Combined virus-like particle-based polyepitope DNA/protein HIV-1 vaccine design, immunogenicity and toxicity studies

We have previously described designing of polyepitope immunogens TBI and TCI, to stimulate the humoral and cellular immune responses to HIV-1. Here, immunogens TBI and TCI were used to create new vaccine construct named CombiHIVvac (Combined HIV-1 vaccine). CombiHIVvac is a virus-like particles (VLP) containing the DNA vaccine pcDNA-TCI as a core encapsulated within a spermidine-polyglucin-TBI conjugate. The immunogenic and toxic properties of the candidate vaccine CombiHIVvac have been studied. CombiHIVvac induces a strong humoral and CTL responses in mice; the antibodies are highly specific and are able to neutralize HIV-1 in vitro. Preclinical study demonstrated that CombiHIVvac does not cause long-term changes in physiological, biochemical and morphological parameters in immunized animals and thus can be recommended for clinical trials.     

Influence of the restorative procedure factors on stress values in premolar with MOD cavity: a finite element study

In order to investigate the influence of cusp reduction, cavity isthmus width, and restorative material on stress values in premolar with mesio-occlusal-distal (MOD) cavity, numerical simulations were done on three-dimensional (3D) models of a maxillary second premolar designed using computerized tomography (CT) scan images. The use of four restorative materials (direct resin composite, direct resin composite with resin-modified glass-ionomer cement as the base, indirect resin composite, ceramic), three cavity preparation designs (without cusp coverage, 2-mm palatal cusp coverage, 2-mm palatal and buccal cusp coverage), and two cavity isthmus widths (1/2 and 2/3 intercuspal width) were simulated. After applying a static load of 200 N on the occlusal surface of the tooth, von Mises stresses in the enamel, dentin, and restoration were calculated using finite element analysis (FEA). Stress values in the enamel were primarily influenced by cavity preparation design, while restorative material showed higher contribution in dentin. The lowest stress values were obtained in models with cusp coverage and indirect restorations. Cavity isthmus width had minimal influence on stress values in tooth structures. None of the investigated factors determined stress values in the restoration. In conclusion, the use of ceramic restoration covering both palatal and buccal cusp provided the most favourable stress distribution of premolars with MOD cavity.

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Graphical abstract ?

     

Detection of misfolded prion protein in blood with conformationally sensitive peptides

BACKGROUND: The long-standing goal of a preclinical diagnostic test for transmissible spongiform encephalopathy (TSE) has recently become urgent because of the discovery that humans with variant Creutzfeldt-Jakob disease can transmit disease via blood transfusions. STUDY DESIGN AND METHODS: The misfolded protein diagnostic (MPD) assay employs a pyrene-labeled palindromic sequence of prion peptides that undergoes a cascade of coil to beta-sheet conversion in the presence of the misfolded prion protein (PrP(TSE)). The ability of the assay to detect PrP(TSE) in brain, serum, and plasma was tested. The basic protocol involved a several-hour incubation of 200-microL sample volumes with the peptide reagent in 96-well plates, after which fluorescence was monitored by a fluorescence plate reader with an excitation wavelength of 350 nm and emission scanning wavelength range of 365 to 600 nm. RESULTS: Target specificity for PrP(TSE) was documented by correlation of assay signal with Western blot signals in brain tissue from TSE-infected, normal, and knockout mice and negative assay signals by use of reagents with different peptide sequences. When applied to plasma or serum, the assay discriminated between samples from a variety of experimental and natural TSE infections compared to uninfected controls, with a sensitivity threshold of approximately 1 infectious dose per mL in pooled plasma from TSE-infected mice. CONCLUSIONS: The MPD assay is a sensitive and specific test for the detection of PrP(TSE) that may be useful in both preclinical and clinical diagnosis of TSE diseases of animals and humans.     

Limited granulomatosis with polyangiitis in an adolescent with Crohn's disease on infliximab therapy: cause or coincidence?

Pulmonary involvement in Crohn's disease (CD) may precede the development of intestinal inflammation, but in most cases occurs during the course of treatment, either as an extra‐intestinal manifestation, because of secondary infections, or as a side effect of the therapy itself. This case highlights the differential diagnosis and work up for multiple pulmonary nodules that developed in a patient with CD who had been in remission on infliximab therapy. Even though infectious causes, such as Mycobacteria and Fungi, account for majority of these cases, the possibility of non‐infectious conditions such as autoimmune disorders should also be considered.     

Romidepsin in peripheral and cutaneous T‐cell lymphoma: mechanistic implications from clinical and correlative data

Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T‐cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long‐term disease control and the ability to retreat patients relapsing off‐therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third‐line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3·5 months to 10 years; in four of six patients, re‐initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics‐mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T‐cell lymphoma, but suggests a complex mechanism of action.     

A novel intravenous iron formulation for treatment of anemia in inflammatory bowel disease: the ferric carboxymaltose (FERINJECT) randomized controlled trial

BACKGROUND AIMS:  Anemia is a common complication of inflammatory bowel diseases (IBD) This multicenter study tested the noninferiority and safety of a new intravenous iron preparation, ferric carboxymaltose (FeCarb), in comparison with oral ferrous sulfate (FeSulf) in reducing iron deficiency anemia (IDA) in IBD.
METHODS:  Two hundred patients were randomized in a 2:1 ratio (137 FeCarb:63 FeSulf) to receive FeCarb (maximum 1,000 mg iron per infusion) at 1-wk intervals until the patients' calculated total iron deficit was reached or FeSulf (100 mg b.i.d.) for 12 wk. The primary end point was change in hemoglobin (Hb) from baseline to week 12.
RESULTS:  The median Hb improved from 8.7 to 12.3 g/dL in the FeCarb group and from 9.1 to 12.1 g/dL in the FeSulf group, demonstrating noninferiority ( P = 0.6967). Response (defined as Hb increase of >2.0 g/dL) was higher for FeCarb at week 2 ( P = 0.0051) and week 4 ( P = 0.0346). Median ferritin increased from 5.0 to 323.5 μg/L at week 2, followed by a continuous decrease in the FeCarb group (43.5 μg/L at week 12). In the FeSulf group, a moderate increase from 6.5 to 28.5 μg/L at week 12 was observed. Treatment-related adverse events (AEs) occurred in 28.5% of the FeCarb and 22.2% of the FeSulf groups, with discontinuation of study medication due to AEs in 1.5% and 7.9%, respectively.
CONCLUSIONS:  FeCarb is effective and safe in IBD-associated anemia. It is noninferior to FeSulf in terms of Hb change over 12 wk, and provides a fast Hb increase and a sufficient refill of iron stores.     

Clinical and virologic outcomes in patients with oseltamivir-resistant seasonal influenza A (H1N1) infections: results from a clinical trial

Nineteen patients with oseltamivir-resistant seasonal influenza A (H1N1) infections were randomized to receive oseltamivir or placebo. Nasopharyngeal swabs were obtained, and clinical and virologic outcomes were compared, stratified by early or late treatment. Neuraminidase inhibition assay and pyrosequencing for H275Y confirmed resistance. Twelve (63%) patients received oseltamivir; 8 (67%) received late treatment. Seven (37%) patients received placebo; 6 (86%) presented >48 hours after onset. Time to 50% decrease in symptom severity, complete symptom resolution, and first negative culture were shortest among the early treatment group. While sample size prohibits a strong conclusion, future studies should evaluate for similar trends.     

Assessing the Awareness of and Willingness to Participate in Cancer Clinical Trials Among Immigrant Latinos

Clinical trials are considered the gold standard of evidence about the efficacy of cancer prevention, early detection, and treatment interventions. A paucity of data exists on determinants of clinical trial participation in the growing US Latino population despite poor cancer outcomes in this group. This study seeks to describe correlates of awareness of and willingness to participate in clinical trials among largely Central, North, and South American Latinos using safety-net clinics. Between June 2007 and November 2008, we conducted an interviewer-administered, Spanish-language cross-sectional survey (n = 944). Logistic regression was used to assess effects of health information sources and psychosocial variables on awareness of and intention to participate in clinical trials. Analyses were completed in spring 2010. While only 48% knew what a clinical trial was, when explained, 65% indicated a willingness to participate. Providers were the most common source of health information. Use of Internet for health information, trust in health information, and higher education each independently increased the odds of clinical trial awareness, but obtaining information from providers did not. Contacting the Cancer Information Service and psychosocial factors were each independently associated with intent to join a clinical trial, while demographic factors were not. Information channels such as the Internet may be effective in conveying clinical trial information to Latinos. Providers being cited as the most common source of health information but not being associated with knowledge about or intent to participate in trials suggests a missed opportunity for communication to this population.