The relationship of rotatable bond count (N rot) and polar surface area (PSA) with oral bioavailability in rats was examined for 434 Pharmacia compounds and compared with an earlier report from Veber ...et al. (J. Med. Chem. 2002, 45, 2615). N rot and PSA were calculated with QikProp or Cerius2. The resulting correlations depended on the calculation method and the therapeutic class within the data superset. These results underscore that such generalizations must be used with caution.
AimsTo assess peripapillary retinal nerve fibre layer (pRNFL) thickness in patients with X-linked retinoschisis (XLRS), as pRNFL thinning may limit functional improvements in gene therapy ...trials.MethodsThis retrospective multicentre study included 49 eyes from 25 patients diagnosed with XLRS. Data collected with multimodal imaging at baseline and last follow-up (when available) included age, best-recorded visual acuity (BRVA), central retinal thickness, macular volume (MV), presence and location of peripheral retinoschisis and pRNFL thickness in the global (G), superotemporal (TS), superonasal (NS), inferotemporal (TI), inferonasal (NI), nasal (N) and temporal (T) sectors. Retinal sensitivity, assessed by microperimetry, was also recorded for seven patients at baseline.ResultspRNFL was thinner (below the fifth percentile) in at least one sector in 72% of right eyes and 79% of left eyes, with thinning across three or more sectors in 20% of right and 17% of left eyes. In 44% of cases, thinning occurred in the temporal sectors of both eyes, with no nasal sectoral thinning. Number of peripheral retinoschisis quadrants matched thinned pRNFL sectors. A strong positive correlation was found between MV and temporal pRNFL thickness (r=0.71, p<0.01), while weak negative correlation trends were noted with age (p=0.05) and BRVA (logMAR; p=0.12) related to temporal thickness of pRNFL sectors.ConclusionpRNFL thinning, predominantly sectoral and linked to macular or peripheral retinoschisis, occurs in about three-quarters of patients with XLRS, while diffuse thinning occurs in one-fifth. Temporal pRNFL thinning might occur only after the collapse of intraretinal cystoid cavities in the macula.
Modulated electro-hyperthermia (mEHT) is a selective cancer treatment used in human oncology complementing other therapies. During mEHT, a focused electromagnetic field (EMF) is generated within the ...tumor inducing cell death by thermal and nonthermal effects. Here we investigated molecular changes elicited by mEHT using multiplex methods in an aggressive, therapy-resistant triple negative breast cancer (TNBC) model. 4T1/4T07 isografts inoculated orthotopically into female BALB/c mice were treated with mEHT three to five times. mEHT induced the upregulation of the stress-related Hsp70 and cleaved caspase-3 proteins, resulting in effective inhibition of tumor growth and proliferation. Several acute stress response proteins, including protease inhibitors, coagulation and heat shock factors, and complement family members, were among the most upregulated treatment-related genes/proteins as revealed by next-generation sequencing (NGS), Nanostring and mass spectrometry (MS). pathway analysis demonstrated that several of these proteins belong to the response to stimulus pathway. Cell culture treatments confirmed that the source of these proteins was the tumor cells. The heat-shock factor inhibitor KRIBB11 reduced mEHT-induced complement factor 4 (C4) mRNA increase. In conclusion, mEHT monotherapy induced tumor growth inhibition and a complex stress response. Inhibition of this stress response is likely to enhance the effectiveness of mEHT and other cancer treatments.
Neuraminidase inhibitors were widely used during the 2009-10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a meta-analysis of individual ...participant data to investigate the association between use of neuraminidase inhibitors and mortality in patients admitted to hospital with pandemic influenza A H1N1pdm09 virus infection.
We assembled data for patients (all ages) admitted to hospital worldwide with laboratory confirmed or clinically diagnosed pandemic influenza A H1N1pdm09 virus infection. We identified potential data contributors from an earlier systematic review of reported studies addressing the same research question. In our systematic review, eligible studies were done between March 1, 2009 (Mexico), or April 1, 2009 (rest of the world), until the WHO declaration of the end of the pandemic (Aug 10, 2010); however, we continued to receive data up to March 14, 2011, from ongoing studies. We did a meta-analysis of individual participant data to assess the association between neuraminidase inhibitor treatment and mortality (primary outcome), adjusting for both treatment propensity and potential confounders, using generalised linear mixed modelling. We assessed the association with time to treatment using time-dependent Cox regression shared frailty modelling.
We included data for 29,234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio OR 0·81; 95% CI 0·70-0·93; p=0·0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0·48; 95% CI 0·41-0·56; p<0·0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0·50; 95% CI 0·37-0·67; p<0·0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each day's delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio HR 1·23 95% CI 1·18-1·28; p<0·0001 for the increasing HR with each day's delay).
We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection.
F Hoffmann-La Roche.
The response of the adaptive immune system is augmented by multimeric presentation of a specific antigen, resembling viral particles. Several vaccines have been designed based on natural or designed ...protein scaffolds, which exhibited a potent adaptive immune response to antigens; however, antibodies are also generated against the scaffold, which may impair subsequent vaccination. In order to compare polypeptide scaffolds of different size and oligomerization state with respect to their efficiency, including anti-scaffold immunity, we compared several strategies of presentation of the RBD domain of the SARS-CoV-2 spike protein, an antigen aiming to generate neutralizing antibodies. A comparison of several genetic fusions of RBD to different nanoscaffolding domains (foldon, ferritin, lumazine synthase, and β-annulus peptide) delivered as DNA plasmids demonstrated a strongly augmented immune response, with high titers of neutralizing antibodies and a robust T-cell response in mice. Antibody titers and virus neutralization were most potently enhanced by fusion to the small β-annulus peptide scaffold, which itself triggered a minimal response in contrast to larger scaffolds. The β-annulus fused RBD protein increased residence in lymph nodes and triggered the most potent viral neutralization in immunization by a recombinant protein. Results of the study support the use of a nanoscaffolding platform using the β-annulus peptide for vaccine design.
X-linked retinoschisis (XLRS) is a potential target for gene supplementation approaches. To establish potential structural and functional endpoints for clinical trials, a comprehensive understanding ...of the inter-eye symmetry, relationship between structural and functional parameters, and disease progression is vital.
In this retrospective multicentre study, 118 eyes of 59 XLRS patients with
mutations were assessed. Information from center databases included:
variant; age at presentation; best-corrected visual acuity (BCVA), central retinal thickness (CRT), macular volume (MV) at presentation and at the last follow up; full-field electroretinogram (ERG) findings; presence of peripheral retinoschisis and complications (vitreous hemorrhage, retinal detachment); treatment with systemic or topical carbonic anhydrase inhibitors (CAI).
Inter-eye symmetry revealed strong correlation in CRT (
= 0.77;
< 0.0001) and moderate correlations in MV (
= 0.51,
< 0.0001) and BCVA (
= 0.49;
< 0.0001). Weak or no correlations were observed between BCVA and structural parameters (CRT, MV). Peripheral retinoschisis was observed in 40 (68%), retinal detachment in 9 (15%), and vitreous hemorrhage in 5 (8%) patients, respectively. Longitudinal examinations (mean, 4.3 years) showed no BCVA changes; however, a reduction of the CRT (
= 0.02), and MV (
= 0.01) was observed. Oral and/or topical CAI treatment did not significantly alter the CRT (
= 0.34).
The XLRS phenotype demonstrates a strong CRT symmetry between the eyes within individual patients and stable BCVA over several years. BCVA exhibits a weak correlation with the morphological parameters of retinal thickness (CRT MV). In our cohort, longitudinal functional changes were not significant, likely attributed to the short average follow-up period. Furthermore, CAI treatment didn't influence both morphological and functional outcomes.
In recent years, many efforts are being devoted to the development of new materials that originate from renewable resources. Polyesters are one of the most important classes of such materials and ...several bio-based monomers are available for their synthesis. In this work, the development of fully bio-based and solvent-free polyester polyol used for two-component polyurethane coatings on industrial scale is presented. Fossil-based raw materials were substituted with bio-based alternatives that are commercially available on a large scale. Properties of polyols and coatings were determined and measured. Polyols were characterized by the determination of acid number, hydroxyl number, glass transition temperature and refractive index, and measurement of viscosity, color and molecular weight. Coatings were characterized by the determination of mechanical properties, such as hardness, elasticity and impact resistance, and the measurement of optical properties such as gloss, haze, distinctness of image (DOI) and reflected image quality (RIQ) and weathering resistance. Three variations of bio-based polyol were synthesized, then the most suitable version was validated in a clear coat. The results showed that the properties of the bio-based polyol and coating met the requirements and were comparable to the properties of the synthetic counterpart. Results indicate that this newly developed 100% bio-based and solvent-free polyol can be used as a drop-in replacement for synthetic polyol. Furthermore, this work implies that the supply chain is established which allows the green transition in the paint industry.
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