JAK2 Loss Arising From Tumor-Spread-Through-Air-Spaces (STAS) Promotes Tumor Progression by Suppressing CD8+ T Cells in Lung Adenocarcinoma: A Machine Learning Approach.

BACKGROUND: Tumor spread through air spaces (STAS) is a recently discovered risk factor for lung adenocarcinoma (LUAD). The aim of this study was to investigate specific genetic alterations and anticancer immune responses related to STAS. By using a machine learning algorithm and drug screening in lung cancer cell lines, we analyzed the effect of Janus kinase 2 (JAK2) on the survival of patients with LUAD and possible drug candidates. METHODS: This study included 566 patients with LUAD corresponding to clinicopathological and genetic data. For analyses of LUAD, we applied gene set enrichment analysis (GSEA), in silico cytometry, pathway network analysis, in vitro drug screening, and gradient boosting machine (GBM) analysis. RESULTS: The patients with STAS had a shorter survival time than those without STAS (P < 0.001). We detected gene set-related downregulation of JAK2 associated with STAS using GSEA. Low JAK2 expression was related to poor prognosis and a low CD8+ T-cell fraction. In GBM, JAK2 showed improved survival prediction performance when it was added to other parameters (T stage, N stage, lymphovascular invasion, pleural invasion, tumor size). In drug screening, mirin, CCT007093, dihydroretenone, and ABT737 suppressed the growth of lung cancer cell lines with low JAK2 expression. CONCLUSION: In LUAD, low JAK2 expression linked to the presence of STAS might serve as an unfavorable prognostic factor. A relationship between JAK2 and CD8+ T cells suggests that STAS is indirectly related to the anticancer immune response. These results may contribute to the design of future experimental research and drug development programs for LUAD with STAS.

Understanding of complex spin up-conversion processes in charge-transfer-type organic molecules.

Despite significant progress made over the past decade in thermally activated delayed fluorescence (TADF) molecules as a material paradigm for enhancing the performance of organic light-emitting diodes, the underlying spin-flip mechanism in these charge-transfer (CT)-type molecular systems remains an enigma, even since its initial report in 2012. While the initial and final electronic states involved in spin-flip between the lowest singlet and lowest triplet excited states are well understood, the exact dynamic processes and the role of intermediate high-lying triplet (T) states are still not fully comprehended. In this context, we propose a comprehensive model to describe the spin-flip processes applicable for a typical CT-type molecule, revealing the origin of the high-lying T state in a partial molecular framework in CT-type molecules. This work provides experimental and theoretical insights into the understanding of intersystem crossing for CT-type molecules, facilitating more precise control over spin-flip rates and thus advancing toward developing the next-generation platform for purely organic luminescent candidates.

Visualization of Multiple-Resonance-Induced Frontier Molecular Orbitals in a Single Multiple-Resonance Thermally Activated Delayed Fluorescence Molecule.

The spatial distribution and electronic properties of the frontier molecular orbitals (FMOs) in a thermally activated delayed fluorescence (TADF) molecule contribute significantly to the TADF properties, and thus, a detailed understanding and sophisticated control of the FMOs are fundamental to the design of TADF molecules. However, for multiple-resonance (MR)-TADF molecules that achieve spatial separation of FMOs by the MR effect, the distinctive distribution of these molecular orbitals poses significant challenges for conventional computational analysis and ensemble averaging methods to elucidate the FMOs' separation and the precise mechanism of luminescence. Therefore, the visualization and analysis of electronic states with the specific energy level of a single MR-TADF molecule will provide a deeper understanding of the TADF mechanism. Here, scanning tunneling microscopy/spectroscopy (STM/STS) was used to investigate the electronic states of the DABNA-1 molecule at the atomic scale. FMOs' visualization and local density of states analysis of the DABNA-1 molecule clearly show that MR-TADF molecules also have well-separated FMOs according to the internal heteroatom arrangement, providing insights that complement existing theoretical prediction methods.

Extracellular Vesicle MicroRNAs as Predictive Biomarkers in Postoperative Delirium after Spine Surgery; Preliminary Study.

Postoperative Delirium (POD) can cause poor patient outcomes in older adults who undergo surgery. In this study, we tested plasma extracellular vesicle (EV) miRNAs obtained before the delirium event to find predictive POD biomarkers after spine surgery. We recruited patients who are over 70 years old and have undergone spine surgery. Finally, POD patients (n=31) were included, with no-POD patients matched in age, sex, medical history, and type of surgery (n=31). Peripheral blood was collected from patients in the operating room after the operation was completed. EVs were isolated from plasma, and the 798 miRNA expression level from EVs was measured using a NanoString platform. Sixty-two patients were included in the study; all were Korean, 67.7% were females, and the median age was 75 years. Preoperative medical history was not statistically different between no-POD and POD patients except for hypertension and the American Society of Anesthesiologists (ASA) physical status. From the miRNA profiling, we identified 142 significantly differentially expressed miRNAs in POD patients compared to no-POD patients, which are associated with psychological/neurological disorders. The top 10 differentially expressed miRNAs including miR-548ar-5p and miR-627-5p were all upregulated in POD patients and the results were validated using qRT-PCR from the independent sets of samples (n=96). We demonstrated the potential of plasma EV-miRNAs as predictive biomarkers to identify the risk group of POD after spine surgery. It also provides opportunities for future studies investigating the role of EV-miRNAs in delirium pathology.

Comparative analysis of recurrence rates between intravesical gemcitabine and bacillus Calmette-Guérin induction therapy following transurethral resection of bladder tumors in patients with intermediate- and high-risk bladder cancer: A retrospective multicenter study.

PURPOSE: This study investigated the efficacy of intravesical gemcitabine as an alternative to bacillus Calmette-Guérin (BCG) therapy. MATERIALS AND METHODS: Data were retrospectively collected across seven institutions from February 1999 to May 2023. Inclusion criteria included patients with intermediate- or high-risk non-muscle invasive bladder cancer (NMIBC) who underwent transurethral resection of bladder tumors (TURBT) and received at least four sessions of intravesical gemcitabine or BCG induction therapy. Patient characteristics, complete remission (CR), occurrence, and progression rates were compared. RESULTS: In total, 149 patients were included in this study (gemcitabine, 63; BCG, 86). No differences were apparent between the two groups in baseline characteristics, except for the follow-up period (gemcitabine, 9.2±5.9 months vs. BCG, 43.9±41.4 months, p<0.001). There were no consistent significant differences observed between the two groups in the 3-month (gemcitabine, 98.4% vs. BCG, 95.3%; p=0.848), 6-month (94.9% vs. 90.0%, respectively; p=0.793) and 1-year CR rates (84.2% vs. 83.3%, respectively; p=0.950). Also, there was no significant statistical difference in progression-free survival between the two groups (p=0.953). The occurrence rates of adverse events were similar between the groups (22.2% vs. 22.1%; p=0.989); however, the rate of Clavien-Dindo grade 2 or higher was significantly higher in the BCG group (1.6% vs. 16.3%, respectively; p<0.001). CONCLUSIONS: Intravesical gemcitabine demonstrated efficacy comparable to BCG therapy for the first year in patients with intermediate- and high-risk NMIBC. However, long-term follow-up studies are warranted.

Low CDKN1B Expression Associated with Reduced CD8+ T Lymphocytes Predicts Poor Outcome in Breast Cancer in a Machine Learning Analysis.

The cyclin-dependent kinase inhibitor 1B (CDKN1B) gene, which encodes the p27Kip1 protein, is important in regulating the cell cycle process and cell proliferation. Its role in breast cancer prognosis is controversial. We evaluated the significance and predictive role of CDKN1B expression in breast cancer prognosis. We investigated the clinicopathologic factors, survival rates, immune cells, gene sets, and prognostic models according to CDKN1B expression in 3794 breast cancer patients. We performed gene set enrichment analysis (GSEA), in silico cytometry, pathway network analyses, gradient boosting machine (GBM) learning, and in vitro drug screening. High CDKN1B expression levels in breast cancer correlated with high lymphocyte infiltration signature scores and increased CD8+ T cells, both of which were associated with improved prognosis in breast cancer. which were associated with a better prognosis. CDKN1B expression was associated with gene sets for the upregulation of T-cell receptor signaling pathways and downregulation of CD8+ T cells. Pathway network analysis revealed a direct link between CDKN1B and the pathway involved in the positive regulation of the protein catabolic process pathway. In addition, an indirect link was identified between CDKN1B and the T-cell receptor signaling pathway. In in vitro drug screening, BMS-345541 demonstrated efficacy as a therapeutic targeting of CDKN1B, effectively impeding the growth of breast cancer cells characterized by low CDKN1B expression. The inclusion of CDKN1B expression in GBM models increased the accuracy of survival predictions. CDKN1B expression plays a significant role in breast cancer progression, implying that targeting CDKN1B might be a promising strategy for treating breast cancer.

Adjuvant chemotherapy for locally advanced upper tract urothelial carcinoma: updated results of the Seoul National university hospital experience

Objectives: The objective of this study was to update the long-term outcome in the treatment of locally advanced upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU) regarding the role of adjuvant chemotherapy. Materials and methods: Clinical data from 138 patients who underwent RNU for locally advanced UTUC (pT3/4 or pN+) were analyzed. Results: The adjuvant chemotherapy group comprised 66 patients, and other 72 patients did not receive adjuvant chemotherapy. Cisplatin-based chemotherapy was the most common regimen, depending on the patient's eligibility and renal function. The median follow-up period was 48.7 months (interquartile range: 29.2-96.9 months). The 3-and 5-year disease-specific survival (DSS) rates were 76.0% and 69.9% for the non-adjuvant chemotherapy group versus 74.6% and 54.5% for the adjuvant chemotherapy group (p=0.301, log-rank test). Overall survival (OS) rates for the same time period were 70.1% and 62.9% for the non-adjuvant chemotherapy group versus 73.8% and 53.2% for the adjuvant chemotherapy group (p=0.931, log-rank test). On multivariate analysis, adjuvant chemotherapy could not predict DSS and OS after surgery. When patients who received cisplatin-based adjuvant chemotherapy (n=59) were compared to those who did not receive adjuvant chemotherapy, similar results were found. Conclusions: There does not appear to be a significant DSS or OS benefit associated with adjuvant chemotherapy. Prospective randomized clinical trials are necessary to verify the effect of adjuvant chemotherapy on locally advanced UTUC.