Synergistic Effects of Vitis vinifera L. and Centella asiatica against CCl4-Induced Liver Injury in Mice.

Liver injury can be acute or chronic, resulting from a variety of factors, including viral hepatitis, drug overdose, idiosyncratic drug reaction, or toxins, while the progression of pathogenesis in the liver rises due to the involvement of numerous cytokines and growth factor mediators. Thus, the identification of more effective biomarker-based active phytochemicals isolated from medicinal plants is a promising strategy to protect against CCl4-induced liver injury. Vitis vinifera L. (VE) and Centella asiatica (CE) are well-known medicinal plants that possess anti-inflammatory and antioxidant properties. However, synergism between the two has not previously been studied. Here, we investigated the synergistic effects of a V. vinifera L. (VE) leaf, C. asiatica (CE) extract combination (VCEC) against CCl4-induced liver injury. Acute liver injury was induced by a single intraperitoneal administration of CCl4 (1 mL/kg). VCEC was administered orally for three consecutive days at various concentrations (100 and 200 mg/kg) prior to CCl4 injection. The extent of liver injury and the protective effects of VCEC were evaluated by biochemical analysis and histopathological studies. Oxidative stress was evaluated by measuring malondialdehyde (MDA) and glutathione (GSH) levels and Western blotting. VCEC treatment significantly reduced serum transaminase levels (AST and ALT), tumor necrosis factor-α (TNF-α), and reactive oxygen species (ROS). CCl4- induced apoptosis was inhibited by VCEC treatment by reducing cleaved caspase-3 and Bcl2-associated X protein (Bax). VCEC-treated mice significantly restored cytochrome P450 2E1, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) expression in CCl4-treated mice. In addition, VCEC downregulated overexpression of proinflammatory cytokines and hepatic nuclear factor kappa B (NF-κB) and inhibited CCl4-mediated apoptosis. Collectively, VCEC exhibited synergistic protective effects against liver injury through its antioxidant, anti-inflammatory, and antiapoptotic ability against oxidative stress, inflammation, and apoptosis. Therefore, VCEC appears promising as a potential therapeutic agent for CCl4-induced acute liver injury in mice.

Clinical significance of p53 protein expression and TP53 variation status in colorectal cancer.

In human colorectal cancer (CRC), TP53 is one of the most important driver genes. Immunohistochemistry (IHC) has been used most often to assess the variational status of TP53. Recently, next-generation sequencing (NGS) of the TP53 gene has increased. However, to our knowledge, a comparison between TP53 status evaluated by IHC and NGS has not been studied. Therefore, the primary aim of this study was to compare the clinical effect of TP53 status evaluated by IHC and NGS in patients with CRC. The secondary aim was to investigate the correlation between expression of p53 by IHC and variational status of TP53 by NGS. We performed immunohistochemical staining of p53 and sequencing of TP53 by NGS in 204 human samples of CRC. We then analyzed the correlation between variational status of TP53 and p53 expression, along with their prognostic impact in CRC patients. There was significant correlation between p53 expression and TP53 variation, TP53 variation and higher N stage, and positive p53 expression and higher N stage. Positive IHC expression of p53 was significantly associated with overall survival (OS) of CRC patients by univariate analysis and was revealed as an independent prognostic factor by multivariate analysis. Additionally, the nonsense/frameshift p53 expression pattern showed a significantly better prognosis than the wild type and missense p53 expression patterns. However, the variational status of TP53 was not significant in OS of CRC patients. These results suggest that IHC expression of p53 protein correlates with variation status of TP53 and expression of p53 protein rather than variation status of TP53 has more significant impact on the OS of CRC patients.

Hepatoprotective Effects of a Natural Flavanol 3,3'-Diindolylmethane against CCl4-Induced Chronic Liver Injury in Mice and TGFß1-Induced EMT in Mouse Hepatocytes via Activation of Nrf2 Cascade.

Hepatic fibrosis is a form of irregular wound-healing response with acute and chronic injury triggered by the deposition of excessive extracellular matrix. Epithelial-mesenchymal transition (EMT) is a dynamic process that plays a crucial role in the fibrogenic response and pathogenesis of liver fibrosis. In the present study, we postulated a protective role of 3,3'-diindolylmethane (DIM) against TGF-ß1 mediated epithelial-mesenchymal transition (EMT) in vitro and carbon tetrachloride (CCl4)-induced liver fibrosis in mice. TGF-ß1-induced AML-12 hepatocyte injury was evaluated by monitoring cell morphology, measuring reactive oxygen species (ROS) and mitochondrial membrane potential, and quantifying apoptosis, inflammatory, and EMT-related proteins. Furthermore, CCl4-induced liver fibrosis in mice was evaluated by performing liver function tests, including serum ALT and AST, total bilirubin, and albumin to assess liver injury and by performing H&E and Sirius red staining to determine the degree of liver fibrosis. Immunoblotting was performed to determine the expression levels of inflammation, apoptosis, and Nrf2/HO-1 signaling-related proteins. DIM treatment significantly restored TGF-ß1-induced morphological changes, inhibited the expression of mesenchymal markers by activating E-cadherin, decreased mitochondrial membrane potential, reduced ROS intensity, and upregulated levels of Nrf2-responsive antioxidant genes. In the mouse model of CCl4-induced liver fibrosis, DIM remarkably attenuated liver injury and liver fibrosis, as reflected by the reduced ALT and AST parameters with increased serum Alb activity and fewer lesions in H&E staining. It also mitigated the fibrosis area in Sirius red and Masson staining. Taken together, our results suggest a possible molecular mechanism of DIM by suppressing TGF-ß1-induced EMT in mouse hepatocytes and CCl4-induced liver fibrosis in mice.

FAM83H and Nectin1 expression are related with survival and relapse of bladder urothelial carcinoma patients.

BACKGROUND: FAM83H was originally reported to be essential for dental enamel formation. However, FAM83H has recently been implicated in tumorigenesis and tumor progression. Analysis of a publicly available gene expression database revealed a significant correlation between FAM83H and Nectin1 mRNA expression and bladder urothelial carcinoma (BUC). Therefore, we investigated the association between FAM83H and Nectin1 expression levels and the survival and recurrence of BUC in BUC patients using a tissue microarray. METHODS: We performed immunohistochemical staining of FAM83H and Nectin1 in 165 human BUC tissue sections, and analyzed the prognostic significance of FAM83H and Nectin1 expression. RESULTS: Both FAM83H and Nectin1 were mainly expressed in the cytoplasm, and their expression was significantly associated. FAM83H expression was significantly correlated with higher histologic grade, higher T stage, higher TNM stage, and recurrence. Nectin1 expression was significantly associated with higher histologic grade and recurrence. Univariate analysis showed FAM83H expression and Nectin1 expression were significantly associated with worse overall survival (OS) and shorter relapse-free survival (RFS) of BUC patients. In multivariate analysis, levels of FAM83H and Nectin1 were independent indicators of shorter survival of BUC patients. CONCLUSIONS: Our results suggest that FAM83H and Nectin1 are important in the progression of BUC, and that expression patterns of these two proteins can be used as prognostic indicators of survival in BUC patients.

Congenital dermoid sinus of the anterior chest region.

BACKGROUND: Congenital dermoid sinus of the anterior chest region (CDACR) is a rare developmental anomaly. Therefore, the aim of our study was to draw attention to this underrecognized lesion. METHODS: From 2011 to 2019, our study group included 11 patients who presented to our hospital with pits and masses of their anterior chest walls. All lesions were surgically excised with histologic confirmation of the diagnosis of CDACR. The medical records of these patients were reviewed for the following data: patient age, gender, clinical characteristics of the lesion and site of involvement, department first visited, diagnostic evaluation, management, postoperative complications, and histopathological findings. RESULTS: There was a clear left-sided predominance, with 10/11 cases occurring on the left and a female predominance of eight cases out of 11. Although the pits were present at birth, the mean age at presentation was 19.7 months. All patients showed clinical signs of infection at the time of presentation and were treated with antibiotics. Seven patients had a history of abscess formation treated with incision and drainage. Ultrasound was performed in eight patients. In all cases, the lesions, including pit and sinus, were completely excised. CONCLUSIONS: Congenital dermoid sinus of the anterior chest region is likely underrecognized. We encountered a high frequency of complications such as infections or abscesses prior to surgical excision. Complete excision of CDACR is not technically difficult. Therefore, surgical removal should be considered, even for asymptomatic lesions, to avoid future complications and for cosmesis.

Short communication: First detection of Panton-Valentine leukocidin-positive methicillin-resistant Staphylococcus aureus ST30 in raw milk taken from dairy cows with mastitis in South Korea.

We identified 199 Staphylococcus aureus isolates from quarter milk samples of 1,289 dairy cattle between 2014 and 2018. About 66% of the isolates were resistant to at least 1 antimicrobial agent; the highest rate of resistance was to penicillin, followed by resistance to ampicillin, erythromycin, and sulfadimethoxine. We obtained 30 methicillin-resistant S. aureus (MRSA) strains from 6 farms in 3 provinces. The MRSA strains exhibited a significantly higher resistance rate to most of the tested antimicrobials than the oxacillin-susceptible strains. The MRSA strains represented 5 genotypes: ST72-t324-SCCmec IV (n = 14), ST30-t1752-SCCmec IV (n = 8), ST188-t189-SCCmec NT (n = 6), ST188-t2284-SCCmec NT (n = 1), and NT-NT-SCCmec IV (n = 1). One of the ST188 MRSA strains represented a novel staphylococcal protein A (spa) type (t2284). In addition, 7 of the 8 ST30 MRSA strains were Panton-Valentine leukocidin (PVL)-positive and carried various staphylococcal enterotoxin encoding genes. This is the first report of PVL-positive ST30 MRSA-t1752-SCCmec IV from bovine mastitis in Korea. All of ST72-t324-SCCmec IV MRSA strains carried staphylococcal enterotoxin and leukotoxin encoding genes. They were also sensitive to most of the tested non-ß-lactam antimicrobials. In contrast, ST188-t189 MRSA strains were resistant to multiple antimicrobials and predominantly carried the leukotoxin encoding gene. Taken together, these findings may indicate that dairy cows could be a major source for spreading MRSA strains, and contaminated milk could be a vehicle for transmission. Suitable hygienic measures should be established in dairy farms and processing plants to limit the likelihood of introducing MRSA into the food chain.

N-3-Hydroxy Dodecanoyl-DL-homoserine Lactone (OH-dDHL) Triggers Apoptosis of Bone Marrow-Derived Macrophages through the ER- and Mitochondria-Mediated Pathways.

Quorum sensing of Acinetobacter nosocomialis for cell-to-cell communication produces N-3-hydroxy dodecanoyl-DL-homoserine lactone (OH-dDHL) by an AnoR/I two-component system. However, OH-dDHL-driven apoptotic mechanisms in hosts have not been clearly defined. Here, we investigated the induction of apoptosis signaling pathways in bone marrow-derived macrophages treated with synthetic OH-dDHL. Moreover, the quorum-sensing system for virulence regulation was evaluated in vivo using wild-type and anoI-deletion mutant strains. OH-dDHL decreased the viability of macrophage and epithelial cells in dose- and time-dependent manners. OH-dDHL induced Ca2+ efflux and caspase-12 activation by ER stress transmembrane protein (IRE1 and ATF6a p50) aggregation and induced mitochondrial dysfunction through reactive oxygen species (ROS) production, which caused cytochrome c to leak. Pretreatment with a pan-caspase inhibitor reduced caspase-3, -8, and -9, which were activated by OH-dDHL. Pro-inflammatory cytokine and paraoxonase-2 (PON2) gene expression were increased by OH-dDHL. We showed that the anoI-deletion mutant strains have less intracellular invasion compared to the wild-type strain, and their virulence, such as colonization and dissemination, was decreased in vivo. Consequently, these findings revealed that OH-dDHL, as a virulence factor, contributes to bacterial infection and survival as well as the modification of host responses in the early stages of infection.

Short communication: Occurrence and persistence of Prototheca zopfii in dairy herds of Korea.

Bovine mastitis caused by Prototheca has been reported globally, and its incidence is increasing in dairy herds. The present study aimed to investigate the occurrence of Prototheca and persistence of Prototheca zopfii strains in Korean dairy herds. A total of 187 (7.5%) P. zopfii strains were isolated from 2,508 quarter milk samples collected from 50 dairy farms throughout Korea from 2015 to 2017. Prototheca zopfii was isolated from one farm among the 50 farms over the 3-yr period. The P. zopfii isolates belonged to genotype 2. Overall, Prototheca-positive quarter milk samples showed high somatic cell counts with an average value of log 6.48 ± 6.54 cells/mL. Prototheca zopfii was found to be persistent in an infected farm over a 2-yr period. To the best of our knowledge, this is the first report on the presence and persistence of protothecal mastitis caused by P. zopfii genotype 2 in a Korean dairy herd. This disease leads to a significant increase in somatic cell counts in milk, which persists for more than 1 yr in the affected cow udder. These results suggest that P. zopfii could pose a serious risk to dairy herds. Thus, strict surveillance for protothecal mastitis is urgently needed and sanitary conditions regarding the environment and milk collection are essential because of the lack of effective treatment options.

Expression of oxidized protein tyrosine phosphatase and γH2AX predicts poor survival of gastric carcinoma patients.

BACKGROUND: Oxidative stress induces various intracellular damage, which might be correlated with tumorigenesis. Accumulated oxidative stresses might inactivate protein tyrosine phosphatase (PTP) by oxidizing it, and inducing the phosphorylation of H2AX (γH2AX) in response to DNA damage. METHODS: We evaluated the clinical significance of the expression of oxidized-PTP and γH2AX in 169 gastric carcinomas. RESULTS: Immunohistochemical expression of nuclear oxidized-PTP, cytoplasmic oxidized-PTP, and γH2AX expression were significantly associated with each other, and their expressions predicted shorter survival of gastric carcinoma patients. In multivariate analysis, nuclear oxidized-PTP (overall survival; p <  0.001, relapse-free survival; P <  0.001) was an independent indicator of poor prognosis of gastric carcinoma patients. In addition, co-expression patterns of nuclear oxidized-PTP and γH2AX were independent indicators of poor prognosis of gastric carcinoma patients (overall survival; P <  0.001, relapse-free survival; P <  0.001). CONCLUSIONS: This study suggests that oxidative stress-mediated oxidation of PTP might be involved in the progression of gastric carcinomas. In addition, this study suggests that individual and co-expression pattern of nuclear oxidized-PTP and γH2AX might be used as a prognostic marker of gastric carcinomas.

Chitosan-Based Hydrogel Microparticles for Treatment of Carcinoma in a Rabbit VX2 Liver Tumor Model.

PURPOSE: To investigate potential of chitosan hydrogel microparticles (CHI) for treatment of VX2 carcinoma. MATERIALS AND METHODS: Two weeks after liver VX2 implantation, contrast-enhanced computerized tomographic scanning was conducted. Rabbits (n = 2) with successful tumor growth were treated with different sizes of 99mTc-labeled CHI (60-80 µm and 100-120 µm) via intra-arterial hepatic catheterization. Liver distribution of 99mTc-labeled CHI was determined by means of autoradiography, a radiation-based photographic technique. In the next part of this study, therapeutic effectiveness was examined with the use of CHI with the size range of 60-80 µm (n = 11). Tumor growth response and levels of blood liver enzymes were studied at baseline and 1 and 2 weeks after CHI treatment. RESULTS: Successful tumor growth was confirmed in all rabbits (24/24). Intrahepatic CHI with the size range of 60-80 µm resulted in liver localization in more close proximity to tumor nodule versus 100-120 µm. Baseline tumor volume was 1,909 ± 575 mm3 in animals receiving CHI versus 1,831 ± 249 mm3 in control animals (P = .342). In control animals, tumor volume markedly increased by 1,544 ± 512% at 2 weeks after sham operation versus baseline. In animals receiving CHI, tumor volume remained relatively unchanged (54 ± 6% increase; P = .007 vs control). Levels of blood aspartate transaminase (AST) and alanine transaminase (ALT) in animals receiving CHI increased 1 week after treatment (P = .032 vs control for AST; P = .000 vs control for ALT), but returned to control levels at 2 weeks. CONCLUSIONS: CHI embolization suppressed tumor growth without appreciable damages in liver function.

CK2α/CSNK2A1 Phosphorylates SIRT6 and Is Involved in the Progression of Breast Carcinoma and Predicts Shorter Survival of Diagnosed Patients.

Recently, the roles of sirtuins (SIRTs) in tumorigenesis have been of interest to oncologists, and protein kinase CK2 α1 (CSNK2A1) has been shown to be involved in tumorigenesis by phosphorylating various proteins, including SIRT1. Therefore, we evaluated the roles of CSNK2A1, SIRT6, and phosphorylated SIRT6 and their relationships in breast carcinoma. Nuclear expression of CSNK2A1 and SIRT6 predicted shorter overall survival and relapse-free survival by multivariate analysis. Inhibition of CSNK2A1 decreased the proliferative and invasive activity of cancer cells. In addition, CSNK2A1 was bound to SIRT6 and phosphorylated SIRT6; evidence for this is provided from immunofluorescence staining, co-immunoprecipitation of CSNK2A1 and SIRT6, a glutathione S-transferase pull-down assay, an in vitro kinase assay, and transfection of mutant CSNK2A1. Knockdown of SIRT6 decreased the proliferation and invasiveness of cancer cells. Overexpression of SIRT6 increased proliferation, but mutation at the Ser338 phosphorylation site of SIRT6 inhibited the proliferation of MCF7 cells. Moreover, both knockdown of SIRT6 and a mutation at the phosphorylation site of SIRT6 decreased expression of matrix metallopeptidase 9, ß-catenin, cyclin D1, and NF-κB. Especially, SIRT6 expression was associated with the nuclear localization of ß-catenin. This study demonstrates that CSNK2A1 and SIRT6 are indicators of poor prognosis for breast carcinomas and that CSNK2A1-mediated phosphorylation of SIRT6 might be involved in the progression of breast carcinoma.

CK2α phosphorylates DBC1 and is involved in the progression of gastric carcinoma and predicts poor survival of gastric carcinoma patients.

CK2α has diverse effects on the tumorigenesis owing to its kinase activity, which phosphorylates various proteins involved in tumorigenesis. We, therefore, investigated the expression and role of CK2α in the phosphorylation of deleted in breast cancer 1 (DBC1) in gastric carcinomas. We used 187 gastric carcinomas and human gastric cancer cells to investigate the roles and relationship between CK2α and DBC1 in gastric carcinomas. Positive expression of CK2α and phospho-DBC1 predicted shorter overall survival and relapse-free survival by univariate analysis. Especially, CK2α expression was an independent prognostic indicator for gastric carcinoma patients. In gastric carcinoma cells, CK2α was bound to DBC1 and phosphorylated DBC1. The phosphorylation of DBC1 by CK2α was evidenced by co-immunoprecipitation of CK2α and DBC1 in a GST pull-down assay, an in vitro kinase assay, and immunofluorescence staining. Inhibition of both CK2α and DBC1 decreased proliferation and invasive activity of cancer cells. Decreased migration and invasive activity was associated with a downregulation of MMP2, MMP9 and the epithelial-mesenchymal transition. A mutation at the phosphorylation site of DBC1 also downregulated the signals related with the epithelial-mesenchymal transition. Our study demonstrated that CK2α is an independent prognostic indicator for gastric carcinoma patients and is involved in tumorigenesis by regulating the phosphorylation of DBC1. In addition, the blocking of CK2α and DBC1 inhibited the proliferation and invasive potential of gastric cancer cells. Therefore, our study suggests that CK2α-DBC1 pathway might be a new therapeutic target for the treatment of gastric carcinoma.

Glutamine protects mice from acute graft-versus-host disease (aGVHD).

Despite current immunosuppressive therapies, acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (HSCT). In the present study, therapeutic effects of intraperitoneal glutamine (Gln) administration (1g/kg/day) in a mouse aGVHD model were evaluated. Gln administration significantly inhibited the GVHD-induced inflammation and tissue injury in the intestine, liver, skin and spleen. Gln therapy improved the score of clinical evidence of aGVHD and prolonged the median survival of aGVHD mice. Gln administration in aGVHD mice increased the fraction of Foxp3+/CD4+/CD25+ cells in the blood measured on day 7, and decreased the serum levels of tumor necrosis factor-α measured on days 7, 14 and 21 after aGVHD induction. These results demonstrated that Gln administration may be useful in protecting the host from aGVHD.

Expression of nerve growth factor and heme oxygenase-1 predict poor survival of breast carcinoma patients.

BACKGROUND: Nerve growth factor (NGF) is a neurotrophin and has been suggested to induce heme oxygenase-1 (HO1) expression. Although the role of HO1 in tumorigenesis remains controversial, recent evidence suggests NGF and HO1 as tumor-progressing factors. However, the correlative role of NGF and HO1 and their prognostic impact in breast carcinoma is unknown. METHODS: We investigated the expression and prognostic significance of the expression of NGF and HO1 in 145 cases of breast carcinoma. RESULTS: Immunohistochemical expression of NGF and HO1 was observed in 31% and 49% of breast carcinoma, respectively. The expression of NGF and HO1 significantly associated with each other, and both have a significant association with histologic grade, HER2 expression, and latent distant metastasis. The expression of NGF and HO1 predicted shorter overall survival of breast carcinoma by univariate and multivariate analysis. NGF expression was an independent prognostic indicator for relapse-free survival by multivariate analysis. The combined expression pattern of NGF and HO1 was also an independent prognostic indicator of overall survival and relapse-free survival. The patients with tumors expressing NGF had the shortest survival and the patients with tumor, which did not express NGF or HO1 showed the longest survival time. CONCLUSIONS: This study has demonstrated that individual expression of NGF or HO1, and the combined NGF/HO1 expression pattern could be prognostic indicators for breast carcinoma patients.

Myoid angioendothelioma of the spleen mimicking metastatic disease in a patient with rectal cancer: a radiologic-pathologic correlation.

Myoid angioendothelioma of the spleen is an uncommon, benign vascular tumor that is morphologically characterized by a composite of vascular spaces and stromal cells with myoid feature. Herein, we report a case of the myoid angioendothelioma of the spleen, concurrent with rectal adenocarcinoma. A 41-year-old woman presented with hematochezia for several weeks. Grossly, the rectal mass was a 2.5 × 2-cm ulcerative fungating lesion. The splenic mass was a 2.2 × 2-cm well-circumscribed lesion. Microscopically, the rectal mass was a well-differentiated adenocarcinoma that invaded into the pericolic adipose tissue. The splenic mass was composed of slit-like vascular spaces and fascicles of elongated stromal cells. Vascular endothelial cells were immunopositive for CD31, factor VIII-related antigen, and CD34 but negative for CD8. Stromal cells were immunopositive for smooth muscle actin but negative for desmin.

p21-activated kinase 4 suppresses fatty acid ß-oxidation and ketogenesis by phosphorylating NCoR1.

PPARα corepressor NCoR1 is a key regulator of fatty acid ß-oxidation and ketogenesis. However, its regulatory mechanism is largely unknown. Here, we report that oncoprotein p21-activated kinase 4 (PAK4) is an NCoR1 kinase. Specifically, PAK4 phosphorylates NCoR1 at T1619/T2124, resulting in an increase in its nuclear localization and interaction with PPARα, thereby repressing the transcriptional activity of PPARα. We observe impaired ketogenesis and increases in PAK4 protein and NCoR1 phosphorylation levels in liver tissues of high fat diet-fed mice, NAFLD patients, and hepatocellular carcinoma patients. Forced overexpression of PAK4 in mice represses ketogenesis and thereby increases hepatic fat accumulation, whereas genetic ablation or pharmacological inhibition of PAK4 exhibites an opposite phenotype. Interestingly, PAK4 protein levels are significantly suppressed by fasting, largely through either cAMP/PKA- or Sirt1-mediated ubiquitination and proteasome degradation. In this way, our findings provide evidence for a PAK4-NCoR1/PPARα signaling pathway that regulates fatty acid ß-oxidation and ketogenesis.

Expression Patterns of PAK4 and PHF8 Are Associated with the Survival of Gallbladder Carcinoma Patients.

BACKGROUND: PAK4 and PHF8 are involved in cancer progression and are under evaluation as targets for cancer therapy. However, despite extensive studies in human cancers, there are limited reports on the roles of PAK4 and PHF8 in gallbladder cancers. METHODS: Immunohistochemical expression of PAK4 and PHF8 and their prognostic significance were evaluated in 148 human gallbladder carcinomas. RESULTS: PAK4 expression was significantly associated with PHF8 expression in gallbladder carcinomas. Positive expression of nuclear PAK4, cytoplasmic PAK4, nuclear PHF8, and cytoplasmic PHF8 were significantly associated with shorter overall survival and relapse-free survival in univariate analysis. Multivariate analysis showed that nuclear PAK4 expression and nuclear PHF8 expression were independent predictors of overall survival and relapse-free survival in gallbladder carcinomas. Furthermore, coexpression of nuclear PAK4 and nuclear PHF8 predicted shorter overall survival (p < 0.001) and relapse-free survival (p < 0.001) of gallbladder carcinoma in multivariate analysis. CONCLUSIONS: This study suggests that the individual and coexpression patterns of PAK4 and PHF8 as the prognostic indicators for gallbladder carcinoma patients.

Comparison of histological and molecular features of pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma.

Pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma are pediatric B cell lymphomas with similar clinical characteristics but distinct histological features. We investigated the differences between pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma by comparing their histological and molecular characteristics. A total of 5 pediatric-type follicular lymphoma and 11 pediatric nodal marginal zone lymphoma patients were included in the study. In the histological review, 5 of the 16 cases showed overlapping morphological features of pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma; hence, they were reclassified as "mixed type." In molecular analysis, using panel-based massively parallel sequencing, MAP2K1, TNFRSF14, and IRF8 mutations were found in 6, 3, and 2 of the 11 pediatric nodal marginal zone lymphoma patients, respectively, and IRF8 mutation was found in one of the five pediatric-type follicular lymphoma patients. There were no significant differences in genetic alterations established from the histologically reclassified diagnosis as well as the initial diagnosis. Pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma showed morphological overlap in some cases, and no difference between the two was found upon molecular analysis. These findings suggest the possibility that pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma are single entity pediatric B-cell lymphoma with broad morphological spectrum.