68Ga labeled EphA2-targeted cyclic peptide: a novel positron imaging tracer for triple-negative breast cancer?

The absence of better biomarkers currently limits early diagnosis and treatment of triple-negative breast cancer (TNBC). Our previously published study reported that the cyclic-peptide SD01 exhibited specific binding to EphA2 (Ephrin type-A receptor 2) on TNBC. To develop a novel PET imaging agent, we prepared gallium-68 (68Ga) labeled-DOTA-SD01 and evaluated its specificity and effectiveness through micro PET/CT imaging in a TNBC-bearing mouse model. SD01 and a control linear peptide YSA were conjugated to DOTA and subsequently labeled with 68Ga, obtaining 68Ga-DOTA-SD01 and 68Ga-DOTA-YSA. Both showed high radiochemical purity, stability, good hydrophilicity, and high binding affinity to 4T1 cells. Micro PET/CT imaging showed high radioactivity accumulation in tumors; SUVmean (mean standardized uptake value) of tumors in the group of 68Ga-DOTA-SD01 was 3.34 ± 0.25 and 2.65 ± 0.32 in the group of 68Ga-DOTA-YSA; T/NT ratios (target to non-target, SUVmean ratios of tumor to muscle) were 3.12 ± 0.06 and 2.77 ± 0.11 at 30 min, respectively (p < 0.05). The biodistribution study showed that tumor uptake % ID per g (percentage of injected dose per gram of tissue) in the group of 68Ga-DOTA-SD01 was 2.73 ± 0.34, and 1.77 ± 0.38 in the group of 68Ga-DOTA-YSA; T/NT ratios (radioactivity of tumor to muscle) were 3.55 ± 0.12 and 3.05 ± 0.10 for both groups at 30 min, respectively (p < 0.05). All these suggest that 68Ga-DOTA-SD01 may act as a better novel PET imaging agent for EphA2 positive tumors, such as TNBC.

A stepwise strategy integrating dynamic stress CT myocardial perfusion and deep learning-based FFRCT in the work-up of stable coronary artery disease.

OBJECTIVES: To validate a novel stepwise strategy in which computed tomography-derived fractional flow reserve (FFRCT) is restricted to intermediate stenosis on coronary computed tomography angiography (CCTA) and computed tomography myocardial perfusion imaging (CT-MPI) was reserved for vessels with gray zone FFRCT values. MATERIALS AND METHODS: This retrospective study included 87 consecutive patients (age, 58 ± 10 years; 70% male) who underwent CCTA, dynamic CT-MPI, interventional coronary angiography (ICA), and fractional flow reserve (FFR) for suspected or known coronary artery disease. FFRCT was computed using a deep learning-based platform. Three stepwise strategies (CCTA + FFRCT + CT-MPI, CCTA + FFRCT, CCTA + CT-MPI) were constructed and their diagnostic performance was evaluated using ICA/FFR as the reference standard. The proportions of vessels requiring further ICA/FFR measurement based on different strategies were noted. Furthermore, the net reclassification index (NRI) was calculated to ascertain the superior model. RESULTS: The CCTA + FFRCT + CT-MPI strategy yielded the lowest proportion of vessels requiring additional ICA/FFR measurement when compared to the CCTA + FFRCT and CCTA + CT-MPI strategies (12%, 22%, and 24%). The CCTA + FFRCT + CT-MPI strategy exhibited the highest accuracy for ruling-out (91%, 84%, and 85%) and ruling-in (90%, 85%, and 85%) functionally significant lesions. All strategies exhibited comparable sensitivity for ruling-out functionally significant lesions and specificity for ruling-in functionally significant lesions (p > 0.05). The NRI indicated that the CCTA + FFRCT + CT-MPI strategy outperformed the CCTA + FFRCT strategy (NRI = 0.238, p < 0.001) and the CCTA + CT-MPI strategy (NRI = 0.233%, p < 0.001). CONCLUSIONS: The CCTA + FFRCT + CT-MPI stepwise strategy was superior to the CCTA + FFRCT strategy and CCTA+ CT-MPI strategy by minimizing unnecessary invasive diagnostic catheterization without compromising the agreement rate with ICA/FFR. CLINICAL RELEVANCE STATEMENT: Our novel stepwise strategy facilitates greater confidence and accuracy when clinicians need to decide on interventional coronary angiography referral or deferral, reducing the burden of invasive investigations on patients. KEY POINTS: • A stepwise CCTA + FFRCT + CT-MPI strategy holds promise as a viable method to reduce the need for invasive diagnostic catheterization, while maintaining a high level of agreement with ICA/FFR. • The CCTA + FFRCT + CT-MPI strategy performed better than the CCTA + FFRCT and CCTA + CT-MPI strategies. • A stepwise CCTA + FFRCT + CT-MPI strategy allows to minimize unnecessary invasive diagnostic catheterization and helps clinicians to referral or deferral for ICA/FFR with more confidence.

Fabricable concentric-ring metalens with high focusing efficiency based on two-dimensional subwavelength unit splicing.

To address the challenges posed by computational resource consumption and data volume in the development of large-aperture metalenses, a design method for concentric-ring metalens based on two-dimensional unit splicing is proposed in this paper. In the method, the unit structure library is constructed through global traversal under the machining process constraints. The phase matching is performed for two polarization states with specific weights and the design of binary-height, concentric-ring structures with arbitrary polarization sensitivity is realized, whose focusing efficiency (the encircled power within 3×FWHM of the focal spot divided by the near-field outgoing power) is up to 90%. Based on this method, a polarization-insensitive metalens with a design wavelength of 10µm, diameter of 2 cm, and numerical aperture of 0.447 is obtained. The method combines the advantages of lower computation requirements for a building block array of a metalens and lower structure data for a concentric-ring metalens. Consequently, it becomes possible to reduce calculation and processing costs by several orders of magnitude during the development process of metalenses with diameters ranging from 103 to 105 wavelengths. The resulting focusing efficiency can approach the upper limit achievable through global structural optimization and significantly surpass that of binary-height Fresnel lenses.

Association between resting myocardial work indices and stress myocardial perfusion in patients with angina and non-obstructive coronary artery disease.

Background: Myocardial work (MW) indices and longitudinal strain (LS) are sensitive markers of early left ventricular systolic dysfunction. Stress computed tomography myocardial perfusion imaging (CT-MPI) can assess early myocardial ischemia. The association between resting MW indices and stress myocardial perfusion remains unclear. This study compares resting MW indices with LS to assess stress myocardial perfusion in angina patients with non-obstructive coronary artery disease (CAD). Methods: Eighty-four patients who underwent resting echocardiography, coronary computed tomography angiography, and stress CT-MPI were reviewed. Seventeen myocardial segments were divided into three regions according to the epicardial coronary arteries. Global indices included global longitudinal strain (GLS), global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE). Regional indices included regional longitudinal strain (RLS), regional work index (RWI), and regional work efficiency (RWE). Reduced global perfusion was defined as an average stress myocardial blood flow (MBF) <116 mL/100 mL/min for the whole heart. Reduced regional perfusion was defined as an average stress MBF <116 mL/100 mL/min for the coronary territories. No patients demonstrated obstructions in the epicardial coronary arteries (stenosis diameter <50%). The MW indices and LS were compared. Receiver operating characteristic curves were constructed and logistic regression analyses were used to investigate the predictors of reduced myocardial perfusion. Results: Patients with reduced stress perfusion demonstrated reduced GLS, GWI, GCW, and GWE (P<0.05) and increased GWW (P<0.05). After adjustment for age and sex, GWE was still independently associated with reduced myocardial perfusion (odds ratio =0.386, 95% confidence interval: 0.214-0.697; P<0.05). Receiver operating characteristic curves reflected the good diagnostic ability of GWE and its superiority to GLS (area under the curve: 0.858 vs. 0.741). The optimal cutoff GWE value was 95% (sensitivity, 70%; specificity, 90%). Regions with lower stress perfusion showed lower RLS, RWI, and RWE (P<0.05). The optimal cutoff value of RWE for predicting reduced regional perfusion was 95%, with an area under the curve of 0.780, a sensitivity of 62%, and a specificity of 83%. Conclusions: Resting MW indices perform well in assessing global and regional stress myocardial perfusion in angina patients with non-obstructive CAD, and GWE is superior to GLS in the global evaluations.

Topologically optimized concentric-nanoring metalens with 1 mm diameter, 0.8†NA and 600†nm imaging resolution in the visible.

Metalenses can achieve diffraction-limited focusing via localized phase modification of the incoming light beam. However, the current metalenses face to the restrictions on simultaneously achieving large diameter, large numerical aperture, broad working bandwidth and the structure manufacturability. Herein, we present a kind of metalenses composed of concentric nanorings that can address these restrictions using topology optimization approach. Compared to existing inverse design approaches, the computational cost of our optimization method is greatly reduced for large-size metalenses. With its design flexibility, the achieved metalens can work in the whole visible range with millimeter size and a numerical aperture of 0.8 without involving high-aspect ratio structures and large refractive index materials. Electron-beam resist PMMA with a low refractive index is directly used as the material of the metalens, enabling a much more simplified manufacturing process. Experimental results show that the imaging performance of the fabricated metalens has a resolution better than 600 nm corresponding to the measured FWHM of 745 nm.

High-Efficiency Achromatic Metalens Topologically Optimized in the Visible.

Metalens, composed of arrays of nano-posts, is an ultrathin planar optical element used for constructing compact optical systems which can achieve high-performance optical imaging by wavefront modulating. However, the existing achromatic metalenses for circular polarization possess the problem of low focal efficiency, which is caused by the low polarization conversion efficiencies of the nano-posts. This problem hinders the practical application of the metalens. Topology optimization is an optimization-based design method that can effectively extend the degree of design freedom, allowing the phases and polarization conversion efficiencies of the nano-posts to be taken into account simultaneously in the optimization procedures. Therefore, it is used to find geometrical configurations of the nano-posts with suitable phase dispersions and maximized polarization conversion efficiencies. An achromatic metalens has a diameter of 40 µm. The average focal efficiency of this metalens is 53% in the spectrum of 531 nm to 780 nm by simulation, which is higher than the previously reported achromatic metalenses with average efficiencies of 20~36%. The result shows that the introduced method can effectively improve the focal efficiency of the broadband achromatic metalens.

One-stop patient-specific myocardial blood flow quantification technique based on allometric scaling law.

Establishing a patient-specific and non-invasive technique to derive blood flow as well as coronary structural information from one single cardiac CT imaging modality. 336 patients with chest pain or ST segment depression on electrocardiogram were retrospectively enrolled. All patients underwent adenosine-stressed dynamic CT myocardial perfusion imaging (CT-MPI) and coronary computed tomography angiography (CCTA) in sequence. Relationship between myocardial mass (M) and blood flow (Q), defined as log(Q) = b · log(M) + log(Q0), was explored based on the general allometric scaling law. We used 267 patients to obtain the regression results and found strong linear relationship between M (gram) and Q (mL/min) (b = 0.786, log(Q0) = 0.546, r = 0.704; p < 0.001). We Also found this correlation was applicable for patients with either normal or abnormal myocardial perfusion (p < 0.001). Datasets from the other 69 patients were used to validate this M-Q correlation and found the patient-specific blood flow could be accurately estimated from CCTA compared to that measured from CT-MPI (146.480 ± 39.607 vs 137.967 ± 36.227, r = 0.816, and 146.480 ± 39.607 vs 137.967 ± 36.227, r = 0.817, for the left ventricle region and LAD-subtended region, respectively, all unit in mL/min). In conclusion, we established a technique to provide general and patient-specific myocardial mass-blood flow correlation obeyed to allometric scaling law. Blood flow information could be directly derived from structural information acquired from CCTA.

CD93 in macrophages: A novel target for atherosclerotic plaque imaging?

Noninvasive imaging atherosclerotic (AS) plaque is of great importance for early diagnosis. Recently, CD93 in MΦ was linked to atherosclerosis development. Herein, we have investigated whether CD93 in MΦ is a potential novel target for atherosclerotic plaque imaging. CD93hi and CD93lo MΦ were prepared with or without LPS stimulation, before biological activity was evaluated. A rat AS model was produced with left carotid artery clamped. Whole-body/ex vivo phosphor autoradiography of the artery and biodistribution were investigated after incorporation of 3 H-2-DG into CD93hi and CD93lo MΦ or after 125 I-α-CD93 (125 I-anti-CD93mAb) injection. The plaque tissue was subjected to CD93/CD68 immunofluorescence/immunohistochemistry staining. CD93hi and CD93lo MΦ cells were successfully prepared without significant effect on bioactivity after incorporative labelled with 3 H-2-DG. The AS model was successfully established. Biodistribution studies showed that adoptive transfer of 3 H-2-DG-CD93hi MΦ or 125 I- α-CD93 injection resulted in accumulation of radioactivity within the atherosclerotic plaque in the clamped left carotid artery. T/NT (target/non-target, left/right carotid artery) ratio was higher in the 3 H-2-DG-CD93hi MΦ adoptive transfer group than in the 3 H-2-DG-CD93lo MΦ group (p < .05). Plaque radioactivity in the 125 I-α-CD93 injection group was significantly higher than in the 125 I-IgG control group (p < .01). The higher radioactivity accumulated in the clamped left carotid artery was confirmed by phosphor autoradiography. More importantly, CD93/CD68 double-positive MΦ accumulated at the atherosclerotic plaque in 3 H-2-DG-CD93hi MΦ adoptive transfer group, which correlated with plaque radioactivity (r = .99, p < .01). In summary, both adoptive-transferred 3 H-2-DG-labelled CD93hi MΦ and 125 I-α-CD93 injection specifically targeted CD93 in atherosclerotic plaque. CD93 is a potential target in atherosclerotic plaque imaging.

Knowledge of Hyperemic Myocardial Blood Flow in Healthy Subjects Helps Identify Myocardial Ischemia in Patients With Coronary Artery Disease.

BACKGROUNDS: Dynamic CT myocardial perfusion imaging (CT-MPI) allows absolute quantification of myocardial blood flow (MBF). Although appealing, CT-MPI has not yet been widely applied in clinical practice, partly due to our relatively limited knowledge of CT-MPI. Knowledge of distribution and variability of MBF in healthy subjects helps in recognition of physiological and pathological states of coronary artery disease (CAD). OBJECTIVES: To describe the distribution and normal range of hyperemic MBF in healthy subjects obtained by dynamic CT-MPI and validate whether it can accurately identify functional myocardial ischemia when the cut-off value of hyperemia MBF is set to the lower limit of the normal range. MATERIALS AND METHODS: Fifty-one healthy volunteers (age, 38 ± 12 years; 15 men) were prospectively recruited. Eighty patients (age, 58 ± 10 years; 55 men) with suspected or known CAD who underwent interventional coronary angiography (ICA) examinations were retrospectively recruited. Comprehensive CCTA + dynamic CT-MPI protocol was performed by the third - generation dual-source CT scanner. Invasive fractional flow reserve (FFR) measurements were performed in vessels with 30-90% diameter reduction. ICA/FFR was used as the reference standard for diagnosing functional ischemia. The normal range for the hyperemic MBF were defined as the mean ± 1.96 SD. The cut-off value of hyperemic MBF was set to the lower limit of the normal range. RESULTS: The global hyperemic MBF were 164 ± 24 ml/100 ml/min and 123 ± 26 ml/100 ml/min for healthy participants and patients. The normal range of the hyperemic MBF was 116-211 ml/100 ml/min. Of vessels with an ICA/FFR result (n = 198), 67 (34%) were functionally significant. In the per-vessel analysis, an MBF cutoff value of <116 ml/100 ml/min can identify myocardial ischemia with a diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of 85.9% (170/198), 91.0% (61/67), 83.2 % (109/131), 73.5% (61/83), and 94.8% (109/115). CT-MPI showed good consistency with ICA/FFR in diagnosing functional ischemia, with a Cohen's kappa statistic of 0.7016 (95%CI, 0.6009 - 0.8023). CONCLUSION: Recognizing hyperemic MBF in healthy subjects helps better understand myocardial ischemia in CAD patients.

Nanoantennas Inversely Designed to Couple Free Space and a Metal-Insulator-Metal Waveguide.

The metal-insulator-metal (MIM) waveguide, which can directly couple free space photons, acts as an important interface between conventional optics and subwavelength photoelectrons. The reason for the difficulty of this optical coupling is the mismatch between the large wave vector of the MIM plasmon mode and photons. With the increase in the wave vector, there is an increase in the field and Ohmic losses of the metal layer, and the strength of the MIM mode decreases accordingly. To solve those problems, this paper reports on inversely designed nanoantennas that can couple the free space and MIM waveguide and efficiently excite the MIM plasmon modes at multiple wavelengths and under oblique angles. This was achieved by implementing an inverse design procedure using a topology optimization approach. Simulation analysis shows that the coupling efficiency is enhanced 9.47-fold by the nanoantenna at the incident wavelength of 1338 nm. The topology optimization problem of the nanoantennas was analyzed by using a continuous adjoint method. The nanoantennas can be inversely designed with decreased dependence on the wavelength and oblique angle of the incident waves. A nanostructured interface on the subwavelength scale can be configured in order to control the refraction of a photonic wave, where the periodic unit of the interface is composed of two inversely designed nanoantennas that are decoupled and connected by an MIM waveguide.

Down-Regulation of Toll-Like Receptor 5 (TLR5) Increased VEGFR Expression in Triple Negative Breast Cancer (TNBC) Based on Radionuclide Imaging.

In this study, GFP-tagged TNBC 4T1 cells with down-regulated TLR5 expression (TLR5- 4T1) and normal TLR5 expression (TLR5+ 4T1) were constructed, respectively. RT-PCR and Western blot studies showed that down-regulation of TLR5 obviously increased the expression of VEGFR in 4T1 cells. Highly stable radio-probes 125I-anti-TLR5 mAb/125I-VEGF/125I-IgG were obtained with labeling rates over 85% and radiochemical purities above 90%. Among these three probes, 125I-anti-TLR5 mAb and 125I-VEGF were used for specifically imaging TNBC, while 125I-IgG was used for comparison. Whole-body phosphorus autoradiography showed clear imaging at 48 h after injection of 125I-anti-TLR5 mAb and 125I-VEGF also provided clear imaging at 24 h. Biodistribution study demonstrated a higher tumor uptake of 125I-anti-TLR5 mAb in TLR5+ group compared with that in TLR5- group (P < 0.05), whereas tumor uptake of 125I-VEGF in TLR5+ group was lower than that in the TLR5- group (P < 0.05). Immunohistochemical staining suggested that the expression of TLR5 was lower, whereas the expression of VEGFR, CD31, and MVD (microvessel density) was higher in TLR5- tumor-bearing mice. In summary, the down-regulation of TLR5 in TNBC promoted the VEGFR expression and angiogenesis, resulting in the proliferation of TNBC cells. TLR5/VEGF might be a better indicator for monitoring the development of TNBC.

Comprehensive understanding of the focal property of lobster-eye optics.

Lobster-eye optics is a promising option to establish an all-sky monitor in the X-ray spectrum. With the development of micromachining technology, the performance of lobster-eye optics is gradually improving and has become more practical. In this paper, from an optical design point of view, the mathematical models of the square-channel lobster-eye lens and the meridional lobster-eye lens have been established based on prism analysis, and the focusing property differences of the two lenses are analyzed. There are several key conclusions: the square-channel lobster lens has no paraxial ideal focal point; the meridional lobster eye lens has better energy concentration for focusing and a weaker capacity for energy collection than the square-channel lobster eye lens in the high-energy X-ray spectrum; and the stray light arms of the square lobster-eye lens appear earlier than those of the meridional lobster-eye lens when the photon energy decreases. These conclusions can help improve the design of a lobster-eye lens for space detection and exploration.

Structural design method of the meridional lobster-eye lens with optimal efficiency.

Lobster-eye optics has been proposed as a high-energy detection device with great potential for astronomical observation and safety inspection due to its large-field-of-view (FOV) focusing ability. In this paper, we study the relationship between the optimal structural parameters of the meridional lobster-eye lens and focusing efficiency. The maximum odd-reflection component, which relates only to the FOV and the channel ratio of depth to width, has been found. Furthermore, the structural constant C, which determines the optimal efficiency structure of the meridional lobster-eye lens, is revealed for hard x-rays. Meanwhile, by introducing accurate reflectivity of iridium in soft x-rays, the constraint of the effective FOV with respect to x-ray wavelength is analyzed. The research results can help to design the optimal structure of the lobster-eye lens in multiple spectra.

Down-regulating cyclin-dependent kinase 9 of alloreactive CD4+ T cells prolongs allograft survival.

CDK9 (Cyclin-dependent kinase 9)/Cyclin T1/RNA polymerase II pathway has been demonstrated to promote the development of several inflammatory diseases, such as arthritis or atherosclerosis, however, its roles in allotransplantation rejection have not been addressed. Here, we found that CDK9/Cyclin T1 were apparently up-regulated in the allogeneic group, which was positively correlated with allograft damage. CDK9 was inhibited obviously in naive splenic CD4+ T cells treated 6 h with 3 µM PHA767491 (a CDK9 inhibitor), and adoptive transfer of these CD4+ T cells into allografted SCID mice resulted in prolonged survival compared with the group without PHA767491 pretreated. Decelerated rejection was correlated with enhanced IL-4 and IL-10 production and with decreased IFN-γ production by alloreactive T cells. More interestingly, we found that CDK942, not CDK955,was high expressed in allorejection group, which could be prominently dampened with PHA767491 treatment. The expression of CDK942 was consistent with its downstream molecule RNA polymerase II. Altogether, our findings revealed the crucial role of CDK9/Cyclin T1/Pol II pathway in promoting allorejection at multiple levels and may provide a new approach for transplantation tolerance induction through targeting CDK9.

Signaling mechanisms of bortezomib in TRAF3-deficient mouse B lymphoma and human multiple myeloma cells.

Bortezomib, a clinical drug for multiple myeloma (MM) and mantle cell lymphoma, exhibits complex mechanisms of action, which vary depending on the cancer type and the critical genetic alterations of each cancer. Here we investigated the signaling mechanisms of bortezomib in mouse B lymphoma and human MM cells deficient in a new tumor suppressor gene, TRAF3. We found that bortezomib consistently induced up-regulation of the cell cycle inhibitor p21(WAF1) and the pro-apoptotic protein Noxa as well as cleavage of the anti-apoptotic protein Mcl-1. Interestingly, bortezomib induced the activation of NF-κB1 and the accumulation of the oncoprotein c-Myc, but inhibited the activation of NF-κB2. Furthermore, we demonstrated that oridonin (an inhibitor of NF-κB1 and NF-κB2) or AD 198 (a drug targeting c-Myc) drastically potentiated the anti-cancer effects of bortezomib in TRAF3-deficient malignant B cells. Taken together, our findings increase the understanding of the mechanisms of action of bortezomib, which would aid the design of novel bortezomib-based combination therapies. Our results also provide a rationale for clinical evaluation of the combinations of bortezomib and oridonin (or other inhibitors of NF-κB1/2) or AD 198 (or other drugs targeting c-Myc) in the treatment of lymphoma and MM, especially in patients containing TRAF3 deletions or relevant mutations.

Serum cyclin-dependent kinase 9 is a potential biomarker of atherosclerotic inflammation.

Atherosclerotic coronary artery disease (CAD) is one of the most prevalent diseases worldwide. Atherosclerosis was considered to be the single most important contributor to CAD. In this study, a distinct serum protein expression pattern in CAD patients was demonstrated by proteomic analysis with two-dimensional gel electrophoresis coupled with mass spectrometry. In particular, CDK9 was found to be highly elevated in serum, monocytes and artery plaque samples of CAD patients. Furthermore, there was high infiltration of CD14+ monocytes/macrophages within artery plaques correlated with the expression of CDK9. Moreover, Flavopiridol (CDK9 inhibitor) could inhibit THP-1 cell (monocytic acute leukemia cell line) proliferation by targeting CDK9. Altogether, These findings indicate that CDK9 represent an important role for inflammation in the pathogenesis of atherosclerosis. It may be a potential biomarker of atherosclerotic inflammation and offer insights into the pathophysiology and targeted therapy for atherosclerotic CAD.

TRAF3: a novel tumor suppressor gene in macrophages.

Tumor necrosis factor receptor-associated factor 3 (TRAF3), a member of the TRAF family of cytoplasmic adaptor proteins with E3 ligase activity, is ubiquitously expressed in various cell types of the immune system. It is shared for signaling by a variety of adaptive and innate immune receptors as well as cytokine receptors. Previous studies examining conditional TRAF3-deficient mouse models that have the Traf3 gene specifically deleted in B lymphocytes or T lymphocytes have revealed the diverse and critical in vivo functions of TRAF3 in adaptive immunity. Although in vitro evidence points to a pivotal and indispensable role for TRAF3 in type I interferon production induced by pattern recognition receptors in macrophages and dendritic cells, the in vivo functions of TRAF3 in the innate immune system had long remained unclear. Three laboratories have recently addressed this gap in knowledge by investigating myeloid cell-specific TRAF3-deficient (genotype: TRAF3flox/floxLysM+/Cre) mice. The new evidence together demonstrates that specific ablation of TRAF3 in myeloid cells leads to inflammatory diseases, altered progression of diabetes, and spontaneous development of different types of tumors and infections in mice. These new findings indicate that TRAF3 acts as an anti-inflammatory factor and is required for optimal innate immunity in myeloid cells. Strikingly, the new evidence also identifies TRAF3 as a novel tumor suppressor gene in macrophages and other myeloid cells. In this review, we discuss and summarize the new findings and current knowledge about the multi-faceted regulatory roles and complex signaling mechanisms of myeloid cell TRAF3 in inflammation, innate immunity, and tumor development.

MiR-135b-5p and MiR-499a-3p Promote Cell Proliferation and Migration in Atherosclerosis by Directly Targeting MEF2C.

Proliferation and migration of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are critical processes involved in atherosclerosis. Recent studies have revealed that microRNAs (miRNAs) can be detected in circulating blood with a stable form and the expression profiles differ in many cellular processes associated with coronary artery disease (CAD). However, little is known about their role, especially serum-derived miRNAs, in ECs and VSMCs phenotype modulation during atherosclerosis. We compared the miRNA expressions in serum samples from 13 atherosclerotic CAD patients and 5 healthy control subjects and identified 36 differentially expressed miRNAs. The expression of selected miRNAs (miR-135b-5p and miR-499a-3p) was further validated in 137 serum samples. Interestingly, miR-135b-5p and miR-499a-3p directly regulated a common target gene: myocyte enhancer factor 2C (MEF2C) which plays an important role in modulating cell phenotype of cardiovascular systems. Furthermore, our results indicated that the 2 elevated miRNAs could jointly promote ECs and VSMCs proliferation and migration by repressing MEF2C expression. Together, our findings demonstrated a serum-based miRNA expression profile for atherosclerotic CAD patients, potentially revealing a previously undocumented mechanism for cell proliferation and migration mediated by miR-135b-5p and miR-499a-3p, and might provide novel insights into the role of circulating miRNAs in atherosclerosis pathogenesis.

Cyclin-dependent kinase 9 may as a novel target in downregulating the atherosclerosis inflammation (Review).

Inflammation is a key component of atherosclerosis. Genes coding for inflammatory or anti-inflammatory molecules are considered good candidates for estimating the risk of developing atherosclerosis. Cyclin-dependent kinase 9 (CDK9), the kinase of positive transcription elongation factor b (P-TEFb), is crucial in the cell cycle and apoptosis. Previous studies have focused on its inhibition of immune cells for the resolution of inflammation. Considering the effects of inflammation in the pathogenicity of atherosclerosis, decreasing inflammation through the inhibition of CDK9 may be useful for the prognosis of atherosclerosis. The aim of this review was to examine whether inhibition of the CDK9 monocyte may affect the process of inflammation by acting on the cytokine secretion and interacting with endothelial cells (ECs). Thus, CDK9 may be a novel target for the diagnosis and therapy of atherosclerosis.

Macrophage migration inhibitory factor plays a pivotal role in hepatocellular carcinoma and may be a noninvasive imaging target.

Macrophage migration inhibitory factor (MIF) has emerged to play a central role in the control of the host inflammatory and immune response. Several reports have documented that MIF can inactivate the tumor suppresser activity of p53; overexpression of MIF was significantly higher in both the sera and the local lesions from patients with HCC than from patients with normal controls. These findings indicate that MIF may contribute to multiple aspects of tumor progression and neoplasia, thus MIF may be an effective therapeutic target molecule. We speculate that MIF is important for the development and progression of hepatocellular carcinoma, and can be used as a marker for tumor detection.