Tumor-infiltrating immune cell score as an independent prognostic predictor for endometrial carcinoma: Insights from a comprehensive analysis of the immune landscape.

BACKGROUND: Immune cells are crucial components in the tumor microenvironment and have a significant impact on the outcomes of patients. AIMS: Here, we aimed to establish a prognostic score based on different types of tumor-infiltrating immune cells for Endometrial Carcinoma (EC). METHODS AND RESULTS: We enrolled and analyzed 516 EC patients from The Cancer Genome Atlas. The relative abundance of 22 immune cells were estimated by using the CIBERSORTx algorithm. Cox regression was performed to identify potential prognostic immune cells, which were used to develop a Tumor-infiltrating Immune Cell Score (TICS). The prognostic and incremental value of TICS for overall survival were compared with traditional prognostic factors using the C-index and decision curves. Clustering analysis using all immune cells identified three immune landscape subtypes, which had weak correlation with survival. A TICS was constructed using CD8T cells, resting memory CD4 T cells, activated NK and activated DCs, and classified patients as low-, moderate- and high-risk subgroups. The low-risk subgroup had higher tumor mutation burden and activation of IL2/STAT5, IL2/STAT3 and IFN-gamma response pathways. Conversely, the high-risk subgroup was associated with DNA copy number variation, hypoxia and EMT process. The TICS subgroups significantly predicted overall survival, which was independent of patient age, tumor stage, grade and molecular classification. Moreover, we developed a nomogram incorporating TICS and clinicopathologic factors, which significantly improved the predictive accuracy compared to the clinicopathologic model alone. CONCLUSION: The TICS is an effective and independent prognostic predictor for EC patients and may serve as a useful supplement to clinicopathological factors and molecular subtyping.

The clinical significance of ischaemia-modified albumin in acute coronary syndrome and hypertension.

BACKGROUND: Early diagnosis of acute coronary syndrome is more and more important because of its mortality and morbidity. Hypertension is one of the pathogenesis of acute coronary syndrome, which often leads to stenosis and ischaemia. Ischaemia-modified albumin is sensitive for the occurrence of ischaemia, which attracted us in the significance of ischaemia-modified albumin in patients with chest pain, especially patients complicated with hypertension. METHODS: In total, 200 patients with acute chest pain were included in the study. According to the diagnostic criteria, patients were divided into acute coronary syndrome group and non-ischaemic chest pain group. Cardiac biomarkers were measured with 30 minutes in emergency department, including cardiac troponin T, creatine kinase MB, and ischaemia-modified albumin. Receiver operating characteristic curve (ROC) analysis was used for the sensitivity and specificity of ischaemia-modified albumin in the early diagnosis of acute coronary syndrome. Comparisons between ischaemia-modified albumin and cardiac Troponin T were done between groups. RESULTS: The demographics in two groups were not significantly different in most aspects. Compared with non-ischaemic chest pain group, serum levels of ischaemia-modified albumin and cardiac Troponin T were significantly higher in acute coronary syndrome group. ROC analysis showed that ischaemia-modified albumin had a good sensitivity and specificity in early diagnosis of acute coronary syndrome. The level of ischaemia-modified albumin in acute coronary syndrome patients with hypertension was higher than that in non-ischaemic chest pain patients. CONCLUSIONS: In patients complained with acute chest pain, the serum measurement of ischaemia-modified albumin is potential valuable for the early diagnosis of acute coronary syndrome, especially combined with ECG. The serum level of ischaemia-modified albumin in acute coronary syndrome patients is significantly associated with hypertension.

Clinical and Pathological Implications of Increases in Tonsillar CD19+CD5+ B Cells, CD208+ Dendritic Cells, and IgA1-positive Cells of Immunoglobulin A Nephropathy.

OBJECTIVE: Several studies indicated that tonsillectomy can improve the prognosis of patients with immunoglobulin A nephropathy (IgAN). However, the relationship between tonsillar immunity and IgAN is still unclear. METHODS: A total of 14 IgAN patients were recruited in the current study from May 2015 to April 2016 in Tongji Hospital. B cells, dendritic cells (DCs), and IgA1 positive cells in human tonsils were detected using immunofluorescence and immunohistochemistry. Correlations between these cells and clinicopathologic features were evaluated. RESULTS: CD19+CD5+ B cells were predominantly located in germinal centers and mantle zones of lymphoid follicles, the CD208+ DCs were distributed in the interfollicular and subepithelial area, and IgA1-positive cells were predominantly detected in mantle zones of lymphoid follicles and subepithelial tissues. The numbers of CD19+CD5+ B cells, CD208+ DCs, and IgA1-positive cells in tonsillar tissues from IgAN patients were significantly higher than those in the normal controls (P<0.01, respectively). CD19+CD5+ B cells, CD208+ DCs, and IgA1-positive cells in tonsillar tissues were significantly associated with 24-h proteinuria levels and tubular atrophy/interstitial fibrosis of IgAN. CONCLUSION: CD19+CD5+ B cells, CD208+ DCs, and IgA1-positive cells in tonsillar tissues might be involved in the pathogenesis of IgAN.

Interleukin-7 Is Associated with Clinical and Pathological Activities in Immunoglobulin A Nephropathy and Protects the Renal Proximal Tubule Epithelium from Cellular Fibrosis.

OBJECTIVE: Diagnosis of immunoglobulin A nephropathy (IgAN) requires the evaluation of renal biopsy specimens. However, renal biopsy is an invasive procedure and is not frequently performed for various reasons. Thus, recognized noninvasive biomarkers for predicting IgAN progression are urgently needed. METHODS: In the present study, we included 86 IgAN patients with renal biopsy from June 2015 to May 2016 and had their plasma interleukin-7 (IL-7) level measured with ELISA. The association between the plasma IL-7 level and clinico-pathological characteristics was analyzed. Immunohistochemical staining was used to assay the in situ expression of IL-7 in vivo. Western blotting was performed to examine the production of extracellular matrix, p-mTOR and the markers of autophagy under the treatment of IL-7 after TGF-ß1 stimulation in renal tubular epithelial cells. RESULTS: IL-7 was significantly decreased in patients with IgAN compared to healthy subjects (2.3077 vs. 8.6294 pg/mL, P<0.0001). There was a significant difference in the plasma IL-7 level between tubular atrophy/interstitial fibrosis T0 and T2 classes (P=0.0064). A lower plasma IL-7 value in patients at the time of biopsy indicated a poor renal outcome. In addition, IL-7 was over-expressed in renal tubular epithelial cells and significantly attenuated transforming growth factor ßl-induced extracellular matrix production by suppression of cellular autophagy via activation of mTOR1 signaling. CONCLUSION: These results suggested that IL-7 might be a noninvasive biomarker for predicating IgAN. It protected renal proximal tubular epithelial cells from cellular fibrosis by inhibiting autophagy via mTORl signaling.

Hemoglobin Fukuoka caused unexpected hemoglobin A1c results: A case report.

BACKGROUND: Glycated hemoglobin (Hb) (HbA1c) is an indicator that is used to diagnose and monitor the treatment of diabetes. Many factors can affect the detection of HbA1c. One of the most important of these factors is the Hb variant. Here, we report a rare Hb variant and evaluate its effect on HbA1c. CASE SUMMARY: A 35-year-old man was suspected of harboring an Hb variant following the measurement of HbA1c with the Variant II Turbo 2.0 Hb detection system during a routine examination. Subsequently, we used the Arkray HA-8160 and ARCHITECT c4000 system to reanalyze HbA1c. Finally, the Hb variant was detected with a Capillary2FP analyzer that operates on the principle of capillary electrophoresis. We also used gene sequencing to investigate the mutation site. The value of HbA1c detected with the Variant II Turbo 2.0 system was 52.7%. However, the Arkray HA-8160 system did not display a result while the ARCHITECT c16000 system showed a result of 5.4%. The Capillary2FP analyzer did not reveal any abnormal Hb zones. However, gene sequencing identified the presence of a mutation in the Hb ß2 chain [CD2(CAC>TAC), His>Tyr, HBB: c.7C>T]; the genotype was Hb Fukuoka. CONCLUSION: Hb variants could cause abnormal HbA1c results. For patients with Hb variants, different methods should be used to detect HbA1c.

[The Clinical Value of Combined Detection of RBC, Ret-He and HbA2 for Thalassemia].

OBJECTIVE: To investigate the distribution of Ret-He and RBC in thalassemia and the value of combining HbA2 in the detection of thalassemia among patients with microcytic or hypochromic. METHODS: 145 patients with microcytic or hypochromic outpatient or hospitalization in our hospital from May 2018 to December 2019 were selected and were divided into the thalassemia group(68 cases) and the non-thalassemia group (77 cases), and at the same time, the patients were divided into four groups of the non-anemia, mild anemia, moderate anemia and severe anemia group according to the degree of anemia. The Ret-He, RBC, RDW-CV and HbA2 in patients were detected, and the distribution of these parameters were compared, and the joint detection of Ret-He, RBC and HbA2 about its sensitivity, specific and other indicators of auxiliary diagnosis of thalassemia were analyzed. RESULTS: Among patients with microcytic or hypochromic, according to the anemia grade Ret-He gradually decreased from the non-anemia group to the severe anemia group (P<0.05); while RDW-CV was increased gradually from the mild anemia group to the severe anemia group (P<0.05); both RBC and Ret-He were increased in the thalassemia group as compared with the non- thalassemia group (P<0.05); while RDW-CV was decreased in the thalassemia group as compared with the non-thalassemia group (P<0.05); meanwhile Ret-He in the α-thalassemia group was higher than that in the ß-thalassemia group. ROC curve analysis showed that combined with HbA2, the specificity was 93.51%, the sensitivity was 66.18%, the positive predictive value was 90% and the negative predictive value was 75.189% when Ret-He was truncated with 19.25 pg and RBC was truncated with 4.95×1012/L. CONCLUSION: Among patients with microcytic or hypochromic, the distribution of RBC, Ret-He and RDW-CV was different in the thalassemia group and the non-thalassemia group, and was also affected by the degree of anemia. Combined Ret-He and RBC could improve the diagnostic specificity for thalassemia, which were screened by HbA2 in patients with microcytic or hypochromic.

Overexpression of FUBP1 is associated with human cervical carcinoma development and prognosis.

AIMS: Far upstream element-binding protein 1 (FUBP1) has been shown to involve in the tumorigenesis and tumor progression of various cancers. However, the expression and function of FUBP1 in cervical carcinoma remains unknown. MAIN METHODS: Transcriptional expression of FUBP1 was initially evaluated using the Oncomine database, followed by evaluation of FUBP1 protein levels using immunohistochemistry in 119 cervical carcinoma patient tissues. In vitro experiments were performed to assess the tumorigenic role of FUBP1. Besides, Gene Set Enrichment Analysis, EnrichmentMap analysis, and protein-protein interaction (PPI) networks were used to evaluate the potential mechanisms of FUBP1 in promoting cervical cancer progression. KEY FUNDINGS: In this research, we found both FUBP1 mRNA transcription and protein expression levels increased significantly in cervical carcinoma tissues compared with adjacent normal cervical tissues. Furthermore, elevated FUBP1 expression was positively correlated with age, T classification, N classification, tumor recurrence, Ki67 expression, and poor prognosis in cervical carcinoma patients. Besides, elevated FUBP1 expression acted as an independent unfavorable predictor for overall survival and disease-free survival in cervical carcinoma. Overexpression of FUBP1 significantly promoted cervical carcinoma cell proliferation and inhibits cell apoptosis in vitro, while knockdown of FUBP1 showed the opposite effect. Mechanistically, bioinformatics analysis revealed that FUBP1 promoted the biological function of cervical carcinoma cells via enhancing DNA repair signal pathways. Our results demonstrate for the first time that FUBP1 is a novel prognostic factor and therapeutic target for cervical carcinoma.

Serum uric acid level is correlated with the clinical, pathological progression and prognosis of IgA nephropathy: an observational retrospective pilot-study.

OBJECTIVES: This study was aimed to assess the relationship between serum uric acid (SUA) level and the clinical, pathological phenotype of IgA nephropathy (IgAN), and to determine the role of SUA level in the progression and prognosis of IgAN. METHODS: A total of 208 patients with IgAN were included in this study, and were classified into the normo-uricemia group and hyperuricemia group according to the SUA level. The clinical data at baseline, IgAN Oxford classification scores (MEST-C scoring system), and other pathological features were collected and further analyzed. All patients were followed up and the prognosis was assessed using Kaplan-Meier survival curves. GraphPad Prism 7.0 and SPSS 23.0 were used for statistical analyses. RESULTS: In clinical indicators, patients with hyperuricemia had the significantly higher proportion of males to females, mean arterial pressure, the levels of total cholesterol, triglyceride, Scr, BUN, 24 hour-urine protein, C3, and C4, the lower levels of high-density lipoprotein cholesterol and eGFR than those without (p < 0.05). In terms of pathological characteristics, the tubular atrophy/interstitial fibrosis scores, vascular injury scores, and glomerular sclerosis percentage were significantly higher in patients with hyperuricemia compared with those without (p < 0.01). There was no significant difference in the scores of mesangial hypercellularity, endocapillary hypercellularity, focal segmental glomerulosclerosis, as well as crescents between the two groups (p > 0.05). As for the depositions of immune complexes deposition in IgAN, the hyperuricemia group had less deposition of immunoglobulin G and FRA than the normo-uricemia group (p < 0.05), while the deposition of immunoglobulin A, immunoglobulin M, and complement C3 in the two groups showed no statistical difference. The survival curve suggested that patients in the hyperuricemia group have significantly poorer renal outcome than those in the normo-uricemia group (p = 0.0147). Results also revealed that the SUA level is a valuable predictor of renal outcome in patients with IgAN. The optimal cutoff value was 361.1 µmol/L (AUC = 0.76 ± 0.08167) and 614 µmol/L (AUC = 0.5728 ± 0.2029) for female and male, respectively. CONCLUSIONS: The level of SUA is associated with renal function level and pathological severity of IgAN, and maybe a prognostic indicator of IgAN.

Clinicopathological features and clinical efficacy of crizotinib in Chinese patients with ROS1-positive non-small cell lung cancer.

C-ros oncogene 1 receptor tyrosine kinase (ROS1) rearrangement forms a novel molecular subgroup of non-small cell lung cancer (NSCLC). The present study explored the clinicopathological features and clinical efficacy of crizotinib in patients with ROS1-positive NSCLC. A retrospective analysis of 2,617 cases of NSCLC diagnosed between January 2013 and December 2016 was performed. ROS1 fusion genes were detected by reverse transcription-quantitative polymerase chain reaction, fluorescence in situ hybridization or next-generation sequencing techniques, and patients positive for the ROS1 fusion gene received oral treatment with crizotinib. The ROS1 fusion was identified in 67 out of 2,617 cases (2.56%), including 21 cases that were male and 46 cases that were female. The median age was 68 years. Among these cases, 59 (88.06%) were adenocarcinoma and 8 were non-adenocarcinoma. According to Tumor-Node-Metastasis (TNM) staging, 4 cases were stage I-IIIa and 63 (94.02%) were stage IIIb-IV. The epidermal growth factor receptor (EGFR) gene status included 60 cases of wild-type, 1 case of co-mutation and 6 unknown cases. Statistically significant differences were identified for sex, TNM staging and EGFR gene status between ROS1 fusion gene-positive and -negative patients (P<0.001). A total of 23 patients received oral treatment with crizotinib, of which 13 (56.52%), 5 (21.74%) and 5 (21.74%) patients demonstrated a partial response, stable disease and progressive disease, respectively. The objective response rate was 56.52% and the disease control rate was 78.26%. Among all patients, the median progression-free survival (mPFS) time was 14.5 months. No differences were revealed in the mPFS time with regard to age, sex, smoking history, performance status score, histopathological type, TNM staging, tumor protein p53 gene status, EGFR gene status and first-line crizotinib treatment, whether by single or multiple factor analysis. The grade 3/4 treatment-associated adverse events included gastrointestinal disturbance, followed by increased transaminase concentration. In conclusion, the rate of ROS1 fusion in NSCLC among the patients is low, and crizotinib is an effective and safe drug for the treatment of ROS1-positive advanced NSCLC.

Blocking Tyr265 nitration of protein phosphatase 2A attenuates nitrosative stress-induced endothelial dysfunction in renal microvessels.

Protein tyrosine (Tyr) nitration, the covalent addition of a nitro group (•NO2) to Tyr residues, is emerging as a candidate mechanism of endothelial dysfunction. Previous studies have shown that Tyr nitration is primarily induced by nitrosative stress, a process characterized by the production of reactive nitrogen species, especially peroxynitrite anion (ONOO-), which is considered a secondary product of NO in the presence of superoxide radicals (O2•-). However, the impact of nitrosative stress-induced Tyr nitration on endothelial dysfunction has not been thoroughly elucidated to date. We developed an endothelial dysfunction model, a process called "endothelial-to-mesenchymal transition (EndMT)," and evaluated the production of NO, O2•-, and protein nitration during EndMT. The results showed that TGF-ß1 stimulation induced EndMT and elevated endothelial NO and O2•- production as well as nitration of the catalytic subunit of protein phosphatase (PP)2A. Mass spectrometry analysis showed that Tyr265 was the nitration site in the catalytic subunit of protein phosphatase (PP)2A, and this Tyr nitration increased PP2A activity and disrupted endothelial integrity. To devise an endothelial-targeted anti-PP2Ac nitration strategy, a mimic peptide, tyrosine 265 wild type (Y265WT), conjugated with the cell-penetrating peptide HIV-1 TAT protein (TAT) was synthesized. PP2Ac nitration and PP2A activity were significantly inhibited by pretreatment with TAT-265WT, and the integrity of endothelial cells was maintained. Furthermore, injection of TAT-265WT attenuated renal nitration formation and caused anticapillary rarefaction in a unilateral urethral obstructive nephropathy model. Taken together, these results offer preclinical proof of concept for TAT-265WT as a tractable agent to protect against nitrosative stress-induced endothelial dysfunction in renal microvessels.-Deng,Y., Cai, Y., Liu, L., Lin, X., Lu, P., Guo, Y., Han, M., Xu, G. Blocking Tyr265 nitration of protein phosphatase 2A attenuates nitrosative stress-induced endothelial dysfunction in renal microvessels.

DAXX promotes ovarian cancer ascites cell proliferation and migration by activating the ERK signaling pathway.

BACKGROUND: The death-domain-associated protein (DAXX) was originally identified as a protein that binds to the transmembrane death receptor FAS and enhances both FAS-induced and transforming growth factor-ß-dependent apoptosis. In a previous study, we found that nude mice injected with DAXX-overexpressing cells (ES-2-DAXX) accumulated large concentrations of first-generation ascites cells (I ascites cells). The role of DAXX in the development of ascites is unknown. The aim of this study was to analyze the effect of DAXX on proliferation and migration of ascites cells in ovarian cancer in vitro and in vivo. METHODS: Nude mice were housed in cages with a 14:10 h light:dark cycle; water and food were provided ad libitum. ES-2-DAXX cells (1×106) were injected intraperitoneally into athymic nude mice (8-week-old female mice). After 4 weeks, I ascites cells were collected. The I ascites cells were injected intraperitoneally into athymic nude mice (8-week-old female mice). After 4 weeks, II ascites cells were collected and cultured. Ascites cell survival, migration, and colony formation were measured using colony formation and cell growth assays. Immunofluorescent staining revealed the co-localization of DAXX and promyelocytic leukemia protein (PML) in ascites cell nuclei. Western blotting and immunohistochemistry showed that extracellular signal-related kinase (p-ERK) 1/2 and CEBP-ß were highly expressed in tumor tissues formed by II ascites cells. Through immunoprecipitation, we also found that DAXX can interact with CEBP-ß. RESULTS: DAXX enhanced ascites cell survival, migration, and colony formation. DAXX and PML nuclear foci dramatically increased in a passage-dependent manner in ascites cells, DAXX promoted the tumor growth of ascites cells in vivo, increased ascites cell proliferation in vivo, and enhanced ascites cell survival and migration by activating the ERK signalling pathway and integrating with CEBP-ß. CONCLUSIONS: DAXX can interact with CEBP-ß. DAXX can induce ovarian cancer ascites formation by activating the ERK signal pathway and binding to CEBP-ß.

Association between BIM polymorphism and lung cancer outcomes: a meta-analysis.

Accumulating evidences have indicated that BIM expression largely decides the development of lung cancer and outcome of EGFR-mutant lung cancers after TKI treatments. BIM polymorphism is a 2,903-bp deletion in the second exon. To clarify the relationship between this BIM polymorphism and clinical outcomes of lung cancers, we conducted this meta-analysis and observed the survival and responses to TKIs. Sixteen cohort studies, covering 4393 WT and 916 BIM deletion patients were included. Overall, BIM deletion polymorphism was associated with significantly shorter progression-free survival (PFS) and slightly shorter overall survival (OS), compared to the WT group. Moreover, patients with BIM deletion polymorphism showed significantly inferior response to EGFR TKIs. In conclusion, our analysis confirmed that lung cancer patients harboring the BIM deletion have inferior survival and TKI responses. Examination of the novel biomarker BIM deletion in lung cancer patients, especially for the EGFR mutant cohort, could provide some prognostic utility.

Factors Influencing the Outcomes of Artificial Hip Replacements.

Hip replacement is one of the most successful surgeries in the clinic for the removal of painful joints. Hip osteoarthritis and femoral head necrosis are the 2 main reasons for hip replacement. Several factors are associated with the outcomes of surgery. Nonsurgical factors include gender, age, body mass index, prosthetic material, and risk factors. Surgical factors are anesthesia, postoperative complications, and rehabilitation. Considering the increasing demand for hip arthroplasty and the rise in the number of revision operations, it is imperative to understand factor-related progress and how modifications of these factors promotes recovery following hip replacement. In this review, we first summarize recent findings regarding crucial factors that influence the outcomes of artificial hip replacement surgery. These findings not only show the time-specific effect for the treatment and recovery from hip arthroplasty in the clinic, but also provide suitable choices for different individuals for clinicians to consider. This, in turn, will help to develop the best possible postoperative program for specific patients.

Concurrent ROS1 gene rearrangement and KRAS mutation in lung adenocarcinoma: A case report and literature review.

Lung adenocarcinomas with gene rearrangement in the receptor tyrosine kinase ROS1 have emerged as a rare molecular subtype. Although these lung adenocarcinomas respond to ROS1tyrosine kinase inhibitors, many patients ultimately acquire resistance. ROS1gene rearrangement is generally mutually exclusive with other driver genomic alterations, such as those in EGFR, KRAS, or ALK, thus multiple genomic alterations are extremely rare. Herein, we report a case of a 42-year-old man diagnosed with lung adenocarcinoma positive for a SDC4-ROS1 fusion, who was treated with crizotinib followed by three cycles of chemotherapy. A biopsy acquired after disease progression revealed the original SDC4-ROS1 fusion along with a KRAS point mutation (p.G12D).We reviewed the related literature to determine the frequency of gene mutations in non-small cell lung cancer patients. A better understanding of the molecular biology of non-small cell lung cancer with multiple driver genomic aberrations will assist in determining optimal treatment.

Hemangioma of the Rib: A Rare Case Report and Literature Review.

Hemangiomas of the rib are extremely rare benign neoplasm. Here we present a case in a 47-year-old female, detected by chest X-ray and underwent a surgical resection. Histologically, the tumor was composed of a homogeneous conglomerate, irregular, thin walled and dilated blood vessels containing red blood cells, supported by fibrous stroma and intermingled to regular bone trabeculae. The postoperative courses were uneventful, and there was no recurrence during 64 months follow-up.

Glutaminolysis Was Induced by TGF-ß1 through PP2Ac Regulated Raf-MEK-ERK Signaling in Endothelial Cells.

Vascular endothelial cells can survive under hypoxic and inflammatory conditions by alterations of the cellular energy metabolism. In addition to high rates of glycolysis, glutaminolysis is another important way of providing the required energy to support cellular sprouting in such situations. However, the exact mechanism in which endothelial cells upregulate glutaminolysis remains unclear. Here we demonstrated that protein phosphatase 2A (PP2A)-mediated Raf-MEK-ERK signaling was involved in glutaminolysis in endothelial cells. Using models of human umbilical vein endothelial cells (HUVECs) treated with transforming growth factor-ß1 (TGF-ß1), we observed a dramatic induction in cellular glutamate levels accompanied by Raf-MEK-ERK activation. By addition of U0126, the specific inhibitor of MEK1/2, the expression of kidney-type glutaminase (KGA, a critical glutaminase in glutaminolysis) was significantly decreased. Moreover, inhibition of PP2A by okadaic acid (OA), a specific inhibitor of PP2A phosphatase activity or by depletion of its catalytic subunit (PP2Ac), led to a significant inactivation of Raf-MEK-ERK signaling and reduced glutaminolysis in endothelial cells. Taken together, these results indicated that PP2A-dependent Raf-MEK-ERK activation was involved in glutaminolysis and inhibition of PP2A signals was sufficient to block Raf-MEK-ERK pathway and reduced glutamine metabolism in endothelial cells.

Elevated Serum Angiopoietin-like Protein 2 in Patients with Acute Coronary Syndrome.

BACKGROUND AND AIMS: Angiopoietin-like protein 2 (Angptl2) is regarded as a proinflammatory factor in the pathogenesis of atherosclerosis and is expressed at high levels in patients with coronary artery disease. However, direct evidence of Angptl2 in acute coronary syndrome (ACS) is lacking. Our study was designed to investigate a possible relationship between serum Angptl2 and ACS. METHODS: We evaluated 251 consecutive patients undergoing coronary angiography, consisting of 132 patients with ACS (unstable angina pectoris n = 60, acute myocardial infarction n = 72), 50 patients with stable angina pectoris, and 69 control patients. Serum Angptl2 concentration was measured in peripheral venous blood by an enzyme-linked immunosorbent assay. RESULTS: Serum Angptl2 levels were significant higher in patients with ACS than in those with stable angina (p <0.05) or controls (p <0.001). The difference between angplt2 levels in unstable angina and acute myocardial infarction subgroups was statistically insignificant (p = 0.831). In multivariable logistic regression models, using quartiles of Angptl2, Angptl2 was closely associated with ACS following adjustment of age, gender, established risk factors and high sensitivity C-reactive protein levels (odds ratio for quartile 4 vs. quartile 1: 10.182, 95% confidence interval 2.440-42.485, p = 0.001). CONCLUSIONS: Serum Angptl2 is a new candidate biomarker for risk stratification of ACS.

Beta-adrenoceptor action on pancreatic cancer cell proliferation and tumor growth in mice.

BACKGROUND/AIMS: There is growing evidence that some cancer progression is closely associated with beta- adrenoreceptors (ß-ARs). However, the underlying mechanisms for ß-ARs mediated proliferation of pancreatic cancer cell are poorly understood. In the current study, we evaluated the possible function of ß-ARs on the proliferation of human pancreatic ductal adenocarcinomas (PDAC) cell line Panc-1 and explored ß-ARsmediated downstream signal pathway. METHODOLOGY: Series of experiments, such as expression of ß1- and ß2-ARs on pancreatic cancer cell line Panc-1, ß-ARsmediated downstream signal pathway activation as well as cell proliferation assay in vitro and in vivo were performed with immunofluorescence, Western blot analysis, BrdU incorporation assays and xenograft tumor growth respectively. RESULTS: Non-selective ß-ARs agonist Isoproterenol (ISO) significantly increased cell proliferation via ß-ARs in a dose-dependent manner, with concomitant activation of ERK/MAPK signal pathway in Panc-1 cells. ISO increased expression level of phosphorylated ERK in Panc-1 cells. Furthermore, in vivo study showed that ISO enhanced xenograft tumor growth and this effect was suppressed by non-selective ß-ARs antagonist (ß-blocker), propranolol (PRO) treatment. CONCLUSIONS: These findings suggest that the development and progression of PDAC is subject to significant modulation by ISO and PRO and the treatment with PRO may be useful for marker-guided cancer intervention of PDAC. Therefore, PRO may be developed a novel drug for the treatment and intervention of PDAC for its high specificity.

Involvement of MAPK phosphatase-1 in dexamethasone-induced chemoresistance in lung cancer.

Dexamethasone (DEX) has been frequently used as a co-medication in cytotoxic cancer therapy, mostly for supportive care in alleviating the acute toxic effects on healthy tissues. Although recent studies have demonstrated DeXinduced resistance to cytotoxic treatment in several solid tumors, no specific molecular mechanism of action has been reported. Here, we assessed the effect of DEX on the cisplatin-induced cytotoxicity in fresh surgically resected specimens from Chinese patients with lung cancer. We also examined the effects of DEX and cisplatin on the apoptotic signaling pathway in the well-established human lung adenocarcinoma cell line A549. Our results show that DEX treatment inhibits cisplatin-induced cell apoptosis by up-regulation of cellular mitogen-activated protein kinase phosphatase-1 (MKP-1) and subsequent deactivation of p38 protein kinase. Knock down of MKP-1 by RNA interference reversed the DEX-induced inhibition of cisplatininduced cell apoptosis. These data suggest that administration of DEX during the clinical therapy of Chinese lung cancer patients must be carefully considered, and indicate that MKP-1 and p38 protein kinase are potential targets for DEX-induced drug resistance.