Hi-C profiling in tissues reveals 3D chromatin-regulated breast tumor heterogeneity and tumor-specific looping-mediated biological pathways.

Current knowledge in three-dimensional (3D) chromatin regulation in normal and disease states was mostly accumulated through Hi-C profiling in in vitro cell culture system. The limitations include failing to recapitulate disease-specific physiological properties and often lacking clinically relevant disease microenvironment. In this study, we conduct tissue-specific Hi-C profiling in a pilot cohort of 12 breast tissues comprising of two normal tissues (NTs) and ten ER+ breast tumor tissues (TTs) including five primary tumors (PTs), and five tamoxifen-treated recurrent tumors (RTs). We find largely preserved compartments, highly heterogeneous topological associated domains (TADs) and intensively variable chromatin loops among breast tumors, demonstrating 3D chromatin-regulated breast tumor heterogeneity. Further cross-examination identifies RT-specific looping-mediated biological pathways and suggests CA2, an enhancer-promoter looping (EPL)-mediated target gene within the bicarbonate transport metabolism pathway, might play a role in driving the tamoxifen resistance. Remarkably, the inhibition of CA2 not only impedes tumor growth both in vitro and in vivo , but also reverses chromatin looping. Our study thus yields significant mechanistic insights into the role and clinical relevance of 3D chromatin architecture in breast cancer endocrine resistance.

A multicenter study of the mid-term outcomes of patients with uncomplicated type B aortic dissection after distal porous Talos stent-graft implantation.

OBJECTIVES: The Talos stent-graft has extended length to improve aortic remodeling, and distal porous design to decrease the rate of spinal cord ischemia. This study retrospectively analyzed its mid-term outcomes for uncomplicated type B aortic dissection in a multicenter study. METHODS: The primary safety endpoint was 30-day major adverse events, including all-cause mortality, dissection-related mortality, conversion to open surgery, and device-related adverse events. The primary efficacy endpoint was treatment success at 12 months post-operation, defined as no technical failure or secondary dissection-related reintervention. The survival status of the patients was visualized using the Kaplan-Meier curve. Aortic growth was assessed at four levels, and spinal cord ischemia was evaluated at 12 months. RESULTS: 113 patients participated with a mean age of 54.4 (11.1) years and 71.7% (81/113) were male. The 30-day mortality was 0.9% (1/113), no conversions to open surgery or device-related adverse events were recorded. The 12-month treatment success rate was 99.1% (112/113), with no dissection-related reinterventions. There was no spinal cord or visceral ischemia at 12 months. At a median of 34 months follow-up, 9 further deaths were recorded and the 3-year survival rate was 91.7%. The percentage of aortic growth was 1.8% (2/111) at the tracheal bifurcation, 3.6% (4/111) below the left atrium, 6.0% (5/83) above the celiac artery, and 12.1% (9/74) below the lower renal artery. The total thrombosis rate of the false lumen at the stented segment was 80.5% (91/113). CONCLUSIONS: The results showed satisfactory results of Talos stent-graft in terms of safety and efficacy. More data are needed to confirm the long-term performance.

Mid-term results of a prospective study for aortic dissection with a gutter-plugging chimney stent graft.

OBJECTIVES: Our goal was to access early and mid-term outcomes of a gutter-plugging chimney stent graft for treatment of Stanford type B aortic dissections in the clinical trial Prospective Study for Aortic Arch Therapy with stENt-graft for Chimney technology (PATENCY). METHODS: Between October 2018 and March 2022, patients with Stanford type B aortic dissections were treated with the Longuette chimney stent graft in 26 vascular centres. The efficiency and the incidence of adverse events over 12 months were investigated. RESULTS: A total of 150 patients were included. The technical success rate was 99.33% (149/150). The incidence of immediate postoperative endoleak was 5.33% (8/150, type I, n = 6; type II, n = 1; type IV, n = 1) neurologic complications (stroke or spinal cord ischaemia); the 30-day mortality was 0.67% (1/150) and 1.33% (2/150), respectively. During the follow-up period, the median follow-up time was 11.67 (5-16) months. The patent rate of the Longuette graft was 97.87%. Two patients with type I endoleak underwent reintervention. The follow-up rate of the incidence of retrograde A type aortic dissection was 0.67% (1/150). There was no paraplegia, left arm ischaemia or stent migration. CONCLUSIONS: For revascularization of the left subclavian artery, the Longuette chimney stent graft can provide an easily manipulated, safe and effective endovascular treatment. It should be considered a more efficient technique to prevent type Ia endoleak. Longer follow-up and a larger cohort are needed to validate these results. CLINICAL TRIAL REGISTRY NUMBER: NCT03767777.

Erianin inhibits tumor growth by promoting ferroptosis and inhibiting invasion in hepatocellular carcinoma through the JAK2/STAT3/SLC7A11 pathway.

Iron has been found to be involved in the tumor cell proliferation process, which can lead to the increased sensitivity of cancer cells to ferroptosis. Since erianin is associated with oxidative stress in hepatocellular carcinoma (HCC), we hypothesized that the therapeutic effect and mechanism of erianin on HCC is related to ferroptosis. HCC cells were stimulated with increase of erianin concentrations for 24 h, and the survival rates of Huh-7 and HepG2 cells gradually decreased. After intervention with different doses of erianin, cell proliferation, clone number, and invasion were prominently decreased, apoptosis ratio was increased. Moreover, Nec-1, CQ, and Z-VAD had no effect on the cell viability induced by erianin, while the combination of ferroptosis inhibitors (deferoxamine mesylate, ferrostatin-1, and liproxstatin-1) and erianin prominently increased cell survival rate. Erianin pretreatment induced ferroptosis by enhancing reactive oxygen species, MDA, and Fe2+ levels, and reducing GSH levels. Erianin activated JAK2/STAT3 pathway and inhibited SLC7A11 and GPX4 expression, thereby inducing ferroptosis. Besides, tumor growth was significantly inhibited in the erianin-treated mice, and there was no obvious toxicity in the mice. Erianin reduced proliferation and invasion of HCC cells by inducing ferroptosis by blocking the JAK2/STAT3/SLC7A11 pathway, thereby impeding tumor growth.

Cold-inducible RNA-binding protein induces inflammatory responses via NF-κB signaling pathway in normal human bronchial epithelial cells infected with streptococcus pneumoniae.

BACKGROUND: Community-acquired pneumonia causes significant illness and death worldwide, requiring further investigation and intervention. The invasion of Streptococcus pneumoniae (S. pneumoniae, S.p) can lead to serious conditions like meningitis, sepsis, or pneumonia. Extracellular Cold-inducible RNA-binding protein (eCIRP) acts as a damage-associated molecular pattern that triggers inflammatory responses and plays an important role in both acute and chronic inflammatory diseases. It remains unclear whether CIRP is involved in the process of S. pneumoniae infection in normal human bronchial epithelial cells (BEAS-2B). METHODS: Cell counting kit (CCK)-8 assay was used to detect the activity of BEAS-2B cells. The subcellular localization of CIRP was detected by immunofluorescence. The mRNA and protein levels of CIRP, nuclear factor kappa-B (NF-κB) p65, toll like receptor-4 (TLR4), interleukin-6 (IL-6) were detected using quantitative real-time PCR (PCR) and Western Blot (WB). The protein expressions of CIRP, IL-1ß, IL-6, tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) were assessed by enzyme-linked immunosorbent assay (ELISA). RESULTS: CIRP affects the activity of BEAS-2B cells induced by S. pneumoniae infection. After infection, CIRP translocates from the nucleus to the cytoplasm, thereby inducing the production of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α, and MCP-1). Additionally, the NF-κB p65 protein increases in infected cells but decreases with si-CIRP interference. Treatment with TLR4 neutralizing antibodies or NF-κB inhibitor effectively reduces the expressions of IL-1ß, IL-6, TNF-α, and MCP-1. CONCLUSIONS: The infection with S. pneumoniae upregulates CIRP expression and translocates it from the nucleus to the cytoplasm in BEAS-2B cells, leading to the release of proinflammatory factors via activation of NF-κB signaling pathway. CIRP as a key mediator in S. pneumoniae-induced inflammation offers potential targets for therapeutic intervention against community-acquired pneumonia.

Timing of Intervention and Long-Term Outcomes of Type B Aortic Intramural Hematoma with Intimal Disruption at Admission.

BACKGROUND: To compare the 30-day and long-term outcomes between patients with concomitant type B intramural hematoma and intimal disruption upon admission who underwent endovascular repair in the acute or subacute phases. METHODS: Data were extracted from January 1, 2010, to December 31, 2019. Logistic regression and Cox regression were performed to evaluate the impact of timing of intervention on 30-day and long-term outcomes, respectively. RESULTS: The study included 241 patients, among which 159 were in the acute group. No significant difference was observed in 30-day mortality (0.6% vs. 0%, P = 1), 30-day complication rate (2.5% vs. 1.2%, P = 0.664), long-term all-cause mortality (10.7% vs. 7.3%, P = 0.540), and aortic reintervention rate (2.5% vs. 2.4%, P = 1) between the acute and subacute group. In multivariable analysis, the timing of intervention was not associated with 30-day mortality (odds ratio (OR) = 0, 95% confidence interval CI: 0-Inf, P = 0.999), 30-day complication (OR = 0.30, 95% CI: 0.02-3.77, P = 0.348), long-term mortality (hazard ratio = 0.56, 95% CI: 0.20-1.61, P = 0.283), and aortic reintervention (OR = 0.97, 95% CI: 0.15-6.08, P = 0.970). CONCLUSIONS: For patients with concomitant type B intramural hematoma and intimal disruption upon admission, there is no significant difference in 30-day and long-term outcomes between those who undergo endovascular treatment in the acute or subacute phase.

Case report: Herbal treatment of neutropenic enterocolitis after chemotherapy for breast cancer.

In this case report, a 53-year-old woman was diagnosed with severe NE after receiving chemotherapy for breast cancer. The patient with breast cancer was treated with a single cycle of docetaxel (140 mg) + epirubicin (130 mg) + cyclophosphamide (0.9 g) chemotherapy. However, the woman presented with symptoms of fatigue and diarrhea 5 days later accompanied with severe neutropenia according to the routine blood test. The computed tomography examination displayed the thickening and swelling of the colorectal wall. After the diagnosis of NE, the woman received antibiotics and supportive treatment, but her symptoms were not improved. The Chinese herbal medicine (CHM) diagnostic pattern was then designed for the patient. The patient was administered with two CHM decoctions. One decoction contained 24 kinds of herbal materials, and the other one was called pure ginseng decoction. These two decoctions were administered to the patient 2 or 3 times per day to tonify the spleen, nourish Qi and blood, and remove phlegm and damp heat symptoms. After the CHM treatment lasting for 10 days, the symptoms of the patient were improved, and she was discharged. In conclusion, CHM treatment played an indispensable role in curing the woman with chemotherapy-induced NE.

Multisequence MRI-based radiomics nomogram for early prediction of osimertinib resistance in patients with non-small cell lung cancer brain metastases.

Background: Osimertinib resistance is a major problem in the course of targeted therapy for non-small cell lung cancer (NSCLC) patients. To develop and validate a multisequence MRI-based radiomics nomogram for early prediction of osimertinib resistance in NSCLC with brain metastases (BM). Methods: Pretreatment brain MRI of 251 NSCLC patients proven with BM were retrospectively enrolled from two centers (training cohort: 196 patients; testing cohort: 55 patients). According to the gene test result of osimertinib resistance, patients were labeled as resistance and non-resistance groups (training cohort: 65 versus 131 patients; testing cohort: 25 versus 30 patients). Radiomics features were extracted from T2WI, T2 fluid-attenuated inversion recovery (T2-FLAIR), diffusion weighted imaging (DWI) and contrast-enhanced T1-weighted imaging (T1-CE) sequences separately and radiomics score (rad-score) were built from the four sequences. Then a multisequence MRI-based nomogram was developed and the predictive ability was evaluated by ROC curves and calibration curves. Results: The rad-scores of the four sequences has significant differences between resistance and non-resistance groups in both training and testing cohorts. The nomogram achieved the highest predictive ability with area under the curve (AUC) of 0.989 (95 % confidence interval, 0.976-1.000) and 0.923 (95 % confidence interval, 0.851-0.995) in the training and testing cohort respectively. The calibration curves showed excellent concordance between the predicted and actual probability of osimertinib resistance using the radiomics nomogram. Conclusions: The multisequence MRI-based radiomics nomogram can be used as a noninvasive auxiliary tool to identify candidates who were resistant to osimertinib, which could guide clinical therapy for NSCLC patients with BM.

Carbonic anhydrase IX inhibitor S4 triggers release of DAMPs related to immunogenic cell death in glioma cells via endoplasmic reticulum stress pathway.

BACKGROUND: Immunogenic cell death (ICD), which releases danger-associated molecular patterns (DAMP) that induce potent anticancer immune response, has emerged as a key component of therapy-induced anti-tumor immunity. The aim of this work was to analyze whether the carbonic anhydrase IX inhibitor S4 can elicit ICD in glioma cells. METHODS: The effects of S4 on glioma cell growth were evaluated using the CCK-8, clonogenic and sphere assays. Glioma cell apoptosis was determined by flow cytometry. Surface-exposed calreticulin (CRT) was inspected by confocal imaging. The supernatants of S4-treated cells were concentrated for the determination of HMGB1and HSP70/90 expression by immunoblotting. RNA-seq was performed to compare gene expression profiles between S4-treated and control cells. Pharmacological inhibition of apoptosis, autophagy, necroptosis and endoplasmic reticulum (ER) stress was achieved by inhibitors. In vivo effects of S4 were evaluated in glioma xenografts. Immunohistochemistry (IHC) was performed to stain Ki67 and CRT. RESULTS: S4 significantly decreased the viability of glioma cells and induced apoptosis and autophagy. Moreover, S4 triggered CRT exposure and the release of HMGB1 and HSP70/90. Inhibition of either apoptosis or autophagy significantly reversed S4-induced release of DAMP molecules. RNA-seq analysis indicated that the ER stress pathway was deregulated upon exposure to S4. Both PERK-eIF2α and IRE1α- XBP1 axes were activated in S4-treated cells. Furthermore, pharmacological inhibition of PERK significantly suppressed S4-triggered ICD markers and autophagy. In glioma xenografts, S4 significantly reduced tumor growth. CONCLUSIONS: Altogether, these findings suggest S4 as a novel ICD inducer in glioma and might have implications for S4-based immunotherapy. Video Abstract.

The application of clinical variable-based nomogram in predicting overall survival in malignant phyllodes tumors of the breast.

Background: We aimed to explore prognostic risk factors in patients with malignant phyllodes tumors (PTs) of the breast and construct a survival prediction model. Methods: The Surveillance, Epidemiology, and End Results database was used to collect information on patients with malignant breast PTs from 2004 to 2015. The patients were randomly divided into training and validation groups using R software. Univariate and multivariate Cox regression analyses were used to screen out independent risk factors. Then, a nomogram model was developed in the training group and validated in the validation group, and the prediction performance and concordance were evaluated. Results: The study included 508 patients with malignant PTs of the breast, including 356 in the training group and 152 in the validation group. Univariate and multivariate Cox proportional hazard regression analyses showed that age, tumor size, tumor stage, regional lymph node metastasis (N), distant metastasis (M) and tumor grade were independent risk factors for the 5-year survival rate of patients with breast PTs in the training group (p < 0.05). These factors were used to construct the nomogram prediction model. The results showed that the C-indices of the training and validation groups were 0.845 (95% confidence interval [CI] 0.802-0.888) and 0.784 (95% CI 0.688-0.880), respectively. The calibration curves of the two groups were close to the ideal 45° reference line and showed good performance and concordance. Receiver operating characteristic and decision curve analysis curves showed that the nomogram has better predictive accuracy than other clinical factors. Conclusion: The nomogram prediction model constructed in this study has good predictive value. It can effectively assess the survival rates of patients with malignant breast PTs, which will aid in the personalized management and treatment of clinical patients.

Comprehensive multimodal management of borderline resectable pancreatic cancer: Current status and progress.

Borderline resectable pancreatic cancer (BRPC) is a complex clinical entity with specific biological features. Criteria for resectability need to be assessed in combination with tumor anatomy and oncology. Neoadjuvant therapy (NAT) for BRPC patients is associated with additional survival benefits. Research is currently focused on exploring the optimal NAT regimen and more reliable ways of assessing response to NAT. More attention to management standards during NAT, including biliary drainage and nutritional support, is needed. Surgery remains the cornerstone of BRPC treatment and multidisciplinary teams can help to evaluate whether patients are suitable for surgery and provide individualized management during the perioperative period, including NAT responsiveness and the selection of surgical timing.

UMRFormer-net: a three-dimensional U-shaped pancreas segmentation method based on a double-layer bridged transformer network.

Background: Methods based on the combination of transformer and convolutional neural networks (CNNs) have achieved impressive results in the field of medical image segmentation. However, most of the recently proposed combination segmentation approaches simply treat transformers as auxiliary modules which help to extract long-range information and encode global context into convolutional representations, and there is a lack of investigation on how to optimally combine self-attention with convolution. Methods: We designed a novel transformer block (MRFormer) that combines a multi-head self-attention layer and a residual depthwise convolutional block as the basic unit to deeply integrate both long-range and local spatial information. The MRFormer block was embedded between the encoder and decoder in U-Net at the last two layers. This framework (UMRFormer-Net) was applied to the segmentation of three-dimensional (3D) pancreas, and its ability to effectively capture the characteristic contextual information of the pancreas and surrounding tissues was investigated. Results: Experimental results show that the proposed UMRFormer-Net achieved accuracy in pancreas segmentation that was comparable or superior to that of existing state-of-the-art 3D methods in both the Clinical Proteomic Tumor Analysis Consortium Pancreatic Ductal Adenocarcinoma (CPTAC-PDA) dataset and the public Medical Segmentation Decathlon dataset (self-division). UMRFormer-Net statistically significantly outperformed existing transformer-related methods and state-of-the-art 3D methods (P<0.05, P<0.01, or P<0.001), with a higher Dice coefficient (85.54% and 77.36%, respectively) or a lower 95% Hausdorff distance (4.05 and 8.34 mm, respectively). Conclusions: UMRFormer-Net can obtain more matched and accurate segmentation boundary and region information in pancreas segmentation, thus improving the accuracy of pancreas segmentation. The code is available at https://github.com/supersunshinefk/UMRFormer-Net.

The splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis.

Pancreatic cancer is characterized by abundant desmoplasia, a dense stroma composed of extra-cellular and cellular components, with cancer associated fibroblasts (CAFs) being the major cellular component. However, the tissue(s) of origin for CAFs remains controversial. Here we determine the tissue origin of pancreatic CAFs through comprehensive lineage tracing studies in mice. We find that the splanchnic mesenchyme, the fetal cell layer surrounding the endoderm from which the pancreatic epithelium originates, gives rise to the majority of resident fibroblasts in the normal pancreas. In a genetic mouse model of pancreatic cancer, resident fibroblasts expand and constitute the bulk of CAFs. Single cell RNA profiling identifies gene expression signatures that are shared among the fetal splanchnic mesenchyme, adult fibroblasts and CAFs, suggesting a persistent transcriptional program underlies splanchnic lineage differentiation. Together, this study defines the phylogeny of the mesenchymal component of the pancreas and provides insights into pancreatic morphogenesis and tumorigenesis.

Surgical treatment patterns and clinical outcomes of type B aortic dissection involving the aortic arch.

OBJECTIVE: In the present report, we have described the outcomes of endovascular repair, hybrid arch repair, and open surgical repair for type B dissection involving the aortic arch (B1-2, D). METHODS: Cases of endovascular repair, hybrid arch repair, and open surgical repair performed between January 2015 and December 2019 for aortic dissection designated as B1-2, D by the Society for Vascular Surgery/Society of Thoracic Surgeons classification were retrospectively analyzed. The primary end point was all-cause mortality at follow-up. The secondary end points included early mortality, early morbidities, and aortic-related late events. Kaplan-Meier curves were created to analyze survival from all-cause mortality and freedom from aortic-related late events in the endovascular, hybrid, and open groups. Propensity score matching and stratification (stratified by proximal dissection extension: B1, D and B2, D) were performed as sensitivity analyses to compare the outcomes among the three treatment patterns after controlling for major confounders. RESULTS: The present study included 151 patients (men, 79.5%; mean age, 47.3 ± 10.5 years), with 72 (47.7%) in the endovascular group, 46 (30.5%) in the hybrid group, and 33 (21.8%) in the open group. No significant difference was noted in early mortality between the endovascular, hybrid, and open groups (1.4% vs 2.2% vs 3.0%; P = .791). The incidence of early endoleak was significantly greater (33.3% vs 13.0% vs 6.1%; P = .002) and the incidence of renal function deterioration was less (4.2% vs 26.1% vs 24.2%; P = .001) after endovascular repair vs hybrid arch repair and open surgery. After a median follow-up of 40.0 months (range, 0-84.0 months), no significant differences were found in all-cause mortality (5.6% vs 4.3% vs 3.0%; P = 1.0), aortic-related late events (16.7% vs 15.2% vs 12.1%; P = .834), or late endoleak (9.7% vs 4.3% vs 6.1%; P = .630) after endovascular, hybrid, and open surgery. The propensity score matching and stratification analyses displayed consistent outcomes for early mortality, all-cause mortality, and aortic-related late events among the three groups. CONCLUSIONS: The mid- to long-term outcomes after endovascular repair, hybrid arch repair, and open surgical repair for type B dissection involving the aortic arch (B1-2, D) were favorable and comparable in selected patients. Extensive experience and multidisciplinary teamwork are prerequisites for individualized strategies for repair of B1-2, D.

Circ_0079530 stimulates THBS2 to promote the malignant progression of non-small cell lung cancer by sponging miR-584-5p.

BACKGROUND: Circ_0079530 has been confirmed to be a novel potential oncogene in non-small cell lung cancer (NSCLC). This study aims to explore the role and mechanism of circ_0079530 in NSCLC progression. METHODS: Levels of circ_0079530, microRNA (miR)-584-5p, thrombospondin-2 (THBS2), PCNA, Bax, E-cadherin, and ki67 were detected by quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry. The proliferation of NSCLC cells was measured using cell counting kit 8 (CCK8) assay, colony formation assay, and EdU staining. Cell apoptosis and motility were respectively detected by flow cytometry and transwell assays. Interaction between miR-584-5p and circ_0079530 or THBS2 was predicted by bioinformatics analysis and confirmed via luciferase reporter assay and RNA immunoprecipitation (RIP) assay. A xenograft tumor model was used to analyze the role of circ_0079530 in tumor growth in vivo. RESULTS: Circ_0079530 was highly expressed in NSCLC tissues and cell lines. Circ_0079530 overexpression facilitated proliferation, migration, and invasion whereas it restrained the apoptosis of NSCLC cells. Circ_0079530 silence showed the opposite effects on the above malignant biological behaviors. Mechanistic analysis showed that circ_0079530 functioned as a sponge of miR-584-5p to relieve the suppressive action of miR-584-5p on its target THBS2. Additionally, circ_0079530 knockdown impeded the growth of xenografts in vivo. CONCLUSION: Circ_0079530 promoted NSCLC progression by regulating the miR-584-5p/THBS2 axis, providing a possible circRNA-targeted therapy for NSCLC.

Integrated profiling uncovers prognostic, immunological, and pharmacogenomic features of ferroptosis in triple-negative breast cancer.

Objective: Ferroptosis is an iron-dependent type of regulated cell death triggered by the toxic buildup of lipid peroxides on cell membranes. Nonetheless, the implication of ferroptosis in triple-negative breast cancer (TNBC), which is the most aggressive subtype of breast carcinoma, remains unexplored. Methods: Three TNBC cohorts-TCGA-TNBC, GSE58812, and METABRIC-were adopted. Consensus molecular subtyping on prognostic ferroptosis-related genes was implemented across TNBC. Ferroptosis classification-relevant genes were selected through weighted co-expression network analysis (WGCNA), and a ferroptosis-relevant scoring system was proposed through the LASSO approach. Prognostic and immunological traits, transcriptional and post-transcriptional modulation, therapeutic response, and prediction of potential small-molecule agents were conducted. Results: Three disparate ferroptosis patterns were identified across TNBC, with prognostic and immunological traits in each pattern. The ferroptosis-relevant scoring system was proposed, with poorer overall survival in high-risk patients. This risk score was strongly linked to transcriptional and post-transcriptional mechanisms. The high-risk group had a higher response to anti-PD-1 blockade or sunitinib, and the low-risk group had higher sensitivity to cisplatin. High relationships of risk score with immunological features were observed across pan-cancer. Two Cancer Therapeutics Response Portal (CTRP)-derived agents (SNX-2112 and brefeldin A) and PRISM-derived agents (MEK162, PD-0325901, PD-318088, Ro-4987655, and SAR131675) were predicted, which were intended for high-risk patients. Conclusion: Altogether, our findings unveil prognostic, immunological, and pharmacogenomic features of ferroptosis in TNBC, highlighting the potential clinical utility of ferroptosis in TNBC therapy.

Association of adenosine signaling gene signature with estrogen receptor-positive breast and prostate cancer bone metastasis.

Bone metastasis is a common and devastating consequence of several major cancer types, including breast and prostate. Osteocytes are the predominant bone cell, and through connexin (Cx) 43 hemichannels release ATP to the bone microenvironment that can be hydrolyzed to adenosine. Here, we investigated how genes related to ATP paracrine signaling are involved in two common bone-metastasizing malignancies, estrogen receptor positive (ER+) breast and prostate cancers. Compared to other sites, bone metastases of both cancer types expressed higher levels of ENTPD1 and NT5E, which encode CD39 and CD73, respectively, and hydrolyze ATP to adenosine. ADORA3, encoding the adenosine A3 receptor, had a similar expression pattern. In primary ER+ breast cancer, high levels of the triplet ENTPD1/NT5E/ADORA3 expression signature was correlated with lower overall, distant metastasis-free, and progression-free survival. In ER+ bone metastasis biopsies, this expression signature is associated with lower survival. This expression signature was also higher in bone-metastasizing primary prostate cancers than in those that caused other tumor events or did not lead to progressive disease. In 3D culture, a non-hydrolyzable ATP analog inhibited the growth of breast and prostate cancer cell lines more than ATP did. A3 inhibition also reduced spheroid growth. Large-scale screens by the Drug Repurposing Hub found ER+ breast cancer cell lines were uniquely sensitive to adenosine receptor antagonists. Together, these data suggest a vital role for extracellular ATP degradation and adenosine receptor signaling in cancer bone metastasis, and this study provides potential diagnostic means for bone metastasis and specific targets for treatment and prevention.

Acinar Cell-Derived Extracellular Vesicle MiRNA-183-5p Aggravates Acute Pancreatitis by Promoting M1 Macrophage Polarization Through Downregulation of FoxO1.

Acute pancreatitis (AP) is a common cause of a clinically acute abdomen. Crosstalk between acinar cells and leukocytes (especially macrophages) plays an important role in the development of AP. However, the mechanism mediating the interaction between acinar cells and macrophages is still unclear. This study was performed to explore the role of acinar cell extracellular vesicles (EVs) in the crosstalk between acinar cells and macrophages involved in the pathogenesis of AP. EVs derived from caerulein-treated acinar cells induced macrophage infiltration and aggravated pancreatitis in an AP rat model. Further research showed that acinar cell-derived EV miR-183-5p led to M1 macrophage polarization by downregulating forkhead box protein O1 (FoxO1), and a dual-luciferase reporter assay confirmed that FoxO1 was directly inhibited by miR-183-5p. In addition, acinar cell-derived EV miR-183-5p reduced macrophage phagocytosis. Acinar cell-derived EV miR-183-5p promoted the pancreatic infiltration of M1 macrophages and increased local and systemic damage in vivo. Subsequently, miR-183-5p overexpression in macrophages induced acinar cell damage and trypsin activation, thus further exacerbating the disease. In clinical samples, elevated miR-183-5p levels were detected in serum EVs and positively correlated with the severity of AP. EV miR-183-5p might play an important role in the development of AP by facilitating M1 macrophage polarization, providing a new insight into the diagnosis and targeted management of pancreatitis. Graphical abstract of the present study. In our caerulein-induced AP model, miR-183-5p was upregulated in injured acinar cells and transported by EVs to macrophages. miR-183-5p could induce M1 macrophage polarization through downregulation of FoxO1 and the release of inflammatory cytokines, which could aggravate AP-related injuries. Therefore, a vicious cycle might exist between injured ACs and M1 macrophage polarization, which is fulfilled by EV-transported miR-183-5p, leading to sustainable and progressive AP-related injuries.

Lactate Dehydrogenase-Inhibitors Isolated from Ethyl Acetate Extract of Selaginella doederleinii by Using a Rapid Screening Method with Enzyme-Immobilized Magnetic Nanoparticles.

BACKGROUND: Lactate dehydrogenase (LDH) is one of the important enzyme systems for glycolysis and gluconeogenesis. It can catalyze the reduction and oxidation reaction between propionic acid and L-lactic acid, which is usually overexpressed in cancer cells. Therefore, inhibiting the activity of LDH is a promising way for the treatment of cancer. In this study, an effective method based on ligand fishing and ultra performance liquid chromatography-mass spectrum (UPLC-MS) was established to screen and identify active ingredients from Selaginella doederleinii with potential inhibitory activity for LDH. METHODS: Firstly, LDH was immobilized on the magnetic nanoparticles (MNPs), three immobilization parameters including LDH concentration, immobilization time and pH were optimized by single factor and response surface methodology for maximum (max) immobilization yield. Then, a mixed model of galloflavin and chlorogenic acid (inhibitors and non-inhibitors of LDH) was used to verify the specificity of immobilized LDH ligand fishing, and the conditions of ligand fishing were further optimized. Finally, combined with UPLC-MS, immobilized LDH was used to simultaneously screen and identify potential LDH inhibitors from the ethyl acetate extract of Selaginella doederleinii. RESULTS: The prepared fishing material was comprehensively characterized by scanning electron microscopy (SEM), transmission electron microscope (TEM), X-ray diffraction (XRD) and fourier transform infrared spectrometer (FT-IR). The optimal immobilization conditions were obtained as LDH concentration of 0.7 mg/mL, pH value of 4.5, and immobilization time of 3.5 h. Under these conditions, the max immobilization yield was (3.79 ± 0.08) × 103 U/g. The specificity analysis showed that immobilized LDH could recognize and capture ligands, and the optimal ligand fishing conditions included that the incubation time was 30 min, the elution time was 20 min, and the concentration of methanol as eluent was 80%. Finally, two LDH inhibitors, amentoflavone and robustaflavone, were screened by immobilized LDH from the ethyl acetate extract of Selaginella doederleinii. CONCLUSIONS: The study provided a meaningful evidence for discovering the bioactive constituents in ethyl acetate extract of Selaginella doederleinii related to cancer treatment, and this ligand fishing method was feasible for screening enzyme inhibitors from similar complex mixtures.

Hydrogel beads based on carboxymethyl cassava starch/alginate enriched with MgFe2O4 nanoparticles for controlling drug release.

Implementing novel oral drug delivery systems with controlled drug release behavior is valuable in cancer therapy. Herein, a green synthetic approach based on the sol-gel technique was adopted to prepare MgFe2O4 nanoparticles at different calcination temperatures using citric acid as a chelating/combustion agent. In this context, pH-responsive and magnetic carboxymethyl starch/alginate hydrogel beads (CMCS-SA) containing the MgFe2O4 nanoparticles were developed as potential drug carriers for the anticancer drug (Doxorubicin, Dox) release in simulated gastrointestinal fluids. Furthermore, in vitro release behaviors validated that these beads illustrated excellent stability in the simulated stomach liquids. In contrast, the data in simulated intestinal fluids showed sustained release of Dox because of their pH-sensitive swelling characteristics. Notably, applying an external magnetic field (EMF) could accelerate drug release from the beads. The in vitro release of drugs from gel beads was mainly accomplished by a combination of diffusion, swelling and erosion. Moreover, the cell cytotoxicity test and laser confocal results showed no harmful effects on normal cells (3T3) but were significant cytotoxic to colon cancer cell lines (HCT116) by drug-loaded hydrogel beads. Therefore, the prepared gel beads could be qualified as latent platforms for controlling the release of anticancer drugs in cancer treatment.