XFab-α4-1BB/CD40L fusion protein activates dendritic cells, improves expansion of antigen-specific T cells, and exhibits antitumour efficacy in multiple solid tumour models.

BACKGROUND: Additional immunotherapies are still warranted for non-responders to checkpoint inhibitors with refractory or relapsing cancers, especially for patients with "cold" tumours lacking significant immune infiltration at treatment onset. We developed XFab-α4-1BB/CD40L, a bispecific antibody targeting 4-1BB and CD40 for dendritic cell activation and priming of tumour-reactive T cells to inhibit tumours. METHODS: XFab-α4-1BB/CD40L was developed by engineering an anti-4-1BB Fab arm into a CD40L trimer based on XFab® platform. Characterisation of the bispecific antibody was performed by cell-based reporter assays, maturation of dendritic cell assays, and mixed lymphocyte reactions. The abilities of antigen-specific T-cell expansion and antitumour efficacy were assessed in syngeneic mouse tumour models. Toxicological and pharmacodynamic profiles were investigated in non-human primates. RESULTS: XFab-α4-1BB/CD40L demonstrated independent CD40 agonistic activity and conditional 4-1BB activity mediated by CD40 crosslinking, leading to dendritic cell maturation and T-cell proliferation in vitro. We confirmed the expansion of antigen-specific T cells in the vaccination model and potent tumour regression induced by the bispecific antibody alone or in combination with gemcitabine in vivo, concomitant with improved tumour-reactive T-cell infiltration. XFab-α4-1BB/CD40L showed no signs of liver toxicity at doses up to 51 mg/kg in a repeated-dose regimen in non-human primates. CONCLUSIONS: XFab-α4-1BB/CD40L is capable of enhancing antitumour immunity by modulating dendritic cell and T-cell functions via targeting 4-1BB agonism to areas of CD40 expression. The focused, potent, and safe immune response induced by the bispecific antibody supports further clinical investigations for the treatment of solid tumours.

H-Bonding Room Temperature Phosphorescence Materials via Facile Preparation for Water-Stimulated Photoluminescent Ink.

Pure organic room-temperature phosphorescence (RTP) materials built upon noncovalent interactions have attracted much attention because of their high efficiency, long lifetime, and stimulus-responsive behavior. However, there are limited reports of noncovalent RTP materials because of the lack of specific design principles and clear mechanisms. Here, we report on a noncovalent material prepared via facile grinding that can emit fluorescence and RTP emission differing from their components' photoluminescent behavior. Exciplex can be formed during the preparation process to act as the minimum emission unit. We found that H-bonds in the RTP system provide restriction to nonradiative transition but also enhance energy transformation and energy level degeneracy in the system. Moreover, water-stimulated photoluminescent ink is produced from the materials to achieve double-encryption application with good resolution.

The synergy of germline C634Y and V292M RET mutations in a northern Chinese family with multiple endocrine neoplasia type 2A.

Genetic analysis for germline mutations of RET proto-oncogene has provided a basis for individual management of medullary thyroid carcinoma (MTC) and pheochromocytoma. Most of compound mutations have more aggressive phenotypes than single point mutations, but the compound C634Y/V292M variant in MTC has never been reported. Thus, we retrospectively investigated synergistic effect of C634Y and V292M RET germline mutations in family members with multiple endocrine neoplasia type 2A. Nine of 14 family members in a northern Chinese family underwent RET mutation screening using next-generation sequencing and PCR followed by direct bidirectional DNA sequencing. Clinical features of nine individuals were retrospectively carefully reviewed. In vitro, the scratch-wound assay was used to investigate the difference between the cells carrying different mutations. We find no patients died of MTC. All 3 carriers of the V292M variant were asymptomatic and did not have biochemical or structural evidence of disease (age: 82, 62 and 58). Among 4 C634Y mutation carriers, 2 patients had elevated calcitonin with the highest (156 pg/mL) in an 87-year-old male. Two carriers of compound C634Y/V292M trans variant had bilateral MTC with pheochromocytoma or lymph node metastasis (age: 54 and 41 years, respectively). Further, the compound C634Y/V292M variant had a faster migration rate than either single point mutation in vitro (P < .05). In conclusion, the V292M RET variant could be classified as 'likely benign' according to ACMG (2015). The compound variant V292M/C634Y was associated with both more aggressive clinical phenotype and faster cell growth in vitro than was either single mutation.

The effect of carbon nanoparticles vs. immune colloidal gold technique test strips on parathyroid protection in total thyroidectomy: A randomized clinical trial study.

BACKGROUND: The long-term effect of intraoperative usage of carbon nanoparticles (CN) and parathyroid hormone (PTH) test strip using immune colloidal gold technique (ICGT) is unclear. This study aims to compare the effect of intraoperative usage of CN and ICGT test strips on PG function. METHODS: This randomized clinical study involved adult patients who underwent total thyroidectomy. They were randomly allocated into three groups (control, CN, and ICGT group). Clinical data were analyzed. RESULTS: Each group involved 98 patients. Serum calcium and PTH concentrations at 24 h postoperatively (PTH24h) were higher in CN group. The parathyroid function recovered quicker in CN group. Use of CN increased in situ PG preservation and PTH24h. Mediation analysis indicated that 23.05% of the total effect of CN on PTH24h was attributed to PGRIS. CONCLUSION: CN holds promise to improve in situ PG preservation and protect PG vasculature, thereby reducing the incidence of early hypoparathyroidism. The value of ICGT test strips for PG protection is dubious.

Obstructive Sleep Apnea Detection Based on Sleep Sounds via Deep Learning.

Purpose: This study aimed to propose a novel deep-learning method for automatic sleep apneic event detection and thus to estimate the apnea hypopnea index (AHI) and identify obstructive sleep apnea (OSA) in an event-by-event manner solely based on sleep sounds obtained by a noncontact audio recorder. Methods: We conducted a cross-sectional study of participants with habitual snoring or heavy breathing sounds during sleep to train and test a deep convolutional neural network named OSAnet for the detection of OSA based on sleep sounds. Polysomnography (PSG) was conducted, and sleep sounds were recorded simultaneously in a regular room without noise attenuation. The study was conducted in two phases. In phase one, eligible participants were enrolled and randomly allocated into training and validation groups for deep learning algorithm development. In phase two, eligible patients were enrolled in a test group for algorithm assessment. Sensitivity, specificity, accuracy, unweighted Cohen kappa coefficient (κ) and the area under the curve (AUC) were calculated using PSG as the reference standard. Results: A total of 135 participants were randomly divided into a training group (n, 116) and a validation group (n, 19). An independent test group of 59 participants was subsequently enrolled. Our algorithm achieved a precision of 0.81 and sensitivity of 0.78 in the test group for overall sleep event detection. The algorithm exhibited robust diagnostic performance to identify severe cases with a sensitivity of 95.6% and specificity of 91.6%. Conclusion: Our results showed that a deep learning algorithm based on sleep sounds recorded by a noncontact voice recorder served as a feasible tool for apneic event detection and OSA identification. This technique may hold promise for OSA assessment in the community in a relatively comfortable and low-cost manner. Further studies to develop a tool based on a home-based setting are warranted.

Real-time prediction of upcoming respiratory events via machine learning using snoring sound signal.

STUDY OBJECTIVES: The aim of the study was to inspect the acoustic properties and sleep characteristics of a preapneic snoring sound. The feasibility of forecasting upcoming respiratory events by snoring sound was also investigated. METHODS: Participants with habitual snoring or a heavy breathing sound during sleep were recruited consecutively. Polysomnography was conducted, and snoring-related breathing sound was recorded simultaneously. Acoustic features and sleep features were extracted from 30-second samples, and a machine learning algorithm was used to establish 2 prediction models. RESULTS: A total of 74 eligible participants were included. Model 1, tested by 5-fold cross-validation, achieved an accuracy of 0.92 and an area under the curve of 0.94 for respiratory event prediction. Model 2, with acoustic features and sleep information tested by Leave-One-Out cross-validation, had an accuracy of 0.78 and an area under the curve of 0.80. Sleep position was found to be the most important among all sleep features contributing to the performance of the 2 models. CONCLUSIONS: Preapneic sound presented unique acoustic characteristics, and snoring-related breathing sound could be deployed as a real-time apneic event predictor. The models, combined with sleep information, serve as a promising tool for an early warning system to forecast apneic events. CITATION: Wang B, Yi X, Gao J, et al. Real-time prediction of upcoming respiratory events via machine learning using snoring sound signal. J Clin Sleep Med. 2021;17(9):1777-1784.

The effect of ultrasonic waves on the nucleation of pure water and degassed water.

In order to clarify the mechanism of nucleation of ice induced by ultrasound, ultrasonic waves have been applied to supercooled pure water and degassed water, respectively. For each experiment, water sample is cooled at a constant cooling rate of 0.15 °C/min and the ultrasonic waves are applied from the water temperature of 0 °C until the water in a sample vessel nucleates. This nucleation temperature is measured. The use of ultrasound increased the nucleation temperature of both degassed water and pure water. However, the undercooling temperature for pure water to nucleate is less than that of degassed water. It is concluded that cavitation and fluctuations of density, energy and temperature induced by ultrasound are factors that affect the nucleation of water. Cavitation is a major factor for sonocrystallisation of ice.

Determination of the ice quantity by quantitative microscopic imaging of vitrification solutions.

Based on Boutron's semi-empirical crystallization theory, a quantitative microscopic imaging method was developed to determine the quantity of ice in thin films of vitrification solutions. A universal equation was obtained for various vitrification solutions. The new method was applied to determine the ice quantity and critical cooling rates (Vcc) for two new vitrification solutions. Results reveal that the new quantitative imaging method is reliable. This new method has several advantages including the fact that it is cheaper than differential scanning calorimetry (DSC) and that it can be used to study vitrification solutions with Vcc values extending beyond the maximum cooling rate of a typical DSC system. Also, this method should permit quantitative imaging of the volume fraction of ice in space and time in microscope samples.