Background: Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder characterized by fibrofatty replacement of cardiomyocytes. The inflammatory episodes of ACM, known as the “hot phase”, can mimic acute myocarditis. It was seldom observed in a DES-associated ACM as a “hot-phase” presentation. Case Presentation: The proband, a 13-year-old female, initially presented with a series of clinical manifestations of fulminant myocarditis. Although recommendation-guided anti-immunotherapy had been provided, this patient still developed into an aggressive cardiomyopathy with biventricular dilation and severe systolic heart failure. Additionally, cardiac magnetic resonance demonstrated circumferential late gadolinium enhancement in left ventricular myocardium with diffuse fibrosis. Whole-exon sequencing identified a de novo missense variant, as c.335T>A (p.L112Q) of the DES gene, resulting in protein dysfunction. And a diagnosis of ACM due to a DES variant had been identified. Finally, this patient received heart transplantation, and biventricular fibrofatty infiltration was confirmed by pathological analysis. Conclusions: This case presented a de novo genetic variant that can induce severe and aggressive heart failure. This finding emphasizes the importance of comprehensive genetic analysis in patients suspected of having fulminant myocarditis, which would greatly benefit the precise clinical management and outcomes.

Early detection of cardiac amyloidosis (CA) is challenging, despite advances in repurposed β -amyloid PET tracers and amyloid-targeted [ 124 I]Evuzamitide. The heterogeneity of CA subtypes requires invasive tests, like tissue biopsy, before targeted therapy can begin. Amyloidogenic light chains (AL) expose negatively charged pockets enriched in acidic residues and N-glycosylated modifications, guiding the design of selective molecular probes. We showed that protonation-driven recognition accomplishes unprecedented selectivity for AL deposits. Using this principle, we developed a fluorinated derivative, [ 18 F] FT-8 , based on a 4-pyridylpiperazine scaffold, which displayed high binding affinity ( K i = 11.52 nM) and selectivity towards AL, as well as favorable pharmacokinetics. In first-in-human PET studies, [ 18 F] FT-8 provided high-contrast visualization of AL deposits in the myocardium and extracardiac organs with significant specificity. These findings position [ 18 F] FT-8 as a promising PET tracer for advancing the non-invasive differential diagnosis of AL-CA and highlighting the role of protonation in developing new-generation molecular probes across diverse disease contexts.

INTRODUCTION:Hypothesis-driven studies have identified many modifiable cancer risk factors, but research focusing on single exposures overlooks their complex interactions. OBJECTIVES:This study applied an exposome-wide approach across multiple cancer types to systematically identify modifiable exposures and evaluate their combined effects with genetic susceptibility. METHODS:We analyzed data from over 460,000 UK Biobank participants with 15 years of follow-up, assessing 93 modifiable exposures in relation to 23 site-specific cancers using Cox models. Exposomic risk scores (ERS) were constructed to quantify the combined effects of identified factors. Population attributable fractions (PAFs) were calculated to estimate the potential population-level burden associated with these factors. Finally, polygenic risk scores (PRS) were incorporated to evaluate the relative contributions of genetic susceptibility and modifiable exposures to cancer risk. RESULTS:We identified 209 significant exposure-cancer risk estimates, with both their number and magnitude varying markedly across cancer types. Lung cancer exhibited the largest number of associations, whereas ovarian, testicular, and brain cancers showed no significant associations. Several exposures were associated with multiple cancers, such as basal metabolic rate, smoking, diabetes, household income, alcohol consumption, and body fat percentage, suggesting pleiotropic effects. ERSs summarized the combined influence of these modifiable exposures, and PAFs estimated their potential contribution to the population-level cancer burden across cancer types (4.5%-75.6%). PRS integration showed larger relative genetic contributions for prostate cancer (48.6%), melanoma (48.9%), and Hodgkin lymphoma (61%), while modifiable exposures were more influential in endometrial cancer (74.2%), lung cancer (71.1%), and liver cancer (57.8%). CONCLUSION:This study provides a pan-cancer, exposome-wide perspective on modifiable and genetic contributions to cancer risk, highlighting the potential value of targeting controllable exposures to reduce population-level cancer burden.

Early detection of cardiac amyloidosis (CA) remains challenging, and a PET tracer capable of directly visualizing amyloid deposits could improve diagnosis. Given the shared β-sheet structure of amyloid deposits in CA and Alzheimer’s disease (AD), this study aimed to evaluate the suitability of the AD amyloid tracer [18F]Florbetazine for non-invasive detection of CA via preclinical assessments and preliminary clinical evaluation. Specific binding and affinity of [18F]Florbetazine to amyloid light-chain (AL) and transthyretin (ATTR) deposits were assessed via in vitro autoradiography on human myocardial sections. Pharmacokinetics and biodistribution were characterized by dynamic micro-PET/CT imaging in healthy Sprague Dawley (SD) rats. Whole-body PET/CT imaging was performed in two healthy volunteers to estimate normal-organ background, and in a single patient with biopsy-proven AL amyloidosis to preliminarily explore diagnostic feasibility. Autoradiography confirmed specific binding of [18F]Florbetazine to both AL and ATTR deposits with high binding affinities (Kd = 20.85 nM and 54.10 nM, respectively). In rats, [18F]Florbetazine exhibited rapid myocardial and renal uptake followed by efficient clearance from normal tissues. In healthy volunteers, background myocardium and renal activity was minimal by 40 min post-injection. In the AL amyloidosis patient, delayed-phase PET/CT imaging (60–70 min) revealed intense myocardium and renal uptake, correlating with renal biopsy findings. These integrated preclinical and preliminary clinical evaluation demonstrates that [18F]Florbetazine binds cardiac amyloid with high affinity and displays favorable pharmacokinetics, warranting further investigation in larger, systematically designed clinical studies. Clinical trial registry NCT06593626 (registered 24 May 2024) and NCT06725706 (registered 5 Dec 2024).

ObjectiveTo establish an epirubicin (EPI)-resistant murine triple-negative breast cancer (TNBC) (4T1/EPI) cell line and evaluate its biological characteristics and drug resistance. MethodsThe EPI-resistant cell line 4T1/EPI was developed through intermittent induction with gradually increasing EPI concentrations in vitro. Morphological changes were observed under an inverted microscope. Drug resistance index (MTT assay), cell doubling time (CCK-8 assay), and migration ability (wound healing assay) were evaluated. Western blot was used to detect the expression of drug resistance-related proteins. Transcriptome sequencing and KEGG pathway enrichment analysis were performed to identify the pathways and targets involved in EPI resistance, followed by experimental validation. ResultsThe 4T1 cells eventually grew normally in a medium containing 100 ng/mL EPI, confirming the establishment of the 4T1/EPI resistant cell line. After stable resistance was acquired, morphological alterations were observed. Compared with their parental 4T1 cells, 4T1/EPI cells showed significantly prolonged doubling time (P<0.01) and enhanced migration ability (P<0.05). Expression levels of drug resistance-related proteins MDR1, MRP1 (P<0.01), and ABCG2 (P<0.05) were elevated in 4T1/EPI cells. In vivo models also demonstrated significant EPI resistance in 4T1/EPI tumors in terms of tumor weight and volume. Transcriptome sequencing highlighted the involvement of the PI3K/Akt signaling pathway and ABC transporter pathway. Validation experiments showed the upregulation of Erbb3, Egfr, PI3K, and Akt (P<0.05) and significant downregulation of Fgfr1 (P<0.01) in 4T1/EPI cells. ConclusionThe EPI-resistant TNBC cell line 4T1/EPI was successfully established, exhibiting significant resistance in vitro and in vivo. The mechanism may involve the EPI-induced upregulation of Egfr and Erbb3, activating the PI3K/Akt pathway and subsequently enhancing ABC transporter expression.

IMPORTANCE:Triple-negative breast cancer (TNBC) is characterized by high tumor mutation burden and frequent programmed cell death ligand 1 (PD-L1) expression, making immune checkpoint inhibitors (ICIs) a promising therapeutic approach. However, randomized trials of chemoimmunotherapy (Chemo-IO) in locally recurrent unresectable or metastatic TNBC have shown inconsistent results, necessitating a clearer understanding of efficacy and patient selection. OBJECTIVE:The aim of this study was to evaluate the efficacy and safety of chemotherapy combined with immunotherapy vs. chemotherapy alone in patients with locally recurrent unresectable or metastatic triple-negative breast cancer and to identify beneficiary populations to guide optimal treatment selection. DATA SOURCES:PubMed, Embase, and the Cochrane Library were searched from database inception through 23 August 2025. STUDY SELECTION:Randomized clinical trials (RCTs) comparing chemotherapy combined with ICIs vs. chemotherapy with placebo or control in patients with locally recurrent unresectable or metastatic TNBC were selected. DATA EXTRACTION AND SYNTHESIS:Two investigators independently performed data extraction and assessed risk of bias using the Cochrane Risk of Bias 2 tool (RoB 2). Heterogeneity was evaluated using the I2 statistic. Data were synthesized using random-effects meta-analysis models to calculate hazard ratios (HRs) for time-to-event outcomes and risk ratios (RRs) for dichotomous outcomes according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. RESULTS:Seven RCTs comprising 3485 patients (2085 in the Chemo-IO group, 1400 in the control group) were included. The median age across trials ranged from 52 to 57 years. Chemo-IO significantly improved PFS (HR, 0.82 [95% CI, 0.76-0.89]; p < 0.01) and OS (HR = 0.88; 95% CI: 0.81-0.96; p = 0.004) in the intention-to-treat (ITT) population, with PFS benefit particularly evident in PD-L1-positive patients (HR = 0.68, 95% CI: 0.59-0.79). However, OS improvement in the PD-L1-positive subgroup was not statistically significant. CBR did not differ significantly in the intention-to-treat population (RR, 1.11 [95% CI, 0.99-1.25]; p =  0.08) but was higher in PD-L1-positive patients (RR, 1.15 [95% CI, 1.01-1.31]; p = 0.04). Safety analyses revealed no significant differences in overall AE (RR, 1.01 [95% CI, 0.99-1.02]; p = 0.35), TEAE (RR, 1.01 [95% CI, 0.99-1.03]; p = 0.19), or grade ≥ 3 TEAE (RR, 1.00; [95% CI, 0.93-1.07]; p =  0.98). However, serious AE (RR, 1.32 [95% CI, 1.11-1.57]; p = 0.001) and irAE (RR, 1.86 [95% CI, 1.41-2.45]; p <  0.01) were more frequent with Chemo-IO. CONCLUSIONS AND RELEVANCE:Chemotherapy combined with immunotherapy significantly improved PFS and OS in patients with locally recurrent unresectable or metastatic TNBC, without substantially increasing chemotherapy-related toxicities. However, the OS benefit in PD-L1-positive patients was not statistically significant, and the combined regimen was associated with higher rates of serious and immune-related adverse events. These findings support the use of Chemo-IO as a treatment option, highlighting the importance of PD-L1 status and careful monitoring of immune-mediated toxicities in clinical practice.

Efficient modal feature fusion strategy is the key to achieve accurate segmentation of brain glioma. However, due to the specificity of different MRI modes, it is difficult to carry out cross-modal fusion with large differences in modal features, resulting in the model ignoring rich feature information. On the other hand, the problem of multi-modal feature redundancy interaction occurs in parallel networks due to the proliferation of feature dimensions, further increase the difficulty of multi-modal feature fusion at the bottom end. In order to solve the above problems, we propose a noval complementary feature compression interaction network (CFCI-Net), which realizes the complementary fusion and compression interaction of multi-modal feature information with an efficient mode fusion strategy. Firstly, we propose a selective complementary feature fusion (SCFF) module, which adaptively fuses rich cross-modal feature information by complementary soft selection weights. Secondly, a modal feature compression interaction (MFCI) transformer is proposed to deal with the multi-mode fusion redundancy problem when the feature dimension surges. The MFCI transformer is composed of modal feature compression (MFC) and modal feature interaction (MFI) to realize redundancy feature compression and multi-mode feature interactive learning. hierarchical interactive attention mechanism based on multi-head attention. Evaluations on the BraTS2019 and BraTS2020 datasets demonstrate that CFCI-Net achieves superior results compared to state-of-the-art models. Code: https://github.com/CDmm0/CFCI-Net

Immune checkpoint inhibitors (ICIs) have demonstrated favorable outcomes in various cancers. However, it has been observed that ICIs may induce life-threatening cardiovascular toxicity. In this study, a meta-analysis was conducted to determine the risk of cardiovascular toxicities in patients exposed to ICIs or in combination with chemotherapy. PubMed, Cochrane Library, and Embase databases were searched from inception to September 24, 2023. This study was conducted in accordance with the PRISMA guidelines. A meta-analysis was conducted on the risk of cardiotoxicity in cancer patients. Data were pooled with a random-effect model. This protocol was registered prospectively in PROSPERO (CRD42023467319). The primary outcome was cardiotoxicity risk in observational studies with ICIs or combined with chemotherapy. The risk factors that affected the occurrence of cardiovascular toxicities were also examined. ICIs or combined with chemotherapy increased the cardiotoxicity risk compared with mono-chemotherapy (OR 1.47; 95

BACKGROUND: KDELR2, a retrograde transport receptor involved in ER protein homeostasis, has emerged as a potential contributor to cancer development. However, its comprehensive expression profile and immunological roles across diverse human tumors remain unclear. METHODS: We performed an integrative pan-cancer analysis of KDELR2 using the TCGA and GTEx datasets, and examined its expression patterns, genetic alterations, methylation status, prognostic significance, and associations with immune infiltration and hallmark cancer pathways. Functional insights were derived from GSEA, GSVA, and immune landscape analyses. Wound healing, transwell and sphere formation assays were performed to investigate the role of KDELR2 in the stem-like properties, migration and invasion of pancreatic cancer cells. RESULTS: KDELR2 was broadly overexpressed in various tumor types and significantly associated with advanced tumor stages and poor clinical outcomes. Copy number amplification was the predominant genomic alteration, while promoter hypomethylation also contributed to its dysregulation. KDELR2 expression was correlated with the activation of oncogenic pathways, including those related to the ER stress response, glycosylation, and membrane trafficking. Moreover, KDELR2 was linked to immunosuppressive microenvironmental features, including enrichment of Tregs, TAMs, and MDSCs and reduced infiltration of cytotoxic immune cells. These trends were validated across multiple immune databases. KDELR2 also showed strong associations with immune checkpoint molecules and chemokine signaling networks, suggesting a dual role in tumor progression and immune evasion. Additionally, in vitro experiments revealed that KDELR2 overexpression promoted the stem-like properties, migration and invasion of PANC-1 cells, whereas KDELR2 knockdown led to the opposite results. CONCLUSION: KDELR2 serves as a potential pan-cancer biomarker associated with tumor aggressiveness and immune modulation. Our findings support KDELR2 as a promising candidate for prognostic evaluation and targeted intervention, particularly in the context of immunotherapy.

To explore the relationship between type 2 diabetes mellitus and the risk of developing breast cancer and its subtypes, and the mediating role of biological aging in it. A two-sample Mendelian randomized analyses were performed to assess the effect of type 2 diabetes mellitus on breast cancer and its subtypes, and the mediating effect of biological aging between type 2 diabetes mellitus with breast cancer and its subtypes was explored by mediation analysis. All the data were based on genome-wide association studies. The data of type 2 diabetes mellitus were obtained from meta-analyses with the UK Biobank and FinnGen. The data of biological aging and breast cancer were obtained from UK Biobank, Breast Cancer Association Consortium, respectively. The results of univariate Mendelian randomized showed that type 2 diabetes mellitus was positively causally associated with the risk of triple-negative breast cancer (OR = 1.076, 95

Microfluidics has been an effective technology to reconstruct the in-vivo physiological hemodynamic microenvironment, which is significantly important for preventing and curing circulatory system-related diseases. However, these existing microfluidic systems have failed to accurately reproduce the arterial blood pressure, shear stress, circumferential strain, as well as their coupling relationship, and have not taken into account whether the cells at various locations in the culture chamber are subjected to consistent mechanical stimulation. To solve the above shortcomings, this study developed an in-vitro endothelial cell culture system (ECCS) containing a microfluidic chip and afterload components based on the hemodynamic principles to reappear the desired hemodynamic signals and their coupling relationship accurately, while a relatively uniform area of stress and strain distribution was selected in the microfluidic chip for a more reliable cell mechanobiology study. The sensitivity of global hemodynamic behaviors of the ECCS was analyzed, and numerical simulation and in-vitro experiments were implemented to verify the performance of the proposed ECCS. Finally, the cellular hemodynamic response was tested using human umbilical vein endothelial cells, demonstrating that the proposed invitro ECCS has better biological effectiveness. In general, the proposed ECCS in this study provided a more accurate and reliable tool for reproducing the in-vivo hemodynamic microenvironment and showed good potential in the mechanobiology study.

Journal Article Accepted manuscript A UFO-like cavernous hemangiomas in the atrial septum visualized by three-dimensional transesophageal echocardiography Get access Xu Yang, MD, Xu Yang, MD Echocardiography Medical Center, Beijing Anzhen Hospital, Capital Medical University; Beijing Key Laboratory of Maternal-Fetus Medicine in Fetal Heart Disease(BZ0308); Beijing, People’s Republic of China https://orcid.org/0000-0002-3438-8061 Search for other works by this author on: Oxford Academic PubMed Google Scholar Jiancheng Han, MD, Jiancheng Han, MD Echocardiography Medical Center, Beijing Anzhen Hospital, Capital Medical University; Beijing Key Laboratory of Maternal-Fetus Medicine in Fetal Heart Disease(BZ0308); Beijing, People’s Republic of China Search for other works by this author on: Oxford Academic PubMed Google Scholar Dong Chen, MD, Dong Chen, MD Department of Pathology, Beijing Anzhen Hospital, Capital Medical University, Beijing, People's Republic of China Corresponding author: Dr. Dong Chen, Department of Pathology, Beijing Anzhen Hospital, Capital Medical University, No.2, Anzhenli, Chaoyang District, Beijing 100029, PR China, Tel: +86 10 84005368, E-mail: azchendong@163.com Search for other works by this author on: Oxford Academic PubMed Google Scholar Yihua He, MD Yihua He, MD Echocardiography Medical Center, Beijing Anzhen Hospital, Capital Medical University; Beijing Key Laboratory of Maternal-Fetus Medicine in Fetal Heart Disease(BZ0308); Beijing, People’s Republic of China Corresponding author: Dr. Yihua He, Echocardiography Medical Center, Beijing Anzhen Hospital, Capital Medical University, No.2, Anzhenli, Chaoyang District, Beijing 100029, PR China, E-mail: yihuaheecho@163.com Search for other works by this author on: Oxford Academic PubMed Google Scholar European Heart Journal - Cardiovascular Imaging, jeae002, https://doi.org/10.1093/ehjci/jeae002 Published: 02 January 2024 Article history Received: 19 December 2023 Accepted: 24 December 2023 Published: 02 January 2024

Ethnopharmacological relevance The treatment options for triple-negative breast cancer (TNBC) are limited. Traditional Chinese Medicine (TCM) plays an important role in the treatment of TNBC. The herb pair Scutellaria barbata D.Don and Scleromitrion diffusum (Willd.) R.J.Wang (SH) is commonly used in clinical practice for its anti-tumor properties. It has been proven to have good therapeutic effects on tumor-related diseases, but the underlying molecular mechanisms are not yet fully explained. Aim of study Through bioinformatics, it was validated that IL6, primarily derived from cancer-associated fibroblasts (CAFs), is associated with poor prognosis. Additionally, cell and animal experiments confirmed that SH inhibits tumor proliferation, migration, and growth in an orthotopic tumor model by suppressing the IL6/NF-κB pathway. Materials and methods GEO, TCGA and HPA databases were used to analyze the prognostic value of CAFs and IL6, then IL6 resource was detected. After the bioinformatics, the influence of CAFs and CAFs-derived IL6 on TNBC was verified by experiments both in vitro and in vivo. Cell clone formation assay, wound-Healing assay, and Transwell assay were used to detect the promotion of CAFs and CAFs-derived IL6 and the inhibition of SH in vitro. TNBC model in mice was used to prove the promotion of CAFs and CAFs-derived IL6 and the inhibition of SH in vivo. The biological pathway of NF-κB was explored by western blotting through detecting unique molecules. Results Bioinformatics analysis revealed that higher proportion of CAFs and elevated level of IL6 were significantly associated with poor prognosis in TNBC. At the same time, IL6 was proved predominantly derived from CAFs. After the indication of bioinformatics, experiments in vitro demonstrated that both CAFs and IL6 could enhance the clone formation and migration ability of MDA-MD-231 cells (231), furthermore, the promotion of CAFs was related with the level of IL6. Based on these data, mechanism was detected that CAFs-derived IL6 enhancement was closely related to the activation of NF-κB signaling pathway, while the activation can be reduced by SH. In the end, the promotion of CAFs/CAFs-derived IL6/NF-κB and the efficacy of SH inhibition were both confirmed by experiments in vivo. Conclusions Bioinformatics data indicates that higher proportion of CAFs and higher level of CAFs-derived IL6 are significantly related to poorer survival of TNBC. CAFs and CAFs-derived IL6 were proved to promote the progression of TNBC both in vitro and in vivo, and the process of which was significantly related to the activation of NF-κB. SH inhibited the progress of TNBC, which was proved to be closely related to CAFs/CAFs-derived IL6/NF-κB.