The impact of human papilloma viruses, matrix metallo-proteinases and HIV protease inhibitors on the onset and progression of uterine cervix epithelial tumors: A review of preclinical and clinical studies

Infection of uterine cervix epithelial cells by the Human Papilloma Viruses (HPV) is associated with the development of dysplastic/hyperplastic lesions, termed cervical intraepithelial neoplasia (CIN). CIN lesions may regress, persist or progress to invasive cervical carcinoma (CC), a leading cause of death worldwide. CIN is particularly frequent and aggressive in women infected by both HPV and the Human Immunodeficiency Virus (HIV), as compared to the general female population. In these individuals, however, therapeutic regimens employing HIV protease inhibitors (HIV-PI) have reduced CIN incidence and/or clinical progression, shedding light on the mechanism(s) of its development. This article reviews published work concerning: (i) the role of HPV proteins (including HPV-E5, E6 and E7) and of matrix-metalloproteinases (MMPs) in CIN evolution into invasive CC; and (ii) the effect of HIV-PI on events leading to CIN progression such as basement membrane and extracellular matrix invasion by HPV-positive CIN cells and the formation of new blood vessels. Results from the reviewed literature indicate that CIN clinical progression can be monitored by evaluating the expression of MMPs and HPV proteins and they suggest the use of HIV-PI or their derivatives for the block of CIN evolution into CC in both HIV-infected and uninfected women

Autophagy up-regulation upon FeHV-1 infection on permissive cells

: FeHV-1 is a member of the Herpesviridae family that is distributed worldwide and causes feline viral rhinotracheitis (FVR). Since its relationship with the autophagic process has not yet been elucidated, the aim of this work was to evaluate the autophagy mediated by FeHV-1 and to determine its proviral or antiviral role. Our data showed that autophagy is induced by FeHV-1 in a viral dose and time-dependent manner. Phenotypic changes in LC3/p62 axis (increase of LC3-II and degradation of p62) were detected from 12 h post infection using western blot and immuno-fluorescence assays. In a second step, by using late autophagy inhibitors and inducers, the possible proviral role of autophagy during FeHV-1 infection was investigating by assessing the effects of each chemical in terms of viral yield, cytotoxic effects, and expression of viral glycoproteins. Our findings suggest that late-stage autophagy inhibitors (bafilomycin and chloroquine) have a negative impact on viral replication. Interestingly, we observed an accumulation of gB, a viral protein, when cells were pretreated with bafilomycin, whereas the opposite effect was observed when an autophagy inducer was used. The importance of autophagy during FeHV-1 infection was further supported by the results obtained with ATG5 siRNA. In summary, this study demonstrates FeHV-1-mediated autophagy induction, its proviral role, and the negative impact of late autophagy inhibitors on viral replication

Effect of exercise training on neuromuscular function of elbow flexors and knee extensors of type 2 diabetic patients

Purpose: The effects of exercise training on neuromuscular function of arm and leg muscles in type 2 diabetic patients (T2D) was investigated. Methods: Eight T2D sedentary male patients (61.0 ± 2.3 years) and eight sedentary healthy age matched control subjects (H, 63.9 ± 3.8 years) underwent a 16-week supervised combined endurance and resistance exercise program. Before and after training, maximal isometric (MVIC), isokinetic (15, 30, 60, 120, 180, 240° s−1) torque and muscle endurance of the elbow flexors (EF) and knee extensors (KE) were assessed. Simultaneously, surface electromyographic signals from biceps brachii (BB) and vastus lateralis (VL) muscles were recorded and muscle fiber conduction velocity (MFCV) estimated. Results: Following training, maximal torque of the KE increased during MVIC and isokinetic contractions at 15 and 30° s−1 in the T2D (+19.1 ± 2.7% on average; p 0.05). MFCV recorded from the VL during MVIC and during isokinetic contractions at 15 and 30° s−1 increased (+11.2 ± 1.6% on average; p < 0.01), but in the diabetic group only. Muscular endurance was lower in T2D (20.1 ± 0.7 s) compared to H (26.9 ± 1.3 s), with an associated increase in the MFCV slope after training in the KE muscles only. Conclusion: The effect of a combined exercise training on muscle torque appears to be angular velocity-specific in diabetic individuals, with a more pronounced effect on KE muscles and at slow contraction velocities, along with an associated increase in the MFCV. MFCV appears to be a more sensitive marker than torque in detecting the early signs of neuromuscular function reconditioning

Fibroblast Growth Factor-2 and the HIV-1 Tat Protein Synergize in Promoting Bcl-2 Expression and Preventing Endothelial Cell Apoptosis: Implications for the Pathogenesis of AIDS-Associated Kaposi's Sarcoma

Kaposi's sarcoma (KS) is a vascular tumor frequently occurring in Human Immunodeficiency Virus- (HIV-) 1-infected individuals. Our previous work indicated that the angiogenic fibroblast growth factor (FGF)-2 and the Tat protein of HIV-1, both expressed in KS lesions of HIV-infected patients, synergize at inducing angioproliferative, KS-like lesions in mice. Here we show that the development of angioproliferative lesions promoted in mice by combined Tat and FGF-2 associates with an increase in the levels of expression of the antiapoptotic Bcl-2 protein. Upregulation of Bcl-2 expression by combined FGF-2 and Tat occurs also in vitro, and this protects human primary endothelial cells from programmed cell death. As Bcl-2 is expressed in human KS lesions in a fashion paralleling the progression of the disease, these findings suggest a molecular mechanism by which Tat and FGF-2 cooperate in KS maintenance and progression in HIV-infected individuals

Metabolic Flexibility in Canine Mammary Tumors: Implications of Carnitine System

Deregulation of fatty acid catabolism provides an alternative energy source to glycolysis for cancer cell survival and proliferation. The regulator enzymes of the carnitine system (CS), responsible for the transport of fatty acids across mitochondrial membranes for β-oxidation are deregulated in tumorigenesis. Recently, we found that Carnitine Palmitoyl Transferase 1 (CPT1), a crucial regulator of CS components, is expressed and dysregulated in canine mammary tumor (CMT) tissues and cells. In this study, we examined the protein expression of the three remaining enzymes of CS (Carnitine Acylcarnitine Translocase (CACT), Carnitine Palmitoyl Transferase 2 (CPT2), Carnitine O-acetyltransferase (CrAT), in canine mammary cells and tissues by Western blot and immunohistochemistry. Protein expression of the components of CS was found in normal mammary glands and a concomitant deregulation of expression in CMT tissues that inversely correlated with the degree of tumor differentiation. Moreover, the expression and a different deregulation of CS-related proteins was also observed in CF33, CMT-U27, CMT-U309, and P114 cell lines used as in vitro model. These results demonstrate for the first time the expression of CS components in CMT tissues and cancer cells; however, further studies are needed to elucidate their roles in dogs as well

First description of Eucoleus garfiai (Gallego and Mas-Coma, 1975) in wild boar (Sus scrofa) in Italy

Eucoleus garfiai (syn. Capillaria garfiai) is a nematode infecting lingual tissue of domestic and wild swine. Prevalence data for this parasite are scant and often related to accidental findings, occurring only in Japan and a few European countries. In this study, an epidemiological survey was performed in order to identify E. garfiai in wild boar from the Campania region, southern Italy. A total of 153 wild boar carcasses were inspected over the course of two hunting seasons (2019–2020). Histological examinations were performed on tongue samples fixed and stained with haematoxylin and eosin. The scraping of dorsal tongue tissue was carried out to collect adult worms for parasitological examination. Out of 153 wild boars, 40 (26.1%, 95% CI: 19.8–33.6%) tested positive for helminths and/or eggs in tongue tissues. Parasites were identified morphologically and identification was confirmed by molecular analysis of the 18S rRNA gene, showing a 99% nucleotide match with E. garfiai sequences available in literature. No statistically significant differences were found according to age, sex nor hunting province. Our findings agree with previous histopathological data confirming the low pathogenic impact of this nematode. The present study represents the first report of E. garfiai in wild boar from Italy

Restricted Kaposi’s Sarcoma (KS) Herpesvirus Transcription in KS Lesions from Patients on Successful Antiretroviral Therapy

Kaposi’s sarcoma (KS) is caused by Kaposi’s sarcoma-associated herpesvirus (KSHV; human herpesvirus 8). KS is an AIDS-defining cancer, and it is changing in the post-antiretroviral therapy (post-ART) era. In countries with ready access to ART, approximately one-third of KS cases present in patients with undetectable HIV loads and CD4 counts of ≥200 cells/µl. This is in contrast to pre-ART era KS, which was associated with systemic HIV replication and CD4 counts of ≤200 cells/µl. Using primary patient biopsy specimens, we identified a novel molecular signature that characterizes AIDS KS lesions that develop in HIV-suppressed patients on ART: KSHV transcription is limited in HIV-suppressed patients. With one exception, only the canonical viral latency mRNAs were detectable. In contrast, early AIDS KS lesions expressed many more viral mRNAs, including, for instance, the viral G protein-coupled receptor (vGPCR)

HIV-1 tat protein enters dysfunctional endothelial cells via integrins and renders them permissive to virus replication

Previous work has shown that the Tat protein of Human Immunodeficiency Virus (HIV)-1 is released by acutely infected cells in a biologically active form and enters dendritic cells upon the binding of its arginine-glycine-aspartic acid (RGD) domain to the α5β1, αvβ3, and αvβ5 integrins. The up-regulation/activation of these integrins occurs in endothelial cells exposed to inflammatory cytokines that are increased in HIV-infected individuals, leading to endothelial cell dysfunction. Here, we show that inflammatory cytokine-activated endothelial cells selectively bind and rapidly take up nano-micromolar concentrations of Tat, as determined by flow cytometry. Protein oxidation and low temperatures reduce Tat entry, suggesting a conformation- and energy-dependent process. Consistently, Tat entry is competed out by RGD-Tat peptides or integrin natural ligands, and it is blocked by anti-α5β1, -αvβ3, and -αvβ5 antibodies. Moreover, modelling-docking calculations identify a low-energy Tat-αvβ3 integrin complex in which Tat makes contacts with both the αv and β3 chains. It is noteworthy that internalized Tat induces HIV replication in inflammatory cytokine-treated, but not untreated, endothelial cells. Thus, endothelial cell dysfunction driven by inflammatory cytokines renders the vascular system a target of Tat, which makes endothelial cells permissive to HIV replication, adding a further layer of complexity to functionally cure and/or eradicate HIV infection

Treatment of Disseminated Classic Type of Kaposi's Sarcoma with Paclitaxel

Classic Kaposi sarcoma (KS) is a rare human herpes virus 8-associated angioproliferative disease, and the disseminated classic type of KS in Korea is even rarer. The treatment options for classic KS vary and range from surgical excision to ionizing irradiation or chemotherapy. Recently, there have been a few reports of treating classic KS with paclitaxel, which has been used to treat AIDS-associated KS and post-transplant KS. We herein report a case of disseminated classic type KS in a 78-year-old Korean male patient who showed dramatic response after only two cycles of paclitaxel treatment

Insomnia and Hypnotic Use, Recorded in the Minimum Data Set, as Predictors of Falls and Hip Fractures in Michigan Nursing Homes

To examine the relationship between insomnia, hypnotic use, falls, and hip fractures in older people. Design : Secondary analysis of a large, longitudinal, assessment database. Setting : Four hundred thirty-seven nursing homes in Michigan. Participants : Residents aged 65 and older in 2001 with a baseline Minimum Data Set assessment and a follow-up 150 to 210 days later. Measurements : Logistic regression modeled any follow-up report of fall or hip fracture. Predictors were baseline reports of insomnia (previous month) and use of hypnotics (previous week). Potential confounds taken into account included standard measures of functional status, cognitive status, intensity of resource utilization, proximity to death, illness burden, number of medications, emergency room visits, nursing home new admission, age, and sex. Results : In 34,163 nursing home residents (76% women, mean age±standard deviation 84±8), hypnotic use did not predict falls (adjusted odds ratio (AOR)=1.13, 95% confidence interval (CI)=0.98, 1.30). In contrast, insomnia did predict future falls (AOR=1.52, 95% CI=1.38, 1.66). Untreated insomnia (AOR=1.55, 95% CI=1.41, 1.71) and hypnotic-treated (unresponsive) insomnia (AOR=1.32, 95% CI=1.02, 1.70) predicted more falls than did the absence of insomnia. After adjustment for confounding variables, insomnia and hypnotic use were not associated with subsequent hip fracture. Conclusion : In elderly nursing home residents, insomnia, but not hypnotic use, is associated with a greater risk of subsequent falls. Future studies will need to confirm these findings and determine whether appropriate hypnotic use can protect against future falls.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66254/1/j.1532-5415.2005.53304.x.pd