Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 is known to inhibit cancer cell growth both in vitro and in vivo . However, whether SHP099-mediated SHP2 inhibition retards tumor growth in vivo via anti-tumor immunity remains elusive. To address this, a CT-26 colon cancer xenograft model was established in mice since this cell line is insensitive to SHP099. Consequently, SHP099 minimally affected CT-26 tumor growth in immuno-deficient nude mice, but significantly decreased the tumor burden in CT-26 tumor-bearing mice with intact immune system. SHP099 augmented anti-tumor immunity, as shown by the elevated proportion of CD8 + IFN- γ + T cells and the upregulation of cytotoxic T-cell related genes including Granzyme B andPerforin , which decreased the tumor load. In addition, tumor growth in mice with SHP2-deficient T-cells was markedly slowed down because of enhanced anti-tumor responses. Finally, the combination of SHP099 and anti-PD-1 antibody showed a higher therapeutic efficacy than either monotherapy in controlling tumor growth in two colon cancer xenograft models, indicating that these agents complement each other. Our study suggests that SHP2 inhibitor SHP099 is a promising candidate drug for cancer immunotherapy.

BackgroundRecent guidelines on iron deficiency anaemia (IDA) have confirmed the aetiological role of Helicobacter pylori (H pylori), but the relationship still remains controversial.MethodsStarting in May 2009, searches of the following databases were undertaken: Medline (1966 to April 2009), Embase (1980 to April 2009), the Cochrane library (1800 to June 2008), Cochrane Central Register of Controlled Trials, Premedline, Healthstar, CBMdisc and the Chinese National Knowledge Infrastructure Database (January 1970 to April 2009). Changes in haemoglobin (Hb) concentrations and serum ferritin (SF) concentrations were recorded for intervention and control groups. The meta-analysis used random effect models and subgroup analyses were performed to explain heterogeneity.ResultsEight studies met the inclusion criteria. All studies were performed in Asia, an area with a high incidence of IDA and H pylori. The pooled analysis of eight studies showed that H pylori eradication therapy can improve IDA, since changes in Hb and SF concentrations in the intervention groups were higher than in controls. The weighted mean difference (WMD) of Hb was 12.88 g/l (95% CI 6.03 to 19.74 g/l, p<0.00001); the WMD of SF was 10.05 μg/l (95% CI 5.48 to 14.63 μg/l, p<0.00001).ConclusionsH pylori eradication therapy combined with iron administration is more effective than iron administration alone for the treatment of IDA. Eradication therapy has different effects on adults and children. Bismuth based triple therapy has a better response in terms of increased Hb and SF concentrations than proton pump inhibitor (PPI) based triple therapy.

Visceral pain secondary to pancreatic cancer is often difficult to control and poses a challenge to the physician. We retrospectively analyzed the efficacy and safety of endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) in patients with unresectable pancreatic cancer. Forty-one patients with severe pain despite treatment with opioids underwent EUS-CPN with absolute alcohol. Patients scored their pain on a scale of 0 to 10 and were interviewed after the procedure. Of the 41 patients, 33, 37, and 25 patients reported improvement in their pain within 3 days, at 1 week, and at 3 months, respectively, following the procedure. Of all the patients, 19 patients reported substantial improvement and 4 patients showed complete disappearance of pain. Complication appeared in 2 patients with transient hypotension. In our study, EUS-CPN is a safe and effective form of treatment for intractable pain secondary to advanced pancreatic cancer.

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Germline pathogenic TERT variants are associated with short telomeres and an increased risk of developing myelodysplastic syndrome (MDS) among patients with a telomere biology disorder. We identified TERT rare variants in 41 of 1514 MDS patients (2.7%) without a clinical diagnosis of a telomere biology disorder who underwent allogeneic transplantation. Patients with a TERT rare variant had shorter telomere length (p&lt;0.001) and younger age at MDS diagnosis (52 vs. 59 years, p=0.03) than patients without a TERT rare variant. In multivariable models, TERT rare variants were associated with inferior overall survival (p=0.034) driven by an increased incidence of non-relapse mortality (NRM) (p=0.015). Death from a non-infectious pulmonary cause was more frequent among patients with a TERT rare variant. The majority of variants were missense substitutions and classified as variants of unknown significance (VUS). Therefore, we cloned all rare missense variants and quantified their impact on telomere elongation in a cell-based assay. We found that 90 percent of TERT rare variants had severe or intermediate impairment in their capacity to elongate telomeres. Using a homology model of human TERT bound to the shelterin protein TPP1, we inferred that TERT rare variants disrupt domain-specific functions, including catalysis, protein-RNA interactions, and recruitment to telomeres. Our results indicate that the contribution of TERT rare variants to MDS pathogenesis and NRM risk is underrecognized. Routine screening for TERT rare variants in MDS patients regardless of age or clinical suspicion may identify clinically inapparent telomere biology disorders and improve transplant outcomes through risk-adapted approaches.

Elevated lead absorptions are hazardous factors in lead-related workers. Previous studies have found its toxic impacts on nervous, circulatory, and metabolic systems. We hypothesized that alteration of miRNAs profile in plasma was closely associated with lead exposure. We analyzed to identify lead-related miRNAs in workers occupationally exposed to lead. Microarray assay was performed to detect plasma miRNA between workers with high and minimal lead exposure in the discovery stage. The following prediction of miRNAs’ candidate target genes was carried out by using miRecords, STRING, and KEGG databases. We finally identified four miRNAs significantly associated with high level of blood lead. miR-520c-3p (*P=0.014), miR-211 (*P=0.019), and miR-148a (*P=0.031) were downexpressed in workers with high lead exposure and with high blood lead level (BLL), while miR-572(*P=0.027) displayed an opposite profile. Functional analysis of miRNAs displayed that these miRNAs could trigger different cellular genes and pathways. People under chronic lead exposure had a diverse ‘fingerprint’ plasma miRNA profile. Our study suggested that miR-520c-3p, miR-211, miR-148a, and miR-572 were the potential biomarkers for lead susceptibility in Chinese.

Background: Few studies have explored the relationship between clinicopathological factors of patients with pancreatic ductal adenocarcinoma (PDAC) and liver metastasis. The aim of this study was to develop and validate a nomogram to predict liver metastasis in patients with PDAC. Patients and methods: Patients diagnosed with PDAC between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively collected. The nomogram was established based on a logistic regression model. The precision of the nomogram was evaluated and compared using concordance index (C-index), and the area under receiver operating characteristic curve (AUC). The clinical use of nomogram was evaluated by making use of a decision curve analysis (DCA). Results: A total of 12,644 eligible patients, which were randomly divided into training (n=9,483) and validation cohorts (n=3,161), were included in this study. The nomograms, which were established on the basis of independent predictors, were well calibrated, and demonstrated good discriminative ability, with C-indexes of 0.784 for the training cohort and 0.790 for validation cohort. The values of AUC for training and validation cohort were 0.792 and 0.800, respectively. When other sites of distant metastases were included into this predictive system, the new predictive model demonstrated a better discriminative ability and greater net benefit in predicting liver metastasis in patients with PDAC in both the training and validation cohorts. Conclusion: Nomograms were constructed to predict liver metastasis in patients with PDAC. Validation revealed excellent discrimination and calibration of the nomograms, suggesting that the nomograms were well calibrated and could serve to improve the prediction of the risks of liver metastasis which can be used to guide the management of patients with PDAC.

Germline pathogenic TERT variants are associated with short telomeres and a heightened risk of developing myelodysplastic syndrome (MDS) among patients with dyskeratosis congenita. The prevalence and clinical significance of TERT variants in MDS patients undergoing allogeneic stem cell transplant is unknown. We identified TERT rare variants in 41 of 1514 MDS patients (2.7%) with genetic and clinical characteristics consistent with a germline origin. TERT rare variants occurred in all structural domains and were associated with shorter telomere length (p<0.001) and younger age at MDS diagnosis (p=0.04). No patients with a TERT rare variant had a known telomere biology disorder. In multivariable analyses, TERT rare variants were associated with inferior overall survival (p=0.034) driven by an increased incidence of non-relapse mortality (NRM) (p=0.015). Deaths from non-infectious pulmonary causes were more frequent in patients with a TERT rare variant. Across all major structural domains, TERT rare variants demonstrated impaired capacity to elongate telomeres in a cell-based assay. Using a homology model of human TERT bound to the shelterin protein TPP1, we inferred that TERT rare variants likely disrupt domain-specific functions. Our results indicate that the contribution of TERT rare variants to MDS pathogenesis and NRM risk is underrecognized. Systematic screening for TERT rare variants in MDS patients regardless of age or clinical suspicion could identify clinically inapparent telomere biology disorders and improve transplant outcomes through risk-adapted approaches. Cell-based functional characterization of TERT rare variants may facilitate TERT-specific variant classifications guidelines with broad clinical applicability.