Novel EGFR inhibitors against resistant L858R/T790M/C797S mutant for intervention of non-small cell lung cancer.

To overcome C797S mutation, the latest and most common resistance mechanism in the clinical treatment of third-generation EGFR inhibitor, a novel series of substituted 6-(2-aminopyrimidine)-indole derivatives were designed and synthesized. Through the structure-activity relationship (SAR) study, compound 11eg was identified as a novel and potent EGFR L858R/T790M/C797S inhibitor (IC50 = 0.053 µM) but had a weak effect on EGFRWT (IC50 = 1.05 µM). 11eg significantly inhibited the proliferation of the non-small cell lung cancer (NSCLC) cells harboring EGFRL858R/T790M/C797S with an IC50 of 0.052 µM. 11eg also showed potent inhibitory activity against other NSCLC cell lines harboring main EGFR mutants. Furthermore, 11eg exhibited much superior activity in arresting cell cycle and inducing apoptosis of NSCLC cells with mutant EGFRC797S. It blocked cellular EGFR signaling. Importantly, 11eg markedly suppressed the tumor growth in in vivo xenograft mouse model with good safety. Additionally, 11eg displayed good microsomal stability. These results demonstrated the potential of 11eg with novel scaffold as a promising lead compound targeting EGFRC797S to guide in-depth structural optimization.

Anionic Metal-Organic Framework Derived Cu Catalyst for Selective CO2 Electroreduction to Hydrocarbons.

Metal-organic frameworks (MOFs)-related Cu materials are promising candidates for promoting electrochemical CO2 reduction to produce valuable chemical feedstocks. However, many MOF materials inevitable undergo reconstruction under reduction conditions; therefore, exploiting the restructuring of MOF materials is of importance for the rational design of high-performance catalyst targeting multi-carbon products (C2). Herein, a facile solvent process is choosed to fabricate HKUST-1 with an anionic framework (a-HKUST-1) and utilize it as a pre-catalyst for alkaline CO2RR. The a-HKUST-1 catalyst can be electrochemically reduced into Cu with significant structural reconstruction under operating reaction conditions. The anionic HKUST-1 derived Cu catalyst (aHD-Cu) delivers a FEC2H4 of 56% and FEC2 of ≈80% at -150 mA cm-2 in alkaline electrolyte. The resulting aHD-Cu catalyst has a high electrochemically active surface area and low coordinated sites. In situ Raman spectroscopy indicates that the aHD-Cu surface displays higher coverage of *CO intermediates, which favors the production of hydrocarbons.

Fumonisin B1 induces endoplasmic reticulum damage and inflammation by activating the NXR response and disrupting the normal CYP450 system, leading to liver damage in juvenile quail.

Fumonisin B1 (FB1) is a mycotoxin affecting animal health through the food chain and has been closely associated with several diseases such as pulmonary edema in pigs and diarrhea in poultry. FB1 is mainly metabolized in the liver. Although a few studies have shown that FB1 causes liver damage, the molecular mechanism of liver damage is unclear. This study aimed to evaluate the role of liver damage, nuclear xenobiotic receptor (NXR) response and cytochrome P450 (CYP450)-mediated defense response during FB1 exposure. A total of 120 young quails were equally divided into two groups (control and FB1 groups). The quails in the control group were fed on a normal diet, while those in the FB1 group were fed on a quail diet containing 30 mg/kg for 42 days. Histopathological and ultrastructural changes in the liver, biochemical parameters, inflammatory factors, endoplasmic reticulum (ER) factors, NXR response and CYP450 cluster system and other related genes were examined at 14 days, 28 days and 42 days. The results showed that FB1 exposure impaired the metabolic function and caused liver injury. FB1 caused ER stress and decreased adenosine triphosphatease activity, induced the expression of inflammation-related genes such as interleukin 6 and nuclear factor kappa-B, and promoted inflammation. In addition, FB1 disrupted the expression of multiple CYP450 isoforms by activating nuclear xenobiotic receptors (NXRs). The present study confirms that FB1 exposure disturbs the homeostasis of cytochrome P450 systems (CYP450s) in quail liver by activating NXR responses and thereby causing liver damage. This study's findings provide insight into the molecular mechanisms of FB1-induced hepatotoxicity.

Extracting Pulmonary Nodules and Nodule Characteristics from Radiology Reports of Lung Cancer Screening Patients Using Transformer Models.

 Pulmonary nodules and nodule characteristics are important indicators of lung nodule malignancy. However, nodule information is often documented as free text in clinical narratives such as radiology reports in electronic health record systems. Natural language processing (NLP) is the key technology to extract and standardize patient information from radiology reports into structured data elements. This study aimed to develop an NLP system using state-of-the-art transformer models to extract pulmonary nodules and associated nodule characteristics from radiology reports. We identified a cohort of 3080 patients who underwent LDCT at the University of Florida health system and collected their radiology reports. We manually annotated 394 reports as the gold standard. We explored eight pretrained transformer models from three transformer architectures including bidirectional encoder representations from transformers (BERT), robustly optimized BERT approach (RoBERTa), and A Lite BERT (ALBERT), for clinical concept extraction, relation identification, and negation detection. We examined general transformer models pretrained using general English corpora, transformer models fine-tuned using a clinical corpus, and a large clinical transformer model, GatorTron, which was trained from scratch using 90 billion words of clinical text. We compared transformer models with two baseline models including a recurrent neural network implemented using bidirectional long short-term memory with a conditional random fields layer and support vector machines. RoBERTa-mimic achieved the best F1-score of 0.9279 for nodule concept and nodule characteristics extraction. ALBERT-base and GatorTron achieved the best F1-score of 0.9737 in linking nodule characteristics to pulmonary nodules. Seven out of eight transformers achieved the best F1-score of 1.0000 for negation detection. Our end-to-end system achieved an overall F1-score of 0.8869. This study demonstrated the advantage of state-of-the-art transformer models for pulmonary nodule information extraction from radiology reports. Supplementary Information: The online version contains supplementary material available at 10.1007/s41666-024-00166-5.

Rates and Impact of Serious Adverse Events after Endovascular Thrombectomy among Large Vessel Occlusion Stroke Patients.

Objective Complications or serious adverse events (SAEs) are common in the treatment of patients with large vessel occlusion stroke. There has been limited study of the impact of SAEs for patients after endovascular thrombectomy (EVT). The goal of this study was to characterize the rates and clinical impact of SAEs following EVT. Methods A post-hoc analysis was performed using pooled databases of the 'DEVT' and 'RESCUE BT' trials. SAEs were designated as symptomatic intracranial hemorrhage, brain herniation or craniectomy, respiratory failure, circulatory failure, pneumonia, deep venous thrombosis, and systemic bleeding. The primary endpoint was functional independence (modified Rankin Scale score 0-2 within 90 days). Logistic regression analysis was used to determine the predictors and associations between SAEs and outcomes. Results Of 1182 enrolled patients, 402 (34%) had a procedural complication, 745 (63%) had 1404 SAEs occurrences with 4.65% in-hospital mortality. The three most frequent SAEs were pneumonia (620, 52.5%), systemic bleeding (174, 14.7%) and respiratory failure (173, 14.6%). Pneumonia, systemic bleeding or deep venous thrombosis were less life-threatening. Patients with advanced age (adjusted odds ratio, 1.28 [95% confidence interval, 1.14-1.43]), higher NIHSS (1.09 [1.06-1.11]), occlusion site (middle cerebral artery-M1 vs. intracranial cerebral artery [ICA]: 0.75 [0.53-1.04]; M2 vs. ICA: 1.30 [0.80-2.12]), longer procedure time (1.01 [1.00-1.01]) and unsuccessful vessel recanalization (1.79 [1.06-2.94]) were more likely to experience SAEs. Compared with no SAE, patients with SAEs had lower odds of functional independence (0.46 [0.40-0.54]). Conclusions Overall, SAEs diagnosed following thrombectomy in patients with stroke were common (more than 60%) and associated with functional dependence. Patients with advanced age, higher NIHSS, longer procedure time and failed recanalization were more likely to experience SAEs. There was no statistical difference in the risk of SAEs among patient with M1 and M2 occluded compared with those ICA occluded. An understanding of the prevalence and predictors of SAEs could alert clinicians to the estimated risk of an SAE for a patient after EVT.

Lead Bromide Complex in Tri-n-octylphosphine Oxide Matrix with Bright Photoluminance and Exceptional Thermoplasticity.

Metal halide materials have recently drawn increasing research interest for their excellent opto-electronic properties and structural diversity, but their resulting rigid structures render them brittle and poor formability during manufacturing. Here we demonstrate a thermoplastic luminant hybrid lead halide solid by integrating lead bromide complex into tri-n-octylphosphine oxide (TOPO) matrix. The construction of the hybrid materials can be achieved by a simple dissolution process, in which TOPO molecules act as the solvents and ligands to yield the monodispersed clusters. The combination of these functional units enables the near-room-temperature melt-processing of the materials into targeted geometry by simple molding or printing techniques, which offer possibilities for fluorescent writing inks with outstanding self-healing capacity to physical damage. The intermarriage between metal halide clusters with functional molecules expands the range of practical applications for hybrid metal halide materials.

Fluorinated chlorin chromophores for red-light-driven CO2 reduction.

The utilization of low-energy photons in light-driven reactions is an effective strategy for improving the efficiency of solar energy conversion. In nature, photosynthetic organisms use chlorophylls to harvest the red portion of sunlight, which ultimately drives the reduction of CO2. However, a molecular system that mimics such function is extremely rare in non-noble-metal catalysis. Here we report a series of synthetic fluorinated chlorins as biomimetic chromophores for CO2 reduction, which catalytically produces CO under both 630 nm and 730 nm light irradiation, with turnover numbers of 1790 and 510, respectively. Under appropriate conditions, the system lasts over 240 h and stays active under 1% concentration of CO2. Mechanistic studies reveal that chlorin and chlorinphlorin are two key intermediates in red-light-driven CO2 reduction, while corresponding porphyrin and bacteriochlorin are much less active forms of chromophores.

A crystal capping layer for formation of black-phase FAPbI3 perovskite in humid air.

Black-phase formamidinium lead iodide (α-FAPbI3) perovskites are the desired phase for photovoltaic applications, but water can trigger formation of photoinactive impurity phases such as δ-FAPbI3. We show that the classic solvent system for perovskite fabrication exacerbates this reproducibility challenge. The conventional coordinative solvent dimethyl sulfoxide (DMSO) promoted δ-FAPbI3 formation under high relative humidity (RH) conditions because of its hygroscopic nature. We introduced chlorine-containing organic molecules to form a capping layer that blocked moisture penetration while preserving DMSO-based complexes to regulate crystal growth. We report power conversion efficiencies of >24.5% for perovskite solar cells fabricated across an RH range of 20 to 60%, and 23.4% at 80% RH. The unencapsulated device retained 96% of its initial performance in air (with 40 to 60% RH) after 500-hour maximum power point operation.

Establishing Virtual Bioequivalence and Clinically Relevant Specifications for Omeprazole Enteric-Coated Capsules by Incorporating Dissolution Data in PBPK Modeling.

Currently, Biopharmaceutics Classification System (BCS) classes I and III are the only biological exemptions of immediate-release solid oral dosage forms eligible for regulatory approval. However, through virtual bioequivalence (VBE) studies, BCS class II drugs may qualify for biological exemptions if reliable and validated modeling is used. Here, we sought to establish physiologically based pharmacokinetic (PBPK) models, in vitro-in vivo relationship (IVIVR), and VBE models for enteric-coated omeprazole capsules, to establish a clinically-relevant dissolution specification (CRDS) for screening BE and non-BE batches, and to ultimately develop evaluation criteria for generic omeprazole enteric-coated capsules. To establish omeprazole's IVIVR based on the PBPK model, we explored its in vitro dissolution conditions and then combined in vitro dissolution profile studies with in vivo clinical trials. The predicted omeprazole pharmacokinetics (PK) profiles and parameters closely matched the observed PK data. Based on the VBE results, the bioequivalence study of omeprazole enteric-coated capsules required at least 48 healthy Chinese subjects. Based on the CRDS, the capsules' in vitro dissolution should not be < 28%-54%, < 52%, or < 80% after two, three, and six hours, respectively. Failure to meet these dissolution criteria may result in non-bioequivalence. Here, PBPK modeling and IVIVR methods were used to bridge the in vitro dissolution of the drug with in vivo PK to establish the BE safety space of omeprazole enteric-coated capsules. The strategy used in this study can be applied in BE studies of other BCS II generics to obtain biological exemptions and accelerate drug development.

A smartphone-assisted portable on-site detection system for organophosphorus pesticides in vegetables and fruits based on all-in-one paper-based sensors: 2,2-Dichlorovinyl dimethyl phosphate as a model.

The improper use of organophosphate pesticides (OPs) can lead to residue posing a serious threat to human health and environment. Therefore, the development of a simple, portable, and sensitive detection method is crucial. Herein, a bioenzyme-nanozyme-chromogen all-in-one paper-based sensor was synthesized. Initially, the Ce/Zr-MOF with peroxidase-like activity was grown on filter paper (FP) using in-situ solvent thermal method, resulting in Ce/Zr-MOF@FP. Subsequently, the AChE-ChO-TMB system was immobilized onto Ce/Zr-MOF@FP using biocompatible gelatin, which enhanced cascade catalysis efficiency through the proximity effect. Based on the inhibition principle of OPs on AChE, we integrated this sensor with Python-based image recognition algorithm to achieve detection of OPs. Using 2,2-dichlorovinyl dimethyl phosphate (DDVP) as a model of OPs, it has good detection performance with a detection limit of 0.32 ng mL-1 and a recovery rate range of 95-107%. The potential for on-site detection of DDVP residues in vegetables and fruit samples is highly promising.

Regio- and Stereoselective Transfer Hydrogenation of Aryloxy Group-Substituted Unsymmetrical 1,2-Diketones: Synthetic Applications and Mechanistic Studies.

Developing a general method that leads to the formation of different classes of chiral bioactive compounds and their stereoisomers is an attractive but challenging research topic in organic synthesis. Furthermore, despite the great value of asymmetric transfer hydrogenation (ATH) in both organic synthesis and the pharmaceutical industry, the monohydrogenation of unsymmetrical 1,2-diketones remains underdeveloped. Here, we report the aryloxy group-assisted highly regio-, diastereo-, and enantioselective ATH of racemic 1,2-diketones. The work produces a myriad of enantioenriched dihydroxy ketones, and further transformations furnish all eight stereoisomers of diaryl triols, polyphenol, emblirol, and glycerol-type natural products. Mechanistic studies and calculations reveal two working modes of the aryloxy group in switching the regioselectivity from a more reactive carbonyl to a less reactive one, and the potential of ATH on 1,2-diketones in solving challenging synthetic issues has been clearly demonstrated.

Red Blood Cell-Like Poly(ethylene glycol) Particles: Influence of Particle Stiffness on Biological Behaviors.

Cell-like particles represent a category of synthetic particles designed to emulate the structures or functions of natural cells. Herein, we present the assembly of cell-like poly(ethylene glycol) (PEG) particles with different stiffnesses and shapes via replication of animal cells and investigate the impact of particle stiffness on their biological behaviors. As a proof of concept, we fabricate red blood cell-like and spherical PEG particles with varying cross-linking densities. A systematic exploration of their properties, encompassing morphology, stiffness, deformability, and biodistribution, reveal the vital influence of particle stiffness on in vivo fate, elucidating its role in governing the traversal of capillaries and the dynamic interactions with phagocytic cells.

Collaborative CRISPR-Cas System-Enabled Detection of Circulating Circular RNA for Reliable Monitoring of Acute Myocardial Infarction.

Acute myocardial infarction (AMI) is one of the major causes of death worldwide, posing significant global health challenges. Circular RNA (circRNA) has recently emerged as a potential diagnostic biomarker for AMI, providing valuable information for timely medical care. In this work, a new electrochemical method for circRNA detection by engineering a collaborative CRISPR-Cas system is developed. This system integrates the unique circRNA-targeting ability with cascade trans-cleavage activities of Cas effectors, using an isothermal primer exchange reaction as the bridge. Using cZNF292, a circulating circRNA biomarker for AMI is identified by this group; as a model, the collaborative CRISPR-Cas system-based method exhibits excellent accuracy and sensitivity with a low detection limit of 2.13 × 10-15 m. Moreover, the method demonstrates a good diagnostic performance for AMI when analyzing whole blood samples. Therefore, the method may provide new insight into the detection of circRNA biomarkers and is expected to have great potential in AMI diagnosis in the future.

Biotransformation characteristics of urate-lowering probiotic fermented apple juice and potential regulatory mechanisms for ameliorating hyperuricemia via mediating gut microbiota and metabolic pathways.

Hyperuricemia has evolved into a global public health concern, and applying probiotics fermented apple juice holds promise for alleviating this condition. This study aimed to investigate the biotransformation and metabolic features of urate-lowering probiotics sequentially fermented dealcoholized apple juice (PSFA), and assess its ameliorative effects and potential mechanisms on hyperuricemia mice. Results showed that CICC 6074 and 20,292 possessed excellent purine, nucleotide and nucleoside degradation and acid and bile salt resistance; sequential fermentation decreased the fructose in apple juice, and viable counts reached 3.76 × 108 CFU/mL. Histopathological analysis showed that PSFA ameliorated kidney damage in hyperuricemia mice. Furthermore, PSFA significantly reduced Urea, Creatinine and Uric acid levels in hyperuricemia mice; and inhibited xanthine oxidase activity and the expression of pro-inflammatory factors. Importantly, PSFA reversed gut microbiota dysbiosis and raised the abundance of beneficial bacteria (Lactobacillush, Faecalibaculum and Lachnospiraceae_NK4A136_group). KEGG and COG functional prediction results revealed that the potential mechanism of PSFA to ameliorate hyperuricemia may be lipid metabolism and glycolysis pathways.

Gradient nanoplasmonic imaging metasurface for rapid and label-free detection of SARS-CoV-2 sequences.

Compact and user-friendly nucleic acid biosensors play a crucial role in advancing infectious disease research, particularly for coronavirus (COVID-19). While nanophotonic metasurface sensors hold promise for high-performance sensing, they face challenges due to their complexity and bulky readout instruments. In this study, we propose a gradient nanoplasmonic imaging (GNI) metasurface that incorporates the concept of an optical potential well, enabling label-free single-step detection of SARS-CoV-2 sequences. The metasurface sensor consists of nanopillars with continuous variations, forming an optical potential well that results in a centimeter-scale dark ring. This dynamic well exhibits high sensitivity to refractive index changes, recorded by a CCD. To further enhance the visualized sensing performance, plasmonic coupling of gold nanoparticles with the gold nanostructure is employed. Our metasurface-based biosensor achieves rapid single-step detection of SARS-CoV-2 sequences, with a low detection limit of 77.2 pM and a detection range of 0.1-100 nM. This biosensor not only demonstrates exceptional reproducibility and outstanding detection performance, but also maintains remarkable specificity in differentiating SARS-CoV-2 from other diseases with similar symptoms. This simple and spectrometer-free refractometric sensing scheme enables the construction of a compact and cost-efficient prototype. Our imaging-based metasurface biosensing strategy demonstrates valuable merits for rapid, sensitive, and quantitative detection, showcasing its potential as a valuable on-site nucleic acid diagnostic tool.

MOTAI: A Novel Method for the Study of O-GalNAcylation and Complex O-Glycosylation in Cancer.

The Tn antigen, an immature truncated O-glycosylation, is a promising biomarker for cancer detection and diagnosis. However, reliable methods for analyzing O-GalNAcylation and complex O-glycosylation are lacking. Here, we develop a novel method, MOTAI, for the sequential analysis of O-glycosylation using different O-glycoproteases. MOTAI conjugates glycopeptides on a solid support and releases different types of O-glycosylation through sequential enzymatic digestion by O-glycoproteases, including OpeRATOR and IMPa. Because OpeRATOR has less activity on O-GalNAcylation, MOTAI enriches O-GalNAcylation for subsequent analysis. We demonstrate the effectiveness of MOTAI by analyzing fetuin O-glycosylation and Jurkat cell lines. We then apply MOTAI to analyze colorectal cancer and benign colorectal polyps. We identify 32 Tn/sTn-glycoproteins and 43 T/sT-glycoproteins that are significantly increased in tumor tissues. Gene Ontology analysis reveals that most of these proteins are ECM proteins involved in the adhesion process of the intercellular matrix. Additionally, the protein disulfide isomerase CRELD2 has a significant difference in Tn expression, and the abnormally glycosylated T345 and S349 O-glycosylation sites in cancer group samples may promote the secretion of CRELD2 and ultimately tumorigenesis through ECM reshaping. In summary, MOTAI provides a powerful new tool for the in-depth analysis of O-GalNAcylation and complex O-glycosylation. It also reveals the upregulation of Tn/sTn-glycoproteins in colorectal cancer, which may provide new insights into cancer biology and biomarker discovery.

Arsenic trioxide regulates the glycolytic pathway to treat acute promyelocytic leukemia by inhibiting RPL22L1.

OBJECTIVE: To investigate the relationship between the treatment of acute promyelocytic leukemia (APL) with arsenic trioxide (ATO) and glycolysis, as well as its underlying molecular mechanism. METHODS: The GEO database was used to analyze alterations in the expression of RPL22L1 in APL patients and its correlation with glycolysis. The levels of RPL22L1 and glycolysis were assessed in 9 paired clinical samples. NB4 cells and NB4 cells with knockdown of RPL22L1 were treated with ATO. The protein and mRNA of RPL22L1 were detected using RT-PCR and Western blot, and the content was determined by using glucose, pyruvate, and lactate detection kits. Finally, detection of cell proliferation using CCK8, migration by scratch assay, and apoptosis by flow cytometry, and the biological function of ATO in NB4 cells was examined. RESULTS: The expression of RPL22L1 in GSE213742 and GSE234103 datasets exhibited a significant increase in human APL cells, specifically NB4 cells. RPL22L1 in GSE213742 and GSE234103 gene expression matrix was significantly elevated in human APL cells NB4 cells, and further analysis found RPL22L1 showed a strong positive correlation with glycolysis. Cellular experiments showed that ATO inhibited RPL22L1 in NB4 cells and inhibited glycolysis in APL cells. The ATO played a pivotal role in suppressing the proliferation, migration, as well as invasion of NH4 cells. CONCLUSION: ATO regulates the blycolytic pathway in APL by inhibiting RPL22L1 expression, and this may contribute to its therapeutic effects.

Rapid Construction of Polycyclic Skeletons via Brønsted-Base-Catalyzed Annulations of Ethylidene 1,3-Indenediones and Vinyl 1,2-Diketones.

Brønsted-base-catalyzed diversified annulations between ethylidene 1,3-indenediones and vinyl 1,2-diketones have been achieved, delivering three types of products containing oxabicyclo[3.2.1]octane, spiro[4.5]decane, and branched triquinane skeletons, respectively, which widely exist in natural products and bioactive substances. Two unprecedented reaction modes have been disclosed, and the reactions could be readily scaled up. The protocol shows the potential of 1,2-diketone-mediated reactions in the rapid construction of complicated polycyclic scaffolds.

Pharmacokinetics and Safety of Oliceridine Fumarate Injection in Chinese Patients with Chronic Non-Cancer Pain: A Phase I, Single-Ascending-Dose, Open-Label Clinical Trial.

Background: Oliceridine is a novel G protein-biased ligand µ-opioid receptor agonist. This study aimed to assess the pharmacokinetics and safety profile of single-ascending doses of oliceridine fumarate injection in Chinese patients with chronic non-cancer pain. Methods: Conducted as a single-center, open-label trial, this study administered single doses of 0.75, 1.5, and 3.0 mg to 32 adult participants. The trial was conducted in two parts. First, we conducted a preliminary test comprising the administration of a single dose of 0.75mg to 2 participants. Then, we conducted the main trial involving intravenous administration of escalating doses of oliceridine fumarate (0.75 to 3 mg) to 30 participants. Pharmacokinetic (PK) parameters were derived using non-compartmental analysis. Additionally, the safety evaluation encompassed the monitoring of adverse events (AEs). Results: 32 participants were included in the PK and safety analyses. Following a 2-min intravenous infusion of oliceridine fumarate injection (0.75, 1.5, or 3 mg), Cmax and Tmax ranged from 51.293 to 81.914 ng/mL and 0.034 to 0.083 h, respectively. AUC0-t and half-life (t1/2) increased more than proportionally with dosage (1.85-2.084 h). Treatment emergent adverse events (TEAEs) were found to be consistent with the commonly reported adverse effects of opioids, both post-administration and as documented in the original trials conducted in the United States. Critically, no serious adverse events were observed. Conclusion: Oliceridine demonstrated comparable PK parameters and a consistent PK profile in the Chinese population, in line with the PK results observed in the original trials conducted in the United States. Oliceridine was safe and well tolerated in Chinese patients with chronic non-cancer pain at doses ranging from 0.75 mg to 3.0 mg. Trial Registration: The trial is registered at chictr.org.cn (ChiCTR2100047180).