Regionally distinct progenitor cells in the lower airway give rise to neuroendocrine and multiciliated cells in the developing human lung.

Using scRNA-seq and microscopy, we describe a cell that is enriched in the lower airways of the developing human lung and identified by the unique coexpression of SCGB3A2/SFTPB/CFTR. To functionally interrogate these cells, we apply a single-cell barcode-based lineage tracing method, called CellTagging, to track the fate of SCGB3A2/SFTPB/CFTR cells during airway organoid differentiation in vitro. Lineage tracing reveals that these cells have a distinct differentiation potential from basal cells, giving rise predominantly to pulmonary neuroendocrine cells and a subset of multiciliated cells distinguished by high C6 and low MUC16 expression. Lineage tracing results are supported by studies using organoids and isolated cells from the lower noncartilaginous airway. We conclude that SCGB3A2/SFTPB/CFTR cells are enriched in the lower airways of the developing human lung and contribute to the epithelial diversity and heterogeneity in this region.

Stable iPSC-derived NKX2-1+ lung bud tip progenitor organoids give rise to airway and alveolar cell types.

Bud tip progenitors (BTPs) in the developing lung give rise to all epithelial cell types found in the airways and alveoli. This work aimed to develop an iPSC organoid model enriched with NKX2-1+ BTP-like cells. Building on previous studies, we optimized a directed differentiation paradigm to generate spheroids with more robust NKX2-1 expression. Spheroids were expanded into organoids that possessed NKX2-1+/CPM+ BTP-like cells, which increased in number over time. Single cell RNA-sequencing analysis revealed a high degree of transcriptional similarity between induced BTPs (iBTPs) and in vivo BTPs. Using FACS, iBTPs were purified and expanded as induced bud tip progenitor organoids (iBTOs), which maintained an enriched population of bud tip progenitors. When iBTOs were directed to differentiate into airway or alveolar cell types using well-established methods, they gave rise to organoids composed of organized airway or alveolar epithelium, respectively. Collectively, iBTOs are transcriptionally and functionally similar to in vivo BTPs, providing an important model for studying human lung development and differentiation.

Shenqi Fuzheng injection facilitates skeletal muscle mitophagy mediated by the ubiquitination of HIF-1α to ameliorate cancer-associated fatigue.

Cancer-related fatigue (CRF) significantly impacts the quality of life of cancer patients. This study investigates the therapeutic potential of Shenqi Fuzheng injection (SFI) in managing CRF, focusing on its mechanistic action in skeletal muscle. We utilized a CRF mouse model to examine the effects of SFI on physical endurance, monitoring activity levels, swimming times and rest periods. Proteomic analysis of the gastrocnemius muscle was performed using isobaric tags and liquid chromatography-tandem mass spectrometry to map the muscle proteome changes post-SFI treatment. Mitochondrial function in skeletal muscle was assessed via ATP bioluminescence assay. Furthermore, the regulatory role of the hypoxia inducible factor 1 subunit alpha (HIF-1α) signalling pathway in mediating SFI's effects was explored through western blotting. In CRF-induced C2C12 myoblasts, we evaluated cell viability (CCK-8 assay), apoptosis (flow cytometry) and mitophagy (electron microscopy). The study also employed pulldown, luciferase and chromatin immunoprecipitation assays to elucidate the molecular mechanisms underlying SFI's action, particularly focusing on the transcriptional regulation of PINK1 through HIF-1α binding at the PINK1 promoter region. Our findings reveal that SFI enhances physical mobility, reduces fatigue symptoms and exerts protective effects on skeletal muscles by mitigating mitochondrial damage and augmenting antioxidative responses. SFI promotes cell viability and induces mitophagy while decreasing apoptosis, primarily through the modulation of HIF-1α, PINK1 and p62 proteins. These results underscore SFI's efficacy in enhancing mitochondrial autophagy, thereby offering a promising approach for ameliorating CRF. The study not only provides insight into SFI's potential therapeutic mechanisms but also establishes a foundation for further exploration of SFI interventions in CRF management.

Efficient Photocatalytic CO2 Reduction in Ellagic Acid-Based Covalent Organic Frameworks.

Employing covalent organic frameworks (COFs) for the photocatalytic CO2 reduction reaction (CDRR) to generate high-value chemical fuels and mitigate greenhouse gas emissions represents a sustainable catalytic conversion approach. However, achieving superior photocatalytic CDRR performance is hindered by the challenges of low charge separation efficiency, poor stability, and high preparation costs associated with COFs. Herein, in this work, we utilized perfluorinated metallophthalocyanine (MPcF16) and the organic biomolecule compound ellagic acid (EA) as building blocks to actualize functional covalent organic frameworks (COFs) named EPM-COF (M = Co, Ni, Cu). The designed EPCo-COF, featuring cobalt metal active sites, demonstrated an impressive CO production rate and selectivity in the photocatalytic CO2 reduction reaction (CDRR). Moreover, following alkaline treatment (EPCo-COF-AT), the COF exposed carboxylic acid anion (COO-) and hydroxyl group (OH), thereby enhancing the electron-donating capability of EA. This modification achieved a heightened CO production rate of 17.7 mmol g-1 h-1 with an outstanding CO selectivity of 97.8% in efficient photocatalytic CDRR. Theoretical calculations further illustrated that EPCo-COF-AT functionalized with COO- and OH can effectively alleviate the energy barriers involved in the CDRR process, which facilitates the proton-coupled electron transfer processes and enhances the photocatalytic performance on the cobalt active sites within EPCo-COF-AT.

Temporally Decoupled Ammonia Splitting by a Zn-NH3 Battery with an Ammonia Oxidation/Hydrogen Evolution Bifunctional Electrocatalyst as a Cathode.

Ammonia splitting to hydrogen is a decisive route for hydrogen economy but is seriously limited by the complex device and low efficiency. Here, we design and propose a new rechargeable Zn-NH3 battery based on temporally decoupled ammonia splitting to achieve efficient NH3-to-H2 conversion. In this system, ammonia is oxidized into nitrogen during cathodic charging (2NH3 + 6OH- → N2 + 6H2O + 6e-) with external electrical energy conversion and storage, while during cathodic discharging, water is reduced to hydrogen (2H2O + 2e- → H2 + 2OH-) with electrical energy generation. In this loop, continuous and efficient H2 production without separation and purification is achieved. With the help of the ammonia oxidation reaction (AOR) and hydrogen evolution reaction (HER) bifunctional catalyst of Mo2C/NiCu@C, a rechargeable Zn-NH3 battery is realized that exhibits a high NH3-to-H2 FE of 91.6% with outstanding durability for 900 cycles (300 h) at 20 mA/cm2, enabling efficient and continuous NH3-to-H2 conversion.

Guidelines for the clinical application of the Xihuang pill for the prevention and treatment of breast hyperplasia diseases.

CONTEXT: The Xihuang pill (XHP) is a traditional Chinese medicine formulation that has been historically used in the prevention and treatment of proliferative breast diseases. However, there is a lack of guidelines that offer recommendations for its clinical use. OBJECTIVE: The task force from the Chinese Guangdong Pharmaceutical Association aims to develop evidence-based guidelines for XHP to prevent and treat proliferative breast diseases. METHODS: We searched six Chinese and English electronic databases, including the China National Knowledge Infrastructure, the Chinese Scientific Journal Database, the Wanfang Medical Database, PubMed, and Embase, up to November 1, 2022. Publications (case reports, clinical observation, clinical trials, reviews) on using XHP to treat proliferative breast diseases were manually searched. The search terms were Xihuang pill, hyperplasia of the mammary gland, breast lump, and mastalgia. The writing team developed recommendations based on the best available evidence. RESULTS: Treatment should be customized based on syndrome identification. We recommend using XHP for the prevention and treatment of breast hyperplasia disease when a patient presents the following syndromes: concurrent blood stasis syndrome, concurrent phlegm-stasis syndrome, and concurrent liver fire syndrome. Safety indicators, including blood analysis and liver and kidney function monitoring, should be performed regularly during treatment. CONCLUSIONS: Current clinical evidence suggests that XHP can be used as a standalone treatment or in conjunction with other medications to prevent and manage breast hyperplasia diseases. More randomized controlled studies are warranted to establish high-quality evidence of its use.

Molecular Engineering of Methylated Sulfone-Based Covalent Organic Frameworks for Back-Reaction Inhibited Photocatalytic Overall Water Splitting.

Solar-to-hydrogen (H2) and oxygen (O2) conversion via photocatalytic overall water splitting (OWS) holds great promise for a sustainable fuel economy, but has been challenged by the backward O2 reduction reaction (ORR) with favored proton-coupled electron transfer (PCET) dynamics. Here, we report that molecular engineering by methylation inhibits the backward ORR of molecular photocatalysts and enables efficient OWS process. As demonstrated by a benchmark sulfone-based covalent organic framework (COF) photocatalyst, the precise methylation of its O2 adsorption sites effectively blocks electron transfer and increases the barrier for hydrogen intermediate desorption that cooperatively obstructs the PCET process of ORR. Methylation also repels electrons to the neighboring photocatalytic sulfone group that promotes the forward H2 evolution. The resultant DS-COF achieves an impressive inhibition of about 70 % of the backward reaction and a three-fold enhancement of the OWS performance with a H2 evolution rate of 124.7 µmol h-1 g-1, ranking among the highest reported for organic-based photocatalysts. This work provides insights for engineering photocatalysts at the molecular level for efficient solar-to-fuel conversion.

The performance of 68Ga-FAPI-04 PET/CT in head and neck squamous cell carcinoma: a prospective comparison with 18F-FDG PET/CT.

PURPOSE: This study was designed to compare the performance of 68Ga-FAPI-04 and 18F-FDG PET/CT for initial staging and recurrence detection of head and neck squamous cell carcinoma (HNSCC). METHODS: Prospectively, 77 patients with histologically proven or highly suspected HNSCC underwent paired 18F-FDG and 68Ga-FAPI-04 PET/CT in a week for either initial staging (n = 67) or restaging (n = 10). The diagnostic performance was compared for the two imaging approaches, especially for N staging. SUVmax, SUVmean, and target-to-background ratio (TBR) were assessed for paired positive lesions. Furthermore, change in management by 68Ga-FAPI-04 PET/CT and histopathologic FAP expression of some lesions were explored. RESULTS: 18F-FDG and 68Ga-FAPI-04 PET/CT exhibited a comparable detection efficiency for primary tumor (100%) and recurrence (62.5%). In the twenty-nine patients receiving neck dissection, 68Ga-FAPI-04 PET/CT showed greater specificity and accuracy in evaluating preoperative N staging than 18F-FDG based on patient (p = 0.031 and p = 0.070), neck side (p = 0.002 and p = 0.006), and neck level (p < 0.001 and p < 0.001). As for distant metastasis, 68Ga-FAPI-04 PET/CT detected more positive lesions than 18F-FDG (25 vs 23) and with higher SUVmax (7.99 ± 9.04 vs 3.62 ± 2.68, p = 0.002) by lesion-based analysis. The type of neck dissection in 9 cases (9/33) was altered by 68Ga-FAPI-04. Overall, clinical management was significantly changed in 10 patients (10/61). Three patients had a follow-up 68Ga-FAPI-04 PET/CT post neoadjuvant therapy: One showed complete remission, and the others showed progression. The 68Ga-FAPI-04 uptake intensity was confirmed to be consistent with FAP expression. CONCLUSION: 68Ga-FAPI-04 outperforms 18F-FDG PET/CT in evaluating preoperative N staging in patients with HNSCC. Furthermore, 68Ga-FAPI-04 PET/CT also shows the potential in clinical management and monitoring response to treatment.

Deoxygenation of ClSO2CF2COOMe with Triphenylphosphine for the Metal-Free Direct Electrophilic Difluoroalkylthiolation of Various Heterocycles.

A direct electrophilic difluoroalkylthiolation reaction of indole derivatives and other electron-rich heterocycles using methyl 2,2-difluoro-2-(chlorsulfonyl)acetate (ClSO2CF2COOMe) derived from Chen's reagent (FSO2CF2COOMe) is described. The ester group in the product can be further utilized in subsequent versatile transformations. The reactions provide good yields of the corresponding difluoroalkylthiolation products and exhibit high functional group compatibility. It is expected to serve as an alternative and practical protocol for difluoroalkylthiolation of various heterocycles.

Nanomedicine for renal cell carcinoma: imaging, treatment and beyond.

The kidney is a vital organ responsible for maintaining homeostasis in the human body. However, renal cell carcinoma (RCC) is a common malignancy of the urinary system and represents a serious threat to human health. Although the overall survival of RCC has improved substantially with the development of cancer diagnosis and management, there are various reasons for treatment failure. Firstly, without any readily available biomarkers, timely diagnosis has been greatly hampered. Secondly, the imaging appearance also varies greatly, and its early detection often remains difficult. Thirdly, chemotherapy has been validated as unavailable for treating renal cancer in the clinic due to its intrinsic drug resistance. Concomitant with the progress of nanotechnological methods in pharmaceuticals, the management of kidney cancer has undergone a transformation in the recent decade. Nanotechnology has shown many advantages over widely used traditional methods, leading to broad biomedical applications ranging from drug delivery, prevention, diagnosis to treatment. This review focuses on nanotechnologies in RCC management and further discusses their biomedical translation with the aim of identifying the most promising nanomedicines for clinical needs. As our understanding of nanotechnologies continues to grow, more opportunities to improve the management of renal cancer are expected to emerge.

Comparisons of Forecasting for Survival Outcome for Head and Neck Squamous Cell Carcinoma by using Machine Learning Models based on Multi-omics.

Background: Machine learning methods showed excellent predictive ability in a wide range of fields. For the survival of head and neck squamous cell carcinoma (HNSC), its multi-omics influence is crucial. This study attempts to establish a variety of machine learning multi-omics models to predict the survival of HNSC and find the most suitable machine learning prediction method. Methods: The HNSC clinical data and multi-omics data were downloaded from the TCGA database. The important variables were screened by the LASSO algorithm. We used a total of 12 supervised machine learning models to predict the outcome of HNSC survival and compared the results. In vitro qPCR was performed to verify core genes predicted by the random forest algorithm. Results: For omics of HNSC, the results of the twelve models showed that the performance of multi-omics was better than each single-omic alone. Results were presented, which showed that the Bayesian network(BN) model (area under the curve [AUC] 0.8250, F1 score=0.7917) and random forest(RF) model (area under the curve [AUC] 0.8002,F1 score=0.7839) played good prediction performance in HNSC multi-omics data. The results of in vitro qPCR were consistent with the RF algorithm. Conclusion: Machine learning methods could better forecast the survival outcome of HNSC. Meanwhile, this study found that the BN model and the RF model were the most superior. Moreover, the forecast result of multi-omics was better than single-omic alone in HNSC.

Development of a triazolobenzodiazepine-based PET probe for subtype-selective vasopressin 1A receptor imaging.

OBJECTIVES: To enable non-invasive real-time quantification of vasopressin 1A (V1A) receptors in peripheral organs, we sought to develop a suitable PET probe that would allow specific and selective V1A receptor imaging in vitro and in vivo. METHODS: We synthesized a high-affinity and -selectivity ligand, designated compound 17. The target structure was labeled with carbon-11 and tested for its utility as a V1A-targeted PET tracer by cell uptake studies, autoradiography, in vivo PET imaging and ex vivo biodistribution experiments. RESULTS: Compound 17 (PF-184563) and the respective precursor for radiolabeling were synthesized in an overall yield of 49% (over 7 steps) and 40% (over 8 steps), respectively. An inhibitory constant of 0.9 nM towards the V1A receptors was measured, while excellent selectivity over the related V1B, V2 and OT receptor (IC50 >10,000 nM) were obtained. Cell uptake studies revealed considerable V1A binding, which was significantly reduced in the presence of V1A antagonists. Conversely, there was no significant blockade in the presence of V1B and V2 antagonists. In vitro autoradiography and PET imaging studies in rodents indicated specific tracer binding mainly in the liver. Further, the pancreas, spleen and the heart exhibited specific binding of [11C]17 ([11C]PF-184563) by ex vivo biodistribution experiments. CONCLUSION: We have developed the first V1A-targeted PET ligand that is suitable for subtype-selective receptor imaging in peripheral organs including the liver, heart, pancreas and spleen. Our findings suggest that [11C]PF-184563 can be a valuable tool to study the role of V1A receptors in liver diseases, as well as in cardiovascular pathologies.

MiR-139-5p, miR-940 and miR-193a-5p inhibit the growth of hepatocellular carcinoma by targeting SPOCK1.

The study was aimed to screen out miRNAs with differential expression in hepatocellular carcinoma (HCC), and to explore the influence of the expressions of these miRNAs and their target gene on HCC cell proliferation, invasion and apoptosis. MiRNAs with differential expression in HCC were screened out by microarray analysis. The common target gene of these miRNAs (miR-139-5p, miR-940 and miR-193a-5p) was screened out by analysing the target genes profile (acquired from Targetscan) of the three miRNAs. Expression levels of miRNAs and SPOCK1 were determined by quantitative real time polymerase chain reaction (qRT-PCR). The target relationships were verified by dual luciferase reporter gene assay and RNA pull-down assay. Through 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide,thiazolyl blue tetrazolium bromide (MTT) and transwell assays and flow cytometry, HCC cell viability, invasion and apoptosis were determined. In vivo experiment was conducted in nude mice to investigate the influence of three miRNAs on tumour growth. Down-regulation of miR-139-5p, miR-940 and miR-193a-5p was found in HCC. Overexpression of these miRNAs suppressed HCC cell viability and invasion, promoted apoptosis and inhibited tumour growth. SPOCK1, the common target gene of miR-139-5p, miR-940 and miR-193a-5p, was overexpressed in HCC. SPOCK1 overexpression promoted proliferation and invasion, and restrained apoptosis of HCC cells. MiR-139-5p, miR-940 and miR-193a-5p inhibited HCC development through targeting SPOCK1.

Zinc-Mediated Intermolecular Reductive Radical Fluoroalkylsulfination of Unsaturated Carbon-Carbon Bonds with Fluoroalkyl Bromides and Sulfur Dioxide.

A versatile and general zinc-mediated intermolecular reductive radical fluoroalkylsulfination of unsaturated C-C bonds has been developed using readily available fluoroalkyl bromides and 1,4-diazabicyclo[2.2.2]octane-bis(sulfur dioxide) adduct (DABSO) with wide substrate scope and excellent functional group tolerance. Sulfur dioxide anion radical generated in situ from the reduction of sulfur dioxide with zinc may be involved in the reaction mechanism.

Treatment of consistent BRAF/HRAS gene mutation and MYC amplification radiation-induced abdominal wall angiosarcoma with low-dose apatinib: a case report.

BACKGROUND: An extremely rare condition, radiation-induced angiosarcoma is characterized by a poor prognosis, high recurrence rate and lack of effective treatment. Herein, we present a case report of a 48-year-old female patient with radiation-induced abdominal wall angiosarcoma who showed a dramatic response to low-dose apatinib. CASE PRESENTATION: The patient, who was diagnosed with cervical squamous cell carcinoma 20 years ago, had received radiotherapy and chemotherapy after operation. Angiosarcomas of the abdominal wall appeared 9 years later. After repeated surgical operations and intravenous chemotherapy for the angiosarcomas, the patient developed tumor recurrence and pulmonary metastasis. The abdominal wall tumors showed repeated rupture and bleeding, with poor wound healing. On evaluation, laboratory findings detected the negative serum tumor markers CEA, CA 125, CA 15-3 and CA 19-9. Imaging showed multiple subcutaneous nodules and masses in the abdominal wall, accompanied by suspected small subpleural nodule at the lower lobe of the right lung. Immunohistochemistry of previous surgical pathology indicated that CD31, ERG and Vim were positive. The result of whole exome sequencing suggested the mutations of BRAF and HRAS, and the amplification of MYC. Based on the above results, the patient was clinically diagnosed with radiation-induced angiosarcoma of the abdominal wall with pulmonary metastasis. The patient was treated with low-dose apatinib and rejected reoperation or chemotherapy. RESULTS: At the 6-month follow-up visit, the abdominal wall lesions that had previously ruptured stopped bleeding and showed significant shrinkage. Imaging showed that most of the abdominal wall lesions had partially regressed, and some of the lesions on the abdominal wall and the suspected lesion of subpleural nodule at the lower lobe of the right lung had disappeared. CONCLUSIONS: We described this case and reviewed the literature on radiation-related angiosarcoma. Importantly, this case suggests that apatinib may be an effective and sensitive treatment for radiation-induced angiosarcoma even at the lowest dosage, without aggravating the bleeding of lesions.

Oxidative Radical Intermolecular Trifluoromethylthioarylation of Styrenes by Arenediazonium Salts and Copper(I) Trifluoromethylthiolate.

An efficient oxidative radical intermolecular trifluoromethylthioarylation of styrenes with arenediazonium salts and copper(I) trifluoromethylthiolate under mild conditions is described for the first time. The reactions provide good yields of the corresponding trifluoromethylthioarylation products with broad substrate scope and excellent functional group compatibility.

Direct trifluoromethylthiolation of unactivated C(sp(3))-H using silver(I) trifluoromethanethiolate and potassium persulfate.

A practical and efficient method for the direct trifluoromethylthiolation of unactivated C(sp(3) )H bonds by AgSCF3 /K2 S2 O8 under mild conditions is described. The reaction has a good functional-group tolerance and good selectivity. Initial mechanistic investigations indicate that the reaction may involve a radical process in which K2 S2 O8 plays key roles in both the activation of the C(sp(3) )H bond and the oxidation of AgSCF3 .

Versatile surface micropatterning and functionalization enabled by microcontact printing of poly(4-aminostyrene).

Microcontact printing (µCP) of polyelectrolytes is a facile and powerful method for surface micro/nanopatterning and functionalization. Poly(4-aminostyrene) (PAS) is a polyelectrolyte that can be converted to aryldiazonium salt and exhibits pH-dependent hydrophobicity. Here we demonstrate µCP of PAS and the expansion of this technique in various directions. First, the microcontact-printed PAS can be diazotized to micropattern biomolecules including DNA and protein and nanomaterials including single-walled carbon nanotubes and gold nanoparticles. Second, the diazotized PAS enables µCP of a metallic structure on a carbon surface. Third, the hydrophobic nature of PAS at the neutral pH allows the microcontact-printed PAS-based polyelectrolyte multilayer to be used as masks for wet etching. Lastly, this technique allows facile fabrication of highly engineered microparticles with a unique structure. Overall, this work has established a novel µCP platform with various potential applications.

A multicomponent triformylphoroglucinol-based covalent organic framework for overall hydrogen peroxide photosynthesis.

A multicomponent covalent organic framework (COF-Tfp-BpyDaaq) integrating bipyridine with diaminoanthraquinone through a triformylphoroglucinol linkage was synthesized for the first time as a photocatalyst for overall H2O2 photosynthesis. It exhibits enhanced photo-charge separation and H2O2 production rate over its two-component counterparts, demonstrating the pivotal role of multicomponent synthesis in designing efficient photocatalysts.