Novel STAT3 oligonucleotide compounds suppress tumor growth and overcome the acquired resistance to sorafenib in hepatocellular carcinoma.

Signal transducer and activator of transcription 3 (STAT3) plays an important role in the occurrence and progression of tumors, leading to resistance and poor prognosis. Activation of STAT3 signaling is frequently detected in hepatocellular carcinoma (HCC), but potent and less toxic STAT3 inhibitors have not been discovered. Here, based on antisense technology, we designed a series of stabilized modified antisense oligonucleotides targeting STAT3 mRNA (STAT3 ASOs). Treatment with STAT3 ASOs decreased the STAT3 mRNA and protein levels in HCC cells. STAT3 ASOs significantly inhibited the proliferation, survival, migration, and invasion of cancer cells by specifically perturbing STAT3 signaling. Treatment with STAT3 ASOs decreased the tumor burden in an HCC xenograft model. Moreover, aberrant STAT3 signaling activation is one of multiple signaling pathways involved in sorafenib resistance in HCC. STAT3 ASOs effectively sensitized resistant HCC cell lines to sorafenib in vitro and improved the inhibitory potency of sorafenib in a resistant HCC xenograft model. The developed STAT3 ASOs enrich the tools capable of targeting STAT3 and modulating STAT3 activity, serve as a promising strategy for treating HCC and other STAT3-addicted tumors, and alleviate the acquired resistance to sorafenib in HCC patients. A series of novel STAT3 antisense oligonucleotide were designed and showed potent anti-cancer efficacy in hepatocellular carcinoma in vitro and in vivo by targeting STAT3 signaling. Moreover, the selected STAT3 ASOs enhance sorafenib sensitivity in resistant cell model and xenograft model.

Fabricating biodegradable calcium phosphate/calcium sulfate cement reinforced with cellulose: in vitro and in vivo studies.

Osteoporosis is a growing public health concern worldwide. To avoid extra surgeries, developing biodegradable bone cement is critical for the treatment of osteoporosis. Herein, we designed calcium phosphate/calcium sulfate cement reinforced with sodium carboxymethyl cellulose (CMC/OPC). It presents an appropriate physicochemical performance for clinical handling. Meanwhile, CMC/OPC bone cement promotes osteogenic differentiation in vitro. Results of the immune response in vitro and in vivo confirmed that increasing the cellulose content triggered macrophage switching into the M2 phenotype and CMC/OPC exhibited significant anti-inflammation. Furthermore, in vitro and in vivo degradation demonstrated that cellulose tailors the degradation rate of composite bone cement, which achieved a linear degradation process and could degrade by more than 90% for 12 weeks. In summary, the composite bone cement CMC/OPC is a promising candidate for bone repair applications.

Flushing as atypical initial presentation of functional gallbladder neuroendocrine carcinoma: A case report.

BACKGROUND: Neuroendocrine neoplasms are rarely located in the gallbladder (GB), and carcinoid syndrome is exceedingly rare in patients with GB neuroendocrine neoplasms. CASE SUMMARY: We report a case of GB neuroendocrine carcinoma (GB-NEC) in a 65-year-old man, who presented with flushing for 2 mo. Pathological specimens of the flushed skin revealed that mucin was deposited between the collagen bundles in the dermis. Computed tomography and magnetic resonance imaging indicated neoplasm in the GB with liver invasion and enlarged lymph nodes in the portacaval space. High fluorodeoxyglucose uptake was detected in lymph nodes in the portacaval space, but distant metastasis was not seen by positron emission tomography. Ultrasound-guided needle biopsy of the GB neoplasm was suggestive of high-grade NEC. Because of the functional characteristics of poorly differentiated NEC, en bloc cholecystectomy, resection of hepatic segments IVb and V, pancreaticoduodenectomy, and regional lymphadenectomy were performed. A diagnosis of poorly differentiated NEC was made by pathological findings and immunohistochemical staining data. Ki-67 index was > 80%. The patient refused adjuvant therapy and passed away in the 7th month. CONCLUSION: Distinctive manifestation combined with imaging helps make correct preoperative diagnosis. Radical surgery and adjuvant chemotherapy might improve prognosis.

Autologous falciform ligament graft as A substitute for mesentericoportal vein reconstruction in pancreaticoduodenectomy.

OBJECTIVE: To evaluate the falciform ligament as an autologous substitute for mesentericoportal vein reconstruction during pancreaticoduodenectomy. BACKGROUND: Mesentericoportal vein reconstruction was needed in some certain cases during pancreaticoduodenectomy, and a rapidly available substitute was required. METHODS: The falciform ligament was used as an autologous substitute during pancreaticoduodenectomy in 6 patients between June 2016 and May 2017. Anticoagulation was not performed at any stage and venous patency was estimated by Color-Doppler ultrasonography and contrast-enhanced computed tomography. RESULTS: 6 patients underwent vascular resection during pancreaticoduodenectomy for malignant tumors. The falciform ligament graft, with a mean length of 26 mm (10-40), was immediately harvested and used as a lateral patch for reconstruction of the mesentericoportal vein (n = 6). Severe morbidity included Clavien grade-III complications occurred in 1(16.7%) patients but there was no graft-related complications. Histological vascular invasion was present in all the patients (n = 6, 100%), and all had an R0 resection (100%). All venous reconstructions were patent (100%) after a mean follow-up of 12 (6-16) months. CONCLUSIONS: An autologous falciform ligament graft can be safely used as a lateral substitute for mesentericoportal vein reconstruction during pancreaticoduodenectomy; this could help improve the radical resection rate of malignant tumors when oncologically required.

Chirality-specific lift forces of helix under shear flows: Helix perpendicular to shear plane.

Chiral objects in shear flow experience a chirality-specific lift force. Shear flows past helices in a low Reynolds number regime were studied using slender-body theory. The chirality-specific lift forces in the vorticity direction experienced by helices are dominated by a set of helix geometry parameters: helix radius, pitch length, number of turns, and helix phase angle. Its analytical formula is given. The chirality-specific forces are the physical reasons for the chiral separation of helices in shear flow. Our results are well supported by the latest experimental observations.

Association of shorter mean telomere length with large artery stiffness in patients with coronary heart disease.

BACKGROUND: Accumulating evidence implicates leukocyte telomere length (LTL) shortening as a potential risk predictor for cardiovascular disease. Arterial stiffness chronicles the cumulative burden of cardiovascular disease risk factors. Therefore, the capacity of LTL to predict arterial stiffness was examined. METHODS: A total of 275 unrelated Chinese males: 163 patients with coronary artery disease (CAD) and 112 healthy controls, 40-73 years of age were included in this study. The relative telomere length of leukocytes was determined by a real-time fluorescence quantitative polymerase chain reaction (PCR). Large artery stiffness was measured with carotid-femoral pulse wave velocity (PWV). RESULTS: The relative telomere length (T/S) ratio was significantly shorter in patients with CAD (0.79 +/- 0.26) than in control subjects (1.08 +/- 0.22) (p<0.001). The correlation between LTL and PWV in patients with CAD was stronger than that in the controls (r= -0.467, r(2)=0.227, p<0.001 for patients with CAD versus r= -0.223; r(2)=0.050; p=0.018 for controls). The log(e)-transformed T/S ratio was inversely correlated with age (r= -0.345; p<0.001), PWV (r= -0.326; p<0.001) and C-reactive protein ( r= -0.133; p=0.027). CONCLUSIONS: The data show an association of leukocyte telomere length shortening with increased arterial stiffness and cardiovascular burden, suggesting that telomere length is a biomarker of large artery elasticity and CAD. Further studies are warranted to study the role of LTL dynamics in the pathogenesis of atherosclerosis.

Microsurgical reconstruction of hepatic artery in living donor liver transplantation: experiences and lessons.

BACKGROUND: Hepatic artery (HA) reconstruction is one of the key steps for living donor liver transplantation (LDLT). The incidence of HA thrombosis has been reduced by the introduction of microsurgical techniques under a high resolution microscope or loupe. METHODS: We report our experience in 101 cases of HA reconstruction in LDLTs using the graft-artery-unclamp and posterior-wall-first technique. The reconstructions were completed by either a plastic surgeon or a transplant surgeon. RESULTS: The rate of HA thrombosis was 2% (2/101). The risk factors for failed procedures appeared to be reduced by participation of the transplant surgeon compared with the plastic surgeon. For a graft with duplicate arteries, we considered no branches should be discarded even with a positive clamping test. CONCLUSIONS: HA reconstruction without clamping the graft artery is a feasible and simplified technique, which can be mastered by transplant surgeons with considerable microsurgical training.

[The relationship between the gene polymorphism of TGF-beta1 and early renal injury in patients with essential hypertension, and the effect of the gene polymorphism of TGF- beta1 on the individual treatment with valsartan].

OBJECTIVE: To analyze the association of transforming growth factor-beta1(TGF-beta1) gene +869T/C polymorphism and the serum level of TGF-beta1 in patients with early essential hypertension and early renal injury. To study the effect of the gene polymorphism of TGF-beta1 on the individual treatment with valsartan. METHODS: Eighty patients with early essential hypertension and early renal injury were treated with valsartan, and their polymorphism of TGF-beta1 gene +869T/C was analyzed by sequence specific primers-polymerase chain reaction method. Before valsartan treatment and 8 weeks after the treatment, their urinary microamount albumin (MA) levels were determined by using radioimmunity method, and their serum levels of TGF-beta1 were determined by enzyme-linked immunosorbent assay. RESULTS: The blood pressure level of patients with TGF-beta 1 gene +869 CC genotype, TT genotype, TC genotype showed no significant difference (P> 0.05) before treatment. The urinary MA level of the three genotypes was CC genotype's > TC genetype's > TT genotype's in sequence, and the urinary MA level of CC genotype was significantly higher than that of TC genotype and of TT genotype (P< 0.01). The serum levels of TGF-beta1 in the three genotypes was CC genotype's > TC genotype's > TT genotype's in sequence (P< 0.01). There was statistically significant positive correlation between the urinary MA level and the serum level of TGF-beta1(P< 0.05). After 8 weeks treatment with valsartan, there was significant decrease of the blood pressure, the urinary MA level, and the serum level of TGF-beta1. However, the blood pressure reduction of the three types had no statistical significant difference in sequence. The absolute value of urinary MA reduction was CC genotype's > TC genotype's > TT genotype's in sequence, the reduction absolute value of urinary MA in CC genotype was higher than that of TC genotype and of TT genotype (P< 0.05), but the reduction percentage of the urinary MA in the three genotypes showed no statistically significant difference (P> 0.05). The reduction of serum levels of TGF-beta1 was CC genotype's > TC genotype's > TT genotype's in sequence, there was significant difference between each other (P< 0.01). However, the reduction percentage of the serum level of TGF-beta 1 in the three types showed no statistically significant difference (P> 0.05). CONCLUSION: (1) The renal injury of CC genotype in patients with early essential hypertension and early renal injury is more serious than that of TC genotype and of TT genotype. (2)The serum level of TGF-beta 1 can accurately indicate the severity of the renal injury and the protective effect on kidney with valsartan in patients with essential hypertension and early renal injury. (3)The treatment effect of valsartan in the patients with different TGF-beta 1 +869T/C genotype has no difference, i.e., besides effectively decreasing the blood pressure and protecting the renal function, valsartan can reduce the serum level of TGF-beta1 without the influence of the gene polymorphism of TGF-beta1.

Expression of NOS and HIF-1alpha in human colorectal carcinoma and implication in tumor angiogenesis.

AIM: To study CD34, CD105, inducible nitric oxide synthase (iNOS), endogenous nitric oxide synthase (eNOS), and hypoxia-inducible factor 1 (HIF-1) alpha expression in human colorectal carcinomas. METHODS: The tissue microarrays (TMAs) were made up of 80 cases of colorectal carcinoma and 80 cases of non-neoplasm colorectal mucosa. The expression of CD34, CD105, NOS and HIF-1alpha was detected by immunohistochemistry (S-P). RESULTS: iNOS and HIF-1alpha expression in colorectal carcinoma was significantly higher than in non-neoplasm colorectal mucosa (c2 = 43.166, P < 0.01; c2 = 10.4278, P < 0.01); eNOS expression in colorectal carcinoma was significantly lower than in non-neoplasm colorectal mucosa (c2 = 11.354, P < 0.01). The expression of iNOS correlated with differentiation (c2 = 18.141, P < 0.01), invasive depth (c2 = 4.748, P < 0.01), and Micro vessel density (MVD) (t = 2.327, P < 0.05). The expression of HIF-1alpha was correlated with infiltrating depth (c2 = 4.397, P < 0.05), Dukeos staging (c2 = 4.255, P < 0.05), and MVD (t = 2.272, P < 0.05). No correlation was found in eNOS expression. CONCLUSION: Over-expression of iNOS and HIF-1alpha in colorectal carcinoma is correlated with the biological character MVD.

Relationship between expression of CD105 and growth factors in malignant tumors of gastrointestinal tract and its significance.

AIM: Angiogenesis is an important step in the growth of solid malignant tumors. A number of angiogenic factors have been found such as transforming growth factor beta1 (TGF-beta1) and vascular endothelial growth factor (VEGF). However, the roles of TGF-beta1 and VEGF in gastrointestinal carcinogenesis are still unclear. This study was to investigate the expressions of TGF-beta1 and VEGF in gastrointestinal tract malignant tumors, as well as their association with microvessel density (MVD). At the same time, we also observed the localization of TGF-beta1 and its receptor CD105 in gastric malignant tumors. METHODS: The expressions of TGF-beta1 and CD105 were detected in 55 fresh specimens of gastric carcinoma and VEGF and CD105 in 44 fresh specimens of colorectal carcinoma by immunohistochemical staining (S-ABC). TGF-beta1 and CD105 in 55 gastric carcinoma tissues on the same slide were detected by using double-stain Immunohistochemistry (DS-ABC). RESULTS: Among the 55 cases of gastric carcinoma tissues, 30 were positive for TGF-beta1 (54.55%). The MVD of TGF-beta1 strong positive group (++ approximately +++ 23.22 +/- 5.8) was significantly higher than that of weak positive group (+17.56 +/- 7.2) and negative group (- 17.46 +/- 3.9) (q=4.5, q=5.3207, respectively, P<0.01). In the areas of high expression of TGF-beta1, MVD and the expression of CD105 were also high. Among the 44 cases of colonic carcinoma tissues, 26 were positive for VEGF (59.1%). The expressions of both VEGF and CD105 (MVD) were related with the depth of invasion (F=5.438, P<0.05; F=4.168, P=0.05), lymph node metastasis (F=10.311, P<0.01; F=20.282, P<0.01) and Dukes stage (F=6.196, P<0.01; F=10.274, P<0.01), but not with histological grade (F=0.487, P>0.05). There was a significant correlation between the expression of VEGF and CD105 (MVD) (r=0.720, P<0.01). CONCLUSION: Over-expression of TGF-beta1 and VEGF acts as stimulating factors of angiogenesis in gastrointestinal tumors. CD105, as a receptor of TGF-beta1, can regulate the biological effect of TGF-beta1 in tumor angiogenesis. MVD marked by CD105 is more suitable for detecting newborn blood vessels.

[The relationship between angiotensin converting enzyme gene polymorphism and hypertensive kidney lesion and PAI-1 in hypertension patients].

The work is to explore the relationship between the polymorphism of angiotensin converting enzyme (ACE) gene and hypertensive kidney lesion/PAI-1 in hypertension patients. ACE genotyping with polymorase chain reaction (PCR) was performed in 96 unrelated healthy controls, 67 hypertensives without kidney lesion and 70 hypertensives complicated with kidney lesion. The plasma PAI-1 were determined with ELISA. No significant differences could be detected between ACE gene I/D polymorphism and hypertension. However, the frequencies of DD genotype and deletion allele among the hypertensives complicated with kidney lesion were higher than those among the healthy controls and those among the hypertensives without kidney lesion."chi2" values were 6.8589,5.6162 and 5.9085,5.372 respectively. The plasma PAI-1 level showed significant differences among DD genotype,ID genotype and II genotype(P<0.05). The DD genotype of ACE gene may be a risk for hypertensive kidney lesion. The plasma PAI-1 level is associated with ACE gene polymorphism.