Gliomas are associated with high mortality because of their exceedingly invasive character. As these tumors acquire their invasiveness from low-grade tumors, it is very important to understand the ...detailed molecular mechanisms of invasion onset. Recent evidences suggest the significant role of microRNAs in tumor invasion. Thus, we hypothesized that deregulation of microRNAs may be important for the malignant progression of gliomas. We found that the aberrant expression of miR-21 is responsible for glioma invasion by disrupting the negative feedback circuit of Ras/MAPK signaling, which is mediated by Spry2. Upregulation of miR-21 was triggered by tumor microenvironmental factors such as hyaluronan and growth factors in glioma cells lacking functional phosphatase and tensin homolog (PTEN), but not harboring wild-type PTEN. Consistently with these in vitro results, Spry2 protein levels were significantly decreased in 79.7% of invasive WHO grade II-IV human glioma tissues, but not in non-invasive grade I and normal tissues. The Spry2 protein levels were not correlated with their mRNA levels, but inversely correlated with miR-21 levels. Taken together, these results suggest that the post-transcriptional regulation of Spry2 by miR-21 has an essential role on the malignant progression of human gliomas. Thus, Spry2 may be a novel therapeutic target for treating gliomas.
Summary
Background
Non‐alcoholic fatty liver disease (NAFLD) is associated with colorectal neoplasia. Yet, NAFLD ranges from simple steatosis to steatohepatitis with advanced fibrosis.
Aim
To ...investigate the risk of colorectal neoplasia according to the presence and severity of NAFLD.
Methods
A total of 26 540 asymptomatic adults who underwent same day first‐time colonoscopy and abdominal ultrasonography as a health check‐up programme were analysed. NAFLD was diagnosed by ultrasonography. Advanced colorectal neoplasia was defined as an invasive cancer or adenoma that was at least 10 mm in diameter, had high‐grade dysplasia, or had villous histological characteristics or any combination thereof.
Results
NAFLD patients had a higher prevalence of any colorectal neoplasia (38.0% vs. 28.9%) and advanced colorectal neoplasia (2.8% vs. 1.9%) compared to those without NAFLD. In a multivariable model adjusted for age, sex, smoking, alcohol, body mass index, first‐degree family history of colorectal cancer, aspirin use and metabolic factors, the odd ratios comparing patients with NAFLD to those without were 1.10 95% confidence interval (CI): 1.03–1.17 for any colorectal neoplasia and 1.21 (95% CI: 0.99–1.47) for advanced colorectal neoplasia. When NAFLD patients were further stratified according to the non‐invasive parameters of liver disease severity, the risk of any colorectal neoplasia or advanced colorectal neoplasia was higher for those with severe liver diseases than those with mild liver diseases.
Conclusions
The presence and severity of NAFLD were closely associated with any colorectal neoplasia and advanced colorectal neoplasia, suggesting that clinicians should be aware of the increased risk of colorectal neoplasia in patients with NAFLD.
Linked ContentThis article is linked to Ahn et al, and Kountouras et al papers. To view these articles visit https://doi.org/10.1111/apt.13911 and https://doi.org/10.1111/apt.13900.
A number of genes involved in tumorigenesis have been known to be controlled by signal transducer and activator of transcription 3 (STAT3) and NF-κB, either synergistically or individually. In ...starved cancer cells, we found that NF-κB was activated through endoplasmic reticulum stress signals, which depend on reactive oxygen species, cytosolic calcium and preserved translation of NF-κB p65 subunit, but independent of IκBα serine phosphorylation, thereby resulting in IL6 induction. STAT3 was required for proper induction of IL6 by NF-κB. They existed as identical nuclear complexes in proximal IL6 promoters, and STAT3 had critical roles in binding to IL6 promoters as well as nuclear retention of NF-κB. The conditioned media from starved cancer cells contained various secretory factors, such as IL6, IL9, VWF (von Willebrand factor), FREM1 (FRAS1 related extracellular matrix 1), SAA1 (serum amyloid A1), SDK1 (sidekick homolog 1) and ADAM12 (ADAM metallopeptidase domain 12), induced by NF-κB and STAT3 and promoted clonogenic capacities of cancer cells, and proliferation and migration of human umbilical vein endothelial cells. These results suggest novel survival strategies of cancer cells by which two oncogenic transcriptional factors, NF-κB and STAT3, are activated simultaneously by an intrinsic mechanism during stressful conditions of cancer cells, and they cooperatively induce various survival factors.
Epidermal growth factor receptor (EGFR) signalings have recently been implicated in the genesis and progression of cholangiocarcinomas. Thus, the EGFR kinase inhibitor appears to be promising in the ...treatment of this cancer. The response-predicting mutations in the tyrosine kinase domain of EGFR gene have recently been detected in non-small cell lung cancers. This study was, therefore, to investigate if these mutations are also found in cholangiocarcinomas.
Twenty-two consecutive cholangiocarcinoma patients who underwent surgical resection were enrolled. Their resected paraffin-embedded cholangiocarcinoma specimens were used for mutation analysis, which was performed by DNA sequencing of exons 18, 19 and 21 in the EGFR gene. Clinical characteristics were compared between each group according to the presence or absence of mutations.
Three patients (13.6%) harbored EGFR mutations. All the mutations found were deletions in exon 19. Mutations were more common in intra-hepatic or poorly differentiated tumors. Differences in age, sex, stage at diagnosis and survival were not observed between mutation-positive and -negative patients.
This study, for the first time, demonstrates that a subset of cholangiocarcinoma patients has response-predicting EGFR mutations. Therefore, a highly selected application of the EGFR kinase inhibitor would be therapeutically effective in these patients.
Single-center retrospective study.
To evaluate the monitoring rate, sensitivity and specificity of intraoperative monitoring (IOM) during removal of intradural extramedullary (IDEM) or epidural ...metastatic spinal tumors. Also, to assess the efficacy of monitoring somatosensory-evoked potentials (SSEP) when motor-evoked potentials (MEP) are not measurable.
The Neuro-Oncology Clinic, National Cancer Center, Korea.
Patients (n=101) with IDEM or epidural metastatic spinal tumors at the cord level underwent surgeries monitored with SSEP and/or MEP. The monitoring rate was defined as negative when MEP or SSEP could not be measured after reversal of the neuromuscular block under general anesthesia. Positive IOM changes included more than a 50% change in the MEP or SSEP amplitude and more than a 10% delay in SSEP latency.
MEP was measurable in 73% of patients. The MEP monitoring rate in patients with motor power grades of 3 or less was 39%, which was lower than that of SSEP (83%). The sensitivity, specificity and predictability of MEP for motor changes were 93, 90 and 91%, respectively. Conversely, the sensitivity, specificity and predictability of SSEP were 62, 97 and 89%, respectively. In patients in whom MEP was not measurable (n=24), SSEP was monitored with a predictability of 83%.
In cases of extramedullary spinal tumors, MEP shows a higher sensitivity than SSEP does. However, the monitoring rate of MEP in non-ambulatory patients was lower than that of SSEP. In those cases, SSEP can be useful to monitor for postoperative neurological deficits.
Abstract We conducted a risk factor analysis for high intraoperative blood loss (IBL) in 555 living donor liver transplantation (LDLT) cases with a simple and objective method of IBL estimation based ...on the concept of red cell mass (RCM): Lost RCM (mL) = patient's estimated blood volume (mL) × (preoperative hematocrit in % − postoperative hematocrit in %) + (transfused leukocyte-depleted red blood cell in units × 213 × 70%) + (transfused Cell Saver blood in mL × 55%). Analysis of 33 preoperative variables revealed that Model for End-stage Liver Disease (MELD) score, albumin, the presence of ascites, and previous abdominal surgery were correlated with high IBL (lost RCM > 1000 mL) in multivariate logistical regression analysis. In conclusion, we found that MELD score, albumin, the presence of ascites, and previous abdominal surgery were significantly correlated with high IBL during adult LDLT.
Abstract Background “Flat-line” (no clot formation) thromboelastography (TEG) is frequently observed after graft reperfusion during liver transplantation (LT). We aimed to evaluate the incidence and ...causes of flat-line TEG after graft reperfusion during LT. Methods With institutional review board approval, data of 208 consecutive recipients who underwent LT from May 2010 to May 2012 were retrospectively reviewed. We performed 3 different types of TEG measurements at 5 minutes after graft reperfusion: native TEG (nTEG), tranexamic acid–added TEG (tTEG), and protamine-added TEG (pTEG). The flat-line TEG was defined as having no trace at all at 60 minutes of TEG. We examined the incidence and causes of flat-line nTEG. We also compared recipients with flat-line nTEG (F group) and clot-forming nTEG (C group). Results One hundred eighty-two recipients were included in the final analysis. The incidence of flat-line nTEG was 27% (49/182 cases). Among 49 recipients in the F group, 28 recipients showed clot formation in both tTEG and pTEG, 19 recipients in only tTEG, and 1 recipient in only pTEG; 1 recipient showed no clot formation in any TEGs. Graft from the deceased donor was more frequently observed in the F group than in the C group ( P = .039). The F group showed decreased platelet count ( P = .001), increased prothrombin time ( P = .002), and decreased fibrinogen ( P = .009) compared with the C group. Conclusions No clot formation was relatively common after reperfusion during LT, and the main causes were hyperfibrinolysis and heparin effect. Liver graft from deceased donors was associated more frequently with no clot formation after reperfusion during LT.
Background: Confirmatory tests for failure of transfer of passive immunity (FTPI) in dairy calves require direct measurements of the serum immunoglobulin G concentration. Enzyme‐linked immunosorbent ...assay (ELISA) has advantages over single radial immunodiffusion (SRID) in terms of cost and time.
Objectives: To evaluate the agreement between ELISA and SRID, and to compare the diagnostic performance of ELISA with indirect methods, in the detection of FTPI in calves.
Animals: One hundred and fifteen dairy calves (aged 0–10 days) from 23 calf‐rearing facilities.
Methods: Prospective, observational study. The agreement between SRID and ELISA was determined by the Bland‐Altman method. Fixed bias (SRID − ELISA) was calculated. For comparison of the diagnostic performance of ELISA with indirect methods, sensitivity, specificity, and area under the curve (AUC) of receiver operating characteristic (ROC) curves were calculated at cut‐off values of 500 and 1,000 mg/dL.
Results: The agreement between SRID and ELISA was 94%. Fixed bias (SRID − ELISA) was 140 ± 364 mg/dL. The AUC and sensitivity of ELISA at the cut‐off value of 1,000 mg/dL were higher than those of indirect methods (P<.004). The specificity of ELISA at the cut‐off value of 1,000 mg/dL was not higher than that of indirect methods, except for serum total protein concentration assay.
Conclusion and Clinical Importance: ELISA exhibited good diagnostic performance and good agreement with SRID. ELISA is an adequate method for both screening and confirmatory tests for FTPI in dairy calves at the cut‐off value of 500 mg/dL.
Summary
What is known and objective
Pharmacogenetic studies of the genetic regulation of warfarin dose requirement have been reported, but few have been on the bleeding complications at therapeutic ...international normalized ratio (INR). This study aimed to evaluate the effect of gene polymorphisms of CYP2C9, VKORC1, thrombomodulin (THBD) and C‐reactive protein (CRP) on the risk of bleeding complications of warfarin at therapeutic INR in Korean patients with mechanical cardiac valves.
Methods
A retrospective warfarin pharmacogenetic association study was performed. One hundred and forty‐two patients with mechanical cardiac valves who were on warfarin anticoagulation therapy and maintained INR levels of 2·0–3·0 for 3 consecutive time intervals were followed up. CYP2C9 rs1057910, VKORC1 rs9934438, CRP rs1205, THBD rs1042580 and THBD rs3176123 were genotyped. The association between genotypes and warfarin bleeding complications was evaluated using logistic regression analysis, adjusted for demographic and clinical factors.
Results and discussion
Of 142 eligible patients, 21 patients (14·8%) had bleeding complications at therapeutic INR. Patients with the G allele in THBD rs1042580 (AG or GG) had a lower risk of bleeding than patients with the AA genotype (adjusted OR: 0·210, 95% CI: 0·050–0·875, P = 0·032). The THBD rs3176123 polymorphism did not show any association with bleeding. For CRP rs1205, patients with the A allele (GA or AA genotype) had a higher risk of bleeding than patients with the GG genotype (adjusted OR: 5·575, 95% CI: 1·409–22·058, P = 0·014). Variant VKORC1 and CYP2C9 genotypes did not confer a significant increase in the risk for bleeding complications.
What is new and conclusions
As expected, no association could be found between bleeding complications and two dose‐related genes (CYP2C9*3 and VKORC1 rs9934438). In contrast, our results suggest that two genetic markers (THBD rs1042580 and CRP rs1205) could be predictors of bleeding complications of warfarin at normal INR. Given the retrospective study design and the relatively small sample size, our hypothesis requires further independent validation using more robust prospective designs. However, additional retrospective studies similar to ours but in populations with different genetic backgrounds should also be useful.
Thrombomodulin rs1042580 and C‐reactive protein rs1205 showed significant association with bleeding complications at therapeutic INR in patients on warfarin.
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