Vaccine-elicited Human T Cells Recognizing Conserved Protein Regions Inhibit HIV-1

Virus diversity and escape from immune responses are the biggest challenges to the development of an effective vaccine against HIV-1. We hypothesized that T-cell vaccines targeting the most conserved regions of the HIV-1 proteome, which are common to most variants and bear fitness costs when mutated, will generate effectors that efficiently recognize and kill virus-infected cells early enough after transmission to potentially impact on HIV-1 replication and will do so more efficiently than whole protein-based T-cell vaccines. Here, we describe the first-ever administration of conserved immunogen vaccines vectored using prime-boost regimens of DNA, simian adenovirus and modified vaccinia virus Ankara to uninfected UK volunteers. The vaccine induced high levels of effector T cells that recognized virus-infected autologous CD4⁺ cells and inhibited HIV-1 replication by up to 5.79 log₁₀. The virus inhibition was mediated by both Gag- and Pol- specific effector CD8⁺ T cells targeting epitopes that are typically subdominant in natural infection. These results provide proof of concept for using a vaccine to target T cells at conserved epitopes, showing that these T cells can control HIV-1 replication in vitro.     

Multicentre randomized trial of sotalol vs amiodarone for chronic malignant ventricular tachyarrhythmias

Sotalol was compared with amiodarone in this open randomizedmulticentre study of patients with ventricular tachycardia orfibrillation not associated with acute myocardial infarctionrefractory to or intolerant of Class I drugs. 16 of 30 patientstreated with amiodarone completed 12 months on therapy, fivewere withdrawn because of recurrent ventricular tachycardiaand nine because of presumed adverse drug reactions, complianceproblems or protocol violation. Four of those who were withdrawndied within 12 months. Sixteen of 29 patients completed 12 months on sotalol, one waswithdrawn because of ventricular tachycardia and nine becauseof presumed adverse drug reactions, poor compliance or the needfor coronary artery surgery. Three died on treatment and twoafter withdrawal but within 12 months of entering the study. When the results are analysed by intention to treat there wasno significant difference in antiarrhythmic efficacy or in theincidence of side-effects severe enough to warrant withdrawalfrom the trial. There was an increase in left ventricular ejectionfraction in those treated with sotalol, which, because of itspharmacokine-tics, is an attractive alternative to amiodaronefor patients with malignant ventricular arrhythmias who cantolerate ß-adrenergic blockade.     

Emerging role of the endothelin axis in ovarian tumor progression

Ovarian cancer is the leading cause of gynecologic cancer-related deaths. The endothelin (ET) axis, which includes ET-1, ET-2, ET-3, and the ET receptors, ET(A)R and ET(B)R, represents a novel target in tumor treatment. ET-1 may directly contribute to tumor growth and indirectly modulate tumor-host interactions in various tumors such as prostatic, ovarian, renal, pulmonary, colorectal, cervical, breast carcinoma, Kaposi's sarcoma, brain tumors and melanoma. Extensive experimental evidence links ET(A)R overexpression with tumor progression in ovarian cancer. ET(A)R engagement can in fact activate multiple signal transduction pathways including protein kinase C, phosphati-dylinositol 3-kinase, mitogen-activated protein kinase and transactivate epidermal growth factor receptor, which play a role in ovarian tumor growth and invasion. The effects of ET(A)R signaling are wide ranging and involve both cancer cells and their surrounding stroma, including the vasculature. Upon being activated, the ET(A)R mediates multiple tumor-promoting activities, including enhanced cell proliferation, escape from apoptosis, angiogenesis, epithelial-mesenchymal transition and increased motility and invasiveness. These findings indicate that activation of ET(A)R by ET-1 is a key mechanism in the cellular signaling network promoting ovarian cancer growth and progression. The predominant role played by ET(A)R in cancer has led to the development of small molecules that antagonize the binding of ET-1 to ET(A)R. The emerging preclinical data presented here provide a rationale for the clinical evaluation of these molecules in which targeting the related signaling cascade via ET(A)R blockade may be advantageous in the treatment of advanced stage ovarian carcinoma.     

Toxicity of photodynamic therapy with LED associated to Photogem®: An in vivo study

The aims of this study were to evaluate the effects of Photogem®-mediated photosensitization on rat palatal mucosa and the biodistribution of the photosensitizer in this tissue. A solution of Photogem® (500 or 1000 mg/l) was applied to the palatal mucosa for 30 min and the exposure time to blue LED (460 nm) was 20 min (144 J/cm²). At 0, 1, 3, and 7 days, palatal mucosa was photographed for macroscopic analysis. After killing, the palate was removed for microscopic analysis. Thermal mapping evaluated temperature change in the tissue during irradiation. All experimental groups revealed intact mucosa in the macroscopic analysis. Tissue alterations were observed microscopically for only four out of 80 animals subjected to PDT. Fluorescence emitted by Photogem® was identified and was limited to the epithelial layer. A temperature increase from 35 to 41°C was recorded. Photogem®- mediated PDT was not toxic to the rat palatal mucosa.     

Low-level laser therapy for osteonecrotic lesions: effects on osteoblasts treated with zoledronic acid

Purpose

Clinical studies have shown that low-level laser therapy (LLLT) can improve local tissue healing of bisphosphonate-induced osteonecrosis of the jaw. However, the effects of laser irradiation on bisphosphonate-treated osteoblasts have not been completely elucidated.

Methods

Human osteoblasts were cultured in plain culture medium (DMEM). After 48 h, plain DMEM was replaced by DMEM with no fetal bovine serum, for a 24-h incubation followed by addition of zoledronic acid (5 μM) for additional 48 h. Cells were subjected to LLLT (InGaAsP; 780?±?3 nm; 0.025 W) at 0.5, 1.5, 3, 5, and 7 J/cm², three times every 24 h. Cell viability, total protein production, alkaline phosphatase activity (ALP), mineral nodule formation, gene expression of collagen type I and ALP, and cell morphology were evaluated.

Results

LLLT at 0.5 J/cm² increased cell viability of cultured osteoblasts. ALP activity and gene expression, in addition to mineral nodule formation and Col-I gene expression, were not increased by LLLT. LLLT applied to ZA-treated cells increased Col-I expression at 0.5, 1.5, and 3 J/cm² but did not improve any other cell activity assessed.

Conclusion

LLLT showed limited effects on bisphosphonate-treated osteoblasts.