IDO1 Inhibition Promotes Activation of Tumor-intrinsic STAT3 Pathway and Induces Adverse Tumor-protective Effects.

Pharmacological inhibition of IDO1 exhibits great promise as a strategy in cancer therapy. However, the failure of phase III clinical trials has raised the pressing need to understand the underlying reasons for this outcome. To gain comprehensive insights into the reasons behind the clinical failure of IDO1 inhibitors, it is essential to investigate the entire tumor microenvironment rather than focusing solely on individual cells or relying on knockout techniques. In this study, we conducted single-cell RNA sequencing to determine the overall response to apo-IDO1 inhibitor administration. Interestingly, although apo-IDO1 inhibitors were found to significantly activate intratumoral immune cells (mouse colon cancer cell CT26 transplanted in BALB/C mice), such as T cells, macrophages, and NK cells, they also stimulated the infiltration of M2 macrophages. Moreover, these inhibitors prompted monocytes and macrophages to secrete elevated levels of IL-6, which in turn activated the JAK2/STAT3 signaling pathway in tumor cells. Consequently, this activation enables tumor cells to survive even in the face of heightened immune activity. These findings underscore the unforeseen adverse effects of apo-IDO1 inhibitors on tumor cells and highlight the potential of combining IL-6/JAK2/STAT3 inhibitors with apo-IDO1 inhibitors to improve their clinical efficacy.

Metformin alleviates ethanol-induced cardiomyocyte injury by activating AKT/Nrf2 signaling in an ErbB2-dependent manner.

BACKGROUND: Metformin, a first-line oral anti-diabetic drug, has recently been reported to exert protective effect on various cardiovascular diseases. However, the potential role of metformin in ethanol-induced cardiomyocyte injury is still unknown. Therefore, this study was aimed to investigate the effect of metformin on ethanol-induced cardiomyocyte injury and its underlying mechanism. METHODS AND RESULTS: H9c2 cardiomyocytes were exposed to ethanol for 24 h to establish an ethanol-induced cardiomyocyte injury model, and followed by treatment with metformin in the presence or absence of Lapatinib (an ErbB2 inhibition). CCK8 and LDH assays demonstrated that metformin improved cell viability in cardiomyocytes exposed to ethanol. Furthermore, metformin suppressed cardiomyocyte apoptosis and reduced the expressions of apoptosis-related proteins (Bax and C-CAS-3). In addition, our results showed that metformin activated the AKT/Nrf2 pathway, and then promoted Nrf2 nuclear translocation and the transcription of its downstream antioxidant genes (HO-1, CAT and SOD2), thereby inhibiting oxidative stress. Interestingly, we found that ErbB2 protein expression was significantly inhibited in ethanol-treated cardiomyocytes, which was markedly reversed by metformin. In contrast, Lapatinib largely abrogated the activation of AKT/Nrf2 signaling by metformin, accompanied by the increases in oxidative stress and cardiomyocyte apoptosis, indicating that metformin prevented ethanol-induced cardiomyocyte injury in an ErbB2-dependent manner. CONCLUSION: In summary, our study provides the first evidence that metformin protects cardiomyocyte against ethanol-induced oxidative stress and apoptosis by activating ErbB2-mediated AKT/Nrf2 signaling. Thus, metformin may be a potential novel treatment approach for alcoholic cardiomyopathy.

FLPP: A Federated-Learning-Based Scheme for Privacy Protection in Mobile Edge Computing.

Data sharing and analyzing among different devices in mobile edge computing is valuable for social innovation and development. The limitation to the achievement of this goal is the data privacy risk. Therefore, existing studies mainly focus on enhancing the data privacy-protection capability. On the one hand, direct data leakage is avoided through federated learning by converting raw data into model parameters for transmission. On the other hand, the security of federated learning is further strengthened by privacy-protection techniques to defend against inference attack. However, privacy-protection techniques may reduce the training accuracy of the data while improving the security. Particularly, trading off data security and accuracy is a major challenge in dynamic mobile edge computing scenarios. To address this issue, we propose a federated-learning-based privacy-protection scheme, FLPP. Then, we build a layered adaptive differential privacy model to dynamically adjust the privacy-protection level in different situations. Finally, we design a differential evolutionary algorithm to derive the most suitable privacy-protection policy for achieving the optimal overall performance. The simulation results show that FLPP has an advantage of 8∼34% in overall performance. This demonstrates that our scheme can enable data to be shared securely and accurately.

[Exploring the mechanisms of ferroptosis in non-obstructive azoospermia based on bioinformatics and machine learning].

OBJECTIVE: To explor the potential mechanisms of ferroptosis involvement in non-obstructive azoospermia based on bioinformatics and machine learning methods. METHODS: To obtain disease-related datasets and ferroptosis-related genes, we utilized the GEO database and FerrDb database, respectively. Using the R software, the disease dataset was subjected to normalization, differential analysis, and GO and KEGG enrichment analysis. The differentially expressed genes from the disease dataset were then intersected with the ferroptosis-related genes to identify common genes. Core genes were selected using three machine learning algorithms, namely LASSO, SVM-RFE, and random forest. Further analysis included exploring immune infiltration correlation, predicting target drugs, and conducting molecular docking simulations. RESULTS: The differential analysis of the GSE45885 dataset yielded 1751 differentially expressed genes, while the GSE145467 dataset yielded 4358 differentially expressed genes. The intersection of these two gene sets resulted in a disease-related gene set consisting of 508 genes. Taking the intersection of the disease-related gene set and the ferroptosis-related gene set, we obtained 17 disease-related ferroptosis genes. After machine learning-based screening, three core genes were identified: GPX4, HSF1, and KLHDC3. CONCLUSION: The mechanism underlying the involvement of ferroptosis in non-obstructive azoospermia may be linked to the downregulation of GPX4, HSF1, and KLHDC3 expression. This finding provides a basis for subsequent in-depth mechanistic and therapeutic studies.

Fast Photostriction in Ferroelectrics.

Light-induced nonthermal strain, known as the photostrictive effect, offers a potential way to excite mechanical strain and acoustic wave remotely. The anisotropic photostrictive effect induced by the combination of bulk photovoltaic effect (BPVE) and converse piezoelectric effect in ferroelectric materials is known as too small and slow for the applications requiring a high strain rate, such as ultrasound generation and high-speed signal transmission. Here, a strategy to achieve high rate dynamic photostrictive strain by utilizing local fast responses under modulating continuous light excitation in the resonance condition is reported. A strain rate of 8.06 × 10-3  s-1 is demonstrated under continuous light excitation, which is at least one order of magnitude higher than previous studies on bulk samples as seen in the literature. The significant photostrictive response exists even in depoled ferroelectric material without overall polarization. The theoretical analyses show that fast ferroelectric photostriction can be obtained through the combinational interaction mechanism of local BPVE and local converse piezoelectric effect existing only in the microscopic scale, thus circumventing the slow and low efficient BPVE charging up process across the macroscopic electrical terminals. The achieved fast photostriction and new understandings will open new opportunities to realize future wireless signal transmission and light-acoustic devices.

Histone deacetylase 3 inhibition alleviates type 2 diabetes mellitus-induced endothelial dysfunction via Nrf2.

BACKGROUND: The mechanism underlying endothelial dysfunction leading to cardiovascular disease in type 2 diabetes mellitus (T2DM) remains unclear. Here, we show that inhibition of histone deacetylase 3 (HDAC3) reduced inflammation and oxidative stress by regulating nuclear factor-E2-related factor 2 (Nrf2), which mediates the expression of anti-inflammatory- and pro-survival-related genes in the vascular endothelium, thereby improving endothelial function. METHODS: Nrf2 knockout (Nrf2 KO) C57BL/6 background mice, diabetic db/db mice, and control db/m mice were used to investigate the relationship between HDAC3 and Nrf2 in the endothelium in vivo. Human umbilical vein endothelial cells (HUVECs) cultured under high glucose-palmitic acid (HG-PA) conditions were used to explore the role of Kelch-like ECH-associated protein 1 (Keap1) -Nrf2-NAPDH oxidase 4 (Nox4) redox signaling in the vascular endothelium in vitro. Activity assays, immunofluorescence, western blotting, qRT-PCR, and immunoprecipitation assays were used to examine the effect of HDAC3 inhibition on inflammation, reactive oxygen species (ROS) production, and endothelial impairment, as well as the activity of Nrf2-related molecules. RESULTS: HDAC3 activity, but not its expression, was increased in db/db mice. This resulted in de-endothelialization and increased oxidative stress and pro-inflammatory marker expression in cells treated with the HDAC3 inhibitor RGFP966, which activated Nrf2 signaling. HDAC3 silencing decreased ROS production, inflammation, and damage-associated tube formation in HG-PA-treated HUVECs. The underlying mechanism involved the Keap1-Nrf2-Nox4 signaling pathway. CONCLUSION: The results of this study suggest the potential of HDAC3 as a therapeutic target for the treatment of endothelial dysfunction in T2DM. Video Abstract.

Development and multicenter validation of a nomogram for preoperative prediction of lymph node positivity in pancreatic cancer (NeoPangram).

BACKGROUND: Neoadjuvant therapy is associated with nodal downstaging and improved oncological outcomes in patients with lymph node (LN)-positive pancreatic cancer. This study aimed to develop and validate a nomogram to preoperatively predict LN-positive disease. METHODS: A total of 558 patients with resected pancreatic cancer were randomly and equally divided into development and internal validation cohorts. Multivariate logistic regression analysis was used to construct the nomogram. Model performance was evaluated by discrimination, calibration, and clinical usefulness. An independent multicenter cohort consisting of 250 patients was used for external validation. RESULTS: A four-marker signature was built consisting of carbohydrate antigen 19-9 (CA19-9), CA125, CA50, and CA242. A nomogram was constructed to predict LN metastasis using three predictors identified by multivariate analysis: risk score of the four-marker signature, computed tomography-reported LN status, and clinical tumor stage. The prediction model exhibited good discrimination ability, with C-indexes of 0.806, 0.742 and 0.763 for the development, internal validation, and external validation cohorts, respectively. The model also showed good calibration and clinical usefulness. A cut-off value (0.72) for the probability of LN metastasis was determined to separate low-risk and high-risk patients. Kaplan-Meier survival analysis revealed a good agreement of the survival curves between the nomogram-predicted status and the true LN status. CONCLUSIONS: This nomogram enables the identification of pancreatic cancer patients at high risk for LN positivity who may have more advanced disease and thus could potentially benefit from neoadjuvant therapy.

Overexpression of miR-623 suppresses progression of hepatocellular carcinoma via regulating the PI3K/Akt signaling pathway by targeting XRCC5.

It has been reported that miR-623 is deregulated in lung adenocarcinoma and inhibits tumor growth and invasion. However, it is unclear whether miR-623 has a role in the progression of hepatocellular carcinoma (HCC). Herein, we found that miR-623 was significantly downregulated in HCC, and that its expression was related to poor clinical outcomes of patients with HCC. Upregulation of miR-623 decreased cell proliferation, viability, migration, and invasion and further promoted apoptosis in 7721, Huh7, and Bel-7402 cells. Moreover, we also observed that miR-623 regulated the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), Wnt/ß-catenin, and extracellular regulated protein kinases/c-Jun N-terminal kinase (ERK/JNK) signaling pathways as well as the expression level of related proteins. Further, X-ray repair cross complementing 5 (XRCC5) was a direct target for miR-623, and the suppression of PI3K/Akt, Wnt/ß-catenin, and ERK/JNK signaling pathways and cell proliferation and invasion abilities caused by miR-623 in HCC cells was significantly reversed by the upregulation of XRCC5. Collectively, our data suggested that miR-623 suppressed the progression of HCC by regulating the PI3K/Akt, Wnt/ß-catenin, and ERK/JNK pathways by targeting XRCC5 in HCC in vitro, indicating that miR-623 may be a target for the therapy of HCC.

The protective role of bFGF in myocardial infarction and hypoxia cardiomyocytes by reducing oxidative stress via Nrf2.

Myocardial infarction (MI) remains a major health-related problem with high incidence and mortality rates. Oxidative stress plays an important role in myocardial ischemia injury and further leads to myocardial remodeling. Basic fibroblast growth factor (bFGF) is a member of the fibroblast growth factors that regulate a variety of biological functions. However the function of bFGF in myocardial infarction is still unknown. Here we aimed to investigate the role of bFGF and its underlying mechanism in ischemia heart and cardiomyocytes apoptosis. We found that bFGF treatment could significantly enhance the cardioprotective effects by reducing oxidative stress both in vivo and vitro. In addition, we found that bFGF activated Nrf2-mediated antioxidant defenses via Akt/GSK3ß/Fyn pathway. Furthermore, Nrf2 knockdown largely counteracted the protective effect of bFGF. In summary, our study suggested that bFGF could alleviate myocardial infarction injury and cardiomyocytes apoptosis via Nrf2.

A four-long noncoding RNA signature predicts survival of hepatocellular carcinoma patients.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common neoplasm located in the liver. Accumulating evidence has highlighted that long noncoding RNAs (lncRNAs) are correlated with the survival of HCC patients. This study focuses on finding a lncRNA signature to predict the prognostic risk of HCC patients. METHODS: Statistical and machine learning analyses were conducted to analyze the lncRNA expression data and corresponding clinical data of 180 HCC patients collected from the public online Tanric and The Cancer Genome Atlas (TCGA) databases. RESULTS: From the training dataset, we obtained the four-lncRNA model comprising RP11-495K9.6, RP11-96O20.2, RP11-359K18.3, and LINC00556 which can divide HCC patients into two different groups with significantly different prognosis (n = 90, median 1.81, 95% confidence interval [CI]: 1.50-4.91 vs 8.56 years, 95% CI: 6.96-9.97, log-rank test P < .001). The test dataset confirmed the prognostic ability of the signature (n = 90, median 1.95, 95% CI: 1.14-4.08 vs 5.80 years, 95% CI: 3.11-6.82, log-rank test P = .007). Receiver operating characteristic curve displayed the better prediction efficiency of the four-lncRNA signature than the tumor/node/metastasis stage. Cox analysis showed the four-lncRNA signature was an independent predictor of HCC prognosis. CONCLUSION: The four-lncRNA signature can be used as an independent biomarker for HCC patients to predict the prognostic risk.

Resveratrol chemosensitizes adriamycin-resistant breast cancer cells by modulating miR-122-5p.

Breast cancer is one of the major malignancies threatening women's health worldwide, and chemotherapy tolerance has become a severe limitation of clinical treatment. Recent findings have revealed that resveratrol, as a dietary agent with antitumour activity, could prevent cancer progression by regulating microRNAs (miRNAs). Additionally, dysregulated miRNAs have been found to contribute significantly to chemoresistance by an increasing number of studies. In this study, experiments were designed to study the functional role of resveratrol in MCF-7 cells (low-invasive breast cancer) in chemosensitivity to adriamycin and to determine the targeted miRNAs of resveratrol and their key target proteins linked to cell activity. We demonstrated that in resveratrol-induced chemosensitivity, cell cycle and apoptosis were arrested in adriamycin-resistant breast cancer cells after modulation of the critical suppresser, miR-122-5p. Further miRNA modulation with miR-122-5p mimics or miR-122-5p inhibitors indicated a major effect of miR-122-5p on the regulation of key antiapoptotic proteins (B-cell lymphoma 2 [Bcl-2]) and cyclin-dependent kinases (CDK2, CDK4, and CDK6) in drug-resistant breast cancer cells in response to resveratrol. In conclusion, our results indicate that resveratrol acts as a potential inducer to enhance the chemosensitivity of breast cancer and also suggest that miR-122-5p is involved in the pathway of cell-cycle arrest by targeting Bcl-2 and CDKs.

Generalized Metropolis acceptance criterion for hybrid non-equilibrium molecular dynamics-Monte Carlo simulations.

A family of hybrid simulation methods that combines the advantages of Monte Carlo (MC) with the strengths of classical molecular dynamics (MD) consists in carrying out short non-equilibrium MD (neMD) trajectories to generate new configurations that are subsequently accepted or rejected via an MC process. In the simplest case where a deterministic dynamic propagator is used to generate the neMD trajectories, the familiar Metropolis acceptance criterion based on the change in the total energy ΔE, min[1, exp{-ßΔE}], guarantees that the hybrid algorithm will yield the equilibrium Boltzmann distribution. However, the functional form of the acceptance probability is more complex when the non-equilibrium switching process is generated via a non-deterministic stochastic dissipative propagator coupled to a heat bath. Here, we clarify the conditions under which the Metropolis criterion remains valid to rigorously yield a proper equilibrium Boltzmann distribution within hybrid neMD-MC algorithm.

Influence of Photodynamic Therapy on Apoptosis and Invasion of Human Cholangiocarcinoma QBC939 Cell Line.

OBJECTIVE: To investigate the effect of photodynamic therapy (PDT) mediated by hematoporphyrin derivative (HPD) on apoptosis and invasion of cholangiocarcinoma QBC939 cell lines. METHODS: In vitro cultured cholangiocarcinoma QBC939 cell line was exposed to 2, 4, 6, 8, 10, 12, and 14 µg/ml HPD with 5, 10, and 15 J/cm2 light intensity, respectively. The optical density at 450 nm of the QBC939 cells was measured by CCK8 assay and its growth inhibition ratio was calculated. Flow cytometry and transwell migration assay were applied to detect cell apoptosis and invasion respectively. RT-PCR and immunocytochemistry analyses were used to detect expressions of vascular endothelial growth factor-C (VEGF-C), cyclooxygenase-2 (COX-2), and proliferating cell nuclear antigen (PCNA). Enzyme-linked immunosorbent assay (ELISA) was carried out to examine the secretion of VEGF-C and COX-2 in QBC939 cells. RESULTS: Exposure to HPD-PDT can significantly suppress the growth of QBC939 cells (all P<0.05). HPD-PDT can promote apoptosis of QBC939 cells at the early stage. When the concentration of HPD was 2 µg/ml and light irradiation was 5 J/cm2, HPD-PDT had no obvious inhibitory effect on QBC939 cell growth, but can obviously inhibit cell invasion, and significant difference was observed between the HPD-PDT and control groups (P<0.01). The HPD-PDT can reduce the mRNA and protein expressions of VEGF-C, COX-2, and PCNA, and decrease the secretion of VEGF-C and COX-2 in QBC939 cells. CONCLUSION: PDT could promote apoptosis and inhibit growth and invasion of cholangiocarcinoma cells QBC939 in vitro.

Efficient hybrid non-equilibrium molecular dynamics--Monte Carlo simulations with symmetric momentum reversal.

Hybrid schemes combining the strength of molecular dynamics (MD) and Metropolis Monte Carlo (MC) offer a promising avenue to improve the sampling efficiency of computer simulations of complex systems. A number of recently proposed hybrid methods consider new configurations generated by driving the system via a non-equilibrium MD (neMD) trajectory, which are subsequently treated as putative candidates for Metropolis MC acceptance or rejection. To obey microscopic detailed balance, it is necessary to alter the momentum of the system at the beginning and/or the end of the neMD trajectory. This strict rule then guarantees that the random walk in configurational space generated by such hybrid neMD-MC algorithm will yield the proper equilibrium Boltzmann distribution. While a number of different constructs are possible, the most commonly used prescription has been to simply reverse the momenta of all the particles at the end of the neMD trajectory ("one-end momentum reversal"). Surprisingly, it is shown here that the choice of momentum reversal prescription can have a considerable effect on the rate of convergence of the hybrid neMD-MC algorithm, with the simple one-end momentum reversal encountering particularly acute problems. In these neMD-MC simulations, different regions of configurational space end up being essentially isolated from one another due to a very small transition rate between regions. In the worst-case scenario, it is almost as if the configurational space does not constitute a single communicating class that can be sampled efficiently by the algorithm, and extremely long neMD-MC simulations are needed to obtain proper equilibrium probability distributions. To address this issue, a novel momentum reversal prescription, symmetrized with respect to both the beginning and the end of the neMD trajectory ("symmetric two-ends momentum reversal"), is introduced. Illustrative simulations demonstrate that the hybrid neMD-MC algorithm robustly yields a correct equilibrium probability distribution with this prescription.

Hydrolytic degradation and biodegradation of polylactic acid electrospun fibers.

Increased use of bioplastics, such as polylactic acid (PLA), helps in reducing greenhouse gas emissions, decreases energy consumption and lowers pollution, but its degradation efficiency has much room for improvement. The degradation rate of electrospun PLA fibers of varying diameters ranging from 0.15 to 1.33 µm is measured during hydrolytic degradation under different pH from 5.5 to 10, and during aerobic biodegradation in seawater supplemented with activated sewage sludge. In hydrolytic conditions, varying PLA fiber diameter had significant influence over percentage weight loss (W%L), where faster degradation was achieved for PLA fibers with smaller diameter. W%L was greatest for PLA-5 > PLA-12 > PLA-16 > PLA-20, with average W%L at 30.7%, 27.8%, 17.2% and 14.3% respectively. While different pH environment does not have a significant influence on PLA degradation, with W%L only slightly higher for basic environments. Similarly biodegradation displayed faster degradation for small diameter fibers with PLA-5 attaining the highest degree of biodegradation at 22.8% after 90 days. Hydrolytic degradation resulted in no significant structural change, while biodegradation resulted in significant hydroxyl end capping products on the PLA surface. Scanning electron microscopy (SEM) imaging of degraded PLA fibers showed a deteriorated morphology of PLA-5 and PLA-12 fibers with increased adhesion structures and irregularly shaped fibers, while a largely unmodified morphology for PLA-16 and PLA-20.

Linear Electro-Optic Effect in 2D Ferroelectric for Electrically Tunable Metalens.

The advent of 2D ferroelectrics, characterized by their spontaneous polarization states in layer-by-layer domains without the limitation of a finite size effect, brings enormous promise for applications in integrated optoelectronic devices. Comparing with semiconductor/insulator devices, ferroelectric devices show natural advantages such as non-volatility, low energy consumption and high response speed. Several 2D ferroelectric materials have been reported, however, the device implementation particularly for optoelectronic application remains largely hypothetical. Here, the linear electro-optic effect in 2D ferroelectrics is discovered and electrically tunable 2D ferroelectric metalens is demonstrated. The linear electric-field modulation of light is verified in 2D ferroelectric CuInP2S6. The in-plane phase retardation can be continuously tuned by a transverse DC electric field, yielding an effective electro-optic coefficient rc of 20.28 pm V-1. The CuInP2S6 crystal exhibits birefringence with the fast axis oriented along its (010) plane. The 2D ferroelectric Fresnel metalens shows efficacious focusing ability with an electrical modulation efficiency of the focusing exceeding 34%. The theoretical analysis uncovers the origin of the birefringence and unveil its ultralow light absorption across a wide wavelength range in this non-excitonic system. The van der Waals ferroelectrics enable room-temperature electrical modulation of light and offer the freedom of heterogeneous integration with silicon and another material system for highly compact and tunable photonics and metaoptics.

U structured network with three encoding paths for breast tumor segmentation.

Breast ultrasound segmentation remains challenging because of the blurred boundaries, irregular shapes, and the presence of shadowing and speckle noise. The majority of approaches stack convolutional layers to extract advanced semantic information, which makes it difficult to handle multiscale issues. To address those issues, we propose a three-path U-structure network (TPUNet) that consists of a three-path encoder and an attention-based feature fusion block (AFF Block). Specifically, instead of simply stacking convolutional layers, we design a three-path encoder to capture multiscale features through three independent encoding paths. Additionally, we design an attention-based feature fusion block to weight and fuse feature maps in spatial and channel dimensions. The AFF Block encourages different paths to compete with each other in order to synthesize more salient feature maps. We also investigate a hybrid loss function for reducing false negative regions and refining the boundary segmentation, as well as the deep supervision to guide different paths to capture the effective features under the corresponding receptive field sizes. According to experimental findings, our proposed TPUNet achieves more excellent results in terms of quantitative analysis and visual quality than other rival approaches.

Genomic profiling, prognosis, and potential interventional targets in young and old patients with cholangiocarcinoma.

Molecular mechanisms behind potentially inferior prognosis of old cholangiocarcinoma (CCA) patients are unclear. Prevalence of interventional targets and the difference between young and old CCA patients are valuable for promising precision medicine. A total of 188 CCA patients with baseline tumor tissue samples were subgrouped into the young (≤45 years) and old (>45 years) sub-cohorts. Somatic and germline mutation profiles, differentially enriched genetic alterations, and actionable genetic alterations were compared. An external dataset was used for the validation of molecular features and the comparison of overall survival (OS). Compared to young patients, KRAS alterations were more common in old patients (P = .04), while FGFR2 fusions were less frequent (P = .05). TERT promoter mutations were exclusively detected in old patients. The external dataset (N = 392) revealed no significant difference in OS between young and old patients; however, old patient-enriched KRAS (hazard ratio [HR]: 1.96, 95% confidence interval [CI]: 1.37-2.80) and TERT alterations (HR: 2.03, 95% CI: 1.22-3.38) were associated with inferior OS. Approximately 38.3% of patients were identified of actionable oncogenic mutations indicative of a potential response to targeted therapy or immunotherapy. Actionable FGFR2 fusions (P = .01) and BRAFV600E (P = .04) mutations were more frequent in young females than old patients. The enrichment of KRAS/TERT alterations in CCA patients over 45 years resulted in inferior OS. Approximately one-third of CCA patients were eligible for targeted therapy or immunotherapy given the actionable mutations carried, especially young females.

Automated 2-Dimensional Measurement of Vestibular Schwannoma: Validity and Accuracy of an Artificial Intelligence Algorithm.

OBJECTIVE: Validation of automated 2-dimensional (2D) diameter measurements of vestibular schwannomas on magnetic resonance imaging (MRI). STUDY DESIGN: Retrospective validation study using 2 data sets containing MRIs of vestibular schwannoma patients. SETTING: University Hospital in The Netherlands. METHODS: Two data sets were used, 1 containing 1 scan per patient (n = 134) and the other containing at least 3 consecutive MRIs of 51 patients, all with contrast-enhanced T1 or high-resolution T2 sequences. 2D measurements of the maximal extrameatal diameters in the axial plane were automatically derived from a 3D-convolutional neural network compared to manual measurements by 2 human observers. Intra- and interobserver variabilities were calculated using the intraclass correlation coefficient (ICC), agreement on tumor progression using Cohen's kappa. RESULTS: The human intra- and interobserver variability showed a high correlation (ICC: 0.98-0.99) and limits of agreement of 1.7 to 2.1 mm. Comparing the automated to human measurements resulted in ICC of 0.98 (95% confidence interval [CI]: 0.974; 0.987) and 0.97 (95% CI: 0.968; 0.984), with limits of agreement of 2.2 and 2.1 mm for diameters parallel and perpendicular to the posterior side of the temporal bone, respectively. There was satisfactory agreement on tumor progression between automated measurements and human observers (Cohen's κ = 0.77), better than the agreement between the human observers (Cohen's κ = 0.74). CONCLUSION: Automated 2D diameter measurements and growth detection of vestibular schwannomas are at least as accurate as human 2D measurements. In clinical practice, measurements of the maximal extrameatal tumor (2D) diameters of vestibular schwannomas provide important complementary information to total tumor volume (3D) measurements. Combining both in an automated measurement algorithm facilitates clinical adoption.

Phenotypic Variation Analysis and Excellent Clone Selection of Alnus cremastogyne from Different Provenances.

Alnus cremastogyne is a rapidly growing broad-leaved tree species that is widely distributed in southwest China. It has a significant economic and ecological value. However, with the expansion of the planting area, the influence of phenotypic variation and differentiation on Alnus cremastogyne has increased, resulting in a continuous decline in its genetic quality. Therefore, it is crucial to investigate the phenotypic variation of Alnus cremastogyne and select excellent breeding materials for genetic improvement. Herein, four growth-related phenotypic traits (diameter at breast height, the height of trees, volume, height under the branches) and twelve reproductive-related phenotypic traits (fresh weight of single cone, dry weight of single cone, seed weight per plant, thousand kernel weight, cone length, cone width, cone length × cone width, fruit shape index, seed rate, germination rate, germination potential, germination index) of 40 clones from four provenances were measured and analyzed. The phenotypic variation was comprehensively evaluated by correlation analysis, principal component analysis and cluster analysis, and excellent clones were selected as breeding materials. The results revealed that there were abundant phenotypic traits variations among and within provenances. Most of the phenotypic traits were highly significant differences (p < 0.01) among provenances. The phenotypic variation among provenances (26.36%) was greater than that of within provenances clones (24.80%). The average phenotypic differentiation coefficient was accounted for 52.61% among provenances, indicating that the phenotypic variation mainly came from among provenances. The coefficient of variation ranged from 9.41% (fruit shape index) to 97.19% (seed weight per plant), and the repeatability ranged from 0.36 (volume) to 0.77 (cone width). Correlation analysis revealed a significantly positive correlation among most phenotypic traits. In principal component analysis, the cumulative contribution rate of the first three principal components was 79.18%, representing the main information on the measured phenotypic traits. The cluster analysis revealed four groups for the 40 clones. Group I and group II exhibited better performance phenotypic traits as compared with group III and group IV. In addition, the four groups are not clearly clustered following the distance from the provenance. Employing the multi-trait comprehensive evaluation method, 12 excellent clones were selected, and the average genetic gain for each phenotypic trait ranged from 4.78% (diameter at breast height) to 32.05% (dry weight of single cone). These selected excellent clones can serve as candidate materials for the improvement and transformation of Alnus cremastogyne seed orchards. In addition, this study can also provide a theoretical foundation for the genetic improvement, breeding, and clone selection of Alnus cremastogyne.