Biodegradable Nanoparticles In The Treatment Of Cutaneous Malignancy

Keratinocyte-derived carcinomas represent the most common type of malignancy worldwide, and while surgical removal is a first-line therapy, surgery may be impractical for certain patients and does not completely eliminate risk of recurrence. Previous studies have demonstrated the advantages of biodegradable poly(lactic acid)-hyperbranched polyglycerol non-bioadhesive nanoparticles (NNPs) and bioadhesive nanoparticles (BNPs) as chemotherapeutic drug delivery vehicles for the treatment of internal solid tumors. We are now investigating the use of this delivery system for the treatment of cutaneous malignancies, with the goal of maximizing drug efficacy while minimizing systemic effects and treatment-associated morbidity. After topical application of fluorescent dye-loaded NNPs to the intact skin of mice, epidermal penetration of the NNPs to the dermal-epidermal junction and accumulation within hair follicles was observed at time points ranging from 4 to 72 hours. Using the PDV squamous cell carcinoma (SCC) murine model, both dye- loaded NNPs and BNPs exhibited a dose- and time- dependent association with PDV cells in vitro by flow cytometry, and BNPs had increased association with cells compared to NNPs. Confocal microscopy confirmed internalization of NPs by cells. Camptothecin (CPT)-loaded NNPs and BNPs were developed; these particles contained 5% by weight CPT. There was no significant difference in effect on PDV cell proliferation in vitro among CPT, CPT/NNP, and CPT/BNP treatment groups. A pilot study using subcutaneously transplanted PDV tumors showed effective and complete destruction of the tumor after intratumoral injection of CPT/BNP. A subsequent study using an increased frequency of treatment and lower concentration of CPT compared CPT/intralipid (CPT/IL), CPT/NNP and CPT/BNP injections and showed prolonged survival in all CPT groups compared to control, and a trend toward prolonged survival in NNP and BNP groups compared to CPT/IL. However, none of the three treatments fully eliminated tumor burden in treated mice, suggesting that a higher concentration of drug may be optimal. Overall, our results indicate that both NNPs and BNPs rapidly associate with PDV tumor cells, and in vitro drug delivery is not inhibited by NP encapsulation. Further studies are needed to optimize the method, concentration, and frequency of nanoparticle and drug delivery to effectively and consistently treat SCC tumors

Supply-side reduction policy and drug-related harm

Large-scale seizures of cocaine, heroin and amphetamine-type substances (ATS) do not result in any reduction in overdoses on these drugs or on arrests for use and possession of these drugs, according to this report. Aim: The aim of this study was to examine the question of whether seizures of heroin, cocaine or amphetamine type substances (ATS) or supplier arrests for heroin, cocaine or ATS trafficking have any effect on the ED admissions related to or arrests for use and possession of these drugs. Method: Two strategies were employed to answer the question. The first involved a time series analysis of the relationship between seizures, supplier arrests, emergency department (ED) admissions and use/possession arrests. The second involved an analysis of three specific operations identified by the NSW Crime Commission as has having had the potential to have affected the market for cocaine. Results: Over the short term (i.e. up to four months), increases in the intensity of high-level drug law enforcement (as measured by seizures and supplier arrests) directed at ATS, cocaine and heroin did not appear to have any suppression effect on ED admissions relating to ATS, cocaine and heroin, or on arrests for use and/or possession of these drugs. The three major operations dealing with cocaine listed by the NSW Crime Commission as significant (Operation Balmoral Athens, Operation Tempest and Operation Collage) did exert a suppression effect on arrests for use and possession of cocaine. Conclusions: Increases in the quantities of ATS, cocaine and heroin drugs seized by law enforcement authorities are normally a signal of increased rather than reduced supply. Very large seizures, however, may temporarily suppress consumption of these drugs. Even if drug seizures and drug supplier arrests have no short term effects on ED admissions and arrests for drug use and/or possession, they may still suppress drug consumption through risk compensation

Utility of the JAX Clinical Knowledgebase in capture and assessment of complex genomic cancer data.

Cancer genomic data is continually growing in complexity, necessitating improved methods for data capture and analysis. Tumors often contain multiple therapeutically relevant alterations, and co-occurring alterations may have a different influence on therapeutic response compared to if those alterations were present alone. One clinically important example of this is the existence of a resistance conferring alteration in combination with a therapeutic sensitizing mutation. The JAX Clinical Knowledgebase (JAX-CKB) (https://ckb.jax.org/) has incorporated the concept of the complex molecular profile, which enables association of therapeutic efficacy data with multiple genomic alterations simultaneously. This provides a mechanism for rapid and accurate assessment of complex cancer-related data, potentially aiding in streamlined clinical decision making. Using the JAX-CKB, we demonstrate the utility of associating data with complex profiles comprising ALK fusions with another variant, which have differing impacts on sensitivity to various ALK inhibitors depending on context

Design of an Automatic Defect Identification Method Based ECPT for Pneumatic Pressure Equipment

In this paper, in order to achieve automatic defect identification for pneumatic pressure equipment, an improved feature extraction algorithm eddy current pulsed thermography (ECPT) is presented. The presented feature extraction algorithm contains four elements: data block selection; variable step search; relation value classification; and between-class distance decision function. The data block selection and variable step search are integrated to decrease the redundant computations in the automatic defect identification. The goal of the classification and between-class distance calculation is to select the typical features of thermographic sequence. The main image information can be extracted by the method precisely and efficiently. Experimental results are provided to demonstrate the capabilities and benefits (i.e., reducing the processing time) of the proposed algorithm in automatic defect identification

Design of Hypervelocity-Impact Damage Evaluation Technique Based on Bayesian Classifier of Transient Temperature Attributes

With the rapid increasement of space debris on earth orbit, the hypervelocity-impact (HVI) of space debris can cause some serious damages to the spacecraft, which can affect the operation security and reliability of spacecraft. Therefore, the damage detection of the spacecrafts has become an urgent problem to be solved. In this paper, a method is proposed to detect the damage of spacecraft. Firstly, a variable-interval method is proposed to extract the effective information from the infrared image sequence. Secondly, in order to mine the physical meaning of the thermal image sequence, five attributes are used to construct a feature space. After that, a Naive Bayesian classifier is established to mine the information of different damaged areas. Then, a maximum interclass distance function is used choose the representative of each class. Finally, in order to visualize damaged areas, the Canny operator is used to extract the edge of the damage. In the experiment, ground tests are used to simulate hypervelocity impacts in space. Historical data of natural damaged material and artificial damaged material are used to build different classifiers. After that, the effective of classifiers is illustrated by accuracy, F-score and AUC. Then, two different types of materials are detected by proposed method, Independent Component Analysis (ICA) and Fuzzy C-means (FCM). The results show that the proposed method is more accurate than other methods

Efficient Prodrug Activator Gene Therapy by Retroviral Replicating Vectors Prolongs Survival in an Immune-Competent Intracerebral Glioma Model.

Prodrug activator gene therapy mediated by murine leukemia virus (MLV)-based retroviral replicating vectors (RRV) was previously shown to be highly effective in killing glioma cells both in culture and in vivo. To avoid receptor interference and enable dual vector co-infection with MLV-RRV, we have developed another RRV based on gibbon ape leukemia virus (GALV) that also shows robust replicative spread in a wide variety of tumor cells. We evaluated the potential of GALV-based RRV as a cancer therapeutic agent by incorporating yeast cytosine deaminase (CD) and E. coli nitroreductase (NTR) prodrug activator genes into the vector. The expression of CD and NTR genes from GALV-RRV achieved highly efficient delivery of these prodrug activator genes to RG-2 glioma cells, resulting in enhanced cytotoxicity after administering their respective prodrugs 5-fluorocytosine and CB1954 in vitro. In an immune-competent intracerebral RG-2 glioma model, GALV-mediated CD and NTR gene therapy both significantly suppressed tumor growth with CB1954 administration after a single injection of vector supernatant. However, NTR showed greater potency than CD, with control animals receiving GALV-NTR vector alone (i.e., without CB1954 prodrug) showing extensive tumor growth with a median survival time of 17.5 days, while animals receiving GALV-NTR and CB1954 showed significantly prolonged survival with a median survival time of 30 days. In conclusion, GALV-RRV enabled high-efficiency gene transfer and persistent expression of NTR, resulting in efficient cell killing, suppression of tumor growth, and prolonged survival upon CB1954 administration. This validates the use of therapeutic strategies employing this prodrug activator gene to arm GALV-RRV, and opens the door to the possibility of future combination gene therapy with CD-armed MLV-RRV, as the latter vector is currently being evaluated in clinical trials

The initiator methionine tRNA drives secretion of type II collagen from stromal fibroblasts to promote tumor growth and angiogenesis

Summary: Expression of the initiator methionine tRNA (tRNAi Met) is deregulated in cancer. Despite this fact, it is not currently known how tRNAi Met expression levels influence tumor progression. We have found that tRNAi Met expression is increased in carcinoma-associated fibroblasts, implicating deregulated expression of tRNAi Met in the tumor stroma as a possible contributor to tumor progression. To investigate how elevated stromal tRNAi Met contributes to tumor progression, we generated a mouse expressing additional copies of the tRNAi Met gene (2+tRNAi Met mouse). Growth and vascularization of subcutaneous tumor allografts was enhanced in 2+tRNAi Met mice compared with wild-type littermate controls. Extracellular matrix (ECM) deposited by fibroblasts from 2+tRNAi Met mice supported enhanced endothelial cell and fibroblast migration. SILAC mass spectrometry indicated that elevated expression of tRNAi Met significantly increased synthesis and secretion of certain types of collagen, in particular type II collagen. Suppression of type II collagen opposed the ability of tRNAi Metoverexpressing fibroblasts to deposit pro-migratory ECM. We used the prolyl hydroxylase inhibitor ethyl- 3,4-dihydroxybenzoate (DHB) to determine whether collagen synthesis contributes to the tRNAi Met-driven pro-tumorigenic stroma in vivo. DHB had no effect on the growth of syngeneic allografts in wild-type mice but opposed the ability of 2+tRNAi Met mice to support increased angiogenesis and tumor growth. Finally, collagen II expression predicts poor prognosis in high-grade serous ovarian carcinoma. Taken together, these data indicate that increased tRNAi Met levels contribute to tumor progression by enhancing the ability of stromal fibroblasts to synthesize and secrete a type II collagen-rich ECM that supports endothelial cell migration and angiogenesis

On the purported "backbone fluorescence" in protein three-dimensional fluorescence spectra

In this study, several proteins (albumin, lysozyme, insulin) and model compounds (Trp, Tyr, homopolypeptides) were used to demonstrate the origin of the fluorescence observed upon their excitation at 220–230 nm. In the last 10 years we have observed a worrying increase in the number of articles claiming that this fluorescence originates from the protein backbone, contrary to the established knowledge that UV protein emission is due to aromatic amino acids only. Overall, our data clearly demonstrate that the observed emission upon excitation at 220–230 nm is due to the excitation of Tyr and/or Trp, with subsequent emission from the lowest excited state (i.e. the same as obtained with 280 nm excitation) in agreement with Kasha's rule. Therefore, this fluorescence peak does not provide any information on backbone conformation, but simply reports on the local environment around the aromatic side chains, just as any traditional protein emission spectrum. The many papers in reputable journals erroneously reporting this peak assignment, contradicting 5 decades of prior knowledge, have led to the creation of a new dogma, where many authors and reviewers now take the purported backbone fluorescence as an established fact. We hope the current paper helps counter this new situation and leads to a reassessment of those papers that make this erroneous claim

Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity

The secretome of cancer and stromal cells generates a microenvironment that contributes to tumour cell invasion and angiogenesis. Here we compare the secretome of human mammary normal and cancer-associated fibroblasts (CAFs). We discover that the chloride intracellular channel protein 3 (CLIC3) is an abundant component of the CAF secretome. Secreted CLIC3 promotes invasive behaviour of endothelial cells to drive angiogenesis and increases invasiveness of cancer cells both in vivo and in 3D cell culture models, and this requires active transglutaminase-2 (TGM2). CLIC3 acts as a glutathione-dependent oxidoreductase that reduces TGM2 and regulates TGM2 binding to its cofactors. Finally, CLIC3 is also secreted by cancer cells, is abundant in the stromal and tumour compartments of aggressive ovarian cancers and its levels correlate with poor clinical outcome. This work reveals a previously undescribed invasive mechanism whereby the secretion of a glutathione-dependent oxidoreductase drives angiogenesis and cancer progression by promoting TGM2-dependent invasion