Safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese: a randomized, double-blind, placebo-controlled, multiple-dose phase 1b study.

BACKGROUND: TG103, a glucagon-like peptide-1 analog, is being investigated as an option for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese without diabetes. METHODS: In this randomized, double-blind, placebo-controlled, multiple-dose phase 1b study, participants aged 18-75 years with a body-mass index (BMI) ≥ 26.0 kg/m2 and body weight ≥ 60 kg were enrolled from three centers in China. The study included three cohorts, and in each cohort, eligible participants were randomly assigned (3:1) to one of three once-weekly subcutaneous TG103 groups (15.0, 22.5 and 30.0 mg) or matched placebo, without lifestyle interventions. In each cohort, the doses of TG103 were escalated in 1-week intervals to the desired dose over 1 to 4 weeks. Then participants were treated at the target dose until week 12 and then followed up for 2 weeks. The primary endpoint was safety and tolerability assessed by the incidence and severity of adverse events (AEs) from baseline to the end of the follow-up period. Secondary endpoints included pharmacokinetic and pharmacodynamic profiles of TG103 and the occurrence of anti-drug antibodies to TG103. RESULTS: A total of 147 participants were screened, and 48 participants were randomly assigned to TG103 (15.0, 22.5 and 30.0 mg groups, n = 12 per group) or placebo (n = 12). The mean (standard deviation, SD) age of the participants was 33.9 (10.0) years; the mean bodyweight was 81.65 (10.50) kg, and the mean BMI was 29.8 (2.5) kg/m2. A total of 466 AEs occurred in 45 of the 48 participants, with 35 (97.2%) in the TG103 group and 10 (83.3%) in the pooled placebo group. Most AEs were grade 1 or 2 in severity, and there were no serious adverse events (SAEs), AEs leading to death, or AEs leading to discontinuation of treatment. The steady-state exposure of TG103 increased with increasing dose and was proportional to Cmax,ss, AUCss, AUC0-t and AUC0-inf. The mean values of Cmax,ss ranged from 951 to 1690 ng/mL, AUC0-t ranged from 150 to 321 µg*h/mL, and AUC0-inf ranged from 159 to 340 µg*h/mL. TG103 had a half-life of 110-116 h, with a median Tmax of 36-48 h. After treatment for 12 weeks, the mean (SD) values of weight loss from baseline in the TG103 15.0 mg, 22.5 mg and 30.0 mg groups were 5.65 (3.30) kg, 5.35 (3.39) kg and 5.13 (2.56) kg, respectively, and that in the placebo group was 1.37 (2.13) kg. The least square mean percent weight loss from baseline to D85 in all the TG103 groups was more than 5% with p < 0.05 for all comparisons with placebo. CONCLUSIONS: In this trial, all three doses of once-weekly TG103 were well tolerated with an acceptable safety profile. TG103 demonstrated preliminary 12-week body weight loss without lifestyle interventions, thus showing great potential for the treatment of overweight and obesity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04855292. Registered on April 22, 2021.

Arterial embolization in the treatment of multiple renal and hepatic hamartomas with spontaneous hemorrhage and 2-year follow-up: a case report.

BACKGROUND: Hamartoma is a common benign tumor that usually occurs in the kidney, liver, lung, and pancreas. Large renal hamartomas may spontaneously rupture and hemorrhage, which is potentially life-threatening. CASE PRESENTATION: This report describes a 46-year-old Han Chinese female patient with multiple renal and hepatic hamartomas with rupture and hemorrhage of giant hamartoma in the left kidney. She underwent arterial embolization three times successively, and her condition was stable during the 2-year follow-up. This report includes a review of the relevant literature CONCLUSIONS: the findings in this report and previous literature suggest that arterial embolization can not only rapidly treat hamartoma hemorrhage in the acute phase but can also effectively control multiple lesions in the long term after repeated multisite arterial embolization.

[Highly sensitive detection of fluorescent whitening agents in flour using sheathless capillary electrophoresis-electrospray ionization-tandem mass spectrometry].

Fluorescent whitening agents (FWAs) are dyes that emit visible blue or blue-purple fluorescence upon ultraviolet-light absorption. Taking advantage of light complementarity, FWAs can compensate for the yellow color of many substances to achieve a whitening effect; thus, they are used extensively in various applications. FWAs are generally stable, but their presence in the environment can lead to pollution and accumulation in the body through the food chain. Recent studies have revealed that some types of FWAs, such as coumarin-based FWAs, may exhibit photo-induced mutagenic effects that can trigger allergic reactions in humans and even pose carcinogenic risks. Hence, the development of an accurate and highly sensitive method for detecting FWAs in food-related samples is a crucial endeavor. Owing to the high polarity and structural similarity of FWAs, the accurate determination of these substances in complex food samples requires an analytical method that offers both efficient separation and sensitive detection. Capillary electrophoresis (CE) exhibits essential features such as high separation efficiency, short analysis times, very small sample injection requirements, minimal use of organic solvents, and simple operation. Thus, it is often used as an effective alternative to liquid chromatographic techniques. Over the past few decades, electrospray ionization mass spectrometry (ESI-MS) has been utilized as a highly sensitive and accurate detection method in numerous chemical analytical fields because it enables the analysis of molecular structures. By combining the high separation efficiency of CE with the high sensitivity of ESI-MS, a powerful tool for identifying and quantifying trace amounts of FWAs in food samples may be obtained. In this study, we present a method based on sheathless CE coupled with electrospray ionization tandem mass spectrometry (ESI-MS/MS) for the simultaneous detection of six trace FWAs in flour. In the proposed method, the CE separation device is directly coupled to the mass spectrometer through a sheathless interface without the need for a sheath liquid for electric contact, thereby avoiding the dilution of the analytes and improving detection sensitivity. Various conditions that could affect extraction recovery, separation efficiency, and detection sensitivity were evaluated and optimized. The FWAs were effectively extracted from the sample matrix with reduced matrix effects by ultrasonic-assisted extraction at a temperature of 30 ℃ for 20 min using CHCl3-MeOH (3∶2, v/v) as the extraction solvent. The extract was centrifuged, dried under N2, and reconstituted in CHCl3-MeOH (1∶4, v/v) for subsequent analysis. During the detection process, the CE device was coupled to the ESI-MS/MS instrument via a highly sensitive porous spray needle, which served as the sheathless electrospray interface. The target FWAs were scanned in positive-ion mode (ESI+) to ensure the stability and intensity of the obtained signals. Additionally, multiple-reaction monitoring (MRM) mode and MS/MS analysis were used to simultaneously quantify the six targets with high selectivity. The developed sheathless CE-ESI-MS/MS method detected the FWAs with high sensitivity over wide linear ranges with low method limits of detection (0.04-0.67 ng/g). The recoveries of the six target FWAs at three spiked levels were between 77.5% and 97.2%, with good interday (RSD≤11.5%) and intraday (RSD≤10.2%) precision. Analyses of the six target FWAs in eight commercial flour samples were performed using this method, and four positive samples were identified. These results demonstrate that the proposed CE-ESI-MS/MS method is a promising strategy for the determination of trace FWAs in complex food sample matrices with efficient separation and high sensitivity.

Hydroxyl silicone oil grafting onto a rough thermoplastic polyurethane surface created durable super-hydrophobicity.

Indwelling medical catheters are frequently utilized in medical procedures, but they are highly susceptible to infection, posing a vital challenge for both health workers and patients. In this study, the superhydrophobic micro-nanostructure surface was constructed on the surface of thermoplastic polyurethane (TPU) membrane using heavy calcium carbonate (CaCO3) template. To decrease the surface free energy, hydroxyl silicone oil was grafted onto the surface, forming a super-hydrophobic surface. The water contact angle (WCA) increased from 91.1° to 143 ± 3° when the concentration of heavy calcium CaCO3 was 20% (weight-to-volume (w/v)). However, the increased WCA was unstable and tended to decrease over time. After grafting hydroxyl silicone oil, the WCA rose to 152.05 ± 1.62° and remained consistently high for a period of 30 min. Attenuated total reflection infrared spectroscopy (ATR-FTIR) analysis revealed a chemical crosslinking between silicone oil and the surface of TPU. Furthermore, Scanning electron microscope (SEM) image showed the presence of numerous nanoparticles on the micro surface. Atomic force microscope (AFM) testing indicated a significant improvement in surface roughness. This method of creating a hydrophobic surface demonstrated several advantages, including resistance to cell, bacterial, protein, and platelet adhesion and good biosecurity. Therefore, it holds promising potential for application in the development of TPU-based medical catheters with antibacterial properties.

In-line RNA-based microreactor direct mass spectrometry for ultrasensitive and rapid assay of terminal deoxynucleotidyl transferase activity.

Terminal deoxynucleotidyl transferase (TdT), a unique template-independent DNA polymerase, plays a crucial role in the human adaptive immune system and is considered a promising biomarker for the diagnosis of various forms of acute or chronic leukemia. The accurate and sensitive detection of trace TdT is of pivotal importance to fulfill the significant medical interest in understanding its pathological functions and diagnosing TdT-related diseases. We hereby present an in-line RNA-based microreactor direct mass spectrometry (MS) method and its application for ultrasensitive, accurate, and rapid analysis of trace TdT activity in leukemic cell samples. A specially designed RNA-based microreactor is fabricated by immobilizing short RNA sequence via covalent Au-S bond on the inner surface of a capillary pre-modified with three-dimensional porous layer (PL) and Au nanoparticles (AuNPs). Utilizing this PL@Au@RNA microreactor, the signal of target TdT is conversed into reporter molecules (adenine), which exhibit a strong MS response. This conversion process enables efficient signal amplification and enhances detection sensitivity. The outlet end of the PL@Au@RNA microreactor is deliberately crafted into a porous tip, serving as an electrospray ionization (ESI) interface to directly couple to ESI-MS in-line. This design facilitates the direct transmission of the generated signaling molecules into the MS system, eliminating the need for laborious sample treatment procedures. By implementing this RNA-based microreactor in direct MS analysis, we have achieved remarkable sensitivity in detecting TdT activity with the limit-of-detection of 4 × 10-9 U, surpassing other reported methods in literature by three to four orders of magnitude. Furthermore, each assay requires a minimal sample volume of merely 10 nL. This method has successfully demonstrated its application in accurately and efficiently detecting TdT activity in leukemia cells, and its detection results are consistent with those obtained by ELISA kits.

Target-induced multiregion MNAzyme nanowires for ultrasensitive homogeneous detection of microRNAs.

A target-induced multiregion MNAzyme nanowire system is designed for the ultrasensitive and homogeneous detection of microRNAs (miRNAs). miRNA-21 and miRNA-375 are chosen as analytes, and a miRNA-induced primer exchange reaction (PER) is utilized to construct a long DNA strand with repetitive sequences. This innovative design enables the efficient anchoring of numerous MNAzymes. This unique architecture significantly boosts the effective local concentration of MNAzymes, thereby enhancing the sensitivity and efficiency of miRNA detection. Notably, the limit of detection (LOD) achieved with our target-induced multiregion MNAzyme nanowire approach is over an order of magnitude lower than most other MNAzyme-based methods, while the MNAzyme reaction time is reduced from several hours to 50 min. The method has demonstrated successful applications in quantitatively determining the expression levels of two miRNAs in cell lysates of MCF-7, HeLa and MCF-10 A cells, highlighting its potential for assaying miRNA biomarkers in clinical samples.