Efficacy of Subgingivally Delivered 1.2% Atorvastatin in the Treatment of Chronic Periodontitis in Patients With Type 2 Diabetes Mellitus: A Randomized Controlled Clinical Trial

Background: The present study was designed to evaluate effectiveness of 1.2% atorvastatin (ATV) gel, as an adjunct to scaling and root planing (SRP) in the treatment of intrabony defects in chronic periodontitis (CP) in patients with type 2 diabetes mellitus (t2DM). Methods: Seventy‐five patients were categorized into two treatment groups: 1) SRP plus 1.2% ATV and 2) SRP plus placebo. Clinical parameters including modified sulcus bleeding index, probing depth (PD), and relative attachment level (RAL) were recorded at baseline and 3, 6, and 9 months. Percentage radiographic defect depth reduction was evaluated using computer‐aided software at baseline and 6 and 9 months. Results: Mean PD reduction and mean RAL gain was greater in the ATV group than the placebo group at 3, 6, and 9 months. Furthermore, ATV group sites presented with a significantly greater percentage of radiographic defect depth reduction at 6 and 9 months. Conclusion: Locally delivered ATV was found to be effective in treatment of intrabony defects in CP in patients with t2DM.     

Phase I Study of a Systemically Delivered p53 Nanoparticle in Advanced Solid Tumors

Selective delivery of therapeutic molecules to primary and metastatic tumors is optimal for effective cancer therapy. A liposomal nanodelivery complex (scL) for systemic, tumor-targeting delivery of anticancer therapeutics has been developed. scL employs an anti-transferrin receptor (TfR), scFv as the targeting molecule. Loss of p53 suppressor function, through mutations or inactivation of the p53 pathway, is present in most human cancers. Rather than being transiently permissive for tumor initiation, persistence of p53 dysfunction is a continuing requirement for maintaining tumor growth. Herein, we report results of a first-in-man Phase I clinical trial of restoration of the normal human tumor suppressor gene p53 using the scL nanocomplex (SGT-53). Minimal side effects were observed in this trial in patients with advanced solid tumors. Furthermore, the majority of patients demonstrated stable disease. One patient with adenoid cystic carcinoma had his status changed from unresectable to resectable after one treatment cycle. More significantly, we observed an accumulation of the transgene in metastatic tumors, but not in normal skin tissue, in a dose-related manner. These results show not only that systemically delivered SGT-53 is well tolerated and exhibits anticancer activity, but also supply evidence of targeted tumor delivery of SGT-53 to metastatic lesions.     

Mechanistic study of solubility enhancement of nifedipine using vitamin E TPGS or solutol HS-15

The objective of our study was to find mechanisms responsible for solubility enhancement of nifedipine in solid dispersions of vitamin E TPGS and/or solutol HS-15. Solid dispersions of nifedipine with selected polymers such as vitamin E TPGS, solutol HS-15, PEG(1,000), and lipocol C-10 of varying drug/polymer ratios were prepared by a fusion method. The solubility enhancement was found to be in the order of vitamin E TPGS > solutol HS-15 > lipocol C-10 > PEG(1,000). Lipocol C-10, with a similar hydrophilic-lipophilic value as vitamin E TPGS, showed a comparable retained solubility enhancement during saturation solubility studies but had lower dissolution profile. Overall, vitamin E TPGS showed the best solubility and dissolution performance, while solutol HS-15 and lipocol C-10 demonstrated moderate solubility enhancements. Solid dispersions of vitamin E TPGS as prepared by microfluidization technique initially showed slightly higher solubility compared with samples prepared by fusion method, but eventually it became the same as the study progressed. However, solid dispersion of solutol HS-15 as prepared by microfluidization demonstrated a significant, sustained increased in solubility over its sample when prepared by fusion method. Based on these results, we concluded that enhanced solubility using vitamin E TPGS and solutol HS-15 resulted from a partial conversion of crystalline drug to the amorphous form, increase in wettability of the drug by water soluble polymers, better separation of drug particles, micellar solubilization of drug by high concentrations of surfactant polymers, and interaction between polymer and drug at the molecular level.     

Generation of a human embryonic stem cell line encoding the cystic fibrosis mutation deltaF508, using preimplantation genetic diagnosis

Human embryonic stem (hES) cells are pluripotent cells isolated from early human embryos. They can be grown in vitro and made to differentiate into many different cell types. These properties have suggested that they may be useful in cell replacement therapy for many degenerative diseases. However, if hES cells could also be manufactured with mutations significant in human disease, they could provide a powerful in-vitro tool for modelling disease processes and progression in a number of different cell types, as well as providing an ideal system for studying in-vitro toxicity and efficacy of drugs and other therapeutic systems such as gene therapy. Embryos with such mutations are generated as part of routine genetic testing during preimplantation genetic diagnosis, providing the opportunity to generate cell lines with significant mutations. A human embryonic stem cell line homozygous for the most common mutation leading to cystic fibrosis in humans (delta F508) has been generated and characterized. This cell line has the same morphology and expresses proteins typical of other unaffected hES cell lines. This cell line represents an important in-vitro tool for understanding the pathophysiology of cystic fibrosis, and presents exciting opportunities to test the efficacy and toxicity of new therapies relevant to CF.     

Evaluation of chemiluminescence, toluidine blue and histopathology for detection of high risk oral precancerous lesions: A cross-sectional study

Background

Chromogenic in situ hybridization (CISH) is fast becoming a well established technique for easy and sensitive determination of HER2 gene status in breast cancer. However, for the chromogenic method to achieve status as a safe and reliable technique, the method needs to be validated against already known and validated FISH techniques.

Methods

Here it is reported from a comparative study where HER2 gene status obtained by HER2 CISH pharmDx? Kit was compared to HER2 gene status obtained by the FDA approved HER2 FISH pharmDx? Kit and the PathVysion HER-2 DNA probe Kit. The study included 365 formalin fixed and paraffin-embedded invasive breast cancer tissue specimens collected consecutively at a US reference laboratory.

Results

The data obtained revealed an overall HER2 status concordance of approximately 98% for comparisons of HER2 CISH pharmDx? Kit to both HER2 FISH pharmDx? Kit and PathVysion HER-2 DNA Probe Kit.

Conclusions

The concordance between results obtained using the recently FDA approved HER2 CISH pharmDx? Kit with previously FDA approved FISH techniques for HER2 gene status determination indicate that the HER2 CISH pharmDx? Kit is a reliable chromogenic alternative to fluorescence-based methods.     

Treatment with dehydroepiandrosterone (DHEA) stimulates oxidative energy metabolism in the cerebral mitochondria. A comparative study of effects in old and young adult rats

The content of the neurosteroids, dehydroepiandrosterone (DHEA) in the brain decreases with aging. Also the oxidative energy metabolism is known to decrease with aging. Hence we examined the effects of treatment with DHEA (0.2 or 1.0 mg/kg body weight for 7 days) on oxidative energy metabolism in brain mitochondria from old and young adult rats. State 3 respiration rates in brain mitochondria from old animals were considerably lower than those in young adults. Treatment with DHEA stimulated state 3 and state 4 respiration rates in both the groups of the animals in a dose-dependent manner. In the old rats following DHEA treatment, the state 3 respiration rates became comparable to or increased beyond those of untreated young adults. In contrast to the old rats, stimulatory effect of DHEA treatment was of greater magnitude in the young adults. However, at higher dose (1.0 mg) the effect declined. Cytochrome aa3 content in the brain mitochondria from old rats was significantly low but the content of cytochrome b was unchanged while the content of cytochromes c+c1 had increased. Treatment with DHEA increased the content of cytochrome aa3 and b in old as well as in young adult animals. Higher dose of DHEA (1.0 mg) had adverse effect on the content of cytochrome c+c1. DHEA treatment stimulated ATPase activity in a dose-dependent manner in young adult rats whereas in the old rats the effect on ATPase activity was marginal. Dehydrogenases activities were somewhat lower in the old rats. DHEA treatment stimulated mitochondrial dehydrogenases activities in both the groups. Results of our studies suggest that judicious use of DHEA treatment can improve oxidative energy metabolism parameters in brain mitochondria from young adult as well as old rats.     

Video-gait analysis of functional recovery of nerve repaired with chitosan nerve guides

Quantitative analysis of peripheral nerve regeneration using nerve guides is commonly evaluated through histomorphometry and walking track analysis. We conducted a unique assessment of functional sciatic nerve recovery treated with chitosan nerve guides. We used video-gait analysis to evaluate the extent of functional nerve recovery by measuring the ankle angle at different gait cycle phases. We also correlated the gastrocnemius muscle weight measurements and histological analysis to functional nerve recovery. The chitosan group showed increased functional improvement compared to the control groups at the end of a 12-week period ( p < 0.05). Although both control and chitosan angle measurements were lower than those recorded for presurgery animals, the angle measurements significantly improved over the 12-week period. Stance phase duration of the gait cycle was also recorded, which showed a significant increase over the 12-week time period. The muscle weight parameter indicated a significant decrease in muscle atrophy and restoration of functional strength. Histological analysis revealed that the chitosan nerve guide provided significantly increased axonal growth. The functional results indicated that chitosan nerve guides enhanced functional improvement over no repair processes.     

Stability and uniqueness of clonal immunoglobulin CDR3 sequences for MRD tracking in multiple myeloma

Minimal residual disease (MRD) tracking, by next generation sequencing of immunoglobulin sequences, is moving towards clinical implementation in multiple myeloma. However, there is only sparse information available to address whether clonal sequences remain stable for tracking over time, and to what extent light chain sequences are sufficiently unique for tracking. Here, we analyzed immunoglobulin repertoires from 905 plasma cell myeloma and healthy control samples, focusing on the third complementarity determining region (CDR3). Clonal heavy and/or light chain expression was identified in all patients at baseline, with one or more subclones related to the main clone in 3.2%. In 45 patients with 101 sequential samples, the dominant clonal CDR3 sequences remained identical over time, despite differential clonal evolution by whole exome sequencing in 49% of patients. The low frequency of subclonal CDR3 variants, and absence of evolution over time in active multiple myeloma, indicates that tumor cells at this stage are not under selective pressure to undergo antibody affinity maturation. Next, we establish somatic hypermutation and non-templated insertions as the most important determinants of light chain clonal uniqueness, identifying a potentially trackable sequence in the majority of patients. Taken together, we show that dominant clonal sequences identified at baseline are reliable biomarkers for long-term tracking of the malignant clone, including both IGH and the majority of light chain clones.