Identification of a pyroptosis-immune-related lncRNA signature for prognostic and immune landscape prediction in bladder cancer patients.

PURPOSE: Individualized medicine has become increasingly important in bladder cancer treatment, whereas useful biomarkers for prognostic prediction are still lacking. The current study, therefore, constructed a novel risk model based on pyroptosis- and immune-related long noncoding RNAs (Pyro-Imm lncRNAs) to evaluate the potential prognosis of bladder cancer. METHODS: Corresponding data of bladder cancer patients were downloaded from the Cancer Genome Atlas (TCGA) database. The univariate Cox regression analysis, least absolute shrinkage and selection operator (LASSO) regression analysis, and multivariate Cox regression analysis were employed to establish a predictive signature, which was evaluated by receiver operator characteristic (ROC) analysis and Kaplan-Meier analysis. Furthermore, the immune infiltration, immune checkpoints, and responses to chemotherapeutic drugs were analyzed with this model. RESULTS: Three Pyro-Imm lncRNAs (MAFG-DT, AC024060.1, AC116914.2) were finally identified. Patients in the low-risk group demonstrated a significant survival advantage. The area under the ROC curve (AUC) at 1, 3, and 5 years was 0.694, 0.709, and 0.736 respectively in the entire cohort. KEGG and GO analyses showed that the Wnt pathway plays a crucial role in the high-risk group. The risk score was significantly related to the degree of infiltration of different immune cells, the expression of multiple immune checkpoint genes, and the sensitivity of various chemotherapeutic drugs. CONCLUSION: This novel signature provides a theoretical basis for cancer immunology and chemotherapy, which might help develop individualized therapy.

Magnetic steering continuum robot for transluminal procedures with programmable shape and functionalities.

Millimeter-scale soft continuum robots offer safety and adaptability in transluminal procedures due to their passive compliance, but this feature necessitates interactions with surrounding lumina, leading to potential medical risks and restricted mobility. Here, we introduce a millimeter-scale continuum robot, enabling apical extension while maintaining structural stability. Utilizing phase transition components, the robot executes cycles of tip-based elongation, steered accurately through programmable magnetic fields. Each motion cycle features a solid-like backbone for stability, and a liquid-like component for advancement, thereby enabling autonomous shaping without reliance on environmental interactions. Together with clinical imaging technologies, we demonstrate the capability of navigating through tortuous and fragile lumina to transport microsurgical tools. Once it reaches larger anatomical spaces such as stomach, it can morph into functional 3D structures that serve as surgical tools or sensing units, overcoming the constraints of initially narrow pathways. By leveraging this design paradigm, we anticipate enhanced safety, multi-functionality, and cooperative capabilities among millimeter-scale continuum robots, opening new avenues for transluminal robotic surgery.

Nickel-Catalyzed Regioselective Hydrothiolation of Allenes Enabled by Visible-Light Photoredox Catalysis.

Hydrothiolation presents an attractive way to transform allenes into allylic thioethers. Herein, we described an efficient visible-light photoredox-promoted nickel-catalyzed hydrothiolation of allenes with functionalized aromatic and aliphatic thiols. This synergistic catalytic system exhibits unprecedentedly high reactivities and regiocontrol for the construction of allylic thioethers, representing the unique synthetic utility of the earth-abundant Ni-catalyzed method compared with the related noble-metal-catalyzed allylation reactions.

NRDE2 deficiency impairs homologous recombination repair and sensitizes hepatocellular carcinoma to PARP inhibitors.

To identify novel susceptibility genes for hepatocellular carcinoma (HCC), we performed a rare-variant association study in Chinese populations consisting of 2,750 cases and 4,153 controls. We identified four HCC-associated genes, including NRDE2, RANBP17, RTEL1, and STEAP3. Using NRDE2 (index rs199890497 [p.N377I], p = 1.19 × 10-9) as an exemplary candidate, we demonstrated that it promotes homologous recombination (HR) repair and suppresses HCC. Mechanistically, NRDE2 binds to the subunits of casein kinase 2 (CK2) and facilitates the assembly and activity of the CK2 holoenzyme. This NRDE2-mediated enhancement of CK2 activity increases the phosphorylation of MDC1 and then facilitates the HR repair. These functions are eliminated almost completely by the NRDE2-p.N377I variant, which sensitizes the HCC cells to poly(ADP-ribose) polymerase (PARP) inhibitors, especially when combined with chemotherapy. Collectively, our findings highlight the relevance of the rare variants to genetic susceptibility to HCC, which would be helpful for the precise treatment of this malignancy.

Aberrant activation of TGF-ß/ROCK1 enhances stemness during prostatic stromal hyperplasia.

Benign prostatic hyperplasia (BPH) is a multifactorial disease in which abnormal growth factor activation and embryonic reawakening are considered important factors. Here we demonstrated that the aberrant activation of transforming growth factor ß (TGF-ß)/Rho kinase 1 (ROCK1) increased the stemness of BPH tissue by recruiting mesenchymal stem cells (MSCs), indicating the important role of embryonic reawakening in BPH. When TGF-ß/ROCK1 is abnormally activated, MSCs are recruited and differentiate into fibroblasts/myofibroblasts, leading to prostate stromal hyperplasia. Further research showed that inhibition of ROCK1 activation suppressed MSC migration and their potential for stromal differentiation. Collectively, our findings suggest that abnormal activation of TGF-ß/ROCK1 regulates stem cell lineage specificity, and the small molecule inhibitor GSK269962A could target ROCK1 and may be a potential treatment for BPH.

Hydrogel-based immunoregulation of macrophages for tissue repair and regeneration.

The rational design of hydrogel materials to modulate the immune microenvironment has emerged as a pivotal approach in expediting tissue repair and regeneration. Within the immune microenvironment, an array of immune cells exists, with macrophages gaining prominence in the field of tissue repair and regeneration due to their roles in cytokine regulation to promote regeneration, maintain tissue homeostasis, and facilitate repair. Macrophages can be categorized into two types: classically activated M1 (pro-inflammatory) and alternatively activated M2 (anti-inflammatory and pro-repair). By regulating the physical and chemical properties of hydrogels, the phenotypic transformation and cell behavior of macrophages can be effectively controlled, thereby promoting tissue regeneration and repair. A full understanding of the interaction between hydrogels and macrophages can provide new ideas and methods for future tissue engineering and clinical treatment. Therefore, this paper reviews the effects of hydrogel components, hardness, pore size, and surface morphology on cell behaviors such as macrophage proliferation, migration, and phenotypic polarization, and explores the application of hydrogels based on macrophage immune regulation in skin, bone, cartilage, and nerve tissue repair. Finally, the challenges and future prospects of macrophage-based immunomodulatory hydrogels are discussed.

Quantitative Pattern of hPTMs by Mass Spectrometry-Based Proteomics with Implications for Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is known for its aggressive nature, and TNBC management is currently challenging due to the lack of effective targets. Despite the importance of histone post-translational modifications (hPTMs) in breast cancer, their associations with molecular subtypes of breast cancer, especially TNBC, are poorly understood. In this study, a combination of untargeted and targeted proteomics approaches, supplemented by a derivatization method, was applied to breast cancer cells and tissue samples. Untargeted proteomics of eight breast cancer cell lines belonging to different molecular subtypes revealed 36 modified peptides with 12 lysine modification sites in histone H3, and the most frequently reported top 5 histone H3 methylation and acetylation sites were covered. Then, targeted proteomics was carried out to quantify the total 20 target hPTMs at the covered modification sites (i.e., mono-, di-, trimethylation, and acetylation for each site), indicating the difficulty in distinguishing TNBC cells from normal cells. Subsequently, the analysis in TNBC patients revealed significant expression differences in 4 specific hPTMs (H3K14ac, H3K27me1, H3K36me2, and H3K36me3) between TNBC and adjacent normal tissue samples. These unique hPTM patterns allowed for the differentiation of TNBC from normal cases. This finding provides promising implications for advancing targeted treatment strategies for TNBC in the future.

Efficacy of adjunctive photodynamic therapy to conventional mechanical debridement for peri-implant mucositis.

OBJECTIVE: This meta-analysis was conducted to assess the effectiveness of photodynamic therapy (PDT) as an adjunct to conventional mechanical debridement (CMD) for the management of peri-implant mucositis (p-iM). METHODS: We systematically searched four databases (PubMed, Embase, Web of Science, and Cochrane Library) for randomized controlled trials (RCTs) investigating PDT + CMD for p-iM from their inception to March 13, 2023. Meta-analysis was performed using RevMan 5.4 software. RESULTS: Seven RCTs met the inclusion criteria. The meta-analysis revealed that PDT + CMD treatment was more effective than CMD alone in reducing probing depth (PD) (Mean Difference [MD]: -1.09, 95% Confidence Interval [CI]: -1.99 to -0.2, P = 0.02) and plaque index (PI) (MD: -2.06, 95% CI: -2.81 to -1.31, P < 0.00001). However, there was no statistically significant difference in the improvement of bleeding on probing (BOP) between the PDT + CMD groups and CMD groups (MD: -0.97, 95% CI: -2.81 to 0.88, P = 0.31). CONCLUSIONS: Based on the current available evidence, this meta-analysis indicates that the addition of PDT to CMD significantly improves PD and PI compared to CMD alone in the treatment of p-iM. However, there is no significant difference in improving BOP.

Interpretable machine learning-based clinical prediction model for predicting lymph node metastasis in patients with intrahepatic cholangiocarcinoma.

OBJECTIVE: Prediction of lymph node metastasis (LNM) for intrahepatic cholangiocarcinoma (ICC) is critical for the treatment regimen and prognosis. We aim to develop and validate machine learning (ML)-based predictive models for LNM in patients with ICC. METHODS: A total of 345 patients with clinicopathological characteristics confirmed ICC from Jan 2007 to Jan 2019 were enrolled. The predictors of LNM were identified by the least absolute shrinkage and selection operator (LASSO) and logistic analysis. The selected variables were used for developing prediction models for LNM by six ML algorithms, including Logistic regression (LR), Gradient boosting machine (GBM), Extreme gradient boosting (XGB), Random Forest (RF), Decision tree (DT), Multilayer perceptron (MLP). We applied 10-fold cross validation as internal validation and calculated the average of the areas under the receiver operating characteristic (ROC) curve to measure the performance of all models. A feature selection approach was applied to identify importance of predictors in each model. The heat map was used to investigate the correlation of features. Finally, we established a web calculator using the best-performing model. RESULTS: In multivariate logistic regression analysis, factors including alcoholic liver disease (ALD), smoking, boundary, diameter, and white blood cell (WBC) were identified as independent predictors for LNM in patients with ICC. In internal validation, the average values of AUC of six models ranged from 0.820 to 0.908. The XGB model was identified as the best model, the average AUC was 0.908. Finally, we established a web calculator by XGB model, which was useful for clinicians to calculate the likelihood of LNM. CONCLUSION: The proposed ML-based predicted models had a good performance to predict LNM of patients with ICC. XGB performed best. A web calculator based on the ML algorithm showed promise in assisting clinicians to predict LNM and developed individualized medical plans.

Young osteocyte-derived extracellular vesicles facilitate osteogenesis by transferring tropomyosin-1.

BACKGROUND: Bone marrow mesenchymal stem cells (BMSCs) can undergo inadequate osteogenesis or excessive adipogenesis as they age due to changes in the bone microenvironment, ultimately resulting in decreased bone density and elevated risk of fractures in senile osteoporosis. This study aims to investigate the effects of osteocyte senescence on the bone microenvironment and its influence on BMSCs during aging. RESULTS: Primary osteocytes were isolated from 2-month-old and 16-month-old mice to obtain young osteocyte-derived extracellular vesicles (YO-EVs) and senescent osteocyte-derived EVs (SO-EVs), respectively. YO-EVs were found to significantly increase alkaline phosphatase activity, mineralization deposition, and the expression of osteogenesis-related genes in BMSCs, while SO-EVs promoted BMSC adipogenesis. Neither YO-EVs nor SO-EVs exerted an effect on the osteoclastogenesis of primary macrophages/monocytes. Our constructed transgenic mice, designed to trace osteocyte-derived EV distribution, revealed abundant osteocyte-derived EVs embedded in the bone matrix. Moreover, mature osteoclasts were found to release osteocyte-derived EVs from bone slices, playing a pivotal role in regulating the functions of the surrounding culture medium. Following intravenous injection into young and elderly mouse models, YO-EVs demonstrated a significant enhancement of bone mass and biomechanical strength compared to SO-EVs. Immunostaining of bone sections revealed that YO-EV treatment augmented the number of osteoblasts on the bone surface, while SO-EV treatment promoted adipocyte formation in the bone marrow. Proteomics analysis of YO-EVs and SO-EVs showed that tropomyosin-1 (TPM1) was enriched in YO-EVs, which increased the matrix stiffness of BMSCs, consequently promoting osteogenesis. Specifically, the siRNA-mediated depletion of Tpm1 eliminated pro-osteogenic activity of YO-EVs both in vitro and in vivo. CONCLUSIONS: Our findings suggested that YO-EVs played a crucial role in maintaining the balance between bone resorption and formation, and their pro-osteogenic activity declining with aging. Therefore, YO-EVs and the delivered TPM1 hold potential as therapeutic targets for senile osteoporosis.

Effects of Aromatherapy on Physical and Mental Health of Cancer Patients Undergoing Radiotherapy and/or Chemotherapy: A Meta-Analysis.

BACKGROUP: Currently, aromatherapy is being increasingly utilized in clinical practice, particularly in managing the side effects associated with radiotherapy and chemoradiotherapy. However, it remains to be established whether aromatherapy can effectively alleviate these symptoms. OBJECTIVE: To investigate the effects of aromatherapy on the physical and mental health of patients with cancer undergoing radiotherapy and chemotherapy. METHODS: Seven databases were researched from inception until September 29, 2023, including PubMed, Scopus, and Web of Science, Chinese National Knowledge Infrastructure, Wanfang database, China Biology Medicine disc and VIP Chinese Medical Journal Database. Review Manager version 5.3 was utilized for data analysis. The Cochrane Risk of Bias tool RoB2 was employed to evaluate the quality of the literature included in the study. Evidence quality rating was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach through the GRADEpro GDT online tool. RESULTS: Nineteen studies involving 1,541 patients were included. Aromatherapy can alleviate nausea [relative risk (RR)=0.64, 95% confidence interval (CI): 0.53 to 0.78, P<0.05, I2=46%; standardized mean difference (SMD)=-0.86, 95% CI: -1.21 to -0.51, P<0.05, I2=64%] and vomiting (RR=0.54, 95% CI: 0.42 to 0.69, P<0.05, I2=35%; SMD=-1.28, 95% CI: -1.52 to -1.03, P<0.05, I2=92%), improve sleep disorders [mean difference (MD)=-3.39, 95% CI: -3.95 to -2.84, P<0.05, I2=0%], relieve pain (SMD=-1.58, 95% CI: -1.96 to -1.21, P<0.05, I2=0%), mitigate fatigue (SMD=-1.28, 95% CI: -2.44 to -0.11, P<0.05, I2=93%) and enhance quality of life (SMD=0.50, 95% CI: 0.22 to 0.79, P<0.05, I2=0%) in cancer patients after radiotherapy and chemotherapy, but it may not have a significant effect on anxiety. The risk of bias was high in the included studies using the Cochrane Risk of Bias tool RoB2, and no studies were considered to be of high grade according to the GRADE system. CONCLUSIONS: Aromatherapy is an efficacious, safe and economic adjunctive therapy for cancer patients, which can mend the physical symptoms and mental health of cancer patients. However, more high-quality studies are needed to verify it. (PROSPERO registration No. CRD42023390171).

Sulforaphane Inhibits Adhesion and Migration of Cisplatin- and Gemcitabine-Resistant Bladder Cancer Cells In Vitro.

Only 20% of patients with muscle-invasive bladder carcinoma respond to cisplatin-based chemotherapy. Since the natural phytochemical sulforaphane (SFN) exhibits antitumor properties, its influence on the adhesive and migratory properties of cisplatin- and gemcitabine-sensitive and cisplatin- and gemcitabine-resistant RT4, RT112, T24, and TCCSUP bladder cancer cells was evaluated. Mechanisms behind the SFN influence were explored by assessing levels of the integrin adhesion receptors ß1 (total and activated) and ß4 and their functional relevance. To evaluate cell differentiation processes, E- and N-cadherin, vimentin and cytokeratin (CK) 8/18 expression were examined. SFN down-regulated bladder cancer cell adhesion with cell line and resistance-specific differences. Different responses to SFN were reflected in integrin expression that depended on the cell line and presence of resistance. Chemotactic movement of RT112, T24, and TCCSUP (RT4 did not migrate) was markedly blocked by SFN in both chemo-sensitive and chemo-resistant cells. Integrin-blocking studies indicated ß1 and ß4 as chemotaxis regulators. N-cadherin was diminished by SFN, particularly in sensitive and resistant T24 and RT112 cells, whereas E-cadherin was increased in RT112 cells (not detectable in RT4 and TCCSup cells). Alterations in vimentin and CK8/18 were also apparent, though not the same in all cell lines. SFN exposure resulted in translocation of E-cadherin (RT112), N-cadherin (RT112, T24), and vimentin (T24). SFN down-regulated adhesion and migration in chemo-sensitive and chemo-resistant bladder cancer cells by acting on integrin ß1 and ß4 expression and inducing the mesenchymal-epithelial translocation of cadherins and vimentin. SFN does, therefore, possess potential to improve bladder cancer therapy.

Omentin-1 inhibits the development of benign prostatic hyperplasia by attenuating local inflammation.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a prevalent disease affecting elderly men, with chronic inflammation being a critical factor in its development. Omentin-1, also known as intelectin-1 (ITLN-1), is an anti-inflammatory protein primarily found in the epithelial cells of the small intestine. This study aimed to investigate the potential of ITLN-1 in mitigating BPH by modulating local inflammation in the prostate gland. METHODS: Our investigation involved two in vivo experimental models. Firstly, ITLN-1 knockout mice (Itln-1-/-) were used to study the absence of ITLN-1 in BPH development. Secondly, a testosterone propionate (TP)-induced BPH mouse model was treated with an ITLN-1 overexpressing adenovirus. We assessed BPH severity using prostate weight index and histological analysis, including H&E staining, immunohistochemistry, and enzyme-linked immunosorbent assay. In vitro, the impact of ITLN-1 on BPH-1 cell proliferation and inflammatory response was evaluated using cell proliferation assays and enzyme-linked immunosorbent assay. RESULTS: In vivo, Itln-1-/- mice exhibited elevated prostate weight index, enlarged lumen area, and higher TNF-α levels compared to wild-type littermates. In contrast, ITLN-1 overexpression in TP-induced BPH mice resulted in reduced prostate weight index, lumen area, and TNF-α levels. In vitro studies indicated that ITLN-1 suppressed the proliferation of prostate epithelial cells and reduced TNF-α production in macrophages, suggesting a mechanism involving the inhibition of macrophage-mediated inflammation. CONCLUSION: The study demonstrates that ITLN-1 plays a significant role in inhibiting the development of BPH by reducing local inflammation in the prostate gland. These findings highlight the potential of ITLN-1 as a therapeutic target in the management of BPH.

Environmental Risk Factors, Protective Factors, and Biomarkers for Hearing Loss: An Umbrella Review.

OBJECTIVE: We aimed to investigate the potential environmental risk factors, protective factors, and biomarkers of hearing loss (HL), and establish a hierarchy of evidence. DATA SOURCES: Embase, PubMed, Cochrane Library, and Web of Science electronic database from inception to June 1, 2023. REVIEW METHODS: We included meta-analyses of observational studies of associations between HL and environmental risk factors, protective factors, or biomarkers. We calculated summary effect estimates, 95% confidence interval, heterogeneity I2 statistic, 95% prediction interval, small study effects, and excess significance biases. RESULTS: Of the 9211 articles retrieved, 60 eligible articles were included. The 60 eligible articles identified 47 potential environmental risk and protective factors (N = 4,123,803) and 46 potential biomarkers (N = 173,701). Evidence of association was convincing (class I) for rheumatoid arthritis (RA) and every 1 cm increase in height. Evidence of association was highly suggestive (class II) for human immunodeficiency virus (HIV), diabetes, cumulative noise exposure (CNE), smoking, congenital cytomegalovirus (CMV) infection, combined exposure to organic solvents and noise, non-Gaussian noise exposure, each 1 kg increase in birth weight, noise exposure, and alopecia areata (AA). CONCLUSION: In this umbrella review, RA, every 1 cm increase in height, HIV, diabetes, CNE, smoking, congenital CMV infection, combined exposure to organic solvents and noise, non-Gaussian noise exposure, each 1 kg increase in birth weight, noise exposure, and AA were strongly associated with HL.

Radiomics-based nomogram guides adaptive de-intensification in locoregionally advanced nasopharyngeal carcinoma following induction chemotherapy.

OBJECTIVES: This study aimed to construct a radiomics-based model for prognosis and benefit prediction of concurrent chemoradiotherapy (CCRT) versus intensity-modulated radiotherapy (IMRT) in locoregionally advanced nasopharyngeal carcinoma (LANPC) following induction chemotherapy (IC). MATERIALS AND METHODS: A cohort of 718 LANPC patients treated with IC + IMRT or IC + CCRT were retrospectively enrolled and assigned to a training set (n = 503) and a validation set (n = 215). Radiomic features were extracted from pre-IC and post-IC MRI. After feature selection, a delta-radiomics signature was built with LASSO-Cox regression. A nomogram incorporating independent clinical indicators and the delta-radiomics signature was then developed and evaluated for calibration and discrimination. Risk stratification by the nomogram was evaluated with Kaplan-Meier methods. RESULTS: The delta-radiomics signature, which comprised 19 selected features, was independently associated with prognosis. The nomogram, composed of the delta-radiomics signature, age, T category, N category, treatment, and pre-treatment EBV DNA, showed great calibration and discrimination with an area under the receiver operator characteristic curve of 0.80 (95% CI 0.75-0.85) and 0.75 (95% CI 0.64-0.85) in the training and validation sets. Risk stratification by the nomogram, excluding the treatment factor, resulted in two groups with distinct overall survival. Significantly better outcomes were observed in the high-risk patients with IC + CCRT compared to those with IC + IMRT, while comparable outcomes between IC + IMRT and IC + CCRT were shown for low-risk patients. CONCLUSION: The radiomics-based nomogram can predict prognosis and survival benefits from concurrent chemotherapy for LANPC following IC. Low-risk patients determined by the nomogram may be potential candidates for omitting concurrent chemotherapy during IMRT. CLINICAL RELEVANCE STATEMENT: The radiomics-based nomogram was constructed for risk stratification and patient selection. It can help guide clinical decision-making for patients with locoregionally advanced nasopharyngeal carcinoma following induction chemotherapy, and avoid unnecessary toxicity caused by overtreatment. KEY POINTS: • The benefits from concurrent chemotherapy remained controversial for locoregionally advanced nasopharyngeal carcinoma following induction chemotherapy. • Radiomics-based nomogram achieved prognosis and benefits prediction of concurrent chemotherapy. • Low-risk patients defined by the nomogram were candidates for de-intensification.

Microbiome analysis reveals the inducing effect of Pseudomonas on prostatic hyperplasia via activating NF-κB signalling.

Benign prostatic hyperplasia (BPH) is a prevalent disease among middle-aged and elderly males, but its pathogenesis remains unclear. Dysbiosis of the microbiome is increasingly recognized as a significant factor in various human diseases. Prostate tissue also contains a unique microbiome, and its dysbiosis has been proposed to contribute to prostate diseases. Here, we obtained prostate tissues and preoperative catheterized urine from 24 BPH individuals, and 8 normal prostate samples as controls, which followed strict aseptic measures. Using metagenomic next-generation sequencing (mNGS), we found the disparities in the microbiome composition between normal and BPH tissues, with Pseudomonas significantly enriched in BPH tissues, as confirmed by fluorescence in situ hybridization (FISH). Additionally, we showed that the prostate microbiome differed from the urine microbiome. In vitro experiments revealed that lipopolysaccharide (LPS) of Pseudomonas activated NF-κB signalling, leading to inflammation, proliferation, and EMT processes, while inhibiting apoptosis in prostatic cells. Overall, our research determines the presence of microbiome dysbiosis in BPH, and suggests that Pseudomonas, as the dominant microflora, may promote the progression of BPH through LPS activation of NF-κB signalling.

Preoperative single-dose camrelizumab and/or microwave ablation in women with early-stage breast cancer: A window-of-opportunity trial.

BACKGROUND: Immune checkpoint blockade has shown low response rates for advanced breast cancer, and combination strategies are needed. Microwave ablation (MWA) may be a trigger of antitumor immunity. This window-of-opportunity trial (ClinicalTrials.gov: NCT04805736) was conducted to determine the safety and feasibility of preoperative camrelizumab (an anti-PD-1 antibody) combined with MWA in the treatment of early-stage breast cancer. METHODS: Sixty participants were randomized to preoperatively receive single-dose camrelizumab alone (n = 20), MWA alone (n = 20), or camrelizumab+MWA (n = 20). A random number table was used to allocate interventions. The primary outcome was the safety and feasibility of MWA combined with camrelizumab. FINDINGS: Camrelizumab and MWA were well tolerated alone and in combination without delays in prescheduled surgery. No treatment-related grade III/IV adverse events were observed. Different from in the single-dose camrelizumab or MWA group, participants showed stable counts of blood cells after combination therapy. After combination therapy, peripheral CD8+ T cells showed enhanced cytotoxic and effect-memory functions. Clonal expansional CD8+ T cells showed higher cytotoxic activity and effector memory- and tumor-specific signatures than emergent clones after combination therapy. Enhanced interactions between clonal expansional CD8+ T cells and monocytes were observed, suggesting that monocytes contributed to the enhanced functions of clonal expansional CD8+ T cells. Major histocompatibility complex (MHC) class I-related pathways and interferon signaling pathways were activated in monocytes by combination therapy. CONCLUSIONS: Camrelizumab combined with MWA was feasible for early-stage breast cancer. Peripheral CD8+ T cells were activated after combination therapy, dependent on monocytes with activated MHC class I pathways. FUNDING: This study was supported by the Natural Science Foundation of Jiangsu Province (BK20230017).

Establishment and comparison of different procedures for modeling intrauterine adhesion in rats: A preliminary study.

The establishment of a stable animal model for intrauterine adhesion (IUA) can significantly enhance research on the pathogenesis and pathological changes of this disease, as well as on the development of innovative therapeutic approaches. In this study, three different modeling methods, including phenol mucilage combined mechanical scraping, ethanol combined mechanical scraping and ethanol modeling alone were designed. The morphological characteristics of the models were evaluated. The underlying mechanisms and fertility capacity of the ethanol modeling group were analyzed and compared to those of the sham surgery group. All three methods resulted in severe intrauterine adhesions, with ethanol being identified as a reliable modeling agent and was subsequently subjected to further evaluation. Immunohistochemistry and RT-PCR results indicated that the ethanol modeling group exhibited an increase in the degree of fibrosis and inflammation, as well as a significant reduction in endometrial thickness, gland number, vascularization, and endometrial receptivity, ultimately resulting in the loss of fertility capacity. The aforementioned findings indicate that the intrauterine perfusion of 95 % ethanol is efficacious in inducing the development of intrauterine adhesions in rats. Given its cost-effectiveness, efficacy, and stability in IUA formation, the use of 95 % ethanol intrauterine perfusion may serve as a novel platform for evaluating innovative anti-adhesion materials and bioengineered therapies.

CCNB1 may as a biomarker for the adipogenic differentiation of adipose-derived stem cells in the postoperative fat transplantation of breast cancer.

Background: Adipose-derived stem cells (ADSCs) are closely associated with the survival rate of transplanted fat in breast reconstruction after breast cancer surgery. Nevertheless, the intrinsic mechanisms regulating ADSCs adipogenic differentiation remain ambiguous. The aim of our study was to explore the relevant genes and pathways to elucidate the potential mechanisms of adipogenic differentiation in ADSCs. Methods: The Gene Expression Omnibus (GEO) dataset GSE61302 was downloaded and analyzed to identify differentially expressed genes (DEGs). Key genes and signaling pathways were obtained through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional and enrichment analysis. Protein-protein interaction (PPI) network and hub gene analyses were performed with the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database and Cytoscape software. Finally, the transcription levels of hub genes in the adipogenic differentiated group and undifferentiated group of ADSCs were compared via real-time quantitative polymerase chain reaction (RT-qPCR). Results: In total, 1,091 DEGs were identified through bioinformatics analysis of the adipogenic differentiated group and undifferentiated group. If was then found that the 10 downregulated key genes, CCNB1, NUSAP1, DLGAP5, TTK, CCNB2, KIF23, BUB1B, CDC20, CDCA8, and KIF11 may play important roles in the adipogenic differentiation of ADSCs. Subsequent in vitro experimental verification also revealed that the messenger RNA (mRNA) expression levels of cyclin B1 in adipogenic differentiated cells and undifferentiated cells were significantly different at the early stage (P<0.05), but there was no significant difference at the late stage (P>0.05). Conclusions: As a key gene, CCNB1 might be a potential biomarker in the adipogenic differentiation of ADSCs at the early stage.