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Methylated DNA in fluids may be a suitable biomarker for cancer patients. XAF1 has been shown to be frequently down-regulated in human gastric cancer (GC). Here, we investigated if XAF1 methylation in GC could be a useful biomarker. Real-time RT-PCR was used to detect XAF1 mRNA expression; immunohistochemistry and western blot were used to examine XAF1 protein expression in GC tissues (n = 202) and their corresponding para-cancerous histological normal tissues (PCHNTs). Real-time methylation specific-PCR was used to investigate XAF1 promoter methylation in the same panel of GC tissues, their PCHNTs and sera. We confirmed frequent XAF1 down-regulation in both mRNA and protein levels in GC tissues as compared to normal controls and PCHNTs. XAF1 hypermethylation was evidenced in 83.2% (168/202) of GC tissues and 27.2% (55/202) of PCHNTs, while no methylation was detected in the 88 normal controls. The methylation level in GC tissues was significantly higher than that in PCHNTs (p<0.05). The hypermethylation of XAF1 significantly correlated with the down-regulation of XAF1 in GC tissues in both mRNA and protein levels (p<0.001 each). Moreover, we detected high frequency of XAF1 methylation (69.8%, 141 out of 202) in the sera DNAs from the same patients, while the sera DNAs from 88 non-tumor controls were negative for XAF1 methylation. The XAF1 methylation in both GC tissues and in the sera could be a good biomarker for diagnosis of GC (AUC = 0.85 for tissue and AUC = 0.91 for sera) and significantly correlated with poorer prognosis (p<0.001). In addition, after-surgery negative-to-positive transition of XAF1 methylation in sera strongly associated with tumor recurrence. 1) Dysfunction of XAF1 is frequent and is regulated through XAF1 promoter hypermethylation; 2) Detection of circulating methylated XAF1 DNAs in the serum may be a useful biomarker in diagnosis, evaluating patient's outcome (prognosis and recurrence) for GC patients.

Background Targeted therapy combined with immune checkpoint inhibitors is considered a promising treatment for primary advanced hepatocellular carcinoma (HCC). Nevertheless, the difference between synchronous and asynchronous treatment of lenvatinib with programmed death receptor‐1 (PD‐1) inhibitor in advanced HCC is still unclear. The aim of this investigation is to evaluate the effectiveness of synchronous and asynchronous of lenvatinib and PD‐1 inhibitor on the advanced HCC beyond oligometastasis. Methods In this study, 213 patients from four institutions in China were involved. Patients were split into two collections: (1) lenvatinib plus PD‐1 inhibitor were used synchronously (synchronous treatment group); (2) patients in asynchronous treatment group received PD‐1 inhibitor after 3 months of lenvatinib treatment prior to tumour progression. To analyse progression‐free survival (PFS), overall survival (OS), efficacy and safety of patients in both groups, we employed propensity score matching (PSM). Results The 6‐, 12‐ and 24‐month OS rates were 100%, 93.4% and 58.1% in the synchronous treatment group and 100%, 71.5% and 25.3% in the asynchronous treatment group, respectively. In contrast to the asynchronous treatment group, the group treated synchronously exhibited a substantially enhanced OS (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.30–0.66; p < .001). The 6‐, 12‐ and 18‐month PFS rates were 82.6%, 42.6% and 10.8% in the synchronous treatment group and 63.3%, 14.2% and 0% in the asynchronous treatment group, respectively. A significant difference was observed in the PFS rate (HR, 0.46; 95% CI, 0.33–0.63; p < .001) between the two collections. Conclusions Patients with advanced HCC beyond oligometastasis, simultaneous administration of lenvatinib and PD‐1 inhibitor led to significant improvements in survival. The treatment of advanced hepatocellular carcinoma still faces many challenges. Lenvatinib combined with programmed death receptor‐1 (PD‐1) inhibitor is a promising treatment for advanced hepatocellular carcinoma. Synchronous combination of lenvatinib with PD‐1 inhibitor resulted in significant survival improvements in patients with advanced hepatocellular carcinoma.

Background Motivated by the first mathematical model for schistosomiasis proposed by Macdonald and Barbour’s classical schistosomiasis model tracking the dynamics of infected human population and infected snail hosts in a community, in our previous study, we incorporated seasonal fluctuations into Barbour’s model, but ignored the effect of bovine reservoir host in the transmission of schistosomiasis. Inspired by the findings from our previous work, the model was further improved by integrating two definitive hosts (human and bovine) and seasonal fluctuations, so as to understand the transmission dynamics of schistosomiasis japonica and evaluate the ongoing control measures in Liaonan village, Xingzi County, Jiangxi Province. Methods The basic reproductive ratio R 0 and its computation formulae were derived by using the operator theory in functional analysis and the monodromy matrix theory. The mathematical methods for global dynamics of periodic systems were used in order to show that R 0 serves as a threshold value that determines whether there was disease outbreak or not. The parameter fitting and the ratio calculation were performed with surveillance data obtained from the village of Liaonan using numerical simulation. Sensitivity analysis was carried out in order to understand the impact of R 0 on seasonal fluctuations and snail host control. The modified basic reproductive ratios were compared with known results to illustrate the infection risk. Results The Barbour’s two-host model with seasonal fluctuations was proposed. The implicit expression of R 0 for the model was given by the spectral radius of next infection operator. The R 0 s for the model ranged between 1.030 and 1.097 from 2003 to 2010 in the village of Liaonan, Xingzi County, China, with 1.097 recorded as the maximum value in 2005 but declined dramatically afterwards. In addition, we proved that the disease goes into extinction when R 0 is less than one and persists when R 0 is greater than one. Comparisons of the different improved models were also made. Conclusions Based on the mechanism and characteristics of schistosomiasis transmission, Barbour’s model was improved by considering seasonality. The implicit formula of R 0 for the model and its calculation were given. Theoretical results showed that R 0 gave a sharp threshold that determines whether the disease dies out or not. Simulations concluded that: (i) ignoring seasonality would overestimate the transmission risk of schistosomiasis, and (ii) mollusiciding is an effective control measure to curtail schistosomiasis transmission in Xingzi County when the removal rate of infected snails is small.

Aim RegIV , a member of the Regenerating (REG) gene family, may be a marker for the prediction of resistance to 5-fluorouracil (5-FU)-based chemotherapy. However, the relationship between the intrinsic drug resistance of gastric cancer (GC) cells to 5-FU used alone (single FU) or in multidrug therapeutic regimens (5-FU combinations) and RegIV expression has not been investigated. Methods The patient cohort comprised 45 patients with primary GC. The chemoresistance of GC cells to therapeutic regimens consisting of single 5-FU or FU combinations was investigated using the ATP-tumor chemosensitivity assay. The level of RegIV mRNA transcripts was determined by real-time reverse transcriptase-PCR. RegIV expression was evaluated as a novel predictive biomarker for the intrinsic drug resistance of primary GC cells to single 5-FU or 5-FU combinations. Results Upregulation of RegIV mRNA transcripts was observed in 36 of the 45 tumor specimens and was positively correlated with the invasive depth of the tumor cells ( p  = 0.000), the clinical stages ( p  = 0.000) and the in vitro intrinsic drug resistance of primary GC cells to 5-FU ( p  = 0.000) or 5-FU combinations. Conclusion RegIV mRNA transcript level was strongly associated with the intrinsic resistance of GC cells to single 5-FU or 5-FU combinations, suggesting that RegIV may play an important role in the intrinsic resistance of GC cells to 5-FU and that targeted therapy against the RegIV gene could be applied to overcome 5-FU resistance in the treatment of GC.

Recent studies have demonstrated that microRNAs (miRNAs/miRs) are involved in osteosarcoma tumorigenesis, progression, invasion and metastasis. For example, miR-505 plays important roles in human carcinogenesis; however, its exact function in osteosarcoma remains unclear. MicroRNA profiles of osteosarcoma and normal tissues were obtained by miRNA microarray assays, which were validated by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Then, high-mobility group box 1 (HMGB1) expression was evaluated by qRT-PCR and western blot analysis. The correlation between miR-505 and HMGB1 was analyzed by Pearson correlation. In vitro, the biological functions of miR-505 were examined by wound healing, MTT and Transwell assays and western blot analysis in MG63 cells transfected with miRNA mimics or empty vector. Luciferase assay was utilized to assess whether HMGB1 is a target of miR-505. miRNA microarrays revealed 26 aberrant miRNAs in osteosarcoma tissues; miR-505 showed the most pronounced decrease (P<0.01), which was significantly associated with TNM stage and metastasis status (P<0.05). In addition, HMGB1 was highly expressed in osteosarcoma tissues (P<0.01), with a significantly negative correlation with miR-505 (r=−0.6679, P<0.001). Furthermore, miR-505 inhibited proliferation, migration and invasion abilities of MG63 cells (P<0.01). Moreover, luciferase activity of the HMGB1-3′-UTR plasmid was suppressed following miR-505 binding (P<0.01). Finally, HMGB1 overexpression partly reversed the effects of miR-505 on MG63 cells. In conclusion, miR-505 levels are decreased in osteosarcoma tissues, and reduced miR-505 expression is significantly associated with poorer clinical prognosis in patients with osteosarcomas. miR-505 inhibits osteosarcoma cell proliferation, migration and invasion by regulating HMGB1.

The resolution of conventional terahertz (THz) imaging techniques is limited to about half wavelength, which is not fine enough for applications of biomedical sensing and nondestructive testing. To improve the resolution, a new superlens, constructed by a monolayer graphene sheet combining with a grating voltage gate, are proposed in this paper to achieve deep super-resolution imaging in the THz frequency range. The main idea is based on the Fabry-Perot resonance of graphene edge plasmon waves. By shaping the voltage gate into a radial pattern, magnified images of subwavelength targets can be obtained. With this approach, the finest resolution can achieve up to λ/150. Besides, the superlens can be conveniently tuned to work in a large frequency band ranging from 4.3 THz to 9 THz. The proposal could find potential applications in THz near-field imaging systems.

Fluid methylated DNA may be a suitable biomarker for cancer patients. To investigate whether circulating methylated tissue inhibitor of metalloproteinase 3 (TIMP-3) DNA in body fluids is a useful prognostic biomarker in gastric cancer (GC). TIMP-3 methylation was detected by real-time methylation-specific polymerase chain reaction in tumor tissues, paired preoperative peritoneal washes (PPWs), and paired serum samples from 92 GC patients. The frequency of TIMP-3 methylation was significantly elevated in GC tissues (63.04%; 58 of 92) compared with that in paired adjacent normal tissue (4.3%; 4 of 92) (P < .001). TIMP-3 methylation correlated closely with peritoneal metastasis and TNM stage (all P < .001). The frequency of TIMP-3 methylation in preoperative peritoneal washes and serum samples was 53.3% (49 of 92) and 58.7% (54 of 92), respectively. The Aζ values of the receiver operator characteristic curve for methylated TIMP-3 were 0.966 and 0.922 for serum and preoperative peritoneal washes, respectively, compared with those in GC tissues. The patients with elevated methylated TIMP-3 levels in body fluids had poorer disease-free survival rates than those without (all P < .001). Cox regression analysis showed that detection of methylated TIMP-3 DNA in body fluids was an independent risk factor for GC patients, with a remarkable decrease in disease-free survival 30 months after surgical resection of the gastric tumor. Presence of methylated TIMP-3 DNA in body fluids is a useful biomarker for predicting the progression and prognosis of GC patients.

Background and Aim Aberrant DNA methylation has been shown to be associated with the growth, development, metastasis, and prognosis of tumors. Methylated DNAs may be suitable biomarkers for cancer patients. Here, we investigated whether circulating methylated MINT2 DNAs represent a potential poor prognostic factor in gastric cancer (GC). Methods MINT2 methylation was detected by real-time methylation-specific PCR in tumor tissues, pairing preoperative peritoneal lavage fluid (PPLF) and blood from 92 GC patients. The theory meaning and clinical practicality value of MINT2 methylation in different specimens were analyzed. Results The methylation status of the MINT2 gene was found to be significantly higher in tumor tissues (44.6 %, 41/92) than in adjacent normal tissues (3.3 %, 3/92). No MINT2 methylation was found in healthy controls, and partial MINT2 methylation was observed in three (6.25 %, 3/48) patients with chronic atrophic gastritis. The frequency of MINT2 methylation in pairing PPLF and blood samples from 92 GC patients was 40.2 % (37/92) and 39.1 % (36/92), respectively. Methylated MINT2 in tumor tissues, pairing PPLF, and blood samples were very approximate. Aberrant MINT2 methylation in tumor tissues and pairing PPLF or blood samples were closely related to peritoneal dissemination, tumor progression, and poor prognosis (all P  < 0.0001). Conclusions Aberrant MINT2 methylation in PPLF/blood may predict peritoneal micrometastasis for GC patients, which is a potential poor prognostic factor in GC.

Natalizumab was approved by the FDA in 2008 for adult patients with moderately to severely active CD with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of TNF-α. The TYSABRI Outreach: Unified Commitment to Health (TOUCH®) Prescribing Program, Crohn's Disease: Investigating Natalizumab through Further Observational Research & Monitoring (CD INFORM), TYSABRI Global Observation Program In Safety (TYGRIS), and TYSABRI® Pregnancy Exposure Registry (TPER) are ongoing risk management activities designed to further evaluate the safety of natalizumab. This report summarizes recent data on natalizumab utilization and safety in patients with Crohn's disease (CD) and relapsing multiple sclerosis (MS).MethodsTOUCH® is a mandatory prescribing program for all patients, prescribers, pharmacies and infusion centers in the US using natalizumab. TOUCH® is designed to inform about the risk of progressive multifocal leukoencephalopathy (PML); warn against concurrent use with antineoplastic, immunosuppressant, or immunomodulating agents, and in patients who are immunocompromised; and promote early diagnosis of PML and timely discontinuation of natalizumab in the event of suspected PML. CD INFORM, a post-marketing commitment, collects patient history, efficacy as assessed by the Harvey Bradshaw Index (HBI), Health Related Quality of Life outcomes, and serious adverse events (SAE) in CD patients on natalizumab therapy. TYGRIS, also a post-marketing commitment, is evaluating the long-term safety of natalizumab in MS. Post-marketing surveillance data are also collected. TPER evaluates the outcomes of pregnancy in women with CD and MS exposed to natalizumab.ResultsAs of 30 June 2012, ˜104,300 patients have been exposed to natalizumab in the post-marketing setting (103,259 MS; 1,041 CD),. As of 01 August 2012, 271 cases of PML have been confirmed (270 MS, 1 CD). Of the 271 natalizumabtreated patients who developed PML, 212 (78%) had survived, exhibiting varying levels of disability and there were 59 (22%) deaths. Presence of anti-JCV antibodies, prior treatment with immunosuppressants and longer treatment duration with natalizumab, especially beyond 2 years, are identified risk factors for potential development of PML. As of 07 August 2012, 163 patients were enrolled in CD INFORM with the number of natalizumab infusions ranging from 1-56, with a mean and median of 14.6 and 10, respectively. The average HBI at time of entry for these patients was 8.2 (range 0 to 28). Of the 99 CD patients with an HBI assessment after receiving 6 months of natalizumab therapy, the average total score was 4.8, a mean decrease of 2.8 points from baseline. Cumulatively, as of 07 August 2012, there were 93 SAEs occurring in 51 patients reported in CD INFORM, 4 patients experienced 8 SAEs that were considered treatment related. As of 23 May 2012, 375 women (7 with CD) were prospectively enrolled in the TPER with372 outcomes reported, including 8 twin pregnancies resulting in 2 outcomes for each pregnancy. Current exposure and safety data from patients receiving natalizumab in both indications will be presented.Conclusion(s)Cumulative data from both indications suggest a safety profile consistent with natalizumab product labeling.