Search

Hsa_circ_0001947 is associated with multiple cancers, but its function in non-small cell lung cancer (NSCLC) is ambiguous and needs further research. The targeting relationship among circ_0001947, miR-661, and downstream of tyrosine kinase 7 (DOK7) was predicted by database and further verified by dual-luciferase reporter assay, while their expressions in cancer tissues and cells were detected by quantitative real-time polymerase chain reaction (qRT-PCR). After transfection, cell biological behaviors and expressions of miRNAs, miR-661 and DOK7 were determined by cell function experiments and qRT-PCR, respectively. Circ_0001947 was low-expressed in NSCLC tissues and cells. Circ_0001947 knockdown intensified cell viability and proliferation, induced cell cycle arrest at S phase, suppressed apoptosis and evidently enhanced miR-510, miR-587, miR-661 and miR-942 levels, while circ_0001947 overexpression did the opposite. MiR-661 was a target gene of circ_0001947 that participated in the regulation of circ_0001947 on cell biological behaviors. Furthermore, DOK7, the target gene of miR-661, partly participated in the regulation of miR-661 on cell viability. Hsa_circ_0001947 acts as a sponge of miR-661 to repress NSCLC development by elevating the expression of DOK7.

Ownership type systems, based on the idea of enforcing unique access paths, have been primarily focused on objects and top-level classes. However, existing models do not as readily reflect the finer aspects of nested lexical scopes, capturing, or escaping closures in higher-order functional programming patterns, which are increasingly adopted even in mainstream object-oriented languages. We present a new type system, λ * , which enables expressive ownership-style reasoning across higher-order functions. It tracks sharing and separation through reachability sets, and layers additional mechanisms for selectively enforcing uniqueness on top of it. Based on reachability sets, we extend the type system with an expressive flow-sensitive effect system, which enables flavors of move semantics and ownership transfer. In addition, we present several case studies and extensions, including applications to capabilities for algebraic effects, one-shot continuations, and safe parallelization.

Cryptographic techniques have the potential to enable distrusting parties to collaborate in fundamentally new ways, but their practical implementation poses numerous challenges. An important class of such cryptographic techniques is known as Secure Multi-Party Computation (MPC). Developing Secure MPC applications in realistic scenarios requires extensive knowledge spanning multiple areas of cryptography and systems. And while the steps to arrive at a solution for a particular application are often straightforward, it remains difficult to make the implementation efficient, and tedious to apply those same steps to a slightly different application from scratch. Hence, it is an important problem to design platforms for implementing Secure MPC applications with minimum effort and using techniques accessible to non-experts in cryptography. In this paper, we present the HACCLE (High Assurance Compositional Cryptography: Languages and Environments) toolchain, specifically targeted to MPC applications. HACCLE contains an embedded domain-specific language Harpoon, for software developers without cryptographic expertise to write MPC-based programs, and uses Lightweight Modular Staging (LMS) for code generation. Harpoon programs are compiled into acyclic circuits represented in HACCLE’s Intermediate Representation (HIR) that serves as an abstraction over different cryptographic protocols such as secret sharing, homomorphic encryption, or garbled circuits. Implementations of different cryptographic protocols serve as different backends of our toolchain. The extensible design of HIR allows cryptographic experts to plug in new primitives and protocols to realize computation. And the use of standard metaprogramming techniques lowers the development effort significantly. We have implemented Harpoon and HACCLE, and used them to program interesting applications (e.g., secure auction) and key computation components of Secure MPC applications (e.g., matrix-vector multiplication and merge sort). We show that the performance is improved by using our optimization strategies and heuristics.

ObjectivesTo develop and validate a radiomic feature-based nomogram for preoperative discriminating the epidermal growth factor receptor (EGFR) activating mutation from wild-type EGFR in non-small cell lung cancer (NSCLC) patients.MaterialA group of 301 NSCLC patients were retrospectively reviewed. The EGFR mutation status was determined by ARMS PCR analysis. All patients underwent nonenhanced CT before surgery. Radiomic features were extracted (GE healthcare). The maximum relevance minimum redundancy (mRMR) and LASSO, were used to select features. We incorporated the independent clinical features into the radiomic feature model and formed a joint model (i.e., the radiomic feature-based nomogram). The performance of the joint model was compared with that of the other two models.ResultsIn total, 396 radiomic features were extracted. A radiomic signature model comprising 9 selected features was established for discriminating patients with EGFR-activating mutations from wild-type EGFR. The radiomic score (Radscore) in the two groups was significantly different between patients with wild-type EGFR and EGFR-activating mutations (training cohort: PConclusionsThe joint model showed favorable performance in the individualized, noninvasive prediction of EGFR-activating mutations in NSCLC patients.

Cardiovascular complications have been well documented as the downside to conventional cancer chemotherapy. As a notable side effect of cisplatin (CDDP), cardiotoxicity represents a major obstacle to the successful treatment of cancer. It has been reported that Salvianolic acid B (SalB) possesses cardioprotective quality. However, the effect of SalB on cardiac damage caused by conventional cancer chemotherapy remains unclear. In this study, we clarified the protective effect of SalB on cisplatin-induced heart injury. Furthermore, in H9c2 cells, SalB dramatically reduced cisplatin-induced apoptosis and oxidative stress by modulating the nuclear factor erythroid-2-related factor 2 (Nrf2) signaling pathway. In conclusion, SalB had great potential in mitigating cisplatin-induced cardiac injury. Furthermore, more attention should be placed on natural active compounds containing SalB with antioxidant effects for the treatment of cardiomyopathy.

As the new platinum drug oxaliplatin has been widely used in clinical treatment of colorectal cancer (CRC), oxaliplatin resistance has become a burning problem. In this study, higher expression of PARP-1 binding protein (PARPBP) was detected in oxaliplatin-resistant CRC (OR-CRC) cells than in non-resistant cells. Further research showed that kinesin family member 18 b (KIF18b) induced the overexpression of PARPBP, sustaining oxaliplatin resistance in OR-CRC cells. Through exploring the PARPBP gene promoter, we found that SP1-recruited DNMT3b methylated PARPBP promoter to suppress transcription in CRC cells, and increased KIF18b attenuated the recruitment of DNMT3b to PARPBP promoter by directly interacting with SP1 in OR-CRC cells. Clinical analysis suggested a positive relationship between KIF18b and PARPBP in CRC tissues and indicated poor prognosis in CRC patients with high level of KIF18b or PARPBP. In summary, KIF18b-induced PARPBP contributes to the resistant phenotype of OR-CRC.

Framing is important for specification and verification, especially in programs that mutate data structures with shared data, such as DAGs. Both separation logic and region logic are successful approaches to framing, with separation logic providing a concise way to reason about data structures that are disjoint, and region logic providing the ability to reason about framing for shared mutable data. In order to obtain the benefits of both logics for programs with shared mutable data, this paper unifies them into a single logic, which can encode both of them and allows them to interoperate. The new logic thus provides a way to reason about program modules specified in a mix of styles.

Acute lung injury (ALI) is a diffuse lung dysfunction disease characterized by high prevalence and high mortality. Thus far, no effective pharmacological treatment has been made for ALI in clinics. Inflammation is critical to the development of ALI. Therefore, anti-inflammation may be a potential therapy strategy for ALI. Indazole-containing derivatives, representing one of the most important heterocycles in drug molecules, are endowed with a broad range of biological properties, such as anti-cancer and anti-inflammation. In the current study, we investigated the biological effects of Cyy-272, a newly synthesized indazole compound, on LPS-induced ALI both in vivo and in vitro. Results show that Cyy-272 can inhibit the release of inflammatory cytokines in LPS-stimulated macrophage and alleviate LPS induced ALI. Further experiment revealed that Cyy-272 exhibit anti-inflammation activity by inhibiting JNK phosphorylation. Overall, our studies show that an indazole derivative, Cyy-272, is effective in suppressing LPS-induced JNK activation and inflammatory signaling.

A lipidomic evaluation was performed on the tilapia muscle, head and viscera, including studying the composition, distribution and stereospecific characteristics of fatty acids and lipid species. The head and viscera lipids were significantly richer than the muscle lipids. Triacylglycerols were the predominant fraction (over 80% of total lipid in the muscle and head). Additionally, polyunsaturated fatty acids had higher percentages in phospholipids (30.35-52.05% of total fatty acids) than in triacylglycerols (18.11-25.15%). The C52:2 and C52:3 were the most abundant triacylglycerols, which indicates the potential application in infant food. Moreover, 622, 530 and 513 lipids were identified using ultraperformance liquid chromatography-quadrupole time-of-flight-mass spectrometry in the muscle, head and viscera, respectively. The three tilapia parts were distinguished using multivariate analysis. Five fatty acids and 33 lipid species were considered as the potential biomarkers. This comprehensive analysis will help to evaluate the lipid nutritional values and facilitate exploitation in tilapia consumption and processing.

In the past decades, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) had been proved as an effective treatment strategy for the patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, the tolerance for the EGFR-TKI always occurred after continuous administration for a period of time and limiting the application of these drugs. Activation of FGFR1 signaling pathway was one of the important escape mechanisms for EGFR-TKI resistant in NSCLC. Here, a novel dual inhibitor of EGFRL858R/T790M and FGFR1, compound15c, was found and can efficiently overcame the EGFR-TKI resistance via its simultaneous inhibition of their kinase activities. Comparison with EGFRL858R/T790M and FGFR1 inhibitor treatment alone or combined revealed that the inhibition of EGFRL858R/T790M and FGFR1 activity by 15c was responsible for surmounting the intrinsic EGFR-TKI resistance in EGFRL858R/T790M-mutated H1975 cells and the acquired resistance in Afatinib-tolerant PC9 cells (AFA-PC9). Flow Cytometry and Caspase3 activity analysis assay showed that 15c induced significant the early apoptosis of H1975 cells. Xenograft tumor formation in BALB/c mice induced by a H1975 cells was suppressed by 15c treatment, with no changes in animal body weight. Generally, 15c may act as a new-generation EGFR-TKI for the therapy of NSCLC patients suffering a resistance to current TKI.

Acid fibroblast growth factor (aFGF) has been shown to prevent epithelial damage under various conditions, suggesting its potential to inhibit GVHD. However, because aFGF receptors are expressed on tumor cells, it may possibly offset the graft- vs. -tumor (GVT) effects of allogeneic bone marrow transplantation (allo-BMT). Here, we addressed these questions in a B6 → B6D2F1 allo-BMT model. Although aFGF administration attenuated GVHD in non-leukemic recipients, aFGF treatment markedly accelerated death in mice that received recipient-type tumor (P815) cells along with allo- or syngeneic-BMT. Similar protection against GVHD was achieved by administration of a non-mitogenic form of aFGF (naFGF). Importantly, GVT effects were fully preserved in naFGF-treated recipients. Furthermore, aFGF, but not naFGF, significantly enhanced P815 cell proliferation both in vitro and in vivo . Our data indicate that the tumor-promoting, but not GVHD-protecting, effect of aFGF largely depends on its mitogenic activity, and suggest that naFGF may provide a safer approach to inhibiting GVHD in patients with malignancies.

As a third-generation platinum drug, oxaliplatin has been widely applied in colorectal cancer (CRC); however, acquired resistance to oxaliplatin has become a major obstacle. In the present study, we found that the nuclear transcription factor Y subunit beta (NFYB) and E2F transcription factor 1 (E2F1) expression levels were significantly higher in oxaliplatin-resistant DLD1 and RKO CRC (OR-CRC) cells than in non-resistant cells. Additionally, highly expressed NFYB transactivated the E2F1 gene, which is important to maintain oxaliplatin resistance in OR-CRC cells. And Sirt1-dependent deacetylation suppresses the proapoptotic activity of E2F1 in OR-CRC cells. Through profiling the transcriptome of OR-CRC cells following E2F1 knockdown, CHK1 was identified as a target of E2F1. Deprivation of CHK1 sensitized OR-CRC cells to oxaliplatin. In vitro and in vivo phenotype experiments confirmed that an intact NFYB-E2F1-CHK1 axis was required to suppress oxaliplatin-induced apoptosis and maintain the tumorigenicity in OR-CRC cells. Knockdown of E2F1 in OR-CRC cells also decreased the expression of Pol κ, which was essential for CHK1 activation. Consistently, a high level of NFYB, E2F1, or CHK1 predicted poor survival in CRC patients, especially with oxaliplatin treatment. Collectively, the NFYB-E2F1 pathway displays a crucial role in the chemoresistance of OR-CRC by inducing the expression and activation of CHK1, providing a possible therapeutic target for oxaliplatin resistance in CRC.

Chronic activation of renin-angiotensin system (RAS) greatly contributes to renal fibrosis through the over expression of angiotensin (Ang) II, ultimately leading to chronic kidney disease (CKD). As the main peptide in the RAS, Ang II is a key regulator of nephrotic inflammation, fibrogenic destruction and hypertensive nephropathy. Controlled by growth factors such as TGF-β, Ang II is thought to be affected by other such growth factors including epidermal growth factor (EGF) due to its ability to stimulate growth, regulate angiogenesis, and desensitize cells from apoptotic stimuli. Here we show that epidermal growth factor receptor (EGFR) plays a key role in Ang II induced renal fibrosis and its inhibition for the use as an effective treatment of CKD. 453, an AG1478 analog, was used to block the EGF-EGFR interaction in vivo in 4-week old mice treated with Ang II and 453. Along with the inhibition of EGFR and its downstream signaling pathways (AKT and ERK), 453 also prevented the activation of fibrotic (collagen, CFGF, TGF-β), inflammatory (COX2, IL-6, IL-1β, TNF-α), apoptosis and oxidative stress pathways. These findings suggest the use of 453 as a novel EGFR-inhibitor for therapeutic use in CKD kidney dysfunction.

Abnormal activation of signal transducer and activator of transcription 3 (STAT3) was reported in some leukemia, and inhibition of STAT3 can be the strategy for the leukemia treatment in clinic. In this study, we tested the anti-tumor effect of compound A13, a water-soluble analogue of curcumin, in vitro and in vivo. Herein, we show that A13 was able to reduce the viability of mastocytoma (P815 cells) and reticulum cell sarcoma (A20 cells) as measured by MTS assay. This effect was accompanied by a marked increase in the proportion of apoptotic cells as measured by flow cytometry. Furthermore, Western blot analysis suggested that the anti-leukemia effect of A13 was realized via STAT3 inhibition. In addition, systemic treatment with A13 in the A20-bearing mice for 60 days resulted in a significant improvement of survival rate and marked reduction of liver metastasis. In summary, our data show that the A13 treatment could effectively be applied to acute leukemia via inhibiting STAT3 signaling pathway.

OBJECTIVE 20-Hydroxyeicosatetraenoic acid (20-HETE), a [omega]-hydroxylation product of arachidonic acid catalyzed by cytochrome P450 4A, may play a role in the cardiovascular system. It is well known that cytochrome P450 [omega]-hydroxylase inhibitors markedly reduced the cardiac ischemia reperfusion injury. However, the direct effect of 20-HETE on cardiomyocytes is still poorly investigated. Here, we studied the effect of 20-HETE on cardiomyocyte apoptosis and the apoptosis-associated signaling pathways. METHODS AND RESULTS The cardiomyocyte apoptosis was measured by fluorescein isothiocyanate conjugated annexin V/propidium iodide double staining cytometry, indicating that the percentage of early apoptotic cells increased from 15.6% +/- 2.6% to 25.5% +/- 2.5% in control and 20-HETE-treated cells, respectively. The mitochondrial membrane potential ([DELTA][PSI]m) was measured by detecting the ratio of JC-1 green/red emission intensity. A significant decrease in the ratio was observed after treatment with 20-HETE for 24 hours in comparison with control group, suggesting the disruptive effect of 20-HETE on mitochondrial [DELTA][PSI]m. In addition, 20-HETE stimulated caspase-3 activity and Bax mRNA expression in cardiomyocytes. In contrast, the Bcl-2 mRNA levels were significantly decreased by 20-HETE treatment. CONCLUSION These results demonstrate that 20-HETE induces cardiomyocyte apoptosis by activation of several intrinsic apoptotic pathways. The 20-HETE-induced apoptosis could contribute to the cytochrome P450 [omega]-hydroxylase-dependent cardiac injure during cardiac ischemia-reperfusion.

Specification languages have long featured ways to describe what does not change when an imperative procedure is executed: the so-called frame problem. Solutions to the frame problem are needed for formal verification in imperative programming, as otherwise a verification would not be able to accumulate information from one statement to the next. Region logic is one of the approaches to solving the frame problem. We present a modified version of region logic with fine granularity and introduce conditional effects that allows one to specify more precise frame conditions.

20-Hydroxyeicosatetraenoic acid (20-HETE), a [omega]-hydroxylation product of arachidonic acid catalyzed by cytochrome P450 4A, may play a role in the cardiovascular system. It is well known that cytochrome P450 [omega]-hydroxylase inhibitors markedly reduced the cardiac ischemia reperfusion injury. However, the direct effect of 20-HETE on cardiomyocytes is still poorly investigated. Here, we studied the effect of 20-HETE on cardiomyocyte apoptosis and the apoptosis-associated signaling pathways.The cardiomyocyte apoptosis was measured by fluorescein isothiocyanate conjugated annexin V/propidium iodide double staining cytometry, indicating that the percentage of early apoptotic cells increased from 15.6% +/- 2.6% to 25.5% +/- 2.5% in control and 20-HETE-treated cells, respectively. The mitochondrial membrane potential ([DELTA][PSI]m) was measured by detecting the ratio of JC-1 green/red emission intensity. A significant decrease in the ratio was observed after treatment with 20-HETE for 24 hours in comparison with control group, suggesting the disruptive effect of 20-HETE on mitochondrial [DELTA][PSI]m. In addition, 20-HETE stimulated caspase-3 activity and Bax mRNA expression in cardiomyocytes. In contrast, the Bcl-2 mRNA levels were significantly decreased by 20-HETE treatment.These results demonstrate that 20-HETE induces cardiomyocyte apoptosis by activation of several intrinsic apoptotic pathways. The 20-HETE-induced apoptosis could contribute to the cytochrome P450 [omega]-hydroxylase-dependent cardiac injure during cardiac ischemia-reperfusion.

The production of 20-hydroxyeicosatetraenoic acid (20-HETE) is increased during ischemia-reperfusion, and inhibition of 20-HETE production has been shown to reduce infarct size caused by ischemia. This study was aimed to discover the molecular mechanism underlying the action of 20-HETE in cardiac myocytes. The effect of 20-HETE on L-type Ca2+ currents ( ICa,L) was examined in rat isolated cardiomyocytes by patch-clamp recording in the whole cell mode. Superfusion of cardiomyocytes with 20-HETE (10–100 nM) resulted in a concentration-dependent increase in ICa,L, and this action of 20-HETE was attenuated by a specific NADPH oxidase inhibitor, gp91ds-tat (5 μM), or a superoxide scavenger, polyethylene glycol-superoxide dismutase (25 U/ml), suggesting that NADPH-oxidase-derived superoxide is involved in the stimulatory action of 20-HETE on ICa,L. Treatment of cardiomyocytes with 20-HETE (100 nM) increased both NADPH oxidase activity and superoxide production by approximately twofold. To study the molecular mechanism mediating the 20-HETE-induced increase in NADPH oxidase activity, PKC activity was measured in cardiomyocytes. Incubation of the cells with 20-HETE (100 nM) significantly increased PKC activity, and pretreatment of cardiomyocytes with a selective PKC inhibitor, GF-109203 (1 μM), attenuated the 20-HETE-induced increases in ICa,L and in NADPH oxidase activity. In summary, 20-HETE stimulates NADPH oxidase-derived superoxide production, which activates L-type Ca2+ channels via a PKC-dependent mechanism in cardiomyocytes. 20-HETE and 20-HETE-producing enzymes could be novel targets for the treatment of cardiac ischemic diseases.