The tumour/normal tissue ratio of Keap1 protein is a predictor for lymphovascular invasion in colorectal cancer: a correlation study between the Nrf2 and KRas pathways.

PURPOSE: Oxidative stress has impacts on the KRas and Nrf2/Keap1 pathways, which have multiple interactions with each other and play important roles in colorectal cancer (CRC). This study investigated the expressions of proteins in the KRas and Nrf2/Keap1 pathways and their associations with clinicopathological features in CRC. METHODS: The protein levels of Nrf2, Keap1, Bach1, p62, HO1, KRas, Erk, Raf1 and PI3K in both the tumour and normal tissues of 60 CRC subjects were determined by Western blot and their T/N (tumour/normal tissue) ratios were correlated with clinicopathological features. RESULTS: The T/N ratios of proteins in the KRas and Nrf2/Keap1 pathways had correlation patterns and proximity profiles in cluster dendrograms different in CRC with different status of lymphovascular invasion (LVI) or lymph node/distant metastases. The Keap1 protein T/N ratio was a significant predictor (odd ratio: 2.24; 95% confidence interval: 1.26 - 4.38) of LVI, which in turn predicted metastases (11.0; 3.49 - 39.8). CONCLUSION: The interactions between the KRas and Nrf2/Keap1 pathways may be affected differently by LVI and metastases, and the protein T/N ratio of Keap1 may be helpful for predicting LVI in CRC.

Inducible liver-specific overexpression of gankyrin in zebrafish results in spontaneous intrahepatic cholangiocarcinoma and hepatocellular carcinoma formation.

Liver cancer is the second leading cause of death worldwide. As such, establishing animal models of the disease is important for both basic and translational studies that move toward developing new therapies. Gankyrin is a critical oncoprotein in the genetic control of liver pathology. In order to evaluate the oncogenic role of gankyrin without cancer cell inoculation and drug treatment, we overexpressed gankyrin under the control of the fabp10a promoter. A Tet-Off system was used to drive expression in hepatocytes. At seven to twelve months of age, gankyrin transgenic fish spontaneously incurred persistent hepatocyte damage, steatosis, cholestasis, cholangitis, fibrosis and hepatic tumors. The tumors were both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). ICC is the second most frequent primary liver cancer in human patients and the first to develop in this tumor model. We further investigated the role of complement C3, a central molecule of the complement system, and found the expression levels of both in mRNA and protein are decreased during tumorigenesis. Together, these findings suggest that gankyrin can promote malignant transformation of liver cells in the context of persistent liver injury. This transformation may be related to compensatory proliferation and the inflammatory microenvironment. The observed decrease in complement C3 may allow transforming cells to escape coordinated induction of the immune response. Herein, we demonstrate an excellent zebrafish model for liver cancers that will be useful for studying the molecular mechanisms of tumorgenesis.

miR-122-mediated translational repression of PEG10 and its suppression in human hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC), a primary liver malignancy, is the most common cancer in males and fourth common cancer in females in Taiwan. HCC patients usually have a poor prognosis due to late diagnosis. It has been classified as a complex disease because of the heterogeneous phenotypic and genetic traits of the patients and a wide range of risk factors. Micro (mi)RNAs regulate oncogenes and tumor suppressor genes that are known to be dysregulated in HCC. Several studies have found an association between downregulation of miR-122, a liver-specific miRNA, and upregulation of paternally expressed gene 10 (PEG10) in HCC; however, the correlation between low miR-122 and high PEG10 levels still remains to be defined and require more investigations to evaluate their performance as an effective prognostic biomarker for HCC. METHODS: An in silico approach was used to isolate PEG10, a potential miR-122 target implicated in HCC development. miR-122S binding sites in the PEG10 promoter were evaluated with a reporter assay. The regulation of PEG10 by miR-122S overexpression was examined by quantitative RT-PCR, western blotting, and immunohistochemistry in miR-122 knockout mice and liver tissue from HCC patients. The relationship between PEG10 expression and clinicopathologic features of HCC patients was also evaluated. RESULTS: miR-122 downregulated the expression of PEG10 protein through binding to 3'-untranslated region (UTR) of the PEG10 transcript. In miR-122 knockout mice and HCC patients, the deficiency of miR-122 was associated with HCC progression. The expression of PEG10 was increased in 57.3 % of HCC as compared to paired non-cancerous tissue samples. However, significant upregulation was detected in 56.5 % of patients and was correlated with Okuda stage (P = 0.05) and histological grade (P = 0.001). CONCLUSIONS: miR-122 suppresses PEG10 expression via direct binding to the 3'-UTR of the PEG10 transcript. Therefore, while PEG10 could not be an ideal diagnostic biomarker for HCC but its upregulation in HCC tissue still has predictive value for HCC prognosis.

Culture supernatants of different colon cancer cell lines induce specific phenotype switching and functional alteration of THP-1 cells.

We developed an in vitro model to evaluate the effect of products secreted from different colorectal cancer (CRC) cell lines on specific phenotypic switching and functional alterations in THP-1 cells. We co-cultured the human monocytic cell line, THP-1, or phorbol-12-myristate-13-acetate (PMA)-treated THP-1 cells, (THP-1p), with supernatants from either the HT-29 (Dukes' B), HCT-15 (Dukes' C), or Colo205 (Dukes' D) cell lines, and assessed the cells for macrophage differentiation. The surface marker and cytokine profiles suggested that secreted CRC factors differentiated THP-1 cells into a "mixed" M1/M2 phenotype, although HT-29 and Colo205 supernatants induced THP-1p cells into predominantly M1-like macrophages and M2-like macrophages, respectively. Further, all three CRC supernatants enhanced the phagocytic capacity and migration of THP-1 and THP-1p cells, altering their phenotype to a more M2-kind. Therefore, different CRC cell lines induced specific phenotype switching and functional polarization of THP-1 cells.

RETRACTED: Lai et al. MicroRNA-21 Plays Multiple Oncometabolic Roles in the Process of NAFLD-Related Hepatocellular Carcinoma via PI3K/AKT, TGF-ß, and STAT3 Signaling. Cancers 2021, 13, 940.

The Cancers Editorial Office retracts the article, "MicroRNA-21 Plays Multiple Oncometabolic Roles in the Process of NAFLD-Related Hepatocellular Carcinoma via PI3K/AKT, TGF-ß, and STAT3 Signaling" [...].

A zebrafish model of intrahepatic cholangiocarcinoma by dual expression of hepatitis B virus X and hepatitis C virus core protein in liver.

UNLABELLED: The mechanisms that mediate the initiation and development of intrahepatic cholangiocarcinoma (ICC) associated with hepatitis B and C virus (HBV and HCV, respectively) infection remain largely unclear. In this study we conditionally coexpressed hepatitis B virus X (HBx) and hepatitis C virus core (HCP) proteins in zebrafish livers, which caused fibrosis and consequently contributed to ICC formation at the age of 3 months. Suppressing the transgene expression by doxycycline (Dox) treatment resulted in the loss of ICC formation. The biomarker networks of zebrafish ICC identified by transcriptome sequencing and analysis were also frequently involved in the development of human neoplasms. The profiles of potential biomarker genes of zebrafish ICC were similar to those of human cholangiocarcinoma. Our data also showed that the pSmad3L oncogenic pathway was activated in HBx and HCP-induced ICC and included phosphorylation of p38 mitogen-activated proteinbase (MAPK) and p44/42 mitogen-activated protein kinase (ERK1/2), indicating the association with transforming growth factor beta 1 (TGF-ß1) signaling pathway in ICC. Bile duct proliferation, fibrosis, and ICC were markedly reduced by knockdown of TGF-ß1 by in vivo morpholinos injections. CONCLUSION: These results reveal that TGF-ß1 plays an important role in HBx- and HCP-induced ICC development. This in vivo model is a potential approach to study the molecular events of fibrosis and ICC occurring in HBV and HCV infection.

A novel model for simultaneous study of neointestinal regeneration and intestinal adaptation.

The use of autologous grafts, fabricated from tissue-engineered neointestine, to enhance insufficient compensation of intestinal adaptation for severe short bowel syndrome is a compelling idea. Unfortunately, current approaches and knowledge for neointestinal regeneration, unlike intestinal adaptation, are still unsatisfactory. Thus, we have designed a novel model of intestinal adaptation with simultaneous neointestinal regeneration and evaluated its feasibility for future basic research and clinical application. Fifty male Sprague-Dawley rats weighing 250-350 g underwent this procedure and sacrificed at 4, 8, and 12 weeks postoperatively. Spatiotemporal analyses were carried out by gross, histology, and DNA/protein quantification. Three rats died of operative complications. In early experiments, the use of hard silicone stent as tissue scaffold in 11 rats was unsatisfactory for neointestinal regeneration. In later experiments, when a soft silastic tube was used, the success rate increased up to 90.9%. Further analyses revealed that no neointestine developed without donor intestine; regenerated lengths of mucosa and muscle were positively related to time postsurgery but independent of donor length with 0.5 or 1 cm. Other parameters of neointestinal regeneration or intestinal adaptation showed no relationship to both time postsurgery and donor length. In conclusion, this is a potentially important model for investigators searching for solutions to short bowel syndrome.

Surface markers of heterogeneous peripheral blood-derived smooth muscle progenitor cells.

OBJECTIVE: Smooth muscle progenitor cells (SMPCs) were intriguingly shown to act as a double-edged sword in the pathogenesis of atherosclerosis. To fully clarify the roles of SMPCs in atherosclerosis, a distinct panel of SMPC surface markers is mandatory to be developed. METHODS AND RESULTS: Microarray gene expression analyses were used to discover potential surface markers of SMPCs. In vitro and in vivo experiments documented that platelet-derived growth factor receptor-ß, carboxypeptidase M, carbonic anhydrase 12, receptor activity-modifying protein 1, and low-density lipoprotein receptor-related protein were the 5 specific surface markers regulating various SMPC functions, including migration, extracellular matrix formation, resistance to hypoxia, and anti-inflammation. In severe combined immunodeficiency/nonobese diabetic mice after femoral arterial wire injury, injected human peripheral blood mononuclear cells contributed to substantial amount of neointimal α-smooth muscle actin-positive cells, coexpressing platelet-derived growth factor receptor-ß, carboxypeptidase M, carbonic anhydrase 12, receptor activity-modifying protein 1, and low-density lipoprotein receptor-related protein. Based on these markers, a novel quantification assay was developed to enumerate circulating early SMPC. Early SMPC numbers were higher in patients with unstable angina compared with those with normal coronary angiograms. In patients with acute ST-elevation myocardial infarction, different patterns of serial early SMPC changes were noted, related to different clinical presentations. CONCLUSIONS: Surface markers of heterogeneous SMPCs exhibit various functions associated with atherosclerotic pathophysiology. Quantification of surface marker-defined SMPCs provides a platform for studying SMPCs in cardiovascular diseases.

Oncocytic-type intraductal papillary mucinous neoplasm (IPMN)-derived invasive oncocytic pancreatic carcinoma with brain metastasis - a case report.

Pancreatic cancer is a lethal disease without effective treatments at present. It ranks as s as 4th and 5th in cancer-related mortality in the western countries and worldwide. Locally advanced pancreatic duct carcinoma (PDAC) and metastatic PDAC, usually found the metastases over liver, peritoneum, or lung, have been shown to be with dismal prognosis. Brain metastasis is a rare entity and most cases reported before were found post-mortem. Intraductal papillary mucinous neoplasms of the pancreas (IPMN) has been deemed as a precursor of PDAC with very slow progression rate. Here we reported a case diagnosed with IPMN-derived PDAC with brain metastasis. After surgeries for PDAC and brain metastasis, subsequent chemotherapy and radiotherapy were also given. One and half year after surgery, this patient is still living with good performance status, which may warrant individualization of therapeutic strategy for PDAC with only brain metastasis.

A rare epidermal growth factor receptor (EGFR) gene mutation in small cell lung carcinoma patients.

AIM: Activating mutations in the epidermal growth factor receptor (EGFR) are predominantly detected in pulmonary adenocarcinoma and have been reported in small cell lung cancer (SCLC) for decades. This retrospective single-center study aimed to determine the frequency and types of EGFR mutations in SCLC in Taiwan. METHODS: This study comprises a consecutive cohort of 161 patients histologically diagnosed with SCLC between January 1992 and August 2014 at the Department of Pathology in Keelung Chang Gung Memorial Hospital, Taiwan. Archived formalin-fixed paraffin-embedded sections from 71 patients were eligible for molecular analysis. EGFR mutation analysis was performed using a fully-automated IdyllaTM EGFR Mutation Test and confirmed a comparable result through Qiagen Therascreen® EGFR RGQ PCR. In addition, EGFR gene copy number was assessed in EGFR-mutated tumors by fluorescence in situ hybridization (FISH). RESULTS: Mutational status of the EGFR gene was successfully analyzed in 63 specimens by both IdyllaTM and Qiagen platforms. Both methods detected L858R point mutation in exon 21 in an 81-year-old female and a 47-year-old male non-smoker. Both tumors show no concurrent EGFR gene amplification. The overall agreement between results obtained with the Idylla™ EGFR Mutation Test and Qiagen Therascreen® EGFR RGQ PCR was 100% Conclusions. Our results showed that EGFR mutation is a rare mutation type in a consecutive series of de novo SCLC. Furthermore, the performance of Idylla™ EGFR Mutation Test and Qiagen Therascreen® EGFR RGQ PCR on archived paraffin sections of limited quantities is available with the high agreement of results.

Correction: Lai et al. MicroRNA-21 Plays Multiple Oncometabolic Roles in the Process of NAFLD-Related Hepatocellular Carcinoma via PI3K/AKT, TGF-ß, and STAT3 Signaling. Cancers 2021, 13, 940.

The authors wish to make the following corrections to this paper [...].

Genetic Disruption of KLF1 K74 SUMOylation in Hematopoietic System Promotes Healthy Longevity in Mice.

The quest for rejuvenation and prolonged lifespan through transfusion of young blood has been studied for decades with the hope of unlocking the mystery of the key substance(s) that exists in the circulating blood of juvenile organisms. However, a pivotal mediator has yet been identified. Here, atypical findings are presented that are observed in a knockin mouse model carrying a lysine to arginine substitution at residue 74 of Krüppel-like factor 1 (KLF1/EKLF), the SUMOylation-deficient Klf1K74R/K74R mouse, that displayed significant improvement in geriatric disorders and lifespan extension. Klf1K74R/K74R mice exhibit a marked delay in age-related physical performance decline and disease progression as evidenced by physiological and pathological examinations. Furthermore, the KLF1(K74R) knockin affects a subset of lymphoid lineage cells; the abundance of tumor infiltrating effector CD8+ T cells and NKT cells is increased resulting in antitumor immune enhancement in response to tumor cell administration. Significantly, infusion of hematopoietic stem cells (HSCs) from Klf1K74R/K74R mice extends the lifespan of the wild-type mice. The Klf1K74R/K74R mice appear to be an ideal animal model system for further understanding of the molecular/cellular basis of aging and development of new strategies for antiaging and prevention/treatment of age-related diseases thus extending the healthspan as well as lifespan.

Dual-colour chromogenic in-situ hybridization is a potential alternative to fluorescence in-situ hybridization in HER2 testing.

AIM: Dual-colour chromogenic in-situ hybridization (dc-CISH) is an emerging methodology for characterizing genomic alterations. This study was aimed at evaluating the performance of a dc-CISH kit (ZytoVision) in determining human epidermal growth factor receptor 2 (HER2) status in breast cancer. METHODS AND RESULTS: Two hundred and twenty-eight invasive breast carcinomas arranged in tissue microarrays were analysed in parallel with dc-CISH, fluorescence in-situ hybridization (FISH), and immunohistochemistry. Of 227 tumours with available FISH and dc-CISH results, HER2 amplification and non-amplification were detected in 49 (21.6%) and 178 (78.4%) tumours, respectively, by both assays. The concordance between dc-CISH and FISH results showed 100% agreement (κ-coefficient=1.00). Immunohistochemically, 162 (71%), 25 (11.0%) and 41 (18%) tumours were scored 0/1+, 2+, and 3+, respectively. The corresponding results with both FISH and dc-CISH demonstrated HER2 amplification in two (3.2%), nine (36%) and 38 (93%) tumours, respectively. Complete consensus among these three methods was observed in 197 cases, representing 98% of all 3+ and 0/1+ tumours (κ-coefficient=0.92). Confirmatory testing of 25 2+ tumours showed complete consensus between FISH and dc-CISH. CONCLUSIONS: dc-CISH is a promising alternative to FISH in HER2 testing, and the single-institute incidence of HER2 amplification in breast cancer in Taiwan is 21.2%.

Toxoplasmic Lymphadenitis Presenting as a Tiny Neck Tumor.

(1) Background: Toxoplasmic lymphadenitis (TL), caused by the protozoan Toxoplasma gondii, is a worldwide zoonosis. We report a case of TL in the head and neck region diagnosed using ultrasound (US)-guided fine needle aspiration cytology (FNAC), serological tests, and pathological findings. (2) Case Presentation: A 51-year-old female with a chief complaint of a left posterior neck mass that had been growing for approximately 2 weeks. TL was confirmed by histopathological examinations and serological tests. US-guided FNAC and en bloc resection of the lymph node were performed. The diagnosis was confirmed as TL in the neck. (3) Conclusions: We suggest that US-guided FNAC should be considered as the first-line test for assessing a tiny mass before a definitive treatment is chosen.

Histopathologic Findings Associated With Matrix Metalloproteinases Proceeding to Recurrence of Primary Spontaneous Pneumothorax in Adolescents.

Background: Primary spontaneous pneumothorax is potentially life-threatening, and its recurrence is always a serious problem. Pathological examination provides molecular insights into the pathophysiology of primary spontaneous pneumothorax. Objectives: To investigate the association of histopathologic features of primary spontaneous pneumothorax with matrix metalloproteinase expression and their relevance to the recurrence. Methods: A total of 217 tissue section slides in 172 adolescent patients with primary spontaneous pneumothorax were retrospectively reviewed from January 2001 to June 2020. All histopathologic features were recorded and pathologic findings related to ipsilateral recurrence and second surgery were analyzed. Serum levels of matrix metalloproteinases were prospectively measured in 25 primary spontaneous pneumothorax patients receiving surgery and 18 healthy controls. Their relevance to the histopathologic features of primary spontaneous pneumothorax related to its recurrence was also examined. Results: The major presenting histopathologic findings of primary spontaneous pneumothorax were bleb/bulla (98%) followed by fibrosis (68%). Low prevalence of the pathologic findings of granulation tissue and macrophage accumulation were significantly associated with recurrent primary spontaneous pneumothorax, whereas fibrosis was significantly higher in patients receiving more than once surgery. Furthermore, the ratios of matrix metalloproteinase-2/tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 were significantly higher in theses pathological findings as well as multinucleated giant cells and mesothelial cell hyperplasia in comparison with healthy controls. Conclusions: Low prevalence of macrophage accumulation and granulation tissue related to the overexpression of matrix metalloproteinase-2 and-9 activities may contribute to healing impairment and primary spontaneous pneumothorax recurrence.

MicroRNA-21 Plays Multiple Oncometabolic Roles in the Process of NAFLD-Related Hepatocellular Carcinoma via PI3K/AKT, TGF-ß, and STAT3 Signaling.

MicroRNA-21 (miR-21) is one of the most frequently upregulated miRNAs in liver diseases such as nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). However, mechanistic pathways that connect NAFLD and HCC remain elusive. We developed a doxycycline (Dox)-inducible transgenic zebrafish model (LmiR21) which exhibited an upregulation of miR-21 in the liver, which in turn induced the full spectrum of NAFLD, including steatosis, inflammation, fibrosis, and HCC, in the LmiR21 fish. Diethylnitrosamine (DEN) treatment led to accelerated liver tumor formation and exacerbated their aggressiveness. Moreover, prolonged miR-21 expression for up to ten months induced nonalcoholic steatohepatitis (NASH)-related HCC (NAHCC). Immunoblotting and immunostaining confirmed the presence of miR-21 regulatory proteins (i.e., PTEN, SMAD7, p-AKT, p-SMAD3, and p-STAT3) in human nonviral HCC tissues and LmiR21 models. Thus, we demonstrated that miR-21 can induce NAHCC via at least three mechanisms: First, the occurrence of hepatic steatosis increases with the decrease of ptenb, pparaa, and activation of the PI3K/AKT pathway; second, miR-21 induces hepatic inflammation (or NASH) through an increase in inflammatory gene expression via STAT3 signaling pathways, and induces liver fibrosis through hepatic stellate cell (HSC) activation and collagen deposition via TGF-ß/Smad3/Smad7 signaling pathways; finally, oncogenic activation of Smad3/Stat3 signaling pathways induces HCC. Our LmiR21 models showed similar molecular pathology to the human cancer samples in terms of initiation of lipid metabolism disorder, inflammation, fibrosis and activation of the PI3K/AKT, TGF-ß/SMADs and STAT3 (PTS) oncogenic signaling pathways. Our findings indicate that miR-21 plays critical roles in the mechanistic perspectives of NAHCC development via the PTS signaling networks.

The -174 G/C polymorphism in interleukin-6 (IL-6) promoter region is associated with serum IL-6 and carcinoembryonic antigen levels in patients with colorectal cancers in Taiwan.

INTRODUCTION: We investigated the associations between -174 G/C polymorphism of interleukin-6 (IL-6) gene promoter and serum IL-6 and carcinoembryonic antigen (CEA) levels in Taiwanese patients with colorectal cancer (CRC). RESULTS AND DISCUSSION: The frequency of the G allele was only 0.043, which is significantly lower compared to Western analogs. On grouping genotypes as G-positive (GG and CG) and G-negative (GG), the average IL-6 level and CEA levels were significantly lower in G-positive patients than in G-negative analogs (IL-6, 3.56 +/- 4.38 vs. 15.38 +/- 9.52 pg/ml, P = 0.021; CEA, 27.7 +/- 25.7 vs. 157.7 +/- 59.6 ng/ml, P = 0.012). The patients without the G allele had higher incidences of synchronous cancers of other origins (P = 0.003). CONCLUSION: In conclusion, ethnicity affects the status of -174 G/C IL-6 polymorphism. This polymorphism status consequently influences the expressions of serum IL-6 and CEA and incidences of synchronous cancers of other origins.

Potential role of bone marrow-derived cells in the turnover of mesothelium.

BACKGROUND: Bone marrow cell has been proposed as a source of new mesothelium, but supporting evidence is rare. This study examines the validity of this hypothesis by using green fluorescent protein (GFP) and Y-chromosome trackers to identify the presence of donor marrow cells in peritoneal membrane of bone marrow transplant recipient mice. METHODS: Cross-gender and GFP-mismatched bone marrow transplantation was undertaken in 20 FVB mice. Five recipients were killed 2, 4, and 6 weeks and 6 months later. Peritoneal tissues were obtained for the detection of GFP and Y chromosome by immunohistochemical staining (IHC) and chromogenic in situ hybridization (CISH). RESULTS: GFP+ cells could be found in the peritoneal membrane of bone marrow transplant recipients. However, the level of engraftment was low, accounting for 0.9%, 0.8%, 0.7%, and 2.2% of the total counted mesothelial cells in intestinal serosa at 2, 4, and 6 weeks and 6 months post-transplantation, respectively. The presence of donor marrow cells within mesothelium was again confirmed by the detection of Y-chromosome-containing cells. Moreover, Y-chromosome+ cells incorporated within the mesothelium were positively stained by anticytokeratin antibody. CONCLUSIONS: Donor marrow cells could attach to mesothelium and exhibit mesothelial marker cytokeratin in bone marrow transplant recipients. This finding suggests that bone marrow-derived cells might participate in the turnover of mesothelium.

Painless gouty tophus in the nasal bridge: A case report and literature review.

RATIONALE: A gouty tophus, arising from the deposition of monosodium urate crystals (MSU), rarely occurs in the nasal bridge. There have been only 7 documented cases of a gouty tophus in the nasal bridge from 1978 to 2018 in English-language literature. PATIENT CONCERNS: A 65-year-old male had a chief complaint of a lump in the nasal bridge that was slowly growing for over 1 year. DIAGNOSIS: MSU crystals were confirmed through ultrasonography (US) and pathological examinations. INTERVENTIONS: A cosmetically less destructive method, ultrasound-guided fine needle aspiration cytology (FNAC) was used to approach the mass lesion of nasal bridge. OUTCOMES: The diagnosis was confirmed as a gouty tophus without performing a nasal subdermal exploration. LESSONS: This case report is the first use of US with FNAC to approach and diagnosed a gouty tophus in the nasal bridge.

Overexpression of matrix metalloproteinase-9 in adolescents with primary spontaneous pneumothorax for surgical intervention.

OBJECTIVE: To determine gene expression profiles associated with bullae formation in patients with primary spontaneous pneumothorax and to identify candidate genes associated with surgical intervention. METHODS: Twenty-four adolescents with primary spontaneous pneumothorax were enrolled prospectively. A global gene expression analysis of 9 paired lung biopsies (lesion and normal adjacent sites) was performed to identify differentially expressed genes associated with spontaneous pneumothorax. Pathway and network analysis was performed using the Database for Annotation, Visualization and Integrated Discovery web tool. Candidate genes and encoding proteins were assessed in blood samples and compared between patients with pneumothorax and healthy control patients. RESULTS: A total of 1519 differentially expressed transcripts corresponding to known genes were identified comparing the lesion lung with paired adjacent normal lung. The altered genes were mainly associated with focal adhesion and extracellular matrix-receptor interaction pathways. Genes involved in proteolysis and peptidase activity were up-regulated predominantly, especially matrix metalloproteinase-1 and -9 genes. Compared with the recovery stage, blood levels of matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 were increased at the acute stage in patients with pneumothorax and, when compared between patients treated operatively with those treated nonoperatively, were also significantly greater. In addition, ratios of their serum levels were significantly greater in patients with pneumothorax compared with healthy control patients. Furthermore, matrix metalloproteinase-9 was predominantly overexpressed in neutrophils, alveolar macrophages, and mesothelial cells of lung biopsies. CONCLUSIONS: An imbalance of cell-extracellular matrix interactions appears to be associated with primary spontaneous pneumothorax. Matrix metalloproteinase-9 overexpression may particularly play a role in contributing to pleural porosity for surgical intervention.