Intestinal tuberculosis with small bowel stricture and hemorrhage as the predominant manifestation: Three case reports.

BACKGROUND: Intestinal tuberculosis is a chronic disease caused by Mycobacterium tuberculosis that mainly affects the ileum and cecum. Small bowel tuberculosis, characterized by predominant involvement of the small intestine, is an extremely rare condition with highly atypical clinical presentations, making diagnosis even more challenging. CASE SUMMARY: We report three cases of small intestinal tuberculosis, two of the patients presented primarily with abdominal pain, and one presented with gastrointestinal bleeding. All patients underwent blood tests and imaging examinations. Small bowel endoscopy (SBE) revealed that the main lesions in these patients were intestinal stenosis or gastrointestinal bleeding caused by small intestinal ulcers. One patient ultimately underwent surgical treatment. Following a complex diagnostic process and comprehensive analysis, all patients were confirmed to have small intestinal tuberculosis and received standard antituberculosis treatment, leading to an improvement in their condition. CONCLUSION: Patients with SBTs present with nonspecific symptoms such as abdominal pain, weight loss, and occasional gastrointestinal bleeding. Accurate diagnosis requires a thorough evaluation of clinical symptoms and various tests to avoid misdiagnosis and complications.

CD93 overexpresses in liver hepatocellular carcinoma and represents a potential immunotherapy target.

Background: Liver hepatocellular carcinoma (LIHC) is one of the malignant tumors with high incidence as well as high death, which is ranked as the sixth most common tumor and the third highest mortality worldwide. CD93, a transmembrane protein, has been widely reported to play an important role in different types of diseases, including many types of cancer by mainly functioning in extracellular matrix formation and vascular maturation. However, there are few researches focusing on the role and potential function of CD93 in LIHC. Methods: In this study, we comprehensively analyzed the relationship between CD93 and LIHC. We not only discovered transcriptional expression of CD93 in LIHC by using the TIMER, GEPIA and UALCAN database, but also performed WB and IHC to verify the protein expression of CD93 in LIHC. Meantime, Kaplan-Meier Plotter Database Analysis were used to assess the prognosis of CD93 in LIHC. After knowing close correlation between CD93 expression and LIHC, there were STRING, GeneMania and GO and KEGG enrichment analyses to find how CD93 functions in LIHC. We further applied CIBERSORT Algorithm to explore the correlation between CD93 and immune cells and evaluate prognostic value of CD93 based on them in LIHC patients. Results: The transcriptional and protein expression of CD93 were both obviously increased in LIHC by above methods. There was also a significant and close correlation between the expression of CD93 and the prognosis of LIHC patients by using Kaplan-Meier Analysis, which showed that LIHC patients with elevated expression of CD93 were associated with a predicted poor prognosis. We found that the functions of CD93 in different cancers are mainly related to Insulin like growth factor binding protein 7 Gene (IGFBP7)/CD93 pathway via STRING, GeneMania and functional enrichment analyses. Further, our data obtained from CIBERSORT Algorithm suggested CD93 was also associated with the immune response. There is a close positive correlation between CD93 expression and the infiltration levels of all six types of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells). Importantly, CD93 can affect the prognosis of patients with LIHC partially due to immune infiltration. Conclusion: Our results demonstrated CD93 may be a candidate predictor of clinical prognosis and immunotherapy response in LIHC.

Differentially expressed liver exosome-related genes as candidate prognostic biomarkers for hepatocellular carcinoma.

Background: Exosomes are involved in cell-to-cell communication, neovascularization, cancer metastasis, and drug resistance, which all play an important role in the occurrence and progression of hepatocellular carcinoma (HCC). Because there are few mechanistic studies about the function of exosomes in HCC, the goals of this study were to identify exosome-related genes in HCC, to establish a reliable prognostic model for HCC, and to explore underlying mechanisms. Methods: The exoRBase and The Cancer Genome Atlas (TCGA) databases were used to analyze differentially expressed genes (DEGs). Cox regression and least absolute shrinkage and selection operator analyses were used to identify DEGs closely related to the overall survival of patients with HCC. An exosome-related prognostic model was then constructed in TCGA and validated in the International Cancer Genome Consortium database. A nomogram was developed to predict survival. CIBERSORT was used to estimate the abundance of different types of immune cells. Immunotherapy-related DEGs were used to predict the effect of immunotherapy. Results: Forty-eight exosome-related DEGs were obtained; of them, five [exportin 1 (XPO1), lysosomal thiol reductase (IFI30), F-box protein 16 (FBXO16), calmodulin 1 (CALM1), MORC family CW-type zinc finger 3 (MORC3)] were selected to construct a predictive model. Patients with HCC were then divided into low- and high-risk groups using the best cut-off value, as determined by the X-tile software. Prognosis was significantly poorer in the high-risk than in the low-risk group (P=0.009; hazard ratio =2.65). Features related to exosomes were found to positively regulate immune response. Further analysis showed a higher risk score was associated with higher expression of immune checkpoint molecules, including programmed death ligand 1 (PD-L1), programmed death ligand 2 (PD-L2), T cell Ig and ITIM domain (TIGIT), and indoleamine-2,3-dioxygenase 1 (IDO1). Conclusions: This study has identified a novel signature based on exosome-related genes that has potential as a prognostic biomarker for HCC. Our research provides an immunological perspective for the development of precision treatment for HCC.

LncRNA NKILA Promotes Epithelial-Mesenchymal Transition of Liver Cancer Cells by Targeting miR-485-5p.

OBJECTIVE: Liver cancer (LC), one of the familiar malignancies, has a very high morbidity all over the world. The onset of the disease is hidden, and the patients usually do not express any special symptoms. Most of them will have been developed to the middle and later stage when they are diagnosed. This is one of the main reasons why the prognosis of LC is extremely pessimistic all the year round. Recently, researchers have focused mainly on molecular studies, among which LncRNA is a hot spot. This research aims to explore the biological behaviors of LncRNA NKILA and miR-485-5p in LC cells and verify the relationship between them, thereby providing a new theoretical basis for future prevention and treatment. METHODS: Ninety-four early LC patients admitted to our hospital from January 2015 to January 2017 were regarded as the research objects. In addition, human LC cells SMMC-7721, HepG2, and normal liver cells HL-7702 were purchased. The LncRNA NKILA and miR-485-5p level in cancer and adjacent tissues, LC, and normal liver cells of patients was tested by PCR. Patients were followed up for 3 years. Then, LncRNA NKILA and miR-485-5p's effects on prognosis and cell biological behavior were analyzed. At last, the relationship between LncRNA NKILA and miR-485-5p was assessed by a dual-luciferase reporter assay. RESULTS: The LncRNA NKILA expression was high in LC tissues and cells (P < 0.050), while miR-485-5p was low compared with the normal adjacent tissues (P < 0.050). Prognostic follow-up manifested that high LncRNA NKILA or low miR-485-5p could predict the poor prognosis and high mortality risk of the patients (P < 0.050). LC cells with downregulated LncRNA NKILA documented inhibited proliferation, invasion, and EMT, while the apoptosis level of the cells increased (P < 0.050). The proliferation, invasion, and EMT were inhibited by miR-485-5p increase, while the apoptosis of the cells decreased after upregulating miR-485-5p (P < 0.050). Online websites predicted that LncRNA NKILA had a binding site with miR-485-5p, and dual-luciferase reporter assay confirmed that LncRNA NKILA could directly target with miR-485-5p (P < 0.050). The miR-485-5p in LC cells increased after LncRNA NKILA was silenced (P < 0.050). The rescue experiment documented that LncRNA NKILA inhibition on LC cells was reversed by inhibiting miR-485-5p (P < 0.050). CONCLUSION: The LncRNA NKILA with high expression advances LC cell proliferation, invasion, and EMT by targeting miR-485-5p.

Identification of growth differentiation factor 15 as a pro-fibrotic factor in mouse liver fibrosis progression.

The aim of this study was elucidate the inhibitory role of growth differentiation factor 15 (GDF15) in liver fibrosis and its possible activation mechanism in hepatic stellate cells (HSCs) of mice. We generated a GDF15-neutralizing antibody that can inhibit TGF-ß1-induced activation of the TGF-ß/Smad2/3 pathway in LX-2 cells. All the mice in this study were induced by carbon tetrachloride and thioacetamide. In addition, primary HSCs from mice were isolated from fresh livers using Nycodenz density gradient separation. The severity and extent of liver fibrosis were evaluated by Sirius Red and Masson staining. The effect of GDF15 on the activation of the TGF-ß pathway was detected using dual-luciferase reporter and Western blotting assays. The expression of GDF15 in cirrhotic liver tissue was higher than that in normal liver tissue. Blocking GDF15 with a neutralizing antibody resulted in a delay in primary hepatic stellate cell activation and remission of liver fibrosis induced by carbon tetrachloride or thioacetamide. Meanwhile, TGF-ß pathway activation was partly inhibited by a GDF15-neutralizing antibody in primary HSCs. These results indicated that GDF15 plays an important role in regulating HSC activation and liver fibrosis progression. The inhibition of GDF15 attenuates chemical-inducible liver fibrosis and delays hepatic stellate cell activation, and this effect is probably mainly attributed to its regulatory role in TGF-ß signalling.

Inhibition of PSMD4 blocks the tumorigenesis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver with high mortality and frequent recurrence. Although various therapies provide potential cure for HCC patients, unfortunately the five-year survival rate of advanced HCC remains dismal. It is critical to explore the pathogenesis of HCC and identify novel biomarkers for early HCC diagnosis. PSMD4 is a major receptor of the 26S proteasome involved in ubiquitindependent and proteasome-mediated protein degradation. In our study, PSMD4 was overexpressed in HCC tissues and cell lines determined by Northern blot, western blot and immunohistochemistry. The silencing of PSMD4 blocked cell proliferation and tumor growth, induced cell apoptosis and inhibited the proteasome activity. Western blot results showed that the knockdown of PSMD4 blocked the expression of cyclooxygenase 2 (COX2), phosphorylated Sarcoma tyrosine kinase (P-SRC) and Bcl-2, but improved the levels of p53 and Bax in HCC, lung cancer, colorectal cancer, breast cancer and endometrial cancer cell lines. Taken together, these findings indicated that the subunit of 26S proteasome PSMD4 exerts as an oncogene in HCC and other cancers via regulating the expression p53, Bcl-2 and Bax. These findings enriched the pathogenesis of HCC, and provided a new biomarker for cancers diagnosis and a new target for cancers therapy.

Epidermal growth factor receptor-targeted immune magnetic liposomes capture circulating colorectal tumor cells efficiently.

AIM: To compare the capacity of newly developed epidermal growth factor receptor (EGFR)-targeted immune magnetic liposomes (EILs) vs epithelial cell adhesion molecule (EpCAM) immunomagnetic beads to capture colorectal circulating tumor cells (CTCs). METHODS: EILs were prepared using a two-step method, and the magnetic and surface characteristics were confirmed. The efficiency of capturing colorectal CTCs as well as the specificity were compared between EILs and EpCAM magnetic beads. RESULTS: The obtained EILs had a lipid nanoparticle structure similar to cell membrane. Improved binding with cancer cells was seen in EILs compared with the method of coupling nano/microspheres with antibody. The binding increased as the contact time extended. Compared with EpCAM immunomagnetic beads, EILs captured more CTCs in peripheral blood from colorectal cancer patients. The captured cells showed consistency with clinical diagnosis and pathology. Mutation analysis showed same results between captured CTCs and cancer tissues. CONCLUSION: EGFR antibody-coated magnetic liposomes show high efficiency and specificity in capturing colorectal CTCs.

Smoc2 potentiates proliferation of hepatocellular carcinoma cells via promotion of cell cycle progression.

AIM: To determine the influence of Smoc2 on hepatocellular carcinoma (HCC) cell proliferation and to find a possible new therapeutic target for preventing HCC progression. METHODS: We detected expression of Smoc2 in HCC tissues and corresponding non-tumor liver (CNL) tissues using PCR, western blot, and immunohistochemistry methods. Subsequently, we down-regulated and up-regulated Smoc2 expression using siRNA and lentivirus transfection assay, respectively. Then, we identified the effect of Smoc2 on cell proliferation and cell cycle using CCK-8 and flow cytometry, respectively. The common cell growth signaling influenced by Smoc2 was detected by western blot assay. RESULTS: The expression of Smoc2 was significantly higher in HCC tissues compared with CNL tissues. Overexpression of Smoc2 promoted HCC cell proliferation and cell cycle progression. Down-regulation of Smoc2 led to inhibition of cell proliferation and cell cycle progression. Smoc2 had positive effect on ERK and AKT signaling. CONCLUSION: Smoc2 promotes the proliferation of HCC cells through accelerating cell cycle progression and might act as an anti-cancer therapeutic target in the future.

Mannose-binding lectin 2 rs11003123 polymorphism is associated with the development of hepatocellular carcinoma in patients with hepatitis B-related cirrhosis in the Chinese population.

BACKGROUND: Mannose-binding lectin 2 (MBL2) plays a key role in the host immune response, but whether it is associated with hepatocellular carcinoma (HCC) is not clear. The present study aimed to identify the association between MBL2 gene polymorphisms and HCC in patients with hepatitis B virus (HBV)-related cirrhosis in the Chinese population. METHODS: A single-nucleotide polymorphism of MBL2, rs11003123, was genotyped and analyzed in a case-control study of HBV-related cirrhotic patients with HCC (n=77) and without HCC (n=40). RESULTS: We found that Child-Pugh profiles, model for end-stage liver disease score, and the incidence of encephalopathy were all higher in the non-HCC group (P<0.05). A significant association between allele mutants and HCC occurrence was demonstrated by allele comparison (A vs G) (OR=0.34; 95% CI: 0.15-0.76; P=0.006). Heterozygous comparison (GA vs GG) revealed that the individuals with GA mutants had a reduced risk of HCC occurrence compared with those with GG wild type (adjusted OR=0.28; 95% CI: 0.10-0.80; P=0.004). In a dominant model (GA+AA vs GG), a decreased risk of HCC occurrence was observed in individuals with variant genotypes (GA and AA) compared with those with the wild type (adjusted OR=0.30; 95% CI: 0.11-0.85; P=0.004). However, no statistically significant associations were observed between rs11003123 and prognosis of patients with HCC after liver transplantation in both recurrence-free survival and overall survival (P=0.449 and P=0.384, respectively). CONCLUSION: MBL2 rs11003123 polymorphism may be a marker for the risk of HCC occurrence in patients with HBV-related cirrhosis in the Chinese population.

Tumor necrosis factor-alpha gene -308G > A polymorphism alters the risk of hepatocellular carcinoma in a Han Chinese population.

BACKGROUND: The aim of the present study was to evaluate the influence of tumor necrosis factor-alpha (TNF-α) -308 G > A polymorphism on hepatocellular carcinoma (HCC) risk. METHODS: The present case-control study was conducted in a Han Chinese population consisting of 753 HCC patients and 760 controls from May 2010 to March 2013. The -308 TNF-a promoter polymorphisms were detected. Conditional logistic regression was performed to analyze the association between TNF-α -308 G > A polymorphism and the risk of HCC, which were estimated by odds ratios (ORs) and their 95% confidence intervals (95% CIs). RESULTS: The genotypic frequencies in the cases were not similar to that of the controls, differences being statistically significant (P = 0.002). Using the GG genotype as the reference genotype, AA was significantly associated with increased risk of HCC (adjusted OR = 5.12, 95% CI = 2.31-7.82). Similarly, AG + AA genotype showed 5.59-fold increased HCC risk in a dominant model. Furthermore, we found A allele was significantly associated with increased risk of HCC, compared with G allele (OR = 4.18, 95% CI = 1.76-6.97). CONCLUSION: The present study showed that TNF-α -308 G > A polymorphism was associated with increased HCC risk in a Han Chinese population. Further prospective studies on large and different ethnic populations will be necessary to confirm our findings and elucidate the underlying molecular mechanism for the development of HCC. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_199.

[The effect of portal hypertension on prognosis in patients with decompensated liver cirrhosis].

OBJECTIVE: To evaluate the effect of portal hypertension on prognosis in patients with decompensated liver cirrhosis. METHODS: The clinical data of decompensated cirrhosis patients in our hospital, between 2003 and 2006, were retrospected and followed up. Model for end-stage liver disease (MELD) score and Child-Turcotte-Pugh (CTP) classification was calculated using the standard formula. Kaplan-Meier survival analysis was used to compare the mortality in subgroups ranked by the syndromes. Cox proportional hazards regression was used to evaluate the effect of the syndromes on prognosis. RESULTS: A cohort of 322 patients was admitted in this study at the end of the follow-up. The mortality of variceal bleeding, hepatic encephalopathy, a large volume ascites, spontaneous bacterial peritonitis, the type I and type II hepatorenal syndrome was 45.9%, 79.4%, 66.7%, 100%, 100% and 84.6% respectively. On the whole, the occurrence of all the syndromes was correlated with CTP classification and MELD score. Kaplan-Meier survival analysis showed that all of these syndromes, except for low to medium volume of ascites, significantly affected the survival rate (P<0.01). In Cox regression analysis, all the syndromes were the independent predictors of prognosis, the regression coefficient values of hepatic encephalopathy, spontaneous bacterial peritonitis, type I and type II hepatorenal syndrome, variceal bleeding and ascites were 0.973, 0.928, 0.935, 0.866, 0.464 and 0.369 respectively. CONCLUSIONS: The portal hypertensive syndromes have significant effect on the prognosis of the patients with decompensated cirrhosis, hepatic encephalopathy is the worst one.