An allosteric PGAM1 inhibitor effectively suppresses pancreatic ductal adenocarcinoma.

Glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) plays a critical role in cancer metabolism by coordinating glycolysis and biosynthesis. A well-validated PGAM1 inhibitor, however, has not been reported for treating pancreatic ductal adenocarcinoma (PDAC), which is one of the deadliest malignancies worldwide. By uncovering the elevated PGAM1 expressions were statistically related to worse prognosis of PDAC in a cohort of 50 patients, we developed a series of allosteric PGAM1 inhibitors by structure-guided optimization. The compound KH3 significantly suppressed proliferation of various PDAC cells by down-regulating the levels of glycolysis and mitochondrial respiration in correlation with PGAM1 expression. Similar to PGAM1 depletion, KH3 dramatically hampered the canonic pathways highly involved in cancer metabolism and development. Additionally, we observed the shared expression profiles of several signature pathways at 12 h after treatment in multiple PDAC primary cells of which the matched patient-derived xenograft (PDX) models responded similarly to KH3 in the 2 wk treatment. The better responses to KH3 in PDXs were associated with higher expression of PGAM1 and longer/stronger suppressions of cancer metabolic pathways. Taken together, our findings demonstrate a strategy of targeting cancer metabolism by PGAM1 inhibition in PDAC. Also, this work provided "proof of concept" for the potential application of metabolic treatment in clinical practice.

Ethnicity modifies the association between functional microRNA polymorphisms and breast cancer risk: a HuGE meta-analysis.

Common functional polymorphisms in the promoter region of microRNAs (miRNAs), based on multiple lines of evidence, might participate in transcriptional regulation and other biological processes, which interact to increase the risk of developing breast cancer. Since 2005, many studies have investigated the association between breast cancer risk and common single nucleotide polymorphisms (SNPs) in miRNAs. However, the findings of several meta-analyses are inconclusive or ambiguous. The aim of this Human Genome Epidemiology meta-analysis was to determine more precisely the relationship between common miRNA polymorphisms and breast cancer risk. Twelve case-control studies with a total of 7,170 breast cancer patients and 8,783 healthy controls were included. Eight SNPs in miRNA genes were examined. When all eligible studies were pooled in the meta-analysis, the miR-196a-2 rs11614913*T, miR-499 rs3746444*T, and miR-605 rs2043556*A alleles predicted a decreased risk of breast cancer among Asians, while not Caucasians. In addition, the miR-27a rs895919*C allele might be a protective factor for breast cancer among Caucasians. However, for the miR-146a rs2910164 (G>C), miR-149 rs2292832 (G>T), miR-373 rs12983273 (C>T), and miR-423 rs6505162 (C>A) polymorphisms, we failed to find any significant association with the risk of breast cancer in any genetic model. In conclusion, the current meta-analysis supports that the miR-196a-2 rs11614913*T, miR-499 rs3746444*T, miR-605 rs2043556*A, and miR-27a rs895919*C alleles might be protective factors for breast cancer.

Performance of magnetic resonance elastography and diffusion-weighted imaging for the staging of hepatic fibrosis: A meta-analysis.

UNLABELLED: A meta-analysis was performed to assess and compare the accuracies of magnetic resonance elastography (MRE) and diffusion-weighted imaging (DWI) for the staging of hepatic fibrosis. Online journal databases and a manual search from January 2000 to May 2011 were used. We identified 41 studies, but only 14 met the criteria to perform a meta-analysis assessing MRE (five trials) or DWI (10 trials). Fibrosis was categorized by redistribution into five stages according to histopathological description. A bivariate binomial model was used to combine the sensitivity and specificity and their 95% confidence intervals (CIs), from which diagnostic odds ratio (DOR), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and summary receiver operating characteristic (sROC) were derived to indicate the diagnostic accuracy of imaging modalities. With MRE, the sensitivity, specificity, DOR, PLR, NLR, and area under sROC curve (with 95% CIs) for staging F0 ∼ F1 versus F2 ∼ F4 and F0 ∼ F2 versus F3 ∼ F4 were 0.94 (0.81-0.98), 0.95 (0.87-0.98), 20 (7-57), 0.06 (0.02-0.22), 317 (55-1,796), 0.98 (0.97-0.99) and 0.92 (0.85-0.96), 0.96 (0.91-0.98), 21 (10-45), 0.08 (0.04-0.16), 251 (103-609), and 0.98 (0.96-0.99), respectively; and with DWI, these values were 0.77 (0.71-0.82), 0.78 (0.69-0.85), 3 (2-5), 0.30 (0.22-0.40), 12 (6-21), 0.83 (0.79-0.86) and 0.72 (0.60-0.81), 0.84 (0.77-0.89), 5 (3-7), 0.34 (0.23-0.50), 13 (6-29), and 0.86 (0.83-0.89), respectively. A z test demonstrated that MRE had a significantly higher accuracy than DWI in those indicators (P < 0.05). CONCLUSION: MRE is more reliable for staging hepatic fibrosis, compared with DWI, with a high combination of sensitivity, specificity, likelihood ratios, DOR, and area under sROC curve.

Appendiceal mucocele: A diagnostic dilemma in differentiating malignant from benign lesions with CT.

OBJECTIVE: The purpose of this study was to assess the feasibility of using CT to differentiate malignant from benign lesions in patients with pathologically confirmed appendiceal mucoceles. MATERIALS AND METHODS: CT scans of 18 consecutively registered patients (11 men, seven women; age range, 21-78 years) with pathologically confirmed appendiceal mucocele were reviewed retrospectively. Patients were classified into three groups according to pathologic results: nonneoplastic mucocele (n = 3), mucinous cystadenoma (n = 10), and mucinous cystadenocarcinoma (n = 5). The nonneoplastic and mucinous cystadenoma groups were formed into a benign group, and the mucinous cystadenocarcinoma constituted the malignant group. Two experienced radiologists working in consensus assessed the shape, short diameter, density, contour, and wall thickness of the masses. The presence of calcifications, internal septations, soft-tissue thickening, periappendiceal fat stranding, intraperitoneal free fluid and pseudomyxoma peritonei were also evaluated. The CT results were compared for malignant and benign appendiceal mucoceles. RESULTS: CT showed statistically significant differences in wall irregularity and soft-tissue thickening between malignant and benign cases (p < 0.05). Short diameter of mucoceles, attenuation of intraluminal contents, maximal wall thickness, calcifications, internal septations, periappendiceal fat stranding, intraperitoneal free fluid, and pseudomyxoma peritonei in the lesions did not differ significantly between the benign and malignant groups (p > 0.05). CONCLUSION: Differentiating malignant from benign mucoceles can be difficult with CT. Irregular walls and soft-tissue thickening are features most likely to be associated with malignancy.

Purification, structural characterization, and anticoagulant activity evaluation of chondroitin sulfate from codfish (Gadus macrocephalus) bones.

Chondroitin sulfate (CCS) was purified from discarded codfish (Gadus macrocephalus) bones, and its chemical structure and anticoagulant activity were assessed. CCS was obtained via enzymatic lysis and ion-exchange column chromatography, with a yield of approximately 0.15%. High-performance gel performance chromatography revealed CCS to be a largely homogeneous polysaccharide with a relatively low molecular weight of 12.3 kDa. FT-IR spectroscopy, NMR spectroscopy, and SAX-HPLC indicated that CCS was composed of monosulfated disaccharides (ΔDi4S 73.85% and ΔDi6S 19.06%) and nonsulfated disaccharides (ΔDi0S 7.09%). In vitro anticoagulation analyses revealed that CCS was able to significantly prolong activated partial thromboplastin time (APTT) and thrombin time (TT) (p < 0.05). At a CCS concentration of 5 µg/mL and 25 µg/mL, APTT and TT were approximately 1.08 and 1.12 times higher, respectively, compared to the negative control group. The results indicated that CCS might offer value as a dietary fiber supplement with the potential to prevent the incidence of coagulation-related thrombosis.

MR Imaging of activated hepatic stellate cells in liver injured by CCl4 of rats with integrin-targeted ultrasmall superparamagnetic iron oxide.

OBJECTIVE: To demonstrate the feasibility of the ultrasmall superparamagnetic iron oxide (USPIO) modified by cyclo (Arg-Gly-Asp-Try-Cys) peptide (c(RGDyC)-USPIO) for targeting hepatic stellate cells (HSCs). MATERIALS AND METHODS: A c(RGDyC)-USPIO probe was prepared by conjugating c(RGDyC) with USPIO through a thiol-maleinide interaction. The specificity of c(RGDyC)-USPIO for HSCs was investigated in vitro. In vivo, normal and fibrosis rats were treated with either c(RGDyC)-USPIO or USPIO, and magnetic resonance imaging (MRI) of the rats performed after administration of the probes for 4 h. The T2 relaxation times changes before and after probe injection were analyzed and the locations of probes in normal or injured mice were identified histologically. RESULTS: The hydrodynamic size of c(RGDyC)-USPIO was 13 ± 3 nm. HSCs took up more specific probes than plain ones. The reduction of T2 relaxation times in fibrosis rat by c(RGDyC)-USPIO was much greater than that by USPIO (P < 0.05). Prussian blue staining and transmission electron microscopy of the injured rat liver treated with c(RGDyC) demonstrated that c(RGDyC)-USPIO were specifically engulfed by the activated HSCs. CONCLUSION: In vivo cellular targeted imaging of activated HSCs in liver fibrosis using c(RGDyC)-USPIO targeting α(v)ß(3) integrins was feasible using a clinical 1.5-Tesla MR system.

OX40 agonist combined with irreversible electroporation synergistically eradicates established tumors and drives systemic antitumor immune response in a syngeneic pancreatic cancer model.

In this study, we intended to explore a novel combination treatment scheme for pancreatic cancer, using irreversible electroporation (IRE) and OX40 agonist. We further aimed to investigate the capacity and mechanism of this combination treatment using an in vivo mouse aggressive pancreatic cancer model. To this end, mice subcutaneously injected with KPC1199 pancreatic tumor cells were treated with IRE, followed by intraperitoneal injection of OX40 agonist. Tumor growth and animal survival were observed. Flow cytometry analysis, immunohistochemistry, and immunofluorescence were used to evaluate the immune cell populations within the tumors. The tumor-specific immunity was assessed using ELISpot assay. Besides, the cytokine patterns both in serum and tumors were identified using Luminex assay. After combination therapy with IRE and OX40 agonist, 80% of the mice completely eradicated the established subcutaneous tumors, during the 120 days observation period. Rechallenging these tumor-free mice at day 120 with KPC1199 tumor cells leads to complete resistance to tumor growth, suggesting that the combination therapy generated long-term-specific antitumor immune memory. Moreover, combination therapy significantly delayed the growth of contralateral untreated tumors, and significantly prolonged animal survival, suggesting that a potent systematic anti-tumor immunity was induced by combination therapy. Mechanically, combination therapy amplified antitumor immune response induced by IRE, as manifested by the increased quality and quantity of CD8+ T cells trigged by IRE. Together, these results provide strong evidence for the clinical assessment of the combination of IRE and OX40 agonist in patients with pancreatic cancer.

[Characteristics of nitrogen transportation in Castanea mollissima forest around the Fushi Reservoir watershed in north Zhejiang Province, China.] / æµ™æ±Ÿèµ‹çŸ³æ°´åº“é›†æ°´åŒºæ¿æ —æž—åœŸå£¤æ°®ç´ è¿ç§»ç‰¹å¾.

In this study, through setting runoff plots in Chinese chestnut (Castanea mollissima) fo-rest, the runoff water samples were collected and tested from January to October, 2013. Combining with soil nitrogen data before and after the rainy season, we analyzed the characteristics of soil nitrogen transportation in chestnut forest around the Fushi Reservoir watershed in north Zhejiang Pro-vince, China. The results showed that among the 10 surface runoff events of Chinese chestnut fo-rest, there exhibited a significant difference in runoff water volume of each runoff plot, and the maximum amount was 0.51 m3. Nitrogen was the major element associated with nutrient loss in the study region. The concentrations of nitrate nitrogen (NO3--N), ammonium nitrogen (NH4+-N), total nitrogen (TN) andchemical oxygen demend (CODMn) in the runoff water ranged from 0.02-1.87, 0.04-3.53, 1.69-5.33 and 5.30-14.07 mg·L-1, respectively. The water quality indexes were greatly affected by the runoff volume, and the relationship between the amount of nitrogen loss and runoff could be well fitted by using a linear equation. The difference in nitrogen contents of the soil in the upper, middle and lower part of the runoff plots was evident both before and after the rainy season. Moreover, the nitrogen content increased with the increasing altitude, but this trend decreased with increasing soil depth. Comparison of the difference between the four forms of soil nitrogen (NO3--N, NH4+-N, TN and hydrolyzable nitrogen Hydro-N of soil) before and after the rainy season showed that there existed significant differences in Hydro-N and TN, and the average diffe-rence values were 20.21 and 307.49 mg·kg-1, respectively. In this area, there was a great risk of nitrogen loss with runoff, and the potential non-point source pollution in Fushi Reservoir should be concerned.

[Roles of endothelin and its receptors in prostate cancer].

Endothelin (ET) is a peptide released by vascular endothelial cells. Except for the potent vasoconstrictor function it plays an important physiological role in tissue differentiation and development, cell proliferation and hormone production. Investigation of the role of ET axis in a variety of tumors such as prostatic, cervical, breast carcinoma has provided evidences of its importance in cancer, recently. Data suggest that multiple functions of the ET axis have associations with mitogenesis, apoptosis inhibition, angiogenesis, and activation of proto-oncogene. The ET axis relates to invasiveness, osteoblast function, and metastatic cancer pain in advanced prostate cancer.

Upper gastrointestinal tract heterotopic pancreas: findings from CT and endoscopic imaging with histopathologic correlation.

OBJECTIVE: To evaluate and describe computed tomographic (CT) and endoscopic (ES) imaging findings in patients with pathologically confirmed upper gastrointestinal (GI) tract heterotopic pancreas (HP). METHODS: Findings from imaging examinations in 11 patients with pathologically confirmed HP were retrospectively reviewed (CT images obtained from 11 patients and ES images from 6 patients were available for review). Two radiologists evaluated lesion location, size, shape and border as well as growth pattern, enhancement pattern, enhancement grade and number of tumors. The presence of surface dimpling, prominent enhancement of overlying mucosa, and low intralesional attenuation were also evaluated. RESULTS: HP in the upper GI tract showed typical features in CT imaging: submucosal masses, ill-defined borders, endoluminal growth patterns, bright enhancement similar to the normal pancreas, surface dimpling and low intralesional attenuation. Endoscopic photographs manifested an endoluminal, ill-defined, submucosal mass in the upper GI tract wall, typically with central umbilication. The LD (long diameter)/SD (short diameter) ratios were found to be significantly different between HP in the stomach and HP in the duodenum (P<.05 for each finding). In addition, HP in the duodenum tended to be small and round. CONCLUSIONS: HP exhibits typical pancreatic pathologic features. Images showed characteristic features in CT imaging: submucosal masses, ill-defined lesions with an endoluminal growth pattern, bright enhancement similar to the normal pancreas, surface dimpling and low intralesional attenuation. ES imaging showed an endoluminal, ill-defined, submucosal mass, typically with central umbilication.

Imaging features of solid pseudopapillary tumor of the pancreas on multi-detector row computed tomography.

AIM: To retrospectively analyze the imaging features of solid-pseudopapillary tumors (SPTs) of the pancreas on multi-detector row computed tomography (MDCT) and define the imaging findings suggestive of malignant potential. METHODS: A total of 24 consecutive cases with surgically and pathologically confirmed SPTs of the pancreas underwent preoperative abdominal MDCT studies in our hospital. All axial CT images, CT angiographic images, and coronally and sagittally reformed images were obtained. The images were retrospectively reviewed at interactive picture archiving and communication system workstations. RESULTS: Of the 24 cases of SPTs, 11 cases (45.8%) occurred in the pancreatic head and seven (29.1%) in the tail. Eighteen were pathologically diagnosed as benign and six as malignant. MDCT diagnosis of SPTs was well correlated with the surgical and pathological results (Kappa = 0.6, P < 0.05). The size of SPTs ranged from 3 to 15 cm (mean, 5.8 cm). When the size of the tumor was greater than 6 cm (including 6 cm), the possibilities of vascular (8 vs 1) and capsular invasion (9 vs 0) increased significantly (P < 0.05). Two pathologically benign cases with vascular invasion and disrupted capsule on MDCT presented with local recurrence and hepatic metastases during follow-up about 1 year after the resection of the primary tumors. CONCLUSION: Vascular and capsular invasion with superimposed spread into the adjacent pancreatic parenchyma and nearby structures in SPTs of the pancreas can be accurately revealed by MDCT preoperatively. These imaging findings are predictive of the malignant potential associated with the aggressive behavior of the tumor, even in the pathologically benign cases.

Imaging features of intraductal papillary mucinous neoplasms of the pancreas in multi-detector row computed tomography.

AIM: To retrospectively evaluate the imaging features of pancreatic intraductal papillary mucinous neoplasms (IPMNs) in multi-detector row computed tomography (MDCT). METHODS: A total of 20 patients with pathologically-confirmed intraductal papillary mucinous neoplasms (IPMNs) were included in this study. Axial MDCT images combined with CT angiography (CTA) and multiplanar volume reformations (MPVR) or curved reformations (CR) were preoperatively acquired. Two radiologists (Tan L and Wang DB) reviewed all the images in consensus using an interactive picture archiving and communication system. The disputes in readings were resolved through consultation with a third experienced radiologist (Chen KM). Finally, the findings and diagnoses were compared with the pathologic results. RESULTS: The pathological study revealed 12 malignant IPMNs and eight benign IPMNs. The diameters of the cystic lesions and main pancreatic ducts (MPDs) were significantly larger in malignant IPMNs compared with those of the benign IPMNs (P < 0.05). The combined-type IPMNs had a higher rate of malignancy than the other two types of IPMNs (P < 0.05). Tumors with mural nodules and thick septa had a significantly higher incidence of malignancy than tumors without these features (P < 0.05). Communication of side-branch IPMNs with the MPD was present in nine cases at pathologic examination. Seven of them were identified from CTA and MPVR or CR images. From comparison with the pathological diagnosis, the sensitivity, specificity, and accuracy of MDCT in characterizing the malignancy of IPMN of the pancreas were determined to be 100%, 87.5% and 95%, respectively. CONCLUSION: MDCT with CTA and MPVR or CR techniques can elucidate the imaging features of IPMNs and help predict the malignancy of these tumors.