The growth factor progranulin (PGRN) has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation, but its receptors remain unidentified. We report that PGRN bound ...directly to tumor necrosis factor receptors (TNFRs) and disturbed the TNFα-TNFR interaction. PGRN-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed inflammatory arthritis. Atsttrin, an engineered protein composed of three PGRN fragments, exhibited selective TNFR binding. PGRN and Atsttrin prevented inflammation in multiple arthritis mouse models and inhibited TNFα-activated intracellular signaling. Collectively, these findings demonstrate that PGRN is a ligand of TNFR, an antagonist of TNFα signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice. They also suggest new potential therapeutic interventions for various TNFα-mediated pathologies and conditions, including rheumatoid arthritis.
There were few studies that investigated health-related quality of life (HRQoL) of the general population in China, and many of them reported limitations in sampling.
To investigate the relationship ...between lifestyles and HRQoL in the Chinese population in both individual and family levels.
Online questionnaires were distributed across China to collect demographic information and participants' HRQoL using EuroQoL 5 Dimension scales. The EuroQoL Group's 5 Dimension scale (EQ-5D) index and EuroQoL Group's visual analog scale (EQ VAS) score were calculated to evaluate the HRQoL.
A total of 1305 valid questionnaires were included. Higher HRQoL was found in people with intend to lower oil intake, intend to lower salt intake, intend to lower sugar intake, balanced diet, moderate sports every week, a sport hobby and joining a fitness organization (all p<.05). HRQoL was higher among male (female as reference), healthy weight (unhealthy weight as reference) (both p<.05). Negative correlation was found between HRQoL and clinical medical history and drinking history. Small families (1-2 persons, 83.19 ± 20.14) had poorer HRQoL (EQ VAS score) than big families (≥3 persons, 85.00 ± 17.96, p <.05).
In China, people with healthy dietary habits, regular sports habits, healthy weight and male groups tended to have better HRQoL. Clinical medical history and drinking history were negatively related to HRQoL. Small families tend to have poorer HRQoL than big families. The finding implicated influence of the number of family members on people's perception of health and provided scientific evidence for the current policies to encourage birth in China. For a better HRQoL, we suggest people live in big families and take measures to lower salt/sugar/oil intake and exercise regularly in daily life.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ObjectivesAssessing the knowledge, attitude and practices (KAP) regarding health self-management among patients with osteogenesis imperfecta (OI) in China.DesignAn online cross-sectional ...survey.SettingA structured questionnaire was distributed online through China-Dolls Center for Rare Disorders (CCRD), a non-governmental charity in China.ParticipantsParticipants were all patients with OI from CCRD. After stratified sampling according to the economic level of residential city, 901 patients were proportionally selected and 869 patients completed the survey (response rate: 96.4%).Main outcome measuresDemographic characteristics and KAP information were gathered using a 5-point Likert scale. The score of each dimension of KAP was the sum of the scores of all included items. Χ2 test or Fisher’s exact test was used to compare scores of different items. Ordinal regression was employed to determine the significant factors influencing KAP.ResultsA total of 802 questionnaires were included for analysis. Male respondents accounted for 57.1%, and 29.1% of respondents were of 26~30 years. More than half (50~60%) of patients knew the main symptoms of OI and the treatment of OI-related complications. Almost 80% of patients showed positive attitude. Nearly 60~70% of the patients were relatively able to take appropriate practice regarding OI management. There was a significant correlation between scores of knowledge and attitude, attitude and practice, as well as knowledge and practice. Patients aged 26~30 years, from urban areas and big cities, had higher KAP scores. Male patients showed better performance in knowledge, and highly educated patients perform better in practice.ConclusionsPatients with OI did not have sufficient knowledge on disease care and up-to-date caring guidelines, and their practice regarding health self-management also needs to be improved. Gender, age, educational level and economic level of residence can affect the level of KAP for patients, thus developing targeted and tailored programmes for patients with OI is highly recommended.
Purpose
Prescription refills are long-term prescriptions for chronic patients in stable status, which varies from country to country. A well-established prescription refill system is beneficial for ...chronic patients’ medication management and facilitates the efficacy of clinical care. Therefore, we carried out a bibliometric analysis to examine the development of this field.
Summary
Publications on prescription refills from 1970 to 2021 were collected in the Web of Science Core Collection (WoSCC). Search strategy TS = “prescri* refill*” OR “medi* refill*” OR “repeat prescri*” OR “repeat dispens*” OR TI = refill* was used for search. VOSviewer was applied to visualize the bibliometric analysis. A total of 319 publications were found in WoSCC. Study attention on prescription refills has shown a steady rise but is still low in recent years. The United States was the most productive country, which had the highest total citations, average citations per publication, and the highest H-index, and participated in international collaboration most frequently. The University of California system was the most productive institution. The U.S. Department of Veterans Affairs was the institution with the most citations, most average citation, and highest H-index. Sundell was the most productive author, and Steiner J. F. was the most influential author. “Adherence,” “medication,” and “therapy” were the most prominent keywords.
Conclusion
Publications on prescription refills have increased rapidly and continue to grow. The United States had the leading position in the area. It is recommended to pay closer attention to the latest hotspots, such as “Opioids,” “Surgery,” “Differentiated care,” and “HIV.”
Delta/Notch-like EGF-related receptor (DNER) has been reported to act as a Notch ligand, despite lacking a Delta/Serrate/Lag (DSL) binding domain common to all other known ligands. The established ...Notch ligand Delta-like 1 (DLL1), but not DNER, activated Notch1 in a luciferase assay, prevented the differentiation of myoblasts through Notch signaling, and bound Notch-fc in a cell-based assay. DNER is not a Notch ligand and its true function remains unknown.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dulaglutide (glucagon like peptide-1/IgG-Fc fusion protein, GLP-1-Fc) is a long lasting GLP-1 agonist, which consists of two arms of GLP-1 moieties fused to IgG Fc fragment. Dulaglutide is a safe and ...effective medication for type 2 diabetes. In an attempt to develop a biosimilar version of dulaglutide, we found that up to 75% of GLP-1-Fc displayed
N
-terminal truncations in one or both GLP-1 arms. We proposed that the
N
-terminal heterogeneity was caused by mis-cleavage of signal peptide and solved this problem through signal peptide optimization. Murine immunoglobulin kappa light chain signal peptide (KASP) significantly improves GLP-1-Fc
N
-terminal integrity and homogeneity. 92.8–95.7% of GLP-1-Fc molecules directed by KASP contain intact
N
-terminus. The productivity of GLP-1-Fc could reach 2.2 g/L in shaking flask fed batch culture. KASP is an optimal signal peptide for GLP-1-Fc expression in Chinese hamster ovary (CHO) cells.
Protein aggregation is a major challenge in the development of therapeutic monoclonal antibodies (mAbs). Several stressors can cause protein aggregation, including temperature shifts, mechanical ...forces, freezing-thawing cycles, oxidants, reductants, and extreme pH. When antibodies are exposed to low pH conditions, aggregation increases dramatically. However, low pH treatment is widely used in protein A affinity chromatography and low pH viral inactivation procedures. In the development of an IgG4 subclass antibody, mAb1-IgG4 showed a strong tendency to aggregate when temporarily exposed to low pH conditions. Our findings showed that the aggregation of mAb1-IgG4 under low pH conditions is determined by the stability of the Fc. The CH2 domain is the least stable domain in mAb1-IgG4. The L309E, Q311D, and Q311E mutations in the CH2 domain significantly reduced the aggregation propensity, which could be attributed to a reduction in the hydrophobicity of the CH2 domain. Protein stabilizers, such as sucrose and mannose, could also attenuate low pH-induced mAb1-IgG4 aggregation by shielding hydrophobic areas and increasing protein stability. Our findings provide valuable strategies for managing the aggregation of protein therapeutics with a human IgG4 backbone.
Background Patients receiving endovascular treatment for unruptured intracranial aneurysms (UIAs) face varying risks and benefits with antithrombotic management. This study aimed to evaluate the ...perioperative and long-term effects of antithrombotic strategies, identify the populations that would benefit, and explore the predictive factors affecting the long-term outcomes. Methods UIA patients undergoing endovascular treatment including stent-assisted coiling or flow diversion between June 2019 and June 2022 were enrolled. We compared perioperative and long-term complications between tirofiban and dual antiplatelet therapy groups. Optimal candidates for each antithrombotic treatment were identified using multivariate logistic regression. Nomograms were developed to determine the significant predictors for thromboembolic complications during follow-up. Results Among 181 propensity-score matched pairs, the tirofiban group showed a trend toward a lower rate of thromboembolic complications than the DAPT group without elevating major bleeding risk in either period. Homocysteine (Hcy) level ≥10 μmol/L was a significant independent factor associated with thromboembolic complication in both periods. Subgroup analysis highlighted that in patients with high Hcy levels, tirofiban and sustained antiplatelet treatment for ≥12 months were protective factors, while a history of stroke was an independent risk factor for thromboembolic events in follow-up. Four variables were selected to construct a prognostic nomogram, history of hypertension, prior stroke, Hcy level, and the duration of antiplatelet therapy. Conclusion Perioperative low-dose tirofiban and extended antiplatelet therapy demonstrated a favorable trend in long-term outcomes for UIA patients with preoperative Hcy levels ≥10 μmol/L undergoing endovascular treatment. The prognostic model offers reliable risk prediction and guides antithrombotic strategy decisions.
IMPORTANCE The anti-Tr immune response is associated with paraneoplastic cerebellar degeneration and Hodgkin lymphoma (HL). One case series has reported that the Delta/notch-like epidermal growth ...factor–related receptor (DNER) is the actual target for anti-Tr antibodies, but this result has not been replicated. OBJECTIVE To describe a patient with anti-Tr and confirm that DNER is the autoantigen for a series of patients with anti-Tr. DESIGN, SETTING, AND PARTICIPANTS Observational study and analysis of biological samples for antibodies to DNER at the hospital of the University of Pennsylvania. We examined a cerebrospinal fluid sample from 1 patient with anti-Tr and serum and/or cerebrospinal fluid samples from 5 other patients with anti-Tr. EXPOSURE Transfection of HEK293T and Hela cells to express DNER coupled to an enhanced green fluorescent protein tag using a plasmid previously used to detect human DNER antibodies. RESULTS A man in his 30s with paraneoplastic cerebellar degeneration and anti-Tr underwent treatment with corticosteroids and intravenous immunoglobulin, resulting in clinical improvement before chemotherapy. Despite close oncologic follow-up, a biopsy, positron emission tomography, and computed tomography, he was not diagnosed as having HL until 6 months after symptom onset. The cerebrospinal fluid sample from this patient reacted with cells transfected to express DNER, as did cerebrospinal fluid and/or serum samples from 5 other patients with paraneoplastic cerebellar degeneration, HL, and anti-Tr. Only 4 of the 5 serum samples reacted to permeabilized cells enough to be distinguished from background, but all 5 serum samples convincingly labeled live cells, which had considerably less background. All 6 control serum samples and 1 serum sample from a patient previously diagnosed as having anti-Tr (but without HL or cerebellitis) did not recognize DNER. CONCLUSIONS AND RELEVANCE This case demonstrates the importance of testing for the anti-Tr immune response in patients with cerebellar degeneration. The strong association of anti-Tr with HL requires careful surveillance for this tumor. We also confirm that DNER is the target antigen of the anti-Tr immune response. Screening for DNER antibodies against living transfected cells may offer an improved signal-to-noise characteristic compared with immunostaining of fixed, permeabilized cells.
This paper introduces a novel multivariate regression approach based on a multiple fitting algorithm that combines fitting functions to accordingly configure different regression models for the ...quantitative analysis of spectra data. The novel regression method employs multivariate fitting functions to characterize the potential functional relationship of spectral information and sample information with the corresponding attributes, and uses single fitting function elements as the independent variables for biased parameters to determine the amplitude of each fitting function. The peak width of the different fitting functions and the biased parameters are optimized by a simulated annealing algorithm. After parameter optimization, the fitting functions are superposed together to form a functional super surface, and a multiple fitting regression model is then used to characterize any functional relationship among the spectral variable information, sample information, and the corresponding analyte information. In this paper, a common fitting function, namely the Gaussian function, is used to create multiple fitting regression models. The simulated dataset and two real near infrared spectral datasets were used to validate the multiple fitting regression model. The results are compared to those obtained using partial least squares regression and least squares support vector regression. It is shown that the proposed multiple fitting regression algorithm achieved an accuracy comparable to the two conventional methods. Therefore, the multiple fitting regression is demonstrated to be a useful tool for spectra multivariate regression analysis and may also be suitable for linear and nonlinear multivariate calibration.
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