An Advanced Machine Learning Model for a Web-Based Artificial Intelligence-Based Clinical Decision Support System Application: Model Development and Validation Study.

BACKGROUND: Breast cancer is a leading global health concern, necessitating advancements in recurrence prediction and management. The development of an artificial intelligence (AI)-based clinical decision support system (AI-CDSS) using ChatGPT addresses this need with the aim of enhancing both prediction accuracy and user accessibility. OBJECTIVE: This study aims to develop and validate an advanced machine learning model for a web-based AI-CDSS application, leveraging the question-and-answer guidance capabilities of ChatGPT to enhance data preprocessing and model development, thereby improving the prediction of breast cancer recurrence. METHODS: This study focused on developing an advanced machine learning model by leveraging data from the Tri-Service General Hospital breast cancer registry of 3577 patients (2004-2016). As a tertiary medical center, it accepts referrals from four branches-3 branches in the northern region and 1 branch on an offshore island in our country-that manage chronic diseases but refer complex surgical cases, including breast cancer, to the main center, enriching our study population's diversity. Model training used patient data from 2004 to 2012, with subsequent validation using data from 2013 to 2016, ensuring comprehensive assessment and robustness of our predictive models. ChatGPT is integral to preprocessing and model development, aiding in hormone receptor categorization, age binning, and one-hot encoding. Techniques such as the synthetic minority oversampling technique address the imbalance of data sets. Various algorithms, including light gradient-boosting machine, gradient boosting, and extreme gradient boosting, were used, and their performance was evaluated using metrics such as the area under the curve, accuracy, sensitivity, and F1-score. RESULTS: The light gradient-boosting machine model demonstrated superior performance, with an area under the curve of 0.80, followed closely by the gradient boosting and extreme gradient boosting models. The web interface of the AI-CDSS tool was effectively tested in clinical decision-making scenarios, proving its use in personalized treatment planning and patient involvement. CONCLUSIONS: The AI-CDSS tool, enhanced by ChatGPT, marks a significant advancement in breast cancer recurrence prediction, offering a more individualized and accessible approach for clinicians and patients. Although promising, further validation in diverse clinical settings is recommended to confirm its efficacy and expand its use.

A Case of Oncocytic Adrenal Cortical Neoplasm with Uncertain Malignant Potential Turned Out to Be Oncocytic Adrenal Cortical Carcinoma with Distant Metastasis: Could Pathology Do Better Initially?

Oncocytic adrenal cortical neoplasms are rare cases and are divided into oncocytoma, oncocytic neoplasms of uncertain malignant potential and oncocytic adrenal cortical carcinomas, based on the Lin-Weiss-Bisceglia (LWB) histological system adopted in the current World Health Organization (WHO). We reported a 42-year-old female diagnosed with an oncocytic neoplasm of uncertain malignant potential initially, which turned out to be a carcinoma owing to distant metastasis to the scalp and lung. To our knowledge, this is the first published case of oncocytic adrenal cortical carcinoma with scalp metastasis. This case also highlights the limitation of the current diagnostic algorithm and emphasizes the importance of two parameters (PHH3 and Ki-67) for determining the malignant potential of oncocytic adrenal cortical neoplasms.

Mechanistic Investigation of Oxidative Decarboxylation Catalyzed by Two Iron(II)- and 2-Oxoglutarate-Dependent Enzymes.

Two non-heme iron enzymes, IsnB and AmbI3, catalyze a novel decarboxylation-assisted olefination to produce indole vinyl isonitrile, an important building block for many natural products. Compared to other reactions catalyzed by this enzyme family, decarboxylation-assisted olefination represents an attractive biosynthetic route and a mechanistically unexplored pathway in constructing a C═C bond. Using mechanistic probes, transient state kinetics, reactive intermediate trapping, spectroscopic characterizations, and product analysis, we propose that both IsnB and AmbI3 initiate stereoselective olefination via a benzylic C-H bond activation by an Fe(IV)-oxo intermediate, and the reaction likely proceeds through a radical- or carbocation-induced decarboxylation to complete C═C bond installation.

Elucidating the Reaction Pathway of Decarboxylation-Assisted Olefination Catalyzed by a Mononuclear Non-Heme Iron Enzyme.

Installation of olefins into molecules is a key transformation in organic synthesis. The recently discovered decarboxylation-assisted olefination in the biosynthesis of rhabduscin by a mononuclear non-heme iron enzyme ( P.IsnB) represents a novel approach in olefin construction. This method is commonly employed in natural product biosynthesis. Herein, we demonstrate that a ferryl intermediate is used for C-H activation at the benzylic position of the substrate. We further establish that P.IsnB reactivity can be switched from olefination to hydroxylation using electron-withdrawing groups appended on the phenyl moiety of the analogues. These experimental observations imply that a pathway involving an initial C-H activation followed by a benzylic carbocation species or by electron transfer coupled ß-scission is likely utilized to complete C═C bond formation.

Emodin modulates epigenetic modifications and suppresses bladder carcinoma cell growth.

The deregulation of epigenetics was involved in early and subsequent carcinogenic events. Reversing cancer epigenetics to restore a normal epigenetic condition could be a rational approach for cancer treatment and specialized prevention. In the present study, we found that the expression levels of two epigenetic markers, histone H3K27 trimethylation (H3K27me3), was low but histone H3S10 phosphorylation (pH3Ser10) was high in human bladder cancer tissues, which showed opposite expression patterns in their normal counterparts. Thus, we investigated whether a natural product, emodin, has the ability to reverse these two epigenetic modifications and inhibit bladder cancer cell growth. Emodin significantly inhibited the cell growth of four bladder cancer cell lines in a dose- and time-dependent manner. Emodin treatment did not induce specific cell cycle arrest, but it altered epigenetic modifications. Emodin treatment resulted in the suppression of pH3Ser10 and increased H3K27me3, contributing to gene silencing in bladder cancer cells. Microarray analysis demonstrated that oncogenic genes including fatty acid binding protein 4 (FABP4) and fibroblast growth factor binding protein 1 (HBP17), RGS4, tissue inhibitor of metalloproteinase 3 (TIMP3), WNT5b, URB, and collagen, type VIII, alpha 1 (COL8A1) responsible for proliferation, survival, inflammation, and carcinogenesis were significantly repressed by emodin. The ChIP assays also showed that emodin increased H3K27me3 but decreased pH3Ser10 modifications on the promoters of repressed genes, which indicate that emodin reverses the cancer epigenetics towards normal epigenetic situations. In conclusion, our work demonstrates the significant anti-neoplastic activity of emodin on bladder cancer cells and elucidates the novel mechanisms of emodin-mediated epigenetic modulation of target genes. Our study warrants further investigation of emodin as an effective therapeutic or preventive agent for bladder cancer.

Enhanced enterovirus 71 virus-like particle yield from a new baculovirus design.

Enterovirus 71 (EV71) is responsible for the outbreaks of hand-foot-and-mouth disease in the Asia-Pacific region. To produce the virus-like particle (VLP) vaccine, we previously constructed recombinant baculoviruses to co-express EV71 P1 polypeptide and 3CD protease using the Bac-to-Bac(®) vector system. The recombinant baculoviruses resulted in P1 cleavage by 3CD and subsequent VLP assembly in infected insect cells, but caused either low VLP yield or excessive VLP degradation. To tackle the problems, here we explored various expression cassette designs and flashBAC GOLD™ vector system which was deficient in v-cath and chiA genes. We found that the recombinant baculovirus constructed using the flashBAC GOLD™ system was insufficient to improve the EV71 VLP yield. Nonetheless, BacF-P1-C3CD, a recombinant baculovirus constructed using the flashBAC GOLD(TM) system to express P1 under the polh promoter and 3CD under the CMV promoter, dramatically improved the VLP yield while alleviating the VLP degradation. Infection of High Five(TM) cells with BacF-P1-C3CD enhanced the total and extracellular VLP yield to ≈268 and ≈171 mg/L, respectively, which enabled the release of abundant VLP into the supernatant and simplified the downstream purification. Intramuscular immunization of mice with 5 µg purified VLP induced cross-protective humoral responses and conferred protection against lethal virus challenge. Given the significantly improved extracellular VLP yield (≈171 mg/L) and the potent immunogenicity conferred by 5 µg VLP, one liter High Five(TM) culture produced ≈12,000 doses of purified vaccine, thus rendering the EV71 VLP vaccine economically viable and able to compete with inactivated virus vaccines.

Galectin-1 upregulates CXCR4 to promote tumor progression and poor outcome in kidney cancer.

Galectin-1, a ß-galactoside-binding lectin, is involved in many physiologic and pathologic processes, including cell adhesion, differentiation, angiogenesis, and tumor progression. However, the role of galectin-1 in kidney cancer remains elusive. This study evaluated the role of galectin-1 in the progression and clinical prognosis of renal cell carcinoma. We found significant overexpression of galectin-1 in both kidney cancer cell lines and metastatic tissue specimens from patients with renal cell carcinoma. Knockdown of galectin-1 gene expression in renal cancer cell lines reduced cell invasion, clonogenic ability, and epithelial-mesenchymal transition in vitro; reduced tumor outgrowth in vivo; and inhibited the angiogenesis-inducing activity of these cells in vitro and in vivo. Galectin-1 knockdown decreased CXCR4 expression levels in kidney cancer cells, and restoration of CXCR4 expression in galectin-1-silenced cells rescued cell motility and clonogenic ability. Additional studies suggested that galectin-1 induced CXCR4 expression through activation of nuclear factor-κB (NF-κB). Analysis of patient specimens confirmed the clinical significance and positive correlation between galectin-1 and CXCR4 expression levels and revealed concomitant overexpression of galectin-1 and CXCR4 associated adversely with overall and disease-free survival. Our findings suggest that galectin-1 promotes tumor progression through upregulation of CXCR4 via NF-κB. The coordinated upregulation of galectin-1 and CXCR4 may be a novel prognostic factor for survival in patients with renal cell carcinoma and the galectin-1-CXCR4 axis may serve as a therapeutic target in this disease.

The triterpenoids of Hibiscus syriacus induce apoptosis and inhibit cell migration in breast cancer cells.

BACKGROUND: Breast cancer-related mortality increases annually. The efficacy of current breast cancer treatments is limited, and they have numerous side effects and permit high recurrence. Patients with estrogen receptor (ER)-negative or triple-negative breast cancer are particularly difficult to treat. Treatment for this type of cancer is lacking, and its prognosis is poor, necessitating the search for alternative treatments. METHODS: This study screened Chinese herb Hibiscus syriacus extracts and identified a novel anti-cancer drug for patients with ER-negative breast cancer. The inhibitory effects on cell viability and migration were evaluated for each compound, and the molecular regulatory effects were evaluated on both mRNA and protein levels. RESULT: We found several triterpenoids including betulin (K02) and its derivatives (K03, K04, and K06) from H. syriacus inhibited human triple-negative breast cancer cell viability and migration but revealed smaller cytotoxic effects on normal mammalian epithelial cells. Betulin and its derivatives induced apoptosis by activating apoptosis-related genes. In addition, they activated p21 expression, which induced cell cycle arrest in breast cancer cells. Betulin (K02) and betulinic acid (K06) had stronger inhibitory effects on cell viability and migration than K03 and K04. CONCLUSIONS: H. syriacus extracts might inhibit breast cancer cell viability and induce apoptosis by activating p53 family regulated pathways and inhibiting AKT activation. H. syriacus extracts may provide important insight into the development of novel alternative therapies for breast cancer.

First total synthesis of ganglioside DSG-A possessing neuritogenic activity.

The first total synthesis of ganglioside DSG-A (1) is achieved via chemoselective glycosylation and a [1 + 1 + 2] synthetic strategy. We have also developed an efficient method that can be handled on large scale (50 g) for the synthesis of the phytosphingosine.

CDH1 polymorphisms and haplotypes in sporadic diffuse and intestinal gastric cancer: a case-control study based on direct sequencing analysis.

BACKGROUND: Findings related to the influence of the -160C → A promoter polymorphism and haplotypes of the E-cadherin (CDH1) gene have not been consistent in previous studies regarding the risk for sporadic gastric cancer. Investigators in most previous studies detected those genotypes using restriction fragment length polymorphism analysis. Therefore, we conducted a case-control study to investigate the association of the CDH1 - 160C → A promoter polymorphism and haplotypes for cancer risk related to sporadic diffuse and intestinal gastric cancer by direct sequencing analysis. METHODS: We included 107 diffuse gastric cancer cases, 60 intestinal gastric cancer cases and 134 controls. The genotypic polymorphisms in the -160 promoter region, exons and intron-exon boundaries of CDH1 were detected by direct sequencing analysis. Genotype frequencies were compared. The CDH1 - 160C → A promoter polymorphism and four polymorphisms (48 + 6 T → C, 2076C → T, 2253C → T and 1937-13 T → C) were included in the haplotype analyses, which were estimated using the expectation-maximization algorithm. RESULTS: Compared to controls, the frequency of the -160A allele was significantly higher in diffuse gastric cancer cases (P = 0.005), but it was not significantly different in intestinal gastric cancer cases (P = 0.119). Two sets of three-marker haplotypes (-160C → A, 48 + 6 T → C, 2076C → T and -160C → A, 1937-13 T → C, 2253C → T) were associated with the risk of diffuse gastric cancer (P = 0.011 and P = 0.042, respectively). CONCLUSION: Based on direct sequencing analysis, our findings suggest that the CDH1 - 160C → A promoter polymorphism and haplotypes play significant roles in cancer risk for sporadic diffuse gastric cancer, but not for intestinal gastric cancer, in a Taiwanese population.