The Amyloidosis Forum: a public private partnership to advance drug development in AL amyloidosis

BACKGROUND: Immunoglobulin light chain (AL) amyloidosis is a rare, multi-systemic disorder characterized by two disease processes: an underlying plasma cell dyscrasia that provides the source of pathologic light chains, and the resulting organ dysfunction caused by deposition of amyloid light chain fibrils. There are no FDA approved treatments for AL amyloidosis; regimens developed for multiple myeloma are used off-label to treat the plasma cell disorder and no therapies are directed at organ deposition. Thus, an unmet medical need persists despite advances in disease management. A public-private partnership was recently formed between the Amyloidosis Research Consortium (ARC) and the US Food and Drug Administration (FDA) to bridge scientific gaps in drug development for the treatment of AL amyloidosis. MAIN BODY: The inaugural Amyloidosis Forum was convened at FDA on 12 November 2019 and led by a multidisciplinary panel of physicians, health outcomes professionals, and representatives from the FDA, ARC, and pharmaceutical companies. Patients provided important perspectives on the pathway to diagnosis, challenges of rigorous treatment, and the burden of disease. The panel reviewed the epidemiology, pathobiology, and clinical features of AL amyloidosis. Hematologic characteristics, staging systems, and response criteria were examined with clear consensus that a "deep response" to plasma cell-directed treatments was critical to overall survival. Emphasis was placed on the heterogeneous clinical phenotypes of AL amyloidosis, including cardiovascular, renal, neurological, and gastrointestinal system manifestations that contribute to morbidity and/or mortality, but render challenges to clinical trial endpoint selection. FDA representatives discussed regulatory perspectives regarding demonstration of clinical benefits of investigational therapies in the context of a rare disease with multi-systemic manifestations. The panel also highlighted the potential importance of well-designed health-related quality of life instruments, quantification of system organ effects, the potential of advanced imaging technologies, and survival prediction models. CONCLUSIONS: The Amyloidosis Forum identified a clear need for novel trial designs that are scientifically rigorous, feasible, and incorporate clinically meaningful endpoints based on an understanding of the natural history of the disease in an evolving therapeutic landscape. Future forums will delve into these issues and seek to include participation from additional stakeholders

Sibilant consonants classification with deep neural networks

Abstract. Many children su ering from speech sound disorders cannot pronounce the sibilant consonants correctly. We have developed a serious game that is controlled by the children's voices in real time and that allows children to practice the European Portuguese sibilant consonants. For this, the game uses a sibilant consonant classi er. Since the game does not require any type of adult supervision, children can practice the production of these sounds more often, which may lead to faster improvements of their speech. Recently, the use of deep neural networks has given considerable improvements in classi cation for a variety of use cases, from image classication to speech and language processing. Here we propose to use deep convolutional neural networks to classify sibilant phonemes of European Portuguese in our serious game for speech and language therapy. We compared the performance of several diferent arti cial neural networks that used Mel frequency cepstral coefcients or log Mel lterbanks. Our best deep learning model achieves classi cation scores of 95:48% using a 2D convolutional model with log Mel lterbanks as input features.info:eu-repo/semantics/publishedVersio

Rationale, application and clinical qualification for NT-proBNP as a surrogate end point in pivotal clinical trials in patients with AL amyloidosis

Amyloid light-chain (LC) amyloidosis (AL amyloidosis) is a rare and fatal disease for which there are no approved therapies. In patients with AL amyloidosis, LC aggregates progressively accumulate in organs, resulting in organ failure that is particularly lethal when the heart is involved. A significant obstacle in the development of treatments for patients with AL amyloidosis, as well as for those with any disease that is rare, severe and heterogeneous, has been satisfying traditional clinical trial end points (for example, overall survival or progression-free survival). It is for this reason that many organizations, including the United States Food and Drug Administration through its Safety and Innovation Act Accelerated Approval pathway, have recognized the need for biomarkers as surrogate end points. The international AL amyloidosis expert community is in agreement that the N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP) is analytically validated and clinically qualified as a biomarker for use as a surrogate end point for survival in patients with AL amyloidosis. Underlying this consensus is the demonstration that NT-proBNP is an indicator of cardiac response in all interventional studies in which it has been assessed, despite differences in patient population, treatment type and treatment schedule. Furthermore, NT-proBNP expression is directly modulated by amyloidogenic LC-elicited signal transduction pathways in cardiomyocytes. The use of NT-proBNP will greatly facilitate the development of targeted therapies for AL amyloidosis. Here, we review the data supporting the use of NT-proBNP, a biomarker that is analytically validated, clinically qualified, directly modulated by LC and universally accepted by AL amyloidosis specialists, as a surrogate end point for survival.Leukemia advance online publication, 2 August 2016; doi:10.1038/leu.2016.191

Prognostic value of NT-proBNP, adrenomedullin, copeptin and proenkephalin in patients with pulmonary hypertension

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017.Introduction: Pulmonary hypertension (PH) comprises a group of progressive diseases characterized by an increase in pulmonary vascular resistance, leading to right ventricular dysfunction. Risk stratification is essential for prognostic evaluation and therapeutic decision, making the determination of new biomarkers important. Purpose: To assess the prognostic value of new biomarkers in the prognostic evaluation of patients with PH. Methods: Prospective cohort study of patients (pts) with PH confirmed by hemodynamic evaluation. Pts underwent clinical and laboratory evaluations at baseline and every 3 months. Follow-up lasted for 18 months. NTproBNP and the new biomarkers (adrenomedullin, copeptin and proenkephalin) were measured. The Mann-Whitney test, Kaplan-Meier survival analysis and Cox regression were used for statistical analysis. Results: Fifty one pts (75% males, mean age: 54±15 years) belonging to all groups of the WHO PH classification were included. At inclusion, all pts were in WHO functional class II or III. During the study period, 17 pts (33%) died. Baseline NTproBNP values were significantly higher in the non-survivors group (1327; 1061–2703pg/ml vs. 353.5; 190–1661pg/ml; p=0.022). The same did not occur for adrenomedullin, copeptin and proenkephalin baseline levels. The maximum NTproBNP, adrenomedullin and copeptin levels recorded during the follow-up period were significantly higher in the non-survivors group [2347.5 (1667–5073.25) pg/ml vs. 642.5 (208.25–4109.5) pg/ml, p=0.007; 53.6 (38.8- 94.2) pg/ml vs. 33.4 (27–48.8) pg/ml, p=0.0075; 20.69 (13.18–35.69) pmol/L vs. 9.97 (6.18–14.74) pmol/L, p=0.022, respectively]. This did not occur for the maximum proenkephalin level. The NT-proBNP level at admission and adremedullin level at 3 months were independent predictors of mortality (HR 2.78, CI95 1.23–6.30, p=0.01; HR 4.36, CI95 1.17–16.2, p=0.03).Conclusion: The maximum level of NTproBNP, adrenomedullin and copeptin during the follow up were associated with higher mortality in pts with PH. NTproBNP level proved to be an independent predictor of mortality in those patients. These results suggest the prognostic importance of these biomarkers in the approach of pts with PH.info:eu-repo/semantics/publishedVersio

Expert Consensus Recommendations for the Suspicion and Diagnosis of Transthyretin Cardiac Amyloidosis

Cardiomyopathy is a manifestation of transthyretin amyloidosis (ATTR), which is an underrecognized systemic disease whereby the transthyretin protein misfolds to form fibrils that deposit in various tissues and organs. ATTR amyloidosis is debilitating and associated with poor life expectancy, especially in those with cardiac dysfunction, but a variety of treatment options have recently become available. Considered a rare disease, ATTR amyloidosis may be more prevalent than thought, particularly in older persons. Diagnosis is often delayed because of a lack of disease awareness and the heterogeneity of symptoms at presentation. Given the recent availability of effective treatments, early recognition and diagnosis are especially critical because treatment is likely more effective earlier in the disease course. The Amyloidosis Research Consortium recently convened a group of experts in ATTR amyloidosis who, through an iterative process, agreed on best practices for suspicion, diagnosis, and characterization of disease. This review describes these consensus recommendations for ATTR associated with cardiomyopathy as a resource to aid cardiologists and others in the recognition and diagnosis of ATTR associated with cardiomyopathy. Included in this review is an overview of red flag signs and symptoms and a recommended diagnostic approach, including testing for monoclonal protein, scintigraphy, or biopsy and, if ATTR associated with cardiomyopathy is identified, TTR genotyping

A comparison of the radiosensitisation ability of 22 different element metal oxide nanoparticles using clinical megavoltage X-rays

Background: A wide range of nanoparticles (NPs), composed of different elements and their compounds, are being developed by several groups as possible radiosensitisers, with some already in clinical trials. However, no systematic experimental survey of the clinical X-ray radiosensitising potential of different element nanoparticles has been made. Here, we directly compare the irradiation-induced (10 Gy of 6-MV X-ray photon) production of hydroxyl radicals, superoxide anion radicals and singlet oxygen in aqueous solutions of the following metal oxide nanoparticles: Al2O3, SiO2, Sc2O3, TiO2, V2O5, Cr2O3, MnO2, Fe3O4, CoO, NiO, CuO, ZnO, ZrO2, MoO3, Nd2O3, Sm2O3, Eu2O3, Gd2O3, Tb4O7, Dy2O3, Er2O3 and HfO2. We also examine DNA damage due to these NPs in unirradiated and irradiated conditions. Results: Without any X-rays, several NPs produced more radicals than water alone. Thus, V2O5 NPs produced around 5-times more hydroxyl radicals and superoxide radicals. MnO2 NPs produced around 10-times more superoxide anions and Tb4O7 produced around 3-times more singlet oxygen. Lanthanides produce fewer hydroxyl radicals than water. Following irradiation, V2O5 NPs produced nearly 10-times more hydroxyl radicals than water. Changes in radical concentrations were determined by subtracting unirradiated values from irradiated values. These were then compared with irradiation-induced changes in water only. Irradiation-specific increases in hydroxyl radical were seen with most NPs, but these were only significantly above the values of water for V2O5, while the Lanthanides showed irradiation-specific decreases in hydroxyl radical, compared to water. Only TiO2 showed a trend of irradiation-specific increase in superoxides, while V2O5, MnO2, CoO, CuO, MoO3 and Tb4O7 all demonstrated significant irradiation-specific decreases in superoxide, compared to water. No irradiation-specific increases in singlet oxygen were seen, but V2O5, NiO, CuO, MoO3 and the lanthanides demonstrated irradiation-specific decreases in singlet oxygen, compared to water. MoO3 and CuO produced DNA damage in the absence of radiation, while the highest irradiation-specific DNA damage was observed with CuO. In contrast, MnO2, Fe3O4 and CoO were slightly protective against irradiation-induced DNA damage. Conclusions: Beyond identifying promising metal oxide NP radiosensitisers and radioprotectors, our broad comparisons reveal unexpected differences that suggest the surface chemistry of NP radiosensitisers is an important criterion for their success