7196 research outputs found
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Mucus plugging, air trapping, and bronchiectasis are important outcome measures in assessing progressive childhood cystic fibrosis lung disease
No full textObjective: To determine which outcome measures could detect early progression of disease in school-age children with mild cystic fibrosis (CF) lung disease over a two-year time interval utilizing chest computed tomography (CT) scores, quantitative CT air trapping (QAT), and spirometric measurements. Methods: Thirty-six school-age children with mild CF lung disease (median [interquartile range] age 12 [3.7] years; percent predicted forced expiratory volume in 1 second (ppFEV1) 99 [12.5]) were evaluated by serial spirometer-controlled chest CT scans and spirometry at baseline, 3-month, 1- and 2-years. Results: No significant changes were noted at 3-month for any variable except for decreased ppFEV1. Mucus plugging score (MPS) and QATA1andA2 increased at 1- and 2-years. The bronchiectasis score (BS), and total score (TS) were increased at 2-year. All variables tested with the exception of bronchial wall thickness score, parenchymal score (PS), and ppFEV1, were consistent with longitudinal worsening of lung disease. Multivariate analysis revealed baseline PS, baseline TS, and 1-year changes in BS and air trapping score were predictive of 2-year changes in BS. Conclusions: MPS and QATA1-A2 were the most sensitive indicators of progressive childhood CF lung disease. The 1-year change in the bronchiectasis score had the most positive predictive power for 2-year change in bronchiectasis
The emerging jamboree of transformative therapies for autoimmune diseases
No full textStandard treatments for autoimmune and autoinflammatory disorders rely mainly on
immunosuppression. These are predominantly symptomatic remedies that do not
affect the root cause of the disease and are associated with multiple side effects.
Immunotherapies are being developed during the last decades as more specific and
safer alternatives to small molecules with broad immunosuppressive activity, but they still
do not distinguish between disease-causing and protective cell targets and thus, they
still have considerable risks of increasing susceptibility to infections and/or malignancy.
Antigen-specific approaches inducing immune tolerance represent an emerging trend
carrying the potential to be curative without inducing broad immunosuppression. These
therapies are based on antigenic epitopes derived from the same proteins that are
targeted by the autoreactive T and B cells, and which are administered to patients
together with precise instructions to induce regulatory responses capable to restore
homeostasis. They are not personalized medicines, and they do not need to be. They are
precision therapies exquisitely targeting the disease-causing cells that drive pathology
in defined patient populations. Immune tolerance approaches are truly transformative
options for people suffering from autoimmune diseases
Optimization of the in vivo potency of pyrazolopyrimidine MALT1 protease inhibitors by reducing metabolism and increasing potency in whole blood
No full textThe paracaspase MALT1 has gained increasing interest as a target for the treatment of subsets of lymphomas as well as autoimmune diseases and there is a need for suitable compounds to explore the therapeutic potential of this target. Here we report the optimization of the in vivo potency of pyrazolopyrimidines, a class of highly selective allosteric MALT1 inhibitors. The initial lead compound led to tumor stasis at high doses in activated B-cell like(ABC) diffuse large B-cell lymphoma (DLBCL) xenograft model but suffered from a short in vivo half-life and suboptimal potency in whole blood. Guided by metabolism studies, we identified compounds with reduced metabolic clearance and increased in vivo half-life. In a second optimization step, masking one of the hydrogen bond donors of the central urea moiety through an intra-molecular interaction reduced unspecific binding. This improved potency in whole blood which was associated with improved in vivo potency in a mechanistic model of B cell activation. The optimized compound led to tumor regression in a CARD11 mutant ABC-DLBCL lymphoma xenograft model
Blockage of bone morphogenetic protein signalling counteracts hypertrophy in a human osteoarthritic micro-cartilage model
No full textBone morphogenetic protein (BMP) signalling plays a significant role during embryonic cartilage development and has been associated with osteoarthritis (OA) pathogenesis, being in both cases involved in triggering hypertrophy. Inspired by recent findings that BMP inhibition counteracts hypertrophic differentiation of human mesenchymal progenitors, we hypothesized that selective inhibition of BMP signalling would mitigate hypertrophic features in OA cartilage. First, a 3D in vitro OA micro-cartilage model was established using minimally expanded OA chondrocytes that was reproducibly able to capture OA-like hypertrophic features. BMP signalling was then restricted by means of two BMP receptor type I inhibitors, resulting in reduction of OA hypertrophic traits while maintaining synthesis of cartilage extracellular matrix. Our findings open potential pharmacological strategies for counteracting cartilage hypertrophy in OA and support the broader perspective that key signalling pathways known from developmental processes can guide the understanding, and possibly the mitigation, of adult pathological features
Phase I study of the antiprogrammed cell death-1 Ab spartalizumab (PDR001) in Japanese patients with advanced malignancies
No full textSpartalizumab is a humanized IgG4/κ mAb directed against human programmed cell death-1 (PD-1). In this phase I study, we investigated safety, pharmacokinetics, preliminary antitumor activity, and toxicity of spartalizumab in patients with advanced malignancies. Patients (n = 18) with a range of tumor types received spartalizumab i.v. at doses of 1, 3, and 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or discontinuation at the discretion of the investigator or patient. Most patients (61%) had received five or more prior lines of therapy. No dose-limiting toxicities were reported and, hence, the maximum tolerated dose was 10 mg/kg or more. Pharmacokinetics in Japanese patients aligned with those reported in a global dose-escalation study. The safety profile was consistent with other approved anti-PD-1 mAbs; the most common drug-related adverse events were maculopapular rash (22%), followed by malaise and increased blood alkaline phosphatase (11% each). Partial responses were reported in two patients (11%), one with transitional cell carcinoma and the other with hepatocellular carcinoma. In conclusion, this study confirmed the safety of spartalizumab given at a dose of up to 10 mg/kg every 2 weeks in Japanese patients with cancers
Recent Progress in Radical Decarboxylative Functionalizations Enabled by Transition-Metal (Ni, Cu, Fe, Co or Cr) Catalysis
No full textAliphatic carboxylic acids are abundant in natural and synthetic sources and are widely used as connection points in many chemical transformations. Radical decarboxylative functionalization promoted by transition-metal catalysis has achieved great success, enabling carboxylic acids to be easily transformed into a wide variety of products. Herein, we highlight the recent advances made on transition-metal (Ni, Cu, Fe, Co or Cr) catalyzed C-X (X = C, N, H, O, B, or Si) bond formation as well as syntheses of ketones, amino acids, alcohols, ethers and difluoromethyl derivatives via radical decarboxylation of carboxylic acids or their derivatives, including, among others, redox-active esters (RAEs), anhydrides, and diacyl peroxides. 1 Introduction 2 Ni-Catalyzed Decarboxylative Functionalizations 3 Cu-Catalyzed Decarboxylative Functionalizations 4 Fe-Catalyzed Decarboxylative Functionalizations 5 Co- and Cr-Catalyzed Decarboxylative Functionalizations 6 Conclusions
Chimeric Antigen Receptor T Cell Therapies: A Review of Cellular Kinetic-Pharmacodynamic Modeling Approaches
No full textChimeric antigen receptor T cell (CAR-T cell) therapies have shown significant efficacy in CD19+ leukemias and lymphomas. There remain many challenges and questions for improving next-generation CAR-T cell therapies, and mathematical modeling of CAR-T cells may play a role in supporting further development. In this review, we introduce a mathematical modeling taxonomy for a set of relatively simple cellular kinetic-pharmacodynamic models that describe the in vivo dynamics of CAR-T cell and their interactions with cancer cells. We then discuss potential extensions of this model to include target binding, tumor distribution, cytokine-release syndrome, immunophenotype differentiation, and genotypic heterogeneity
Revisiting NO2 as Protecting group of Arginine in Solid-Phase Peptide Synthesis
No full textThe protection of side-chain arginine in solid-phase peptide synthesis requires attention since current protecting groups have several drawbacks. Herein, the NO2 group, which is scarcely used, has been revisited. This work shows that it prevents the formation of δ-lactam—the most severe side-reaction during the incorporation of Arg. Moreover, it is stable in solution for long periods and can be removed in a friendly manner. Thus, this protecting group can be removed while the protected peptide is still anchored to the resin, using SnCl2 as reducing agent in mild acid conditions using 2-MeTHF as solvent at 55°C Furthermore, we demonstrate that sonochemistry can facilitate the removal of NO2 from multiple Arg-containing peptides
It's in Our Blood: A Glimpse of Personalized Medicine
No full textRecent advances in protein profiling technology has facilitated simultaneous measurement of thousands of proteins in large population studies, exposing the depth and complexity of the plasma and serum proteomes. This revealed that proteins in circulation were organized into regulatory modules under genetic control and closely associated with current and future common diseases. Unlike networks in solid tissues, serum protein networks comprise members synthesized across different tissues of the body. Genetic analysis reveals that this cross-tissue regulation of the serum proteome participates in systemic homeostasis and mirrors the global disease state of individuals. Here, we discuss how application of this information in routine clinical evaluations may transform the future practice of medicine
A Roadmap to Inform Development, Validation and Approval of Digital Mobility Outcomes: The Mobilise-D Approach
No full textHealth care has had to adapt rapidly to COVID-19, and this in turn has highlighted a pressing need for tools to facilitate remote visits and monitoring. Digital health technology, including body-worn devices, offers a solution using digital outcomes to measure and monitor disease status and provide outcomes meaningful to both patients and health care professionals. Remote monitoring of physical mobility is a prime example, because mobility is among the most advanced modalities that can be assessed digitally and remotely. Loss of mobility is also an important feature of many health conditions, providing a read-out of health as well as a target for intervention. Real-world, continuous digital measures of mobility (digital mobility outcomes or DMOs) provide an opportunity for novel insights into health care conditions complementing existing mobility measures. Accepted and approved DMOs are not yet widely available. The need for large collaborative efforts to tackle the critical steps to adoption is widely recognised. Mobilise-D is an example. It is a multidisciplinary consortium of 34 institutions from academia and industry funded through the European Innovative Medicines Initiative 2 Joint Undertaking. Members of Mobilise-D are collaborating to address the critical steps for DMOs to be adopted in clinical trials and ultimately health care. To achieve this, the consortium has developed a roadmap to inform the development, validation and approval of DMOs in Parkinson's disease, multiple sclerosis, chronic obstructive pulmonary disease and recovery from proximal femoral fracture. Here we aim to describe the proposed approach and provide a high-level view of the ongoing and planned work of the Mobilise-D consortium. Ultimately, Mobilise-D aims to stimulate widespread adoption of DMOs through the provision of device agnostic software, standards and robust validation in order to bring digital outcomes from concept to use in clinical trials and health care