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.

Identification of IL-7 as a candidate disease mediator in osteoarthritis in Chinese Han population: a case-control study.

OBJECTIVES: Little is known about the biochemical mediators IL-7 that correlate with the initiation and progression of OA. We performed this study to assess the role of variants of IL-7 in OA susceptibility in the Chinese Han population. METHODS: We performed a retrospective, case-control study in the Chinese Han population from 2013 to 2015. Four single nucleotide polymorphisms were genotyped (using a ligase detection reaction) in 602 patients and 454 controls. Differences between groups were analysed, and association was assessed by the odds ratio (OR) and 95% CI. RESULTS: Among these polymorphisms, rs2583764, rs2583760 and rs6993386 showed no significant association with OA in the Chinese Han population {rs2583764 [P-allele = 0.98651, P-genotype = 0.40392, OR (95% CI): 1.00162 (0.83066, 1.20775)]; rs2583760 [P-allele = 0.384500, P-genotype = 0.58752, OR (95% CI): 0.69859 (0.30996, 1.57449)]; rs6993386 [P-allele = 0.69525, P-genotype = 0.50712, OR (95% CI): 0.96432 (0.80406, 1.15653)]}. However, the results showed that the rs2583759 polymorphism was significantly associated with OA [P-allele = 0.00 P-genotype = 3.86 × 10(-30), OR (95% CI): 0.27794 (0.22407, 0.34476)], even when the 10 000 times permutation was performed (P-allele-permutation < 0.00010, P-genotype-permutation = 0.00010). Haplotype analyses showed A-G-A-C, A-G-A-T and G-G-G-C of rs2583764-rs2583760-rs6993386-rs2583759 were risk factors for OA, both before or after the 10 000 times permutation, indicating IL-7 to be associated with OA. CONCLUSION: There was a significant association between IL-7, especially rs2583759, and OA in the Chinese Han population.

NLRP3 gene is associated with ulcerative colitis (UC), but not Crohn's disease (CD), in Chinese Han population.

OBJECTIVE: This study aimed to investigate whether NLRP3 is associated with IBD in Chinese Han population. METHODS: Three SNPs were genotyped using polymerase chain reaction with sequence-specific primers in 288 patients [232 Crohn's disease (CD) patients, 56 ulcerative colitis (UC) patients] and 274 controls. RESULTS: In IBD group, the results showed no significant association. When subdivided to CD and UC, it showed in CD subgroup, there was no significant association. However, in UC subgroup, rs10754558 (P allele=0.015272, P genotype=0.029776, OR [95% CI]=0.604190[0.401200-0.909886]) and rs10925019 (P allele=0.013042, P genotype=0.037045, OR [95% CI]=2.022613[1.149854-3.557812]) have significant associations with UC. The G and T alleles were risk factors of the susceptibility of UC, the GG and TT genotypes may increase risk of this disease. Rs4925648 has no association with UC. The haplotypes analysis results showed as follow: for rs4925648-rs10925019, CC and TT are risk factors for UC (for CC, χ2=3.605, P=0.057613, OR [95% CI]=1.645 [0.980-2.761], for TT, χ2=5.522, P=0.018804, OR [95% CI]=0.426[0.205-0.884]), and for rs10754558-rs10925019, CT and GC haplotypes are risk factors for UC (for CT, χ2=3.545, P=0.059739, OR [95% CI]=0.571[0.317-1.029], for GC, χ2=9.359, P=0.002228, OR [95% CI]=1.904 [1.255-2.887]). CONCLUSIONS: We first demonstrated that rs10754558 and rs10925019 are significantly associated with the susceptibility of UC, but not CD in Chinese Han population, suggesting that NLRP3 may play an important role in the pathogenesis of UC.

Clinical significance of RECK promoter methylation in pancreatic ductal adenocarcinoma.

The aim of this study was to analyze the clinical significance of reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) promoter methylation in pancreatic ductal adenocarcinoma (PDA). Methylation-specific polymerase chain reaction was used to examine the promoter methylation status of RECK in 60 pairs of PDA tissue samples and adjacent non-cancerous tissue samples. Statistical analyses were applied to test the associations between RECK promoter methylation status, clinicopathologic factors, and prognosis. The rate of RECK promoter methylation was significantly higher in PDA tissues than in adjacent non-cancerous tissues (P < 0.001). RECK methylation status was significantly associated with clinical stage (P = 0.017), histological differentiation (P = 0.046), and lymph node metastasis (P = 0.003), but was not associated with gender, age, and tumor location (all P > 0.05). Additionally, RECK promoter methylation is associated with malignant behavior and poor prognosis. In conclusion, determination of RECK promoter methylation status in tumor tissues may assist in the identification of patients who require aggressive postoperative intervention in order to improve prognosis.

PIWIL1 interacting RNA piR-017061 inhibits pancreatic cancer growth via regulating EFNA5.

PIWI (P element induced wimpy testis) integrating RNAs (piRNAs) are small non-coding RNAs with the length of approximately 30 nucleotides that plays crucial roles in germ cells and adult stem cells. Recently, accumulating data have shown that piRNA and PIWI proteins are involved in tumorigenesis. However, the roles of PIWI proteins and piRNAs in pancreatic cancer are still elusive. Here, we showed that piR-017061 is significantly downregulated in pancreatic cancer patients' samples and pancreatic cancer cell lines. Furthermore, we studied the function of piR-017061 in pancreatic cancer and our data revealed that piR-017061 inhibits pancreatic cancer cell growth in vitro and in vivo. Moreover, we analyzed the genomic loci around piR-017061 and identified EFNA5 as a novel target of piR-017061. Importantly, our data further revealed a direct binding between piR-017061 and EFNA5 mRNA mediated by PIWIL1. Mechanically, piR-017061 cooperates with PIWIL1 to facilitate EFNA5 mRNA degradation and loss of piR-017061 results in accumulation of EFNA5 which facilitates pancreatic cancer development. Hence, our data provided novel insights into PIWI/piRNA-mediated gene regulation and their function in pancreatic cancer. Since PIWI proteins and piRNA predominately express in germline and cancer cells, our study provided novel therapeutic strategy for pancreatic cancer treatment.

Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: sensitivity and trim and fill studies.

OBJECTIVE: This study carried out sensitivity analysis and trim-fill analysis between bisphosphonates and subtrochanteric, femoral shaft, and atypical femur fracture. METHODS: A random-effects model was used finally. Sensitivity, trim and fill, and publication bias analyses were done. RESULTS: Under a random-effects model (I(2)=87.535), the Z-value=5.672, p-value of test of null<0.001. Bisphosphonate exposure was associated with an increased risk of atypical femur fracture (3.243 [95% CI 2.160-4.870]). When any study is removed, the remaining sensitivity analysis results are still significant. Trim and fill results show that two studies were missed. After filling them, a funnel plot of precision by log risk ratio was more symmetrical. CONCLUSION: This study suggests that (1) there is an increased risk of subtrochanteric, femoral shaft, and atypical femur fracture in bisphosphonate users; (2) any single study does not influence the total sensitivity; (3) two studies have been lost, theoretically.