Efficacy and Safety of Fruquintinib-Based Treatment in Patients with Refractory Bone and Soft Tissue Sarcoma after Developing Resistance to Several TKIs: A Multicenter Retrospective Study.

OBJECTIVE: Multitargeted tyrosine kinase inhibitors (TKIs) have been approved as second-line therapy in refractory sarcoma, prolonging progression-free survival (PFS) but with short-lived duration of disease control. Fruquintinib is a TKI that specifically inhibits vascular endothelial growth factor receptor-1,2,3 with no metabolism by liver enzymes. In this retrospective study, we assessed the efficacy and safety of fruquintinib-based treatment in patients with refractory sarcoma after developing several lines of TKI resistance. METHODS: We retrospectively analyzed the clinical data of patients with refractory sarcoma after they had developed several lines of resistance to TKIs and who received fruquintinib-based treatment from November 2021 to August 2023. The primary endpoint was the progression-free survival rate at 4 months (4m-PFSR). Secondary endpoints were the median PFS, overall survival (OS), objective response rate, disease control rate, and adverse effects (AEs). PFS and OS were estimated using the Kaplan-Meier method. A log-rank test was used to compare survival curves between different clinical and pathological factors. Cox proportional hazards analysis was performed to identify PFS-related prognostic factors. RESULTS: We included 124 patients: 56 (45.2%) with osteosarcoma, 28 (22.6%) with Ewing sarcoma, seven (5.6%) with chondrosarcoma, and 33 (26.6%) with soft tissue sarcomas (STS). Only 18 (14.5%) patients received monotherapy with fruquintinib. With a median follow-up time of 6.8 (interquartile range [IQR], 4.6-9.4) months, 22 (17.7%) patients had partial response and 78 (62.9%) had stable disease. The 4m-PFSR was 58.4% (95% confidence interval [CI], 49.6%-67.1%). The median PFS and OS were 4.4 (95% CI, 3.9-5.0) months and 11.4 (95% CI, 10.3-12.5) months. In multivariate analysis, a high hazard ratio for progression was associated with target lesions located outside the lung and bone with 1.79 (95% CI, 1.10-2.93; p = 0.020). Eighty-eight AEs were recorded in 47 (37.9%) patients; the most common were pneumothorax (18/124, 14.5%), diarrhea (8/124, 6.5%), oral mucositis (7/124, 5.6%), and thrombocytopenia (7/124, 5.6%). CONCLUSIONS: Fruquintinib may be a potential option for patients with refractory sarcoma after developing several lines of TKI resistance, with a satisfactory efficacy and safety profile in combination therapy. However, the degree of contribution of fruquintinib to results is unclear when combined with other effective substances. Additional prospective trials of fruquintinib should be conducted, especially involving different pathological types and combination regimens.

Deep learning driven diagnosis of malignant soft tissue tumors based on dual-modal ultrasound images and clinical indexes.

Background: Soft tissue tumors (STTs) are benign or malignant superficial neoplasms arising from soft tissues throughout the body with versatile pathological types. Although Ultrasonography (US) is one of the most common imaging tools to diagnose malignant STTs, it still has several drawbacks in STT diagnosis that need improving. Objectives: The study aims to establish this deep learning (DL) driven Artificial intelligence (AI) system for predicting malignant STTs based on US images and clinical indexes of the patients. Methods: We retrospectively enrolled 271 malignant and 462 benign masses to build the AI system using 5-fold validation. A prospective dataset of 44 malignant masses and 101 benign masses was used to validate the accuracy of system. A multi-data fusion convolutional neural network, named ultrasound clinical soft tissue tumor net (UC-STTNet), was developed to combine gray scale and color Doppler US images and clinic features for malignant STTs diagnosis. Six radiologists (R1-R6) with three experience levels were invited for reader study. Results: The AI system achieved an area under receiver operating curve (AUC) value of 0.89 in the retrospective dataset. The diagnostic performance of the AI system was higher than that of one of the senior radiologists (AUC of AI vs R2: 0.89 vs. 0.84, p=0.022) and all of the intermediate and junior radiologists (AUC of AI vs R3, R4, R5, R6: 0.89 vs 0.75, 0.81, 0.80, 0.63; p <0.01). The AI system also achieved an AUC of 0.85 in the prospective dataset. With the assistance of the system, the diagnostic performances and inter-observer agreement of the radiologists was improved (AUC of R3, R5, R6: 0.75 to 0.83, 0.80 to 0.85, 0.63 to 0.69; p<0.01). Conclusion: The AI system could be a useful tool in diagnosing malignant STTs, and could also help radiologists improve diagnostic performance.

Granulomatous mastitis and pectoralis major muscle defect following polyacrylamide hydrogel injection: a case report and literature review.

Background: Breast augmentation through the injection of polyacrylamide hydrogel (PAAG) was a popular procedure in the past, but it has since been prohibited due to various complications, including masses, migration, infection, inflammation, and even cancer. However, there were rare cases of granulomatous mastitis with pectoralis major muscle defect following PAAG injection for breast augmentation. Case Description: A 40-year-old female patient presented with a swollen and suppurative mass in her left breast and was insensitive to antibiotics. She was admitted to our department for further treatment after 7 months with progressive local and general symptoms. Ultrasound imaging showed ill-defined heterogeneous echoes, and contrast-enhanced magnetic resonance imaging (MRI) revealed non-mass enhancement lesions in the multiregional distribution in Breast Imaging-Reporting and Data System 4A (BI-RADS 4A) with oedema in the retroglandular space and multiple enlarged lymph nodes in the ipsilateral axilla. Intraoperative observations revealed necrotic tissues, multiple abscesses, residual mucoid PAAG prosthesis diffused into the mammary glands and intramuscularly into the pectoralis muscle, and partial loss of pectoralis major muscle. Histopathological results revealed foreign-body granulomas accompanied by gel-like granular PAAG and proliferative inflammatory cells. She recovered after undergoing the characteristic surgical management in our center under general anesthesia and had no recurrence during the 2-year follow-up. Conclusions: This case revealed that PAAG injection for augmentation mammaplasty, even after the removal operation, could result in subsequent complications, including granulomatous mastitis and pectoralis major muscle damage. PAAG filler complications are difficult to treat, therefore, it is essential to establish appropriate and effective therapeutic procedures.

LC3-dependent extracellular vesicles promote M-MDSC accumulation and immunosuppression in colorectal cancer.

For a long time, myeloid-derived suppressor cells (MDSCs) dilated in circulation system of colorectal cancer (CRC) patients have been puzzling clinicians. Various evidence shows that MDSCs constitute the bulk of immunosuppression in CRC, which is related to tumor growth, adhesion, invasion, metastasis, and immune escape. However, the mechanisms underlying these cells formation remain incompletely understood. In this study, we reported that CRC cell-derived LC3-dependent extracellular vesicles (LDEVs)-mediated M-MDSCs formation via TLR2-MYD88 pathway. Furthermore Hsp60 was the LDEVs surface ligand that triggered these MDSCs induction. In clinical studies, we reported that accumulation of circulating M-MDSCs as well as IL-10 and arginase1 secretion were reliant upon the levels of tumor cell-derived LDEVs in CRC patients. These findings indicated how local tumor cell-derived extracellular vesicles influence distal hematopoiesis and provided novel justification for therapeutic targeting of LDEVs in patients with CRC.

Prediction models for postoperative recurrence of non-lactating mastitis based on machine learning.

OBJECTIVES: This study aims to build a machine learning (ML) model to predict the recurrence probability for postoperative non-lactating mastitis (NLM) by Random Forest (RF) and XGBoost algorithms. It can provide the ability to identify the risk of NLM recurrence and guidance in clinical treatment plan. METHODS: This study was conducted on inpatients who were admitted to the Mammary Department of Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine between July 2019 to December 2021. Inpatient data follow-up has been completed until December 2022. Ten features were selected in this study to build the ML model: age, body mass index (BMI), number of abortions, presence of inverted nipples, extent of breast mass, white blood cell count (WBC), neutrophil to lymphocyte ratio (NLR), albumin-globulin ratio (AGR) and triglyceride (TG) and presence of intraoperative discharge. We used two ML approaches (RF and XGBoost) to build models and predict the NLM recurrence risk of female patients. Totally 258 patients were randomly divided into a training set and a test set according to a 75%-25% proportion. The model performance was evaluated based on Accuracy, Precision, Recall, F1-score and AUC. The Shapley Additive Explanations (SHAP) method was used to interpret the model. RESULTS: There were 48 (18.6%) NLM patients who experienced recurrence during the follow-up period. Ten features were selected in this study to build the ML model. For the RF model, BMI is the most important influence factor and for the XGBoost model is intraoperative discharge. The results of tenfold cross-validation suggest that both the RF model and the XGBoost model have good predictive performance, but the XGBoost model has a better performance than the RF model in our study. The trends of SHAP values of all features in our models are consistent with the trends of these features' clinical presentation. The inclusion of these ten features in the model is necessary to build practical prediction models for recurrence. CONCLUSIONS: The results of tenfold cross-validation and SHAP values suggest that the models have predictive ability. The trend of SHAP value provides auxiliary validation in our models and makes it have more clinical significance.

Corrigendum: The oxidative aging model integrated various risk factors in type 2 diabetes mellitus at system level.

[This corrects the article DOI: 10.3389/fendo.2023.1196293.].

ITPRIPL1 binds CD3ε to impede T cell activation and enable tumor immune evasion.

Cancer immunotherapy has transformed treatment possibilities, but its effectiveness differs significantly among patients, indicating the presence of alternative pathways for immune evasion. Here, we show that ITPRIPL1 functions as an inhibitory ligand of CD3ε, and its expression inhibits T cells in the tumor microenvironment. The binding of ITPRIPL1 extracellular domain to CD3ε on T cells significantly decreased calcium influx and ZAP70 phosphorylation, impeding initial T cell activation. Treatment with a neutralizing antibody against ITPRIPL1 restrained tumor growth and promoted T cell infiltration in mouse models across various solid tumor types. The antibody targeting canine ITPRIPL1 exhibited notable therapeutic efficacy against naturally occurring tumors in pet clinics. These findings highlight the role of ITPRIPL1 (or CD3L1, CD3ε ligand 1) in impeding T cell activation during the critical "signal one" phase. This discovery positions ITPRIPL1 as a promising therapeutic target against multiple tumor types.

Identification of pyruvic and maleic acid as potential markers for disease activity and prognosis in chronic urticaria.

BACKGROUND: Population-based studies have highlighted the link between chronic urticaria (CU) and metabolic syndrome, and metabolic alterations have been revealed in CU. However, to our knowledge, a comprehensive metabolomics study on a large cohort of patients with CU has not been reported. OBJECTIVE: We sought to explore the underlying metabolic subtypes and novel metabolite biomarkers for CU diagnosis and therapy. METHODS: Plasma samples from 80 patients with CU and 82 healthy controls were collected for metabolomics quantification and bioinformatics analysis. Another independent cohort consisting of 144 patients with CU was studied to validate the findings. Bone marrow-derived mast cells and mice with IgE-induced passive cutaneous anaphylaxis were used for in vitro and in vivo experiments, respectively. RESULTS: We observed clear metabolome differences between CU patients and healthy controls. Meanwhile, differential metabolites N6-acetyl-l-lysine, l-aspartate, maleic acid, and pyruvic acid were used to construct random forest classifiers and achieved area under receiver operating characteristic curve values greater than 0.85, suggesting their potential as diagnostic biomarkers of CU. More importantly, by exploring the underlying metabolic subtypes of CU, we found that the low abundance of pyruvic acid and maleic acid was significantly related to the activity of CU, poor efficacy of second-generation H1 antihistamines, and short relapse-free time. The results were validated in the independent cohort. Moreover, supplementation with pyruvate or maleate could significantly attenuate IgE-mediated mast cell activation in vitro and in vivo. CONCLUSIONS: Plasma pyruvic acid and maleic acid may be effective biomarkers for predicting disease activity, therapeutic efficacy, and prognosis for patients with CU.

Staged operation in the surgical treatment of granulomatous lobular mastitis.

Background: Granulomatous lobular mastitis (GLM) is a chronic inflammatory breast condition characterized by an unclear etiology and an undefined therapeutic approach. Surgical intervention is considered an alternative modality for managing GLM. Staged operation is the predominant and characteristic surgical approach in the treatment of GLM in our center; therefore, we evaluated the efficacy of staged operative techniques in this cohort study. Methods: We retrospectively reviewed 212 patients with GLM who underwent staged operation between August 2020 and July 2022 in the inpatient department of our institute. Their clinical history information, clinic complaints, treatment details, surgical outcomes, follow-up results, and scores on the satisfaction questionnaire were analyzed. The patients were called for follow-up and consultation with a deadline of August 2023. Results: The median follow-up time was 27 months (range, 14-37 months). In total, 212 patients were treated with three different staged procedures according to the individual assessment and patient willingness, including 168 patients who underwent one-stage debridement operation and two-stage suture operation (DO + SO), 25 patients who underwent one-stage debridement operation without suture (DO), and 19 patients who underwent one-stage debridement and simultaneous suture operation (DSO). The median recovery time was 29 days (range, 14-60 days). A minority of patients developed postoperative complications, including effusion (1.89%), flap ischemia (0.94%), areola-nipple ischemia (0.94%) and sinus tract formation (2.36%). The scores of the satisfaction questionnaire were 43.10±3.09, and 186 patients (87.74%) gave high scores for postoperative breast appearance. Only 5 of 212 patients (2.36%) developed recurrence. Conclusions: Staged operation performed in our institute is an effective and safe surgical therapy in patients with GLM, yielding a short recovery time, low recurrence and good cosmetic results.

Effects of light qualities on growth and physiological-biochemical traits of Scutellaria baicalensis.

Canopy spectral composition significantly affects growth and functional traits of understory plants. In this study, we explored the optimal light condition suitable for enhancing Scutellaria baicalensis's yield and quality, aiming to provide scientific reference for the exploitation and utilization of medicinal plant resources in the understory of forests. We measured the responses of growth, morphology, biomass allocation, physiological traits, and secon-dary metabolites of S. baicalensis to different light qualities. S. baicalensis was cultured under five LED-light treatments including full spectrum light (control), ultraviolet-A (UV-A) radiation, blue, green, and red light. Results showed that UV-A significantly reduced plant height, base diameter, leaf thickness, leaf area ratio, and biomass of each organ. Red light significantly reduced base diameter, biomass, effective quantum yield of photosystem Ⅱ (ФPSⅡ), and total flavonoid concentration. Under blue light, root length and total biomass of S. baicalensis significantly increased by 48.0% and 10.8%, respectively, while leaf number and chlorophyll content significantly decreased by 20.0% and 31.6%, respectively. The other physiological and biochemical traits were consistent with their responses in control. Our results suggested that blue light promoted photosynthesis, biomass accumulation, and secondary metabolite synthesis of S. baicalensis, while red light and UV-A radiation negatively affected physiological and biochemical metabolic processes. Therefore, the ratio of blue light could be appropriately increased to improve the yield and quality of S. baicalensis.

The Value of Nerve Ultrasound to Diagnose and Follow Up the Multifocal Neurolyphomatosis in the Upper Limb---- Case Report and Literature Review.

INTRODUCTION: Neurolymphomatosis (NL) is a rare disease. Ultrasound (US) plays a crucial role in diagnosing and following up the NL. CASE PRESENTATION: A 59-year-old man was hospitalized with acute pain in the left upper extremity. Ultrasound revealed segmental swelling of multiple nerves around his left elbow with abundant blood flow signals. Contrast-Enhanced Ultrasound (CEUS) showed a rapid, complete and homogenous enhancement in the nerve lesions in the early arterial phase. The NL was confirmed by imaging and flow cytometry, and he accepted chemotherapy. The posttherapeutic ultrasound showed that the nerves in the left upper limb were basically normal. Unfortunately, the patient died of cerebral metastasis in 5 months. CONCLUSION: The nerve US and CEUS can show specific manifestations and provide more diagnostic information about NL.

The efficacy and safety of vincristine, irinotecan and anlotinib in Epithelioid Sarcoma.

BACKGROUND: Epithelioid sarcoma is a rare soft tissue sarcoma characterized by SMARCB1/INI1 deficiency. Much attention has been paid to the selective EZH2 inhibitor tazemetostat, where other systemic treatments are generally ignored. To explore alternative treatment options, we studied the effects of irinotecan-based chemotherapy in a series of epithelioid sarcoma patients. METHODS: We retrospectively reviewed data from patients with metastatic or unresectable epithelioid sarcoma at the Peking University People's Hospital treated with irinotecan (50 mg/m2/d d1-5 Q3W) in combination with Anlotinib (12 mg Qd, 2 weeks on and 1 week off) from July 2015 to November 2021. RESULTS: A total of 54 courses were administered. With a median follow up of 21.2 months (95% CI, 12.2, 68.1), the 5-year overall survival rate was 83.3%. Five of eight (62.5%) patients presented with unresectable localized lesions, including local tumor thrombosis and lymphatic metastasis. The other patients had unresectable pulmonary metastases. Six of eight (75%) patients had progressed following two lines of systemic therapy. The objective response rate reached 37.5% (three of eight patients) while stabilized disease was observed in 62.5% (five of eight) of patients. No patient had progressed at initial evaluation. At the last follow up, two patients were still using the combination and three patients had ceased the therapy due to toxicities such as diarrhea, nausea, and emesis. One patient changed to tazemetostat for maintenance and one patient stopped treatment due to coronavirus disease 2019 (COVID-19). Another patient stopped therapy as residual lesions had been radiated. CONCLUSIONS: The combination of irinotecan and Anlotinib as a salvage regimen may be considered another effective treatment option for refractory epithelioid sarcoma. TRIAL REGISTRATION: This study was approved in the Medical Ethics Committee of Peking University People's Hospital on October 28, 2022 (No.: 2022PHD015-002). The study was registered in Clinicaltrials.gov with identifier no. NCT05656222.

Postnatal treatment and evolution patterns of giant fetal hepatic hemangioma: a case series of 29 patients.

OBJECTIVES: To explore the clinical characteristics, postnatal treatment and prognosis of giant fetal hepatic hemangioma (GFHH). METHOD: Retrospective analysis was performed on children with giant fetal hepatic hemangioma (maximum tumor diameter > 40 mm) diagnosed by prenatal ultrasound and MRI from December 2016 to December 2020. These patients were observed and treated at the Children's Hospital of Fudan University after birth. The clinical data were collected to analyze the clinical characteristics, treatment, and prognosis of GFHH using independent sample t tests or Fisher's exact tests. RESULTS: Twenty-nine patients who were detected by routine ultrasound in the second and third trimester of pregnancy with giant fetal hepatic hemangiomas were included. The first prenatal ultrasound diagnosis of gestational age was 34.0 ± 4.3 weeks, ranging from 22 to 39 weeks. Of the patients, 28 had focal GFHHs and 1 had multifocal GFHHs. Surgery was performed, and the diagnosis was confirmed histopathologically in two patients. There were 8 cases with echocardiography-based evidence of pulmonary hypertension, 11 cases had a cardiothoracic ratio > 0.6, and 4 cases had hepatic arteriovenous fistula (AVF). The median follow-up time was 37 months (range: 14-70 months). During the follow-up, 12 patients received medical treatment with propranolol as the first-line therapy. The treatment group had a higher ratio of cardiothoracic ratio > 0.6 (P = 0.022) and lower albumin levels (P = 0.018). Four (14.8%) lesions showed postnatal growth before involuting. Complete response was observed in 13 (13/29) patients, and partial response was observed in 16 (16/29) patients. CONCLUSIONS: Fetal giant hepatic hemangioma is mainly localized, and its clinical outcome conforms to RICH (rapidly involuting) and PICH (partially involuting), but some fetal giant hepatic hemangiomas will continue to grow after birth and then gradually decrease. For uncomplicated giant fetal hepatic hemangioma, postnatal follow-up is the main concern, while those with complications require aggressive medical treatment. Propranolol may have no effect on the volume change of GFHH.

Application of Machine Learning and Deep EfficientNets in Distinguishing Neonatal Adrenal Hematomas From Neuroblastoma in Enhanced Computed Tomography Images.

Background: The aim of the study was to employ a combination of radiomic indicators based on computed tomography (CT) imaging and machine learning (ML), along with deep learning (DL), to differentiate between adrenal hematoma and adrenal neuroblastoma in neonates. Methods: A total of 76 neonates were included in this retrospective study (40 with neuroblastomas and 36 with adrenal hematomas) who underwent CT and divided into a training group (n = 38) and a testing group (n = 38). The regions of interest (ROIs) were segmented by two radiologists to extract radiomics features using Pyradiomics package. ML classifications were done using support vector machine (SVM), AdaBoost, Extra Trees, gradient boosting, multi-layer perceptron (MLP), and random forest (RF). EfficientNets was employed and classified, based on radiometrics. The area under curve (AUC) of the receiver operating characteristic (ROC) was calculated to assess the performance of each model. Results: Among all features, the least absolute shrinkage and selection operator (LASSO) logistic regression selected nine features. These radiomics features were used to construct radiomics model. In the training cohort, the AUCs of SVM, MLP and Extra Trees models were 0.967, 0.969 and 1.000, respectively. The corresponding AUCs of the test cohort were 0.985, 0.971 and 0.958, respectively. In the classification task, the AUC of the DL framework was 0.987. Conclusion: ML decision classifiers and DL framework constructed from CT-based radiomics features offered a non-invasive method to differentiate neonatal adrenal hematoma from neuroblastoma and performed better than the clinical experts.

Gut microbiota facilitate chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) comes with gut dysbiosis, but its relevance remains elusive. Here we use metagenomics sequencing and short-chain fatty acids metabolomics and assess the effects of human CSU fecal microbial transplantation, Klebsiella pneumoniae, Roseburia hominis, and metabolites in vivo. CSU gut microbiota displays low diversity and short-chain fatty acids production, but high gut Klebsiella pneumoniae levels, negatively correlates with blood short-chain fatty acids levels and links to high disease activity. Blood lipopolysaccharide levels are elevated, link to rapid disease relapse, and high gut levels of conditional pathogenic bacteria. CSU microbiome transfer and Klebsiella pneumoniae transplantation facilitate IgE-mediated mast cell(MC)-driven skin inflammatory responses and increase intestinal permeability and blood lipopolysaccharide accumulation in recipient mice. Transplantation of Roseburia hominis and caproate administration protect recipient mice from MC-driven skin inflammation. Here, we show gut microbiome alterations, in CSU, may reduce short-chain fatty acids and increase lipopolysaccharide levels, respectively, and facilitate MC-driven skin inflammation.

Adolescent Non-Puerperal Mastitis: Risk Factors, Clinical Characteristics, and Prognosis Analysis.

Purpose: To determine the risk factors, clinical characteristics, and prognosis of adolescent non-puerperal mastitis patients. Patients and methods: A retrospective analysis was conducted on 10 cases of NPM in adolescents who underwent surgical treatment at Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine from August 2021 to August 2023. We analyze the patient's general information, clinical characteristics, related medical history, laboratory indicators, breast magnetic resonance imaging examination, postoperative pathology, prognosis, etc. Results: The clinical manifestations of NPM in adolescents mainly included redness, swelling and pain in the breasts, congenital nipple retraction, and extensive lesion range. Inflammatory markers and prolactin were elevated. Magnetic resonance imaging showed circular enhancement with abscess formation as the main type. All patients underwent surgical treatment with a fast recovery time after surgery. No recurrence was observed during follow-up and the postoperative breast appearance was satisfactory. Multivariate Logistic regression analysis indicated that congenital nipple retraction, elevated prolactin levels and trauma were independent risk factors for adolescents non-puerperal mastitis. Conclusion: Adolescent non-puerperal mastitis is a rare and unique type. Summarizing its main risk factors, clinical characteristics, and prognosis provides a basis for further research.

Deciphering the Immune Microenvironment at the Forefront of Tumor Aggressiveness by Constructing a Regulatory Network with Single-Cell and Spatial Transcriptomic Data.

The heterogeneity and intricate cellular architecture of complex cellular ecosystems play a crucial role in the progression and therapeutic response of cancer. Understanding the regulatory relationships of malignant cells at the invasive front of the tumor microenvironment (TME) is important to explore the heterogeneity of the TME and its role in disease progression. In this study, we inferred malignant cells at the invasion front by analyzing single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) data of ER-positive (ER+) breast cancer patients. In addition, we developed a software pipeline for constructing intercellular gene regulatory networks (IGRNs), which help to reduce errors generated by single-cell communication analysis and increase the confidence of selected cell communication signals. Based on the constructed IGRN between malignant cells at the invasive front of the TME and the immune cells of ER+ breast cancer patients, we found that a high expression of the transcription factors FOXA1 and EZH2 played a key role in driving tumor progression. Meanwhile, elevated levels of their downstream target genes (ESR1 and CDKN1A) were associated with poor prognosis of breast cancer patients. This study demonstrates a bioinformatics workflow of combining scRNA-seq and ST data; in addition, the study provides the software pipelines for constructing IGRNs automatically (cIGRN). This strategy will help decipher cancer progression by revealing bidirectional signaling between invasive frontline malignant tumor cells and immune cells, and the selected signaling molecules in the regulatory network may serve as biomarkers for mechanism studies or therapeutic targets.

A new insight into material basis of rhizoma Paridis saponins in alleviating pain.

ETHNOPHARMACOLOGICAL RELEVANCE: Paris polyphylla, as a traditional Chinese herbal medicine, was often used to relieve inflammation and pain. Rhizoma Paridis saponins (RPS) as the main active components of Paris polyphylla have excellent analgesic effects. AIM OF THE STUDY: Determine the analgesic material basis of RPS. MATERIALS AND METHODS: LC-MS/MS was used to analyze RPS, plasma after intravenous injection of RPS, and oral administration of RPS. H22 plantar pain model was established to explore the analgesic material basis of RPS. Moreover, correlation analysis, network pharmacology, RT-PCR and molecular docking were applied in this research. RESULTS: RPS had dose-dependently analgesic effects in acetic acid- and formalin-induced pain models. LC-MS/MS detection indicated that diosgenin as the metabolite of RPS mainly distributed in brain tissues. The addition of antibiotics increased the anti-tumor effect of RPS, but reduced its analgesic effect. Network pharmacology, RT-PCR and molecular docking showed that diosgenin exerted its analgesic effect through SRC and Rap1 signaling pathway. CONCLUSION: Diosgenin exhibited analgesic effects, while saponins had good anti-tumor effects in RPS. This discovery provided a better indication for the later application of RPS in anti-tumor and analgesic settings.

Targeting gut microbial nitrogen recycling and cellular uptake of ammonium to improve bortezomib resistance in multiple myeloma.

The gut microbiome has been found to play a crucial role in the treatment of multiple myeloma (MM), which is still considered incurable due to drug resistance. In previous studies, we demonstrated that intestinal nitrogen-recycling bacteria are enriched in patients with MM. However, their role in MM relapse remains unclear. This study highlights the specific enrichment of Citrobacter freundii (C. freundii) in patients with relapsed MM. Through fecal microbial transplantation experiments, we demonstrate that C. freundii plays a critical role in inducing drug resistance in MM by increasing levels of circulating ammonium. The ammonium enters MM cells through the transmembrane channel protein SLC12A2, promoting chromosomal instability and drug resistance by stabilizing the NEK2 protein. We show that furosemide sodium, a loop diuretic, downregulates SLC12A2, thereby inhibiting ammonium uptake by MM cells and improving progression-free survival and curative effect scores. These findings provide new therapeutic targets and strategies for the intervention of MM progression and drug resistance.