Cytosolic DNA‒Mediated STING-Dependent Inflammation Contributes to the Progression of Psoriasis.

Psoriasis is a chronic inflammatory skin disease characterized by an active dynamic interplay between immune cells and keratinocytes (KCs). STING is a universal receptor that recognizes cytosolic DNA and triggers innate immune activation. This study aims to elucidate the role of STING in the inflammation in psoriasis. STING deficiency alleviated psoriatic symptoms and inflammation in mouse models of psoriasis. Stimulation of macrophages with double-stranded DNA induced STING-dependent release of TNF-α and hydrogen peroxide in vitro. Furthermore, incubation of KCs with TNF-α or hydrogen peroxide increased oxidative DNA damage, induced nuclear DNA release into the cytosol, and inhibited double-stranded DNA‒induced degradation of STING protein. More importantly, transfection of KCs with double-stranded DNA synergized with TNF-α or hydrogen peroxide to induce STING-dependent activation of NF-κB and subsequent expression of Il1b, Ccl20, and Cxcl10. Finally, exposure to 5,6-dimethylxanthenone-4-acetic acid (a STING agonist) aggravated psoriatic symptoms and inflammation in wild-type mice but not in STING-deficient mice. Collectively, STING functioned as a self-DNA sensor in macrophages and KCs of psoriatic skin. Cytosolic DNA-induced activation of STING in immune cells and KCs acted synergistically and contributed to the inflammation in psoriasis.

Improvement of LV Reverse Remodeling Using Dynamic Programming of Fusion-Optimized Atrioventricular Intervals in Cardiac Resynchronization Therapy.

Background: The patient-tailored SyncAV algorithm shortens the QRS duration (QRSd) beyond what conventional biventricular (BiV) pacing can. However, evidence of the ability of SyncAV to improve the cardiac resynchronization therapy (CRT) response is lacking. The aim of this study was to evaluate the impact of CRT enhanced by SyncAV on echocardiographic and clinical responses. Methods and Results: Consecutive heart failure (HF) patients from three centers treated with a quadripolar CRT system (Abbott) were enrolled. The total of 122 patients were divided into BiV+SyncAV (n = 68) and BiV groups (n = 54) according to whether they underwent CRT with or without SyncAV. Electrocardiographic, echocardiographic, and clinical data were assessed at baseline and during follow-up. Echocardiographic response to CRT was defined as a ≥15% decrease in left ventricular end-systolic volume (LVESV), and clinical response was defined as a NYHA class reduction of ≥1. At the 6-month follow-up, the baseline QRSd and LVESV decreased more significantly in the BiV+SyncAV than in the BiV group (QRSd -36.25 ± 16.33 vs. -22.72 ± 18.75 ms, P < 0.001; LVESV -54.19 ± 38.87 vs. -25.37 ± 36.48 ml, P < 0.001). Compared to the BiV group, more patients in the BiV+SyncAV group were classified as echocardiographic (82.35 vs. 64.81%; P = 0.036) and clinical responders (83.82 vs. 66.67%; P = 0.033). During follow-up, no deaths due to HF deterioration or severe procedure related complications occurred. Conclusion: Compared to BiV pacing, BiV combined with SyncAV leads to a more significant reduction in QRSd and improves LV remodeling and long-term outcomes in HF patients treated with CRT.

Identification of LPCAT1 expression as a potential prognostic biomarker guiding treatment choice in acute myeloid leukemia.

Changes in lipid metabolism affect numerous cellular processes that are relevant to cancer biology, including cell proliferation, death, differentiation and motility. In the phosphatidylcholine biosynthesis pathway, the conversion of lysophosphatidylcholine (LPC) to phosphatidylcholine is catalyzed by cytosolic enzymes of the LPC acyltransferase (LPCAT) family. A number of studies have demonstrated that LPCAT1 overexpression is a frequent event in diverse human cancer types, and that it is associated with unfavorable pathological characteristics and patient survival. The aim of the present study was to explore the prognostic role of the expression of LPCAT family members in acute myeloid leukemia (AML). Using Cox regression analysis, only LPCAT1 expression was identified as an independent prognostic biomarker in AML. In a cohort from The Cancer Genome Atlas, Kaplan-Meier analysis revealed that patients with AML and higher expression levels of LPCAT1 had shorter overall survival (OS) and leukemia-free survival (LFS) times compared with those with lower expression levels of LPCAT1. This was further confirmed using an independent cohort from the Gene Expression Omnibus. Using a third cohort comprising patients with AML and healthy volunteers, it was confirmed that LPCAT1 expression was significantly increased in newly diagnosed AML cases compared with healthy controls. Moreover, higher expression of LPCAT1 was associated with French-American-British subtype-M4/M5 and nucleophosmin 1 mutations. Notably, patients who underwent hematopoietic stem cell transplantation (HSCT) following induction therapy exhibited significantly longer OS and LFS times compared with patients who only received chemotherapy after induction therapy in the higher LPCAT1 expression group, whereas no significant differences in OS and LFS times were observed between the HSCT and chemotherapy groups among total cases of AML in the lower LPCAT1 expression group. These results suggest that patients with AML who exhibit higher LPCAT1 expression levels may benefit from HSCT. Collectively, the findings of the present study indicate that LPCAT1 expression may serve as an independent prognostic biomarker that can guide the choice between HSCT and chemotherapy in patients with AML.

High level of circulating microRNA-142 is associated with acute myocardial infarction and reduced survival.

BACKGROUND: Recent study reported that microRNA-142 (miR-142) were up-regulated in the atherosclerotic plaques, which may be responsible for pathogenesis of atherosclerosis. However, whether it associates with presence of acute myocardial infarction (AMI), and its prognostic value is still unknown. We, therefore, investigated the association between miR-142 expression and presence of AMI, and its prognostic value in AMI patients. METHODS: We included 300 AMI patients and 100 subjects as the control group. MiR-142 content was detected by quantitative real-time polymerase chain reaction. MiR-142 level was identified in all subjects. The multivariate logistic regression analysis were performed to evaluate the risk factors of AMI. The Kaplan-Meier analysis was performed to determine the major adverse cardiovascular and cerebrovascular events (MACCE)-free survival. RESULTS: AMI group had significantly higher miR-142 level in comparison to the controls [4.10 (2.03-7.43) vs. 1.92 (0.91-2.91), p < 0.001], moreover, miR-142 content was significantly associated with cardiac troponin I (cTnI) level (r = 0.707, p < 0.001). The MACCE-free survival was significantly lower over 24-month for patients in miR-142 high expression group (72.4% ± 5.6% vs. 76.4% ± 5.1%) (p = 0.022). After adjusting for the traditional risk factors, the odds ratios of miR-142 was 14.74 (95% CI, 2.15-101.24). The multivariate logistic regression analysis revealed that miR-142 level significantly associated with presence of AMI (p < 0.001). CONCLUSION: The serum level of miR-142 was increased in AMI patients when compared with health population. Furthermore, use of this marker may allow a certain predictor of the MACCE in AMI patients.

INPP4B exerts a dual function in the stemness of colorectal cancer stem-like cells through regulating Sox2 and Nanog expression.

Inositol polyphosphate 4-phosphatase type II (INPP4B), a lipid phosphatase, was identified as a negative regulator of phosphatidylinositol 3-kinase (PI3K)/Akt signaling in several cancers. The expression and biological function of INPP4B in human colorectal cancer (CRC) are controversial, while the role and molecular mechanism of INPP4B in colorectal cancer stem-like cells (CR-CSLCs) remains unclear. Here, we observed that INPP4B expression was markedly decreased in primary non-metastatic CR-CSLCs and increased in highly metastatic CR-CSLCs compared with corresponding control non-CSLCs. INPP4B overexpression inhibited self-renewal, and chemoresistance of primary non-metastatic CR-CSLCs, but exerted the opposite roles in highly metastatic CR-CSLCs in vitro. Similarly, INPP4B knockdown had dual functions in the self-renewal and chemoresistance of different CR-CSLCs. In addition, we demonstrated that INPP4B overexpression suppressed the tumorigenicity of primary non-metastatic CR-CSLCs while induced the tumorigenicity of highly metastatic CR-CSLCs in nude mice. Furthermore, INPP4B was found to modulate the stemness of CR-CSLCs by regulating Sox2 and Nanog expression, which was dependent on PI3K/PTEN/Akt signaling. In conclusion, our results highlight an important role of INPP4B in the stemness of CR-CSLCs for the first time and emphasize INPP4B as a dual therapeutic target for suppressing primary cancer cell proliferation and for preventing metastasis in CRC patients.

The independent and incremental value of ultrasound carotid plaque length to predict the presence and severity of coronary artery disease: analysis from the carotid plaque length prospective registry.

AIMS: Data regarding the relationship between carotid plaque length (CPL) and coronary artery disease (CAD) are lacking. This study aimed to assess the predictive value of CPL for the severity of CAD. METHODS AND RESULTS: We prospectively enrolled 2149 consecutive patients who underwent both first coronary angiography and carotid ultrasonography with measurements of intima-media thickness (IMT), plaque score (PS), and CPL. In total, 1408 (65.5%) patients had CAD (defined as stenosis ≥50%), and 741 (34.5%) patients had no CAD. Patients with CAD had longer maximal CPL than those without CAD (P < 0.001). The severity of CAD, measured by the Gensini score (GS), was closely correlated with max-CPL (rs = 0.560), followed by PS (rs = 0.486) and mean-IMT (rs = 0.292). Multivariate analysis revealed that max-CPL remained independently associated with CAD and high-GS after adjustment for traditional risk factors (TRF). Max-CPL, compared with PS or mean-IMT, had significantly higher discrimination value for predicting high-GS [area under the curve (AUC) 0.819 vs. 0.769 vs. 0.634, P < 0.001]. At a cut-off value for the max-CPL of 6.3 mm, the sensitivity and negative predictive value for high-GS were 84.6% and 89.1%, respectively. Furthermore, the addition of max-CPL significantly improved the discrimination (AUC 0.832 vs. 0.720, P < 0.001) and reclassification (net reclassification improvement = 0.431, P < 0.001) over TRF for high-GS. CONCLUSION: Ultrasound max-CPL provides independent and incremental predictive value for the clinical severity of CAD over TRF and seems a simple useful marker in CAD risk stratification.

INPP4B inhibits cell proliferation, invasion and chemoresistance in human hepatocellular carcinoma.

Background: Inositol polyphosphate 4-phosphatase type II (INPP4B) has been identified as a negative regulator of phosphatidyl inositol 3-kinase (PI3K)/Akt signaling in human several cancers. However, the expression, clinical significance and biological function of INPP4B in human hepatocellular carcinoma (HCC) clinical tissues and cell lines are little known. Materials and methods: We evaluated the expression of INPP4B in 86 cases of paired human HCC samples by immunohistochemistry, and the clinical significance of INPP4B expression was analyzed. The expression of INPP4B in five HCC cell lines was detected through using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analyses. The role of INPP4B gene on HCC cell proliferation, apoptosis, migration, invasion as well as epithelial-to-mesenchymal transition (EMT) and chemoresistance was examined via INPP4B mammalian expression vector and small interfering RNA (siRNA) transfection in vitro. Western blot analysis was used to explore the downstream molecules modulated by INPP4B. Results: Immunohistochemistry analysis revealed that INPP4B was significantly downregulated in HCC tissues compared with the corresponding normal tissues. The rate of INPP4B-positive staining was markedly lower in metastatic samples than in those of non-metastatic samples. Univariate analysis showed that INPP4B expression was indicated to have a marked association with histological grades, tumor size and tumor metastasis. Moreover, INPP4B overexpression suppressed cell proliferation, migration, invasion and EMT, but induced cell apoptosis and chemosensitivity in human HCC cell lines. In contrast, INPP4B knockdown had the opposite effects on the biological behaviors of HCC cells. Furthermore, INPP4B was found to inhibit the activation of PI3K/Akt signaling in HCC cells. Conclusion: Our findings suggest that INPP4B is a tumor suppressing gene in human HCC, and might act as a novel therapeutic target for HCC patients.

The PEAK1-PPP1R12B axis inhibits tumor growth and metastasis by regulating Grb2/PI3K/Akt signalling in colorectal cancer.

Pseudopodium enriched atypical kinase 1 (PEAK1), a novel non-receptor tyrosine kinase, was recently implicated in cancer pathogenesis. However, its functional role in colorectal cancer (CRC) is not well known. Herein, we demonstrated that PEAK1 was frequently downregulated in CRC and significantly associated with tumor size, differentiation status, metastasis, and clinical stage. PEAK1 overexpression suppressed CRC cell growth, invasion, and metastasis in vitro and in vivo, whereas knockout had the opposite effects. Further evaluation revealed that PEAK1 expression was positively correlated with protein phosphatase 1 regulatory subunit 12B (PPP1R12B) in CRC cell lines and clinical tissues, and this protein was found to suppress activation of the Grb2/PI3K/Akt pathway. Moreover, PPP1R12B knockdown markedly abrogated PEAK1-mediated tumor suppressive effects, whereas its upregulation recapitulated the effects of PEAK1 knockout on cell behaviours and the activation of signalling. Mechanistically, PI3K and Akt inhibitors reversed impaired the effect of PEAK1 function on cell proliferation, migration, and invasion. Our results provide compelling evidence that the PEAK1-PPP1R12B axis inhibits colorectal tumorigenesis and metastasis through deactivation of the Grb2/PI3K/Akt pathway, which might provide a novel therapeutic strategy for CRC treatment.

Intestinal microbiota: a novel perspective in colorectal cancer biotherapeutics.

It is believed that genetic factors, immune system dysfunction, chronic inflammation, and intestinal microbiota (IM) dysbiosis contribute to the pathogenesis of colorectal cancer (CRC). The beneficial role played by the direct regulation of IM in inflammatory bowel disease treatment is identified by the decreased growth of harmful bacteria and the increased production of anti-inflammatory factors. Interestingly, gut microbiota has been proven to inhibit tumor formation and progression in inflammation/carcinogen-induced CRC mouse models. Recently, evidence has indicated that IM is involved in the negative regulation of tumor immune response in tumor microenvironment, which then abolishes or accelerates anticancer immunotherapy in several tumor animals. In clinical trials, a benefit of IM-based CRC therapies in improving the intestinal immunity balance, epithelial barrier function, and quality of life has been reported. Meanwhile, specific microbiota signature can modulate host's sensitivity to chemo-/radiotherapy and the prognosis of CRC patients. In this review, we aim to 1) summarize the potential methods of IM-based therapeutics according to the recent results; 2) explore its roles and underlying mechanisms in combination with other therapies, especially in biotherapeutics; 3) discuss its safety, deficiency, and future perspectives.

Overexpression of PEAK1 contributes to epithelial-mesenchymal transition and tumor metastasis in lung cancer through modulating ERK1/2 and JAK2 signaling.

Pseudopodium-enriched atypical kinase 1 (PEAK1), a novel non-receptor tyrosine kinase, has been demonstrated to act as an oncogenic regulator in breast and pancreatic cancers. However, the role of PEAK1 in the progression and metastasis of lung cancer is still unknown. Here, we observed that ectopic PEAK1 expression promoted lung cancer cell migration and invasion, while PEAK1 knockout resulted in suppressed cell migration and invasion. Interestingly, cell proliferation did not significantly increase or decrease in either the PEAK1 overexpression or knockout groups compared with the corresponding control cells. In addition, PEAK1 overexpression could induce epithelial-to-mesenchymal transition (EMT) and the expression of matrix metalloproteinase-2 (MMP2) and MMP9 both in vitro and in vivo, whereas PEAK1 knockout had the opposite effects. Then, we had confirmed that PEAK1 was significantly upregulated in lung cancer tissues, and correlated with a higher tumor node metastasis stage. Moreover, PEAK1 upregulation markedly enhanced the activation of extracellular signal-regulated kinase-1/2 (ERK1/2) and Janus kinase-2 (JAK2) signaling in lung cancer cells. Further work demonstrated that the combination of PD98059 with AZD1480 could reverse the effects of PEAK1-induced EMT, cell migration and invasion. Our findings highlight a newer mechanism for PEAK1 in regulating EMT and metastasis in lung cancer, which might serve as a therapeutic target for lung cancer patients.