Cutaneous Dengue Virus Inoculation Triggers Strong B Cell Reactions but Contrastingly Poor T Cell Responses

Virologica Sinica - Dengue is a global health problem without current specific treatment nor safe vaccines available. While severe dengue is related to pre-existing non-neutralizing dengue virus...     

Role of miR‐218‐GREM1 axis in epithelial‐mesenchymal transition of oral squamous cell carcinoma: An in vivo and vitro study based on microarray data

Oral squamous cell carcinoma (OSCC) is a prevalent cancer that develops in the head and neck area and has high annual mortality despite optimal treatment. microRNA‐218 (miR‐218) is a tumour inhibiting non‐coding RNA that has been reported to suppress the cell proliferation and invasion in various cancers. Thus, our study aims to determine the mechanism underlying the inhibitory role of miR‐218 in OSCC. We conducted a bioinformatics analysis to screen differentially expressed genes in OSCC and their potential upstream miRNAs. After collection of surgical OSCC tissues, we detected GREM1 expression by immunohistochemistry, RT‐qPCR and Western blot analysis, and miR‐218 expression by RT‐qPCR. The target relationship between miR‐218 and GREM1 was assessed by dual‐luciferase reporter gene assay. After loss‐ and gain‐of‐function experiments, OSCC cell proliferation, migration and invasion were determined by MTT assay, scratch test and Transwell assay, respectively. Expression of TGF‐β1, Smad4, p21, E‐cadherin, Vimentin and Snail was measured by RT‐qPCR and Western blot analysis. Finally, effects of miR‐218 and GREM1 on tumour formation and liver metastasis were evaluated in xenograft tumour‐bearing nude mice. GREM1 was up‐regulated, and miR‐218 was down‐regulated in OSCC tissues, and GREM1 was confirmed to be the target gene of miR‐218. Furthermore, after up‐regulating miR‐218 or silencing GREM1, OSCC cell proliferation, migration and invasion were reduced. In addition, expression of TGF‐β signalling pathway‐related genes was diminished by overexpressing miR‐218 or down‐regulating GREM1. Finally, up‐regulated miR‐218 or down‐regulated GREM1 reduced tumour growth and liver metastasis in vivo. Taken together, our findings suggest that the overexpression of miR‐218 may inhibit OSCC progression by inactivating the GREM1‐dependent TGF‐β signalling pathway.     

Selective autophagy against membranous compartments: Canonical and unconventional purposes and mechanisms

Selective autophagic degradation of cellular components underlies many of the important physiological and pathological implications that autophagy has for mammalian cells. Cytoplasmic vesicles, just like other intracellular items, can be subjected to conventional autophagic events where double-membrane autophagosomes specifically isolate and deliver them for lysosomal destruction. However, intracellular membranes appear to constitute common platforms for unconventional versions of the autophagic pathway, a notion that has become apparent during the past few years. For instance, in many cases of autophagy directed against bacterial phagosomes, subversion of the process results in multimembrane vacuoles that promote bacterial replication instead of the usual degradative outcome. In a different atypical modality, single-membrane vesicles can be labeled with LC3 to direct their contents for lysosomal degradation. In fact, single-membrane compartments of various kinds often provide an assembly site for the autophagic machinery to perform unanticipated nondegradative activities that range from localized secretion of lysosomal contents to melanosome function. Interestingly, many of these unconventional processes seem to be initiated through engagement of relevant nodes of the autophagic signaling network that, once activated, promote LC3 decoration of the targeted membrane, and some cases of inducer/receptor proteins that specifically engage those important signaling hubs have recently been described. Here we review the available examples of all autophagic variants involving membranous compartments, with a main focus on the more recently discovered unconventional phenomena where the usual degradation purpose of autophagy or its canonical mechanistic features are not completely conserved.     

Red Blood Cells Protein Profile Is Modified in Breast Cancer Patients

Metastasis is the primary cause of death for most breast cancer (BC) patients who succumb to the disease. During the hematogenous dissemination, circulating tumor cells interact with different blood components. Thus, there are microenvironmental and systemic processes contributing to cancer regulation. We have recently published that red blood cells (RBCs) that accompany circulating tumor cells have prognostic value in metastatic BC patients. RBC alterations are related to several diseases. Although the principal known role is gas transport, it has been recently assigned additional functions as regulatory cells on circulation. Hence, to explore their potential contribution to tumor progression, we characterized the proteomic composition of RBCs from 53 BC patients from stages I to III and IV, compared with 33 cancer-free controls. In this work, we observed that RBCs from BC patients showed a different proteomic profile compared to cancer-free controls and between different tumor stages. The differential proteins were mainly related to extracellular components, proteasome, and metabolism. Embryonic hemoglobins, not expected in adults’ RBCs, were detected in BC patients. Besides, lysosome-associated membrane glycoprotein 2 emerge as a new RBCs marker with diagnostic and prognostic potential for metastatic BC patients. Seemingly, RBCs are acquiring modifications in their proteomic composition that probably represents the systemic cancer disease, conditioned by the tumor microenvironment.     

Laser immunotherapy

Laser immunotherapy is a novel approach for the treatment of metastatic tumors. It combines a selective photothermal laser-tissue interaction for direct tumor destruction and an immunoadjuvant-directed simulation for immune responses. In experiments using a rat metastatic tumor model, laser immunotherapy resulted in the eradication of both treated primary tumors and untreated metastases at remote sites. It also induced anti-tumor resistance.     

Efficacy and adverse events of five targeted agents in the treatment of advanced or metastatic non-small-cell lung cancer: A network meta-analysis of nine eligible randomized controlled trials involving 5,059 patients

Recently, targeted agents were reported to improve overall survival, progression-free survival (PFS), response rate, and quality of life compared with cytotoxic chemotherapies, which provides hope for the treatment of non-small-cell lung cancer (NSCLC). The network meta-analysis is applied to compare the efficacies and adverse events of five targeted agents (erlotinib, gefitinib, vandetanib, dacomitinib, and icotinib) for advanced or metastatic NSCLC. Nine eligible randomized controlled trials from PubMed and Cochrane Library database were included. Weighted mean difference, odds ratio, and surface under the cumulative ranking curve (SUCRA) values were evaluated for the efficacy and adverse events of the five targeted agents in the treatment of NSCLC. With regard to efficacy, the overall response rate (ORR) of advanced or metastatic NSCLC patients treated with gefitinib was relatively higher than those treated with placebo. Compared with patients treated with placebo, the disease control rate (DCR) of patients treated with erlotinib and with gefitinib was relatively higher. Furthermore, in terms of PFS and DCR, the SUCRA value of icotinib was the highest among the five targeted drugs. With regard to ORR, the SUCRA value of gefitinib was the highest among the five targeted drugs. In terms of fatigue, rash, and cough, erlotinib had the lowest SUCRA value, whereas vandetanib exhibited the lowest SUCRA value in terms of diarrhea. Our study suggests that the efficacies of gefitinib and icotinib for advanced or metastatic NSCLC were comparatively better, whereas the toxicities of erlotinib and vandetanib were relatively greater.     

Trypanosoma equiperdum: Movement from the dermis

Twelve dogs were injected intradermally with 352,770 to 14,391,660 Trypanosoma equiperdum and afferent and efferent lymph, lymph nodes, and blood examined by mouse inoculation at minute, hourly, and daily intervals following inoculation. The log dosage of trypanosomes given each dog was closely related to their body weight (P < 0.01). Afferent lymph contained trypanosomes as soon as 5 and 27 min after inoculation. Lymph nodes on the side of injection became positive within 5 min of injection, while those on the contralateral side remained negative for at least 120 min after injection. Blood contained trypanosomes as soon as 5 min after injection, although the average time for all dogs, before trypanosomes were demonstrated in the blood, was 40 min postinjection. Efferent lymph did not contain organisms until 25–76 hr after inoculation. We consider this sequence to indicate that T. equiperdum can leave the dermis in afferent lymphatics, reach the local lymph node, invade the blood stream from this site, and only after a day or longer do they leave the node via the efferent lymphatics.     

Protocols for Vaginal Inoculation and Sample Collection in the Experimental Mouse Model of Candida vaginitis

Vulvovaginal candidiasis (VVC), caused by Candida species, is a fungal infection of the lower female genital tract that affects approximately 75% of otherwise healthy women during their reproductive years^18,32-34. Predisposing factors include antibiotic usage, uncontrolled diabetes and disturbance in reproductive hormone levels due to pregnancy, oral contraceptives or hormone replacement therapies^33,34. Recurrent VVC (RVVC), defined as three or more episodes per year, affects a separate 5 to 8% of women with no predisposing factors³³.An experimental mouse model of VVC has been established and used to study the pathogenesis and mucosal host response to Candida^{3,4,11,16,17,19,21,25,37}. This model has also been employed to test potential antifungal therapies in vivo^13,24. The model requires that the animals be maintained in a state of pseudoestrus for optimal Candida colonization/infection^6,14,23. Under such conditions, inoculated animals will have detectable vaginal fungal burden for weeks to months. Past studies show an extremely high parallel between the animal model and human infection relative to immunological and physiological properties^3,16,21. Differences, however, include a lack of Candida as normal vaginal flora and a neutral vaginal pH in the mice.Here, we demonstrate a series of key methods in the mouse vaginitis model that include vaginal inoculation, rapid collection of vaginal specimens, assessment of vaginal fungal burden, and tissue preparations for cellular extraction/isolation. This is followed by representative results for constituents of vaginal lavage fluid, fungal burden, and draining lymph node leukocyte yields. With the use of anesthetics, lavage samples can be collected at multiple time points on the same mice for longitudinal evaluation of infection/colonization. Furthermore, this model requires no immunosuppressive agents to initiate infection, allowing immunological studies under defined host conditions. Finally, the model and each technique introduced here could potentially give rise to use of the methodologies to examine other infectious diseases of the lower female genital tract (bacterial, parasitic, viral) and respective local or systemic host defenses.     

Arylpropionic acid-derived NSAIDs: New insights on derivatization,anticancer activity and potential mechanism of action

NSAIDs displayed chemopreventive and anticancer effects against several types of cancers. Moreover, combination of NSAIDs with anticancer agents resulted in enhanced anticancer activity. These findings have attracted much attention of researchers working in this field. The 2-arylpropionic acid-derived NSAIDs represent one of the most widely used anti-inflammatory agents. Additionally, they displayed antiproliferative activities against different types of cancer cells. Large volume of research was performed to identify molecular targets responsible for this activity. However, the exact mechanism underlying the anticancer activity of profens is still unclear. In this review article, the anticancer potential, structure activity relationship and synthesis of selected profen derivatives were summarized. This review is focused also on non-COX targets which can mediate the anticancer activity of this derivatives. The data in this review highlighted profens as promising lead compounds in future research to develop potent and safe anticancer agents.