Achondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications. Vosoritide is a biologic ...analogue of C-type natriuretic peptide, a potent stimulator of endochondral ossification.
In a multinational, phase 2, dose-finding study and extension study, we evaluated the safety and side-effect profile of vosoritide in children (5 to 14 years of age) with achondroplasia. A total of 35 children were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 μg per kilogram of body weight (8 patients in cohort 1), 7.5 μg per kilogram (8 patients in cohort 2), 15.0 μg per kilogram (10 patients in cohort 3), or 30.0 μg per kilogram (9 patients in cohort 4). After 6 months, the dose in cohort 1 was increased to 7.5 μg per kilogram and then to 15.0 μg per kilogram, and in cohort 2, the dose was increased to 15.0 μg per kilogram; the patients in cohorts 3 and 4 continued to receive their initial doses. At the time of data cutoff, the 24-month dose-finding study had been completed, and 30 patients had been enrolled in an ongoing long-term extension study; the median duration of follow-up across both studies was 42 months.
During the treatment periods in the dose-finding and extension studies, adverse events occurred in 35 of 35 patients (100%), and serious adverse events occurred in 4 of 35 patients (11%). Therapy was discontinued in 6 patients (in 1 because of an adverse event). During the first 6 months of treatment, a dose-dependent increase in the annualized growth velocity was observed with vosoritide up to a dose of 15.0 μg per kilogram, and a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 μg per kilogram for up to 42 months.
In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild. Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov numbers, NCT01603095, NCT02055157, and NCT02724228.).
4-Aminobenzoic acid (PABA) is one of the earliest patented and most commonly used sunscreen components. There is however a long-lasting controversy on its photo-protective efficacy owing to the lack ...of information on its protolytic equilibrium and photo-dynamics after absorption of ultraviolet radiation in physiologically relevant aqueous solution. The excitation dynamics in water also remains largely unknown for analogs of PABA such as 4-dimethylaminoacetophenone (DMAAP) and 4-dimethylaminobenzaldehyde (DMABA) which are recognized as prototypes for photo-induced twisted intramolecular charge transfer (TICT). Herein we report a combined application of femtosecond broadband time-resolved fluorescence and transient absorption coupled with density functional theoretical study for PABA, DMAAP, and DMABA under several solvent conditions with representative properties in terms of the pH, polarity and hydrogen bonding capacity. The results we gained demonstrate that, in a neutral aqueous solution, PABA taking the deprotonated anion form in the ground state undergoes rapid protonation after excitation, producing excited state species in the neutral form that may shift effectively by intersystem crossing (ISC) to the long-lasting triplet state capable of damaging nucleic acids. This provides evidence at the molecular level for the detrimental effect of PABA if used as a sunscreen ingredient. In contrast, our investigation on DMAAP and DMABA unveils an unusual solvent controlled deactivation dynamics rendered by the participation of the carbonyl oxygen associated nOπ* state featuring energy and structure strongly responsive to solvent properties. In particular, these molecules in water exhibit solute-solvent hydrogen bonding at the sites of the carbonyl oxygen and the amino nitrogen which is, respectively, weakened and strengthened after the excitation, leading to state reversal and formation of a nOπ* state with a peculiar non-planar structure. This quenches strongly the excitation, eliminates the TICT, suppresses the ISC and opens up the otherwise inaccessible internal conversion (IC) to account for ∼80% of the entire deactivation. The IC, observed to proceed at a rate of ∼2.5 ps, allows the effective recovery of the ground state, providing substantial protection against ultraviolet irradiation. Moreover, the revelation of highly solvent sensitive fluorescence emission from DMABA and DMAAP implies the potential application of these molecules as the functional element in the design of sensory materials for probing the polarity and hydrogen bonding character of the surrounding environment.
Background and Aim
Patients with functional dyspepsia (FD) often have concomitant anxiety and depression. Mindfulness‐based cognitive therapy (MBCT) combines the principles of cognitive behavioral ...therapy and mindfulness. It is a group‐based therapy and has been shown to be efficacious in functional gastrointestinal disorders. There are no randomized controlled trials (RCTs) evaluating MBCT in FD. We aimed to evaluate feasibility and efficacy of MBCT in FD management.
Methods
We performed a mixed‐method single‐center pilot randomized trial of 28 patients fulfilling ROME‐III criteria for FD. Fifteen patients were randomized to an 8‐week MBCT program while 13 underwent treatment‐as‐usual (TAU). Patients completed questionnaires at baseline and at week 8. Two focus‐groups were conducted. Feasibility of recruitment, acceptability of randomization, procedures and intervention, handout compliance and feasibility of quantitative measures were assessed. The primary outcome was subjective‐clinical‐assessment of FD symptoms (SCA‐FD). Secondary outcome measures included Short‐form Nepean Dyspepsia Index (SF‐NDI), subjective‐clinical‐assessment of general health (SCA‐GH), EuroQoL‐Visual Analog Scale (EuroQoL‐VAS), and Depression, Anxiety and Stress Scale–21 Items (DASS‐21).
Results
Twelve of 15 patients in the MBCT group completed the program. There was a trend towards symptom improvement, with 90% in the MBCT group reporting improvement in SCA‐FD compared with 45% in TAU(P = 0.063). Patients who underwent MBCT reported greater improvement in SF‐NDI (mean change: −8.8 (SD: 7.5) vs −0.7 (7.2), P = 0.018) and DASS‐21 (−19.8 (29.5) vs −5.5 (6.6) P = 0.13) compared with TAU. There was no difference in SCA‐GH and EuroQoL‐VAS. Based on SCA‐FD improvement, the eventual RCT will require 50 patients (25 in each group).
Conclusions
Mindfulness‐based cognitive therapy is likely efficacious for FD, and it would be feasible to conduct a RCT.
The primary triggers that stimulate the body to generate platelet antibodies via immune mechanisms encompass events such as pregnancy, transplantation, and blood transfusion. Interestingly, our ...findings revealed that a subset of male patients with hepatocellular carcinoma (HCC), despite having no history of transplantation or blood transfusion, has shown positive results in platelet antibody screenings. This hints at the possibility that certain factors, potentially related to the tumor itself or its treatment, may affect antibody production. To delve the causes we initiated this study. We employed a case-control study approach to analyze potential influential factors leading to the positive results via univariate and multivariate regression analysis. We utilized Kendall's tau-b correlation to examine the relationship between the strength of platelet antibodies and peripheral blood cytopenia. Antitumor medication emerged as an independent risk factor for positive results in HCC patients, and the strength of platelet antibodies positively correlated with the severity of anemia and thrombocytopenia. Without history of blood transfusion, transplantation, pregnancy, those HCC patients underwent recent tumor medication therapy are experiencing peripheral erythrocytopenia or thrombocytopenia, for them platelet antibody screenings holds potential clinical value for prevention and treatment of complications like drug-immune-related anemia and/or bleeding.
Magnetically switchable molecular solids with stimuli-responsive ON/OFF characteristics are promising candidates for smart switches and magnetic storage. In addition to conventional ...spin-crossover/charge-transfer materials whose magnetic responses arise from changes in the electronic structure of the metal centers, peripheral chemical entities that exhibit tunability provide an alternative and promising tactic for the construction of magnetic multi-stable materials. Temperature changes can trigger a reversible structural phase transition that can affect the coordination environment of a transition-metal center because of the thermal-induced motion of ligands, counterions, neutral guests, and/or changes in coordination number, thus potentially realizing magnetic bistability which can arise from a concomitant spin state change or the modulation of orbital angular momentum. Perspectives and challenges are also highlighted to provide insights into its development.
IntroductionCurrent international guidelines recommend ECG monitoring after an ischaemic stroke to detect atrial fibrillation (AF) in order to prevent stroke recurrence. However, optimal strategies ...to detect AF and the downstream management to prevent stroke recurrence remain to be established. The objective of the study was to explore the use of long-term home-based ECG monitoring for AF detection and stroke prevention in patients with a history of stroke.Methods and analysisThis prospective, randomised, open-label trial with blinded endpoint adjudication aimed to evaluate the efficacy of long-term home-based ECG monitoring for AF detection and stroke prevention in a 24-month period. Patients aged >18 years with a history of ischaemic stroke will be stratified according to the time from the index ischaemic stroke: <1, 1–3 and >3 years and then randomised in 1:1 to (1) home-based AF screening and (2) control. The home-based AF screening system comprises (1) a handheld single-lead ECG recorder (Comfit Healthcare Devices, Hong Kong SAR, China) and (2) a patient-facing smartphone application specially designed for the study. Patients randomised to the home-based AF group will record a 30 s single-lead ECG using a specially designed handheld ECG device every morning or when symptomatic. All remotely obtained data will be automatically transmitted in real-time through the study smartphone application to a secured cloud hosting and analysed using an artificial intelligence-based diagnostic system. When a diagnosis of AF is made with the system, the patients will be called back for a formal cardiology consultation within 1 week. The primary endpoint is the time to first detection of AF at 24 months of follow-up. Secondary endpoints include recurrent stroke or transient ischaemic attack, initiation of long-term anticoagulation therapy, hospitalisation for heart failure, cardiovascular death and all-cause death.Ethics and disseminationThe study protocol has been approved by the institutional review board of The University of Hong Kong, and Hong Kong West Cluster, Hospital Authority, Hong Kong SAR, China. Results will be published in peer-reviewed journals.Trial registration numberNCT04523649.
Umbilical cord (UC) and placenta (P) have been suggested as alternatives to bone marrow (BM) as sources of mesenchymal stem cells (MSC) for cell therapy, with both UC- and P-MSC possess ...immunophenotypic and functional characteristics similar to BM-MSC. However, their migration capacity, which is indispensable during tissue regeneration process, is unclear. Under defined conditions, the migration capacity of BM- and P-MSC was found 5.9- and 3.2-folds higher than that of UC-MSC, respectively. By the use of 2-DE and combined MS and MS/MS analysis, six differentially expressed proteins were identified among these MSC samples, with five of them known to be involved in cell migration as migration enhancing or inhibiting proteins. Consistent with their migration capacity, the levels of migration enhancing proteins including cathepsin B, cathepsin D and prohibitin,were significantly lower in UC-MSC when compared with those in BM- and P-MSC. For the migration inhibiting proteins such as plasminogen activator inhibitor-1 (PAI-1) and manganese superoxide dismutase, higher expression was found in the UC-MSC. We also showed that the overexpression of the PAI-1 impaired the migration capacity of BM- and P-MSC while silencing of PAI-1 enhanced the migration capacity of UC-MSC. Our study indicates that PAI-1 and other migration-related proteins are pivotal in governing the migration capacity of MSC.
Abstract Combined treatment using nonviral agent-mediated enzyme/prodrug therapy and immunotherapy had been proposed as a powerful alternative method of cancer therapy. The present study was aimed to ...evaluate the cytotoxicity in vitro and the therapeutic efficacy in vivo when the cytosine deaminase/5-fluorocytosine (CD/5-FC) and TNF-related apoptosis-inducing ligand (TRAIL) genes were jointly used against rat C6 glioma cells. The potency of the FA-PEG-PEI used as a nonviral vector was tested in the FR-expressed C6 glioma cells and Wistar rats. The C6 glioma cells and animal model were treated by the combined application of FA-PEG-PEI/pCD/5-FC and FA-PEG-PEI/pTRAIL. The antitumor effect was evaluated by survival assays and tumor volume. This study revealed a significant increase of cytotoxicity in vitro following the combined application of FA-PEG-PEI/pCD/5-FC and FA-PEG-PEI/pTRAIL treatments in C6 glioma cells. Animal studies showed a significant growth inhibition of the C6 glioma xenografts using the combined treatment. These results demonstrated that the combined treatment generated additive cytotoxic effect in C6 glioma cells in both in vitro and in vivo conditions, and indicated that such treatment method using both enzyme/prodrug therapy and TRAIL immunotherapy might be a promising therapeutic strategy in treating glioma.
•Butanol production from microalgae biodiesel residues via ABE fermentation.•More than twofold of butanol yield increase with additional butyrate of 18–20g/L.•The highest butanol production of ...3.86g/L was achieved with residues of 300g/L.•The highest butanol yield of 0.13g/g-carbohydrate was with residues of 100g/L.•One third of carbohydrate from residues cannot be utilized by C. acetobutylicum.
This study conducted batch experiments to evaluate the potential of butanol production from microalgae biodiesel residues by Clostridium acetobutylicum. The results indicated that with 90g/L of glucose as the sole substrate the highest butanol yield of 0.2g/g-glucose was found, but the addition of butyrate significantly enhanced the butanol yield. The highest butanol yield of 0.4g/g-glucose was found with 60g/L of glucose and 18g/L of butyrate. Using microalgae biodiesel residues as substrate, C. acetobutylicum produced 3.86g/L of butanol and achieved butanol yield of 0.13g/g-carbohydrate via ABE fermentation, but the results indicated that approximately one third of carbohydrate was not utilized by C. acetobutylicum. Biological butanol production from microalgae biodiesel residues can be possible, but further research on fermentation strategies are required to improve production yield.
PDF
