Exploring the impact of PDGFD in osteosarcoma metastasis through single-cell sequencing analysis.

PURPOSE: The overall survival rate for metastatic osteosarcoma hovers around 20%. Responses to second-line chemotherapy, targeted therapies, and immunotherapies have demonstrated limited efficacy in metastatic osteosarcoma. Our objective is to validate differentially expressed genes and signaling pathways between non-metastatic and metastatic osteosarcoma, employing single-cell RNA sequencing (scRNA-seq) and additional functional investigations. We aim to enhance comprehension of metastatic mechanisms and potentially unveil a therapeutic target. METHODS: scRNA-seq was performed on two primary osteosarcoma lesions (1 non-metastatic and 1 metastatic). Seurat package facilitated dimensionality reduction and cluster identification. Copy number variation (CNV) was predicted using InferCNV. CellChat characterized ligand-receptor-based intercellular communication networks. Differentially expressed genes underwent GO function enrichment analysis and GSEA. Validation was achieved through the GSE152048 dataset, which identified PDGFD-PDGFRB as a common ligand-receptor pair with significant contribution. Immunohistochemistry assessed PDGFD and PDGFRB expression, while multicolor immunofluorescence and flow cytometry provided insight into spatial relationships and the tumor immune microenvironment. Kaplan-Meier survival analysis compared metastasis-free survival and overall survival between high and low levels of PDGFD and PDGFRB. Manipulation of PDGFD expression in primary osteosarcoma cells examined invasion abilities and related markers. RESULTS: Ten clusters encompassing osteoblasts, osteoclasts, osteocytes, fibroblasts, pericytes, endothelial cells, myeloid cells, T cells, B cells, and proliferating cells were identified. Osteoblasts, osteoclasts, and osteocytes exhibited heightened CNV levels. Ligand-receptor-based communication networks exposed significant fibroblast crosstalk with other cell types, and the PDGF signaling pathway was activated in non-metastatic osteosarcoma primary lesion. These results were corroborated by the GSE152048 dataset, confirming the prominence of PDGFD-PDGFRB as a common ligand-receptor pair. Immunohistochemistry demonstrated considerably greater PDGFD expression in non-metastatic osteosarcoma tissues and organoids, correlating with extended metastasis-free and overall survival. PDGFRB expression showed no significant variation between non-metastatic and metastatic osteosarcoma, nor strong correlations with survival times. Multicolor immunofluorescence suggested co-localization of PDGFD with PDGFRB. Flow cytometry unveiled a highly immunosuppressive microenvironment in metastatic osteosarcoma. Manipulating PDGFD expression demonstrated altered invasive abilities and marker expressions in primary osteosarcoma cells from both non-metastatic and metastatic lesions. CONCLUSIONS: scRNA-seq illuminated the activation of the PDGF signaling pathway in primary lesion of non-metastatic osteosarcoma. PDGFD displayed an inhibitory effect on osteosarcoma metastasis, likely through the suppression of the EMT signaling pathway.

Multi-wavelength multi-distance diffuse correlation spectroscopy system for assessment of premature infants' cerebral hemodynamics.

Infants born at an extremely low gestational age (ELGA, < 29 weeks) are at an increased risk of intraventricular hemorrhage (IVH), and there is a need for standalone, safe, easy-to-use tools for monitoring cerebral hemodynamics. We have built a multi-wavelength multi-distance diffuse correlation spectroscopy device (MW-MD-DCS), which utilizes time-multiplexed, long-coherence lasers at 785, 808, and 853 nm, to simultaneously quantify the index of cerebral blood flow (CBFi) and the hemoglobin oxygen saturation (SO2). We show characterization data on liquid phantoms and demonstrate the system performance on the forearm of healthy adults, as well as clinical data obtained on two preterm infants.

Supercharged precision killers: Genetically engineered biomimetic drugs of screened metalloantibiotics against Acinetobacter baumanni.

To eliminate multidrug-resistant bacteria of Acinetobacter baumannii, we screened 1100 Food and Drug Administration-approved small molecule drugs and accessed the broxyquinoline (Bq) efficacy in combination with various metal ions. Antibacterial tests demonstrated that the prepared Zn(Bq)2 complex showed ultralow minimum inhibitory concentration of ~0.21 micrograms per milliliter with no resistance after 30 passages. We then constructed the nano zeolitic imidazolate framework-8 (ZIF-8) as a drug carrier of Zn(Bq)2 and also incorporated the photosensitizer chlorin e6 (Ce6) to trace and boost the antibacterial effect. To further ensure the stable and targeted delivery, we genetically engineered outer membrane vesicles (OMVs) with the ability to selectively target A. baumannii. By coating the ZnBq/Ce6@ZIF-8 core with these OMV, the resulted drug (ZnBq/Ce6@ZIF-8@OMV) exhibited exceptional killing efficacy (>99.9999999%) of A. baumannii. In addition, in vitro and in vivo tests were also respectively carried out to inspect the remarkable efficacy of this previously unknown nanodrug in eradicating A. baumannii infections, including biofilms and meningitis.

SiRNA-HIF-1α delivered by attenuated Salmonella enhances the efficacy of Lenvatinib against hepatocellular carcinoma.

The treatment of hepatocellular carcinoma (HCC) remains a major challenge in the medical field. Lenvatinib, a multi-target tyrosine kinase inhibitor, has demonstrated anti-HCC effects by targeting and inhibiting pathways such as vascular endothelial growth factor receptor 1-3 (VEGFR1-3). However, the therapeutic efficacy of Lenvatinib is subject to various influences, with the hypoxic microenvironment of the tumor being a pivotal factor. Consequently, altering the hypoxic milieu of the tumor emerges as a viable strategy to augment the efficacy of Lenvatinib. Hypoxia-inducible factor-1α (HIF-1α), synthesized by tumor cells in response to oxygen-deprived conditions, regulates the expression of resistance genes, promotes tumor angiogenesis and cell proliferation, enhances tumor cell invasion, and confers resistance to radiotherapy and chemotherapy. Thus, we constructed a self-designed siRNA targeting HIF-1α to suppress its expression and improve the efficacy of Lenvatinib in treating HCC. The therapeutic efficacy of siRNA-HIF-1α in combination with Lenvatinib on HCC were evaluated through in vivo and in vitro experiments. The results showed that the recombinant Salmonella delivering siRNA-HIF-1α in combination with Lenvatinib effectively inhibited tumor growth and prolonged the survival of tumor-bearing mice. This treatment approach reduced cell proliferation and angiogenesis in HCC tissues while promoting tumor cell apoptosis. Additionally, this combined therapy significantly increased the infiltration of T lymphocytes and M1 macrophages within the tumor microenvironment, as well as elevated the proportion of immune cells in the spleen, thereby potentiating the host's immune response against the tumor.

New-onset tachycardia-bradycardia syndrome following acute non-medullary brainstem infarction.

Tachycardia-bradycardia syndrome (TBS) is a variant of sick sinus syndrome (SSS) characterized by alternating tachycardia and bradycardia. A few cases of SSS secondary to structural lesions in the medulla have been reported, but there has never been a reported case of the rare sign akin to TBS following acute non-medullary brainstem infarction. Furthermore, new-onset cardiac arrhythmias in stroke often presented in one continuous pattern - either as bradycardia or tachycardia, but instances of an alternating fashion have been rarely reported. We present the case of a 46-year-old female who developed severe dizziness with vomiting, diplopia, and slurred speech, which gradually worsened to quadriplegia, severe hypophonia, and dysphagia. Brain magnetic resonance imaging (MRI) demonstrated acute midbrain and pontine infarction. Except for neurological symptoms, the patient experienced unexpected TBS with the symptoms of excessive sweating, palpitations, and irritability without any other predisposing factors. The frequency of the episodes gradually declined until it spontaneously disappeared the 5th day after admission. Given the unpredictable nature of the tachycardia and bradycardia, it was challenging to manage the arrythmias with medications. A pacemaker was recommended, but financial reasons led the patient to reject this option. Two weeks after antithrombotic therapy and rehabilitation, she was discharged with residual symptoms of diplopia, moderate dysarthria, mild quadriplegia, and no cardiac symptoms. Our case highlighted the occurrence of TBS as a new-onset arrhythmia that can manifest during the acute phase of non-medullary brainstem infarcts. Further research into brainstem lesions contributing to TBS is warranted us to elucidate the underlying mechanisms.

Efficient and Selective Extraction of Rhamnogalacturonan-I-Enriched Pectic Polysaccharides from Tartary Buckwheat Leaves Using Deep-Eutectic-Solvent-Based Techniques.

Tartary buckwheat green leaves are considered to be among the most important by-products in the buckwheat industry. Although Tartary buckwheat green leaves are abundant in pectic polysaccharides, their potential applications in the food industry are quite scarce. Therefore, to promote their potential applications as functional or fortified food ingredients, both deep-eutectic-solvent-assisted extraction (DESE) and high-pressure-assisted deep eutectic solvent extraction (HPDEE) were used to efficiently and selectively extract pectic polysaccharides from Tartary buckwheat green leaves (TBP). The results revealed that both the DESE and HPDEE techniques not only improved the extraction efficiency of TBP but also regulated its structural properties and beneficial effects. The primary chemical structures of TBP extracted using different methods were stable overall, mainly consisting of homogalacturonan and rhamnogalacturonan-I (RG-I) pectic regions. However, both the DESE and HPDEE methods could selectively extract RG-I-enriched TBP, and the proportion of the RG-I pectic region in TBP obviously improved. Additionally, both the DESE and HPDEE methods could improve the antioxidant and anti-glycosylation effects of TBP by increasing its proportion of free uronic acids and content of bound polyphenolics and reducing its molecular weight. Moreover, both the DESE and HPDEE methods could partially intensify the immunostimulatory effect of TBP by increasing its proportion of the RG-I pectic region. These findings suggest that DES-based extraction techniques, especially the HPDEE method, can be promising techniques for the efficient and selective extraction of RG-I-enriched TBP.

Transcriptome analysis of frontal fibrosis alopecia revealed involvement of immune cells and ferroptosis.

BACKGROUND: Frontal fibrosis alopecia (FFA) is a primary cicatricial alopecia and has received increasing attention in recent years. However, the pathogenesis of FFA has not been fully elucidated. METHODS AND RESULTS: Herein, we collected the transcriptome data of scalp lesions of seven patients with FFA and seven healthy controls. The differential expression analysis and weighted gene co-expression network analysis were conducted and we identified 458 differentially expressed genes (DEGs) in two key modules. Later, we performed functional enrichment analysis and functional modules identification, revealing the participation of immune response and fatty acid metabolism. Based on the results, we processed further studies. On the one hand, we analyzed the infiltrating immune cells of FFA through CIBERSORT algorithm, indicating the activation of M1 macrophage and CD8+ T cell. On the other hand, considering lipid metabolism of FFA and oxidative stress of hair follicle cells in alopecia, we explored the potential ferroptosis of FFA. By intersection of DEGs and ferroptosis-related genes from FerrDb database, 19 genes were identified and their expression was validated in an external dataset containing 36 FFA cases and 12 controls. Then, we used LASSO algorithms to construct a four-gene diagnostic model, which achieved an AUC of 0.924 in validation dataset. Additionally, the immune cells were found to be related to ferroptosis in FFA. CONCLUSION: Taken together, this study contributed to reveal the molecular mechanisms of FFA and is expected to inspire future research on treatment.

Nanotechnology's frontier in combatting infectious and inflammatory diseases: prevention and treatment.

Inflammation-associated diseases encompass a range of infectious diseases and non-infectious inflammatory diseases, which continuously pose one of the most serious threats to human health, attributed to factors such as the emergence of new pathogens, increasing drug resistance, changes in living environments and lifestyles, and the aging population. Despite rapid advancements in mechanistic research and drug development for these diseases, current treatments often have limited efficacy and notable side effects, necessitating the development of more effective and targeted anti-inflammatory therapies. In recent years, the rapid development of nanotechnology has provided crucial technological support for the prevention, treatment, and detection of inflammation-associated diseases. Various types of nanoparticles (NPs) play significant roles, serving as vaccine vehicles to enhance immunogenicity and as drug carriers to improve targeting and bioavailability. NPs can also directly combat pathogens and inflammation. In addition, nanotechnology has facilitated the development of biosensors for pathogen detection and imaging techniques for inflammatory diseases. This review categorizes and characterizes different types of NPs, summarizes their applications in the prevention, treatment, and detection of infectious and inflammatory diseases. It also discusses the challenges associated with clinical translation in this field and explores the latest developments and prospects. In conclusion, nanotechnology opens up new possibilities for the comprehensive management of infectious and inflammatory diseases.

Genome-wide DNA methylation of lesional and peri-lesional skin in vitiligo: a comparative and integrated analysis of multi-omics in Chinese population.

Several studies have emphasized the role of DNA methylation in vitiligo. However, its profile in human skin of individuals with vitiligo remains unknown. Here, we aimed to study the DNA methylation profile of vitiligo using pairwise comparisons of lesions, peri-lesions, and healthy skin. We investigated DNA methylation levels in six lesional skin, six peri-lesional skin, and eight healthy skin samples using an Illumina 850 K methylation chip. We then integrated DNA methylation data with transcriptome data to identify differentially methylated and expressed genes (DMEGs) and analyzed their functional enrichment. Subsequently, we compared the methylation and transcriptome characteristics of all skin samples, and the related genes were further studied using scRNA-seq data. Finally, validation was performed using an external dataset. We observed more DNA hypomethylated sites in patients with vitiligo. Further integrated analysis identified 264 DMEGs that were mainly functionally enriched in cell division, pigmentation, circadian rhythm, fatty acid metabolism, peroxidase activity, synapse regulation, and extracellular matrix. In addition, in the peri-lesional skin, we found that methylation levels of 102 DMEGs differed prior to changes in their transcription levels and identified 16 key pre-DMEGs (ANLN, CDCA3, CENPA, DEPDC1, ECT2, DEPDC1B, HMMR, KIF18A, KIF18B, TTK, KIF23, DCT, EDNRB, MITF, OCA2, and TYRP1). Single-cell RNA analysis showed that these genes were associated with cycling keratinocytes and melanocytes. Further analysis of cellular communication indicated the involvement of the extracellular matrix. The expression of related genes was verified using an external dataset. To the best of our knowledge, this is the first study to report a comprehensive DNA methylation profile of clinical vitiligo and peri-lesional skin. These findings would contribute to future research on the pathogenesis of vitiligo and potential therapeutic strategies.

Recent advances on the Role of Gut Microbiota in the Development of Heart Failure by Mediating Immune Metabolism.

The association between gut microbiota and the development of heart failure has become a research hotspot in recent years and the impact of gut microbiota on heart failure has attracted growing interest. From 2006 to 2021, the global research on gut microbiota and heart failure has gradually expanded, indicating a developed and promising research field. There were 40 countries, 196 institutions, and 257 authors involved in the publication on the relationship between gut microbiota and heart failure, respectively. In patients with heart failure, inadequate visceral perfusion leads to ischemia and intestinal edema, which compromise the gut barrier. This subsequently results in the translocation of bacteria and bacterial metabolites into the circulatory system and causes local and systemic inflammatory responses. The gastrointestinal tract contains the largest number of immune cells in the human body and gut microbiota play important roles in the immune system by promoting immune tolerance to symbiotic bacteria. Studies have shown that probiotics can act on gut microorganisms, thereby increasing choline metabolism and reducing plasma TMA and TMAO concentrations, thus inhibiting the development of heart failure. Meanwhile, probiotics induce the production of inflammatory suppressors to maintain gut immune stability and inhibit the progression of heart failure by reducing ventricular remodeling. Here, we review the current understanding of gut microbiota-driven immune dysfunction in experimental and clinical heart failure, as well as the therapeutic interventions that could be used to address these issues.

Exosome-transmitted ANGPTL1 suppresses angiogenesis in glioblastoma by inhibiting the VEGFA/VEGFR2/Akt/eNOS pathway.

OBJECTIVE: Glioblastoma (GBM) is a highly vascularized malignancy that relies on new vessel generation, and thus targeting angiogenesis has been a promising anti-GBM approach. ANGPTL1 is well-known for its anti-angiogenic property; nevertheless, its role in GBM is yet to be explored. Recently, the crucial role of exosomes (Exos) as intercellular communication mediators has gained prominence in GBM therapy. This work aimed to explore the role of exosomal ANGPTL1 in GBM angiogenesis and its mechanisms. METHODS: Bioinformatic analysis was performed to evaluate ANGPTL expression in GBM. Human GBM cell lines (U87 and U251) and a xenograft mouse model were employed. Exos were isolated from oe-NC- and oe-ANGPTL-transfected bone mesenchymal stem cells and identified. Cell proliferation, migration, and apoptosis were detected. Immunofluorescence, qRT-PCR, western blotting, co-immunoprecipitation, and immunohistochemistry were used to determine the molecular mechanisms underlying exosomal ANGPTL1 against GBM angiogenesis. Besides, tube generation and transmission electron microscope assays were conducted to assess GBM angiogenesis. RESULTS: Low ANGPTL1 expression was observed in GBM tumor tissues and cells. Functionally, e-ANGPTL-Exos inhibited GBM malignant progression and angiogenesis in vitro and in vivo. Mechanically, e-ANGPTL-Exos reduced VEGFA expression and blocked the VEGFR2/Akt/eNOS pathway in GBM cells and tumor tissues. Co-immunoprecipitation revealed a link between ANGPTL1 and VEGFA in GBM cells. Notably, oe-VEGFA abolished the suppressive functions of e-ANGPTL-Exos in GBM progression and angiogenesis and the VEGFR2/Akt/eNOS axis. The VEGFR2 inhibitor, vandetanib, eliminated the promotive effects of oe-VEGFA on GBM angiogenesis with suppressed VEGFR2/Akt/eNOS pathway. CONCLUSIONS: Exosomal ANGPTL1 suppressed GBM angiogenesis by inhibiting the VEGFA/VEGFR2/Akt/eNOS axis.

Plasmid co-expressing siRNA-PD-1 and Endostatin carried by attenuated Salmonella enhanced the anti-melanoma effect via inhibiting the expression of PD-1 and VEGF on tumor-bearing mice.

Melanoma, the most perilous form of skin cancer, is known for its inherent resistance to chemotherapy. Even with advances in tumor immunotherapy, the survival of patients with advanced or recurrent melanomas remains poor. Over time, melanoma tumor cells may produce excessive angiogenic factors, necessitating the use of combinations of angiogenesis inhibitors, including broad-spectrum options, to combat melanoma. Among these inhibitors, Endostatin is one of the most broad-spectrum and least toxic angiogenesis inhibitors. We found Endostatin significantly increased the infiltration of CD8+ T cells and reduced the infiltration of M2 tumor-associated macrophages (TAMs) in the melanoma tumor microenvironment (TME). Interestingly, we also observed high expression levels of programmed death 1 (PD-1), an essential immune checkpoint molecule associated with tumor immune evasion, within the melanoma tumor microenvironment despite the use of Endostatin. To address this issue, we investigated the effects of a plasmid expressing Endostatin and PD-1 siRNA, wherein Endostatin was overexpressed while RNA interference (RNAi) targeted PD-1. These therapeutic agents were delivered using attenuated Salmonella in melanoma-bearing mice. Our results demonstrate that pEndostatin-siRNA-PD-1 therapy exhibits optimal therapeutic efficacy against melanoma. We found that pEndostatin-siRNA-PD-1 therapy promotes the infiltration of CD8+ T cells and the expression of granzyme B in melanoma tumors. Importantly, combined inhibition of angiogenesis and PD-1 significantly suppresses melanoma tumor progression compared with the inhibition of angiogenesis or PD-1 alone. Based on these findings, our study suggests that combining PD-1 inhibition with angiogenesis inhibitors holds promise as a clinical strategy for the treatment of melanoma.

Treatment patterns in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma post covalent Bruton tyrosine kinase inhibitor treatment: a Japanese claims database study.

Standard treatment has not been established for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after discontinuation of covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy. This retrospective, administrative database (Medical Data Vision) study described the patient characteristics, treatment patterns, and factors associated with receiving post-first-cBTKi treatment in Japanese patients with CLL/SLL. Patients aged ≥18 years with confirmed CLL/SLL diagnosis and treated with anti-neoplastic drugs indicated for CLL/SLL between March 2013 and February 2022 were included. Patient characteristics at baseline (first line), first cBTKi exposure (first-cBTKi), post-first-cBTKi treatment received, and the treatment sequence of CLL drugs received first line through third line, were described. Time-to-event analyses used the Kaplan-Meier method. Multivariable logistic regression analysis was used to explore factors associated with receiving post-first-cBTKi treatment among patients who discontinued first-cBTKi treatment. Among 2,424 eligible patients (median age: 72.0 years, 61.9% male), 450 (18.6%) received cBTKi in any treatment line. Among patients treated with cBTKi, 273 (60.7%) discontinued treatment; 56.0% of them (n = 153/273) received subsequent treatment. Median duration of post-first-cBTKi treatment was 2.2 months (95% confidence interval [CI]: 1.8, 3.5). The most common regimens post-first-cBTKi were cBTKi therapy (47.7%), bendamustine-based therapy (17.0%), and venetoclax-based therapy (13.1%). Patients aged <75 years (odds ratio [OR] [95% CI]: 2.0 [1.2, 3.4]) and those who did not receive blood transfusion during cBTKi treatment (OR [95% CI]: 2.3 [1.3, 4.1]) were more likely to receive post-first-cBTKi treatment. In conclusion, Japanese patients with CLL/SLL received various treatments for short duration after first-cBTKi discontinuation.

Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth.

Wnt signaling pathways are transmitted via 10 homologous frizzled receptors (FZD1-10) in humans. Reagents broadly inhibiting Wnt signaling pathways reduce growth and metastasis of many tumors, but their therapeutic development has been hampered by the side effect. Inhibitors targeting specific Wnt-FZD pair(s) enriched in cancer cells may reduce side effect, but the therapeutic effect of narrow-spectrum Wnt-FZD inhibitors remains to be established in vivo. Here, we developed a fragment of C. difficile toxin B (TcdBFBD), which recognizes and inhibits a subclass of FZDs, FZD1/2/7, and examined whether targeting this FZD subgroup may offer therapeutic benefits for treating breast cancer models in mice. Utilizing 2 basal-like and 1 luminal-like breast cancer models, we found that TcdBFBD reduces tumor-initiating cells and attenuates growth of basal-like mammary tumor organoids and xenografted tumors, without damaging Wnt-sensitive tissues such as bones in vivo. Furthermore, FZD1/2/7-positive cells are enriched in chemotherapy-resistant cells in both basal-like and luminal mammary tumors treated with cisplatin, and TcdBFBD synergizes strongly with cisplatin in inhibiting both tumor types. These data demonstrate the therapeutic value of narrow-spectrum Wnt signaling inhibitor in treating breast cancers.

A pilot study of multi-antigen stimulated cell therapy-I plus camrelizumab and apatinib in patients with advanced bone and soft-tissue sarcomas.

BACKGROUND: Cell-based  immunotherapy shows the therapeutic potential in sarcomas, in addition to angiogenesis-targeted tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI). Multi-antigen stimulated cell therapy-I (MASCT-I) technology is a sequential immune cell therapy for cancer, which composes of multiple antigen-loaded dendritic cell (DC) vaccines followed by the adoptive transfer of anti-tumor effector T-cells. METHODS: In this phase 1 study, we assessed MASCT-I plus camrelizumab (an ICI against PD-1) and apatinib (a highly selective TKI targeting VEGFR2) in patients with unresectable recurrent or metastatic bone and soft-tissue sarcoma after at least one line of prior systemic therapy. One MASCT-I course consisted of 3 DC subcutaneous injections, followed by 3 active T cell infusions administered 18-27 days after each DC injection. In schedule-I group, 3 DC injections were administered with a 28-day interval in all courses; in schedule-II group, 3 DC injections were administered with a 7-day interval in the first course and with a 28-day interval thereafter. All patients received intravenous camrelizumab 200 mg every 3 weeks and oral apatinib 250 mg daily. RESULTS: From October 30, 2019, to August 12, 2021, 19 patients were enrolled and randomly assigned to schedule-I group (n = 9) and schedule-II group (n = 10). Of the 19 patients, 11 (57.9%) experienced grade 3 or 4 treatment-related adverse events. No treatment-related deaths occurred. Patients in schedule-II group showed similar objective response rate (ORR) with those in schedule-I group (30.0% versus 33.3%) but had higher disease control rate (DCR; 90.0% versus 44.4%) and longer median progression-free survival (PFS; 7.7 versus 4.0 months). For the 13 patients with soft-tissue sarcomas, the ORR was 30.8%, DCR was 76.9%, and median PFS was 12.9 months; for the 6 patients with osteosarcomas, the ORR was 33.3%, the DCR was 50.0%, and median PFS was 5.7 months. CONCLUSIONS: Overall, MASCT-I plus camrelizumab and apatinib was safe and showed encouraging efficacy in advanced bone and soft-tissue sarcoma, and schedule-II administration method was recommended. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04074564.

Exploring the chemical composition, medicinal benefits, and antioxidant activity of Plumula nelumbinis essential oil from different habitats in China.

Plumula nelumbinis, a widely used traditional Chinese medicine known for its calming and nerve-soothing properties, contains essential oil as a primary component. However, research on P. nelumbinis essential oil (PNEO) is limited. This study aimed to investigate PNEO components, network target analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and antioxidant activity of P. nelumbinis from ten different habitats. GC-MS analysis identified 14 compounds in the essential oil, with CP12 (ß-Sitosterol) having the highest concentration. Five compounds were identified for the first time in P. nelumbinis, with three of them reported for the first time in the Nelumbo. Network target analysis revealed 185 potential targets for 11 compounds and GO and KEGG enrichment analyses showed that PNEO was mainly located in the plasma membrane and could regulate a variety of molecular functions. KEGG pathway enrichment analysis revealed that the essential oil was primarily enriched in pathways related to cancer and the nervous system. PNEO demonstrated strong antioxidant activity, with N8 (Fujiannanping) showing the highest ABTS scavenging capacity and N7 (Hunanxiangtan) showing the highest DPPH radical scavenging capacity. Cell experiments showed that CP4, CP5 and CP10 had protective effects against H2O2-induced oxidative damage. The study suggests that P. nelumbinis from different regions may have slightly different pharmacological effects due to the presence of unique compounds, and further research is necessary to explore the potential therapeutic benefits of PNEO.

Immunometabolism changes in fibrosis: from mechanisms to therapeutic strategies.

Immune cells are essential for initiating and developing the fibrotic process by releasing cytokines and growth factors that activate fibroblasts and promote extracellular matrix deposition. Immunometabolism describes how metabolic alterations affect the function of immune cells and how inflammation and immune responses regulate systemic metabolism. The disturbed immune cell function and their interactions with other cells in the tissue microenvironment lead to the origin and advancement of fibrosis. Understanding the dysregulated metabolic alterations and interactions between fibroblasts and the immune cells is critical for providing new therapeutic targets for fibrosis. This review provides an overview of recent advances in the pathophysiology of fibrosis from the immunometabolism aspect, highlighting the altered metabolic pathways in critical immune cell populations and the impact of inflammation on fibroblast metabolism during the development of fibrosis. We also discuss how this knowledge could be leveraged to develop novel therapeutic strategies for treating fibrotic diseases.

Design, Synthesis, and Biological Evaluation of Esculetin-Furoxan-DEAC Ternary Hybrids for Anti-Triple Negative Breast Cancer.

Twelve new hybrid compounds of Esculetin with nitric oxide (NO) donors and/or mitochondrial targeting groups were designed, synthesized, and evaluated for their anti-tumor activity and mechanism in vitro and in vivo. Notably, the most potent compound A11 exhibited nanomolar antiproliferative activity on triple-negative breast cancer (TNBC) MDA-MB-231 cells (IC50 = 8 nM) with a strikingly selective inhibitory effect. The mechanism of A11 involves targeting MDA-MB-231 cells' mitochondria, releasing a high NO concentration, and increasing the expression of cyclophilin D (CypD), leading to increased reactive oxygen species (ROS) and triggering cancer cell apoptosis. Additionally, A11 could arrest the cell cycle at the G2/M phase to achieve anti-tumor effects. Moreover, A11 demonstrated a superior TNBC inhibition rate and diminished toxicity relative to doxorubicin (DOX) in vivo. In summary, A11 serves as a noteworthy contender for TNBC treatment with high potency and minimal toxicity.

Microcystin-leucine-arginine impairs bone microstructure and biomechanics by activating osteoimmune response and inhibiting osteoblasts maturation in developing rats.

Microcystin-LR (MC-LR) affects bone health in adult mice via osteo-immunomodulation. However, its effect on osteoblasts and bone development is unclear. This study investigated the effect of MC-LR on bone osteoimmune and osteoblasts in the developing period. 18 Four-week-old male Sprague Dawley rats were divided into two groups (n = 9 per group) and exposed to 0 (control) and 1 µg/kg b.w. MC-LR (exposure) by intraperitoneal injection for four weeks. The heart blood was collected for serological examination, and the femur for morphological, histopathological, and biomechanical analysis. MC-LR exposure significantly weakened bone microstructures (bone volume, bone volume/total volume, bone trabecular number, connectivity density) and biomechanics (maximum loads and maximum deflection) (P < 0.05). Besides, MC-LR decreased serum procollagen type І car-boxy-terminal propeptide, osteocalcin, bone morphogenetic protein-2, osteoprotegerin, and receptor activator of nuclear factor κB ligand, while elevating osteoclasts number, matrix metalloproteinase-9, ß-catenin, Runt-related transcription factor 2, and osterix in bone, and bone alkaline phosphate, C-terminal cross-linked telopeptide of type-I collagen, tartrate-resistant acid phosphatase-5b in serum (P < 0.05). Moreover, MC-LR increased CD4+ T-cells, CD4+/CD8+, M1 and M2 macrophages, and cells apoptosis in the bone marrow, interleukin-6, interleukin-17, and tumor necrosis factor-α in serum, decreased serum interleukin-10 (P < 0.05). Overall, MC-LR can promote bone resorption by activating osteoclasts via osteoimmunology, which may involve macrophages besides lymphocytes. MC-LR may inhibit bone formation by stopping the osteoblasts at an immature stage. Thus, MC-LR weakened bone microstructure and biomechanics in developing period. Its risk on bone development needs further study.

Analysis of electromagnetic response of cells and lipid membranes using a model-free method.

Electromagnetic radiation (EMR) is omnipresent on earth and may interact with the biological systems in diverse manners. But the scope and nature of such interactions remain poorly understood. In this study, we have measured the permittivity of cells and lipid membranes over the EMR frequency range of 20 Hz to 4.35 × 1010 Hz. To identify EMR frequencies that display physically intuitive permittivity features, we have developed a model-free method that relies on a potassium chloride reference solution of direct-current (DC) conductivity equal to that of the target sample. The dielectric constant, which reflects the capacity to store energy, displays a characteristic peak at 105-106 Hz. The dielectric loss factor, which represents EMR absorption, is markedly enhanced at 107-109 Hz. The fine characteristic features are influenced by the size and composition of these membraned structures. Mechanical disruption results in abrogation of these characteristic features. Enhanced energy storage at 105-106 Hz and energy absorption at 107-109 Hz may affect certain membrane activity relevant to cellular function.