Defining three ferroptosis-based molecular subtypes and developing a prognostic risk model for high-grade serous ovarian cancer.

BACKGROUND: As a newly defined regulated cell death, ferroptosis is a potential biomarker in ovarian cancer (OV). However, its underlying mechanism in tumor microenvironment (TME) and clinical prediction significance in OV remained to be elucidated. METHODS: The transcriptome data of high-grade serous OV from The Cancer Genome Atlas (TCGA) database were downloaded. Molecular subtypes were classified based on ferroptosis-correlated genes from the FerrDb database by performing consensus clustering analysis. The associations between the subtypes and clinicopathologic characteristics, mutation, regulatory pathways and immune landscape were assessed. A ferroptosis-related prognostic model was constructed and verified using International Cancer Genome Consortium (ICGC) cohort and GSE70769. RESULTS: Three molecular subtypes of OV were defined. Patients in subtype C3 tended to have the most favorable prognosis, while subtype C1 showing more mesenchymal cells, increased immune infiltration of Macrophages_M2, lower tumor purity, and epithelial-to-mesenchymal transition (EMT) features had the poorest prognosis. A ferroptosis-related risk model was constructed using 8 genes (PDP1, FCGBP, EPHA4, GAS1, SLC7A11, BLOC1S1, SPOCK2, and CXCL9) and manifested a strong prediction performance. High-risk patients had enriched EMT pathways, more Macrophages_M2, less plasma cells and CD8 cell infiltration, greater tendency of immune escape and worse prognosis. The risk score has negatively correlated relation with LAG3, TIGIT, CTLA4, IDO1, CD27, ICOS, and IL2RB but positively correlated with PVR, CD276, and CD28. Moreover, low-risk patients were more sensitive to Cisplatin and Gefitinib, Gemcitabine. CONCLUSIONS: Our results could improve the understanding of ferroptosis in OV, providing promising insights for the clinical targeted therapy for the cancer.

(±)-hypermonanones A-G, seven pairs of monoterpenoid polyprenylated acylphloroglucinol enantiomers from Hypericum monanthemum.

Seven pairs of undescribed monoterpenoid polyprenylated acylphloroglucinol enantiomers [(±)-hypermonanones A-G (1-7)], together with three known analogues, were identified from the whole plant of Hypericum monanthemum Hook. The structures of these compounds were determined by analyses of their UV, HRESIMS, 1D/2D NMR spectroscopic data, and NMR calculations. The absolute configurations of these compounds were assigned by ECD calculations after chiral HPLC separation. Diverse monoterpene moieties were fused at C-3/C-4 of the dearomatized acylphloroglucinol core, which led to 3,4-dihydro-2H-pyran-integrated angular or linear type 6/6/6 tricyclic skeletons in 1-7. Compounds (-)-2 and (+)-2 exhibited significant NO inhibitory activity against LPS induced RAW264.7 cells with the IC50 values of 7.07 ± 1.02 µM and 11.39 ± 0.24 µM, respectively.

Garciyunnanones A-R: Caged polycyclic polyprenylated acylphloroglucinols decorated with a lavandulyl substituent from Garcinia yunnanensis.

Garciyunnanones A-R (1-18), eighteen undescribed caged polycyclic polyprenylated acylphloroglucinols, two undescribed biogenetic congeners (19-20), and nineteen known analogues (21-39), were isolated from the stem barks of Garcinia yunnanensis Hu. All of these isolates are decorated with a C-5 lavandulyl substituent. Their structures and absolute configurations were confirmed by HRESIMS, 1D & 2D NMR spectroscopic analysis, quantum chemical calculations of electronic circular dichroism data, and single-crystal X-ray diffraction analysis. The X-ray crystallographic data of ten isolated caged compounds ascertained the absolute configuration of C-23 in the lavandulyl as S. The cytotoxicity on three cancer cell lines and the anti-nonalcoholic steatohepatitis activity of the isolates were tested. In a free fatty acid-induced L02 cell model, compounds 33 and 39 decreased intracellular lipid accumulation significantly.

Cost-effectiveness of ivosidenib versus chemotherapy for previously treated IDH1-mutant advanced intrahepatic cholangiocarcinoma in Taiwan.

BACKGROUND: International guidelines recommend ivosidenib followed by modified FOLFOX (mFOLFOX) for advanced intrahepatic cholangiocarcinoma (ICC) with isocitrate dehydrogenase 1 (IDH1) mutations. Taiwan National Health Insurance covers only fluorouracil/leucovorin (5-FU/LV) chemotherapy for this ICC group, and there has been no prior economic evaluation of ivosidenib. Therefore, we aimed to assess ivosidenib's cost-effectiveness in previously treated, advanced ICC-presenting IDH1 mutations compared with mFOLFOX or 5-FU/LV. METHODS: A 3-state partitioned survival model was employed to assess ivosidenib's cost-effectiveness over a 10-year horizon with a 3% discount rate, setting the willingness-to-pay threshold at 3 times the 2022 GDP per capita. Efficacy data for Ivosidenib, mFOLFOX, and 5-FU/LV were sourced from the ClarIDHy, ABC06, and NIFTY trials, respectively. Ivosidenib's cost was assumed to be NT$10,402/500 mg. Primary outcomes included incremental cost-effectiveness ratios (ICERs) and net monetary benefit. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analyses (PSA) were employed to evaluate uncertainty and explore price reduction scenarios. RESULTS: Ivosidenib exhibited ICERs of NT$6,268,528 and NT$5,670,555 compared with mFOLFOX and 5-FU/LV, respectively, both exceeding the established threshold. PSA revealed that ivosidenib was unlikely to be cost-effective, except when it was reduced to NT$4,161 and NT$5,201/500 mg when compared with mFOLFOX and 5-FU/LV, respectively. DSA underscored the significant influence of ivosidenib's cost and utility values on estimate uncertainty. CONCLUSIONS: At NT$10,402/500 mg, ivosidenib was not cost-effective for IDH1-mutant ICC patients compared with mFOLFOX or 5-FU/LV, indicating that a 50-60% price reduction is necessary for ivosidenib to be cost-effective in this patient group.

Prediction significance of autophagy-related genes in survival probability and drug resistance in diffuse large B-cell lymphoma.

BACKGROUND/AIMS: Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, has significant prognostic heterogeneity. This study aimed to generate a prognostic prediction model based on autophagy-related genes for DLBCL patients. METHODS: Utilizing bioinformatics techniques, we analyzed the clinical information and transcriptome data of DLBCL patients from the Gene Expression Omnibus (GEO) database. Through unsupervised clustering, we identified new autophagy-related molecular subtypes and pinpointed differentially expressed genes (DEGs) between these subtypes. Based on these DEGs, a prognostic model was constructed using Cox and Lasso regression. The effectiveness, accuracy, and clinical utility of this prognostic model were assessed using numerous independent validation cohorts, survival analyses, receiver operating characteristic (ROC) curves, multivariate Cox regression analysis, nomograms, and calibration curves. Moreover, functional analysis, immune cell infiltration, and drug sensitivity analysis were performed. RESULTS: DLBCL patients with different clinical characterizations (age, molecular subtypes, ECOG scores, and stages) showed different expression features of autophagy-related genes. The prediction model was constructed based on the eight autophagy-related genes (ADD3, IGFBP3, TPM1, LYZ, AFDN, DNAJC10, GLIS3, and CCDC102A). The prognostic nomogram for overall survival of DLBCL patients incorporated risk level, stage, ECOG scores, and molecular subtypes, showing excellent agreement between observed and predicted outcomes. Differences were noted in the proportions of immune cells (native B cells, Treg cells, CD8+ T cell, CD4+ memory activated T cells, gamma delta T cells, macrophages M1, and resting mast cells) between high-risk and low-risk groups. LYZ and ADD3 exhibited correlations with drug resistance to most chemotherapeutic drugs. CONCLUSIONS: This study established a novel prognostic assessment model based on the expression profile of autophagy-related genes and clinical characteristics of DLBCL patients, explored immune infiltration and predicted drug resistance, which may guide precise and individualized immunochemotherapy regimens.

Lung-PNet: An Automated Deep Learning Model for the Diagnosis of Invasive Adenocarcinoma in Pure Ground-Glass Nodules on Chest CT.

BACKGROUND. Pure ground-glass nodules (pGGNs) on chest CT representing invasive adenocarcinoma (IAC) warrant lobectomy with lymph node resection. For pGGNs representing other entities, close follow-up or sublobar resection without node dissection may be appropriate. OBJECTIVE. The purpose of this study was to develop and validate an automated deep learning model for differentiation of pGGNs on chest CT representing IAC from those representing atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), and minimally invasive adenocarcinoma (MIA). METHODS. This retrospective study included 402 patients (283 women, 119 men; mean age, 53.2 years) with a total of 448 pGGNs on noncontrast chest CT that were resected from January 2019 to June 2022 and were histologically diagnosed as AAH (n = 29), AIS (n = 83), MIA (n = 235), or IAC (n = 101). Lung-PNet, a 3D deep learning model, was developed for automatic segmentation and classification (probability of IAC vs other entities) of pGGNs on CT. Nodules resected from January 2019 to December 2021 were randomly allocated to training (n = 327) and internal test (n = 82) sets. Nodules resected from January 2022 to June 2022 formed a holdout test set (n = 39). Segmentation performance was assessed with Dice coefficients with radiologists' manual segmentations as reference. Classification performance was assessed by ROC AUC and precision-recall AUC (PR AUC) and compared with that of four readers (three radiologists, one surgeon). The code used is publicly available (https://github.com/XiaodongZhang-PKUFH/Lung-PNet.git). RESULTS. In the holdout test set, Dice coefficients for segmentation of IACs and of other lesions were 0.860 and 0.838, and ROC AUC and PR AUC for classification as IAC were 0.911 and 0.842. At threshold probability of 50.0% or greater for prediction of IAC, Lung-PNet had sensitivity, specificity, accuracy, and F1 score of 50.0%, 92.0%, 76.9%, and 60.9% in the holdout test set. In the holdout test set, accuracy and F1 score (p values vs Lung-PNet) for individual readers were as follows: reader 1, 51.3% (p = .02) and 48.6% (p = .008); reader 2, 79.5% (p = .75) and 75.0% (p = .10); reader 3, 66.7% (p = .35) and 68.3% (p < .001); reader 4, 71.8% (p = .48) and 42.1% (p = .18). CONCLUSION. Lung-PNet had robust performance for segmenting and classifying (IAC vs other entities) pGGNs on chest CT. CLINICAL IMPACT. This automated deep learning tool may help guide selection of surgical strategies for pGGN management.

Comparing the impact of three-dimensional digital visualization technology versus traditional microscopy on microsurgeons in microsurgery: a prospective self-controlled study.

BACKGROUND: Emerging three-dimensional digital visualization technology (DVT) provides more advantages than traditional microscopy in microsurgery; however, its impact on microsurgeons' visual and nervous systems and delicate microsurgery is still unclear, which hinders the wider implementation of DVT in digital visualization for microsurgery. METHODS AND MATERIAL: Forty-two microsurgeons from the Zhongshan Ophthalmic Center were enrolled in this prospective self-controlled study. Each microsurgeon consecutively performed 30 min conjunctival sutures using a three-dimensional digital display and a microscope, respectively. Visual function, autonomic nerve activity, and subjective symptoms were evaluated before and immediately after the operation. Visual functions, including accommodative lag, accommodative amplitude, near point of convergence and contrast sensitivity function (CSF), were measured by an expert optometrist. Heart rate variability was recorded by a wearable device for monitoring autonomic nervous activity. Subjective symptoms were evaluated by questionnaires. Microsurgical performance was assessed by the video-based Objective Structured Assessment of Technical Skill (OSATS) tool. RESULTS: Accommodative lag decreased from 0.63 (0.18) diopters (D) to 0.55 (0.16) D ( P =0.014), area under the log contrast sensitivity function increased from 1.49 (0.15) to 1.52 (0.14) ( P =0.037), and heart rate variability decreased from 36.00 (13.54) milliseconds (ms) to 32.26 (12.35) ms ( P =0.004) after using the DVT, but the changes showed no differences compared to traditional microscopy ( P >0.05). No statistical significance was observed for global OSATS scores between the two rounds of operations [mean difference, 0.05 (95% CI: -1.17 to 1.08) points; P =0.95]. Subjective symptoms were quite mild after using both techniques. CONCLUSIONS: The impact of DVT-based procedures on microsurgeons includes enhanced accommodation and sympathetic activity, but the changes and surgical performance are not significantly different from those of microscopy-based microsurgery. Our findings indicate that short-term use of DVT is reliable for microsurgery and the long-term effect of using DVT deserve more consideration.

Cuproptosis-related lncRNAs ovarian cancer: Multi-omics analysis of molecular mechanisms and potential therapeutic targets.

Ovarian cancer (OV) is an aggressive malignancy that poses a significant threat to the health and lives of women. Cuproptosis is a newly discovered form of programmed cell death that offers a promising therapeutic target, although its significance in cancer progression remains uncertain. In this study, we established a prognostic model of OV with six cuproptosis-related long non-coding RNAs (lncRNAs), including CTC.246B18.8, LINC00337, RP11.568N6.1, RP11.158I9.8, RP11.678G14.3 and CYP4F26P, based on the data of The Cancer Genome Atlas (TCGA). Lower risk scores were associated with favorable prognosis. In addition, a negative outcome was associated with high expression of CTC.246B18.8. According to the ESTIMATE algorithm, CTC.246B18.8 was negatively correlated with the ImmuneScore, and positively with immune checkpoints, immune cell infiltration, and tumor mutation burden (TMB). Moreover, gene set enrichment analysis (GSEA) revealed that pathways related to immunosuppression are likely activated in response to CTC-246B18.8 overexpression. Furthermore, CTC-246B18.8 expression was also associated with the sensitivity to various chemotherapy drugs. The expression patterns of the above lncRNAs were verified in ovarian tumor cell lines (SK-OV-3, COC1, and A2780) and normal ovarian epithelial cells (IOSE - 80). Six cuproptosis-related genes (CRGs), including ATP7B, MTF1, SLC31A1, DLD, ATP7A and DLAT, were differentially expressed between CTC-246B18.8high and CTC-246B18.8low patient groups, and exhibited organ-specific expression patterns pan-cancer. Small molecule drugs that target these CRGs were predicted, and potential candidates included DIAMIDE, bathocuproine disulfonate, D-penicillamine, etc. To summarize, our findings provide molecular insights into the role of cuproptosis in OV, and the signature lncRNAs and CRGs should be investigated further as immunotherapy biomarkers of OV.

Surgery for severe mitral regurgitation: The etiology matters.

BACKGROUND: While surgery has been the standard treatment for patients with severe primary mitral regurgitation (PMR), the role of surgery for severe secondary mitral regurgitation (SMR) remained debated. We therefore investigated the prognostic differences of surgery for patients with either severe PMR or SMR. METHODS: Subjects hospitalized for heart failure were enrolled from 2002 to 2012. The severity of MR was assessed by continuity equation, and an effective regurgitant orifice area of ≥40 mm 2 was defined as severe. Long-term survival was then identified by the National Death Registry. RESULTS: A total of 1143 subjects (66.4 ± 16.6 years, 65% men, and 59.7% PMR) with severe MR were analyzed. Compared with PMR, patients with SMR were older, had more comorbidities, greater left atrial and ventricular diameter, and less left ventricular ejection fraction (all p < 0.05). While 47.8% of PMR patients received mitral valve surgery, only 6.9% of SMR patients did. Surgical intervention crudely was associated with 54% reduction of all-cause mortality in PMR (hazard ratio, 0.46; 95% confident interval, 0.32-0.67), and 48% in the subpopulation with SMR (0.52, 0.30-0.91). Propensity score matching analysis demonstrated the survival benefits of mitral valve surgery was observed in patients with PMR (log rank p = 0.024), but not with SMR. Among the unoperated subjects, age, renal function, and right ventricular systolic pressure were common risk factors of mortality, regardless of MR etiology. CONCLUSION: Mitral valve surgery for patients with heart failure and severe MR was associated with better survival in patients with PMR, but not in those with SMR.

Safety and feasibility of preferential manual bronchoplasty in 2-3 cm single-port video-assisted thoracoscopic lobectomy.

BACKGROUND: This retrospective study aimed to compare preferential manual bronchoplasty (PMB) and mechanical stapler closure (MSC) of the bronchial stump after 2-3 cm single-port (SP) video-assisted thoracoscopic surgery (VATS) lobectomy in patients with pathological T1 (pT1) stage lung cancer. METHODS: Between January 2019 and March 2022, patients with pulmonary neoplasms who underwent 2-3 cm SP VATS lobectomy were retrospectively screened. After propensity-matched analysis, we compared perioperative outcomes and analyzed the safety and feasibility of PMB and MSC of the bronchial stump while performing VATS lobectomy. RESULTS: In this study, 280 and 832 patients were enrolled in the PMB and MSC groups, respectively. Propensity score matching produced 280 pairs. The operation time was shorter in the PMB group, whereas the average number of lymph nodes dissected was higher in the PMB group. The conversion rate was significantly lower in the PMB group. The following were similar between the PMB and MSC groups, respectively: average blood loss volume, postoperative hospital stay, and chest tube removal time. Postoperatively, the incidence of atelectasis was significantly higher in the MSC group. As per subgroup analyses, PMB was associated with a shorter operation time in left and right upper lobectomies. Particularly in left upper lobectomy, PMB had more lymph node dissections and less conversion to open and postoperative atelectasis. CONCLUSIONS: In comparison with MSC of the bronchial stump, PMB showed better safety and feasibility in 2-3 cm SP VATS left and right superior lobectomies in patients with pT1 stage lung cancer.

Severe Hemoptysis Secondary to Actinomycosis: A Case Report.

Pulmonary actinomycosis (PA) is an uncommon, asymptomatic, and frequently misdiagnosed pulmonary infectious illness. Our patient remained undiagnosed despite extensive regular and invasive testing, significant intermittent hemoptysis, and repeated bronchial artery embolization. Ultimately, a left lower lobectomy was performed via video-assisted thoracoscopic surgery, and a histopathological examination revealed an actinomycete infection.

The joint role of methylation and immune-related lncRNAs in ovarian cancer: Defining molecular subtypes and developing prognostic signature.

INTRODUCTION: Complex outcome of ovarian cancer (OC) stems from the tumor immune microenvironment (TIME) influenced by genetic and epigenetic factors. This study aimed to comprehensively explored the subclasses of OC through lncRNAs related to both N6-methyladenosine (m6A)/N1-methyladenosine (m1A)/N7-methylguanosine (m7G)/5-methylcytosine (m5C) in terms of epigenetic variability and immune molecules and develop a new set of risk predictive systems. MATERIAL AND METHODS: The lncRNA data of OC were collected from TCGA. Spearman correlation analysis on lncRNA data of OC with immune-related gene expression and with m6A/m5C/m1A/m7G were respectively conducted. The m6A/m5C/m1A/m7G-related m6A/m5C/m1A/m7G related immune lncRNA subtypes were identified on the basis of the prognostic lncRNAs. Heterogeneity among subtypes was evaluated by tumor mutation analysis, tumor microenvironment (TME) component analysis, response to immune checkpoint blocked (ICB) and chemotherapeutic drugs. A risk predictive system was developed based on the results of Cox regression analysis and random survival forest analysis of the differences between each specific cluster and other clusters. RESULTS: Three m6A/m5C/m1A/m7G-related immune lncRNA subtypes of OC showing distinct differences in prognosis, mutation pattern, TIME components, immunotherapy and chemotherapy response were identified. A set of risk predictive system consisting of 10 lncRNA for OC was developed, according to which the risk score of samples in each OC dataset was calculated and risk type was defined. CONCLUSIONS: This study classified three m6A/m5C/m1A/m7G-related immune lncRNA subtypes with distinct heterogeneous mutation patterns, TME components, ICB therapy and immune response, and provided a set of risk predictive system consisted of 10 lncRNA for OC.

The value on SUV-derived parameters assessed on 18F-FDG PET/CT for predicting mediastinal lymph node metastasis in non-small cell lung cancer.

PURPOSE: To explore valuable predictors for mediastinal lymph node metastasis in non-small cell lung cancer (NSCLC) patients, we analyzed the potential roles of standardized uptake value (SUV)-derived parameters from preoperative 18F-FDG PET/CT combined with clinical characteristics. METHODS: Data from 224 NSCLC patients who underwent preoperative 18F-FDG PET/CT scans in our hospital were collected. Then, a series of clinical parameters including SUV-derived features [SUVmax of mediastinal lymph node and primary-tumor SUVmax, SUVpeak, SUVmean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG)] were evaluated. The best possible cutoff points for all measuring parameters were calculated using receiver operating characteristic curve (ROC) analysis. Predictive analyses were performed using a Logistic regression model to determine the predictive factors for mediastinal lymph node metastasis in NSCLC and lung adenocarcinoma patients. After multivariate model construction, data of another 100 NSCLC patients were recorded. Then, 224 patients and 100 patients were enrolled to validate the predictive model by the area under the receiver operating characteristic curve (AUC). RESULTS: The mediastinal lymph node metastasis rates in 224 patients for model construction and 100 patients for model validation were 24.1% (54/224) and 25% (25/100), respectively. It was found that SUVmax of mediastinal lymph node ≥ 2.49, primary-tumor SUVmax ≥ 4.11, primary-tumor SUVpeak ≥ 2.92, primary-tumor SUVmean ≥ 2.39, primary-tumor MTV ≥ 30.88 cm3, and primary-tumor TLG ≥ 83.53 were more prone to mediastinal lymph node metastasis through univariate logistic regression analyses. The multivariate logistic regression analyses showed that the SUVmax of mediastinal lymph nodes (≥ 2.49: OR 7.215, 95% CI 3.326-15.649), primary-tumor SUVpeak (≥ 2.92: OR 5.717, 95% CI 2.094-15.605), CEA (≥ 3.94 ng/ml: OR 2.467, 95% CI 1.182-5.149), and SCC (< 1.15 ng/ml: OR 4.795, 95% CI 2.019-11.388) were independent predictive factors for lymph node metastasis in the mediastinum. It was found that SUVmax of the mediastinal lymph node (≥ 2.49: OR 8.067, 95% CI 3.193-20.383), primary-tumor SUVpeak (≥ 2.92: OR 9.219, 95% CI 3.096-27.452), and CA19-9 (≥ 16.6 U/ml: OR 3.750, 95% CI 1.485-9.470) were significant predictive factors for mediastinal lymph node metastasis in lung adenocarcinoma patients. The AUCs for the predictive value of the NSCLC multivariate model through internal and external validation were 0.833 (95% CI 0.769- 0.896) and 0.811 (95% CI 0.712-0.911), respectively. CONCLUSION: High SUV-derived parameters (SUVmax of mediastinal lymph node and primary-tumor SUVmax, SUVpeak, SUVmean, MTV and TLG) might provide varying degrees of predictive value for mediastinal lymph node metastasis in NSCLC patients. In particular, the SUVmax of mediastinal lymph nodes and primary-tumor SUVpeak could be independently and significantly associated with mediastinal lymph node metastasis in NSCLC and lung adenocarcinoma patients. Internal and external validation confirmed that the pretherapeutic SUVmax of the mediastinal lymph node and primary-tumor SUVpeak combined with serum CEA and SCC can effectively predict mediastinal lymph node metastasis of NSCLC patients.

Left versus right approach for middle and lower esophageal squamous cell carcinoma: A propensity score-matched study.

Background: Despite superior short-term outcomes, there is considerable debate about the oncological efficacy of the left approach esophagectomy for middle and lower squamous esophageal carcinoma (ESCC). A propensity score-matched retrospective study was conducted to evaluate the left approach's short- and long-term effects. Methods: We recorded data from patients with ESCC who underwent curative resection via the left or right approach between January 2010 and December 2015. Propensity score matching (PSM) was performed, and maximally selected rank statistics (MSRS) were utilized to determine the appropriate number of lymph nodes to resect during esophagectomy. Results: One hundred and forty-eight ESCC patients underwent esophagectomy via the right approach, and 108 underwent the left approach esophagectomy. After PSM, the left approach esophagectomy showed statistically significant superiority in operative time and time to oral intake, and there was a trend toward a shorter length of hospital stay. Fewer cervical, upper thoracic, and recurrent laryngeal nerve lymph nodes were harvested via the left approach than the right approach; the total number of lymph nodes harvested via the left and right approaches was similar. Similar long-term survival outcomes were achieved. MSRS suggested that at least 25 lymph nodes are needed to be resected during esophagectomy to improve survival in N0 patients. Conclusions: The left approach esophagectomy might facilitate postoperative recovery in patients with middle and lower ESCC. With adequate lymphadenectomy, the left approach esophagectomy might achieve similar long-term outcomes for middle and lower ESCC patients.

Signatures associated with homologous recombination deficiency and immune regulation to improve clinical outcomes in patients with lung adenocarcinoma.

PARP inhibitors can be used to treat solid tumors that often have mutations in important homologous recombination (HR) genes, such as BRCA1/2. While other kinds of tumors could also experience HR deficiencies, including those associated with lung cancer, there is little information on the frequency of these occurrences. Homologous recombination deficiency (HRD) was used to induce particular DNA aberration profiles and related transcriptome alterations. Their presence can identify whether an HR deficiency is present or absent in a particular tumor sample, even without observed HR gene changes. From whole-exome sequencing data in lung adenocarcinoma obtained from TCGA, we obtained several mutational signatures associated with HRD and determined that these HRD-associated mutational signatures are related to genomic installability. We then constructed a prediction model, which found that 11 genes associated with HRD scores could be used as predictors of survival outcomes in LUAD patients. These genes are related to PI3K-Akt, T cell receptors, and the Chemokine pathway. Other GEO datasets validated the survival prediction, which was independent of the PD1/PDL1 treatment. Collectively, our study provides transcriptome biomarkers of lung adenocarcinoma complementary to the HRD score and introduces a novel method of identifying prognostic biomarkers of immunotherapy.

Comparison of perinephric fat measurements between malignant and benign renal tumours.

OBJECTIVE: To investigate different parameters derived from the quantity and quality of perinephric fat, and to compare their effectiveness in predicting the malignant pathology of renal tumours. METHODS: Data from patients diagnosed with renal tumour between April 2014 and December 2020 were retrospectively reviewed, and patients were categorized into malignant or benign tumour groups. Fat parameters, including perinephric fat volume (PFV), perinephric fat area (PFA), perinephric fat thickness (PFT), and Mayo adhesive probability (MAP) score were measured using abdominal computed tomography scans. Between-group differences were assessed by analysis of variance and χ2-test. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the performance of perinephric fat parameters in diagnosing malignancy. RESULTS: A total of 109 patients were included. MAP score, PFV, PFA, and PFT were significantly increased in the malignant versus benign tumour group, and after correction for body mass index (BMI), the indexed PFV/BMI, PFA/BMI, and PFT/BMI values remained significantly higher in the malignant tumour group. All parameters showed fair predictivity of malignancy, with comparable area under the curve values in the ROC curve. CONCLUSION: An increased amount of perinephric fat is predictive of malignant pathology for renal tumours. The predictive accuracy for each perinephric fat parameter remained fair after correcting for BMI.

Neuroprotective Effects of Estrogen Through BDNF-Transient Receptor Potential Channels 6 Signaling Pathway in the Hippocampus in a Rat Model of Perimenopausal Depression.

Estradiol (E2) has been proven to be effective in treating perimenopausal depression (PD); however, the downstream signaling pathways have not been fully elucidated. Transient receptor potential channels 6 (TRPC6) plays a vital role in promoting neuronal development and the formation of excitatory synapses. At present, we found that the serum levels of E2 and brain-derived neurotrophic factor (BDNF) declined significantly in the women with PD compared to perimenopausal women, which was accompanied by a clear reduction in TRPC6 levels. To further reveal the effects of TRPC6 on neuronal survival and excitability, the PD-like rat model was established by the total removal of left ovary and 80% removal of right ovary followed by 21 days of the chronic unpredictable mild stress. Intragastric administration of E2 (2 mg/kg), intraperitoneal injection of BDNF/TrB signaling pathway inhibitor (K252a, 100 µg/kg) and TRPC6 agonist (OAG, 0.6 mg/kg), and intracerebroventricular infusion of anti-BDNF antibody for blocking BDNF (0.5 µg/24 µl/rat) daily for 21 days were conducted. The levels of BDNF and TRPC6 in rat serum were lower in PD rats compared to the control rats; the depression-like behavior was induced, the neuronal death rate in the hippocampus increased, and the thickness of postsynaptic density (PSD) and the number of asymmetric synapses decreased significantly in the PD group. E2 treatment greatly upregulated the serum levels of BDNF and TRPC6, the neuronal excitability indicated by an elevation in the PSD thickness and the numbers of asymmetric synapses, and these actions were reversed by K252a; co-administration of TRPC6 agonist and K252a improved neuronal degeneration and increased the neuronal excitability induced in the E2-treated PD rats. K252a or anti-BDNF antibody inhibited the increased neuronal BDNF and TRPC6 expression in E2-treated PD rats; co-treatment of TRPC6 agonist and anti-BDNF antibody reduced neuronal death and increased the BDNF and TRPC6 expression in the hippocampal CA1 neurons in the E2-treated PD rats. These results suggest that the neuroprotective role of E2 in PD is closely related to enhance the activity of BDNF/TRPC6 pathway and is helpful to provide new prevention and strategies.

Impaired renal function and mortalities in acute heart failure with different phenotypes.

AIMS: Impaired renal function (IRF) prevails in patients with acute heart failure. The study aimed to investigate the prevalence of on-admission IRF and its association with short-term and long-term mortalities in patients hospitalized for HF with reduced (HFrEF), mildly reduced (HFmrEF), and preserved (HFpEF) left ventricular ejection fraction (LVEF). METHODS: Patients hospitalized for acute heart failure were enrolled and stratified by LVEF into three phenotypes as HFpEF (≥50%), HFmrEF (40-49%), and HFrEF (<40%). IRF was defined as an estimated glomerular filtration rate of ≤60 mL/min/1.73m2 on admission. National Death Registry was linked for the identification of mortality. RESULTS: Of 2613 patients enrolled, 673 (25.7%) had HFrEF, 367 (14.0%) had HFmrEF, and 1573 (60.1%) had HFpEF, whereas IRF was prevalent among 63.7, 68.6, and 67.5% of them, respectively. IRF significantly correlated with higher long-term mortality in each phenotype of HF. However, IRF was associated with 90-day and 1-year mortality in subjects with HFrEF and HFmrEF, but not HFpEF. After accounting for age, gender, hypertension, diabetes, coronary artery disease, atrial fibrillation, stroke, serum sodium, de novo heart failure, date of enrolment, and systolic blood pressure <90 mmHg or use of inotropic agents, IRF remained related to 5-year mortality in patients with HFrEF (hazard ratio and 95% confidence interval: 1.346, 1.034-1.751), HFmrEF (2.210, 1.435-3.404), and HFpEF (1.493, 1.237-1.801). CONCLUSIONS: On-admission IRF was independently predictive of long-term mortality in patients hospitalized for HF, irrespective of HF phenotypes. Furthermore, IRF was also associated with short-term mortality in HFrEF and HFmrEF, but not in HFpEF.

Complete and durable response to crizotinib in a patient with malignant pleural mesothelioma harboring CD74-ROS1 fusion.

Malignant pleural mesothelioma (MPM) is a rare and deadly malignancy with an extremely poor prognosis. The median overall survival (OS) of this disease is 12-18 months. However, the oncogenic driver mutations of MPM are rarely understood, and the targeted therapy for it is still under investigation. In this report, we describe a case of MPM with CD74-ROS1 fusion who obtains complete and durable response after receiving crizotinib. By the time of submission, the progression-free survival (PFS) with crizotinib has been 6.0 years, and the patient has survived for 7.6 years. Currently, he is still in complete remission (CR). To the best of our knowledge, this case represents the first report of CD74-ROS1 fusion identified in MPM. Meanwhile, it is also the first report of complete and long-term response to crizotinib in a patient with MPM positive for CD74-ROS1 fusion. This case report might contribute to the tumorigenesis and targeted therapy of this deadly disease.

Pulmonary vascular volume is associated with DLCO and fibrotic score in idiopathic pulmonary fibrosis: an observational study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a disease that primarily occurs in elderly individuals. However, it is difficult to diagnose and has a complex disease course. High-resolution computed tomography (HRCT) and lung function testing are crucial for its diagnosis and follow-up. However, the correlation of HRCT findings with lung function test results has not been extensively investigated. METHODS: This study retrospectively analysed the medical records and images of patients with IPF. Patients with evident emphysema and lung cancer were excluded. The diagnosis of all the included cases was confirmed following a discussion among specialists from multiple disciplines. The correlation of HRCT findings, including fibrotic score, HRCT lung volume, pulmonary artery trunk (PA) diameter and pulmonary vascular volume (PVV), with lung function test parameters, such as forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), was analysed. RESULTS: A total of 32 patients were included. Higher fibrotic and PVV scores were significantly correlated with lower DLCO (r = - 0.59, p = 0.01; r = - 0.43, p = 0.03, respectively) but not with FVC. Higher PVV score significantly correlated with higher fibrotic score (r = 0.59, p < 0.01) and PA diameter (r = 0.47, p = 0.006). CONCLUSION: Our study demonstrated the structural and functional correlation of IPF. The extent of lung fibrosis (fibrotic score) and PVV score were associated with DLCO but not with FVC. The PA diameter, which reflects the pulmonary artery pressure, was found to be associated with the PVV score.