The features associated with mammography-occult MRI-detected newly diagnosed breast cancer analysed by comparing machine learning models with a logistic regression model.

PURPOSE: To compare machine learning (ML) models with logistic regression model in order to identify the optimal factors associated with mammography-occult (i.e. false-negative mammographic findings) magnetic resonance imaging (MRI)-detected newly diagnosed breast cancer (BC). MATERIAL AND METHODS: The present single-centre retrospective study included consecutive women with BC who underwent mammography and MRI (no more than 45 days apart) for breast cancer between January 2018 and May 2023. Various ML algorithms and binary logistic regression analysis were utilized to extract features linked to mammography-occult BC. These features were subsequently employed to create different models. The predictive value of these models was assessed using receiver operating characteristic curve analysis. RESULTS: This study included 1957 malignant lesions from 1914 patients, with an average age of 51.64 ± 9.92 years and a range of 20-86 years. Among these lesions, there were 485 mammography-occult BCs. The optimal features of mammography-occult BC included calcification status, tumour size, mammographic density, age, lesion enhancement type on MRI, and histological type. Among the different ML models (ANN, L1-LR, RF, and SVM) and the LR-based combined model, the ANN model with RF features was found to be the optimal model. It demonstrated the best discriminative performance in predicting mammography false- negative findings, with an AUC of 0.912, an accuracy of 86.90%, a sensitivity of 85.85%, and a specificity of 84.18%. CONCLUSION: Mammography-occult MRI-detected breast cancers have features that should be considered when performing breast MRI to improve the detection rate for breast cancer and aid in clinician management.

In-Depth Serum Proteomics Reveals the Trajectory of Hallmarks of Cancer in Hepatitis B Virus-Related Liver Diseases.

Hepatocellular carcinoma (HCC) is a prevalent cancer in China, with chronic hepatitis B (CHB) and liver cirrhosis (LC) being high-risk factors for developing HCC. Here, we determined the serum proteomes (762 proteins) of 125 healthy controls and Hepatitis B virus-infected CHB, LC, and HCC patients and constructed the first cancerous trajectory of liver diseases. The results not only reveal that the majority of altered biological processes were involved in the hallmarks of cancer (inflammation, metastasis, metabolism, vasculature, and coagulation) but also identify potential therapeutic targets in cancerous pathways (i.e., IL17 signaling pathway). Notably, the biomarker panels for detecting HCC in CHB and LC high-risk populations were further developed using machine learning in two cohorts comprised of 200 samples (discovery cohort = 125 and validation cohort = 75). The protein signatures significantly improved the area under the receiver operating characteristic curve of HCC (CHB discovery and validation cohort = 0.953 and 0.891, respectively; LC discovery and validation cohort = 0.966 and 0.818, respectively) compared to using the traditional biomarker, alpha-fetoprotein, alone. Finally, selected biomarkers were validated with parallel reaction monitoring mass spectrometry in an additional cohort (n = 120). Altogether, our results provide fundamental insights into the continuous changes of cancer biology processes in liver diseases and identify candidate protein targets for early detection and intervention.

The breakdown of both strange metal and superconducting states at a pressure-induced quantum critical point in iron-pnictide superconductors.

Here we report the first observation of the concurrent breakdown of the strange metal (SM) normal state and superconductivity at a pressure-induced quantum critical point in Ca10(Pt4As8)((Fe0.97Pt0.03)2As2)5 superconductor. We find that, upon suppressing the superconducting state, the power exponent (α) changes from 1 to 2, and the slope of the temperature-linear resistivity per FeAs layer (A□) gradually diminishes. At a critical pressure, A□ and superconducting transition temperature (Tc) go to zero concurrently, where a quantum phase transition from a superconducting state with a SM normal state to a non-superconducting Fermi liquid state occurs. Scaling analysis reveals that the change of A□ with Tc obeys the relation of Tc ~ (A□)0.5, similar to what is seen in other chemically doped unconventional superconductors. These results suggest that there is a simple but powerful organizational principle of connecting the SM normal state with the high-Tc superconductivity.

S100A11 Promotes Metastasis via AKT and ERK Signaling Pathways and Has a Diagnostic Role in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common and malignant liver tumor worldwide, although the treatment approaches for HCC continue to evolve, metastasis is the main reason for high mortality rates. S100 calcium-binding protein A11 (S100A11), an important member of the S100 family of small calcium-binding proteins, is overexpressed in various cells and regulates tumor development and metastasis. However, few studies report the role and underlying regulatory mechanisms of S100A11 in HCC development and metastasis. Herein, we discovered that S100A11 is overexpressed and associated with poor clinical outcomes in HCC cohorts, and we provided the first demonstration that S100A11 could serve as a novel diagnostic biomarker used in conjunction with AFP for HCC. Further analysis implied that S100A11 outperforms AFP in determining whether HCC patients have hematogenous metastasis or not. Using in vitro cell culture model, we demonstrated that S100A11 is overexpressed in metastatic hepatoma cells, knockdown of S100A11 decreases hepatoma cells proliferation, migration, invasion, and epithelial-mesenchymal transition process by inhibiting AKT and ERK signaling pathways. Altogether, our study provides new sights into the biological function and mechanisms underlying S100A11 in promoting metastasis of HCC and explores a novel target for HCC diagnosis and treatment.

Respiratory immune status and microbiome in recovered COVID-19 patients revealed by metatranscriptomic analyses.

Coronavirus disease 2019 (COVID-19) is currently a severe threat to global public health, and the immune response to COVID-19 infection has been widely investigated. However, the immune status and microecological changes in the respiratory systems of patients with COVID-19 after recovery have rarely been considered. We selected 72 patients with severe COVID-19 infection, 57 recovered from COVID-19 infection, and 65 with non-COVID-19 pneumonia, for metatranscriptomic sequencing and bioinformatics analysis. Accordingly, the differentially expressed genes between the infected and other groups were enriched in the chemokine signaling pathway, NOD-like receptor signaling pathway, phagosome, TNF signaling pathway, NF-kappa B signaling pathway, Toll-like receptor signaling pathway, and C-type lectin receptor signaling pathway. We speculate that IL17RD, CD74, and TNFSF15 may serve as disease biomarkers in COVID-19. Additionally, principal coordinate analysis revealed significant differences between groups. In particular, frequent co-infections with the genera Streptococcus, Veillonella, Gemella, and Neisseria, among others, were found in COVID-19 patients. Moreover, the random forest prediction model with differential genes showed a mean area under the curve (AUC) of 0.77, and KCNK12, IL17RD, LOC100507412, PTPRT, MYO15A, MPDZ, FLRT2, SPEG, SERPINB3, and KNDC1 were identified as the most important genes distinguishing the infected group from the recovered group. Agrobacterium tumefaciens, Klebsiella michiganensis, Acinetobacter pittii, Bacillus sp. FJAT.14266, Brevundimonas naejangsanensis, Pseudopropionibacterium propionicum, Priestia megaterium, Dialister pneumosintes, Veillonella rodentium, and Pseudomonas protegens were selected as candidate microbial markers for monitoring the recovery of COVID patients. These results will facilitate the diagnosis, treatment, and prognosis of COVID patients recovering from severe illness.

The expression of cuproptosis-related genes in hepatocellular carcinoma and their relationships with prognosis.

Background: The mechanism of cuproptosis has recently been reported in lipoylated proteins of the tricarboxylic acid (TCA) cycle. Besides, the role of copper was previously recognized in cancer progression. We evaluated the prognostic value of cuproptosis-related gene expression in hepatocellular carcinoma (HCC). Methods: Remarkable genes were selected both in differential expression analysis and Kaplan-Meier survival analysis from ninety-six cuproptosis-related genes using The Cancer Genome Atlas (TCGA) database. The relationships between clinical characteristics and gene expression were performed with Wilcoxon signed-rank test, Kruskal-Wallis test, and logistic regression. Clinicopathologic factors correlated with overall survival in HCCs conducting univariate and multivariate Cox regression analysis. Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and Human Protein Atlas (HPA) databases were utilized to verify the results. Furthermore, Gene Set Enrichment Analysis (GSEA) identified the potential key pathways that dominate cuproptosis in HCC. Results: Elevated ATP7A, SLC25A3, SCO2, COA6, TMEM199, ATP6AP1, LIPT1, DLAT, PDHA1, MTF1, ACP1, FDX2, NUBP2, CIAPIN1, ISCA2 and NDOR1 expression, as well as declined AOC1, FDX1, MT-CO1, and ACO1 expression were significantly emerged in HCC tumor tissues and were significantly associated with HCCs poor survival. The expressions of screened cuproptosis-related genes were prominently related to clinical features. GSEA analysis reported many key signaling pathways (such as natural killer cell mediated cytotoxicity, TCA cycle, glutathione metabolism, ATP-binding cassette (ABC) transporters, Notch signaling pathway, ErbB signaling pathway, and metabolism of xenobiotics by cytochrome p450) were differentially enriched in HCCs with varying degrees of cuproptosis-related genes expression. Conclusions: The twenty cuproptosis-related genes might be utilized as new candidate prognostic biomarkers for HCC.

The association between several autophagy-related genes and their prognostic values in hepatocellular carcinoma: a study on the foundation of TCGA, GEPIA and HPA databases.

BACKGROUND: The purpose of this study was to investigate the relationship between the expression of autophagy-related genes and prognosis in hepatocellular carcinoma (HCC). METHODS AND RESULTS: We selected three autophagy-related genes (ATG3, ATG7, and ATG9A) from gene expression data of liver cancer patients in The Cancer Genome Atlas (TCGA) database by Kaplan-Meier survival analysis, univariate and multivariate Cox regression analysis, and Gene Set Enrichment Analysis (GSEA). Human Protein Atlas (HPA) and Gene Expression Profiling Interactive Analysis (GEPIA) databases were applied to testify the credibility of our results. The expression levels of ATG3, ATG7, and ATG9A were verified by real-time quantitative PCR (RT-qPCR) in normal liver cells (L02) and three HCC cell lines (HepG2, Hep3b, and Li-7). Data analysis results from TCGA showed high ATG3, ATG7, ATG9A expression in HCC tumor tissues. Kaplan-Meier survival analysis showed that the survival rate of the high expression group of ATG3, ATG7, and ATG9A was all significantly lower than the low expression group. GSEA analysis showed that many signaling pathways (such as the regulation of autophagy, glycine serine and threonine metabolism, pathways in cancer, mitogen-activated protein kinase (MAPK) signaling pathway, mammalian target of rapamycin (mTOR) signaling pathway, as well as P53 signaling pathway) were differentially enriched in HCCs with ATG3, ATG7, and ATG9A expression. GEPIA and RT-qPCR also identified that the mRNA expression level of ATG3, ATG7, and ATG9A in normal liver cells were significantly lower than in HCC cells. High protein expression of ATG3, ATG7, and ATG9A was displayed in HCCs from the HPA database. CONCLUSIONS: The ATG3, ATG7, ATG9A might be utilized as prognostic biomarkers for liver cancer.

Comparison of Survival and Risk Factors of Differentiated Thyroid Cancer in the Geriatric Population.

Purpose: The incidence rate of differentiated thyroid cancer (DTC), the most common type of thyroid cancer, has increased in the past two decades. The present study analyzed the clinical and pathological characteristics of DTC, and discussed the risk factors for survival in elderly age-risk DTC patients. Methods: Elderly patients who were diagnosed with DTC, and subsequently underwent surgery for DTC, were identified from the SEER database (1988-2008). Based on histology, these patients were divided into C-PTC, FV-PTC, and FTC. The clinical characteristics, pathological features, and treatments undertaken were compared among these patients. Cox proportional hazards analysis was performed to evaluate the risk factors to disease-specific survival (DSS). Results: In elderly DTC patients, FV-PTC shows intermediate tumor features compared to C-PTC and FTC, but presented a better outcome. Being male, African-American, tumors sized bigger than 4 cm, extrathyroidal extension, lymph node metastasis, and distant metastasis, were all strong risk factors for DSS in elderly DTC patients (all p < 0.05). No difference was found between lobectomy and total thyroidectomy with respect to DSS, and radiation therapy conferred no apparent advantage with respect to DSS (both p > 0.05). Discussion: Patients with FV-PTC needed more specific histology cataloging and risk assessment, suggesting conservative therapy. Risk stratification should be paid attention to, and treatment should be individualized for elderly patients.

R-spondin3 promotes the tumor growth of choriocarcinoma JEG-3 cells.

R-spondin3 (RSPO3), an activator of Wnt/ß-catenin signaling, plays a key role in tumorigenesis of various cancers, but its role in choriocarcinoma remains unknown. To investigate the effect of RSPO3 on the tumor growth of choriocarcinoma JEG-3 cells, the expression of RSPO3 in human term placenta was detected, and a stable RSPO3-overexpressing JEG-3 cell line was established via lentivirus-mediated transduction. The expression of biomarkers involved in tumorigenicity was detected in the RSPO3-overexpressing JEG-3 cells, and cell proliferation, invasion, migration, and apoptosis were investigated. Moreover, soft agar clonogenic assays and xenograft tumorigenicity assays were performed to assess the effect of RSPO3 on tumor growth in vitro and in vivo. The results showed that RSPO3 was widely expressed in human term placenta and overexpression of RSPO3 promoted the proliferation and inhibited the migration, invasion, and apoptosis of the JEG-3 cells. Meanwhile, RSPO3 overexpression promoted tumor growth both in vivo and in vitro. Further investigation showed that the phosphorylation levels of Akt, phosphatidylinositol 3-kinase (PI3K), and ERK as well the expression of ß-catenin and proliferating cell nuclear antigen (PCNA) were increased in the RSPO3-overexpressing JEG-3 cells and tumor xenograft. Taken together, these data indicate that RSPO3 promotes the tumor growth of choriocarcinoma via Akt/PI3K/ERK signaling, which supports RSPO3 as an oncogenic driver promoting the progression of choriocarcinoma.

Targeting delivery of partial VAR2CSA peptide guided N-2-Hydroxypropyl trimethyl ammonium chloride chitosan nanoparticles for multiple cancer types.

To developing a multiple cancer types targeting drug delivery carrier system, a 28 amino acids from the VAR2CSA was synthesized as the placental CSA-binding peptide (plCSA-BP). Its specific binding ability to cancer cells was tested on cancer tissue array, and the results showed that plCSA-BP could bind to multiple cancer types. Then, the plCSA-BP was used as a guiding peptide to coat nanoparticles synthesized from N-2-HACC (CSA/HACC-NPs) which were loaded with prodigiosin (CSA/HACC-PNPs) or indocyanine green (CSA/HACC-INPs). The cancer cells specific targeting and efficacy of the CSA/HACC-PNPs were tested by different cancer cells in vitro and various cancer xenograft model in vivo. A scramble peptide (SCR) was used as control and synthesized SCR/HACC-PNPs and SCR/HACC-INPs. The results showed that the CSA/HACC-INPs could specifically uptake by JEG-3, PC3 and A594 cells, and the CSA/HACC-PNPs exhibited better anti-cancer activity and lower toxic effect in subcutaneous choriocarcinoma and prostatic tumor models compared with the free prodigiosin, HACC-PNPs and SCR/HACC-PNPs. So, the CSA/HACC-NPs could be used as a specific delivery carrier for multiple cancer types, and provided an alternate treatment option of various cancers with a single recipe.

Targeted Delivery Prodigiosin to Choriocarcinoma by Peptide-Guided Dendrigraft Poly-l-lysines Nanoparticles.

The available and effective therapeutic means to treat choriocarcinoma is seriously lacking, mainly due to the toxic effects caused by chemotherapy and radiotherapy. Accordingly, we developed a method for targeting delivery of chemotherapeutical drugs only to cancer cells, not normal cells, in vivo, by using a synthetic placental chondroitin sulfate (CSA)-binding peptide (plCSA-BP) derived from malarial protein VAR2CSA. A 28 amino acids placental CSA-binding peptide (plCSA-BP) from the VAR2CSA was synthesized as a guiding peptide for tumor-targeting delivery, dendrigraft poly-L-lysines (DGL) was modified with plCSA-BP and served as a novel targeted delivery carrier. Choriocarcinoma was selected to test the effect of targeted delivery carrier, and prodigiosin isolated from Serratia marcescens subsp. lawsoniana was selected as a chemotherapeutical drug and encapsulated in the DGL modified by the plCSA-BP nanoparticles (DGL/CSA-PNPs). DGL/CSA-PNPs had a sustained slow-release feature at pH 7.4, which could specifically bind to the JEG3 cells and exhibited better anticancer activity than that of the controls. The DGL/CSA-PNPs induced the apoptosis of JEG3 cells through caspase-3 and the P53 signaling pathway. DGL/CSA-PNPs can be used as an excellent targeted delivery carrier for anticancer drugs, and the prodigiosin could be an alternative chemotherapeutical drug for choriocarcinoma.

Comprehensive Evaluation of the Effectiveness and Safety of Placenta-Targeted Drug Delivery Using Three Complementary Methods.

No effective treatments currently exist for placenta-associated pregnancy complications, and developing strategies for the targeted delivery of drugs to the placenta while minimizing fetal and maternal side effects remains challenging. Targeted nanoparticle carriers provide new opportunities to treat placental disorders. We recently demonstrated that a synthetic placental chondroitin sulfate A binding peptide (plCSA-BP) could be used to guide nanoparticles to deliver drugs to the placenta. In this protocol, we describe in detail a system for assessing the efficiency of drug delivery to the placenta by plCSA-BP that employs three separate methods used in combination: in vivo imaging, high-frequency ultrasound (HFUS), and high-performance liquid chromatography (HPLC). Using in vivo imaging, plCSA-BP-guided nanoparticles were visualized in the placentas of live animals, while HFUS and HPLC demonstrated that plCSA-BP-conjugated nanoparticles efficiently and specifically delivered methotrexate to the placenta. Thus, a combination of these methods can be used as an effective tool for the targeted delivery of drugs to the placenta and development of new treatment strategies for several pregnancy complications.

Targeted delivery of doxorubicin by CSA-binding nanoparticles for choriocarcinoma treatment.

Gestational trophoblastic neoplasia (GTN) can result from the over-proliferation of trophoblasts. Treatment of choriocarcinoma, the most aggressive GTN, currently requires high doses of systemic chemotherapeutic agents, which result in indiscriminate drug distribution and severe toxicity. To overcome these disadvantages and enhance the chemotherapeutic efficacy, chondroitin sulfate A (CSA)-binding nanoparticles were developed for the targeted delivery of doxorubicin (DOX) to choriocarcinoma cells using a synthetic CSA-binding peptide (CSA-BP), derived from malarial protein, which specifically binds to the CSA exclusively expressed in the placental trophoblast. CSA-BP-conjugated nanoparticles rapidly bonded to choriocarcinoma (JEG3) cells and were efficiently internalized into the lysosomes. Moreover, CSA-BP modification significantly increased the anti-cancer activity of the DOX-loaded nanoparticles in vitro. Intravenous injections of CSA-BP-conjugated nanoparticles loaded with indocyanine green (CSA-INPs) were rapidly localized to the tumor. The CSA-targeted nanoparticles loaded with DOX (CSA-DNPs) strongly inhibited primary tumor growth and, more importantly, significantly suppressed metastasis in vivo. Collectively, our results highlight the potential of the CSA-BP-decorated nanoparticles as an alternative targeted delivery system of chemotherapeutic agents for treating choriocarcinoma and for developing new GTN therapies based on drug targeting.