from 51 non-diabetic subjects: 9 healthy controls and 42 NAFLD patients, and analyzed associations of these molecules with each other and with detailed pathological and clinical biochemistry data. RESULTS: In NAFLD patients, insulin receptor substrate (IRS)-2 expression was decreased, while those of key enzymes for gluconeogenesis were increased. These alterations of IRS-2 and gluconeogenesis enzymes were induced both in simple steatosis (SS) and non-alcoholic steatohepatitis (NASH), while these expression levels did not differ between SS and NASH. Furthermore, alterations in the expressions of IRS-2 and gluconeogenesis enzymes showed strong negative correlations and were concurrently induced in the early histological stage of NAFLD. In contrast, fatty acid synthase (FAS) expression was not decreased in NAFLD, despite IRS-2 downregulation, but correlated strongly with IRS-1 expression. Furthermore, no histological scores were associated with these molecules. Thus, IRS-1 signaling, which is not impaired in NAFLD, appears to modulate FAS expression. CONCLUSION: These analyses revealed that selective insulin resistance is present in human NAFLD livers and occurs in its early phases. The effect of insulin, during the IRS step, on gene expressions for lipogenesis and gluconeogenesis are apparently distinct and preferential downregulation of IRS-2 may contribute to selective resistance to the suppressive effects of insulin on gluconeogenesis.

Steroidogenesis in ovarian-like mesenchymal stroma of hepatic and pancreatic mucinous cystic neoplasms.

STEROIDOGENESIS IN HEPATIC MUCINOUS CYSTIC NEOPLASM: Aim Mucinous cystic neoplasms (MCNs) occur in the ovary, pancreas, and retroperitoneum but very rarely in the liver. Mucinous cystic neoplasms are known to harbor ovarian-like mesenchymal stroma (OLS) expressing progesterone and estrogen receptors. In this study we evaluated steroidogenesis in OLS of 25 hepatic MCNs and 24 pancreatic MCNs. Methods Both steroid receptors and steroidogenic factors were immunohistochemically evaluated using H-scores and results were compared with those in 15 ovarian MCNs and 10 normal ovaries. Results Androgen receptor (AR) H-scores in OLS were significantly higher in hepatic, pancreatic, and ovarian MCN than those in normal ovaries. H-scores of cytochrome P450 17α-hydroxylase/c17-20 lyase (P450c17) and 5α-reductase-1 (5αRED-1) in the stroma were significantly higher in OLS of hepatic and pancreatic MCN than in the stroma of ovarian MCN and normal ovary. In tumor epithelium, AR H-scores were significantly higher in hepatic and pancreatic MCN than in ovarian MCN. In both hepatic and pancreatic MCN, a significant positive correlation was detected between AR H-score in the epithelium and P450c17 H-score in OLS (hepatic MCN: Pearson's r = 0.446, P = 0.025; pancreatic MCN: r = 0.432, P = 0.035). In pancreatic MCN, a significantly positive correlation was detected between AR H-score in the tumor epithelium and 5αRED-1 H-score in OLS (Pearson's r = 0.458, P = 0.024). Conclusions These results indicated that locally produced androgens in OLS could be pivotal for tumorigenesis of both hepatic and pancreatic MCN and influence epithelial cells, possibly in a paracrine fashion, which could represent biological significance of OLS in these neoplasms.

Association of post-transplant donor-specific HLA antibody with liver graft fibrosis during long-term follow-up after pediatric liver transplantation.

The aim of this study was to evaluate the significance of post-transplant DSA as a predictor of liver fibrosis during long-term follow-up after pediatric LT. We evaluated the histological findings in 18 LT recipients who underwent liver biopsy after DSA screening. Liver fibrosis was scored based on the METAVIR fibrosis staging. Patients were divided into 2 groups based on histological findings, and clinical characteristics among patients with liver fibrosis were assessed. Of 18 patients, 7 were included in the fibrosis group. No significant between-group differences were found regarding peritransplant characteristics, including age, sex, primary disease, ABO incompatibility, and immunosuppressive regimen. Episodes of acute rejection and non-adherence to immunosuppressive drugs were comparable between both groups. The MFI for anti-DR DSA and positive rate were significantly higher in the fibrosis group (1655 vs 216; P = .019, 86% vs 27%; P = .012, respectively). MFI for anti-DQ DSA was higher in the fibrosis group, but non-significantly (2052 vs 384; P = .46). Post-transplant anti-DR DSA is associated with graft fibrosis during long-term follow-up. This finding seems useful for the implementation of valid histological examinations of liver grafts for patients with higher MFI, especially for anti-DR DSA, after pediatric LT.