Various methods to synthesize diverse nanoparticles with their different applications.

Mature T-cell lymphomas, including peripheral T-cell lymphoma (PTCL) and extranodal NK/T-cell lymphoma (NKTL), represent a heterogeneous group of non-Hodgkin lymphomas with dismal outcomes and limited treatment options. To determine the extent of involvement of the JAK/STAT pathway in this malignancy, we performed targeted capture sequencing of 188 genes in this pathway in 171 PTCL and NKTL cases. A total of 272 nonsynonymous somatic mutations in 101 genes were identified in 73% of the samples, including 258 single-nucleotide variants and 14 insertions or deletions. Recurrent mutations were most frequently located in and (15%), followed by and (6%) and (4%). A high prevalence of mutation (21%) was observed specifically in NKTL. Novel mutations (p.D427H, E616G, p.E616K, and p.E696K) were shown to increase STAT3 phosphorylation and transcriptional activity of in the absence of cytokine, in which p.E616K induced programmed cell death-ligand 1 (PD-L1) expression by robust binding of activated STAT3 to the PD-L1 gene promoter. Consistent with these findings, PD-L1 was overexpressed in NKTL cell lines harboring hotspot mutations, and similar findings were observed by the overexpression of p.E616K and p.E616G in the wild-type NKTL cell line. Conversely, STAT3 silencing and inhibition decreased PD-L1 expression in mutant NKTL cell lines. In NKTL tumors, STAT3 activation correlated significantly with PD-L1 expression. We demonstrated that STAT3 activation confers high PD-L1 expression, which may promote tumor immune evasion. The combination of PD-1/PD-L1 antibodies and STAT3 inhibitors might be a promising therapeutic approach for NKTL, and possibly PTCL.

Miltefosine causes leishmanial death, but the possible mechanism(s) of action is not known. The mode of action of miltefosine was investigated in vitro in Leishmania donovani promastigotes as well as in extra-and intracellular amastigotes. Here, we demonstrate that miltefosine induces apoptosis-like death in L. donovani based on observed phenomena such as nuclear DNA condensation, DNA fragmentation with accompanying ladder formation, and in situ labeling of DNA fragments by the terminal deoxyribonucleotidyltransferasemediated dUTP-biotin nick end labeling method. Understanding of miltefosine-mediated death will facilitate the design of new therapeutic strategies against Leishmania parasites.Miltefosine (1-O-hexadecylphosphocholine), an alkylphosphocholine and a membrane-active synthetic ether-lipid analogue originally developed for the treatment of cutaneous metastasis from mammary carcinomas (21, 32), has proved to be an effective treatment for human visceral leishmaniasis (25,38,(52)(53)(54)(55). It has been hailed as potentially the first oral treatment of human leishmaniasis (8,15,16,20,25,31,47,50). The leishmaniacidal activities of miltefosine have been associated with perturbation of the alkyl-phospholipid metabolism and the biosynthesis of alkyl-anchored glycolipids and glycoproteins (33,34). Although potential antitumor cell mechanisms of action of miltefosine have been elaborated in mammalian cells (13,44), its exact mode(s) of cytotoxicity has not been determined in Leishmania spp. (9,25,39,46,48,55). It has been known to induce apoptotic death in various cancer cell lines (13,28,32,43,60). However, it is not yet established whether miltefosine can bring about apoptosis-like death in all the forms of Leishmania parasite.There are now increasing numbers of reports regarding unicellular organisms undergoing apoptosis-like death, whose induction is not obligatory but activated under threatening circumstances (1,36,49). Cell death resembling metazoan apoptosis has been reported in several parasitic protozoans (4,10,30,36,49,59,61). Apoptosis greatly affects the host-parasite relationship, since the survival of the parasite inside the vector as well as in the macrophage requires strict control of the population of the parasite (12, 58). Apoptosis could be a useful mechanism to avoid killing of the entire population (36) and thus influence the chemotherapeutic strategies to limit the parasite (11).In the present study we sought to determine the mode of action of miltefosine in Leishmania donovani promastigotes as well as extra-and intracellular amastigotes. We have demonstrated that miltefosine causes apoptosis-like death in L. donovani. Our data set the stage for future development of this class of drug for better treatment of leishmaniasis. MATERIALS AND METHODSReagents. Miltefosine was a kind gift from Zentaris (Frankfurt, Germany). RPMI 1640 culture medium was from Gibco BRL. Fetal calf serum was obtained from Biological Industries (Kibbutz Beit Haemek, Israel). ApoAlert DNA fragmentation assay kit was ...

There is a growing demand for durable advanced wound dressings for the management of persistent infections after deep burn injuries. Herein, we demonstrated the preparation of durable antimicrobial nanofiber mats, by taking advantage of strong interfacial interactions between polyhydroxy antibiotics (with varying number of OH groups) and gelatin and their in-situ crosslinking with polydopamine (pDA) using ammonium carbonate diffusion method. Polydopamine crosslinking did not interfere with the antimicrobial efficacy of the loaded antibiotics. Interestingly, incorporation of antibiotics containing more number of alcoholic OH groups (N ≥ 5) delayed the release kinetics with complete retention of antimicrobial activity for an extended period of time (20 days). The antimicrobials-loaded mats displayed superior mechanical and thermal properties than gelatin or pDA-crosslinked gelatin mats. Mats containing polyhydroxy antifungals showed enhanced aqueous stability and retained nanofibrous morphology under aqueous environment for more than 4 weeks. This approach can be expanded to produce mats with broad spectrum antimicrobial properties by incorporating the combination of antibacterial and antifungal drugs. Direct electrospinning of vancomycin-loaded electrospun nanofibers onto a bandage gauze and subsequent crosslinking produced non-adherent durable advanced wound dressings that could be easily applied to the injured sites and readily detached after treatment. In a partial thickness burn injury model in piglets, the drug-loaded mats displayed comparable wound closure to commercially available silver-based dressings. This prototype wound dressing designed for easy handling and with long-lasting antimicrobial properties represents an effective option for treating life-threatening microbial infections due to thermal injuries.