Juvenile polyposis syndrome might be misdiagnosed as familial adenomatous polyposis: a case report and literature review.

BACKGROUND: Juvenile polyposis syndrome (JPS) is a rare disorder characterized by the presence of multiple juvenile polyps in the gastrointestinal tract, and germline mutations in SMAD4 or BMPR1A. Due to its rarity and complex clinical manifestation, misdiagnosis often occurs in clinical practice. CASE PRESENTATION: A 42-year-old man with multiple pedunculated colorectal polyps and concomitant rectal adenocarcinoma was admitted to our hospital. His mother had died of colon cancer. He was diagnosed with familial adenomatous polyposis (FAP) and underwent total proctocolectomy and ileal pouch anal anastomosis. Two polyps were selected for pathological examination. One polyp had cystically dilated glands with slight dysplasia. The other polyp displayed severe dysplasia and was diagnosed as adenoma. Three years later, his 21-year-old son underwent a colonoscopy that revealed more than 50 pedunculated colorectal juvenile polyps. Both patients harbored a germline pathogenic mutation in BMPR1A. Endoscopic resection of all polyps was attempted but failed. Finally, the son received endoscopic resection of polyps in the rectum and sigmoid colon, and laparoscopic subtotal colectomy. Ten polyps were selected for pathological examination. All were revealed to be typical juvenile polyps, with cystically dilated glands filled with mucus. Thus, the diagnosis of JPS was confirmed in the son. A review of the literatures revealed that patients with JPS can sometimes have adenomatous change. Most polyps in patients with JPS are benign hamartomatous polyps with no dysplasia. A review of 767 colorectal JPS polyps demonstrated that 8.5% of the polyps contained mild to moderate dysplasia, and only 0.3% had severe dysplasia or cancer. It is difficult to differentiate juvenile polyps with dysplasia from adenoma, which could explain why juvenile polyps have been reported to have adenomatous changes in patients with JPS. Therefore, patients with JPS, especially those with concomitant dysplasia and adenocarcinoma, might be easily diagnosed as FAP in clinical practice. CONCLUSIONS: Juvenile polyp with dysplasia is often diagnosed as adenoma, which might lead to the misdiagnosis of JPS as FAP. The differential diagnosis of JPS versus FAP, should be based on comprehensive evaluation of clinical presentation, endoscopic appearance and genetic investigations; not on the presence or absence of adenoma.

Clinical significance of multiple gene detection with a 22-gene panel in formalin-fixed paraffin-embedded specimens of 207 colorectal cancer patients.

BACKGROUND: Simultaneous detection of multiple molecular biomarkers is helpful in the prediction of treatment response and prognosis for colorectal cancer (CRC) patients. METHODS: A 22-gene panel consisting of 103 hotspot regions was utilized in the formalin-fixed paraffin-embedded (FFPE) tissue samples of 207 CRC patients, using the next-generation sequencing (NGS)-based multiplex PCR technique. Those 22 genes included AKT1, ALK, BRAF, CTNNB1, DDR2, EGFR, ERBB2, ERBB4, FBXW7, FGFR1, FGFR2, FGFR3, KRAS, MAP2K1, MET, NOTCH1, NRAS, PIK3CA, PTEN, SMAD4, STK11, and TP53. RESULTS: Of the 207 patients, 193 had one or more variants, with 170, 20, and 3 having one, two, and three mutated genes, respectively. Of the total 414 variants identified in this study, 384, 25, and 5 were single-nucleotide variants, deletion, and insertion. The top four frequently mutated genes were TP53, KRAS, PIK3CA, and FBXW7. There was high consistency between the results of NGS-PCR technique and routine ARMS-PCR in KRAS and BRAF mutation detection. Univariate and multivariate analyses demonstrated that advanced TNM stage, elevated serum CEA, total variants number ≥ 2, AKT1 and PTEN mutation were independent predictors of shorter DFS; poor differentiation, advanced TNM stage, total variants number ≥ 2, BRAF, CTNNB1 and NRAS mutation were independent predictors of shorter OS. CONCLUSIONS: It is feasible to detect multiple gene mutations with a 22-gene panel in FFPE CRC specimens. TNM stage and total variants number ≥ 2 were independent predictors of DFS and OS. Detection of multiple gene mutations may provide additional prognostic information to TNM stage in CRC patients.

The Endoplasmic Reticulum Stress Sensor IRE1α in Intestinal Epithelial Cells Is Essential for Protecting against Colitis.

Intestinal epithelial cells (IECs) have critical roles in maintaining homeostasis of intestinal epithelium. Endoplasmic reticulum (ER) stress is implicated in intestinal epithelium homeostasis and inflammatory bowel disease; however, it remains elusive whether IRE1α, a major sensor of ER stress, is directly involved in these processes. We demonstrate here that genetic ablation of Ire1α in IECs leads to spontaneous colitis in mice. Deletion of IRE1α in IECs results in loss of goblet cells and failure of intestinal epithelial barrier function. IRE1α deficiency induces cell apoptosis through induction of CHOP, the pro-apoptotic protein, and sensitizes cells to lipopolysaccharide, an endotoxin from bacteria. IRE1α deficiency confers upon mice higher susceptibility to chemical-induced colitis. These results suggest that IRE1α functions to maintain the intestinal epithelial homeostasis and plays an important role in defending against inflammation bowel diseases.

PHD3 Stabilizes the Tight Junction Protein Occludin and Protects Intestinal Epithelial Barrier Function.

Prolyl hydroxylase domain proteins (PHDs) control cellular adaptation to hypoxia. PHDs are found involved in inflammatory bowel disease (IBD); however, the exact role of PHD3, a member of the PHD family, in IBD remains unknown. We show here that PHD3 plays a critical role in maintaining intestinal epithelial barrier function. We found that genetic ablation of Phd3 in intestinal epithelial cells led to spontaneous colitis in mice. Deletion of PHD3 decreases the level of tight junction protein occludin, leading to a failure of intestinal epithelial barrier function. Further studies indicate that PHD3 stabilizes occludin by preventing the interaction between the E3 ligase Itch and occludin, in a hydroxylase-independent manner. Examination of biopsy of human ulcerative colitis patients indicates that PHD3 is decreased with disease severity, indicating that PHD3 down-regulation is associated with progression of this disease. We show that PHD3 protects intestinal epithelial barrier function and reveal a hydroxylase-independent function of PHD3 in stabilizing occludin. These findings may help open avenues for developing a therapeutic strategy for IBD.

Changing trends, clinicopathological characteristics, surgical treatment patterns, and prognosis of schistosomiasis-associated versus non-schistosomiasis-associated colorectal cancer: a large retrospective cohort study of 31 153 cases in Shanghai, China (2001-2021).

BACKGROUND: With the elimination of schistosomiasis in China, its role in the pathogenesis of colorectal cancer (CRC) has decreased. However, the trends, clinicopathological features, surgical treatment patterns, and prognosis of schistosomiasis-associated CRC (SACRC) versus non-schistosomiasis-associated CRC (NSACRC) in China remain unclear. MATERIALS AND METHODS: The percentage trend of SACRC in CRC patients in China was analyzed using data retrieved from the Pathology Registry of Changhai Hospital (2001-2021). Clinicopathological characteristics, surgical treatment patterns, and prognosis-related parameters were compared between the two groups. Multivariate Cox regression analyses were performed for disease-free survival (DFS) and overall survival (OS). RESULTS: A total of 31 153 CRC cases were included, with 823 (2.6%) cases of SACRC and 30 330 (97.4%) cases of NSACRC. The average percentage of SACRC cases has decreased continuously from 3.8 to 1.7% (from 2001 to 2021). Compared with the NSACRC group, the SACRC group had more men, older age at diagnosis, lower BMI, fewer symptoms; higher rates of rectal cancer, comorbidities, KRAS mutation, multiple primary CRC and concomitant polyps; less lymph node metastasis, distant metastasis, vascular invasion, and tumor budding; less preoperative radiotherapy and preoperative chemotherapy; and more positive resection margins and postoperative targeted therapy. There were no significant differences between the two groups regarding laparoscopic surgery, palliative resection, extended radical resection, or ostomy. Moreover, the SACRC group had adverse DFS and similar OS compared with the NSACRC group. In multivariate analyses, schistosomiasis was not an independent predictor of DFS or OS. CONCLUSION: The percentage of SACRC in CRC (2.6%) in our hospital was very low, and it decreased continuously over the last two decades, indicating that schistosomiasis is no longer an important risk factor for CRC in Shanghai, China. Patients with SACRC have distinct clinicopathological, molecular, and treatment-related features and survival rates similar to those with NSACRC.

DNA topoisomerase II alpha: a favorable prognostic factor in colorectal caner.

PURPOSE: There is a lack of study concerning expression of Topoisomerase IIα (Topo IIα) and long-term results in colorectal cancer patients. We aimed to investigate the relationship between expression of Topo IIα and clinicopathological parameters including overall survival in colorectal cancer. METHODS: Paraffin-fixed specimens from a large prospective cohort of colorectal cancer patients who had been followed up for 4 years were assayed immunohistochemically. RESULTS: Of 490 colorectal cancer patients accessible for Topo IIα expression, expression of Topo IIα was scored as (-) in 4 (0.8%) patients, (+) in 41 (8.4%) patients, (++) in 396 (80.8%) patients, and (+++) in 49 (10.0%) patients. Overexpression of Topo IIα was found to be related with lower T stage (p = 0.042), lower N stage (p = 0.038), and a lower incidence of recurrence with nearly significance (p = 0.053). Kaplan-Meier analyses showed that overexpression of Topo IIα was related with prolonged overall survival (p = 0.022) and disease-free survival (p = 0.036). Multivariate analyses showed that elevated serum CEA (p < 0.001), elevated serum CA199 (p = 0.002), poor differentiation (p = 0.001), advanced Dukes stage (p < 0.001), and lower expression of Topo IIα (p = 0.017) were independent predictive factors for poor prognosis. CONCLUSIONS: Topo IIα expression is a valuable prognostic indicator for colorectal cancer and would be useful in treatment selection for early colorectal cancer and malignant colorectal polyps resected under endoscopy, especially when it is used in combination with serum CEA, CA199, and differentiation.

Trends, clinicopathological features, surgical treatment patterns and prognoses of early-onset versus late-onset colorectal cancer: A retrospective cohort study on 34067 patients managed from 2000 to 2021 in a Chinese tertiary center.

BACKGROUND: In recent decades, the incidence of early-onset colorectal cancer (EOCRC) has reportedly increased in several developed countries, whereas that of late-onset colorectal cancer (LOCRC) has decreased continuously. The trends, clinicopathological features, surgical treatment patterns, and prognoses of EOCRC and LOCRC in China remain unclear. MATERIALS AND METHODS: This retrospective cohort study was performed in China using data from our pathology registry collected in 2000-2021. Pathologically confirmed cases of colorectal cancer (CRC) were analyzed. The average annual percentage change (AAPC) was estimated to quantify the secular trends. Clinicopathological features, surgical treatment patterns, and prognoses were compared between the two groups. Multivariate Cox regression analyses were performed for disease-free survival and overall survival. RESULTS: A total of 34,067 cases of CRC were included, with 6,369 cases of EOCRC and 27,698 cases of LOCRC. Overall, the numbers of EOCRC (AAPC = 8.4%), LOCRC (AAPC = 11.6%), and CRC (AAPC = 11.0%) cases increased significantly from 2000 to 2021. Compared to the LOCRC group, the EOCRC group had fewer men, comorbidities, concomitant cancers, polyps, and KRAS mutations; more symptoms, rectal cancers, multiple primary CRCs, deficient mismatch repair tumors, poorly differentiated, mucinous adenocarcinoma or signet ring cell carcinoma, advanced TNM stage, vascular invasion, perineural invasion; less laparoscopic surgery and sphincter-preserving surgery; more extended radical resection, perioperative chemoradiotherapy and targeted therapy; and similar disease-free and overall survival rates. CONCLUSION: The numbers of EOCRC and LOCRC cases have continuously increased over the last two decades. The EOCRC group has more aggressive features, advanced TNM stage, intensified surgical treatment and perioperative treatment than the LOCRC group, but similar disease-free and overall survival rates. More CRC screening programs are recommended for younger adults to combat the rapidly increasing trend of EOCRC.

Comparison of Fresh Frozen Tissue With Formalin-Fixed Paraffin-Embedded Tissue for Mutation Analysis Using a Multi-Gene Panel in Patients With Colorectal Cancer.

Background: Next generation sequencing (NGS)-based multi-gene panel tests have been performed to predict the treatment response and prognosis in patients with colorectal cancer (CRC). Whether the multi-gene mutation results of formalin-fixed paraffin-embedded (FFPE) tissues are identical to those of fresh frozen tissues remains unknown. Methods: A 22-gene panel with 103 hotspots was used to detect mutations in paired fresh frozen tissue and FFPE tissue from 118 patients with CRC. Results: In our study, 117 patients (99.2%) had one or more variants, with 226 variants in FFPE tissue and 221 in fresh frozen tissue. Of the 129 variants identified in this study, 96 variants were present in both FFPE and fresh frozen tissues; 27 variants were found in FFPE tissues only; 6 variants were found only in fresh frozen tissues. The mutation results demonstrated >94.0% concordance in all variants, with Kappa coefficient >0.500 in 64.3% (83/129) of variants. At the gene level, concordance ranged from 73.8 to 100.0%, with Kappa coefficient >0.500 in 81.3% (13/16) of genes. Conclusions: The results of mutation analysis performed with a multi-gene panel and FFPE and fresh frozen tissue were highly concordant in patients with CRC, at both the variant and gene levels. There were, however, some important differences in mutation results between the two tissue types. Therefore, fresh frozen tissue should not routinely be replaced with FFPE tissue for mutation analysis with a multi-gene panel. Rather, FFPE tissue is a reasonable alternative for fresh frozen tissue when the latter is unavailable.

Which Definition of Upper Rectal Cancer Is Optimal in Selecting Stage II or III Rectal Cancer Patients to Avoid Postoperative Adjuvant Radiation?

BACKGROUND: In most guidelines, upper rectal cancers (URC) are not recommended to take neoadjuvant or adjuvant radiation. However, the definitions of URC vary greatly. Five definitions had been commonly used to define URC: 1) >10 cm from the anal verge by MRI; 2) >12 cm from the anal verge by MRI; 3) >10 cm from the anal verge by colonoscopy; 4) >12 cm from the anal verge by colonoscopy; 5) above the anterior peritoneal reflection (APR). We hypothesized that the fifth definition is optimal to identify patients with rectal cancer to avoid adjuvant radiation. METHODS: The data of stage II/III rectal cancer patients who underwent radical surgery without preoperative chemoradiotherapy were retrospectively reviewed. The height of the APR was measured, and compared with the tumor height measured by digital rectal examination (DRE), MRI and colonoscopy. The five definitions were compared in terms of prediction of local recurrence, survival, and percentages of patients requiring radiation. RESULTS: A total of 576 patients were included, with the intraoperative location of 222 and 354 tumors being above and straddle/below the APR, respectively. The median distance of the APR from anal verge (height of APR) as measured by MRI was 8.7 (range: 4.5-14.3) cm. The height of APR positively correlated with body height (r=0.862, P<0.001). The accuracy of the MRI in determining the tumor location with respect to the APR was 92.1%. Rectal cancer above the APR had a significantly lower incidence of local recurrence than those straddle/below the APR (P=0.042). For those above the APR, there was no significant difference in local recurrence between the radiation and no-radiation group. Multivariate analyses showed that tumor location regarding APR was an independent risk factor for LRFS. Tumor height as measured by DRE, MRI and colonoscopy were not related with survival outcomes. Fewer rectal cancer patients required adjuvant radiation using the definition by the APR, compared with other four definitions based on a numerical tumor height measured by MRI and colonoscopy. CONCLUSIONS: The definition of URC as rectal tumor above the APR, might be the optimal definition to select patients with stage II/III rectal cancer to avoid postoperative adjuvant radiation.

Integrated Omics of Metastatic Colorectal Cancer.

We integrate the genomics, proteomics, and phosphoproteomics of 480 clinical tissues from 146 patients in a Chinese colorectal cancer (CRC) cohort, among which 70 had metastatic CRC (mCRC). Proteomic profiling differentiates three CRC subtypes characterized by distinct clinical prognosis and molecular signatures. Proteomic and phosphoproteomic profiling of primary tumors alone successfully distinguishes cases with metastasis. Metastatic tissues exhibit high similarities with primary tumors at the genetic but not the proteomic level, and kinase network analysis reveals significant heterogeneity between primary colorectal tumors and their liver metastases. In vivo xenograft-based drug tests using 31 primary and metastatic tumors show personalized responses, which could also be predicted by kinase-substrate network analysis no matter whether tumors carry mutations in the drug-targeted genes. Our study provides a valuable resource for better understanding of mCRC and has potential for clinical application.

Self-renewal and chemotherapy resistance of p75NTR positive cells in esophageal squamous cell carcinomas.

BACKGROUND: p75NTR has been used to isolate esophageal and corneal epithelial stem cells. In the present study, we investigated the expression of p75NTR in esophageal squamous cell carcinoma (ESCC) and explored the biological properties of p75NTR+ cells. METHODS: p75NTR expression in ESCC was assessed by immunohistochemistry. p75NTR+ and p75NTR- cells of 4 ESCC cell lines were separated by fluorescence-activated cell sorting. Differentially expressed genes between p75NTR+ and p75NTR- cells were determined by real-time quantitative reverse transcription-PCR. Sphere formation assay, DDP sensitivity assay, 64copper accumulation assay and tumorigenicity analysis were performed to determine the capacity of self-renewal, chemotherapy resistance and tumorigenicity of p75NTR+ cells. RESULTS: In ESCC specimens, p75NTR was found mainly confined to immature cells and absent in cells undergoing terminal differentiation. The percentage of p75NTR+ cells was 1.6%-3.7% in Eca109 and 3 newly established ESCC cell lines. The expression of Bmi-1, which is associated with self-renewal of stem cells, was significantly higher in p75NTR+ cells. p63, a marker identified in keratinocyte stem cells, was confined mainly to p75NTR+ cells. The expression of CTR1, which is associated with cisplatin (DDP)-resistance, was significantly decreased in p75NTR+ cells. Expression levels of differentiation markers, such as involucrin, cytokeratin 13, beta1-integrin and beta4-integrin, were lower in p75NTR+ cells. In addition, p75NTR+ cells generated both p75NTR+ and p75NTR- cells, and formed nonadherent spherical clusters in serum-free medium supplemented with growth factors. Furthermore, p75NTR+ cells were found to be more resistant to DDP and exhibited lower 64copper accumulation than p75NTR- cells. CONCLUSION: Our results demonstrated that p75NTR+ cells possess some characteristics of CSCs, namely, self-renewal and chemotherapy resistance. Chemotherapy resistance of p75NTR+ cells may probably be attributable to decreased expression of CTR1.

[Transforming effect of PDGFRA gene mutant on the cell function in gastrointestinal stromal tumor].

OBJECTIVE: To explore the effect of malignant transformation of the L839P, a new mutation site of the PDGFRA gene, on the pathogenesis of gastrointestinal stromal tumors. METHODS: All recombinant plasmids were stably transfected into CHO cells by liposomes. Western blotting was used to detect the expression of PDGFRA protein. The cell growth curve was plotted by cell counting. Flow cytometry was used to detect the cell cycle and apoptosis of CHO cell, respectively. The stably transformed cells were inoculated subcutaneously into the back of nude mice and the mice were used to observe the tumorigenesis. Transient transfection of the mutant-type plasmids of PDGFRA gene and the wild-type plasmids of kit gene into the CHO cells was performed. Western blot was used to detect the expression of kit protein and its phosphorylated forms. RESULTS: PDGFRA protein expressed in the negative control, experimental group and positive control, except the empty vector. The growth curve showed that it was accelerated in the experimental group and positive control. The ratios of cells in proliferative phase were 28.4% (blank), 24.5% (negative control), 43.8% (experimental group) and 40.9% (positive control). Their apoptotic indexes were 1.8%, 1.9%, 1.5% and 1.6%, respectively. After three weeks, tumors were observed in the nude mice of experimental group and positive control, inoculated with the stably transformed cells. Moreover, the expression of phosphorylated protein of kit was enhanced after cotransfection of the mutant-type plasmids of PDGFRA and the wild-type plasmid of kit. CONCLUSION: The PDGFRA mutant L839P is a gain-of-function mutation and has obviously malignant transforming effect on normal cells, and may activate kit protein accelerating the tumorigenesis. Gastrointestinal stromal tumors;

Therapeutic potential of angiogenin modified mesenchymal stem cells: angiogenin improves mesenchymal stem cells survival under hypoxia and enhances vasculogenesis in myocardial infarction.

BACKGROUND: To examine the effects of angiogenin modified mesenchymal stem cells (MSCs) on ventricular remodeling and cardiac function in a rat model of acute myocardial infarction. METHODS: MSCs were transfected with adenoviral vectors carrying either angiogenin (MSC(AdANG)) or EGFP (MSC(AdEGFP)). Angiogenin gene amplification, protein expression and cell death were assayed after hypoxic treatment. DiI labeled MSC(AdANG) and MSC(AdEGFP) were injected into infracted heart. Six weeks after cell transplantation, echocardiography and histological study were performed. RESULTS: After hypoxia treatment, angiogenin modified MSCs effectively expressed angiogenin for at least 14 days. The death of MSC(AdANG) was one-third of MSCAd(EGFP), and 50% of untreated MSCs. In the infracted myocardium, the number of DiI labeling cells in MSC(AdANG) group with high angiogenin expression was three-fold that in MSC(AdEGFP) group. Echocardiograms suggested that angiogenin modified MSCs significantly improved left ventricular (LV) systolic and diastolic function. Histological study confirmed that ventricular remodeling was attenuated significantly in MSC(AdANG) group. Furthermore, vasculogenesis was enhanced significantly in MSC(AdANG) group as measured by both factor VIII and alpha-SMA staining. CONCLUSION: Angiogenin modified MSCs enhanced the tolerance of engrafted MSCs to hypoxia injury in vitro and improved their viability in infracted hearts, thus helping preserve the LV contractile function and attenuate LV remodeling through vasculogenesis.

Angiopoietin-1 targeted RNA interference suppresses angiogenesis and tumor growth of esophageal cancer.

AIM: To determine the inhibitory effect of the adenovirus-based angiopoietin-1 (Ang-1) targeted small interfering RNA expression system (Ad/Ang-1si) on the expression of the Ang-1 gene, cell growth and apoptosis in human esophageal cancer cell line Eca109. METHODS: siRNA-expressing adenovirus targeting Ang-1 gene was constructed using the Ad Easy System. Cultured Eca109 cells were transfected with Ad/Ang-1si (Eca109/Ang-1si), and Ad/si was used to infect Eca109 cells as control (Eca109/si). Ang-1 gene expression and concentration was determined with RT-PCR and ELISA, respectively. Human umbilical vein endothelial cell (HUVEC) migration and proliferation were analyzed. After s.c. injection into athymic nu/nu mice, the tumor growth, vessel density and apoptosis of each group was also determined. RESULTS: HUVEC migration induced by conditioned medium from Ang-1si-transfected Eca109 cells was significantly less than that induced by conditioned medium from Eca109 cells and control adenovirus-transfected Eca109 cells. Furthermore, after s.c. injection into athymic nu/nu mice, the tumor growth and cell apoptosis of Ad/Ang-1si -expressing Eca109 cells was significantly lower than that of parental or control adenovirus-transfected cells. Vessel density assessed by CD31 immunohistochemical analysis and Ang-1 expression by RT-PCR were also decreased. CONCLUSION: The targeting Ang-1 may provide a therapeutic option for esophageal cancer.

Seizure syndrome as a first manifestation of solitary tumor-like mass lesion of PACNS: Two case reports.

RATIONALE: Primary angiitis of the central nervous system (PACNS) is an inflammatory disease involving cerebrovascular and parenchymal, and solitary tumor-like mass lesion of PACNS (TLML-PACNS) is frequently misdiagnosed as neoplastic or other inflammatory diseases. However, seizure syndrome as a first manifestation of TLML-PACNS has rarely reported before. PATIENT CONCERNS: Here, we report 2 cases of seizure syndrome, which was the first sign that presented prior to the diagnosis of TLML-PACNS by brain biopsy. DIAGNOSES: A mass lesion in the white and gray matters was detected by magnetic resonance imaging. The pathology for leptomeningeal lesion biopsy observed a transmural inflammation of the artery, with T lymphocyte infiltration. Patients were diagnosed with PACNS and epileptic seizure by biopsy and electroencephalogram. INTERVENTIONS: Patients were treated with glucocorticoid pulse therapy for 3 days, and subsequently oral prednisone was continued, in combination with immunosuppressant. OUTCOMES: Luckily, both two patients were improved after treatment, and only mild cognitive impairment remained without adverse event. LESSONS: Patient with mass lesion in CNS, which is similar to tumor, presented with seizure, headache, or cerebrovascular events without any other risk factors for stroke or tumor, should be considered the feasible with the disease of TLML-PACNS.

Differences of protein expression profiles, KRAS and BRAF mutation, and prognosis in right-sided colon, left-sided colon and rectal cancer.

To compare protein expression levels, gene mutation and survival among Right-Sided Colon Cancer (RSCC), Left-Sided Colon Cancer (LSCC) and rectal cancer patients, 57 cases of RSCC, 87 LSCC and 145 rectal cancer patients were included retrospectively. Our results demonstrated significant differences existed among RSCC, LSCC and rectal cancer regarding tumor diameter, differentiation, invasion depth and TNM stage. No significant difference was identified in expression levels of MLH1, MSH2, MSH6, PMS2, ß-Tubulin III, P53, Ki67 and TOPIIα, and gene mutation of KRAS and BRAF among three groups. Progression Free Survival (PFS) of RSCC was significantly lower than that of LRCC and rectal cancer. In univariate analyses, RSCC, preoperative chemoradiotherapy, poor differentiation, advanced TNM stage, elevated serum CEA and CA19-9 level, tumor deposit, perineural and vascular invasion were found to be predictive factors of shorter PFS. In multivariate analyses, only differentiation and TNM stages were found to be independent predictors of PFS. In conclusion, compared with LSCC and rectal cancer, RSCC has larger tumor size, poor differentiation, advanced TNM stage and shorter survival. The shorter survival in RSCC might be attributed to the advanced tumor stage caused by its inherent position feature of proximal colon rather than genetic difference.

Dishevelled2 promotes apoptosis and inhibits inflammatory cytokine secretion in rheumatoid arthritis fibroblast-like synoviocytes through crosstalk with the NF-κB pathway.

Dishevelled (Dvl) not only links the canonical Wnt and non-canonical Wnt pathways but can also crosstalk with other pathways. As there is no systematic study to date on Dvl in rheumatoid arthritis (RA), we explored the impact of Dvl2 on proliferation and inflammatory cytokine secretion in RA fibroblast-like synoviocytes (FLSs). Expression of Dvl2 in RA synovial tissue and RA-FLSs was measured. Dvl2 was overexpressed in collagen-induced arthritis rats and human RA-FLSs,. the apoptosis and secretion of inflammatory cytokines were observed. Genetic changes and corresponding mechanisms caused by overexpressing Dvl2 in RA-FLSs were assessed. Dvl2 was found to be overexpressed in RA synovial tissue and RA-FLSs. Overexpression of Dvl2 increased apoptosis and inhibited inflammatory cytokine secretion by RA-FLSs in vivo and in vitro, and Dvl2 inhibited expression of anti-apoptotic and inflammatory genes. One possible mechanism is that Dvl2 decreases the nuclear translocation of P65 and inhibits its ability to bind to the promoters of NF-κB target genes. Our findings reveal an underappreciated role of Dvl2 in regulating inflammation and RA-FLS apoptosis and provide insight into crosstalk between the Wnt and nuclear factor-κB (NF-κB) pathways.