Unraveling the role of cancer-associated fibroblasts in colorectal cancer

Within the intricate milieu of colorectal cancer(CRC)tissues,cancer-associated fibroblasts(CAFs)act as pivotal orchestrators,wielding considerable influence over tumor progression.This review endeavors to dissect the multifaceted functions of CAFs within the realm of CRC,thereby highlighting their indispensability in fostering CRC malignant microenvironment and indicating the development of CAFs-targeted therapeutic interventions.Through a comprehensive synthesis of current knowledge,this review delineates insights into CAFsmediated modulation of cancer cell proliferation,invasiveness,immune evasion,and neovascularization,elucidating the intricate web of interactions that sustain the pro-tumor metabolism and secretion of multiple factors.Additionally,recognizing the high level of heterogeneity within CAFs is crucial,as they encompass a range of subtypes,including myofibroblastic CAFs,inflammatory CAFs,antigen-presenting CAFs,and vessel-associated CAFs.Innovatively,the symbiotic relationship between CAFs and the intestinal microbiota is explored,shedding light on a novel dimension of CRC pathogenesis.Despite remarkable progress,the orchestrated dynamic functions of CAFs remain incompletely deciphered,underscoring the need for continued research endeavors for therapeutic advancements in CRC management.

Association of CagA and VacA presence with ulcer and non-ulcer dyspepsia in a Turkish population

AIM:The mostly known genotypic virulence features,of H.pylori are cytotoxin associated gene A (cagA) and Vacuolating cytotoxin gene A (VacA).We investigated the association of these major virulence factors with ulcer and non-ulcer dyspepsia in our region. METHODS:One hundred and forty two dyspeptic patients were studied (average age 44.8±15.9 years,range 15-87 years,64 males and 78 females).Antral and corpus biopsies were taken for detecting and genotyping of H.pylori.107 patients who were H.pylori positive by histological assessment were divided into three groups according to endoscopic findings:Duodenal ulcer (DU),gastric ulcer (GU) and non-ulcer dyspepsia (NUD).The polymerase chain reaction (PCR) was used to detect CagA and VacA genes of H.pylori using specific primers. RESULTS:H.pyloriwas isolated from 75.4% (107/142) of the patients.Of the 107 patients,66 (61.7%) were cagA- positive and 82 (76.6%) were VacA-positive.CagA gene was positively associated with DU and GU (P<0.01,P<0.02), but not with NUD (P>0.05).Although VacA positivity in ulcer patients was higher than that in NUD group,the difference was not statistically significant (P>0.05). CONCLUSION:There is a significantly positive association between CagA genes and DU and GU.The presence of VacA is not a predictive marker for DU,GU,and NUD in our patients.

Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis

AIM: To characterize how insulin-like growth factor 2 (IGF2) mRNA binding protein p62/IMP2-2 promotes steatohepatitis in the absence of dietary cholesterol.

An unusual mixed germ cell tumor of the testis consisting of rhabdomyosarcoma, mature teratoma and yolk sac tumor

Dear Editor, We recently encountered a rare case of testicular mixed germ cell tumor （MGCT） in a 32-year-old man. The tumor was composed of a combination of a yolk sac tumor, teratoma and rhabdomyosarcomatous somatic type malignancy.

Cholesterol granuloma of the right epididymis mimicking an acute scrotum

Dear Sir, I am B. Spajic, the urologist from Clinical Department of Urology, Sestre Milosrdnice University Hospital, Zagreb, Croatia. Recently, we had a rare case of a cholesterol granuloma of the right epididymis at our department, showing clinical signs of acute scrotum. The case described here appears to be the second reporting cholesterol granuloma in the epididymis and the first one presenting with clinical signs of acute scrotum.

Correlation of image textures of a polarization feature parameter and the microstructures of liver fibrosis tissues

Mueller matrix imaging is emerging for the quantitative characterization of pathological microstructures and is especially sensitive to fibrous structures.Liver fibrosis is a characteristic of many types of chronic liver diseases.The clinical diagnosis of liver fibrosis requires time-consuming multiple staining processes that specifically target on fibrous structures.The staining proficiency of technicians and the subjective visualization of pathologists may bring inconsistency to clinical diagnosis.Mueller matrix imaging can reduce the multiple staining processes and provide quantitative diagnostic indicators to characterize liver fibrosis tissues.In this study,a fibersensitive polarization feature parameter(PFP)was derived through the forward sequential feature selection(SFS)and linear discriminant analysis(LDA)to target on the identification of fibrous structures.Then,the Pearson correlation coeffcients and the statistical T-tests between the fiber-sensitive PFP image textures and the liver fibrosis tissues were calculated.The results show the gray level run length matrix(GLRLM)-based run entropy that measures the heterogeneity of the PFP image was most correlated to the changes of liver fibrosis tissues at four stages with a Pearson correlation of 0.6919.The results also indicate the highest Pearson correlation of 0.9996 was achieved through the linear regression predictions of the combination of the PFP image textures.This study demonstrates the potential of deriving a fiber-sensitive PFP to reduce the multiple staining process and provide textures-based quantitative diagnostic indicators for the staging of liver fibrosis.

Multiple metastases to the small bowel from large cell bronchial carcinomas

AIM: Metastases from lung cancer to gastrointestinal tract are not rare at postmortem studies but the development of clinically significant symptoms from the gastrointestinal metastases is very unusual. METHODS: Formalin-fixed, paraffin-embedded tissues were cut into 5 urn thick sections and routinely stained with hematoxylin and eosin. Some slides were also stained with Alcian-PAS. Antibodies used were primary antibodies to pancytokeratin, cytokeratin 7, cytokeratin 20, epithelial membrane antigen, vimentin, smooth muscle actin and CD-117. RESULTS: We observed three patients who presented with multiple metastases from large cell bronchial carcinoma to small intestine. Two of them had abdominal symptoms (sudden onset of abdominal pain, constipation and vomiting) and in one case the tumor was incidentally found during autopsy. Microscopically, all tumors showed a same histological pattern and consisted almost exclusively of strands and sheets of poorly cohesive, polymorphic giant cells with scanty, delicate stromas. Few smaller polygonal anaplastic cells dispersed between polymorphic giant cells, were also observed. Immunohistochemistry showed positive staining of the tumor cells with cytokeratin and vimentin. Microscopically and immunohistochemically all metastases had a similar pattern to primary anaplastic carcinoma of the small intestine. CONCLUSION: In patients with small intestine tumors showing anaplastic features, especially with multiple tumors, metastases from large cell bronchial carcinoma should be first excluded, because it seems that they are more common than expected.

Heparanase Expression Correlates with Angiogenesis and Lymphangiogenesis in Human Lung Cancer

Background and objective Heparanase has been thought to be a good molecular marker of tumor,and the heparanase expression level was correlated closely with tumor metastasis. In this study,we investigate the effects of heparanase on angiogenesis and lymphangiogenesis of lung cancer and the relationship between heparanase expression and vascular endothelial growth factor (VEGF),vascular endothelial growth factor-C (VEGF-C). Methods Immunohistochemistry was used to detect the expression of heparanase,VEGF,VEGF-C protein and microvascular density (MVD),lymphatic vessel density (LVD) in 115 cases of non-small cell lung cancer (NSCLC) and 45 cases of adjacent normal tissue samples. Results Our results showed that heparanase expression was significantly increased in 91 (79.13%) of the 115 cases and correlated with lymph node metastasis (node positive rate 87.0%; node negative rate 36.8%; P=0.003). Heparanase positive expression cases have significantly higher concentration of microvascular density (MVD) and lymphatic vessel density (LVD) as compared with heparanase negative expression cases (P<0.01,P<0.01,respectively),heparanase expression was significantly correlated with VEGF,VEGF-C expression in NSCLC. Conclusion Heparanase overexpression was associated with angiogenesis and lymphangiogenesis of lung cancer,targeting of heparanase may represent a significant therapeutic potential for lung cancer.

Increased ΤGF-β3 in primary biliary cirrhosis: An abnormality related to pathogenesis?

AIM: To investigate the transforming growth factor-β (TGF-β) isoforms in the peripheral and hepatic venous blood of primary biliary cirrhosis (PBC) patients. METHODS: We examined TGF-β1, TGF-β2 and TGF-β3 (enzyme-linked immunosorbent assay), in 27 stage Ⅳ PBC patients (27 peripheral and 15 hepatic vein sera), 35 early (Ⅰ-Ⅱ) PBC and 60 healthy controls. As disease controls 28 hepatitis C virus (HCV) cirrhosis (28 peripheral and 17 hepatic vein serum), 44 chronic HCV hepatitis and 38 HCV-related hepatocellular carcinomas were included. We also tested liver tissue by immunohistochemistry to identify localization of TGF isoforms. RESULTS: TGF-β1 was significantly decreased in all cirrhotics (PBC Ⅲ-Ⅳ: median 13.4 ng/mL; range, 7.4-26.2, HCV cirrhosis: 11.6 ng/mL; range, 5.0-33.8), compared to controls (30.9 ng/mL; range, 20.9-37.8). TGF-β2 was increased in viral cirrhosis but not in PBC and chronic hepatitis. TGF-β3 (47.2 pg/mL; range, 27.0-79.7 in healthy controls) was increased in early and late PBC (Ⅰ-Ⅱ: 94.3 pg/mL; range, 41.5-358.6; Ⅲ-Ⅳ: 152.8 pg/mL; range, 60.4-361.2; P < 0.001) and decreased in viral cirrhosis (37.4 pg/mL; range, 13.3-84.0; P < 0.05). Hepatic vein TGF-β levels were analogous to those in peripheral blood. Immunohistochemistry identified all isoforms in portal tract lymphocytes, sinusoidal cells and cholangiocytes. TGF-β3 was additionally overexpressed in hepatocytes in PBC patients. CONCLUSION: The serum profile of TGF-β isoforms is different in cirrhotics. Increased TGF-β3 is characteristic of PBC. These findings may be related to the immunological abnormalities of PBC.

LncRNA MEG3 acts a biomarker and regulates cell functions by targeting ADAR1 in colorectal cancer

BACKGROUND Colorectal cancer (CRC) is the third most prevalent malignancy and has the fourth highest global cancer mortality rate. Early diagnosis and prompt medical attention can improve quality of life and the prognosis of CRC patients. Accumulating evidence reveals that long non-coding RNAs (lncRNAs) function as oncogenes or anti-oncogenes, as well as biomarkers in various cancers. AIM To investigate the levels and molecular mechanism of the lncRNA maternally expressed gene 3 (MEG3) in CRC. METHODS The levels of lncRNA MEG3 in CRC tissue, serum and cell line samples were explored via qRT-PCR. The relationship between MEG3 levels and clinicopathological features in CRC was investigated. The diagnostic and prognostic values of serum MEG3 levels were analyzed with ROC curves and KaplanMeier survival curves, respectively. RESULTS Significant decreased levels of MEG3 existed in CRC tissue, cell lines and serum. CRC patients with down-regulated serum MEG3 levels had larger tumor sizes, and advanced clinical stages. The sensitivity and specificity of serum MEG3 levels in CRC detection was 0.667 and 0.875, respectively. Tumor size, T stages, and serum MEG3 levels are indie factors that produce an effect on CRC patients' prognosis. KaplanMeier survival curves suggested that CRC patients with high levels of MEG3 had a remarkably better overall survival rate. CONCLUSION LncRNA MEG3 is down-regulated in CRC, and regulates cell functions by targeting adenosine deaminase’s effect on RNA 1 in CRC.

Correlation study between dendritic cell and eosinophil in refractory rhinosinusitis

Objective:To investigate the correlation of refractory rhinosinusitis by detecting the expression of dendritic cells and eosinophils infiltration in nasal mucosa.Methods:Histological staining was performed to detect eosinophils infiltration respectively in 30 normal nasal mucosa,30 chronic rhinosinusitis tissues and 30 refractory rhinosinusitis tissues,Immunohistochemistry and immunofluorescence double labeling were performed to detect the expression of CD83 and CD11c in each group,and univariate anova was used to analyze the differences among groups.The correlation between the co-expression of CD83 and CD11c and the infiltration of eosinophilic cells was measured by Pearson correlation analysis.Results:The positive expression of dendritic cells immune markers CD83 and CD11c and eosinophils infiltration of refractory rhinosinusitis was significantly increased compared with the other two groups(P<0.05).Through Pearson correlation analysisthe,correlation coefficient r between CD83 and CD11c co-expression and eosinophils infiltration in each group was positive and P<0.05,both were positively correlated.Conclusion:The number of dendritic cells in refractory rhinosinusitis increased significantly and was positively correlated with the infiltration of eosinophils,which was involved in the development of refractory rhinosinusitis.

对子宫内胎儿双眼发育性白内障的诊断的临床病理研究

Background: We report a case of unusual, bilateral developmental cataracts in a fetus with a supernumerary chromosome. Methods: A 42- year-old woman presented during her 6th pregnancy for assessment of fetal karyotype. This showed a supernumerary chromosome derived from chromosome 21. Subsequently fetal ultrasound suggested the presence of bilateral cataracts and the pregnancy was terminated at 19 weeks and 3 days’ gestation. Both eyes were submitted for histopathological and electron microscopical examination. Results: Histopathological examination revealed unusual bilateral developmental cataracts with abnormal bladder-type cells lining the posterior aspect of the lens vesicle, a poorly formed nuclear bow and a central mass of fibrillar material associated with macrophages lying within an area of liquefaction. Transmission electron microscopy revealed the presence of peg and socket joints in both central and posterior regions and degenerate crystallins in the posterior region. Conclusions: We described an unusual case of developmental cataract diagnosed in utero by ultrasound. The morphological appearances suggest that the defect occurred during or after formation of the secondary lens fibres. Detailed descriptions of cases such as this one may contribute to our understanding of lens development and cataract formation.

原发性皮肤黏液纤维肉瘤类似多形性透明变性血管扩张性肿瘤(PHAT):潜在的诊断缺陷

Myxofibrosarcoma (MFS) is one of the most common sarcomas of adults, and includes lesions ranging from low to high grade based on increasing cellularity, nuclear pleomorphism, and mitotic activity. We present an unusual case of MFS, which initially showed features of a pleomorphic hyalinizing angiectatic tumor (PHAT), a rare soft- tissue tumor considered benign in the WHO classification. The initial lesion showed a subcutaneous proliferation of spindled to polygonal eosinophilic cells with striking cellular pleomorphism, set in amyxoid to sclerotic stroma with prominent hyalinized and angiectatic vasculature, classic characteristics of PHAT. Rare mitotic figures were identified. The preliminary diagnosis of PHAT was confirmed by a consultant expert soft- tissue pathologist. Four months after the initial surgery, local recurrencewas noted. The recurrent tumor demonstrated findings of a high- grade MFS, with a diffuse and cellular proliferation of atypical spindle cells set in a prominent myxoid stroma. Multiple mitoses, including atypical ones, were present. In light of these findings, the original specimen was reexamined and the initial diagnosis was amended to MFS. MFS may mimic or be confused with several benign soft- tissue lesions. Cases mimicking PHAT have not been previously reported. We describe a unique case of a high- grade MFS that initially showed characteristic features of a PHAT, to illuminate the fact that MFS may rarely arise in, or have areas that masquerade as, PHAT. It is also conceivable, although speculative, that at least some cases of PHAT, currently considered a benign tumor by the WHO, may actually represent or evolve into a unique form of MFS of low malignant potential.

Relationship of RhoA signaling activity with ezrin expression and its significance in the prognosis for breast cancer patients

Background We have recently reported that RhoA may regulate the invasion and metastasis of breast cancer cells as an upstream signal of ezrin in vitro. In this study, we examined the relationship of RhoA signaling activity with ezrin expression in breast cancer and its prognostic significance in patients with breast cancer. Methods Paraffin tumor sections of breast cancer were collected retrospectively from 487 patients diagnosed between 2001 and 2004. Immunohistochemical methods were used to detect the expression of RhoA, phosphorylated （activated） RhoA, and ezrin. Results Ezrin overexpression was detectable in 15.2% of 487 invasive breast cancers. The majority （85.1%） of ezrin-overexpressing tumors coexpressed phosphorylated RhoA; 78.8% of tumors with phosphorylated RhoA cooverexpressed ezrin. Patients whose cancers showed overexpression of ezrin or expression of phosphorylated RhoA had shorter survival rates. Conclusions RhoA activation is important in human breast cancer due to its upregulation of ezrin; thus, agents that target phosphorylated RhoA may be useful in the treatment of tumors with ezrin overexpression.

The distribution of parotid gland neoplasms in a veteran population

Objective:Salivary gland tumors account for 6%-8%of head and neck neoplasms with the parotid gland as the most common primary site.Pleomorphic adenomas(PA)are considered the most common benign parotid gland neoplasms,followed by Warthin tumors(WT).The goal of this study was to investigate the distribution of parotid gland neoplasms among a United States veteran population.Design:Retrospective chart review.Setting:Washington DC Veterans Affairs Medical Center.Participants:Veterans who underwent fine needle aspiration(FNA)for a parotid gland mass from 2000 to 2018 were included.Medical records were reviewed for gender,age,tobacco use,surgery date,and pathology results.Main outcome measures:Changes in the distribution of parotid neoplasms and tobacco use over an 18-year period.Results:Of 141 patients with parotid gland masses,86.5%(n=122)were benign,9.9%(n=14)were malignant,and 3.5%(n=5)were indeterminate.Of benign tumors,WT accounted for the majority at 51.6%,followed by PA at 40.2%.When stratified by decade(2000-2009 and 2010-2018),the proportion of WT compared to all other benign and malignant neoplasms increased from 31.6%to 53.6%,whereas the proportion of PA decreased from 36.8%to 33.3%.The rate of tobacco use was unchanged at approximately 32.0%among our cohort from 2000 to 2018.Conclusion:Among our cohort of veteran patients,WT was the most common benign parotid tumor and has increased in incidence over the last two decades despite an unchanged smoking rate.

The novel long noncoding RNA LOC283070 is involved in the transition of LNCaP cells into androgen-independent cells via its interaction with PHB2

We sought to investigate the underlying mechanism of action of the long noncoding RNA （IncRNA） LOC283070 in the development of androgen independence in prostate cancer. The interactions between LOC283070 and target proteins were investigated by RNA pull-down and RNA-binding protein immunoprecipitation （RIP） assays. Subceilular fractionation and quantitative reverse transcription-polymerase chain reaction （qRT-PCR） were used to detect the subcellular localization of LOC283070. Western blotting was performed to detect the expression of prohibitin 2 （PHB2）. Luciferase activity assays were performed to evaluate the effects of LOC283070 and PHB2 on the androgen receptor （AR） signaling pathway. A methyl thiazolyl tetrazolium （MTT） assay and a growth curve assay were used to test cell viability. Flow cytometry was performed to analyze cell cycles. A transwell assay was employed to test cell migration. We identified PHB2 as an interaction partner of LOC283070 in the pull-down and RIP experiments. Furthermore, we confirmed that the enrichment of L0C283070 with PHB2 in androgen-independent LNCaP （LNCaP-AI） cells was much greater than that in LNCaP cells. Moreover, the expression of PHB2 was not significantly different between the two cell lines, and the expression of LOC283070 in the nuclei of the LNCaP-AI cells was significantly greater than that in the LNCaP cells. In vitro data revealed that PHB2 overexpression significantly inhibited AR activity and cell proliferation and migration and induced accumulation of prostate cancer cells in GO/G1 phase. Moreover, the overexpression of LOC283070 fully abrogated the effects of PHB2 overexpression. In conclusion, we found that LOC283070 can bind to PHB2 located in the nucleus and inhibit its effect, and this is one of the mechanisms by which LOC283070 is involved in the transition of LNCaP cells into androgen-independent cells.

New perspectives on DNA methylation modifications in ocular diseases

The methylation of DNA is a prevalent epigenetic modification that plays a crucial role in the pathological progression of ocular diseases.DNA methylation can regulate gene expression,thereby affecting cell function and signal transduction.Ophthalmic diseases are a kind of complex diseases,and their pathogenesis involves many factors such as genetic,environmental and individual differences.In addition,inflammation,oxidative stress and lipid metabolism,which abnormal DNA methylation is closely related to,are also considered to be major factors in eye diseases.The current understanding of DNA methylation in eye diseases is becoming more complex and comprehensive.In addition to the simple suppression of gene expression by hypermethylation,factors such as hypomethylation or demethylation,DNA methylation in non-promoter regions,interactions with other epigenetic modifications,and dynamic changes in DNA methylation must also be considered.Interestingly,although some genes are at abnormal methylation levels,their expression is not significantly changed,which indirectly reflects the complexity of gene regulation.This review aims to summarize and compare some relevant studies,and provide with new ideas and methods for the prevention and treatment of different eye diseases,such as glaucoma,retinoblastoma,and diabetic retinopathy.