Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in priming immune responses to tumor. Interleukin (IL)-23 can act directly on DC to promote immunogenic ...presentation of tumor peptide in vitro. Here, we evaluated the combination of bone marrow-derived DC and IL-23 on the induction of antitumor immunity in a mouse intracranial glioma model. DCs can be transduced by an adenoviral vector coding single-chain mouse IL-23 to express high levels of bioactive IL-23. Intratumoral implantation of IL-23-expressing DCs produced a protective effect on intracranial tumor-bearing mice. The mice consequently gained systemic immunity against the same tumor rechallenge. The protective effect of IL-23-expressing DCs was comparable with or even better than that of IL-12-expressing DCs. IL-23-transduced DC (DC-IL-23) treatment resulted in robust intratumoral CD8(+) and CD4(+) T-cell infiltration and induced a specific TH1-type response to the tumor in regional lymph nodes and spleen at levels greater than those of nontransduced DCs. Moreover, splenocytes from animals treated with DC-IL-23 showed heightened levels of specific CTL activity. In vivo lymphocyte depletion experiments showed that the antitumor immunity induced by DC-IL-23 was mainly dependent on CD8(+) T cells and that CD4(+) T cells and natural killer cells were also involved. In summary, i.t. injection of DC-IL-23 resulted in significant and effective systemic antitumor immunity in intracranial tumor-bearing mice. These findings suggest a new approach to induce potent tumor-specific immunity to intracranial tumors. This approach may have therapeutic potential for treating human glioma.
OBJECTIVES/SPECIFIC AIMS: I would like to make clinicians aware about prescription opioid use and glycemic control among patients with diabetes. This is a quality of care issue that increases the ...disease burden for two conditions opioid dependence and diabetic complications. Big data analytics can bring out this quality of care issue and help in changing clinical practice through precision medicine METHODS/STUDY POPULATION: This is a population health study of patients on prescription opioid pain medications in Erie county medical center and local out patient clinic. The electronic data from the hospital records and Outpatient were collected, merged and de identified. The database was saved in a protected environment and made accessible to researchers through a secure login. The data was queried for the number of patients with diabetes. The glycohemoglobin levels were collected and then the analysis was made RESULTS/ANTICIPATED RESULTS: It was found that only 63 of the 89 patients with DPN and 156 of the 570 patients without DPN had any measurement of HbA1c in our data. It was found that 86 out of 156 patients without DPN had suboptimal glycemic control with a glycohemoglobin level > 7% while 36 out of 63 patients with DPN had a glycohemoglobin > 6.7%. The odds of patients with DPN having poor glycemic control is 0.57 while the odds of having poor glycemic control without DPN is.55. The relative risk being 1.03. DISCUSSION/SIGNIFICANCE OF IMPACT: Our population study revealed suboptimal glycemic control among a large set of patients in Western New York with a diagnosis of diabetes mellitus and a concurrent prescription for an opioid pain medication. A significant percentage of patients in our study population with a diagnosis of DPN might benefit in terms of decreased painful symptoms of neuropathy from monitoring and attempting to improve glycemic control. Additionally, in our patient population, there were no patients with diabetic peripheral neuropathy prescribed pregabalin or duloxetine, the first-line FDA-approved medications for painful DPN, Based on our population study, the quality of care for diabetic patients with DPN who are prescribed opioid pain medications should be monitored closely. First-line, FDA approved anticonvulsants and antidepressants should be considered for the treatment of painful symptoms when necessary. Attention should be directed towards monitoring and improving glycemic control in patients without DPN receiving opioid pain medications to attempt to prevent or delay the microvascular complications of diabetes, including the onset of painful peripheral neuropathy.
Chemotherapeutic drugs and newly developed therapeutic monoclonal antibodies are adequately delivered to most solid and systemic tumors. However, drug delivery into primary brain tumors and ...metastases is impeded by the blood-brain tumor barrier (BTB), significantly limiting drug use in brain cancer treatment.
We examined the effect of phosphodiesterase 5 (PDE5) inhibitors in nude mice on drug delivery to intracranially implanted human lung and breast tumors as the most common primary tumors forming brain metastases, and studied underlying mechanisms of drug transport. In vitro assays demonstrated that PDE5 inhibitors enhanced the uptake of (14)Cdextran and trastuzumab (Herceptin, a humanized monoclonal antibody against HER2/neu) by cultured mouse brain endothelial cells (MBEC). The mechanism of drug delivery was examined using inhibitors for caveolae-mediated endocytosis, macropinocytosis and coated pit/clathrin endocytosis. Inhibitor analysis strongly implicated caveolae and macropinocytosis endocytic pathways involvement in the PDE5 inhibitor-enhanced Herceptin uptake by MBEC. Oral administration of PDE5 inhibitor, vardenafil, to mice with HER2-positive intracranial lung tumors led to an increased tumor permeability to high molecular weight (14)Cdextran (2.6-fold increase) and to Herceptin (2-fold increase). Survival time of intracranial lung cancer-bearing mice treated with Herceptin in combination with vardenafil was significantly increased as compared to the untreated, vardenafil- or Herceptin-treated mice (p<0.01). Log-rank survival analysis of mice bearing HER2-positive intracranial breast tumor also showed a significant survival increase (p<0.02) in the group treated with Herceptin plus vardenafil as compared to other groups. However, vardenafil did not exert any beneficial effect on survival of mice bearing intracranial breast tumor with low HER2 expression and co-treated with Herceptin (p>0.05).
These findings suggest that PDE5 inhibitors may effectively modulate BTB permeability, and enhance delivery and therapeutic efficacy of monoclonal antibodies in hard-to-treat brain metastases from different primary tumors that had metastasized to the brain.
High‐grade serous ovarian carcinoma (HGSOC) is a major form of ovarian epithelial tumor that is often diagnosed only at an advanced stage when it is already highly aggressive. We performed ...comprehensive genomic profiling using an analytically validated clinical next‐generation sequencing assay to identify genomic alterations in 450 cancer‐related genes in a cohort of 88 Chinese HGSOC patients. Overall, we detected 547 genomic alterations with an average of 6.2 alterations per tumor. Most of these HGSOC tumors had low tumor mutation burden and were microsatellite stable. Consistent with earlier studies, TP53 mutations were present in the majority (96.6%) of the tumors studied, and mutations in BRCA1/2 that affect DNA repair were also detected frequently in 20.5% of the tumors. However, we observed a 10.2% of mutated genes in the Ras/Raf pathway, all co‐occurring with TP53 mutations in the same tumor, which was unrecognized previously. Our results show that in HGSOC patients, there may be an unrecognized co‐occurrence of TP53 mutations with mutations in Ras/Raf pathway.
In Chinese high‐grade serous ovarian carcinoma (HGSOC) patients, we observed 10.2% of mutated genes in the Ras/Raf pathway, all co‐occurring with TP53 mutations in the same tumor, which was unrecognized previously. Our results show that in HGSOC patients, there may be an unrecognized co‐occurrence of TP53 mutations with mutations in Ras/Raf pathway.
Objective To investigate the alterations of soluble molecule programmed death 1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1), as well as related Th1 cytokines IFN-γ and Th2 cytokines IL-4 ...in patients infected with Brucella. Methods The study enrolled 56 patients infected with Brucella and 48 healthy controls. Serum sPD-1 and sPD-L1 were detected by ELISA and the levels of Th1/Th2 cytokines were measured with cytometric bead array (CBA). Among them, 37 patients received follow-up. Results Compared with the control group, the serum levels of sPD-1/sPD-L1 and IL-4 increased significantly, while the level of IFN-γ decreased significantly. In the 37 patients receiving follow-up after treatment, serum levels of sPD-1/sPD-L1 and IL-4 were remarkably lower than those in pretherapy, while the level of IFN-γ was obviously higher than that in pretherapy. Conclusion The increase of sPD-1 and sPD-L1 may be involved in the process of Brucella infection.
Objective To investigate the expression and clinical significance of interleukin 9 (IL-9) in patients with primary biliary cirrhosis (PBC). Methods The study enrolled 80 PBC patients and 100 healthy ...subjects. Levels of serum IL-9, interferon γ (IFN-γ), IL-6, tumor necrosis factor α (TNF-α), IL-10 and IL-17 were determined by cytometric beads array (CBA); level of IL-9 mRNA in peripheral blood mononuclear cells (PBMCs) was detected by quantitative real-time PCR; the expression and location of IL-9 in liver tissues were detected by immunohistochemistry. Results Serum levels of IL-9, TNF-α, IL-6, IL-17, IFN-γ and IL-10 significantly increased in PBC patients in comparison with healthy controls, and a positively correlation between IL-9 and IgG was observed in PBC patients. In addition, the expression of IL-9 mRNA in PBC groups increased. Immunohistochemical results suggested that positive cells appeared in the PBC liver tissue, mainly in the portal area. Conclusion Expression of IL-9 remarkably increases in peri
In the present study, the formation and structure of the inclusion compound of large‐ring cyclodextrin and 4‐terpineol were obtained through different experiments and molecular dynamics (MD) ...simulation. The analysis of FTIR, 1H‐NMR, and thermodynamic results confirmed the formation of clathrates. Analysis of molecular structure (root‐mean‐square deviation and radius of gyration), solubility, and interaction energy (Coul, H bond) based on MD simulations further clarified the nature of the clathrate and the conformational changes caused by guest molecules as well as inclusion complexes process trends. The inclusion complex reportedly has a new crystal structure with improved thermal stability.
Practical Application
This is the first work to demonstrate the complex formation between 4‐terpineol and large‐ring cyclodextrin by molecular dynamics simulation. Molecular dynamics simulation confirmed the formation of inclusion complexes theoretically. Conformational changes of the molecules and the formation of complexes with improved thermal stability were observed. Complexing with large‐ring cyclodextrin can be used as an effective means to encapsulate the aroma/flavor compounds.
Hydraulic pump constitutes the key component in hydraulic power system and its fault diagnosis is of great importance. The structure of the pump is very complex and the relationship among parameters ...of pump is highly nonlinear. As a result, data-driven diagnosis method is commonly used for the pump. In this article, a new intelligent fault diagnosis scheme based on many signal processing techniques, such as Wavelet Packet Transform (WPT), Local Tangent Space Alignment (LTSA), Empirical Mode Decomposition (EMD) and Local Mean Decomposition (LMD), and recognition technique Extreme Learning Machine (ELM) is proposed to manage the fault detection on slipper abrasion of axial piston pump. Three feature extraction methods were utilized to seek for sensitive fault features. A novel classifier, ELM, was introduced in this study to diagnose the slipper abrasion fault. ELM has been proved to be extremely fast and can provide good generalization performance on many pattern recognition cases. The performance of ELM classifiers has been compared with the performance of other state-of-art techniques. The empirical results showed that ELM classifiers are really fast in learning and perform well on slipper abrasion fault detection.
Collaboration among virtual organizations enables domains to effectively share resources. However, it also opens ways for several security and privacy breaches; the problem becomes severe along with ...the increasing complexity and dynamics of grid environments. As such, in this paper, we propose a flexible secure collaboration framework: called
RAR (Role-And-Risk). We introduce the architecture of
RAR, and two major components of
RAR. The first component is for generating inter-domain role mappings (
IDRM) as a basis for collaboration. We study the complexity of
IDRM while taking the
separation of duty constraints and administrative cost into account; it turns out to be intractable for most cases.
RAR addresses
IDRM related problems by reducing them to well-known problems (e.g., the satisfiability problem
SAT), which have been studied for decades and various mature solvers exist in literature. On the other hand, to deal with the dynamics and uncertainty of distributed environments, we employ the notion of
risk to monitor and manage the security threat induced by collaboration.
RAR’s flexibility lies in the tunable interoperability and the use of risk for timely monitoring users’ accesses.
► A framework for secure collaboration in multi-domain environments is presented. ► Computational complexity of role mapping generation problems is studied. ► Maximal and tunable interoperability among domains is supported. ► Risk management mechanism is used to deal with dynamics and uncertainty.
Separation-of-Duty (SoD) policy is a fundamental security principle for prevention of fraud and errors in computer security. The research of static SoD (SSoD) policy in recently presented usage ...control (UCON) model has not been explored. Consequently, this paper attempts to address two important issues: the specification and enforcement of SSoD in UCON. We give a set-based specification scheme, which is simpler and more general than existing approaches. As for the enforcement, we study the problem of determining whether an SSoD policy is enforceable, and show that directly enforcing an SSoD policy is a coNP-complete problem. In indirect enforcement, we generate the least restrictive static mutually exclusive attribute (SMEA) constraints to enforce SSoD policies, by using the attribute level SSoD requirement as an intermediate step. The results are fundamental to understanding the effectiveness of using constraints to enforce SSoD policies in UCON.
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