Multi-modal molecular determinants of clinically relevant osteoporosis subtypes.

Due to a rapidly aging global population, osteoporosis and the associated risk of bone fractures have become a wide-spread public health problem. However, osteoporosis is very heterogeneous, and the existing standard diagnostic measure is not sufficient to accurately identify all patients at risk of osteoporotic fractures and to guide therapy. Here, we constructed the first prospective multi-omics atlas of the largest osteoporosis cohort to date (longitudinal data from 366 participants at three time points), and also implemented an explainable data-intensive analysis framework (DLSF: Deep Latent Space Fusion) for an omnigenic model based on a multi-modal approach that can capture the multi-modal molecular signatures (M3S) as explicit functional representations of hidden genotypes. Accordingly, through DLSF, we identified two subtypes of the osteoporosis population in Chinese individuals with corresponding molecular phenotypes, i.e., clinical intervention relevant subtypes (CISs), in which bone mineral density benefits response to calcium supplements in 2-year follow-up samples. Many snpGenes associated with these molecular phenotypes reveal diverse candidate biological mechanisms underlying osteoporosis, with xQTL preferences of osteoporosis and its subtypes indicating an omnigenic effect on different biological domains. Finally, these two subtypes were found to have different relevance to prior fracture and different fracture risk according to 4-year follow-up data. Thus, in clinical application, M3S could help us further develop improved diagnostic and treatment strategies for osteoporosis and identify a new composite index for fracture prediction, which were remarkably validated in an independent cohort (166 participants).

A novel therapy for fracture healing by increasing lymphatic drainage.

Background: The musculoskeletal system contains an extensive network of lymphatic vessels. Decreased lymph flow of the draining collecting lymphatics usually occurs in clinic after traumatic fractures. However, whether defects in lymphatic drainage can affect fracture healing is unclear. Methods: To investigate the effect of lymphatic dysfunction on fracture healing, we used a selective VEGFR3 tyrosine kinase inhibitor to treat tibial fractured mice for 5 weeks versus a vehicle-treated control. To ensure successfully establishing deceased lymphatic drainage model for fractured mice, we measured lymphatic clearance by near infrared indocyanine green lymphatic imaging (NIR-ICG) and the volume of the draining popliteal lymph nodes (PLNs) by ultrasound at the whole phases of fracture healing. In addition, hindlimb edema from day 0 to day 7 post-fracture, pain sensation by Hargreaves test at day 1 post-fracture, bone histomorphometry by micro-CT and callus composition by Alcian Blue-Hematoxylin/Orange G staining at day 14 post-fracture, and bone quality by biomechanical testing at day 35 post-fracture were applied to evaluate fracture healing. To promote fracture healing via increasing lymphatic drainage, we then treated fractured mice with anti-mouse podoplanin (PDPN) neutralizing antibody or isotype IgG antibody for 1 week to observe lymphatic drainage function and assess bone repair as methods described above. Results: Compared to vehicle-treated group, SAR-treatment group significantly decreased lymphatic clearance and the volume of draining PLNs. SAR-treatment group significantly increased soft tissue swelling, and reduced bone volume (BV)/tissue volume (TV), trabecular number (Tb.N), woven bone and biomechanical properties of fracture callus. In addition, anti-PDPN treated group significantly reduced the number of CD41+ platelets in PLNs and increased the number of pulsatile lymphatic vessels, lymphatic clearance and the volume of PLNs. Moreover, anti-PDPN treated group significantly reduced hindlimb edema and pain sensation and increased BV/TV, trabecular number (Tb.Th), woven bone and biomechanical properties of fracture callus. Conclusions: Inhibition of proper lymphatic drainage function delayed fracture healing. Use of a anti-PDPN neutralizing antibody reduced lymphatic platelet thrombosis (LPT), increased lymphatic drainage and improved fracture healing. The translational potential of this article: (1) We demonstrated lymphatic drainage function is crucial for fracture healing. (2) To unblock the lymphatic drainage and prevent the risk of bleeding and mortality by blood thinner, we demonstrated PDPN neutralizing antibody is a novel and safe way forward in the treatment of bone fracture healing by eliminating LPT and increasing lymphatic drainage.

Network pharmacology analysis and animal experiment validation of neuroinflammation inhibition by total ginsenoside in treating CSM.

BACKGROUND: Cervical spondylotic myelopathy (CSM) is a degenerative pathology that affects both upper and lower extremity mobility and sensory function, causing significant pressure on patients and society. Prior research has suggested that ginsenosides may have neuroprotective properties in central nervous system diseases. However, the efficacy and mechanism of ginsenosides for CSM have yet to be investigated. PURPOSE: This study aims to analyze the composition of ginsenosides using UPLC-MS, identify the underlying mechanism of ginsenosides in treating CSM using network pharmacology, and subsequently confirm the efficacy and mechanism of ginsenosides in rats with chronic spinal cord compression. METHODS: UPLC-Q-TOF-MS was utilized to obtain mass spectrum data of ginsenoside samples. The chemical constituents of the samples were analyzed by consulting literature reports and relevant databases. Ginsenoside and CSM targets were obtained from the TCMSP, OMIM, and GeneCards databases. GO and KEGG analyses were conducted, and a visualization network of ginsenosides-compounds-key targets-pathways-CSM was constructed, along with molecular docking of key bioactive compounds and targets, to identify the signaling pathways and proteins associated with the therapeutic effects of ginsenosides on CSM. Chronic spinal cord compression rats were intraperitoneally injected with ginsenosides (50 mg/kg and 150 mg/kg) and methylprednisolone for 28 days, and motor function was assessed to investigate the therapeutic efficacy of ginsenosides for CSM. The expression of proteins associated with TNF, IL-17, TLR4/MyD88/NF-κB, and NLRP3 signaling pathways was assessed by immunofluorescence staining and western blotting. RESULTS: Using UPLC-Q-TOF-MS, 37 compounds were identified from ginsenoside samples. Furthermore, ginsenosides-compounds-key targets-pathways-CSM visualization network indicated that ginsenosides may modulate the PI3K-Akt signaling pathway, TNF signaling pathway, MAPK signaling pathway, IL-17 signaling pathway, Toll-like receptor signaling pathway and Apoptosis by targeting AKT1, TNF, MAPK1, CASP3, IL6, and IL1B, exerting a therapeutic effect on CSM. By attenuating neuroinflammation through the TNF, IL-17, TLR4/MyD88/NF-κB, and MAPK signaling pathways, ginsenosides restored the motor function of rats with CSM, and ginsenosides 150 mg/kg showed better effect. This was achieved by reducing the phosphorylation of NF-κB and the activation of the NLRP3 inflammasome. CONCLUSIONS: The results of network pharmacology indicate that ginsenosides can inhibit neuroinflammation resulting from spinal cord compression through multiple pathways and targets. This finding was validated through in vivo tests, which demonstrated that ginsenosides can reduce neuroinflammation by inhibiting NLRP3 inflammasomes via multiple signaling pathways, additionally, it should be noted that 150 mg/kg was a relatively superior dose. This study is the first to verify the intrinsic molecular mechanism of ginsenosides in treating CSM by combining pharmacokinetics, network pharmacology, and animal experiments. The findings can provide evidence for subsequent clinical research and drug development.

A Robust TabNet-Based Multi-Classification Algorithm for Infrared Spectral Data of Chinese Herbal Medicine with High-Dimensional Small Samples.

Robust classification algorithms for high-dimensional, small-sample datasets are valuable in practical applications. Faced with the infrared spectroscopic dataset with 568 samples and 3448 wavelengths (features) to identify the origins of Chinese medicinal materials, this paper proposed a novel embedded multiclassification algorithm, ITabNet, derived from the framework of TabNet. Firstly, a refined data pre-processing (DP) mechanism was designed to efficiently find the best adaptive one among 50 DP methods with the help of Support Vector Machine (SVM). Following this, an innovative focal loss function was designed and joined with a cross-validation experiment strategy to mitigate the impact of sample imbalance on algorithm. Detailed investigations on ITabNet were conducted, including comparisons of ITabNet with SVM for the conditions of DP and Non-DP, GPU and CPU computer settings, as well as ITabNet against XGBT (Extreme Gradient Boosting). The numerical results demonstrate that ITabNet can significantly improve the effectiveness of prediction. The best accuracy score is 1.0000, and the best Area Under the Curve (AUC) score is 1.0000. Suggestions on how to use models effectively were given. Furthermore, ITabNet shows the potential to apply the analysis of medicinal efficacy and chemical composition of medicinal materials. The paper also provides ideas for multi-classification modeling data with small sample size and high-dimensional feature.

A comprehensive and systematic review of the potential neuroprotective effect of quercetin in rat models of spinal cord injury.

CONTEXT: Spinal cord injury (SCI) is a potentially fatal neurological disease with severe complications and a high disability rate. An increasing number of animal experimental studies support the therapeutic effect of quercetin, which is a natural anti-inflammatory and antioxidant bioflavonoid. OBJECTIVE: This paper reviewed the therapeutic effect of quercetin on a rat SCI model and summarized the relevant mechanistic research. DATA SOURCES: PubMed, EMBASE, Web of Science, Science Direct, WanFang Data, SinoMed databases, the China National Knowledge Infrastructure, and the Vip Journal Integration Platform were searched from their inception to April 2023 for animal experiments applying quercetin to treat SCI. STUDY SELECTION: Based on the PICOS criteria, a total of 18 eligible studies were included, of which 14 were high quality. RESULTS: In this study, there was a gradual increase in effect based on the Basso, Beattie, and Bresnahan (BBB) score after three days (p < 0.0001). Furthermore, gender differences also appeared in the efficacy of quercetin; males performed better than females (p = 0.008). Quercetin was also associated with improved inclined plane test score (p = 0.008). In terms of biochemical indicators, meta-analysis showed that MDA (p < 0.0001) and MPO (p = 0.0002) were significantly reduced after quercetin administration compared with the control group, and SOD levels were increased (p = 0.004). Mechanistically, quercetin facilitates the inhibition of oxidative stress, inflammation, autophagy and apoptosis that occur after SCI. CONCLUSIONS: Generally, this systematic review suggests that quercetin has a neuroprotective effect on SCI.

GSH-Responsive Prodrug Nanoassembly as a Carrier-Free Nanoplatform for Tumor-Targeting Delivery and Chemo-Photothermal Therapy.

Photothermal therapy, combined with chemotherapy, holds promising prospects for the therapeutic outcome of malignant tumors. However, the synergistic therapeutic effect suffers from low coloading capacity and inefficient synchronous tumor-targeting delivery of chemodrug and photothermal photosensitizers. Herein, we designed a versatile carrier-free nanoplatform to seek improvement for chemo-photothermal therapy. An NIR photosensitizer IR-808 was used for noninvasive cancer imaging, diagnosis, and imaging-guided photothermal therapy. A reduction-sensitive paclitaxel prodrug (PTX-SS-PEG2k) was rationally synthesized by covalently linking paclitaxel with polyethylene glycol 2000 via a disulfide bond. Then, the carrier-free nanoassemblies were constructed with an inner core of IR-808 and an amphiphilic paclitaxel prodrug shell. PTX-SS-PEG2k served as a stabilizer and chemodrug and could facilitate the self-assembly of IR-808 nanoparticles with high coloading efficiency and reduction-sensitive drug release. The versatile nanoplatform exhibited multiple advantages, including high drug payload, reduction-sensitive drug release, tumor-targeting drug delivery, and potent synergistic antitumor effect. We provide a versatile theranostic nanoplatform, which improves the effectiveness of synergetic chemo-photothermal therapy and reduces the off-target toxicity.

Photochemically induced thalamus infarction impairs cognition in a mouse model.

BACKGROUND: Small subcortical infarcts account for up to 25% of ischaemic strokes. Thalamus is one of the subcortical structures that commonly manifest with lacunar infarcts on MRI of the brain. Studies have shown that thalamus infarction is associated with cognitive decline. However, due to the lack of proper animal models, little is known about the mechanism. We aimed to establish a focal thalamus infarction model, characterise the infarct lesion and assess functional effects. METHODS: Male C57BL/6J mice were anaesthetised, and Rose Bengal dye was injected through the tail vein. The right thalamus was illuminated with green laser light by stereotactic implantation of optic fibre. Characteristics of the infarct and lesion evolution were evaluated by histological analysis and 7T MRI at various times. The cognitive and neurological functions were assessed by behavioural tests. Retrograde tracing was performed to analyse neural connections. RESULTS: An ischaemic lesion with small vessel occlusion was observed in the thalamus. It became a small circumscribed infarct with reactive astrocytes accumulated in the infarct periphery on day 21. The mice with thalamic infarction demonstrated impaired learning and memory without significant neurological deficits. Retrogradely labelled neurons in the retrosplenial granular cortex were reduced. CONCLUSION: This study established a mouse model of thalamic lacunar infarction that exhibits cognitive impairment. Neural connection dysfunctions may play a potential role in post-stroke cognitive impairment. This model helps to clarify the pathophysiology of post-stroke cognitive impairment and to develop potential therapies.

Super-high procoagulant activity of gecko thrombin: A gift from sky dragon.

AIMS: Gecko, the "sky dragon" named by Traditional Chinese Medicine, undergoes rapid coagulation and scarless regeneration following tail amputation in the natural ecology, providing a perfect opportunity to develop the efficient and safe drug for blood clotting. Here, gecko thrombin (gthrombin) was recombinantly prepared and comparatively studied on its procoagulant activity. METHODS: The 3D structure of gthrombin was constructed using the homology modeling method of I-TASSER. The active gthrombin was prepared by the expression of gecko prethrombin-2 in 293 T cells, followed by purification with Ni2+ -chelating column chromatography prior to activation by snake venom-derived Ecarin. The enzymatic activities of gthrombin were assayed by hydrolysis of synthetic substrate S-2238 and the fibrinogen clotting. The vulnerable nerve cells were used to evaluate the toxicity of gthrombin at molecular and cellular levels. RESULTS: The active recombinant gthrombin showed super-high catalytic and fibrinogenolytic efficiency than those of human under different temperatures and pH conditions. In addition, gthrombin made nontoxic effects on the central nerve cells including neurons, contrary to those of mammalian counterparts, which contribute to neuronal damage, astrogliosis, and demyelination. CONCLUSIONS: A super-high activity but safe procoagulant candidate drug was identified from reptiles, which provided a promising perspective for clinical application in rapid blood clotting.

A Novel Extract From Ginkgo biloba Inhibits Neuroinflammation and Maintains White Matter Integrity in Experimental Stroke.

Ginkgo biloba L. leaf extract (GBE) has been added in many commercial herbal formulations such as EGb 761 and Shuxuening Injection to treat cardiovascular diseases and stroke worldwide. However, the comprehensive effects of GBE on cerebral ischemia remained unclear. Using a novel GBE (nGBE), which consists of all the compounds of traditional (t)GBE and one new compound, pinitol, we investigated its effect on inflammation, white matter integrity, and long-term neurological function in an experimental stroke model. Both transient middle cerebral artery occlusion (MCAO) and distal MCAO were conducted in male C57/BL6 mice. We found that nGBE significantly reduced infarct volume at 1, 3, and 14 days after ischemia. Sensorimotor and cognitive functions were superior in nGBE treated mice after MCAO. nGBE inhibited the release of IL-1ß in the brain, promoted microglial ramification, and regulated the microglial M1 to M2 phenotype shift at 7 days post injury. In vitro analyses showed that nGBE treatment reduced the production of IL-1ß and TNFα in primary microglia. Administration of nGBE also decreased the SMI-32/MBP ratio and enhanced myelin integrity, thus exhibiting improved white matter integrity at 28 days post stroke. These findings demonstrate that nGBE protects against cerebral ischemia by inhibiting microglia-related inflammation and promoting white matter repair, suggesting that nGBE is a promising therapeutic strategy for long-term recovery after stroke.

Silicon Waveguide-Integrated Carbon Nanotube Photodetector with Low Dark Current and 48 GHz Bandwidth.

Low-dimensional materials with excellent optoelectronic properties and complementary metal-oxide-semiconductor (CMOS) process compatibility have the potential to construct high-performance photodetectors used in a cost-efficient monolithic or hybrid integrated optical communication system. Carbon nanotubes (CNTs) have attracted a lot of attention due to special geometric structure and broad band response, high optical absorption coefficient, ps-level intrinsic light response, high carrier mobility and wafer-scaled production process. Here, we demonstrated a high-performance waveguide-integrated CNT photodetector with asymmetric palladium (Pd) and hafnium (Hf) contact electrodes. The ideal photodetector structure was realized via comparing with simulation and experimental results, where the optimized device achieved a high 3 dB bandwidth ∼48 GHz at 0 V, as well as a responsivity ∼73.62 mA/W and dark current ∼0.157 µA at -2 V bias voltage. This waveguide-integrated CNT photodetector with low dark current and high bandwidth is helpful for next-generation optical communication and high-speed optical interconnects.

Network pharmacology, a promising approach to reveal the pharmacology mechanism of Chinese medicine formula.

ETHNOPHARMACOLOGICAL RELEVANCE: Network pharmacology is a new discipline based on systems biology theory, biological system network analysis, and multi-target drug molecule design specific signal node selection. The mechanism of action of TCM formula has the characteristics of multiple targets and levels. The mechanism is similar to the integrity, systematization and comprehensiveness of network pharmacology, so network pharmacology is suitable for the study of the pharmacological mechanism of Chinese medicine compounds. AIM OF THE STUDY: The paper summarizes the present application status and existing problems of network pharmacology in the field of Chinese medicine formula, and formulates the research ideas, up-to-date key technology and application method and strategy of network pharmacology. Its purpose is to provide guidance and reference for using network pharmacology to reveal the modern scientific connotation of Chinese medicine. MATERIALS AND METHODS: Literatures in this review were searched in PubMed, China National Knowledge Infrastructure (CNKI), Web of Science, ScienceDirect and Google Scholar using the keywords "traditional Chinese medicine", "Chinese herb medicine" and "network pharmacology". The literature cited in this review dates from 2002 to 2022. RESULTS: Using network pharmacology methods to predict the basis and mechanism of pharmacodynamic substances of traditional Chinese medicines has become a trend. CONCLUSION: Network pharmacology is a promising approach to reveal the pharmacology mechanism of Chinese medicine formula.

Molecular targets of metformin against ovarian cancer based on network pharmacology.

The objective of this study was to analyze potential targets of metformin against ovarian cancer (OC) through network pharmacology. Pharmacodynamic targets of metformin were predicted using the Bioinformatics Analysis Tool for the molecular mechanism of traditional Chinese medicine (BATMAN), Drugbank, PharmMapper, SwissTargetPrediction, and TargetNet databases. R was utilized to analyze the gene expression of OC tissues, normal/adjacent noncancerous tissues, and screen differentially expressed genes (DEGs) in the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) + Genotype-Tissue Expression (GTEx) datasets. STRING 11.0 was utilized to explore the protein-protein interaction (PPI) of metformin target genes differentially expressed in OC. Cytoscape 3.8.0 was used to construct the network and screen the core targets. Additionally, gene ontology (GO) annotation and enrichment and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed for the common targets of metformin and OC through the DAVID 6.8 database. A total of 95 potential common targets of metformin and OC were identified from the intersection of 255 potential pharmacodynamic targets of metformin and 10,463 genes associated with OC. Furthermore, 10 core targets were screened from the PPI network [e.g., interleukin (IL) 1B, KCNC1, ESR1, HTR2C, MAOB, GRIN2A, F2, GRIA2, APOE, PTPRC]. In addition, it was shown in GO enrichment analysis that the common targets were mainly associated with biological processes (i.e., response to stimuli or chemical, cellular processes, and transmembrane transport), cellular components (i.e., plasma membrane, cell junction, and cell projection), and molecular functions (i.e., binding, channel activities, transmembrane transporter activity, and signaling receptor activities). Furthermore, it was indicated by KEGG pathway analysis that the common targets were enriched in metabolic pathways. The critical molecular targets and molecular pathways of metformin against OC were preliminarily determined by bioinformatics-based network pharmacology analysis, providing a basis, and reference for further experimental studies.

Biomimetic virus-like mesoporous silica nanoparticles improved cellular internalization for co-delivery of antigen and agonist to enhance Tumor immunotherapy.

Nanocarrier antigen-drug delivery system interacts specifically with immune cells and provides intelligent delivery modes to improve antigen delivery efficiency and facilitate immune progression. However, these nanoparticles often have weak adhesion to cells, followed by insufficient cell absorption, leading to a failed immune response. Inspired by the structure and function of viruses, virus-like mesoporous silica nanoparticles (VMSNs) were prepared by simulating the surface structure, centripetal-radialized spike structure and rough surface topology of the virus and co-acted with the toll-like receptor 7/8 agonist imiquimod (IMQ) and antigens oocyte albumin (OVA). Compared to the conventional spherical mesoporous silica nanoparticles (MSNs), VMSNs which was proven to be biocompatible in both cellular and in vivo level, had higher cell invasion ability and unique endocytosis pathway that was released from lysosomes and promoted antigen cross-expression. Furthermore, VMSNs effectively inhibited B16-OVA tumor growth by activating DCs maturation and increasing the proportion of CD8+ T cells. This work demonstrated that virus-like mesoporous silica nanoparticles co-supply OVA and IMQ, could induce potent tumor immune responses and inhibit tumor growth as a consequence of the surface spike structure induces a robust cellular immune response, and undoubtedly provided a good basis for further optimizing the nanovaccine delivery system.

Prognostic value and adverse events of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in primary advanced and platinum-sensitive recurrent epithelial ovarian cancer: a systematic review and meta-analysis.

BACKGROUND: The original meta-analysis of hyperthermic intraperitoneal chemotherapy (HIPEC) is already outdated, owing to the latest trial results. This study aimed to clarify the efficacy and adverse events of cytoreductive surgery with HIPEC compared to conventional therapy for advanced and platinum-sensitive recurrent epithelial ovarian cancer (OC). METHODS: In this meta-analysis, phase II/III controlled trials regarding 'HIPEC' and 'ovarian cancer' were searched for in electronic databases from inception to March 2022. RESULTS: Twenty-one studies were included in the quantitative synthesis. The pooled hazard ratio [HR] in the HIPEC group for progression-free survival (PFS) (HR = 0.61, 95% confidence interval [CI]: 0.45-0.83, p = .002) and overall survival (OS) (HR = 0.65, 95% CI: 0.51-0.82, p < .001) were improved in the HIPEC group compared with the non-HIPEC group. For primary advanced disease, OS and PFS were significantly increased in patients receiving interval debulking surgery + HIPEC, whereas PFS was not significantly different between primary debulking surgery (PDS) + HIPEC and PDS alone. For platinum-sensitive recurrent disease, no correlation was observed for PFS and OS between the HIPEC and non-HIPEC groups (p < .05). The incidence of procedure-related complications was higher in the HIPEC group than in the non-HIPEC group (odds ratio = 1.93, 95% CI: 1.24-3.01, p < .01). The morbidity of leukopenia, neutropenia, nausea, hypoalbuminemia, and grades III-IV electrolyte disturbance was higher in the HIPEC group than in the non-HIPEC group. However, HIPEC administration reduced the risk of intra-abdominal bleeding and constipation. CONCLUSION: HIPEC-based regimens improved the clinical prognosis for primary advanced OC, whereas no significant value was elicited for recurrent OC.

The characteristics of solid-phase substrate during the co-fermentation of lignite and straw.

Co-fermentation of lignite and biomass has been considered as a new approach in achieving clean energy. Moreover, the study of the characteristics of solid phase in the synergistic degradation process is of great significance in revealing their synergistic relationship. Accordingly, in order to produce biogas, lignite, straw, and the mixture of the two were used as the substrates, the solid phase characteristics of which were analyzed before and after fermentation using modern analytical methods. The results revealed that the mixed fermentation of lignite and straw promoted the production of biomethane. Moreover, the ratios of C/O and C/H were found to be complementary in the co-fermentation process. Furthermore, while the relative content of C-C/C-H bonds was observed to be significantly decreased, the aromatics degree of lignite was weakened. Also, while the degree of branching increased, there found to be an increase in the content of cellulose amorphous zone, which, consequently, led to an increase in the crystallinity index of the wheat straw. Hence, the results provide a theoretical guidance for the efficient utilization of straw and lignite.

Cost-effectiveness analysis of pembrolizumab vs. chemotherapy as second-line treatment for advanced esophageal carcinoma in the United States.

Background: The national Comprehensive Cancer Network has suggested pembrolizumab as a second-line therapy for esophageal squamous cell carcinoma (ESCC) patients with a programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 10. However, despite the increased survival rate associated with pembrolizumab in these patient population, the high cost of pembrolizumab may influence its antitumor effect. This study aimed to evaluate the cost-effectiveness of pembrolizumab compared to chemotherapy as second-line treatments for esophageal carcinoma (EC) based on KEYNOTE-181 trial. Methods: A Markov model was constructed using TreeAge 2021 based on three different groups: all intent-to-treat patients (ITT population), patients with ESCC (ESCC population), and patients with a PD-L1 CPS ≥10 (CPS ≥10 population). Incremental cost, Incremental effect, Life-years, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER) were calculated. Analyses were conducted on the setting of a willingness-to-pay threshold of $150,000 from the US perspective. Results: The ICERs for pembrolizumab were $157,589.545 per QALY, $60,238.823 per QALY, and $100,114.929 per QALY compared with chemotherapy in the ITT, ESCC, and CPS≥10 populations, respectively. The ICER of the ITT population was higher than $150,000, suggesting that pembrolizumab was not a cost-effective treatment scheme in patients with a PD-L1 CPS ≤ 10 or esophageal adenocarcinoma. The ICER was < $150,000 in the ESCC and CPS≥10 populations, indicating that pembrolizumab was cost-effective in these two subgroups. Conclusion: The determining of pembrolizumab as a cost-effective second-line therapy for EC in the United States depends on the histologic type and PD-L1 expression.

Effects of the Duration of Ying Yang Bao Consumption on Hemoglobin Concentration in Infants and Young Children in Less Developed Areas of China.

Ying Yang Bao (YYB) is conventionally prescribed as a nutritional supplement to infants and young children (IYC) in less developed areas of China. However, whether 18-month YYB consumption is reasonable needs assessment. This study examined the influence of the duration of YYB consumption on hemoglobin (Hb) levels and anemia prevalence. Data from the Nutrition Improvement Project on Children in Poor Areas of China in 2018-2019 were used. Questionnaires were used to collect information on basic characteristics, dietary status, and YYB consumption. Propensity score matching (PSM) was used to balance confounders. Hb levels and anemia prevalence in IYC with different durations of YYB consumption were compared. After PSM, all covariates were well-balanced, and 1151 pairs of IYC were included in subsequent analyses. During the 1st-9th months of intervention, YYB effectively increased Hb levels and reduced anemia prevalence in the intervention group. During the 10th-18th months of intervention, Hb levels in the control group increased and anemia prevalence decreased, while Hb levels and anemia prevalence fluctuated in the intervention group. In conclusion, YYB was effective in improving nutritional status of infants, but had a limited effect in young children. Nutritional supplements with different quantities or nutrients should be considered for young children.

Photosynthetic carbon and nitrogen metabolism of Camellia oleifera Abel during acclimation to low light conditions.

Tea-oil tree (Camellia oleifera Abel) is an important woody oil crop with high economic value. However, it has low photosynthetic production considering the low light intensity of its growth environment. To understand the acclimation mechanism of tea-oil trees to low light conditions, three light intensity treatments were conducted: high light (450-500 µmol. m-2. s-1), medium light (180-200 µmol. m-2. s-1), and low light (45-50 µmol. m-2. s-1). The carbon (C) and nitrogen (N) metabolism network were constructed by investigating the leaf anatomy, photosynthetic characteristics, N partitioning, transcriptome and metabolome. Results demonstrated that a larger proportion light energy was used for photochemical reactions in an environment with lower light intensity, which resulted in an increase in photosystem II photochemical efficiency and instantaneous light use efficiency (LUE) at the leaf level. As the light intensity increased, decreased electron transfer and carboxylation efficiencies, photorespiration and dark respiration rates, LUE at plant level, and N use efficiency (PNUE) were observed. Leaves trended to harvest more light using higher expression levels of light-harvesting protein genes, higher chlorophyll content, more granum and more tightly stacked granum lamella under lower light intensity. At transcriptional and metabolic levels, the TCA cycle, and the synthesis of starch and saccharides were weakened as light intensity decreased, while the Calvin cycle did not show the regularity between different treatments. Less N was distributed in Rubisco, respiration, and cell wall proteins as light decreased. Storage N was prominently accumulated in forms of amino acids (especially L-arginine) and amino acid derivatives as under medium and low light environments, to make up for C deficiency. Therefore, tea-oil trees actively improve light-harvesting capacity and enlarges the storage N pool to adapt to a low light environment, at the cost of a decrease of photosynthetic C assimilation and PNUE.

Dihydromyricetin ameliorates osteogenic differentiation of human aortic valve interstitial cells by targeting c-KIT/interleukin-6 signaling pathway.

Aims: Calcific aortic valve disease (CAVD) is a chronic cardiovascular disease with high morbidity that lacks effective pharmacotherapeutics. As a natural flavonoid extracted from Ampelopsis grossedentata, dihydromyricetin (DHM) has been shown to be effective in protecting against atherosclerosis; yet, the therapeutic role of DHM in CAVD remains poorly understood. Herein, we aimed to clarify the therapeutic implications of DHM in CAVD and the underlying molecular mechanisms in human valvular interstitial cells (hVICs). Methods and Results: The protein levels of two known osteogenesis-specific genes (alkaline phosphatase, ALP; runt-related transcription factor 2, Runx2) and calcified nodule formation in hVICs were detected by Western blot and Alizarin Red staining, respectively. The results showed that DHM markedly ameliorated osteogenic induction medium (OM)-induced osteogenic differentiation of hVICs, as evidenced by downregulation of ALP and Runx2 expression and decreased calcium deposition. The SwissTargetPrediction database was used to identify the potential AVC-associated direct protein target of DHM. Protein-protein interaction (PPI) analysis revealed that c-KIT, a tyrosine-protein kinase, can act as a credible protein target of DHM, as evidenced by molecular docking. Mechanistically, DHM-mediated inhibition of c-KIT phosphorylation drove interleukin-6 (IL-6) downregulation in CAVD, thereby ameliorating OM-induced osteogenic differentiation of hVICs and aortic valve calcification progression. Conclusion: DHM ameliorates osteogenic differentiation of hVICs by blocking the phosphorylation of c-KIT, thus reducing IL-6 expression in CAVD. DHM could be a viable therapeutic supplement to impede CAVD.

Prevention and treatment of natural products from Traditional Chinese Medicine in depression: Potential targets and mechanisms of action.

The molecular pathology involved in the development of depression is complex. Many signaling pathways and transcription factors have been demonstrated to display crucial roles in the process of depression occurrence and development. The multi-components and multi-targets of Traditional Chinese Medicine (TCM) are uniquely advantageous in the prevention and treatment of chronic diseases. This review summarizes the pharmacological regulations of natural products from TCM in the prevention and treatment of depression from the aspects of transcription factors (CREB, NF-κB, Nrf2) and molecular signaling pathways (BDNF-TrkB, MAPK, GSK-3ß, TLR-4).