A bioinspired doxorubicin-carried albumin Nanocage against aggressive Cancer via systemic targeting of tumor and lymph node metastasis.

Cancer metastasis and recurrence are obstacles to successful treatment of aggressive cancer. To address this challenge, chemotherapy is indispensable as an essential part of comprehensive cancer treatment, particularly for subsequent therapy after surgical resection. However, small-molecule drugs for chemotherapy always cause inadequate efficacy and severe side effects against cancer metastasis and recurrence caused by lymph node metastases. Here, we developed doxorubicin-carried albumin nanocages (Dox-AlbCages) with appropriate particle sizes and pH/enzyme-responsive drug release for tumor and lymph node dual-targeted therapy by exploiting the inborn transport properties of serum albumin. Inspired by the protein-templated biomineralization and remote loading of doxorubicin into liposomes, we demonstrated the controlled synthesis of Dox-AlbCages via the aggregation or crystallization of doxorubicin and ammonium sulfate within albumin nanocages using a biomineralization strategy. Dox-AlbCages allowed efficient encapsulation of Dox in the core protected by the albumin corona shell, exhibiting favorable properties for enhanced tumor and lymph node accumulation and preferable cellular uptake for tumor-specific chemotherapy. Intriguingly, Dox-AlbCages effectively inhibited tumor growth and metastasis in orthotopic 4T1 breast tumors and prevented postsurgical tumor recurrence and lung metastasis. At the same time, Dox-AlbCages had fewer side effects than free Dox. This nanoplatform provides a facile strategy for designing tumor- and lymph node-targeted nanomedicines for suppressing cancer metastasis and recurrence.

Initial and follow-up high-resolution vessel wall MRI study of spontaneous cervicocranial artery dissection.

OBJECTIVES: To explore the factors associated with ischemic stroke secondary to spontaneous cervicocranial artery dissection (sCCAD) and evaluate the initial imaging markers related to outcomes. METHODS: Initial and follow-up high-resolution vessel wall MRI (VW-MRI) in consecutive patients with sCCAD were retrospectively analyzed. The associations of clinical and imaging factors and variants of the circle of Willis (COW) with ischemic stroke were evaluated using binary logistic regression analyses. The anatomical outcomes were categorized as complete, partial, and no remodeling based on changes of the vessel wall and lumen. Ordinal logistic regression analysis was used to assess associations between initial features and outcomes. RESULTS: A total of 115 dissected arteries (79 strokes, 36 non-strokes) were detected in 103 patients. Follow-up VW-MRI was available in 46 patients (44.7%, with 51 vessels), with a median interval of 8.5 months. Pseudoaneurysm (odd ratio [OR], 0.178; 95% confidence interval [CI], 0.039-0.810; p = 0.026) tended to rarely cause ischemic stroke, while intraluminal thrombus (OR, 5.558; 95% CI, 1.739-17.765; p = 0.004), incomplete COW (OR, 9.309; 95% CI, 2.122-40.840; p = 0.003), and partial complete COW (OR, 4.463; 95% CI, 1.211-16.453; p = 0.025) were independently associated with stroke occurrence. Furthermore, the presence of double lumen (OR, 5.749; 95% CI, 1.358-24.361; p = 0.018) and occlusion (OR, 12.975; 95% CI, 3.022-55.645; p = 0.001) were associated with no remodeling of sCCAD. CONCLUSIONS: Multiple initial factors were found to be related to stroke occurrence and anatomical outcomes of sCCAD. High-resolution VW-MRI may provide valuable insights into the pathophysiology and evolution of sCCAD. CLINICAL RELEVANCE STATEMENT: Initial and follow-up high-resolution vessel wall MRI may help elucidate the pathophysiology of spontaneous cervicocranial artery dissection and provide important insights into the evolution and further facilitate the optimal management of patients with spontaneous cervicocranial artery dissection. KEY POINTS: • Clinical and imaging factors, as well as the status of primary collateral circulation, are associated with ischemic stroke secondary to spontaneous cervicocranial artery dissection. • The follow-up high-resolution vessel wall MRI provides valuable insights into the long-term evolution and anatomical outcomes of spontaneous cervicocranial artery dissection. • The high-resolution vessel wall MRI features related to ischemic stroke and anatomical outcomes may further facilitate the optimal management of patients with spontaneous cervicocranial artery dissection.

Feasibility study of expressing epcam + /vimentin + CTC in prostate cancer diagnosis.

PURPOSE: Prostate cancer (PCa) is one of the most common malignancies in men and one of the leading causes of cancer-related deaths; circulating tumor cells (CTC) are malignant cells that have broken off from original tumor or metastatic sites and extravasated into the blood vessels either naturally or maybe as a consequence of surgical procedures. This study aims to explore the feasibility of liquid biopsy technique to diagnose prostate cancer. METHOD: We constructed an assay platform integrating magnetic separation and fluorescence in situ hybridization (FISH) to effectively capture prostate cancer CTCs and evaluate the distribution between healthy volunteers and prostate cancer patients, respectively. RESULTS: There was a significant difference in the number of CTCs between the healthy population and prostate cancer patients (P < 0.001). The results of the study showed that the CTCs capture identification system has good sensitivity and specificity in identifying prostate cancer patients. CONCLUSION: The CTCs test allows us to accurately identify patients who are at high risk for prostate cancer, allowing for early intervention and treating patients effectively.

Clinical Characteristics and Gene Mutation Analysis of Poststroke Epilepsy.

Epilepsy is one of the most common brain disorders worldwide. Poststroke epilepsy (PSE) affects functional retrieval after stroke and brings considerable social values. A stroke occurs when the blood circulation to the brain fails, causing speech difficulties, memory loss, and paralysis. An electroencephalogram (EEG) is a tool that may detect anomalies in brain electrical activity, including those induced by a stroke. Using EEG data to determine the electrical action in the brains of stroke patients is an effort to measure therapy. Hence in this paper, deep learning assisted gene mutation analysis (DL-GMA) was utilized for classifying poststroke epilepsy in patients. This study suggested a model categorizing poststroke patients based on EEG signals that utilized wavelet, long short-term memory (LSTM), and convolutional neural networks (CNN). Gene mutation analysis can help determine the cause of an individual's epilepsy, leading to an accurate diagnosis and the best probable medical management. The test outcomes show the viability of noninvasive approaches that quickly evaluate brain waves to monitor and detect daily stroke diseases. The simulation outcomes demonstrate that the proposed GL-GMA achieves a high accuracy ratio of 98.3%, a prediction ratio of 97.8%, a precision ratio of 96.5%, and a recall ratio of 95.6% and decreases the error rate 10.3% compared to other existing methods.

Follow-up assessment of atherosclerotic plaques in acute ischemic stroke patients using high-resolution vessel wall MR imaging.

PURPOSE: Data on evolution of intracranial plaques in acute ischemic stroke patients after receiving medical therapy is still limited. We aimed to investigate the plaque features associated with culprit lesions and to explore the plaque longitudinal changes during treatment using high-resolution vessel wall MR imaging (VW-MRI). METHODS: Twenty-three patients (16 men; mean age, 51.4 years ± 11.1) with acute ischemic stroke underwent 3-T VW-MRI for intracranial atherosclerosis and were taken follow-up assessments. Each identified plaque was retrospectively classified as culprit, probably culprit, or nonculprit. Plaque features were analyzed at both baseline and follow-up and were compared using paired t-test, paired Wilcoxon test, or McNemar's test. RESULTS: A total of 87 intracranial plaques were identified (23 [26.4%] culprit, 10 [11.5%] probably culprit, and 54 [62.1%] nonculprit plaques). The median time interval between initial and follow-up MRI scans was 8.0 months. In the multiple ordinal logistic regression analysis, plaque contrast ratio (CR) (OR, 1.037; 95% CI, 1.013-1.062; P = 0.002) and surface irregularity (OR, 4.768; 95% CI, 1.064-21.349; P = 0.041) were independently associated with culprit plaques. During follow-up, plaque length, maximum thickness, normalized wall index (NWI), stenosis degree, and CR significantly decreased (all P-values < 0.05) in the culprit plaque group. The plaque NWI and CR dropped in the probably culprit plaques (P = 0.041, 0.026, respectively). In the nonculprit plaque group, only plaque NWI and stenosis degree showed significant decrement (P = 0.017, 0.037, respectively). CONCLUSION: Follow-up VW-MRI may contribute to plaque risk stratification and may provide valuable insights into the evolution of different plaques in vivo.

HHLA2 Used as a Potential Prognostic and Immunological Biomarker and Correlated with Tumor Microenvironment in Pan-Cancer.

BACKGROUND: The role of HERV-H LTR-associating 2 (HHLA2) in cancer remains still unclear. This study analyzed the correlation between the prognosis and immune infiltrate function of HHLA2 in pan-cancers. METHODS: HHLA2 expression in pan-cancers was analyzed using the databases of TCGA, GTEx, TIMER, GEPIA, UALCAN, and GSEA databases. Multiple bioinformatic methods were used to investigate the correlation of HHLA2 expression with survival, pathological stage, tumor mutation burden (TMB), microsatellite instability (MSI), tumor microenvironment (TME), immune cell infiltration, and immune checkpoint gene (ICG), and gene functional enrichment was performed by Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA). RESULTS: HHLA2 was aberrantly expressed and was strongly correlated with positive or negative prognosis in multiple human cancers, which revealed that HHLA2 might play a vital role during cancer formation and development. Kaplan-Meier (KM) curves across cancers revealed that HHLA2 expression was correlated with overall survival (OS) in eight cancers, disease-specific survival (DSS) in seven cancers, disease-free interval (DFI) in four cancers, and progression-free interval (PFI) in nine cancers. Furthermore, HHLA2 expression was positively correlated with TMB in 6 cancer types and negatively associated with TMB in 7 cancer types, respectively. The former included ESCA, HNSC, KIRP, PAAD, PRAD, and PCPG; the latter contained COAD, LGG, LUAD, LUSC, THYM, THCA, and UCEC. Additionally, we found HHLA2 expression was negatively related to MSI in ACC, COAD, PAAD, and UCEC. More importantly, HHLA2 expression was remarkably correlated with the degree of tumor-infiltrating immune in many cancers, including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells and strongly associated with immune checkpoint genes in 13 tumor types. Furthermore, KEGG pathway analyses indicated that HHLA2 could potentially impact cancer etiology or pathogenesis by functioning in amino sugar and nucleotide sugar metabolism, cytosolic DNA sensing pathway, and peroxisome pathways. Meanwhile, GSVA analysis results all indicate that HHLA2 was correlated with TSC/mTOR, RTK, RAS/MAPK, PI3K/AKT, EMT, DNA Damage Response, Cell Cycle, and Apoptosis pathways in various cancers. CONCLUSION: HHLA2 can function as a prognostic biomarker and correlate with tumor immunity in human pan-cancer due to its important role in tumorigenesis and immune infiltration, which provides new insight into developing new targeted treatments in cancers.

Significance of KDM6A mutation in bladder cancer immune escape.

BACKGROUND: Bladder cancer (BC) is the fourth most prevalent neoplasm in men and is associated with high tumour recurrence rates, leading to major treatment challenges. Lysine-specific demethylase 6A (KDM6A) is frequently mutated in several cancer types; however, its effects on tumour progression and clinical outcome in BC remain unclear. Here, we explored the potential role of KDM6A in regulating the antitumor immune response. METHODS: We mined The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases for somatic mutation and clinical data in patients with BC. RESULTS: We found frequent mutations in 12 genes in both cohorts, including TP53, KDM6A, CSMD3, MUC16, STAG2, PIK3CA, ARID1A, RB1, EP300, ERBB2, ERBB3, and FGFR3. The frequency o KDM6A mutations in the TCGA and ICGC datasets was 25.97 and 24.27%, respectively. In addition, KDM6A mutation was associated with a lower number of tumour-infiltrating immune cells (TIICs) and indicated a state of immune tolerance. KDM6A mutation was associated with lower KDM6A mRNA level compared with that in samples carrying the wild-type gene. Further, survival analysis showed that the prognosis of patients with low KDM6A expression was worse than that with high KDM6A expression. Using the CIBERSORT algorithm, Tumor Immune Estimation Resource site, and Gene Set Enrichment Analysis, we found that KDM6A mutation downregulated nine signalling pathways that participate in the immune system and attenuated the tumour immune response. CONCLUSION: Overall, we conclude that KDM6A mutation is frequent in BC and promotes tumour immune escape, which may serve as a novel biomarker to predict the immune response.

Gene diagnosis and pedigree analysis of two Han ethnicity families with propionic acidemia in Fujian.

ABSTRACT: Propionic acidemia is associated with pathogenic variants in PCCA or PCCB gene. We investigated the potential pathogenic variants in PCCA or PCCB genes in Fujian Han population.Two probands and their families of Han ethnicity containing two generations were subject to newborn screening using tandem mass spectrometry, followed by diagnosis using urine gas chromatography mass spectrometry. Sanger sequencing was used to identify potential mutations in PCCA and PCCB genes.Compound heterozygous variants were identified in PCCB gene in two siblings of the first family, the youngest girl showed a novel missense variant c.1381G>C (p.Ala461Pro) in exon 13 and a heterozygous missense variant c.1301C>T (p.Ala434Val) in exon 13, which were inherited respectively from their parents. The oldest boy is a carrier with a novel missense variant c.1381G>C (p.Ala461Pro) in exon 13 which were inherited from his father. In the second family, c.1535G>A homozygous mutations were identified in the baby girl, which were inherited respectively from their parents. In silico analysis, several different types of bioinformatic software were utilized, which predicted that the novel variant c.1381G>C in PCCB gene was damaged. According to ACMG principle, the missense variant c.1381G>C (p.Ala461Pro) in exon 13 was a Variant of Undetermined Significance (VUS).One novel missense variant and two missense variants in PCCB gene were identified in the study. The novel variant of PCCB gene identified VUS was identified for the first time in the Chinese population, which enriched the mutational spectrum of PCCB gene.

Dynamic contrast-enhanced magnetic resonance imaging and diffusion-weighted imaging in the activity staging of terminal ileum Crohn's disease.

BACKGROUND: The activity staging of Crohn's disease (CD) in the terminal ileum is critical in developing an accurate clinical treatment plan. The activity of terminal ileum CD is associated with the microcirculation of involved bowel walls. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) can reflect perfusion and permeability of bowel walls by providing microcirculation information. As such, we hypothesize that DCE-MRI and DWI parameters can assess terminal ileum CD, thereby providing an opportunity to stage CD activity. AIM: To evaluate the value of DCE-MRI and DWI in assessing activity of terminal ileum CD. METHODS: Forty-eight patients with CD who underwent DCE-MRI and DWI were enrolled. The patients' activity was graded as remission, mild and moderate-severe. The transfer constant (Ktrans), wash-out constant (Kep), and extravascular extracellular volume fraction (Ve) were calculated from DCE-MRI and the apparent diffusion coefficient (ADC) was obtained from DWI. Magnetic Resonance Index of Activity (MaRIA) was calculated from magnetic resonance enterography. Differences in these quantitative parameters were compared between normal ileal loop (NIL) and inflamed terminal ileum (ITI) and among different activity grades. The correlations between these parameters, MaRIA, the Crohn's Disease Activity Index (CDAI), and Crohn's Disease Endoscopic Index of Severity (CDEIS) were examined. Receiver operating characteristic curve analyses were used to determine the diagnostic performance of these parameters in differentiating between CD activity levels. RESULTS: Higher Ktrans (0.07 ± 0.04 vs 0.01 ± 0.01), Kep (0.24 ± 0.11 vs 0.15 ± 0.05) and Ve (0.27 ± 0.07 vs 0.08 ± 0.03), but lower ADC (1.41 ± 0.26 vs 2.41 ± 0.30) values were found in ITI than in NIL (all P < 0.001). The Ktrans, Kep, Ve and MaRIA increased with disease activity, whereas the ADC decreased (all P < 0.001). The Ktrans, Kep, Ve and MaRIA showed positive correlations with the CDAI (r = 0.866 for Ktrans, 0.870 for Kep, 0.858 for Ve, 0.890 for MaRIA, all P < 0.001) and CDEIS (r = 0.563 for Ktrans, 0.567 for Kep, 0.571 for Ve, 0.842 for MaRIA, all P < 0.001), while the ADC showed negative correlations with the CDAI (r = -0.857, P < 0.001) and CDEIS (r = -0.536, P < 0.001). The areas under the curve (AUC) for the Ktrans, Kep, Ve, ADC and MaRIA values ranged from 0.68 to 0.91 for differentiating inactive CD (CD remission) from active CD (mild to severe CD). The AUC when combining the Ktrans, Kep and Ve was 0.80, while combining DCE-MRI parameters and ADC values yielded the highest AUC of 0.95. CONCLUSION: DCE-MRI and DWI parameters all serve as measures to stage CD activity. When they are combined, the assessment performance is improved and better than MaRIA.

Assessment of pediatric Crohn's disease activity: validation of the magnetic resonance enterography global score (MEGS) against endoscopic activity score (SES-CD).

OBJECTIVE: The aim of this study is to evaluate the ability of magnetic resonance enterography global score (MEGS) to diagnose the activity of pediatric Crohn's disease (CD) and its correlation with endoscopic activity score. MATERIALS AND METHODS: 70 pediatric CD patients (between the ages of 6 and 17) were enrolled who underwent ileocolonoscopy and magnetic resonance enterography (MRE) within 7 days. The simplified endoscopic activity score for Crohn's disease (SES-CD) and MEGS were acquired in the terminal ileum. Sensitivity and specificity of MEGS for detection disease activity against SES-CD was compared using the McNemar test. The correlation between MEGS and SES-CD was assessed by Spearman's rank estimation. The diagnostic accuracy of MEGS for active disease defined by SES-CD was calculated. Receiver operating characteristic curves (ROC) were constructed. RESULTS: Fifty-two pediatric CD patients (median age, 12 years old; 28 girls, 24 boys) were included. The incidence of upper gastrointestinal (GI) tract (23%) involvement and perianal lesions (42%) is high in pediatric Crohn's patients, and most of them suffer from internal hemorrhoids (86.5%). MEGS showed strong correlation to SES-CD (r = 0.70, P < 0.001). With endoscopic as the standard of reference, the MEGS had a high accuracy for the detection of inflammation (area under the ROC curve (AUC) of 0.89, sensitivity 0.95 and specificity 0.82) and for disease activity (AUC of 0.81, sensitivity 0.88 and specificity 0.75) in the terminal ileum. CONCLUSION: Pediatric Crohn's disease is unique. Our study has shown a good correlation between MEGS and endoscopy activity score with equal diagnostic efficacy. MEGS is a promising method to assess disease activity and perhaps be a valuable tool in following therapeutic changes.

Comparison of [68Ga]Ga-DOTA-FAPI-04 and [18F] FDG PET/CT for the diagnosis of primary and metastatic lesions in patients with various types of cancer.

PURPOSE: We evaluated the potential usefulness of [68Ga]Ga-DOTA-FAPI-04 positron emission tomography/computed tomography (PET/CT) for the diagnosis of primary and metastatic lesions in various types of cancer, compared with [18F] FDG PET/CT. METHODS: A total of 75 patients with various types of cancer underwent contemporaneous [68Ga]Ga-DOTA-FAPI-04 and [18F] FDG PET/CT either for an initial assessment or for recurrence detection. Tumour uptake was quantified by the maximum standard uptake value (SUVmax). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of [18F] FDG and [68Ga]Ga-DOTA-FAPI-04 PET/CT were calculated and compared to evaluate the diagnostic efficacy. RESULTS: The study cohort consisted of 75 patients (47 males and 28 females; median age, 61.5 years; age range, 32-85 years). Fifty-four patients with 12 different tumour entities underwent paired [68Ga]Ga-DOTA-FAPI-04 and [18F] FDG PET/CT for initial assessment, while the other 21 patients underwent paired scans for recurrence detection. [68Ga]Ga-DOTA-FAPI-04 PET/CT was able to clearly identify 12 types of malignant tumours with favourable tumour-to-background contrast, which resulted in a higher detection rate of primary tumours than did [18F] FDG PET/CT (98.2% vs. 82.1%, P = 0.021). Meanwhile, [68Ga]Ga-DOTA-FAPI-04 PET/CT showed a better sensitivity than [18F] FDG PET/CT in the detection of lymph nodes (86.4% vs. 45.5%, P = 0.004) and bone and visceral metastases (83.8% vs. 59.5%, P = 0.004). CONCLUSION: [68Ga]Ga-DOTA-FAPI-04 PET/CT showed a superior diagnostic efficacy than [18F] FDG PET/CT for the diagnosis of primary and metastatic lesions in patients with various types of cancer, especially in identifying liver metastases, peritoneal carcinomatosis, and brain tumours.

Differentiation between benign and malignant palatal tumors using conventional MRI: a retrospective analysis of 130 cases.

OBJECTIVES: To evaluate the discriminative value of conventional magnetic resonance imaging between benign and malignant palatal tumors. STUDY DESIGN: Conventional magnetic resonance imaging features of 130 patients with palatal tumors confirmed by histopathologic examination were retrospectively reviewed. Clinical data and imaging findings were assessed between benign and malignant tumors and between benign and low-grade malignant salivary gland tumors. The variables that were significant in differentiating benign from malignant lesions were further identified using logistic regression analysis. Moreover, imaging features of each common palatal histologic entity were statistically analyzed with the rest of the tumors to define their typical imaging features. RESULTS: Older age, partially defined and ill-defined margins, and absence of a capsule were highly suggestive of malignant palatal tumors, especially ill-defined margins (ß = 6.400). The precision in determining malignant palatal tumors achieved a sensitivity of 92.8% and a specificity of 85.6%. In addition, irregular shape, ill-defined margins, lack of a capsule, perineural spread, and invasion of surrounding structures were more often associated with low-grade malignant salivary gland tumors. CONCLUSION: Conventional magnetic resonance imaging is useful for differentiating benign from malignant palatal tumors as well as benign salivary gland tumors from low-grade salivary gland malignancies.

Design, Synthesis, and Biological Evaluation of N,N-Disubstituted-4-Arylthiazole-2-Methylamine Derivatives as Cholesteryl Ester Transfer Inhibitors.

Cholesteryl ester transfer protein (CETP) has been identified as a potential target for cardiovascular disease (CVD) for its important role in the reverse cholesteryl transfer (RCT) process. In our previous work, compound 5 was discovered as a moderate CETP inhibitor. The replacement of the amide linker by heterocyclic aromatics and then a series of N,N-substituted-4-arylthiazole-2-methylamine derivatives were designed by utilizing a conformational restriction strategy. Thirty-six compounds were synthesized and evaluated for their CETP inhibitory activities. Structure-activity relationship studies indicate that electron donor groups substituted ring A, and electron-withdrawing groups at the 4-position of ring B were critical for potency. Among these compounds, compound 30 exhibited excellent CETP inhibitory activity (IC50 = 0.79 ± 0.02 µM) in vitro and showed an acceptable metabolic stability.