Bifunctional inhibition of HIV-1 reverse transcriptase: a first step in designing a bifunctional triphosphate.

The onset of resistance to approved anti-AIDS drugs by HIV necessitates the search for novel inhibitors of HIV-1 reverse transcriptase (RT). Developing single molecular agents concurrently occupying the nucleoside and nonnucleoside binding sites in RT is an intriguing idea but the proof of concept has so far been elusive. As a first step, we describe molecular modeling to guide focused chemical syntheses of conjugates having nucleoside (d4T) and nonnucleoside (TIBO) moieties tethered by a flexible polyethylene glycol (PEG) linker. A triphosphate of d4T-6PEG-TIBO conjugate was successfully synthesized that is recognized as a substrate by HIV-1 RT and incorporated into a double-stranded DNA.

Screening for HPV-related oropharyngeal, anal, and penile cancers in middle-aged men: Initial report from the HOUSTON clinical trial.

BACKGROUND: The Human papillomavirus (HPV)-related Oropharyngeal and Uncommon Cancers Screening Trial of Men (HOUSTON) was designed to determine the prevalence of IgG antibodies to HPV type 16 E proteins (HPV16EAbs), to screen for persistence of HPV and/or detect HPV-related premalignancies and cancers, and to assess acceptance of screening among middle-aged men. METHODS: HOUSTON consists of a cross-sectional study and a longitudinal cohort study of men aged 50-64 years. Serologic HPV16EAb status and oral rinse HPV16 status were determined. All HPV16EAb-positive (HPV16EAb+) men and a matched cohort of HPV16EAb-negative (HPV16EAb-) men as well as all oral rinse HPV16-positive (HPV16+) men were included in the longitudinal study (blinded to their results) and underwent oropharyngeal screening every 6 months as well as one-time anal and penile screening. RESULTS: Of 553 men enrolled in the cross-sectional study, six (1.1%) were HPV16EAb+ (two were also oral rinse HPV16+), and 41 (7.4%) were HPV16EAb- but oral rinse HPV16+. These 47 men, along with five matched controls, were invited to participate in the longitudinal study, and 42 (81%) agreed and completed baseline in-person screening, with 93% and 90% completeing 6-month and 12-month follow-up visits. One HPV16EAb+ (also oral rinse HPV16+) man, who declined participation in the longitudinal study, presented 4 months after enrollment with an early-stage HPV16-related pharyngeal cancer. Additionally, one HPV16EAb+ (oral rinse HPV16-) man and two oral rinse HPV16+ (HPV16EAb-) men were diagnosed with oncogenic HPV-associated anal dysplasia. CONCLUSIONS: This biomarker panel deserves further prospective study to explore potential utility for HPV-related cancer screening among men.

[d4U]-spacer-[HI-236] double-drug inhibitors of HIV-1 reverse-transcriptase.

Four double-drug HIV NRTI/NNRTI inhibitors 15a-d of the type [d4U]-spacer-[HI-236] in which the spacer is varied as 1-butynyl (15a), propargyl-1-PEG (15b), propargyl-2-PEG (15c) and propargyl-4-PEG (15d) have been synthesized and biologically evaluated as RT inhibitors against HIV-1. The key step in their synthesis involved a Sonogashira coupling of 5-iodo d4U's benzoate with an alkynylated tethered HI-236 precursor followed by introduction of the HI-236 thiourea functionality. Biological evaluation in both cell-culture (MT-2 cells) as well as using an in vitro RT assay revealed 15a-c to be all more active than d4T. However, overall the results indicate the derivatives are acting as chain-extended NNRTIs in which for 15b-d the nucleoside component is likely situated outside of the pocket but with no evidence for any synergistic double binding between the NRTI and NNRTI sites. This is attributed, in part, to the lack of phosphorylation of the nucleoside component of the double-drug as a result of kinase recognition failure, which is not improved upon with the phosphoramidate of 15d incorporating a 4-PEG spacer.

Salivary and serum HPV antibody levels before and after definitive treatment in patients with oropharyngeal squamous cell carcinoma.

BACKGROUND: HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) is increasing in incidence. Laboratory assays that identify virally-mediated disease and predict HPV clearance in OPSCC may have important prognostic implications. OBJECTIVE: Here we investigated serum, salivary HPV16 early (E) antibodies before and after definitive chemoradiotherapy (CRT) in patients with locoregionally advanced OPSCC. METHODS: We prospectively measured salivary, serum samples at the beginning of and 6-7 weeks following the completion of CRT in 44 patients. IgG antibodies targeting N- and C-terminal fragments of E2 (NE2, CE2), E6 and E7 were measured by programmable enzyme-linked immunosorbent assay. RESULTS: We observed serum antibodies directed against HPV-associated E proteins in patients with HPV-associated OPSCC. E7 directed antibodies were detected in saliva in the majority of patients, and were associated with HPV status (p= 0.03). When analyzed longitudinally, median salivary E7 antibody levels decreased significantly post-treatment (p= 0.007). CONCLUSIONS: Our results demonstrate the feasibility of measuring HPV16 E antibodies in saliva and serum. E7 antibodies, in particular, are more detectable in saliva as compared with other E protein antibodies. Measuring E7 salivary antibody levels at various time points may have utility in understanding HPV clearance and should be explored for their ability to predict the risk of recurrence.

Health promotion training in dental and oral health degrees: a scoping review.

Dental diseases are a major burden on health; however, they are largely preventable. Dental treatment alone will not eradicate dental disease with a shift to prevention required. Prevention of dental diseases is a role of dental professionals, with most countries having formalized health promotion competencies for dental and oral health graduates. In spite of this, there may be minimal health promotion being undertaken in clinical practice. Therefore, the aim of this study was to conduct a scoping review to identify some published studies on health promotion training in dental and oral health degrees. Key search terms were developed and used to search selected databases, which identified 84 articles. Four articles met the inclusion/exclusion criteria and were included in the review. Of these studies, the type of oral health promotion tasks and instructions received before the tasks varied. However, for all studies the health promotion content was focused on health education. In terms of evaluation of outcomes, only two studies evaluated the health promotion content using student reflections. More good-quality information on health promotions training is needed to inform practice.

Bifunctional inhibition of human immunodeficiency virus type 1 reverse transcriptase: mechanism and proof-of-concept as a novel therapeutic design strategy.

Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is a major target for currently approved anti-HIV drugs. These drugs are divided into two classes: nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). This study illustrates the synthesis and biochemical evaluation of a novel bifunctional RT inhibitor utilizing d4T (NRTI) and a TMC-derivative (a diarylpyrimidine NNRTI) linked via a poly(ethylene glycol) (PEG) linker. HIV-1 RT successfully incorporates the triphosphate of d4T-4PEG-TMC bifunctional inhibitor in a base-specific manner. Moreover, this inhibitor demonstrates low nanomolar potency that has 4.3-fold and 4300-fold enhancement of polymerization inhibition in vitro relative to the parent TMC-derivative and d4T, respectively. This study serves as a proof-of-concept for the development and optimization of bifunctional RT inhibitors as potent inhibitors of HIV-1 viral replication.