The combination of breast cancer PDO and mini-PDX platform for drug screening and individualized treatment.

The majority of advanced breast cancers exhibit strong aggressiveness, heterogeneity, and drug resistance, and currently, the lack of effective treatment strategies is one of the main challenges that cancer research must face. Therefore, developing a feasible preclinical model to explore tailored treatments for refractory breast cancer is urgently needed. We established organoid biobanks from 17 patients with breast cancer and characterized them by immunohistochemistry (IHC) and next generation sequencing (NGS). In addition, we in the first combination of patient-derived organoids (PDOs) with mini-patient-derived xenografts (Mini-PDXs) for the rapid and precise screening of drug sensitivity. We confirmed that breast cancer organoids are a high-fidelity three-dimension (3D) model in vitro that recapitulates the original tumour's histological and genetic features. In addition, for a heavily pretreated patient with advanced drug-resistant breast cancer, we combined PDO and Mini-PDX models to identify potentially effective combinations of therapeutic agents for this patient who were alpelisib + fulvestrant. In the drug sensitivity experiment of organoids, we observed changes in the PI3K/AKT/mTOR signalling axis and oestrogen receptor (ER) protein expression levels, which further verified the reliability of the screening results. Our study demonstrates that the PDO combined with mini-PDX model offers a rapid and precise drug screening platform that holds promise for personalized medicine, improving patient outcomes and addressing the urgent need for effective therapies in advanced breast cancer.

Early evaluation of circulating tumor DNA as marker of therapeutic efficacy and prognosis in breast cancer patients during primary systemic therapy.

BACKGROUND: We assessed the potential role of serial circulating tumor DNA (ctDNA) as a biomarker to monitor treatment response to primary systemic therapy (PST) in breast cancer and evaluated the predictive value of ctDNA to further identify patients with residual disease. METHODS: We prospectively enrolled 208 plasma samples collected at three time points (before PST, after 2 cycles of treatment, before surgery) of 72 patients with stage Ⅱ-III breast cancer. Somatic mutations in plasma samples were identified using a customized 128-gene capture panel with next-generation sequencing. The correlation between early change in ctDNA levels and treatment response or long-term clinical outcomes was assessed. RESULTS: 37 of 72 (51.4%) patients harbored detectable ctDNA alterations at baseline. Patients with complete response showed a larger decrease in ctDNA levels during PST. The median relative change of variant allele fraction (VAF) was -97.4%, -46.7%, and +21.1% for patients who subsequently had a complete response (n = 11), partial response (n = 11), and no response (n = 15) (p = 0.0012), respectively. In addition, the relative change of VAF between the pretreatment and first on-treatment blood draw exhibited the optimal predictive value to tumor response after PST (area under the curve, AUC = 0.7448, p = 0.02). More importantly, early change of ctDNA levels during treatment have significant prognostic value for patients with BC, there was a significant correlation between early decrease of VAF and longer recurrence-free survival compared to those with an VAF increase (HR = 12.54; 95% CI, 2.084 to 75.42, p = 0.0063). CONCLUSION: Early changes of ctDNA are strongly correlated with therapeutic efficacy to PST and clinical outcomes in BC patients. The integration of preoperative ctDNA evaluation could help improving the perioperative management for BC patients receiving PST.

PROTACs Targeting BRM (SMARCA2) Afford Selective In Vivo Degradation over BRG1 (SMARCA4) and Are Active in BRG1 Mutant Xenograft Tumor Models.

The identification of VHL-binding proteolysis targeting chimeras (PROTACs) that potently degrade the BRM protein (also known as SMARCA2) in SW1573 cell-based experiments is described. These molecules exhibit between 10- and 100-fold degradation selectivity for BRM over the closely related paralog protein BRG1 (SMARCA4). They also selectively impair the proliferation of the H1944 "BRG1-mutant" NSCLC cell line, which lacks functional BRG1 protein and is thus highly dependent on BRM for growth, relative to the wild-type Calu6 line. In vivo experiments performed with a subset of compounds identified PROTACs that potently and selectively degraded BRM in the Calu6 and/or the HCC2302 BRG1 mutant NSCLC xenograft models and also afforded antitumor efficacy in the latter system. Subsequent PK/PD analysis established a need to achieve strong BRM degradation (>95%) in order to trigger meaningful antitumor activity in vivo. Intratumor quantitation of mRNA associated with two genes whose transcription was controlled by BRM (PLAU and KRT80) also supported this conclusion.

Novel disulfidptosis-derived gene blueprint stratifying patients with breast cancer.

INTRODUCTION: Breast cancer remains the predominant cancer among females, accounting for about 24.2% of all cancer cases. Alarmingly, it is the primary cause of cancer-related mortality in women under 45. METHODS: This research analyzed RNA sequencing data from 1082 TCGA-BRCA and 107 GSE58812 breast cancer patients. Single-cell RNA data from five patients in the GSE118389 data set were also studied. Using Random forest and COX regression, we developed a prognostic model. Pathway analysis employed GSVA and GO, while immune profiles were assessed via ssGSEA and MCPcounter. Mutation patterns utilized maftools, and drug sensitivity scores were derived from the GDSC database with oncoPredict. RESULTS: Analysis of the GSE118389 data set identified three distinct cell types: immune, epithelial, and stromal. P53 and VEGF were notably enriched. Five key genes (TMEM251, ADAMTSL2, CDC123, PSMD1, TLE1) were pinpointed for their prognostic significance. We introduced a disulfidptosis-associated score as a novel risk factor for breast cancer prognosis. Survival outcomes varied significantly between training and validation sets. Comprehensive immune profiling revealed no difference in activated CD8-positive T cells between risk groups, but a positive correlation of NK cells, neutrophils, cytotoxic lymphocytes, and monocytic cells with the riskscore was noted. Importantly, a negative association between the drug Nelarabine and riskscore was identified. CONCLUSION: This research underscores the significance of a disulfidptosis-associated gene signature in breast cancer prognosis.

Update on the relationship between the SLC4A7 variant rs4973768 and breast cancer risk: a systematic review and meta-analysis.

OBJECTIVE: This meta-analysis aimed to update knowledge about the association between the SLC4A7 variant rs4973768 and breast cancer incidence. METHODS: Studies were identified from relevant digital databases. Fixed- or random-effects models were used to calculate odds ratios and 95% confidence intervals. Statistical Q and I2 tests and sensitivity analyses were used to detect interstudy heterogeneity and test the statistical stability of overall estimates, respectively. Egger's tests were applied to detect publication bias among included studies. In silico analysis was used to ascertain increased expression of SLC4A7 mRNA in rs4973768 with the mutant allele. Trial sequential analysis was used to calculate the study's sample size. RESULTS: The overall odds ratios reflected a positive correlation between the SLC4A7 rs4973768 polymorphism and susceptibility to breast cancer in five genetic comparisons of alleles T and C, and tests revealed significant heterogeneity in the allele comparison. After stratification by ethnicity, heterogeneity in Asian and White populations substantially decreased (Ph = 0.984, I2 = 0%) and remained stable (Ph = 0.083, I2 = 46.3%), respectively. The mutant allele was associated with increased expression of SLC4A7 mRNA in rs4973768. The cumulative z curve indicated that our conclusions were robust. CONCLUSIONS: Our updated consequence shows that the SLC4A7 rs4973768 polymorphism is associated with increased breast cancer risk.

Bioinformatics analysis reveals lipid metabolism may play an important role in the SiO2-stimulated rat model.

Silicosis is a progressive and irreversible common occupational disease caused by long-term inhalation of a large amount of free silica dust. Its pathogenesis is complex, and the existing prevention and treatment methods can not effectively improve silicosis injury. To uncover potential differential genes in silicosis, SiO2-stimulated rats and their control original transcriptomic data sets GSE49144, GSE32147 and GSE30178 were downloaded for further bioinformatics analysis. We used R packages to extract and standardize transcriptome profiles, then screened differential genes, and enriched GO and KEGG pathways through clusterProfiler packages. In addition, we investigated the role of lipid metabolism in the progression of silicosis by qRT-PCR validation and transfection with si-CD36. A total of 426 differential genes were identified in this study. Based on GO and KEGG enrichment analysis, it was found that lipid and atherosclerosis were significantly enriched. qRT-PCR was used to detect the relative expression level of differential genes in this signaling pathway of silicosis rat models. mRNA levels of Abcg1, Il1b, Sod2, Cyba, Cd14, Cxcl2, Ccl3, Cxcl1, Ccl2 and CD36 increased, mRNA levels of Ccl5, Cybb and Il18 decreased. In addition, at the cellular level, SiO2-stimulated lead to lipid metabolism disorder in NR8383, and silencing CD36 inhibited SiO2-induced lipid metabolism disorder. These results indicate that lipid metabolism plays an important role in the progression of silicosis, and the genes and pathways reported in this study may provide new ideas for the pathogenesis of silicosis.

USF1-CHCHD4 axis promotes lung adenocarcinoma progression partially via activating the MYC pathway.

BACKGROUND: This study aimed to identify genes related to lung adenocarcinoma (LUAD) and investigate the effects and molecular mechanisms of coiled-coil-helix-coiled-coil-helix domain containing 4 (CHCHD4) in the progression of LUAD. METHODS: The GEPIA database was used to evaluate the differential expression of CHCHD4 and the survival data of LUAD patients compared to controls. TCGA-LUAD database, JASPAR website, and GSEA were used to analyse the relationship between CHCHD4 and the upstream stimulating factor 1 (USF1) or MYC pathways. The proliferation, apoptosis, migration, and invasion of LUAD cells were evaluated using cell counting kit-8, 5-ethynyl-2'-deoxyuridine, colony formation, flow cytometry, wound healing, and transwell assays. qRT-PCR, western blotting, and immunohistochemistry were used to detect the mRNA and protein expression, respectively. Furthermore, xenograft tumours from nude mice were used to verify the effect of CHCHD4 on LUAD in vivo. RESULTS: CHCHD4 overexpression was found in LUAD tumor tissues and cells, and high CHCHD4 was associated with a poor prognosis. Interestingly, CHCHD4 knockdown suppressed the malignant phenotype of the LUAD cells. Moreover, we found that USF1 upregulated CHCHD4 and promoted LUAD progression. CHCHD4 knockdown also inhibited the progression of LUAD. In addition, CHCHD4 knockdown suppressed xenograft tumour growth. CONCLUSION: USF1-CHCHD4 axis can promote LUAD progress, which may be through activating MYC pathway.

Apolipoprotein C1 (APOC1), A Candidate Diagnostic Serum Biomarker for Breast Cancer Identified by Serum Proteomics Study.

Purpose - The present study aimed to identify differently expressed peptides involved in BC as potential biomarkers. Experimental Design - The serum proteomic profiling of 128 serum samples from 64 BC patients and 64 healthy controls (HC), using magnetic beads based immobilized metal ion affinity chromatography (MB-IMAC-Cu) separation followed by MALDI-TOF MS. ClinProTools software identified a number of distinct markers. Then, we performed liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) to identify the candidate serum biomarker based on serum proteomics analysis. Finally, enzyme-linked immunosorbent assays (ELISAs) were used to verify the expression of the candidate serum biomarker in BC patients. Results - BC patients could be identified with sensitivity of 87.32% and specificity of 89.46%. Of 41 m/z peaks that differed between BC and HC, six peaks were significantly different between BC and HC (P < 0.01, fold change > 1.5), with peak 1 upregulated and peaks 2-6 downregulated in the BC group. The upregulated peak 1 (m/z: 6638.63) is identified as a region of apolipoprotein C1 (APOC1), and validation showed that APOC1 expression increased from healthy controls to those with FA as well as mastopathy, and finally BC patients. Conclusions and Clinical Relevance - The present study indicates that APOC1 could serve as a candidate serum diagnostic biomarker for BC.

Ultrasound targeted microbubble destruction-mediated SOCS3 attenuates biological characteristics and epithelial-mesenchymal transition (EMT) of breast cancer stem cells.

SOCS3 is low-expressed in breast cancer and may be a potential target. Ultrasound targeted microbubble destruction (UTMD) improved the efficiency of gene transfection. We explored the effects of UTMD-mediated transfection of SOCS3 on the biological characteristics and epithelial-mesenchymal transition (EMT) of breast cancer stem cells (BCSCs). The expression of SOCS3 in breast cancer (BC) and its association with prognosis were evaluated by GEPIA and The Cancer Genome Atlas (TCGA) websites. BCSCs were sorted by flow cytometry and immunomagnetic bead method, followed by sphere formation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and xenograft assays to test their effects in vitro and in vivo. The levels of SOCS3, EMT- and STAT3 pathway-related genes were determined by RT-qPCR and Western blot, respectively. The effects of liposome and UTMD on BCSCs and mice were compared by the gain-of-function experiments. Low expression of SOCS3 was associated with poor prognosis of BC patients, and found in BC and BCSCs. BCSCs were successfully sorted, with high viability and tumorigenicity. UTMD increased the transfection rate of SOCS3. Moreover, UTMD- and liposome-mediated SOCS3 reduced cell viability, proliferation, migration and invasion, blocked cell cycle, inhibited sphere formation in BCSCs, and retarded tumor growth in mice. Mechanistically, overexpressed SOCS3 inhibited the expressions of EMT-related genes and the activation of STAT3 pathway in BCSCs and mice. The regulatory effects of UTMD-mediated SOCS3 on the above-mentioned biological characteristics were better than liposome-mediated SOCS3. UTMD-mediated SOCS3 has a better therapeutic effect in BC, providing new experimental evidence for the treatment of BC.

Mesenchymal stem cell-derived exosome mir-342-3p inhibits metastasis and chemo-resistance of breast cancer through regulating ID4.

BACKGROUND: The mesenchymal stem cell-derived exosome (MSCs-exo) carrying microRNAs have been proved to regulate tumor biological activities. Clarifying molecular mechanism and identifying predictive microRNAs will be of great value in anti-tumor therapy improvement. OBJECTIVE: We aimed to investigate the regulatory role of microRNA-342-3p (miR-342-3p) in MSCs-exo on breast cancer. METHODS: Breast cancer tissues and cell lines were used to evaluate miR-342-3p expression in patients with or without lymph node/distal organ metastasis. The impact of MSCs-exo expression on tumor cell chemo-resistance and invasion/migration was measured. Dual-luciferase reporter gene assay was applied to identify binding site. Inhibitor of differentiation 4 (ID4) siRNA and miR-342-3p inhibitor transfection was conducted to further explore the miR-342-3p/ID4 axis on chemo-resistance and metastasis of breast cancer cells. RESULTS: Breast cancer cells revealed significantly lower level of miR-342-3p in patients with metastatic diseases. miR-342-3p suppressed invasive and chemo-resistant behavior of breast cancer tumor cells. Binding site between miR-342-3p and ID4 was proved. ID4 could reverse the influence of miR-342-3p on chemo-resistance. The tumor inhibition effect of IDA siRNA in vivo was also identified. CONCLUSIONS: This study demonstrated that miR-342-3p acted as potential tumor suppressor by inhibiting metastasis and chemo-resistance of breast cancer cells through targeting ID4. This study might provide potential therapy targets for the treatment of breast cancer.

ARHGEF19 promotes the growth of breast cancer in vitro and in vivo by the MAPK pathway.

OBJECTIVE: To assess the expression of ARHGEF19 in human breast cancer, investigate its role in breast cancer, and clarify the mechanism. METHODS: Bioinformatics analysis, immunoblot, quantitative PCR, and immunohistochemical (IHC) assays were performed to assess ARHGEF19 expression in breast cancer. CCK-8 and Edu assays were conducted to reveal its role in breast cancer cell proliferation. Flow cytometry (FCM) assays and immunoblot were performed to confirm its effects on breast cancer apoptosis. Immunoblot was also performed to clarify the mechanism. Finally, tumor growth assays were aimed to confirm the role of ARHGEF19 in mice. RESULTS: We observed that ARHGEF19 was highly expressed in human breast cancer. ARHGEF19 promoted breast cancer cell growth in vitro, and suppressed apoptosis. In addition, we found that ARHGEF19 could activate the MAPK pathway in breast cancer cells. Our findings further confirmed that ARHGEF19 contributed to breast cancer growth in mice. CONCLUSION: We observed that ARHGEF19 promoted the growth of breast cancer in vitro and in vivo via MAPK pathway, and presume it could serve as a breast cancer therapeutic target.

Haemorrhagic ileal haemolymphangioma: a case report and review of the literature.

We describe herein a 37-year-old woman with a 2-week history of melena who was eventually diagnosed with ileal haemolymphangioma, a rare benign tumour. Local mucosal congestion and swelling were found through single-balloon enteroscopy, which showed an irregular protuberance approximately 10 cm long, located 3.2 m from the Treitz ligament. We performed a laparoscopic-assisted partial resection of the small intestine combined with intestinal adhesiolysis. According to postoperative pathology, the final diagnosis was ileal haemolymphangioma with haemorrhage.

Mesenchymal Stem Cell-Mediated Mitochondrial Transfer: a Therapeutic Approach for Ischemic Stroke.

Stroke is the leading cause of death and adult disability worldwide. Mitochondrial dysfunction is one of the hallmarks of stroke-induced neuronal death, and maintaining mitochondrial function is essential in cell survival and neurological progress following ischemic stroke. Stem cell-mediated mitochondrial transfer represents an emerging therapeutic approach for ischemic stroke. Accumulating evidence suggests that mesenchymal stem cells (MSCs) can directly transfer healthy mitochondria to damaged cells, and rescue mitochondrial damage-provoked tissue degeneration. This review summarizes the research on MSCs-mediated mitochondrial transfer as a therapeutic strategy against ischemic stroke.

Effects of velvet antler polypeptides on Alzheimer's disease cell model via miR-613 HDAC6 pathway.

To study the effect of velvet antler polypeptides (VAP) on Alzheimer's disease (AD) cell model, Aß25-35 was used to induce SK-N-SH cells to obtain AD cell model. The MDA, SOD, GSH-Px levels were determined using relevant kits. Flow cytometry was conducted to detect apoptosis, Western blot was employed to measure Bcl-2, Bax, HDAC6 protein expression, and qPCR was used to assay microRNA (miR)-613 and HDAC6 mRNA levels. Target Scan prediction combined with dual luciferase reporting experiments was conducted to analyze the targeting relationship between miR-613 and HDAC6. miR-613 was transfected in SK-N-SH cells; Alternatively, anti-miR-613 was transfected, followed by Aß25-35 and 80 mg/L of VAP. The AD model cells showed increased MDA content, apoptosis rate, Bax protein expression, HDAC6 mRNA and protein expression, but lower SOD, GSH-Px activities, Bcl-2 protein level, and miR-613 expression (p<0.05). VAP reduced MDA content, apoptosis rate, Bax protein expression, HDAC6 mRNA and protein expression, but enhanced SOD, GSH-Px activities, Bcl-2 protein level, and miR-613 expression (p<0.05). Over-expression of miR-613 increased SOD, GSH-Px activities, and Bcl-2 protein expression in AD model cells, but reduced HDAC6 protein levels, MDA content, apoptosis rate, and Bax protein levels (p<0.05). VAP may regulate Aß25-35-induced apoptosis so as to treat Alzheimer's disease.

Loss of HOXB3 correlates with the development of hormone receptor negative breast cancer.

BACKGROUND: The homeobox gene family, encoding a specific nuclear protein, is essential for embryonic development, differentiation, and homeostasis. The role of the HOXB3 protein varies in different tumors. This study aims to explore the role of the HOXB3 gene in breast cancer. METHOD: Differentially expressed genes were screened by analyzing metastatic breast cancer gene chip data from TCGA and GEO databases. The function of the selected HOXB3 gene was also analyzed in different databases and through molecular biology methods, such as qRT-PCR, western blot and IF to verify bioinformatics findings. RESULTS: Both bioinformatics analyses and western blot showed that HOXB3 was lost in breast cancer compared to normal breast tissue. Survival analysis also showed that lower expression of HOXB3 was associated with poor prognosis. Bioinformatics analyses further showed that HOXB3 was positively correlated with hormone receptors. Metascape for GO analysis of GEO data provided possible mechanisms that HOXB3 could positively regulate cell adhesion, inhibit cell proliferation and activate immune response in breast cancer; moreover, GSEA included several cancer-associated pathways. CONCLUSION: In summary, HOXB3 expression was decreased in breast cancer, and it was associated with poor prognosis. It might become a new biomarker to predict prognosis of breast cancer.

Effect of Organic Cage Nucleating Agent Structure on Nucleating Efficiency and the Structure-Property Relationship.

Three types of organic cage compounds, namely, cucurbit[6]uril (Q[6]), hemicucurbit[6]uril (HQ[6]), and ß-cyclodextrin (BC), with different cavity structures as heterogeneous nucleation agents were selected for a polypropylene (PP) foaming injection molding process. The experimental results showed that Q[6] with a "natural" cavity structure possessed the best nucleation efficiency of these three cage compounds. The nucleation mechanism of organic cage compounds was explored through classical nucleation theory, molecular structure, and in situ visual injection molding analysis.

Osteoblast-derived lipocalin-2 regulated by miRNA-96-5p/Foxo1 advances the progression of Alzheimer's disease.

Aim: Alzheimer's disease (AD) is the most frequent cause of dementia and characterized by the accumulation of ß-amyloid peptides in plaques and vessel walls. This study proposed a hypothesis of an inhibitory role of miR-96-5p in AD via regulating Foxo1. Methods & methods: AD mouse models were established by injecting with 1% pentobarbital. Results: Knockdown of miR-96-5p in the presence of naringin was shown to reduce the expression of Foxo1 and contents of superoxide dismutase, catalase and glutathione peroxidase, yet increase lipocalin-2 expression as well as hydroxyproline and malondialdehyde contents. Also, Foxo1-mediated lipocalin-2 inhibition attenuated AD. Conclusion: Our study shows downregulating miR-96-5p limited AD progression, highlighting miR-96-5p a potential therapeutic target in treating AD.

Association between body mass index and clinical characteristics, as well as with management, in Chinese patients with breast cancer.

OBJECTIVE: Body mass index (BMI) is a risk factor associated with breast cancer in postmenopausal women. This study aimed to identify the associations of BMI with clinical characteristics and management of breast cancer in female Chinese patients. METHODS: Clinicopathological information on 1296 women who were diagnosed with breast cancer was collected at our hospital. We recorded the clinicopathological characteristics, molecular phenotypes, manner of diagnosis, implementation rate of preoperative examinations, and surgical method used. RESULTS: Significant differences were found in the tumor size, disease stage, manner of diagnosis, implementation rate of preoperative examinations, and the surgical method among different BMI groups. In premenopausal patients, significant differences were found in the distribution of molecular phenotypes and surgical approach among different BMI groups. In postmenopausal patients, different BMI groups showed significant differences in the tumor size, disease stage, distribution of molecular phenotypes, manner of diagnosis, rate of implementation of preoperative mammography, and surgical method. CONCLUSION: Higher BMI is associated with a larger tumor size, more advanced disease stage, diagnosis by physical examination, higher implementation rate of preoperative examinations, and lower radical surgery rate in Chinese women with breast cancer. However, the relationship between BMI and molecular phenotypes differs between pre- and postmenopausal women.

Accessory spleen originating from the intrinsic muscularis of the stomach misdiagnosed as gastrointestinal stromal tumor: a case report.

A 34-year-old man presented to our hospital with a 2-month history of repeated dull upper abdominal pain. Gastroscopy and endoscopic ultrasonography indicated a hemispherical mass at the junction of the greater curvature and the gastric fundus, with hypoechogenicity originating from the intrinsic muscular layer. He was diagnosed with a gastric body submucosal lesion and gastrointestinal stromal tumor, and underwent endoscopic full-thickness resection. However, postoperative pathological examination of the mass unexpectedly revealed heterotopic spleen tissue (accessory spleen). Intragastric ectopic spleen tissue originating from the intrinsic muscular layer of the stomach is a rare clinical condition, with no specific clinical symptoms. This finding is of great clinical significance for the identification of gastric submucosal tumors.