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Pancreatic cancer (PC) is a highly devastating neoplasm due to its irrepressible characteristics and propensity to override the available treatment strategies. Rapid prevalence and enormous severity of this cancer urgently demand the exploration of novel approaches for the development of effective therapeutic measures. Metabolic derangement is one of the hallmarks of cancers which restructures mitochondrial activities and biological pathways. Apart from their bioenergetic and biosynthetic functions, mitochondria are also implicated in a myriad of cellular functions including proliferation, differentiation, apoptosis, senescence, homeostasis, and other cell regulatory mechanisms. It has been noted that PC, like other types of cancers, exploits these activities in favor of tumor growth and survival by inducing mitochondrial dysfunctions such as mitochondrial-DNA mutation, metabolic enzyme modification, ROS generation, mitophagy, evasion of apoptosis, and mitochondrial biogenesis. During pancreatic carcinogenesis, a large number of onco-factors including Bcl-2 family proteins, NF-κB, HIFs, NRF2, NOX, MFNs, DRP1, DUSP6, Cyp-D, PARKIN, and others are dysregulated, resulting into reprogramming of metabolic pathways and cellular kinetics. Hence, targeted interventions in these metabolic derangements may present some effective anticancer approaches. The current review gives an insight into various mitochondrial disorders and their targetable molecules in PC which may provide certain novel opportunities in the pursuit of therapeutic development. Furthermore, we have also discussed certain treatment perspectives in PC based on specific mitochondrial activities. • Mitochondrial derangements can switch the metabolic phenotype to impart numerous tumorigenic features. • Mitochondrial derangements reinforce the oncogenic mechanisms of development, progression, and chemoresistance in pancreatic cancer. • The metabolic alterations present plausible mitochondrial targets and therapeutic opportunities. • The natural agents and small bioactive compounds are promising anticancer effects based on mitochondrial targets. [ABSTRACT FROM AUTHOR]

[Display omitted] Pancreatic Cancer (PC) is a severe form of malignancy all over the world. Delayed diagnosis and chemoresistance are the major factors contributing to its poor prognosis and high mortality rate. The genetic and epigenetic regulations of biological pathways further complicate the progression and chemotherapy response to this cancer. MicroRNAs (MiRNAs) involvement has been observed in all types of cancers including PC. The understanding and categorization of miRNAs according to their specific targets are very important to develop early diagnostic and therapeutic interventions. The current review, emphasizing recent research findings, has categorized miRNAs that directly target the potential onco-factors that act as central converging signal-nodes in five major cancer-related pathways i.e., MAPK/ERK, JAK/STAT, Wnt/β-catenin, AKT/mTOR, and TGFβ in PC. The therapeutic perspectives of miRNAs in PC have also been discussed. This will help to understand the interplay of various miRNAs within foremost signaling pathways and develop a multifactorial approach to treat difficult-to-treat PC. [ABSTRACT FROM AUTHOR]

[Display omitted] • Trop2 played a vital role in metastasis by Trop2/β-catenin positive feedback loop. • Bruceine D inhibited cancer cells proliferation and metastasis by targeting Trop2. • Bruceine D suppressed Trop2-driven ECM-remodeling and EMT to reduce lung metastatic colonization in vivo. • Bruceine D blocked Trop2/β-catenin complex, inducing β-catenin degradation though ubiquitin. Tumor-associated calcium signal transducer 2 (Trop2) has been used as a transport gate for cytotoxic agents into cells in antibody–drug conjugate designs because of its expression in a wide range of solid tumors. However, the specific role of Trop2 itself in breast cancer progression remains unclear and small molecules targeting Trop2 have not yet been reported. To screen small molecules targeting Trop2, and to reveal its pharmacological effects and the molecular mechanisms of action. Small molecule targeting Trop2 was identified by cell membrane chromatography, and validated by cellular thermal shift assay and point mutation analyses. We investigated the pharmacological effects of Trop2 inhibitor using RNA-seq, human foreskin fibroblast (HFF)-derived extracellular matrix (ECM), Matrigel drop invasion assays, colony-forming assay, xenograft tumor model, 4T1 orthotopic metastasis model and 4T1 experimental metastasis model. The molecular mechanism was determined using immunoprecipitation, mass spectrometry, immunofluorescence, immunohistochemistry and Western blotting. Here we identified Bruceine D (BD) as the inhibitor of Trop2, and demonstrated anti-metastasis effects of BD in breast cancer. Notably, Lys307 and Glu310 residues of Trop2 acted as critical sites for BD binding. Mechanistically, BD suppressed Trop2-induced cancer metastasis by blocking the formation of Trop2/β-catenin positive loop, in which the Trop2/β-catenin complex prevented β-catenin from being degraded via the ubiquitin-proteosome pathway. Destabilized β-catenin caused by BD reduced nucleus translocation, leading to the reduction of transcription of Trop2, the reversal of epithelial-mesenchymal transition (EMT) process, and the inhibition of ECM remodeling, further inhibiting cancer metastasis. Additionally, the inhibitory effects of BD on lung metastatic colonization and the beneficial effects of BD on prolongation of survival were validated in 4T1 experimental metastasis model. These results support the tumor-promoting role of Trop2 in breast cancer by stabilizing β-catenin in Trop2/β-catenin positive loop, and suggest Bruceine D as a promising candidate for Trop2 inhibition. [ABSTRACT FROM AUTHOR]

High low-density lipoprotein (LDL) cholesterol and the presence of metabolic syndrome (MS) are established risk factors for clinical and subclinical cardiovascular disease (CVD). However, the relative contribution to CVD risk of MS and high LDL cholesterol is not well defined. Therefore, the aim was assess the relative risk for the presence of coronary artery calcification (CAC) with metabolic syndrome (MS) compared with that of moderate or high LDL cholesterol. A total of 440 consecutive asymptomatic men (mean age 46 ± 7 years, range 29 to 65) presenting for CVD risk stratification were studied. MS was defined using National Cholesterol Education Program Adult Treatment Panel III criteria (n = 112; 24%). Moderate LDL cholesterol was defined as 130 to 159 mg/dl, and high LDL cholesterol as ≥160 mg/dl (n = 76; 17%). Overall, CAC was observed in 190 men (40%). The prevalence of CAC >0 was lowest in MS-negative men with LDL cholesterol <130 (35%) or 130 to 159 mg/dl (34%) and highest in MS-positive men with LDL cholesterol ≥160 mg/dl (80%). MS-positive men with LDL cholesterol of 130 to 159 mg/dl had CAC prevalence similar to that of MS-negative men with LDL cholesterol ≥160 mg/dl (54% vs 57%, respectively). This relation persisted with additional adjustment for age, smoking status, and cholesterol-lowering medication. In logistic regression analyses, the odds ratio for CAC >0 was highest in MS-positive men combined with high LDL cholesterol. In conclusion, these results suggest that the risk of CAC in asymptomatic men with moderate or high LDL cholesterol is magnified in persons with MS. [Copyright &y& Elsevier]

[Display omitted] The host stimulator of interferon genes (STING) signaling pathway is a major innate immune sensing pathway, and the stimulation of this pathway within antigen-presenting cells shows promise in targeting immune-suppressed tumors. Macrophages resident in tumors exhibit anti-inflammatory properties and enhance tumor growth and development. Polarizing such macrophages towards a pro-inflammatory phenotype is an effective strategy for tumor suppression. In the present study, we observed that the STING pathway was inactivated in breast and lung carcinomas, and a positive correlation existed between STING and macrophage markers in these tumors. We found that vanillic acid (VA) could stimulate the STING/TBK1/IRF3 pathway. VA mediated the production of type I IFN and promoted macrophage polarization into the M1 phenotype; this activity was dependent on STING activation. A direct-contact co-culture model and a transwell co-culture model revealed that macrophages with VA-induced STING activation exhibited anti-proliferative effects on SKBR3 and H1299 cells, although a STING antagonist and M2 macrophage-related cytokines alleviated this anti-proliferative effect. Further investigation indicated that phagocytosis and apoptosis-inducing effects were the major mediators of the anti-tumor effect of VA-treated macrophages. Mechanistically, VA promoted the polarization of macrophages to a M1 phenotype via IL-6R/JAK signaling, resulting in enhanced phagocytosis and apoptosis-induction effects. Additionally, STING activation-induced IFNβ production also participated in the apoptosis mediated by VA-treated macrophage in SKBR3 and H1299 cells. Mouse models with 4 T1 tumors confirmed the anti-tumor properties of VA in vivo and revealed the infiltration of VA-induced cytotoxic T cells into the tumors. These data suggest that VA is an effective agonist of STING and provides a new perspective for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To determine the accuracy of dual-source CT (DSCT) to quantify coronary stenosis compared to intravascular ultrasound (IVUS) and quantitative coronary angiography (QCA). Methods: 21 patients (23 vessels) were examined with DSCT, IVUS and invasive coronary angiography. Coronary minimal luminal diameter (MLD) and area (MLA) were measured in cross-sectional multi-planar reformatted images perpendicular to the vessel long-axis. The vessel cross-sectional area stenosis (MLA/CSA ratio) was calculated. DSCT results were compared with IVUS and QCA. Results: A good correlation between DSCT and IVUS was noted for diameter and area stenosis (r =0.69 and r =0.73), with an overestimation of MLD stenosis by DSCT (+9.1%) and an underestimation of MLA stenosis (−5.8%). For MLD and MLA, high correlation coefficients (r =0.78 and r =0.90, respectively) were found between DSCT and IVUS; and the bias was almost zero (−0.41mm and +0.1mm2, respectively). The correlation between DSCT and QCA was moderate (r =0.60) for MLD stenosis with minor overestimation by DSCT (+4.0%) and moderate (r =0.59) for MLD (bias, +0.01mm). The cross-sectional area stenosis showed a moderate correlation (r =0.59) between DSCT and IVUS (+0.00). Conclusions: DSCT allows accurate quantification of coronary stenosis as compared to IVUS. An excellent correlation was found for the MLA between DSCT and IVUS. [Copyright &y& Elsevier]

Objectives: This study sought to determine the feasibility of performing a comprehensive cardiac computed tomographic (CT) examination incorporating stress and rest myocardial perfusion imaging together with coronary computed tomography angiography (CTA). Background: Although cardiac CT can identify coronary stenosis, very little data exist on the ability to detect stress-induced myocardial perfusion defects in humans. Methods: Thirty-four patients who had a nuclear stress test and invasive angiography were included in the study. Dual-source computed tomography (DSCT) was performed as follows: 1) stress CT: contrast-enhanced scan during adenosine infusion; 2) rest CT: contrast-enhanced scan using prospective triggering; and 3) delayed scan: acquired 7 min after rest CT. Images for CTA, computed tomography perfusion (CTP), and single-photon emission computed tomography (SPECT) were each read by 2 independent blinded readers. Results: The DSCT protocol was successfully completed for 33 of 34 subjects (average age 61.4 ± 10.7 years; 82% male; body mass index 30.4 ± 5 kg/m2) with an average radiation dose of 12.7 mSv. On a per-vessel basis, CTP alone had a sensitivity of 79% and a specificity of 80% for the detection of stenosis ≥50%, whereas SPECT myocardial perfusion imaging had a sensitivity of 67% and a specificity of 83%. For the detection of vessels with ≥50% stenosis with a corresponding SPECT perfusion abnormality, CTP had a sensitivity of 93% and a specificity of 74%. The CTA during adenosine infusion had a per-vessel sensitivity of 96%, specificity of 73%, and negative predictive value of 98% for the detection of stenosis ≥70%. Conclusions: Adenosine stress CT can identify stress-induced myocardial perfusion defects with diagnostic accuracy comparable to SPECT, with similar radiation dose and with the advantage of providing information on coronary stenosis. [Copyright &y& Elsevier]

Cardiac magnetic resonance (CMR) has been shown to predict left ventricular (LV) recovery in patients after acute ST-segment elevation myocardial infarction. The purpose of this investigation was to determine the relative values of infarct transmurality and microvascular obstruction (MVO) using delayed enhancement CMR to predict LV recovery. We studied 17 patients (mean age 60 ± 10 years, 14 men) presenting with first acute ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention who underwent CMR within 6 days after presentation and again at 6 months. In total 680 myocardial segments were evaluated, of which 267 (39%) demonstrated delayed hyperenhancement (DHE) and 116 (18%) demonstrated MVO. Unadjusted odds ratio (OR) for any improvement in regional LV function with increasing DHE category (<50%, 51% to 75%, >75% transmurality) was 0.20 (95% confidence interval [CI] 0.13 to 0.30, p <0.0001), whereas it was 0.40 (95% CO 0.28 to 0.55, p <0.0001) with increasing MVO category (0, <50th, >50th percentile). However, when coadjusted together, the relation remained robust with regard to degree of transmurality of DHE (OR 0.21, 95% CI 0.13 to 0.36, p <0.0001), but the relation was lost for MVO (OR 0.90, 95% CI 0.58 to 1.40, p = 0.64). In conclusion, when using the delayed enhancement technique for assessment of DHE and MVO, degree of infarct transmurality appears to be a more powerful predictor of LV recovery by CMR. [Copyright &y& Elsevier]