CLDN18.2 BiTE Engages Effector and Regulatory T Cells for Antitumor Immune Response in Preclinical Models of Pancreatic Cancer.

BACKGROUND & AIMS: BiTE (bispecific T-cell engager) immune therapy has demonstrated clinical activity in multiple tumor indications, but its influence in the tumor microenvironment remains unclear. CLDN18.2 is overexpressed in solid tumors including gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC), both of which are characterized by the presence of immunosuppressive cells, including regulatory T cells (Tregs) and few effector T cells (Teffs). METHODS: We evaluated the activity of AMG 910, a CLDN18.2-targeted half-life extended (HLE) BiTE molecule, in GC and PDAC preclinical models and cocultured Tregs and Teffs in the presence of CLDN18.2-HLE-BiTE. RESULTS: AMG 910 induced potent, specific cytotoxicity in GC and PDAC cell lines. In GSU and SNU-620 GC xenograft models, AMG 910 engaged human CD3+ T cells with tumor cells, resulting in significant antitumor activity. AMG 910 monotherapy, in combination with a programmed death-1 (PD-1) inhibitor, suppressed tumor growth and enhanced survival in an orthotopic Panc4.14 PDAC model. Moreover, Treg infusion enhanced the antitumor efficacy of AMG 910 in the Panc4.14 model. In syngeneic KPC models of PDAC, treatment with a mouse surrogate CLDN18.2-HLE-BiTE (muCLDN18.2-HLE-BiTE) or the combination with an anti-PD-1 antibody significantly inhibited tumor growth. Tregs isolated from mice bearing KPC tumors that were treated with muCLDN18.2-HLE-BiTE showed decreased T cell suppressive activity and enhanced Teff cytotoxic activity, associated with increased production of type I cytokines and expression of Teff gene signatures. CONCLUSIONS: Our data suggest that BiTE molecule treatment converts Treg function from immunosuppressive to immune enhancing, leading to antitumor activity in immunologically "cold" tumors.

Dual Stromal Targeting Sensitizes Pancreatic Adenocarcinoma for Anti-Programmed Cell Death Protein 1 Therapy.

BACKGROUND & AIMS: The stroma in pancreatic ductal adenocarcinoma (PDAC) contributes to its immunosuppressive nature and therapeutic resistance. Herein we sought to modify signaling and enhance immunotherapy efficacy by targeting multiple stromal components through both intracellular and extracellular mechanisms. METHODS: A murine liver metastasis syngeneic model of PDAC was treated with focal adhesion kinase inhibitor (FAKi), anti-programmed cell death protein 1 (PD-1) antibody, and stromal hyaluronan (HA) degradation by PEGylated recombinant human hyaluronidase (PEGPH20) to assess immune and stromal modulating effects of these agents and their combinations. RESULTS: The results showed that HA degradation by PEGPH20 and reduction in phosphorylated FAK expression by FAKi leads to improved survival in PDAC-bearing mice treated with anti-PD-1 antibody. HA degradation in combination with FAKi and anti-PD-1 antibody increases T-cell infiltration and alters T-cell phenotype toward effector memory T cells. FAKi alters the expression of T-cell modulating cytokines and leads to changes in T-cell metabolism and increases in effector T-cell signatures. HA degradation in combination with anti-PD-1 antibody and FAKi treatments reduces granulocytes, including granulocytic- myeloid-derived suppressor cells and decreases C-X-C chemokine receptor type 4 (CXCR4)-expressing myeloid cells, particularly the CXCR4-expressing granulocytes. Anti-CXCR4 antibody combined with FAKi and anti-PD-1 antibody significantly decreases metastatic rates in the PDAC liver metastasis model. CONCLUSIONS: This represents the first preclinical study to identify synergistic effects of targeting both intracellular and extracellular components within the PDAC stroma and supports testing anti-CXCR4 antibody in combination with FAKi as a PDAC treatment strategy.

Dichromic Allophycocyanin Trimer Covering a Broad Spectral Range (550-660†nm).

Phycobilisomes, the light-harvesting complexes of cyanobacteria and red algae, are a resource for photosynthetic, photonic and fluorescence labeling elements. They cover an exceptionally broad spectral range, but the complex superstructure and assembly have been an obstacle. By replacing in Synechocystis sp. PCC 6803 the biliverdin reductases, we studied the role of chromophores in the assembly of the phycobilisome core. Introduction of the green-absorbing phycoerythrobilin instead of the red-absorbing phycocyanobilin inhibited aggregation. A novel, trimeric allophycocyanin (Dic-APC) was obtained. In the small (110 kDa) unit, the two chromophores, phycoerythrobilin and phytochromobilin, cover a wide spectral range (550 to 660 nm). Due to efficient energy transfer, it provides an efficient artificial light-harvesting element. Dic-APC was generated in vitro by using the contained core-linker, LC , for template-assisted purification and assembly. Labeling the linker provides a method for targeting Dic-APC.

Regulative Roles of Metabolic Plasticity Caused by Mitochondrial Oxidative Phosphorylation and Glycolysis on the Initiation and Progression of Tumorigenesis.

One important feature of tumour development is the regulatory role of metabolic plasticity in maintaining the balance of mitochondrial oxidative phosphorylation and glycolysis in cancer cells. In recent years, the transition and/or function of metabolic phenotypes between mitochondrial oxidative phosphorylation and glycolysis in tumour cells have been extensively studied. In this review, we aimed to elucidate the characteristics of metabolic plasticity (emphasizing their effects, such as immune escape, angiogenesis migration, invasiveness, heterogeneity, adhesion, and phenotypic properties of cancers, among others) on tumour progression, including the initiation and progression phases. Thus, this article provides an overall understanding of the influence of abnormal metabolic remodeling on malignant proliferation and pathophysiological changes in carcinoma.

The phycobilisome core-membrane linkers from Synechocystis sp. PCC 6803 and red-algae assemble in the same topology.

The phycobilisomes (PBSs) of cyanobacteria and red-algae are unique megadaltons light-harvesting protein-pigment complexes that utilize bilin derivatives for light absorption and energy transfer. Recently, the high-resolution molecular structures of red-algal PBSs revealed how the multi-domain core-membrane linker (LCM ) specifically organizes the allophycocyanin subunits in the PBS's core. But, the topology of LCM in these structures was different than that suggested for cyanobacterial PBSs based on lower-resolution structures. Particularly, the model for cyanobacteria assumed that the Arm2 domain of LCM connects the two basal allophycocyanin cylinders, whereas the red-algal PBS structures revealed that Arm2 is partly buried in the core of one basal cylinder and connects it to the top cylinder. Here, we show by biochemical analysis of mutations in the apcE gene that encodes LCM , that the cyanobacterial and red-algal LCM topologies are actually the same. We found that removing the top cylinder linker domain in LCM splits the PBS core longitudinally into two separate basal cylinders. Deleting either all or part of the helix-loop-helix domain at the N-terminal end of Arm2, disassembled the basal cylinders and resulted in degradation of the part containing the terminal emitter, ApcD. Deleting the following 30 amino-acids loop severely affected the assembly of the basal cylinders, but further deletion of the amino-acids at the C-terminal half of Arm2 had only minor effects on this assembly. Altogether, the biochemical data are consistent with the red-algal LCM topology, suggesting that the PBS cores in cyanobacteria and red-algae assemble in the same way.

The altering in sensory sensitivity: a current issue of female breast surgery.

Breast surgery is an important treatment for women with malignant breast diseases. In addition to breast appearance, the integrity of breast function is increasing in patients with breast diseases. As the basis of breast physiological function, breast skin sensitivity is important to the quality of life of patients after surgery. Breast skin sensitivity gives the patient a "real" breast feeling. The sensory recovery after breast surgery has also become one of the important goals of breast surgery. In this review, we aim to discuss the research progress on recovery of breast skin sensitivity after different treatment modalities for breast disease.

Testing software's changing features with environment-driven abstraction identification.

ions are significant domain terms that have assisted in requirements elicitation and modeling. To extend the assistance toward requirements validation, we present in this paper an automated approach to identifying the abstractions for supporting requirements-based testing. We select relevant Wikipedia pages to serve as a domain corpus that is independent from any specific software system. We further define five novel patterns based on part-of-speech tagging and dependency parsing, and frame our candidate abstractions in the form of pairs for better testability, where the "key" helps locate "what to test", and the "value" helps guide "how to test it" by feeding in concrete data. We evaluate our approach with six software systems in two application domains: Electronic health records and Web conferencing. The results show that our abstractions are more accurate than those generated by a state-of-the-art technique. While the initial findings indicate our abstractions' capabilities of revealing bugs and matching the environmental assumptions created manually, we articulate a new way to perform requirements-based testing by focusing on a software system's changing features. Specifically, we hypothesize that the same feature would behave differently under a pair of opposing environmental conditions and assess our abstractions' applicability to this new form of feature testing.

The role of lyases, NblA and NblB proteins and bilin chromophore transfer in restructuring the cyanobacterial light-harvesting complex‡.

Phycobilisomes are large light-harvesting complexes attached to the stromal side of thylakoids in cyanobacteria and red algae. They can be remodeled or degraded in response to changing light and nutritional status. Both the core and the peripheral rods of phycobilisomes contain biliproteins. During biliprotein biosynthesis, open-chain tetrapyrrole chromophores are attached covalently to the apoproteins by dedicated lyases. Another set of non-bleaching (Nb) proteins has been implicated in phycobilisome degradation, among them NblA and NblB. We report in vitro experiments with lyases, biliproteins and NblA/B which imply that the situation is more complex than currently discussed: lyases can also detach the chromophores and NblA and NblB can modulate lyase-catalyzed binding and detachment of chromophores in a complex fashion. We show: (i) NblA and NblB can interfere with chromophorylation as well as chromophore detachment of phycobiliprotein, they are generally inhibitors but in some cases enhance the reaction; (ii) NblA and NblB promote dissociation of whole phycobilisomes, cores and, in particular, allophycocyanin trimers; (iii) while NblA and NblB do not interact with each other, both interact with lyases, apo- and holo-biliproteins; (iv) they promote synergistically the lyase-catalyzed chromophorylation of the ß-subunit of the major rod component, CPC; and (v) they modulate lyase-catalyzed and lyase-independent chromophore transfers among biliproteins, with the core protein, ApcF, the rod protein, CpcA, and sensory biliproteins (phytochromes, cyanobacteriochromes) acting as potential traps. The results indicate that NblA/B can cooperate with lyases in remodeling the phycobilisomes to balance the metabolic requirements of acclimating their light-harvesting capacity without straining the overall metabolic economy of the cell.

Nuclear respiratory factor 1 protects H9C2 cells against hypoxia-induced apoptosis via the death receptor pathway and mitochondrial pathway.

Hypoxia-induced cardiomyocyte apoptosis is one of the leading causes of heart failure. Nuclear respiratory factor 1 (NRF-1) was suggested as a protector against cell apoptosis; However, the mechanism is not clear. Therefore, the aim of this study was to elucidate the role of NRF-1 in hypoxia-induced H9C2 cardiomyocyte apoptosis and to explore its effect on regulating the death receptor pathway and mitochondrial pathway. NRF-1 was overexpressed or knocked down in H9C2 cells, which were then exposed to a hypoxia condition for 0, 3, 6, 12, and 24 h. Changes in cell proliferation, cell viability, reactive oxygen species (ROS) generation, and mitochondrial membrane potential (MMP) were investigated. The activities of caspase-3, -8, and -9, apoptosis rate, and the gene and protein expression levels of the death receptor pathway and mitochondrial pathway were analyzed. Under hypoxia exposure, NRF-1 overexpression improved the proliferation and viability of H9C2 cells and decreased ROS generation, MMP loss, caspase activities, and the apoptosis rate. However, the NRF-1 knockdown group showed the opposite results. Additionally, NRF-1 upregulated the expression of antiapoptotic molecules involved in the death receptor and mitochondrial pathways, such as CASP8 and FADD-like apoptosis regulator, B-cell lymphoma 2, B-cell lymphoma-extra-large, and cytochrome C. Conversely, the expression of proapoptotic molecules, such as caspase-8, BH3-interacting domain death agonist, Bcl-2-associated X protein, caspase-9, and caspase-3 was downregulated by NRF-1 overexpression in hypoxia-induced H9C2 cells. These results suggest that NRF-1 functions as an antiapoptotic factor in the death receptor and mitochondrial pathways to mitigate hypoxia-induced apoptosis in H9C2 cardiomyocytes.

Laparoscopic pancreaticoduodenectomy versus open pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: oncologic outcomes and long-term survival.

OBJECTIVE: The study aimed to compare the oncologic outcomes and long-term survival of laparoscopic pancreaticoduodenectomy (LPD) and open pancreaticoduodenectomy (OPD) for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Substantial evidence demonstrated that LPD is technically safe and feasible with perioperative outcomes equivalent to that of OPD. However, for patients with malignancy, especially PDAC, the oncologic outcomes and long-term survival of patients who underwent LPD remains to be elucidated. METHODS: Studies on LPD for the treatment of PDAC published before December 25, 2018 were searched online. The oncologic outcomes (e.g., numbers of lymph nodes retrieved, negative margin (R0) resection), and long-term survival (postoperative survival from 1 to 5 year) of LPD were compared to that of ODP. RESULTS: After screening 1507 studies, six comparative cohort studies, which reported the oncologic outcomes and long-term survival of patients with PDAC were included. No significant difference was found between LPD and OPD regarding lymph nodes harvested (OR 1.96, 95% CI - 1.17 to 5.09, p = 0.22), R0 rate (OR 1.44, 95% CI 1.00 to 2.06, p = 0.05), number of positive lymph nodes (OR - 0.44, 95% CI - 1.06 to 0.17, p = 0.16), rate of adjuvant treatment (OR 1.04, 95% CI 0.68 to 1.59, p = 0.86) and time to adjuvant treatment (OR - 6.21, 95% CI - 16.00 to 3.59, p = 0.21). LPD showed similar 1-year (OR 1.20, 95% CI 0.87 to 1.65, p = 0.28), and 2-year survival (OR 1.25, 95% CI 0.94 to 1.66, p = 0.13) to that of OPD. The 3-year (OR 1.50, 95% CI 1.12 to 2.02, p = 0.007), 4-year (OR 1.73, 95% CI 1.02 to 2.93, p = 0.04), and 5-year survival (OR 2.11, 95% CI 1.35 to 3.31, p = 0.001) were significantly longer in LPD group. CONCLUSION: For the treatment of PDAC, the oncologic outcomes of LPD were equivalent to that of OPD; LPD seemed promising regarding the postoperative long-term survival.

Discovering Metamorphic Relations for Scientific Software From User Forums.

Scientific software can be used for decades and is constantly evolving. Recently, metamorphic testing, a property-based testing technique, has shown to be effective in testing scientific software, and the necessary properties are expressed as metamorphic relations. However, the development of metamorphic relations is difficult: it requires considerable practical expertise for the software tester. In this article, we report our experience of uncovering metamorphic relations from a user forum's questions of the United States Environmental Protection Agency's Storm Water Management Model (SWMM). Our study not only illustrates a wealth of end users' expertise in interpreting software results, but also demonstrates the usefulness of classifying the user-oriented metamorphic relations into a nominal, ordinal, and functional hierarchy mainly from the software output perspective.

Scientific Software Testing Goes Serverless: Creating and Invoking Metamorphic Functions.

Our function-as-a-service (FaaS) framework transformed end users' questions into automated tests for scientific software. Our case study illustrates the FaaSification of scientific software testing and the importance of value-driven evaluations by focusing on real-world defect detection.

Blockage of macrophage migration inhibitory factor (MIF) suppressed uric acid-induced vascular inflammation, smooth muscle cell de-differentiation, and remodeling.

Hyperuricemia contributes to vascular injury and dysfunction, yet the potential mechanisms are not well understood. Uric acid (UA) has been found to stimulate macrophage migration inhibitory factor (MIF) up-regulation in renal tubules from rats subjected to UA-induced nephropathy. Given that MIF is able to induce vascular smooth muscle cell (VSMC) de-differentiation (from contractile state to a secretory state), we thus hypothesized that UA-induced vascular injury is via up-regulating of MIF in VSMCs, which enhancing vascular inflammation and VSMC transition. Within a mouse model of UA injection (500 mg/kg, twice/day, 14 days), we measured circulating and vascular MIF levels under UA stimulation at 6 h, day 1, and 14. We tested the efficacy of MIF inhibitor (10 mg/kg, twice/day, 14 days) on UA-induced vascular inflammation and remodeling. High plasma level of UA induced vascular MIF release into the plasma at acute phase. In the chronic phase, the protein level of MIF is up-regulated in the vessels. MIF inhibitor suppressed vascular inflammatory responses, repressed VSMC de-differentiation, and attenuated vascular remodeling and dysfunction following UA stimulation. Knockdown of MIF in cultured VSMCs repressed UA-induced de-differentiation. Our results provided a novel mechanism for MIF-mediated vascular injury in response to UA stimulation, and suggested that anti-MIF interventions may be of therapeutic value in hyperuricemic patients.

Optimization of expression of orange carotenoid protein in Escherichia coli.

Naturally-occurring orange carotenoid protein (OCP) is synthesized in cyanobacteria and red algae for photoprotection. Holo-OCP can be produced with three plasmids in E. coli, which needs two inducers (arabinose and isopropyl ß-D-thiogalactoside) to initiate two processes: one for generation of carotenoid and the other for generation of apo-OCP, so takes about two days. Afterwards, a two-plasmid method using two plasmids in E. coli is established, in which E. coli cells are induced only by isopropyl ß-D-thiogalactoside, so can yield different holo-OCPs from several cyanobacteria within three days. In this work, we optimized the two-plasmid method as follows: (1) re-organization of the two plasmids, letting carotenoid-generating gene, crtW, be arranged together with apo-OCP-generating gene, ocp, in a single plasmid, which causes that both carotenoid and apo-protein were properly produced, (2) modification of several amino acids at the N-terminus of apo-OCP, in this way increasing the yield and purity of holo-OCP. After these optimizations, we can generate much more amount of holo-OCP within shorter time of only 16 h, and pure holo-OCP be conveniently prepared after routine purification. Comparing with the reported data, the general yield of holo-OCP is increased by ∼10-fold under similar conditions. The high quality of the prepared holo-OCPs is verified by fluorescence quenching of the phycobilisomes.

Exploratory Metamorphic Testing for Scientific Software.

Scientific model developers are able to verify and validate their software via metamorphic testing, even when the expected output of a given test case is not readily available. The tenet is to check whether certain relations hold among the expected outputs of multiple related inputs. Contemporary approaches require the relations to be defined before tests. Our experience shows that it is often straightforward to first define the multiple iterations of tests for performing continuous simulations, and then keep multiple and even competing metamorphic relations open for investigating the testing-result patterns. We call this new approach exploratory metamorphic testing, and report our experience of applying it to detect bugs, mismatches, and constraints in automatically calibrating parameters for the United States Environmental Protection Agency's Storm Water Management Model (SWMM).

Distinctive signature of indium gallium nitride quantum dot lasing in microdisk cavities.

Low-threshold lasers realized within compact, high-quality optical cavities enable a variety of nanophotonics applications. Gallium nitride materials containing indium gallium nitride (InGaN) quantum dots and quantum wells offer an outstanding platform to study light-matter interactions and realize practical devices such as efficient light-emitting diodes and nanolasers. Despite progress in the growth and characterization of InGaN quantum dots, their advantages as the gain medium in low-threshold lasers have not been clearly demonstrated. This work seeks to better understand the reasons for these limitations by focusing on the simpler, limited-mode microdisk cavities, and by carrying out comparisons of lasing dynamics in those cavities using varying gain media including InGaN quantum wells, fragmented quantum wells, and a combination of fragmented quantum wells with quantum dots. For each gain medium, we use the distinctive, high-quality (Q ∼ 5,500) modes of the cavities, and the change in the highest-intensity mode as a function of pump power to better understand the dominant radiative processes. The variations of threshold power and lasing wavelength as a function of gain medium help us identify the possible limitations to lower-threshold lasing with quantum dot active medium. In addition, we have identified a distinctive lasing signature for quantum dot materials, which consistently lase at wavelengths shorter than the peak of the room temperature gain emission. These findings not only provide better understanding of lasing in nitride-based quantum dot cavity systems but also shed insight into the more fundamental issues of light-matter coupling in such systems.

Pre-emptive analgesia and its supraspinal mechanisms: enhanced descending inhibition and decreased descending facilitation by dexmedetomidine.

KEY POINTS: Despite the clinical importance of pre-emptive analgesia, the mechanisms by which it attenuates pain associated with central sensitization are poorly understood. We find that fentanyl and the α2-adrenoceptor agonist dexmedetomidine (Dex) differ significantly in their modulatory actions on noxious mechanical and noxious heat-evoked nociception in vivo. Unlike fentanyl, Dex modified descending control of nociception by decreasing the threshold for descending inhibition and/or increasing the threshold for descending facilitation. Dex exhibited after-actions on activities of thalamus in prolongation of noxious heat-evoked paw withdrawal latency that persisted for at least 7 days. This study provides insight into the organization of thalamic modulation in pre-emptive analgesia. ABSTRACT: We investigated and compared the antinociceptive effects of intraperitoneal administration of fentanyl (2-60 µg kg(-1)) and dexmedetomidine (Dex, 1-10 µg kg(-1); a highly selective α2-adrenoceptor agonist) in the regulation of nociception assessed by measuring noxious paw withdrawal reflexes in rats. Fentanyl elevated noxious mechanical paw withdrawal threshold and prolonged paw withdrawal heat latency within 1-1.5 h (P < 0.05). Dex failed to affect the mechanical paw withdrawal threshold, yet significantly prolonged the paw withdrawal heat latency in a bi-phasic manner; a short transient 1-1.5 h period followed by a second, slowly developing increase in latency that persisted for at least 7 days (P < 0.05). Lesion of the dorsolateral funiculus (DLF) did not influence fentanyl-induced antinociceptive effects, indicating peripheral and spinal antinociceptive mechanisms. By contrast, the Dex-induced second, but not the first, phase of the prolonged paw withdrawal heat latency was significantly blocked by the lesion of either DLF or thalamic ventromedial (VM) nuclei, and was attenuated by intracerebral administration of either atipamezole (α2-adrenoceptor antagonist) or WAY-100635 (5-HT1A receptor antagonist) into the VM nuclei (P < 0.05). Upon intramuscular 5.8% saline-induced muscle nociception, pre-emptive injection of fentanyl enhanced mechanical hyperalgesia and blocked heat hypoalgesia, whereas Dex significantly prevented the occurrence of mechanical hyperalgesia and enhanced heat hypoalgesia. It is suggested that Dex, but not fentanyl, significantly enhances descending inhibition and/or decreases descending facilitation to modulate pain and nociception. The present study provides novel insight into thalamus-mediated mechanisms in pre-emptive analgesia.

Sodium glycididazole enhances the radiosensitivity of laryngeal cancer cells through downregulation of ATM signaling pathway.

The purpose of this study was to evaluate the radiation-enhancing effect of sodium glycididazole, and the corresponding mechanisms of action on laryngeal cancer cells. Two laryngeal cancer cell lines (Hep-2 and UT-SCC-19A) were irradiated with X-rays in the presence or absence of sodium glycididazole. Cell survival, DNA damage and repair, cell apoptosis, cell cycle distribution, expression of proteins related to cell cycle checkpoint, and apoptosis were measured. Significantly increased DNA damages, decreased cells in the G1 phase, arrested cells at G2/M phase, decreased DNA repair protein XRCC1 foci formation, and enhanced cell apoptosis were observed in laryngeal cell lines treated by sodium glycididazole combined with irradiation compared with the irradiation alone. The combined treatment downregulated the protein expressions of ataxia-telangiectasia mutated (ATM), p-ATM, CHK2, and P53 but upregulated the protein expressions of MDM2 and Cdk2. This study indicates that sodium glycididazole enhances the radiosensitivity of laryngeal cancer cells through downregulation of ATM signaling pathway in vitro and in vivo.

Correlation of NLRP3 with severity and prognosis of coronary atherosclerosis in acute coronary syndrome patients.

We decided to assess the prognostic value of NLRP3 inflammasome level in acute coronary syndrome (ACS) patients and whether it was related to coronary atherosclerotic severity. Study population included one-hundred and twenty-three (123) subjects. Peripheral blood monocyte NLRP3 protein level was correlated with clinical presentation, angiographic characteristics and its scoring systems as well as GRACE and TIMI risk scores. Follow-up for major adverse cardiac events (MACE) was carried out at 180 days. Peripheral blood monocyte NLRP3 was found to be elevated in ACS patients (P < 0.05) and showed positive correlation with GRACE score (r = 0.619), TIMI score (r = 0.580), SYNTAX score (r = 0.550), Clinical SYNTAX score (r = 0.564) and Gensini score (r = 0.516). NLRP3 was also increased with increasing number of vessels, the number of lesions present and the presence bifurcation lesions (P < 0.05). Multivariate Cox regression analysis showed NLRP3 to be an independent predictor of MACE (P = 0.043). Kaplan-Meier analysis and receiver operating characteristic curves for NLRP3 showed good predictive value for MACE. There is a positive correlation of NLRP3 level with severity of coronary atherosclerosis. NLRP3 level is a promising prognostic utility and is efficient in event prediction for MACE.

Sestrin2 protects the myocardium against radiation-induced damage.

The purpose of this study was to investigate the role of Sestrin2 in response to radiation-induced injury to the heart and on the cardiomyopathy development in the mouse. Mice with genetic deletion of the Sestrin2 (Sestrin2 knockout mice [Sestrin2 KO]) and treatment with irradiation (22 or 15 Gy) were used as independent approaches to determine the role of Sestrin2. Echocardiography (before and after isoproterenol challenge) and left ventricular (LV) catheterization were performed to evaluate changes in LV dimensions and function. Masson's trichrome was used to assess myocardial fibrosis. Immunohistochemistry and Western blot were used to detect the capillary density. After 22 or 15 Gy irradiation, the LV ejection fraction (EF) was impaired in wt mice at 1 week and 4 months after irradiation when compared with sham irradiation. Compared to wt mice, Sestrin2 KO mice had significant reduction in reduced LVEF at 1 week and 4 months after irradiation. A significant increase in LV end-diastolic pressure and myocardial fibrosis and a significant decrease in capillary density were observed in irradiation-wt mice, as well as in irradiation-Sestrin2 KO mice. Sestrin2 involved in the regulation of cardiomyopathy (such as myocardial fibrosis) after irradiation. Overexpression of Sestrin2 might be useful in limiting radiation-induced myocardial injury.