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BackgroundMelanoma is a heterogeneous tumor in which phenotype-switching and CD133 marker have been associated with metastasis promotion and chemotherapy resistance. CD133 positive (CD133+) subpopulation has also been suggested as putative cancer stem cell (CSC) of melanoma tumor. Human endogenous retrovirus type K (HERV-K) has been described to be aberrantly activated during melanoma progression and implicated in the etiopathogenesis of disease. Earlier, we reported that stress-induced HERV-K activation promotes cell malignant transformation and reduces the immunogenicity of melanoma cells. Herein, we investigated the correlation between HERV-K and the CD133+ melanoma cells during microenvironmental modifications.MethodsTVM-A12 cell line, isolated in our laboratory from a primary human melanoma lesion, and other commercial melanoma cell lines (G-361, WM-115, WM-266-4 and A375) were grown and maintained in the standard and stem cell media. RNA interference, Real-time PCR, flow cytometry analysis, self-renewal and migration/invasion assays were performed to characterize cell behavior and HERV-K expression.ResultsMelanoma cells, exposed to stem cell media, undergo phenotype-switching and expansion of CD133+ melanoma cells, concomitantly promoted by HERV-K activation. Notably, the sorted CD133+ subpopulation showed stemness features, characterized by higher self-renewal ability, embryonic genes expression, migration and invasion capacities compared to the parental cell line. RNA interference-mediated downregulation experiments showed that HERV-K has a decisive role to expand and maintain the CD133+ melanoma subpopulation during microenvironmental modifications. Similarly, non nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine were effective to restrain the activation of HERV-K in melanoma cells, to antagonize CD133+ subpopulation expansion and to induce selective high level apoptosis in CD133+ cells.ConclusionsHERV-K activation promotes melanoma cells phenotype-switching and is strictly required to expand and maintain the CD133+ melanoma cells with stemness features in response to microenvironmental modifications.

Antibiotic resistance is an increasingly serious threat to human health that needs an urgent action. The aim of this study was to determine the prevalence and antibiotic susceptibility profiles of bacteria isolated from patient ear discharges suspected of otitis media. A retrospective analysis was performed using culture and antibiotic susceptibility test results of 1225 patients who visited Dessie Regional Health Research Laboratory from 2001 to 2011. Results showed a strong association (P < 0.001) between age and the risk of acquiring middle ear infection. The predominant bacterial isolates were Proteus spp. (28.8%), Staphylococcus aureus (23.7%), and Pseudomonas spp. (17.2%). Most of the isolated bacteria showed high resistance to ampicillin (88.5%), ceftriaxone (84.5%), amoxicillin (81.9%), and tetracycline (74.5%). About 72.5% of Proteus spp. and 62.2% of Pseudomonas spp. have developed resistance to one and more antibiotics used to treat them. This retrospective study also revealed the overall antibiotic resistance rate of bacterial isolates was increased nearly twofold (P = 0.001) over the last decade. Relatively, ciprofloxacin and gentamicin were the most effective antibiotics against all the isolates. In conclusion, antibiotic-resistant bacteria are alarmingly increasing in Wollo area, northeastern Ethiopia, and becoming a major public health problem in the management of patients with middle ear infection.

Human endogenous retroviruses (HERVs) have been implicated in human physiology and in human pathology. A better knowledge of the retroviral transcriptional activity in the general population and during the life span would greatly help the debate on its pathologic potential. The transcriptional activity of four HERV families (H, K, W, and E) was assessed, by qualitative and quantitative PCR, in PBMCs from 261 individuals aged from 1 to 80 years. Our results show that HERV-H, HERV-K, and HERV-W, but not HERV-E, are transcriptionally active in the test population already in the early childhood. In addition, the transcriptional levels of HERV-H, HERV-K, and HERV-W change significantly during the life span, albeit with distinct patterns. Our results, reinforce the hypothesis of a physiological correlation between HERVs activity and the different stages of life in humans. Studies aiming at identifying the factors, which are responsible for these changes during the individual's life, are still needed. Although the observed phenomena are presumably subjected to great variability, the basal transcriptional activity of each individual, also depending on the different ages of life, must be carefully considered in all the studies involving HERVs as causative agents of disease.

The Autism Spectrum Disorder (ASD) is a heterogeneous group of neurodevelopmental disorders, only clinically diagnosed since the lack of reliable biomarkers. Autism etiology is probably attributable to the combination of genetic vulnerability and environmental factors, and recently, maternal immune activation has been linked to derailed neurodevelopment, resulting in ASD in the offspring. Human endogenous retroviruses (HERVs) are relics of ancestral infections, stably integrated in the human DNA. Given the HERV persistence in the genome, some of HERVs have been co-opted for physiological functions during evolution, while their reactivation has been associated with several pathological conditions, including cancer, autoimmune, and neurological and psychiatric disorders. Particularly, due to their intrinsic responsiveness to external stimuli, HERVs can modulate the host immune response and in turn HERVs can be activated by the immune effectors. In previous works we demonstrated high expression levels of HERV-H in blood of autistic patients, closely related with the severity of the disease. Moreover, in a preclinical ASD model we proved changes of expression of several ERV families and cytokines from the intrauterine life to the adulthood, and across generations via maternal lineage. Here we analyzed the expression of HEMO and of selected HERVs and cytokines in blood from ASD patients and their parents and corresponding healthy controls, to look for a common molecular trait within family members. ASD patients and their mothers share altered expression of HERV-H and HEMO and of cytokines such as TNF-α, IFN-γ, IL-10. The multivariate regression models showed a mother-child association by HEMO activity and demonstrated in children and mothers an association between HERV-H and HEMO expression and, only in mothers, between HEMO, and TNF-α expression. Furthermore, high diagnostic performance for HERV-H and HEMO was found, suggesting their potential application for the identification of ASD children and their mothers. The present data support the involvement of HERVs in ASD and suggest HERVs and cytokines as ASD-associated traits. Since ASD is a heterogeneous group of neurodevelopmental disorders, a single determinant alone could be not enough to account for the complexity, and HERV/cytokines expression could be considered in a set of biomarkers, easily detectable in blood, and potentially useful for an early diagnosis.

In spite of the consistent benefits for HIV-1 infected patients undergoing antiretroviral therapy, a complete immune reconstitution is usually not achieved. Actually, antiretroviral therapy may be frequently accompanied by immunological unresponsiveness, persistent inflammatory conditions and inefficient cytotoxic T-cell response. Thymosin alpha 1 is a thymic peptide that demonstrates a peculiar ability to restore immune system homeostasis in different physiological and pathological conditions (i.e., infections, cancer, immunodeficiency, vaccination and aging) acting as multitasking protein depending on the host state of inflammation or immune dysfunction. This review reports the present knowledge on the in vitro and in vivo studies concerning the use of thymosin alpha 1 in HIV-1 infection. Recent findings and future perspectives of therapeutic intervention are discussed.

Retroelements, such as Human Endogenous Retroviruses (HERVs), have been implicated in many complex diseases, including neurological and neuropsychiatric disorders. Previously, we demonstrated a distinctive expression profile of specific HERV families in peripheral blood mononuclear cells from Autistic Spectrum Disorders (ASD) patients, suggesting their involvement in ASD. Here we used two distinct ASD mouse models: inbred BTBR T+tf/J mice and CD-1 outbred mice prenatally exposed to valproic acid. Whole embryos, blood and brain samples from the offspring were collected at different ages and the expression of several ERV families (ETnI, ETnII-α, ETnII-β, ETnII-γ, MusD and IAP), proinflammatory cytokines (IL-1β, IL-6 and TNF-α) and Toll-like receptors (TLR3 and TLR4) was assessed. In the two distinct mouse models analysed, the transcriptional activity of the ERV families was significant higher in comparison with corresponding controls, in whole embryos, blood and brain samples. Also the expression levels of the proinflammatory cytokines and TLRs were significantly higher than controls. Current results are in agreement with our previous findings in ASD children, supporting the hypothesis that ERVs may serve as biomarkers of atypical brain development. Moreover, the changes in ERVs and proinflammatory cytokines expression could be related with the autistic-like traits acquisition in the two mouse models.

Abnormal activation of human endogenous retroviruses (HERVs) has been associated with several diseases such as cancer, autoimmunity, and neurological disorders. In particular, in cancer HERV activity and expression have been specifically associated with tumor aggressiveness and patient outcomes. Cancer cell aggressiveness is intimately linked to the acquisition of peculiar plasticity and heterogeneity based on cell stemness features, as well as on the crosstalk between cancer cells and the microenvironment. The latter is a driving factor in the acquisition of aggressive phenotypes, associated with metastasis and resistance to conventional cancer therapies. Remarkably, in different cell types and stages of development, HERV expression is mainly regulated by epigenetic mechanisms and is subjected to a very precise temporal and spatial regulation according to the surrounding microenvironment. Focusing on our research experience with HERV-K involvement in the aggressiveness and plasticity of melanoma cells, this perspective aims to highlight the role of HERV-K in the crosstalk between cancer cells and the tumor microenvironment. The implications for a combination therapy targeted at HERVs with standard approaches are discussed.