Enhancing diagnosis of benign lesions and lung cancer through ensemble text and breath analysis: a retrospective cohort study.

Early diagnosis of lung cancer (LC) can significantly reduce its mortality rate. Considering the limitations of the high false positive rate and reliance on radiologists' experience in computed tomography (CT)-based diagnosis, a multi-modal early LC screening model that combines radiology with other non-invasive, rapid detection methods is warranted. A high-resolution, multi-modal, and low-differentiation LC screening strategy named ensemble text and breath analysis (ETBA) is proposed that ensembles radiology report text analysis and breath analysis. In total, 231 samples (140 LC patients and 91 benign lesions [BL] patients) were screened using proton transfer reaction-time of flight-mass spectrometry and CT screening. Participants were randomly assigned to a training set and a validation set (4:1) with stratification. The report section of the radiology reports was used to train a text analysis (TA) model with a natural language processing algorithm. Twenty-two volatile organic compounds (VOCs) in the exhaled breath and the prediction results of the TA model were used as predictors to develop the ETBA model using an extreme gradient boosting algorithm. A breath analysis model was developed based on the 22 VOCs. The BA and TA models were compared with the ETBA model. The ETBA model achieved a sensitivity of 94.3%, a specificity of 77.3%, and an accuracy of 87.7% with the validation set. The radiologist diagnosis performance with the validation set had a sensitivity of 74.3%, a specificity of 59.1%, and an accuracy of 68.1%. High sensitivity and specificity were obtained by the ETBA model compared with radiologist diagnosis. The ETBA model has the potential to provide sensitivity and specificity in CT screening of LC. This approach is rapid, non-invasive, multi-dimensional, and accurate for LC and BL diagnosis.

A combined screening study for evaluating the potential of exhaled acetone, isoprene, and nitric oxide as biomarkers of lung cancer.

Background: the early lung cancer (LC) screening strategy significantly reduces LC mortality. According to previous studies, lung cancer can be effectively diagnosed by analyzing the concentration of volatile organic compounds (VOCs) in human exhaled breath and establishing a diagnosis model based on the different VOCs. This method, called breath analysis, has the advantage of being rapid and non-invasive. To develop a non-invasive, portable breath detection instrument based on cavity ring-down spectroscopy (CRDS), we explored the feasibility of establishing a model with acetone, isoprene, and nitric oxide (NO) exhaled through human breath, which can be detected on the CRDS instrument. Methods: a total of 511 participants were recruited from the Cancer Institute and Hospital, Tianjin Medical University as the discovery set and randomly split (2 : 1) into training set and internal validation set with stratification. For external validation, 51 participants were recruited from the General Hospital, Tianjin Medical University. Acetone and isoprene from exhaled breath were detected by proton-transfer-reaction time-of-flight mass spectrometry (PTR-TOF-MS), and NO was measured using CRDS. The model was constructed using the ensemble learning method that set eXtreme gradient boosting and logistic regression as the basis model and logistic regression as the senior model. The model was evaluated based on accuracy, sensitivity, and specificity. Results: the model achieved an accuracy of 78.8%, sensitivity of 81.0%, specificity of 70.0%, and area under the receiver operating curve (ROC, AUC) of 0.8341 (95% CI from 0.8055 to 0.8852) in the internal validation set. Furthermore, it attained an accuracy of 66.7%, sensitivity of 68.2%, specificity of 65.5%, and AUC of 0.6834 (95% CI from 0.5259 to 0.7956) in the external validation set. Conclusion: the model, established with acetone, isoprene, and NO as predictors, possesses the ability to identify LC patients from healthy control (HC) participants. The CRDS instrument, which simultaneously detects acetone, isoprene, and NO, is expected to be a non-invasive, rapid, portable, and accurate device for early screening of LC.

Application of Organoids in Regenerative Medicine.

Regenerative medicine mainly relies on heterologous transplantation, often hindered by sample availability and ethical issues. Furthermore, patients are required to take immunosuppressive medications to prevent adverse side effects. Stem cell-derived 3D-organoid culture has provided new alternatives for transplantation and regenerative medicine. Scholars have combined organoids with tissue engineering technology to improve reproducibility, the accuracy of constitution and throughput, and genetic correction to achieve a more personalized therapy. Here, we review the available applications of organoids in regenerative medicine and the current challenges concerning this field.

The effect of resveratrol, curcumin and quercetin combination on immuno-suppression of tumor microenvironment for breast tumor-bearing mice.

Resveratrol, curcumin, and quercetin are the secondary metabolites from medicinal food homology plants, that have been proven their potency in cancer treatment. However, the antitumor effect of a single component is weak. So, herein, we designed an antitumor compound named RCQ composed of resveratrol, curcumin, and quercetin. This study examined the effect on tumorigenesis and development of 4T1 breast cancer-bearing mice following administering RCQ by intragastric administration. RCQ increased the recruitment of T cells and reduced the accumulation of neutrophils and macrophages in the tumor microenvironment. Meanwhile, RCQ suppressed the development of tumor-infiltrating lymphocytes into immunosuppressive cell subpopulations, including CD4+ T cells to T helper Type 2 type (Th2), tumor-associated neutrophils (TANs) to the N2 TANs, and tumor-associated macrophages (TAMs) cells to M2 TAMs. RCQ reversed the predominance of immunosuppressive infiltrating cells in the tumor microenvironment and tipped the immune balance toward an immune activation state. In vitro the study showed that RCQ significantly increased reactive oxygen species (ROS), reduce mitochondrial membrane potentials in cancer cells, and modulate pro-apoptotic Bcl-2 family members. In conclusion, RCQ can promote the ROS apoptosis mechanism of tumor cells and alleviate immunosuppression of the tumor microenvironment to enhance the anti-tumor effect.

Preparation, characterization, and evaluation of the antitumor effect of kaempferol nanosuspensions.

Kaempferol (KAE) is a naturally occurring flavonoid compound with antitumor activity. However, the low aqueous solubility, poor chemical stability, and suboptimal bioavailability greatly restrict its clinical application in cancer therapy. To address the aforementioned limitations and augment the antitumor efficacy of KAE, we developed a kaempferol nanosuspensions (KAE-NSps) utilizing D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) as a stabilizing agent, screened the optimal preparation process, and conducted a comprehensive investigation of their fundamental properties as well as the antitumor effects in the study. The findings indicated that the particle size was 186.6 ± 2.6 nm of the TPGS-KAE-NSps optimized, the shape of which was fusiform under the transmission electron microscope. The 2% (w/v) glucose was used as the cryoprotectant for TPGS-KAE-NSps, whose drug loading content was 70.31 ± 2.11%, and the solubility was prominently improved compared to KAE. The stability and biocompatibility of TPGS-KAE-NSps were favorable and had a certain sustained release effect. Moreover, TPGS-KAE-NSps clearly seen to be taken in the cytoplasm exhibited a stronger cytotoxicity and suppression of cell migration, along with increased intracellular ROS production and higher apoptosis rates compared to KAE in vitro cell experiments. In addition, TPGS-KAE-NSps had a longer duration of action in mice, significantly improved bioavailability, and showed a stronger inhibition of tumor growth (the tumor inhibition rate of high dose intravenous injection group was 68.9 ± 1.46%) than KAE with no obvious toxicity in 4T1 tumor-bearing mice. Overall, TPGS-KAE-NSps prepared notably improved the defect and the antitumor effects of KAE, making it a promising nanodrug delivery system for KAE with potential applications as a clinical antitumor drug.

A diagnostic test of three-dimensional magnetic resonance elastography imaging for preoperative prediction of microvascular invasion in patients with T1 stage clear cell renal carcinoma.

Background: Detection of microvascular invasion (MVI) of kidney tumors is important for selecting the optimal therapeutic strategy. Currently, the prediction of MVI lacks an accurate imaging biomarker. This study evaluated the performance of three-dimensional (3D) magnetic resonance elastography (MRE) imaging in predicting microvascular invasion (MVI) of T1 stage clear cell renal carcinoma (ccRCC). Methods: In this prospective study, we conducted pre-surgical imaging with a clinical 3.0 T magnetic resonance imaging (MRI) system. Firstly, 83 consecutive patients were enrolled in this study. A 3D MRE stiffness map was generated and transferred to a post-processing workstation. Contrast-enhanced computed tomography (CT) was conducted to calculate the tumor enhancement ratio. The presence of MVI was evaluated by histopathological analysis and graded according to the risk stratification based upon the number and distribution. The mean stiffness and CT tumor enhancement ratio was calculated for tumors with or without MVI. The diagnostic performance [sensitivity, specificity, positive predictive value, negative predictive value, area under the curve (AUC)] and independent predicting factors for MVI were investigated. Results: Finally, A total of 80 patients (aged 46.7±13.2 years) were enrolled, including 22 cases of tumors with MVI. The mean MRE stiffness of kidney parenchyma and kidney tumors was 4.8±0.2 and 4.5±0.7 kPa, respectively. There was significant difference in the mean MRE stiffness between tumors with MVI (5.4±0.6 kPa) and tumors without MVI (4.1±0.3 kPa) (P<0.05). The sensitivity, specificity, positive predictive value, negative predictive value, and the AUC for mean stiffness in the prediction of MVI were 100%, 75%, 63%, 96%, and 0.87 [95% confidence interval (CI): 0.72, 0.94], respectively. The corresponding values for the CT tumor enhancement ratio were 90%, 80%, 63%, 96%, and 0.88 (95% CI: 0.71, 0.93), respectively. The odds ratio (OR) value for MRE tumor stiffness and CT kidney tumor enhancement ratio in the prediction of MVI was 2.9 (95% CI: 1.8, 3.7) and 1.2 (95% CI: 1.0, 1.7), respectively (P>0.05). Conclusions: 3D MRE imaging has promising diagnostic performance for predicting MVI in T1 stage ccRCC, which may improve the reliability of surgical strategy selection with T1 stage ccRCC.

Reproductive Toxicity Evaluation of Graphene-Based Tumor Cell Nucleus-Targeting Fluorescent Nanoprobes on Reproduction and Offspring Health.

A new graphene-based fluorescent nanoprobe for tumor cell nucleus (GTTNs) was synthesized in our laboratory that penetrates the cell membrane and particularly targets cancer cell nucleus and displays tremendous potential for clinical applications. Although acute and subacute toxicity studies have been conducted on GTTNs, a primary result could be drawn that GTTNs appear to have almost no acute and subacute toxicity. However, as an important part of safety evaluation, the influences on reproductive and offspring developmental toxicity are still absent. In this study, male mice were injected intravenously with GTTNs, and the survival status, histopathology of the testes and epididymides, proliferation and apoptosis of testicular tissue, and sperm motility of mice were measured. To evaluate the short- and long-term fertility in male mice, different male mice resided with untreated female mice on days 1 and 30 after the end of the last treatment, and the offspring health parameters were assessed by measuring pup numbers, body weight, and organ indexes of the pups. The results indicated that GTTNs-exposed male mice retained good fertility, healthy structure of testes and epididymides, and production of healthy sperm. Meanwhile, there were no significant differences between the offspring and the control group. In consideration of GTTNs with broad prospects for biomedical applications, our results contribute a basis for further understanding of its biosafety.

Polydopamine-guarded metal-organic frameworks as co-delivery systems for starvation-assisted chemo-photothermal therapy.

Cutting off glucose provision by glucose oxidase (GOx) to famish tumors can be an assistance with chemotherapy to eliminate cancer cells. Co-encapsulation of GOx and chemotherapeutics (doxorubicin) within pH-sensitive metal-organic frameworks (MOFs) could disorder metabolic pathways of cancer cells and generate excessive intracellular reactive oxygen species (ROS), together. To prevent premature leach of GOx from the porous channels of MOFs, polydopamine (PDA) was deposited on the surface of MOFs, which endowed the delivery system with photothermal conversion ability. Our nanoscaled co-delivery system (denoted as DGZPNs) remains stable with low amount of drug leakage under simulated physiological conditions in vitro and internal environment, while they are triggered to release doxorubicin (DOX) and GOx in acid tumor microenvironment and at high temperature for reinforced chemotherapy. NIR laser irradiation also activates superior photothermal conversion efficiency of PDA (36.9 %) to initiate hyperthermia to ablate tumor tissue. After being phagocytized by 4 T1 cells (breast cancer cells), the DGZPNs delivery system showed a superior therapeutic efficacy with a tumor growth inhibition of 88.9 ± 6.6 % under NIR irradiation, which indicated that the starvation-assisted chemo-photothermal therapy prompts the significant advance of synergistic therapy in a parallelly controlled mode.

[Ameliorative Effects of Cang-ai Volatile Oil on Left Ventricular Remodeling in Rats].

Objective: To evaluate with 7T cardiac magnetic resonance tissue tracking imaging (CMR-TT) the ameliorative effect of Cang-ai volatile oil (CAVO) on left ventricular remodeling (LVR) in rats induced by isoproterenol (ISO), and to make preliminary investigation into CAVO's effects on endothelial dysfunction in LVR. Methods: A total of 35 healthy male Sprague-Dawley (SD) rats were randomly assigned to two groups, the experimental group ( n=27) and the normal control group ( n=8). The rat model of LVR was established by subcutaneous injection of ISO solution at 10 mg·kg -1·d -1 at multiple sites for 10 consecutive days. After modeling was completed, the surviving rats ( n=24) in the experimental group were then randomly assigned to the blank experimental group, CAVO group, and Shexiang Baoxin pill (SXBXP) group ( n=8 in each group). Rats in each group were given via gavage the corresponding intervention medicine or an equivalent amount of normal saline solution for 28 consecutive days. At the end of modeling and intragastric intervention, 7T CMR cine sequence scanning was conducted to collect data. Then, post-processing software CVI42 was used to analyze the images and to compare and contrast the changes in the parameters of left ventricular cardiac function and myocardial strain in each group before and after the administration of the medication. The rats were sacrificed after MRI scanning, and their hearts were harvested for pathological examination. The levels of serum biochemical indicators were measured by enzyme-linked immunosorbent assay (ELISA). Results: CAVO significantly increased LV ejection fraction and overall myocardial strain parameters in LVR rats, while it decreased LV volume, mass, and serum levels of endothelial function indicators in LVR rats. In addition, pathological staining showed marked improvements in the hypertrophy, necrosis and interstitial fibrosis of cardiomyocytes. Conclusion: Through the regulation of myocardial vascular endothelial function, CAVO can significantly improve cardiac functions in LVR rats, delay the process of ventricular remodeling, and have a certain amount of protective effect on cardiac structure and function in rats.

Does the Level of Syndesmotic Screw Insertion Affect Clinical Outcome after Ankle Fractures with Syndesmotic Instability?

OBJECTIVE: Ankle fractures are often combined with syndesmotic instability, requiring reduction and stabilization. However, the optimal level for syndesmotic screw positioning remains unclear. This study aims to evaluate the effect of different syndesmotic screw insertion levels on postoperative clinical outcomes and determine whether an optimal level exists. METHODS: This retrospective study included data from 43 adult patients with acute closed ankle fractures combined with intraoperative evidence of unstable syndesmotic injuries who underwent open reduction internal fixation from January 1, 2017 to March 1, 2018 according to the inclusion and exclusion criteria. All 43 patients were divided into three groups based on the syndesmotic screw placement level: trans-syndesmotic group: screw level of 2-3 cm; inferior-syndesmotic group: screw level <2 cm; and supra-syndesmotic group: screw level >3 cm. Clinical outcomes were measured at the final follow-up, including the American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot score, Olerud-Molander Ankle Score (OMAS), short-form 36-item questionnaire (SF-36), visual analogue scale (VAS) score and restrictions in ankle range of motion (ROM). The relationships between screw placement level and clinical outcomes were analyzed with the Kruskal-Wallis H-test and Spearman correlation analysis. RESULTS: The median follow-up duration was 15 months (range, 10-22 months). No patients developed fracture nonunion or malunion or experienced hardware failure. The outcome scoring systems showed an overall score for the entire group of 94.91 points for the AOFAS ankle-hindfoot score, 83.14 for the OMAS, 96.65 for the SF-36, 1.77 for the VAS, 9.14° for the restrictions in dorsiflexion, and 1.30° for the restrictions in plantarflexion. There were no significant differences among three groups in clinical outcomes (P > 0.05). Neither the AOFAS score nor OMAS had significant correlations with screw insertion level (P = 0.825 and P = 0.585, respectively). No postoperative arthritis or widening of the tibiofibular space was observed at the final follow-up. CONCLUSION: Different syndesmotic screw placement levels appear not to affect the clinical outcomes of ankle fractures with syndesmotic instability. No optimal level was observed in this study. Our findings suggest other clinically acceptable options apart from syndesmotic screw placement 2-3 cm above the ankle.

MRI Fat-Saturated T2-Weighted Radiomics Model for Identifying the Ki-67 Index of Soft Tissue Sarcomas.

BACKGROUND: Ki-67 expression has been shown to be an important risk factor associated with prognosis in patients with soft tissue sarcomas (STSs). Its assessment requires fine-needle biopsy and its accuracy can be influenced by tumor heterogeneity. PURPOSE: To develop and test an MRI-based radiomics nomogram for identifying the Ki-67 status of STSs. STUDY TYPE: Retrospective. POPULATION: A total of 149 patients at two independent institutions (training cohort [high Ki-67/low ki-67]: 102 [52/50], external validation cohort [high Ki-67/low ki-67]: 47 [28/19]) with STSs. FIELD STRENGTH/SEQUENCE: Fat-saturated T2-weighted imaging (FS-T2WI) with a fat-suppressed fast spin/turbo spin echo sequence at 1.5 T or 3 T. ASSESSMENT: After radiomics feature extraction, logistic regression (LR), random forest (RF), support vector machine (SVM), and k-nearest neighbor (KNN) were used to construct radiomics models to distinguish between high and low Ki-67 status. Clinical-MRI characteristics included age, gender, location, size, margin, and MRI morphological features (size, margin, signal intensity, and peritumoral hyperintensity) were assessed. Univariate and multivariate logistic regression analysis were applied for screening significant risk factors. Radiomics nomogram was constructed by radiomics signature and risk factors. STATISTICAL TESTS: Model performances (discrimination, calibration, and clinical usefulness) were validated in the validation cohort. The nomogram was assessed using the Harrell index of concordance (C-index), calibration curve analysis. The clinical utility of the model was assessed by decision curve analysis (DCA). RESULTS: LR, RF, SVM, and KNN models represented AUCs of 0.789, 0.755, 0.726, and 0.701 in the validation cohort (P > 0.05). The nomogram had a C-index of 0.895 (95% CI: 0.837-0.953) in the training cohort and 0.852 (95% CI: 0.796-0.957) in the validation cohort and it demonstrated good calibration and clinical utility (P = 0.972 for the training cohort and P = 0.727 for the validation cohort). DATA CONCLUSION: This MRI-based radiomics nomogram developed showed good performance in identifying Ki-67 expression status in STSs. TECHNICAL EFFICACY STAGE: 2.

Risk factors of cardiovascular and cerebrovascular diseases in young and middle-aged adults: A meta-analysis.

BACKGROUND: The risk factors for cardiovascular and cerebrovascular diseases in young and middle-aged people have not yet been determined. We conducted a meta-analysis to find the risk factors for cardiovascular and cerebrovascular diseases, in order to provide guidance for the prevention of diseases in the young and middle-aged population. METHODS: We searched PubMed, Embase, Cochrane Library from the establishment of the database to Mar 2022. We included case-control or cohort studies reporting risk factors for cardiovascular and cerebrovascular disease in young and middle-aged adults. We excluded repeated publication, research without full text, incomplete information or inability to conduct data extraction and animal experiments, reviews and systematic reviews. STATA 15.1 was used to analyze the data. RESULTS: The pooled results indicated that increased systolic blood pressure was significantly associated with increased risk of any stroke, ischemic stroke and hemorrhagic stroke. Body Mass Index (BMI), current smoking, hypertension, and diabetes were significantly associated with increased risk of any stroke and ischemic stroke. Atrial fibrillation was only significantly associated with increased risk of any stroke. Increased total cholesterol was significantly associated with an increased risk of ischemic stroke, whereas increased triglycerides were significantly associated with a decreased risk of ischemic stroke. In addition, increased hypertension was also significantly associated with an increased risk of acute coronary syndrome. CONCLUSION: Our pooled results show that BMI, current smoking, atrial fibrillation, hypertension, systolic blood pressure, and total cholesterol can be used as risk factors for cardiovascular and cerebrovascular diseases in young people, while triglycerides can be used as protective factors for cardiovascular and cerebrovascular diseases in young and middle-aged adults.

Core immune cell infiltration signatures identify molecular subtypes and promote precise checkpoint immunotherapy in cutaneous melanoma.

Yutao Wang, China Medical University, ChinaThe tumor microenvironment (TME) has been shown to impact the prognosis of tumors in patients including cutaneous melanoma (CM); however, not all components of TME are important. Given the aforementioned situation, the functional immune cell contents correlated with CM patient prognosis are needed to optimize present predictive models and reflect the overall situation of TME. We developed a novel risk score named core tumor-infiltrating immune cell score (cTICscore), which showed certain advantages over existing biomarkers or TME-related signatures in predicting the prognosis of CM patients. Furthermore, we explored a new gene signature named cTILscore-related module gene score (cTMGs), based on four identified TME-associated genes (GCH1, GZMA, PSMB8, and PLAAT4) showing a close correlation with the cTICscore, which was generated by weighted gene co-expression network analysis and least absolute shrinkage and selection operator analysis to facilitate clinical application. Patients with low cTMGs had significantly better overall survival (OS, P = 0.002,< 0.001, = 0.002, and = 0.03, respectively) in the training and validating CM datasets. In addition, the area under the curve values used to predict the immune response in four CM cohorts were 0.723, 0.723, 0.754, and 0.792, respectively, and that in one gastric cohort was 0.764. Therefore, the four-gene signature, based on cTICscore, might improve prognostic information, serving as a predictive tool for CM patients receiving immunotherapy.cutaneous melanoma, tumor microenvironment, prognosis, immunotherapy, cTICscore.

Cuproptosis-Related Risk Score Predicts Prognosis and Characterizes the Tumor Microenvironment in Hepatocellular Carcinoma.

Aims: Cuproptosis is a recently identified form of programmed cell death; however, its role in hepatocellular carcinoma (HCC) remains unclear. Methods: A set of bioinformatic tools was integrated to analyze the expression and prognostic significance of ferredoxin 1 (FDX1), the key regulator of cuproptosis. A cuproptosis-related risk score (CRRS) was developed via correlation analyses, least absolute shrinkage and selection operator (LASSO) Cox regression, and multivariate Cox regression. The metabolic features, mutation signatures, and immune profile of CRRS-classified HCC patients were investigated, and the role of CRRS in therapy guidance was analyzed. Results: FDX1 was significantly downregulated in HCC, and its high expression was associated with longer survival time. HCC patients in the high-CRRS group showed a significantly lower overall survival (OS) and enriched in cancer-related pathways. Mutation analyses revealed that the high-CRRS HCC patients had a high mutational frequency of some tumor suppressors such as tumor protein P53 (TP53) and Breast-cancer susceptibility gene 1 (BRCA1)-associated protein 1 (BAP1) and a low frequency of catenin beta 1 (CTNNB1). Besides, HCC patients with high CRRS showed an increase of protumor immune infiltrates and a high expression of immune checkpoints. Moreover, the area under the curve (AUC) values of CRRS in predicting the efficiency of sorafenib and the non-responsiveness to transcatheter arterial chemoembolization (TACE) in HCC patients reached 0.877 and 0.764, respectively. Significance: The cuproptosis-related signature is helpful in prognostic prediction and in guiding treatment for HCC patients.

Bioinformatics-based analysis of SUMOylation-related genes in hepatocellular carcinoma reveals a role of upregulated SAE1 in promoting cell proliferation.

The function of small ubiquitin-like modifier (SUMO)-related genes in hepatocellular carcinoma (HCC) remains unclear. This study aimed to analyze the expression profile and prognostic relevance of SUMO-related genes using publicly available data. A set of bioinformatics tools and experiments were integrated to explore the mechanism of the genes of interest. The least absolute shrinkage and selection operator Cox regression analysis was used to construct a prognostic model. SUMO-2 and SUMO-activating enzyme subunit 1 (SAE1) were upregulated in HCC. The enrichment analysis indicated that SUMO-2 and SAE1 might regulate the cell cycle. The downregulation of SAE1 inhibited the proliferation of HCC cells, whereas the upregulation of the gene promoted cell proliferation. IGF2BP3 contributed to the upregulation of SAE1 in an N6-methyladenosine (m6A)-dependent way. Eventually, an SAE1-related risk score (SRRS) was developed and validated in HCC. SRRS could serve as an independent prognostic factor and predict the efficiency of transarterial chemoembolization in patients with HCC.

HIF-PH Encoded by EGLN1 Is a Potential Therapeutic Target for Chronic Lymphocytic Leukemia.

Owing to the recent emergence of drug resistance to Bruton's tyrosine kinase inhibitors (BTK) in chronic lymphocytic leukemia (CLL) treatment, it is crucial to identify alternative therapeutic targets. Therefore, we aimed to identify therapeutic options for CLL besides BTK. We identified that HIF1A expression was higher in CLL patients than in controls, which may suggest good prognosis. We used a lentiviral knockdown of EGLN1 (encoding hypoxia-inducible factor prolyl hydroxylase [HIF-PH]) and found that the growth of MEC-1 cells slowed in the knockdown group. Treatment of CLL cell lines MEC-1 and HG3 with the HIF-PH inhibitor molidustat showed that molidustat could induce apoptosis in a concentration-dependent manner in CLL cells and had low cytotoxicity at this concentration. CXCR4, HIF1A, SLC2AI, and VEGF, the downstream molecules of the HIF pathway, were upregulated after molidustat treatment. Western blotting results indicated that molidustat increased HIF1A expression in CLL cell lines and cells from CLL patients, and sequencing/quantitative PCR analysis demonstrated that the ribosome biogenesis pathway was inhibited in MEC-1 cells after molidustat treatment. We further identified synergistic cytotoxicity of molidustat in combination with ibrutinib on the MEC-1 and HG3 cell lines at certain concentrations. Therefore, molidustat is a potential therapeutic option for CLL.

Accuracy of CT texture analysis for differentiating low-grade and high-grade renal cell carcinoma: systematic review and meta-analysis.

OBJECTIVES: This study aimed to assess the accuracy of CT texture analysis (CTTA) for differentiating low-grade and high-grade renal cell carcinoma (RCC). DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Cochrane Library, Embase, Web of Science, OVID Medline, Science Direct and Springer were searched to identify the included studies. ELIGIBILITY CRITERIA FOR INCLUDING STUDIES: Clinical studies that report about the accuracy of CTTA in differentiating low-grade and high-grade RCC. METHODS: Multiple databases were searched to identify studies from their inception to 20 October 2021. Two radiologists independently extracted data from the primary studies. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic OR (DOR) were calculated to assess CTTA performance. The summary receiver operating characteristic (SROC) curve was plotted, and the area under the curve (AUC) was calculated to evaluate the accuracy of CTTA in grading RCC. RESULTS: This meta-analysis included 11 studies, with 1603 lesions observed in 1601 patients. Values of the pooled sensitivity, specificity, PLR, NLR, DOR were 0.79 (95% CI 0.73 to 0.84), 0.84 (95% CI 0.81 to 0.87), 5.1 (95% CI 4.0 to 6.4), 0.24 (95% CI 0.19 to 0.32) and 21 (95% CI 13 to 33), respectively. The SROC curve showed that the AUC was 0.88 (95% CI 0.84 to 0.90). Deeks' test found no significant publication bias among the studies (p=0.42). CONCLUSIONS: The findings of this meta-analysis suggest that CTTA has a high accuracy in differentiating low-grade and high-grade RCC. A standardised methodology and large sample-based study are necessary to certain the diagnostic accuracy of CTTA in RCC grading for clinical decision making.

Analysis of Glucosinolate Content and Metabolism Related Genes in Different Parts of Chinese Flowering Cabbage.

Glucosinolates (GSLs) are important secondary metabolites that play important defensive roles in cruciferous plants. Chinese flowering cabbage, one of the most common vegetable crops, is rich in GSLs and thus has the potential to reduce the risk of cancer in humans. Many genes that are involved in GSL biosynthesis and metabolism have been identified in the model plant Arabidopsis thaliana; however, few studies investigated the genes related to GSL biosynthesis and metabolism in Chinese flowering cabbage. In the present study, the GSL composition and content in three different organs of Chinese flowering cabbage (leaf, stalk, and flower bud) were determined. Our results showed that the total GSL content in flower buds was significantly higher than in stalks and leaves, and aliphatic GSLs were the most abundant GSL type. To understand the molecular mechanisms underlying the variations of GSL content, we analyzed the expression of genes encoding enzymes involved in GSL biosynthesis and transport in different tissues of Chinese flowering cabbage using RNA sequencing; the expression levels of most genes were found to be consistent with the pattern of total GSL content. Correlation and consistency analysis of differentially expressed genes from different organs with the GSL content revealed that seven genes (Bra029966, Bra012640, Bra016787, Bra011761, Bra006830, Bra011759, and Bra029248) were positively correlated with GSL content. These findings provide a molecular basis for further elucidating GSL biosynthesis and transport in Chinese flowering cabbage.

Overexpression of growth and differentiation factor-5 inhibits inflammatory factors released by intervertebral disc cells.

Low back pain (LBP) is one of the most common musculoskeletal diseases in the world. The incidence is ~70% in adults and many of them suffer from disability. Recently, intervertebral disc degeneration (IDD) has been deemed as a main cause of LBP. The present study aimed to investigate the potentials of growth and differentiation factor-5 (GDF-5) in IDD. The protein levels of prostaglandin-E2 (PGE2), tumor necrosis factor (TNF)-α and interleukin (IL)-1ß in culture medium were evaluated by ELISA. mRNA and protein expression levels in nucleus pulposus (NP) cells were evaluated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. Griess reaction was applied to test the nitric oxide (NO) concentration in the culture supernatant. The expression levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in NP cells were measured by RT-qPCR. Collagen-II, aggrecan, IκBα and phosphorylated (p)-p65 expression levels were detected by western blotting. Compared with the control group, protein expression levels of TNF-α, IL-1ß and PGE2, and NO concentration in culture medium were upregulated by LPS, which were significantly repressed by GDF-5 overexpression (P<0.05). Additionally, GDF-5 overexpression reduced lipopolysaccharide-induced upregulation of TNF-α, IL-1ß, iNOS, COX-2, collagen-II, aggrecan, IκBα and p-p65 expression levels in NP cells.

Comparison of Posteromedial Versus Posterolateral Approach for Posterior Malleolus Fixation in Trimalleolar Ankle Fractures.

OBJECTIVE: To compare clinical and radiographic outcomes of posterior malleolar fractures (PMF) treated with lag screws from anterior to posterior versus posterior to anterior approach. METHODS: We retrospectively analyzed 48 patients with trimalleolar fractures who underwent open reduction and internal fixation (ORIF) with either posteromedial (PM) or posterolateral (PL) approaches between January 2012 and December 2014. Fixation of the posterior malleolus was made with anteroposterior screws in 20 patients using the PM approach and posteroanterior screws in 28 patients using the PL approach. The American Orthopedic Foot and Ankle Society (AOFAS) scores and range of motion (ROM) of the ankle were used as the main outcome measurements, and results were evaluated at the 6-month, 12-month and final follow-up. Postoperative radiographs and computed tomography scans were used to evaluate the residual gap/step-off. The degree of arthritis was evaluated on final follow-up using Bargon criteria. Other complications were also recorded to compare the clinical outcomes of the two approaches. RESULT: The mean duration of follow-up regardless of the approaches was 21.1 months (range, 15-54 months). None of the patients developed delayed union or nonunion. Functional bone healing was obtained in all patients at 10.7 weeks (range, 8-16 weeks). The mean AOFAS scores of the PM group at the postoperative 6-mouth, 12-month, and final follow-up were 91.4 (range, 82-100), 92.5 (range, 84-100), and 92.9 (range, 86-100), respectively. In the PL group, the mean AOFAS scores were 89.9 (range, 72-100), 91.4 (range, 77-100), and 91.9 (range, 77-100), respectively. At the final follow-up, the median loss of range of motion (ROM) for dorsiflexion and plantaflexion were 0°(0°, 5°) and 0°(0°, 0°), respectively, in both groups. There were no significant differences between the two approaches in AOFAS scores and ROM of the ankle in each period postoperatively (P > 0.05). Two patients in the PL group and 1 in the PM group developed Bargon grade 2 or 3 arthritis. We detected a 2-mm and 3-mm step-off in 1 patient in the PM and PL groups, respectively. CONCLUSION: Satisfactory results were obtained by using the two approaches for fixation of posterior malleolus, and the approaches have similar clinical and radiographic outcomes. Surgeons should choose the appropriate approach based on their experience.