102 research outputs found
Birtamimab plus standard of care in light-chain amyloidosis: the phase 3 randomized placebo-controlled VITAL trial
Amyloid light-chain (AL) amyloidosis is a rare, typically fatal disease characterized by the accumulation of misfolded immunoglobulin light chains (LCs). Birtamimab is an investigational humanized monoclonal antibody designed to neutralize toxic LC aggregates and deplete insoluble organ-deposited amyloid via macrophage-induced phagocytosis. VITAL was a phase 3 randomized, double-blind, placebo-controlled clinical trial assessing the efficacy and safety of birtamimab + standard of care (SOC) in 260 newly diagnosed, treatment-naive patients with AL amyloidosis. Patients received 24 mg/kg IV birtamimab + SOC or placebo + SOC every 28 days. The primary composite end point was the time to all-cause mortality (ACM) or centrally adjudicated cardiac hospitalization ≥91 days after the first study drug infusion. The trial was terminated early after an interim futility analysis; there was no significant difference in the primary composite end point (hazard ratio [HR], 0.826; 95% confidence interval [CI], 0.574-1.189; log-rank P = .303). A post hoc analysis of patients with Mayo stage IV AL amyloidosis, those at the highest risk of early mortality, showed significant improvement in the time to ACM with birtamimab at month 9 (HR, 0.413; 95% CI, 0.191-0.895; log-rank P = .021). At month 9, 74% of patients with Mayo stage IV AL amyloidosis treated with birtamimab and 49% of those given placebo survived. Overall, the rates of treatment-emergent adverse events (TEAEs) and serious TEAEs were generally similar between treatment arms. A confirmatory phase 3 randomized, double-blind, placebo-controlled clinical trial of birtamimab in patients with Mayo stage IV AL amyloidosis (AFFIRM-AL; NCT04973137) is currently enrolling. The VITAL trial was registered at www.clinicaltrials.gov as #NCT02312206
Treatment of advanced, recurrent, resistant to previous treatments basal and squamous cell skin carcinomas with a synergistic formulation of interferons. Open, prospective study
<p>Abstract</p> <p>Background</p> <p>Aggressive non-melanoma skin cancer (deeply infiltrating, recurrent, and morphea form lesions) are therapeutically challenging because they require considerable tissue loss and may demand radical disfiguring surgery. Interferons (IFN) may provide a non-surgical approach to the management of these tumors. The aim of this work was to evaluate the effect of a formulation containing IFNs-α and -γ in synergistic proportions on patients with recurrent, advanced basal cell (BCC) or squamous cell skin carcinomas (SCSC).</p> <p>Methods</p> <p>Patients with extensive, recurrent, resistant to other procedures BCC or SCSC received the IFN formulation peri- and intralesionally, three times per week for 3 weeks. They had been previously treated with surgery and/or radiotherapy or chemotherapy. Thirteen weeks after the end of treatment, the original lesion sites were examined for histological evidence of remaining tumor.</p> <p>Results</p> <p>Sixteen elder (median 70 years-old) patients were included. They beared 12 BCC and 4 SCSC ranging from 1.5 to 12.5 cm in the longest dimension. At the end of treatment 47% CR (complete tumor elimination), 40% PR (>30% tumor reduction), and 13% stable disease were obtained. None of the patients relapsed during the treatment period. The median duration of the response was 38 months. Only one patient with complete response had relapsed until today. Principal adverse reactions were influenza-like symptoms well known to occur with interferon therapy, which were well tolerated.</p> <p>Conclusion</p> <p>The peri- and intralesional combination of IFNs-α and -γ was safe and showed effect for the treatment of advanced, recurrent and resistant to previous treatments of BCC and SCSC in elder patients. This is the first report of such treatment in patients with advance non-melanoma skin cancer. The encouraging result justifies further confirmatory trials.</p> <p>Trial registration</p> <p>Current Controlled Trials RPCEC00000052.</p
Noradrenergic Control of Gene Expression and Long-Term Neuronal Adaptation Evoked by Learned Vocalizations in Songbirds
Norepinephrine (NE) is thought to play important roles in the consolidation and retrieval of long-term memories, but its role in the processing and memorization of complex acoustic signals used for vocal communication has yet to be determined. We have used a combination of gene expression analysis, electrophysiological recordings and pharmacological manipulations in zebra finches to examine the role of noradrenergic transmission in the brain’s response to birdsong, a learned vocal behavior that shares important features with human speech. We show that noradrenergic transmission is required for both the expression of activity-dependent genes and the long-term maintenance of stimulus-specific electrophysiological adaptation that are induced in central auditory neurons by stimulation with birdsong. Specifically, we show that the caudomedial nidopallium (NCM), an area directly involved in the auditory processing and memorization of birdsong, receives strong noradrenergic innervation. Song-responsive neurons in this area express α-adrenergic receptors and are in close proximity to noradrenergic terminals. We further show that local α-adrenergic antagonism interferes with song-induced gene expression, without affecting spontaneous or evoked electrophysiological activity, thus dissociating the molecular and electrophysiological responses to song. Moreover, α-adrenergic antagonism disrupts the maintenance but not the acquisition of the adapted physiological state. We suggest that the noradrenergic system regulates long-term changes in song-responsive neurons by modulating the gene expression response that is associated with the electrophysiological activation triggered by song. We also suggest that this mechanism may be an important contributor to long-term auditory memories of learned vocalizations
The Impact of Hydrogen Bonding on Amide 1H Chemical Shift Anisotropy Studied by Cross-Correlated Relaxation and Liquid Crystal NMR Spectroscopy
Site-specific (1)H chemical shift anisotropy (CSA) tensors have been derived for the well-ordered backbone amide moieties in the B3 domain of protein G (GB3). Experimental input data include residual chemical shift anisotropy (RCSA), measured in six mutants that align differently relative to the static magnetic field when dissolved in a liquid crystalline Pf1 suspension, and cross-correlated relaxation rates between the (1)H(N) CSA tensor and either the (1)H-(15)N, the (1)H-(13)C', or the (1)H-(13)C(alpha) dipolar interactions. Analyses with the assumption that the (1)H(N) CSA tensor is symmetric with respect to the peptide plane (three-parameter fit) or without this premise (five-parameter fit) yield very similar results, confirming the robustness of the experimental input data, and that, to a good approximation, one of the principal components orients orthogonal to the peptide plane. (1)H(N) CSA tensors are found to deviate strongly from axial symmetry, with the most shielded tensor component roughly parallel to the N-H vector, and the least shielded component orthogonal to the peptide plane. DFT calculations on pairs of N-methyl acetamide and acetamide in H-bonded geometries taken from the GB3 X-ray structure correlate with experimental data and indicate that H-bonding effects dominate variations in the (1)H(N) CSA. Using experimentally derived (1)H(N) CSA tensors, the optimal relaxation interference effect needed for narrowest (1)H(N) TROSY line widths is found at similar to 1200 MHz
Advances, challenges and future directions for stem cell therapy in amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative condition where loss of motor neurons within the brain and spinal cord leads to muscle atrophy, weakness, paralysis and ultimately death within 3–5 years from onset of symptoms. The specific molecular mechanisms underlying the disease pathology are not fully understood and neuroprotective treatment options are minimally effective.
In recent years, stem cell transplantation as a new therapy for ALS patients has been extensively investigated, becoming an intense and debated field of study. In several preclinical studies using the SOD1G93A mouse model of ALS, stem cells were demonstrated to be neuroprotective, effectively delayed disease onset and extended survival. Despite substantial improvements in stem cell technology and promising results in preclinical studies, several questions still remain unanswered, such as the identification of the most suitable and beneficial cell source, cell dose, route of delivery and therapeutic mechanisms. This review will cover publications in this field and comprehensively discuss advances, challenges and future direction regarding the therapeutic potential of stem cells in ALS, with a focus on mesenchymal stem cells. In summary, given their high proliferation activity, immunomodulation, multi-differentiation potential, and the capacity to secrete neuroprotective factors, adult mesenchymal stem cells represent a promising candidate for clinical translation. However, technical hurdles such as optimal dose, differentiation state, route of administration, and the underlying potential therapeutic mechanisms still need to be assessed
How can climate change and engineered water conveyance affect sediment dynamics in the San Francisco Bay-Delta system?
Association Between HbA1c Level and Hearing Impairment in a Nondiabetic Adult Population
Mapping of multiple quantitative trait loci for growth and carcass traits in a complex commercial sheep pedigree
The confirmation of the segregation of experimentally discovered quantitative trait loci (QTL) in a variety of commercial populations is required before their commercial significance can be fully realized. The use of complex pedigrees in the design of such confirmation experiments has the potential to increase the probability of the QTL segregating within the pedigree while maintaining the power to detect this segregation. Here a QTL analysis is applied across candidate chromosomes of a complex pedigree of 570 Charollais sheep from commercial flocks in the UK. This pedigree also contained a moderately sized half-sib family which was analysed separately. Two QTL significant at the 5% chromosome-wide level were detected in the half-sib analysis and seven were detected in a maximum likelihood variance component analysis of the complex pedigree using identity-by-descent values estimated by Markov chain Monte Carlo methods. The estimation of OTL effects was achieved by fitting all QTL for a specific trait simultaneously, reducing the large upward bias observed in the single QTL models. Both methods of analysis detected QTL for live weight, although these mapped to different regions, and the variance components method detected QTL for ultrasonically measured fat depth. This analysis demonstrates the viability of applying a variance component analysis to large pedigrees with the presence of considerable inbreeding
Mapping of quantitative trait loci for growth and carcass traits in commercial sheep populations
Quantitative trait loci analyses were applied to data from Suffolk and Texel commercial sheep flocks in the United Kingdom. The populations comprised 489 Suffolk animals in three half-sib families and 903 Texel animals in nine half-sib families. Phenotypic data comprised measurements of live weight at 8 and 20 wk of age and ultrasonically measured fat and muscle depth at 20 wk. Lambs and their sires were genotyped across candidate regions on chromosomes 1, 2, 3, 4, 5, 6, 11, 18, and 20. Data were analyzed at the breed level, at the family level, and across extended families when families were genetically related. The breed-level analyses revealed a suggestive QTL on chromosome 1 in the Suffolk breed, between markers BM8246 and McM130, affecting muscle depth, although the effect was only significant in one of the three Suffolk families. A two-QTL analysis suggested that this effect may be due to two adjacent QTL acting in coupling. In total, 24 suggestive QTL were identified from individual family analyses. The most significant QTL affected fat depth and was segregating in a Texel family on chromosome 2, with an effect of 0.62 mm. The QTL was located around marker ILSTS030, 26 cM distal to myostatin. Two of the Suffolk and two of the Texel sires were related, and a three-generation analysis was applied across these two extended families. Seven suggestive QTL were identified in this analysis, including one that had not been detected in the individual family analysis. The most significant QTL, which affected muscle depth, was located on chromosome 18 near the callipyge and Carwell loci. Based on the pheno-typic effect and location of the QTL, the data suggest that a locus similar to the Carwell locus may be segregating in the United Kingdom Texel population
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