Cancer-associated fibroblasts: heterogeneity and their role in the tumor immune response.

In recent decades, many reports have been published on the composition and function of the tumor microenvironment (TME), among which cancer-associated fibroblasts (CAFs) have received much attention. CAFs have different degrees of heterogeneity in terms of their origin, phenotype, and function and can be divided into different subpopulations. These subgroups may play different roles in the occurrence and development of tumors. In addition, CAFs are closely associated with tumor immunity and have been found to regulate immune cell activity and to suppress the tumor immune response. In this review, we systematize the heterogeneity and characteristics of CAFs, discuss how specific CAF subgroups contribute to cancer progression by inducing an immunosuppressive microenvironment, and finally, we examine the future clinical applications of CAF subgroups.

The levels of soluble CD137 are increased in tuberculosis patients and associated with disease severity and prognosis.

Tuberculosis (TB) was the leading cause of death from a single infectious agent before the coronavirus pandemic. Therefore, it is important to search for severity biomarkers and devise appropriate therapies. A total of 139 pulmonary TB (PTB) patients and 80 healthy controls (HCs) were recruited for plasma soluble CD137 (sCD137) detection through ELISA. Moreover, pleural effusion sCD137 levels were measured in 85 TB patients and 36 untreated lung cancer patients. The plasma cytokine levels in 64 patients with PTB and blood immune cell subpopulations in 68 patients with PTB were analysed via flow cytometry. Blood sCD137 levels were higher in PTB patients (p = 0.012) and correlated with disease severity (p = 0.0056). The level of sCD137 in tuberculous pleurisy effusion (TPE) was markedly higher than that in malignant pleurisy effusion (p = 0.018). Several blood cytokines, such as IL-6 (p = 0.0147), IL-8 (p = 0.0477), IP-10 (p ≤ 0.0001) and MCP-1 (p = 0.0057), and some laboratory indices were significantly elevated in severe PTB (SE) patients, but the percentages of total lymphocytes (p = 0.002) and cytotoxic T cells (p = 0.036) were significantly lower in SE patients than in non-SE patients. In addition, the sCD137 level was negatively correlated with the percentage of total lymphocytes (p = 0.0008) and cytotoxic T cells (p = 0.0021), and PTB patients with higher plasma sCD137 levels had significantly shorter survival times (p = 0.0041). An increase in sCD137 is a potential biomarker for severe TB and indicates a poor prognosis.

Nomogram prediction of vessels encapsulating tumor clusters in small hepatocellular carcinoma ≤ 3 cm based on enhanced magnetic resonance imaging.

BACKGROUND: Vessels encapsulating tumor clusters (VETC) represent a recently discovered vascular pattern associated with novel metastasis mechanisms in hepatocellular carcinoma (HCC). However, it seems that no one have focused on predicting VETC status in small HCC (sHCC). This study aimed to develop a new nomogram for predicting VETC positivity using preoperative clinical data and image features in sHCC (≤ 3 cm) patients. AIM: To construct a nomogram that combines preoperative clinical parameters and image features to predict patterns of VETC and evaluate the prognosis of sHCC patients. METHODS: A total of 309 patients with sHCC, who underwent segmental resection and had their VETC status confirmed, were included in the study. These patients were recruited from three different hospitals: Hospital 1 contributed 177 patients for the training set, Hospital 2 provided 78 patients for the test set, and Hospital 3 provided 54 patients for the validation set. Independent predictors of VETC were identified through univariate and multivariate logistic analyses. These independent predictors were then used to construct a VETC prediction model for sHCC. The model's performance was evaluated using the area under the curve (AUC), calibration curve, and clinical decision curve. Additionally, Kaplan-Meier survival analysis was performed to confirm whether the predicted VETC status by the model is associated with early recurrence, just as it is with the actual VETC status and early recurrence. RESULTS: Alpha-fetoprotein_lg10, carbohydrate antigen 199, irregular shape, non-smooth margin, and arterial peritumoral enhancement were identified as independent predictors of VETC. The model incorporating these predictors demonstrated strong predictive performance. The AUC was 0.811 for the training set, 0.800 for the test set, and 0.791 for the validation set. The calibration curve indicated that the predicted probability was consistent with the actual VETC status in all three sets. Furthermore, the decision curve analysis demonstrated the clinical benefits of our model for patients with sHCC. Finally, early recurrence was more likely to occur in the VETC-positive group compared to the VETC-negative group, regardless of whether considering the actual or predicted VETC status. CONCLUSION: Our novel prediction model demonstrates strong performance in predicting VETC positivity in sHCC (≤ 3 cm) patients, and it holds potential for predicting early recurrence. This model equips clinicians with valuable information to make informed clinical treatment decisions.

Clinical significance of miR-9-5p in NSCLC and its relationship with smoking.

Purpose: Dysregulated expression of microRNA (miRNAs) in lung cancer has been wildly reported. The clinicopathologic significance of miR-9-5p in non-small-cell lung cancer (NSCLC) patients and its effect on NSCLC progression were explored in this study. Patients and methods: A total of 76 NSCLC patients were included. miR-9-5p expression was evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Then, in vitro experiments including cell growth curve assays, colony formation assays, and transwell migration assays were performed. Further clinicopathological and prognostic values were explored using bioinformatics analysis of the TCGA database. Results: miR-9-5p expression was significantly increased in tumor tissues (both P < 0.0001). miR-9-5p expression was relatively higher in larger tumors (P = 0.0327) and in lung squamous carcinoma (LUSC) (P = 0. 0143). In addition, miR-9-5p was significantly upregulated in the normal lung tissues of cigarette smokers (P = 0.0099). In vitro, miR-9-5p was correlated with cell proliferation and migration. After that, bioinformatics analysis of the TCGA database indicated that miR-9-5p was correlated with tumor size (P = 0.0022), lymphatic metastasis (P = 0.0141), LUSC (P < 0.0001), and smoking history (P < 0.0001). Finally, a prognostic study indicated high miR-9-5p expression was correlated with poor prognosis in LUAD (P = 0.0121). Conclusion: Upregulation of miR-9-5p may have an oncogenic effect in NSCLC and may be related to smoking. The conclusion of this study may help find new prognostic and therapeutic targets for NSCLC and the exploration of the relationship between smoking and lung cancer.

[Retracted] Interaction of YAP1 and mTOR promotes bladder cancer progression.

Following the publication of the above article, a concerned reader drew to the Editor's attention that certain of the immunohistochemical data shown in Fig. 1C on p. 236, and immunofluorescence data featured in Figs. 2G and 5G on p. 237 and 239 respectively, were strikingly similar to data that had appeared in other articles written by different authors at different research institutes which had already been published.  In view of the fact that certain of the data in the above article had already been published at the time of the paper's submission, the Editor of International Journal of Oncology has decided that this paper should be retracted from the publication. After having been in contact with the authors, they accepted the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Oncology 56: 232­242, 2020; DOI: 10.3892/ijo.2019.4922].

Value of perfusion parameters from golden-angle radial sparse parallel dynamic contrast-enhanced magnetic resonance imaging in predicting pathological complete response after neoadjuvant chemoradiotherapy for locally advanced rectal cancer.

PURPOSE: Non-invasive methods for predicting pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) can provide distinct leverage in the management of patients with locally advanced rectal cancer (LARC). This study aimed to investigate whether including the golden-angle radial sparse parallel (GRASP) dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) perfusion parameter (Ktrans), in addition to tumor regression grading (TRG) and apparent diffusion coefficient (ADC) values, can improve the predictive ability for pCR. METHODS: Patients with LARC who underwent nCRT and subsequent surgery were included. The imaging parameters were compared between patients with and without pCR. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive ability of these parameters for pCR. RESULTS: A total of 111 patients were included in the study. A pCR was obtained in 32 patients (28.8%). MRI-based TRG (mrTRG) showed a negative correlation with pCR (r = -0.61, P < 0.001), and the average ADC value showed a positive correlation with pCR (r = 0.62, P < 0.001). Before nCRT, Ktrans in the pCR group was significantly higher than in the non-pCR group (1.30 ± 0.24 vs. 0.88 ± 0.34, P < 0.001), but no difference was identified after nCRT. Following ROC curve analysis, the area under the curve (AUC) of mrTRG (level 1-2), average ADC value, and Ktrans value for predicting pCR were 0.738 [95% confidence interval (CI): 0.65-0.82], 0.78 (95% CI: 0.69-0.86), and 0.84 (95% CI: 0.77-0.92), respectively. The model combining the three parameters had significantly higher predictive ability for pCR (AUC: 0.94, 95% CI: 0.88-0.98). CONCLUSION: The use of a combination of the GRASP DCE-MRI Ktrans with mrTRG and ADC can lead to a better pCR predictive performance.

The Ribonuclease ZC3H12A is required for self-inflicted DNA breaks after DNA damage in small cell lung cancer cells.

Radiotherapy is the first line treatment for small cell lung cancer (SCLC); However, radio-resistance accompanies with the treatment and hampers the prognosis for SCLC patients. The underlying mechanisms remains elusive. Here we discovered that self-inflicted DNA breaks exist in SCLC cells after radiation. Moreover, using nuclease siRNA screening combined with high-content ArrayScan™ cell analyzer, we identified that Ribonuclease ZC3H12A is required for the self-inflicted DNA breaks after radiation and for SCLC cell survival after DNA damage. ZC3H12A expression was increased in response to DNA damage and when ZC3H12A was knocked down, the DNA repair ability of the cells was impaired, as evidenced by decreased expression of the DNA damage repair protein BRCA1, and increased γH2AX at DNA damage sites. Colony formation assay demonstrates that ZC3H12A knocked down sensitized small cell lung cancer radiotherapy. Therefore, the Ribonuclease ZC3H12A regulates endogenous secondary breaks in small cell lung cancer and affects DNA damage repair. ZC3H12A may act as an important radiotherapy target in small cell lung cancer.

Radiomics of Preoperative Multi-Sequence Magnetic Resonance Imaging Can Improve the Predictive Performance of Microvascular Invasion in Hepatocellular Carcinoma.

Background: The aim of the study is to demonstrate that radiomics of preoperative multi-sequence magnetic resonance imaging (MRI) can indeed improve the predictive performance of microvascular invasion (MVI) in hepatocellular carcinoma (HCC). Methods: A total of 206 patients with pathologically confirmed HCC who underwent preoperative enhanced MRI were retrospectively recruited. Univariate and multivariate logistic regression analysis identified the independent clinicoradiologic predictors of MVI present and constituted the clinicoradiologic model. Recursive feature elimination (RFE) was applied to select radiomics features (extracted from six sequence images) and constructed the radiomics model. Clinicoradiologic model plus radiomics model formed the clinicoradiomics model. Five-fold cross-validation was used to validate the three models. Discrimination, calibration, and clinical utility were used to evaluate the performance. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were used to compare the prediction accuracy between models. Results: The clinicoradiologic model contained alpha-fetoprotein (AFP)_lg10, radiological capsule enhancement, enhancement pattern and arterial peritumoral enhancement, which were independent risk factors of MVI. There were 18 radiomics features related to MVI constructed the radiomics model. The mean area under the receiver operating curve (AUC) of clinicoradiologic, radiomics and clinicoradiomics model were 0.849, 0.925 and 0.950 in the training cohort and 0.846, 0.907 and 0.933 in the validation cohort, respectively. The three models' calibration curves fitted well, and decision curve analysis (DCA) confirmed the clinical usefulness. Compared with the clinicoradiologic model, the NRI of radiomics and clinicoradiomics model increased significantly by 0.575 and 0.825, respectively, and the IDI increased significantly by 0.280 and 0.398, respectively. Conclusions: Radiomics of preoperative multi-sequence MRI can improve the predictive performance of MVI in HCC.

The Clinical Value of Apparent Diffusion Coefficient of Readout Segmentation of Long Variable Echo Trains and Correlation With Ki-67 Expression in Distal Rectal Cancer.

OBJECTIVE: The aim of the study is to explore the clinical value of the apparent diffusion coefficient (ADC) derived from the readout segmentation of long variable echo trains (RESOLVE) technique for identifying clinicopathologic features of distal rectal cancer and correlations between ADC and Ki-67 expression. METHODS: The data of 112 patients with a proven pathology of distal rectal cancer who underwent preoperative magnetic resonance imaging were retrospectively analyzed. The mean ADC value was measured using the "full-layer and center" method. Differences in ADC values and Ki-67 expression in different clinical stages, pathological types, and tumor differentiation were compared using analysis of variance. Correlations between ADC value and clinicopathologic features were assessed using Spearman correlation analysis. RESULTS: Interobserver agreement of confidence levels from 2 radiologists was excellent for ADC measurement ( k =  0.85). Patients with a lower clinical stage, well-differentiated adenocarcinomas, and a higher possibility of mucinous adenocarcinoma exhibited a positive correlation with higher ADC values, but these factors were negatively correlated with Ki-67 expression (all P < 0.05). We found that ADC value was negatively correlated with Ki-67 expression ( r = -0.62, P < 0.001). CONCLUSIONS: The ADC value generated by RESOLVE sequences was significantly associated with clinicopathologic features and Ki-67 expression in patients with distal rectal cancer in this study. Thus, the ADC value could be considered a new noninvasive imaging biomarker that could be helpful in predicting the biological properties of distal rectal cancer.

Endogenous Zinc-Ion-Triggered In Situ Gelation Enables Zn Capture to Reprogram Benign Hyperplastic Prostate Microenvironment and Shrink Prostate.

Benign prostatic hyperplasia (BPH) as the leading cause of urination disorder is still a refractory disease, and there have no satisfied drugs or treatment protocols yet. With identifying excessive Zn2+ , inflammation, and oxidative stress as the etiology of aberrant hyperplasia, an injectable sodium alginate (SA) and glycyrrhizic acid (GA)-interconnected hydrogels (SAGA) featuring Zn2+ -triggered in situ gelation are developed to load lonidamine for reprogramming prostate microenvironment and treating BPH. Herein, SAGA hydrogels can crosslink with Zn2+ in BPH via coordination chelation and switch free Zn2+ to bound ones, consequently alleviating Zn2+ -arisen inflammation and glycolysis. Beyond capturing Zn2+ , GA with intrinsic immunoregulatory property can also alleviate local inflammation and scavenge reactive oxygen species (ROS). Intriguingly, Zn2+ chelation-bridged interconnection in SAGA enhances its mechanical property and regulates the degradation rate to enable continuous lonidamine release, favoring hyperplastic acini apoptosis and further inhibiting glycolysis. These multiple actions cooperatively reprogram BPH microenvironment to alleviate characteristic symptoms of BPH and shrink prostate. RNA sequencing reveals that chemotaxis, glycolysis, and tumor necrosis factor (TNF) inflammation-related pathways associated with M1-like phenotype polarization are discerned as the action rationales of such endogenous Zn2+ -triggered in situ hydrogels, providing a candidate avenue to treat BPH.

Human umbilical cord mesenchymal stem cells alleviated TNBS-induced colitis in mice by restoring the balance of intestinal microbes and immunoregulation.

AIMS: Human umbilical cord mesenchymal stem cells (HUMSCs) have been documented to be effective for several immune disorders including inflammatory bowel diseases (IBD). However, it remains unclear how HUMSCs function in regulating immune responses and intestinal flora in the trinitrobenzene sulfonic acid (TNBS)-induced IBD model. MATERIALS AND METHODS: We assessed the regulatory effects of HUMSCs on the gut microbiota, T lymphocyte subpopulations and related immune cytokines in the TNBS-induced IBD model. The mice were divided into the normal, TNBS, and HUMSC-treated groups. The effect of HUMSCs was evaluated by Hematoxylin and Eosin (H&E) staining, fluorescence-activated cell sorting (FACS), and enzyme-linked immunosorbent assay (ELISA) analyses. Metagenomics Illumina sequencing was conducted for fecal samples. KEY FINDINGS: We demonstrated that the disease symptoms and pathological changes in the colon tissues of TNBS-induced colitis mice were dramatically ameliorated by HUMSCs, which improved the gut microbiota and rebalanced the immune system, increasing the abundance of healthy bacteria (such as Lactobacillus murinus and Lactobacillus johnsonii), the Firmicutes/Bacteroidetes ratio, and the proportion of Tregs; the Th1/Th17 ratio was decreased. Consistently, the expression levels of IFN-γ and IL-17 were significantly decreased, and transforming growth factor-ß1 (TGF-ß1) levels were significantly increased in the plasma of colitis mice HUMSC injection. SIGNIFICANCE: Our experiment revealed that HUMSCs mitigate acute colitis by regulating the rebalance of Th1/Th17/Treg cells and related cytokines and remodeling the gut microbiota, providing potential future therapeutic targets in IBD.

An engineered nanoplatform cascade to relieve extracellular acidity and enhance resistance-free chemotherapy.

Tumor extracellular acidity and chemoresistance are regarded as the main obstacles to achieving optimal chemotherapeutic efficacy in tumor therapy. Herein, a new kind of acid-cascade P-S-Z nanoparticles (NPs) is developed to relieve extracellular acidosis and enhance chemotherapy without causing drug resistance. The P-S-Z NPs selectively accumulate in tumors and then regulate the release of S-Z NPs containing syrosingopine (Syr) and acid-activated prodrug ZMC1-Pt depending on the extracellular acidity. Benefiting from their small size and positive surface charge, S-Z NPs are easily internalized by tumor cells in deep tumor tissue, facilitating the release of Syr to inhibit lactic acid excretion and ultimately enhance cell acidosis. The prolonged intracellular acidosis not only inhibits tumor cell proliferation, but also continuously triggers the activation of ZMC1-Pt prodrug, a platinum-based chemotherapeutic drug that effectively eliminates cancer cells and restores wild-type p53 function to prevent tumor chemoresistance. As a proof of concept, this is a promising strategy to transfer the adverse effect of intracellular acidosis to facilitate chemotherapy. This well-designed delivery system effectively kills tumor cells without causing significant tumor drug resistance, thus opening a new window to treat cancer.

Exploration of diagnostic biomarkers, microenvironment characteristics, and ursolic acid's therapeutic effect for benign prostate hyperplasia.

Benign prostatic hyperplasia (BPH) and early-stage prostate cancer (PC) have similar symptoms, making it challenging to differentially diagnose these two conditions. The study used Weighted Gene Co-Expression Network Analysis, as well as two machine learning strategies to identify BPH-specific biomarkers based on an integrated transcriptome data from 922 samples. Eight prognostic genes (ALCAM, COL6A2, CRISP2, FOXF2, IGF1, PTN, SCN7A, and UAP1) were identified to be BPH-specific biomarkers with high accuracy and specificity. Moreover, we constructed a seven-gene diagnostic classifier to distinguish BPH from PC. The infiltrations of plasmacytoid dendritic cells and neutrophil cells showed distinct differences between BPH and non-BPH groups. Additionally, ursolic acid can reverse transcriptional features associated with the occurrence and progression of BPH. Both in vivo and in vitro experiments have confirmed that it induces apoptosis of BPH cells and inhibits cell proliferation by promoting cell cycle S-phase arrest. The diagnostic biomarkers, microenvironment characteristics, and therapeutic effect of ursolic acid explored in this study offer new diagnostic and therapeutic strategies for BPH.

Population pharmacokinetics of Amisulpride in Chinese patients with schizophrenia with external validation: the impact of renal function.

Introduction: Amisulpride is primarily eliminated via the kidneys. Given the clear influence of renal clearance on plasma concentration, we aimed to explicitly examine the impact of renal function on amisulpride pharmacokinetics (PK) via population PK modelling and Monte Carlo simulations. Method: Plasma concentrations from 921 patients (776 in development and 145 in validation) were utilized. Results: Amisulpride PK could be described by a one-compartment model with linear elimination where estimated glomerular filtration rate, eGFR, had a significant influence on clearance. All PK parameters (estimate, RSE%) were precisely estimated: apparent volume of distribution (645 L, 18%), apparent clearance (60.5 L/h, 2%), absorption rate constant (0.106 h-1, 12%) and coefficient of renal function on clearance (0.817, 10%). No other significant covariate was found. The predictive performance of the model was externally validated. Covariate analysis showed an inverse relationship between eGFR and exposure, where subjects with eGFR= 30 mL/min/1.73 m2 had more than 2-fold increase in AUC, trough and peak concentration. Simulation results further illustrated that, given a dose of 800 mg, plasma concentrations of all patients with renal impairment would exceed 640 ng/mL. Discussion: Our work demonstrated the importance of renal function in amisulpride dose adjustment and provided a quantitative framework to guide individualized dosing for Chinese patients with schizophrenia.

Immunoassay with Novel Paired Antibodies for Detection of Lipoarabinomannan in the Pleural Fluid and Plasma of Patients with Tuberculous Pleurisy.

Tuberculous pleurisy (TP) is one of the most common forms of extrapulmonary tuberculosis, but its diagnosis is challenging. Lipoarabinomannan (LAM) antigen is a biomarker for Mycobacterium tuberculosis (Mtb) infection. LAM detection has potential as an auxiliary diagnostic method for TP. We have successfully generated five rabbit anti-LAM monoclonal antibodies (BJRbL01, BJRbL03, BJRbL20, BJRbL52, and BJRbL76). Here, anti-LAM antibodies were tested to detect LAM in the pleural fluid and plasma of patients with TP by sandwich enzyme-linked immunosorbent assays (ELISAs). The results revealed that all of the anti-LAM antibodies were successfully used as capture and detection antibodies in sandwich ELISAs. The BJRbL01/BJRbL01-Bio pair showed better performance than the other antibody pairs for detecting mycobacterial clinical isolates and had a limit of detection of 62.5 pg/mL for purified LAM. LAM levels were significantly higher in the pleural fluid and plasma of patients with TP than in those of patients with malignant pleural effusion or the plasma of non-TB, and LAM levels in the pleural fluid and plasma were positively correlated. Moreover, LAM levels in the pleural fluid sample were significantly higher in confirmed TP patients than in clinically diagnosed TP patients. Our studies provide novel LAM detection choices in the pleural fluid and plasma of TP patients and indicate that LAM detection assay has an auxiliary diagnostic value for TP, which may help to improve the diagnosis of TP.

Intra-Operative Definition of Glioma Infiltrative Margins by Visualizing Immunosuppressive Tumor-Associated Macrophages.

Accurate delineation of glioma infiltrative margins remains a challenge due to the low density of cancer cells in these regions. Here, a hierarchical imaging strategy to define glioma margins by locating the immunosuppressive tumor-associated macrophages (TAMs) is proposed. A pH ratiometric fluorescent probe CP2-M that targets immunosuppressive TAMs by binding to mannose receptor (CD206) is developed, and it subsequently senses the acidic phagosomal lumen, resulting in a remarkable fluorescence enhancement. With assistance of CP2-M, glioma xenografts in mouse models with a tumor-to-background ratio exceeding 3.0 for up to 6 h are successfully visualized. Furthermore, by intra-operatively mapping the pH distribution of exposed tissue after craniotomy, the glioma allograft in rat models is precisely excised. The overall survival of rat models significantly surpasses that achieved using clinically employed fluorescent probes. This work presents a novel strategy for locating glioma margins, thereby improving surgical outcomes for tumors with infiltrative characteristics.

[Progress on the researches of acupuncture preconditioning before surgery].

This paper reviews the researches on acupuncture preconditioning before surgery in recent years and explores its application value from three aspects, i.e. relieving preoperative anxiety, preventing from postoperative cognitive dysfunction, and preventing from postoperative gastrointestinal dysfunction. As a relatively safe non-drug treatment, acupuncture has the underlying advantages in participating into multidisciplinary coordination in the enhanced recovery after surgery (ERAS). By building up higher-quality medical evidences and revealing the effect mechanism of acupuncture from multi-dimenisonal aspects, it is expected that acupuncture technology can be coordinated with ERAS to optimize the clinical path in the perioperative period, and boost the development of the perioperative medicine ultimately.

UHRF1/DNMT1-MZF1 axis-modulated intragenic site-specific CpGI methylation confers divergent expression and opposing functions of PRSS3 isoforms in lung cancer.

As confusion mounts over RNA isoforms involved in phenotypic plasticity, aberrant CpG methylation-mediated disruption of alternative splicing is increasingly recognized as a driver of intratumor heterogeneity (ITH). Protease serine 3 (PRSS3), possessing four splice variants (PRSS3-SVs; PRSS3-V1-V4), is an indispensable trypsin that shows paradoxical effects on cancer development. Here, we found that PRSS3 transcripts and their isoforms were divergently expressed in lung cancer, exhibiting opposing functions and clinical outcomes, namely, oncogenic PRSS3-V1 and PRSS3-V2 versus tumor-suppressive PRSS3-V3, by targeting different downstream genes. We identified an intragenic CpG island (iCpGI) in PRSS3. Hypermethylation of iCpGI was mediated by UHRF1/DNMT1 complex interference with the binding of myeloid zinc finger 1 (MZF1) to regulate PRSS3 transcription. The garlic-derived compound diallyl trisulfide cooperated with 5-aza-2'-deoxycytidine to exert antitumor effects in lung adenocarcinoma cells through site-specific iCpGI demethylation specifically allowing MZF1 to upregulate PRSS3-V3 expression. Epigenetic silencing of PRSS3-V3 via iCpGI methylation (iCpGIm) in BALF and tumor tissues was associated with early clinical progression in patients with lung cancer but not in those with squamous cell carcinoma or inflammatory disease. Thus, UHRF1/DNMT1-MZF1 axis-modulated site-specific iCpGIm regulates divergent expression of PRSS3-SVs, conferring nongenetic functional ITH, with implications for early detection of lung cancer and targeted therapies.

Interpretable deep learning survival predictive tool for small cell lung cancer.

Background: Small cell lung cancer (SCLC) is an aggressive and almost universally lethal neoplasm. There is no accurate predictive method for its prognosis. Artificial intelligence deep learning may bring new hope. Methods: By searching the Surveillance, Epidemiology, and End Results database (SEER), 21,093 patients' clinical data were eventually included. Data were then divided into two groups (train dataset/test dataset). The train dataset (diagnosed in 2010-2014, N = 17,296) was utilized to conduct a deep learning survival model, validated by itself and the test dataset (diagnosed in 2015, N = 3,797) in parallel. According to clinical experience, age, sex, tumor site, T, N, M stage (7th American Joint Committee on Cancer TNM stage), tumor size, surgery, chemotherapy, radiotherapy, and history of malignancy were chosen as predictive clinical features. The C-index was the main indicator to evaluate model performance. Results: The predictive model had a 0.7181 C-index (95% confidence intervals, CIs, 0.7174-0.7187) in the train dataset and a 0.7208 C-index (95% CIs, 0.7202-0.7215) in the test dataset. These indicated that it had a reliable predictive value on OS for SCLC, so it was then packaged as a Windows software which is free for doctors, researchers, and patients to use. Conclusion: The interpretable deep learning survival predictive tool for small cell lung cancer developed by this study had a reliable predictive value on their overall survival. More biomarkers may help improve the prognostic predictive performance of small cell lung cancer.