Significance and applications of nanoparticles in siRNA delivery for cancer therapy

RNAi is a powerful gene silencing process that holds great promise in cancer therapy by the use of siRNA. The aim of this review is to give an outline on different approaches to deliver siRNA and to describe the advantages and disadvantages of these systems. The prospects for siRNA are to be substantially better than other therapies, as they are easily applicable to any therapeutic target. They also promise potent gene inhibition with exquisite selectivity, down to the level of a single nucleotide polymorphism, and can easily identify offending proteins or variants by screening across a gene sequence. The main obstacle of using RNAi technology in cancer treatment is to protect such a fragile and quickly metabolized biological molecule and to efficiently deliver it in vivo to the target cells. Therefore, there is a requirement for new systems, such as nanoparticles, for siRNA delivery to help the siRNAs reach, and improve their biodistribution in, target tissues.     

Estimands in clinical trials – broadening the perspective

Defining the scientific questions of interest in a clinical trial is crucial to align its planning, design, conduct, analysis, and interpretation. However, practical experience shows that oftentimes specific choices in the statistical analysis blur the scientific question either in part or even completely, resulting in misalignment between trial objectives, conduct, analysis, and confusion in interpretation. The need for more clarity was highlighted by the Steering Committee of the International Council for Harmonization (ICH) in 2014, which endorsed a Concept Paper with the goal of developing a new regulatory guidance, suggested to be an addendum to ICH guideline E9. Triggered by these developments, we elaborate in this paper what the relevant questions in drug development are and how they fit with the current practice of intention‐to‐treat analyses. To this end, we consider the perspectives of patients, physicians, regulators, and payers. We argue that despite the different backgrounds and motivations of the various stakeholders, they all have similar interests in what the clinical trial estimands should be. Broadly, these can be classified into estimands addressing (a) lack of adherence to treatment due to different reasons and (b) efficacy and safety profiles when patients, in fact, are able to adhere to the treatment for its intended duration. We conclude that disentangling adherence to treatment and the efficacy and safety of treatment in patients that adhere leads to a transparent and clinical meaningful assessment of treatment risks and benefits. We touch upon statistical considerations and offer a discussion of additional implications. Copyright © 2016 John Wiley & Sons, Ltd.     

Melatonin ingestion before intradialytic exercise improves immune responses in hemodialysis patients

International Urology and Nephrology - The present study aimed to investigate the effects of melatonin (MEL) intake on systemic inflammation and immune responses during intradialytic exercise....     

Synthesis and biological activity of sinefungin analogues

A series of nucleosides (2-4) that derive from adenosine by chain extension at the 5'-end have been synthesized starting from the known phosphonate 7. The latter was first combined with 4-pentenal to give 8, which underwent chemical manipulations to provide triacetate 11, which was found suitable for the adenylation step. Further transformations, among them the Hofmann degradation of the amide group of compound 13, and final deprotection gave nucleosides 2-4. They were considered as analogues of sinefungin (1) and tested for their antileishmanial activity together with compounds 5 and 6, which were obtained independently. All the modifications with respect to sinefungin resulted in nearly complete loss of growth inhibitory activity. These results indicate that the 9' terminal amino and carboxyl groups are necessary for the activity and that the presence of the amino group at C-6' is not sufficient to maintain the antileishmanial effect. Some of the analogues however could antagonize or reverse the inhibitory activity of sinefungin (1).     

An autologous epidermal equivalent tissue-engineered from follicular outer root sheath keratinocytes is as effective as split-thickness skin autograft in recalcitrant vascular leg ulcers

The outer root sheath of hair follicles plays an important role in epidermal regeneration in vivo. Keratinocytes isolated by explantation of outer root sheath tissue have extensive proliferative capacity irrespective of donor age, which probably depends on pluripotent epithelial stem cells residing in the outer root sheath. These keratinocytes can be organotypically grown to epidermal equivalents in vitro. We report here that in a multicenter, randomized phase II study, EpiDex trade mark, a tissue-engineered, fully differentiated autologous epidermal equivalent derived from keratinocytes of the outer root sheath of plucked anagen hair follicles, is as effective as split-thickness skin autografting in the promotion of healing and complete closure of recalcitrant vascular leg ulcers.     

Surgical treatment of secondary hyperparathyroidism in patients with chronic renal failure

ObjectiveTo identify the indications for subtotal parathyroidectomy (PTX) in secondary hyperparathyroidism (SHPT) and report postoperative, early and late complications of PTX.Patients and methodsWe conducted a retrospective study of subjects with chronic renal failure operated in Tunisian hospitals who received subtotal PTX over 10 years from January 1997 to December 2007. We analyzed the clinical, biological and radiological parameters pre- and postoperatively.ResultsWe included 70 patients with average age of 39.4 years, 55.7% men and 44.3% in dialysis for 7.75 ± 4.8 years before PTX. The initial nephropathy was interstitial in 50% of cases. No cases of diabetic nephropathy have been reported. The clinical signs were bone pain (88.6%), muscle pain (85.6%), pruritus (81.4%). Radiological signs of osteitis fibrosa were observed in the majority of patients mainly resorption of extremities (92.9%), thinning of cortical (85.7%) and osteosclerosis (87.1%). The most common indication of PTX (85.7% of cases) was the persistence of serum PTH of more than 800 pg/ml associated with hypercalcemia and/or hyperphosphatemia refractory to medical treatment. A subtotal PTX (3/4 or 7/8) was performed after ultrasound and scintigraphy in the majority of cases. The histology of the parathyroid glands showed diffuse hyperplasia (51.4%), nodular hyperplasia (45.7%) and adenoma (2.8%). The postoperative evolution was marked by an improvement of the clinical and radiological criteria in 80% of cases. A PTH level of less than 15 pg/ml was rarely observed (10% of cases), and a PTH level of more than 300 pg/ml concerned 13% of patients. We noted a low morbidity and mortality (no cases laryngeal paralysis or cervical hematoma).ConclusionSurgical treatment of SHPT in Tunisia is very effective in our experience. The biological results are comparable to treatment with calcimimetics, not available in Tunisia and whose price is higher. An early treatment of disorders of bone and mineral metabolism should reduce the incidence of SHPT.     

Anti-xanthine oxidase antibodies in sera and synovial fluid of patients with rheumatoid arthritis and other joint inflammations

OBJECTIVE: To study anti-bovine milk xanthine oxidoreductase XOR antibody levels in synovial fluid as well as in serum of patients suffering from rheumatoid affections to assess a possible correlation between antibody titres and severity of disease. METHODS: Sera and synovial fluids were collected from volunteer donors at Setif University Hospital, Setif, Algeria from 2001--2007 with the consent of patients. Human IgG and IgM levels of free and bound anti-bovine milk XOR antibodies were determined using bovine XOR as antigen, with enzyme-linked immunosorbent assay ELISA. RESULTS: Serum IgG anti-bovine milk XOR titres in 30 healthy normal subjects 2.74+/-2.31 microgram/mL are in agreement with that reported in the literature. Immunoglobulin G and IgM anti-bovine milk XOR antibody titres were found to be significantly higher in serum from patients with rheumatoid arthritis RA, and latex positives subjects. Synovial IgM antibody titres to bovine XOR were found to be significantly higher in rheumatoid arthritis patients compared to patients with other joint inflammations. CONCLUSION: In rheumatoid arthritis patients, high concentrations of antibodies against XOR were noticed. These antibodies may play a major role in RA by inhibiting both xanthine and NADH oxidase activities of XOR. They may also play a key role in eliminating XOR from serum and synovial fluid positive role but unfortunately, immune complex formation could also activate complement and participate in self maintenance of inflammation.