Recent progress on engineered micro/nanomaterials mediated modulation of gut microbiota for treating inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a type of chronic recurrent inflammation disease that mainly includes Crohn's disease and ulcerative colitis. Currently, the treatments for IBD remain highly challenging, with clinical treatment drugs showing limited efficacy and adverse side effects. Thus, developing drug candidates with comprehensive therapeutic effects, high efficiency, and low toxicity is urgently needed. Recently, micro/nanomaterials have attracted considerable interest because of their bioavailability, multitarget and efficient effects on IBD. In addition, gut modulation plays a substantial role in restoring intestinal homeostasis. Therefore, efficient microbiota-based strategies modulating gut microenvironment have great potential in remarkably treating IBD. With the development of micro- and nanomaterials for the treatment of IBD and more in-depth studies of their therapeutic mechanisms, it has been found that these treatments also have a tendency to positively regulate the intestinal flora, resulting in an increase in the beneficial flora and a decrease in the level of pathogenic bacteria, thus regulating the composition of the intestinal flora to a normal state. In this review, we first present the interactions among the immune system, intestinal barrier, and gut microbiome. In addition, recent advances in administration routes and methods that positively arouse the regulation of intestinal flora for IBD using probiotics, prebiotics, and redox-active micro/nanomaterials have been reviewed. Finally, the key challenges and critical perspectives of gut microbiota-based micro/nanomaterial treatment are also discussed.

Imaging features and deep learning for prediction of pulmonary epithelioid hemangioendothelioma in CT images.

Background: Pulmonary epithelioid hemangioendothelioma (PEH) is a rare vascular tumour, and its early diagnosis remains challenging. This study aims to comprehensively analyse the imaging features of PEH and develop a model for predicting PEH. Methods: Retrospective and pooled analyses of imaging findings were performed in PEH patients at our center (n=25) and in published cases (n=71), respectively. Relevant computed tomography (CT) images were extracted and used to build a deep learning model for PEH identification and differentiation from other diseases. Results: In this study, bilateral multiple nodules/masses (n=19) appeared to be more common with most nodules less than 2 cm. In addition to the common types and features, the pattern of mixed type (n=4) and isolated nodules (n=4), punctate calcifications (5/25) and lymph node enlargement were also observed (10/25). The presence of pleural effusion is associated with a poor prognosis in PEH. The deep learning model, with an area under the receiver operating characteristic curve (AUC) of 0.71 [95% confidence interval (CI): 0.69-0.72], has a differentiation accuracy of 100% and 74% for the training and test sets respectively. Conclusions: This study confirmed the heterogeneity of the imaging findings in PEH and showed several previously undescribed types and features. The current deep learning model based on CT has potential for clinical application and needs to be further explored in the future.

A Highly Active Porous Mo2C-Mo2N Heterostructure on Carbon Nanowalls/Diamond for a High-Current Hydrogen Evolution Reaction.

Developing non-precious metal-based electrocatalysts operating in high-current densities is highly demanded for the industry-level electrochemical hydrogen evolution reaction (HER). Here, we report the facile preparation of binder-free Mo2C-Mo2N heterostructures on carbon nanowalls/diamond (CNWs/D) via ultrasonic soaking followed by an annealing treatment. The experimental investigations and density functional theory calculations reveal the downshift of the d-band center caused by the heterojunction between Mo2C/Mo2N triggering highly active interfacial sites with a nearly zero ∆GH* value. Furthermore, the 3D-networked CNWs/D, as the current collector, features high electrical conductivity and large surface area, greatly boosting the electron transfer rate of HER occurring on the interfacial sites of Mo2C-Mo2N. Consequently, the self-supporting Mo2C-Mo2N@CNWs/D exhibits significantly low overpotentials of 137.8 and 194.4 mV at high current densities of 500 and 1000 mA/cm2, respectively, in an alkaline solution, which far surpass the benchmark Pt/C (228.5 and 359.3 mV) and are superior to most transition-metal-based materials. This work presents a cost-effective and high-efficiency non-precious metal-based electrocatalyst candidate for the electrochemical hydrogen production industry.

Causal role of lipid metabolism in pulmonary alveolar proteinosis: an observational and mendelian randomisation study.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease characterised by the accumulation of lipoprotein material in the alveoli. Although dyslipidaemia is a prominet feature, the causal effect of lipid traits on PAP remains unclear. This study aimed to explore the role of lipid traits in PAP and evaluate the potential of lipid-lowering drug targets in PAP. METHODS: Clinical outcomes, lipid profiles and lung function tests were analysed in a clinical cohort of diagnosed PAP patients and propensity score-matched healthy controls. Genome-wide association study data on PAP, lipid metabolism, blood cells and variants of genes encoding potential lipid-lowering drug targets were obtained for Mendelian randomisation (MR) and mediation analyses. FINDINGS: Observational results showed that higher levels of total cholesterol (TC), triglycerides and low-density lipoprotein (LDL) were associated with increased risks of PAP. Higher levels of TC and LDL were also associated with worse PAP severity. In MR analysis, elevated LDL was associated with an increased risk of PAP (OR: 4.32, 95% CI: 1.63 to 11.61, p=0.018). Elevated monocytes were associated with a lower risk of PAP (OR 0.34, 95% CI: 0.18 to 0.66, p=0.002) and mediated the risk impact of LDL on PAP. Genetic mimicry of PCSK9 inhibition was associated with a reduced risk of PAP (OR 0.03, p=0.007). INTERPRETATION: Our results support the crucial role of lipid and metabolism-related traits in PAP risk, emphasising the monocyte-mediated, causal effect of elevated LDL in PAP genetics. PCSK9 mediates the development of PAP by raising LDL. These finding provide evidence for lipid-related mechanisms and promising lipid-lowering drug target for PAP.

Gabapentin alleviated the cough hypersensitivity and neurogenic inflammation in a guinea pig model with repeated intra-esophageal acid perfusion.

OBJECTIVE: The anti-tussive effect of gabapentin and its underlying neuromodulatory mechanism were investigated via a modified guinea pig model of gastroesophageal reflux-related cough (GERC). METHODS: Intra-esophageal perfusion with hydrochloric acid (HCl) was performed every other day 12 times to establish the GERC model. High-dose gabapentin (48 mg/kg), low-dose gabapentin (8 mg/kg), or saline was orally administered for 2 weeks after modeling. Cough sensitivity, airway inflammation, lung and esophagus histology, levels of substance P (SP), and neurokinin-1 (NK1)-receptors were monitored. RESULTS: Repeated intra-esophageal acid perfusion aggravated the cough sensitivity in guinea pigs in a time-dependent manner. The number of cough events was significantly increased after 12 times HCl perfusion, and the hypersensitivity period was maintained for 2 weeks. The SP levels in BALF, trachea, lung, distal esophagus, and vagal ganglia were increased in guinea pigs receiving HCl perfusion. The intensity of cough hypersensitivity in the GERC model was significantly correlated with increased SP expression in the airways. Both high and low doses of gabapentin administration could reduce cough hypersensitivity exposed to HCl perfusion, attenuate airway inflammatory damage, and inhibit neurogenic inflammation by reducing SP expression from the airway and vagal ganglia. CONCLUSIONS: Gabapentin can desensitize the cough sensitivity in the GERC model of guinea pig. The anti-tussive effect is associated with the alleviated peripheral neurogenic inflammation as reflected in the decreased level of SP.

Efficacy and safety of pharmacotherapy for refractory or unexplained chronic cough: a systematic review and network meta-analysis.

Background: Refractory chronic cough (RCC) has a significant impact on patient's health-related quality of life and represents a challenge in clinical management. However, the optimal treatment for RCC remains controversial. This study aimed to investigate and compare the efficacy and safety of the current pharmacological therapeutic options for RCC. Methods: A systematic review was performed by searching PubMed, Web of Science, Embase, and Ovid databases from January 1, 2008 to March 1, 2023. All randomised control trials (RCTs) reporting outcomes of efficacy or/and safety were included in the Bayesian network meta-analysis. Here, we compared the effects on Leicester Cough Questionnaire (LCQ), Visual Analogue Scale (VAS), and objective cough frequency of patients with RCC. Besides, we also compared the incidence of adverse events (AEs) for analysis of safety. PROSPERO registration: CRD42022345940. Findings: 19 eligible RCTs included 3326 patients and 7 medication categories: P2X3 antagonist, GABA modulator, Transient Receptor Potential (TRP) modulator, NK-1 agonist, opioid analgesic, macrolide, and sodium cromoglicate. Compared with placebo, mean difference (MD) of LCQ and 24 h cough frequency for P2X3 antagonist relief were 1.637 (95% CI: 0.887-2.387) and -11.042 (P = 0.035). Compared with placebo, effect sizes (MD for LCQ and cough severity VAS) for GABA modulator were 1.347 (P = 0.003) and -7.843 (P = 0.003). In the network meta-analysis, gefapixant is the most effective treatment for patients with RCC (The Surface Under the Cumulative Ranking Curves (SUCRA) is 0.711 in LCQ, 0.983 in 24 h cough frequency, and 0.786 in cough severity VAS). Lesogaberan had better efficacy than placebo (SUCRA: 0.632 vs. 0.472) in 24 h cough frequency. Eliapixant and lesogaberan had better efficacy than placebo in cough severity VAS. However, TRP modulator had worse efficacy than placebo. In the meta-analysis of AEs, the present study found P2X3 antagonist had a significant correlation to AEs (RR: 1.129, 95% CI: 1.012-1.259), especially taste-related AEs (RR: 6.216, P < 0.05). Interpretation: In this network meta-analysis, P2X3 antagonist showing advantages in terms of efficacy is currently the most promising medication for treatment of RCC. GABA modulator also showed potential efficacy for RCC but with AEs of the central system. Nevertheless, the role of TRP modulator needed to be revisited. Further research is needed to determine the potential beneficiary population for optimizing the pharmacological management of chronic cough. Funding: National Natural Science Foundation of China (81870079), Guangdong Science and Technology Project (2021A050520012), Incubation Program of National Science Foundation for Distinguished Young Scholars (GMU2020-207).

T Cells in Colorectal Cancer: Unravelling the Function of Different T Cell Subsets in the Tumor Microenvironment.

Therapeutic options for metastatic colorectal cancer (mCRC) are very limited, and the prognosis using combination therapy with a chemotherapeutic drug and a targeted agent, e.g., epidermal growth factor receptor or tyrosine kinase, remains poor. Therefore, mCRC is associated with a poor median overall survival (mOS) of only 25-30 months. Current immunotherapies with checkpoint inhibitor blockade (ICB) have led to a substantial change in the treatment of several cancers, such as melanoma and non-small cell lung cancer. In CRC, ICB has only limited effects, except in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, which comprise about 15% of sporadic CRC patients and about 4% of patients with metastatic CRC. The vast majority of sporadic CRCs are microsatellite-stable (MSS) tumors with low levels of infiltrating immune cells, in which immunotherapy has no clinical benefit so far. Immunotherapy with checkpoint inhibitors requires the presence of infiltrating T cells into the tumor microenvironment (TME). This makes T cells the most important effector cells in the TME, as evidenced by the establishment of the immunoscore-a method to estimate the prognosis of CRC patients. The microenvironment of a tumor contains several types of T cells that are anti-tumorigenic, such as CD8+ T cells or pro-tumorigenic, such as regulatory T cells (Tregs) or T helper 17 (Th17) cells. However, even CD8+ T cells show marked heterogeneity, e.g., they can become exhausted, enter a state of hyporesponsiveness or become dysfunctional and express high levels of checkpoint molecules, the targets for ICB. To kill cancer cells, CD8+ T cells need the recognition of the MHC class I, which is often downregulated on colorectal cancer cells. In this case, a population of unconventional T cells with a γδ T cell receptor can overcome the limitations of the conventional CD8+ T cells with an αßT cell receptor. γδ T cells recognize antigens in an MHC-independent manner, thus acting as a bridge between innate and adaptive immunity. Here, we discuss the effects of different T cell subsets in colorectal cancer with a special emphasis on γδ T cells and the possibility of using them in CAR-T cell therapy. We explain T cell exclusion in microsatellite-stable colorectal cancer and the possibilities to overcome this exclusion to enable immunotherapy even in these "cold" tumors.

Cytoplasmic Hsp70s promote EcR transport into the nucleus by responding to various stimuli.

Metamorphosis is one of the most important physiological processes in insects, which is coordinated by juvenile hormone (JH) and 20-hydroxyecdysone (20E). Ecdysone receptor (EcR) is a steroid receptor (SR), which usually presents in cytoplasm and transfers into nucleus after binding to 20E. Heat shock proteins (Hsps) are suggested to be important members of the SR complex. However, their role in nucleocytoplasmic shuttle of the EcR remains unclear. In the present study, we found that apoptozole (Hsp70 inhibitor) suppressed the larval molting by decreasing the expression of ecdysone signaling genes. Two cytoplasmic (Cy) Hsp70s (Hsp72 and Hsp73) interacted with both EcR and ultraspiracle (USP, the heterodimer partner of EcR). By immunohistochemistry experiments, we revealed that CyHsp70 co-localized with EcR in the cytoplasm, and that both apoptozole and interfering of CyHsp70 significantly inhibited the process of EcR entering the nucleus under 20E induction, while reducing the expression of ecdysone signaling genes. Interestingly, the nuclear localization of EcR was also promoted by two other stimuli, including JH and heat stress, and this promotion was inhibited by apoptozole. This implies that various stimuli can induce EcR entry into the nucleus, and that this process is mediated by CyHsp70. Curiously, neither JH nor heat stress activated the ecdysone signaling genes; instead, they have a significant inhibitory effect on them. Taken together, it seems that Cytoplasmic Hsp70s promote EcR transport into the nucleus by responding to various stimuli, and that the biological effects of various stimuli passing through the EcR are different. Thus, our data provide a new viewpoint to understand the mechanism of nucleocytoplasmic shuttle of EcR.

Risk factors and prognosis of airway complications in lung transplant recipients: A systematic review and meta-analysis.

BACKGROUND: Airway complications (AC) are one of leading causes of morbidity and mortality after lung transplant (LTx), but their predictors and outcomes remain controversial. This study aimed to identify potential risk factors and prognosis of AC. METHODS: A systematic review was performed by searching PubMed, Embase, and Cochrane Library. All observational studies reporting outcome and potential factors of AC after LTx were included. The incidence, mortality, and estimated effect of each factor for AC were pooled by using the fixed-effects model or random-effects model. RESULTS: Thirty-eight eligible studies with 52,116 patients undergoing LTx were included for meta-analysis. The pooled incidence of AC was 12.4% (95% confidence interval [CI] 9.5-15.8) and the mean time of occurrence was 95.6 days. AC-related mortality rates at 30-days, 90-days, 6 months, 1 year, and 5 years were 6.7%, 17.9%, 18.2%, 23.6%, and 66.0%, respectively. Airway dehiscence was the most severe type with a high mortality at 30 days (60.9%, 95% CI 20.6-95.2). We found that AC was associated with a higher risk of mortality in LTx recipients (hazard ratio [HR] 1.71, 95% CI 1.04-2.81). Eleven significant predictors for AC were also identified, including male donor, male recipient, diagnosis of COPD, hospitalization, early rejection, postoperative infection, extracorporeal membrane oxygenation, mechanical ventilation, telescopic anastomosis, and bilateral and right-sided LTx. CONCLUSION: AC was significantly associated with higher mortality after LTx, especially for dehiscence. Targeted prophylaxis for modifiable factors and enhanced early bronchoscopy surveillance after LTx may improve the disease burden of AC.

The Association Between Insulin Use and Asthma: An Epidemiological Observational Analysis and Mendelian Randomization Study.

BACKGROUND: Asthma is a common respiratory disease caused by genetic and environmental factors, but the contribution of insulin use to the risk of asthma remains unclear. This study aimed to investigate the association between insulin use and asthma in a large population-based cohort, and further explore their causal relationship by Mendelian randomization (MR) analysis. METHODS: An epidemiological study including 85,887 participants from the National Health and Nutrition Examination Survey (NHANES) 2001-2018 was performed to evaluate the association between insulin use and asthma. Based on the inverse-variance weighted approach, MR analysis were conducted to estimate the causal effect of insulin use on asthma from the UKB and FinnGen datasets, respectively. RESULTS: In the NHANES cohort, we found that insulin use was associated with an increased risk of asthma [odd ratio (OR) 1.38; 95% CI 1.16-1.64; p < 0.001]. For the MR analysis, we found a causal relationship between insulin use and a higher risk of asthma in both Finn (OR 1.10; p < 0.001) and UK Biobank cohorts (OR 1.18; p < 0.001). Meanwhile, there was no causal association between diabetes and asthma. After multivariable adjustment for diabetes in UKB cohort, the insulin use remained significantly associated with an increased risk of asthma (OR 1.17, p < 0.001). CONCLUSIONS: An association between insulin use and an increased risk of asthma was found via the real-world data from the NHANES. In addition, the current study identified a causal effect and provided a genetic evidence of insulin use and asthma. More studies are needed to elucidate the mechanisms underlying the association between insulin use and asthma.

The regulating role of miR-494 on HCCR1 in cervical cancer cells.

This study focused on miR-494 inhibiting the proliferation, migration and invasion of cervical cancer cells by regulating HCCR1. During the study, 30 pairs of primary cervical cancer tissues and adjacent tissues diagnosed by pathology were collected, and then placed in a cryopreservation tube, immediately placed in liquid nitrogen to freeze, and then moved to a -80 °C refrigerator for storage until use. They were dipped with crystal violet staining solution for 20 minutes, washed 3 times with PBS, and dried at room temperature. The polycarbonate film on the chamber was gently cut, placed on a glass slide, and covered with neutral resin. The number of cells in 5 random fields was counted under a microscope, and the differences between the groups were compared. The qRT-PCR results showed that compared with the normal cervical tissue cell line HCCR1, the expression levels of miR-494 in cervical cancer cell lines HCCR1 and C-33A were significantly reduced. Compared with the transfection of mimics NC, the level of HCCR1mRNA and protein decreased significantly when transfected with miRNA-494mimics (P <0.05); compared with the transfection of inhibitor NC, the level of HCCR1 mRNA and protein increased significantly when transfected with miRNA-494 inhibitor (P <0.05).

Preventing autosomal-dominant hearing loss in Bth mice with CRISPR/CasRx-based RNA editing.

CRISPR/RfxCas13d (CasRx) editing system can specifically and precisely cleave single-strand RNAs, which is a promising treatment for various disorders by downregulation of related gene expression. Here, we tested this RNA-editing approach on Beethoven (Bth) mice, an animal model for human DFNA36 due to a point mutation in Tmc1. We first screened 30 sgRNAs in cell cultures and found that CasRx with sgRNA3 reduced the Tmc1Bth transcript by 90.8%, and the Tmc1 wild type transcript (Tmc1+) by 44.3%. We then injected a newly developed AAV vector (AAV-PHP.eB) based CasRx into the inner ears of neonatal Bth mice, and we found that Tmc1Bth was reduced by 70.2% in 2 weeks with few off-target effects in the whole transcriptome. Consistently, we found improved hair cell survival, rescued hair bundle degeneration, and reduced mechanoelectrical transduction current. Importantly, the hearing performance, measured in both ABR and DPOAE thresholds, was improved significantly in all ages over 8 weeks. We, therefore, have validated the CRISPR/CasRx-based RNA editing strategy in treating autosomal-dominant hearing loss, paving way for its further application in many other hereditary diseases in hearing and beyond.

Value of contrast-enhanced CT based radiomic machine learning algorithm in differentiating gastrointestinal stromal tumors with KIT exon 11 mutation: a two-center study.

PURPOSE Knowing the genetic phenotype of gastrointestinal stromal tumors (GISTs) is essential for patients who receive therapy with tyrosine kinase inhibitors. The aim of this study was to develop a radiomic algorithm for predicting GISTs with KIT exon 11 mutation. METHODS We enrolled 106 patients (80 in the training set, 26 in the validation set) with clinicopathologically confirmed GISTs from two centers. Preoperative and postoperative clinical characteristics were selected and analyzed to construct the clinical model. Arterial phase, venous phase, delayed phase, and tri-phase combined radiomics algorithms were generated from the training set based on contrast-enhanced computed tomography (CE-CT) images. Various radiomics feature selection methods were used, namely least absolute shrinkage and selection operator (LASSO); minimum redundancy maximum relevance (mRMR); and generalized linear model (GLM) as a machine-learning classifier. Independent predictive factors were determined to construct preoperative and postoperative radiomics nomograms by multivariate logistic regression analysis. The performances of the clinical model, radiomics algorithm, and radiomics nomogram in distinguishing GISTs with the KIT exon 11 mutation were evaluated by area under the curve (AUC) of the receiver operating characteristics. RESULTS Of 106 patients who underwent genetic analysis, 61 had the KIT exon 11 mutation. The combined radiomics algorithm was found to be the best prediction model for differentiating the expression status of the KIT exon 11 mutation (AUC = 0.836; 95% confidence interval [CI], 0.640-0.951) in the validation set. The clinical model, and preoperative and postoperative radiomics nomograms had AUCs of 0.606 (95% CI, 0.397-0.790), 0.715 (95% CI, 0.506-0.873), and 0.679 (95% CI, 0.468-0.847), respectively, with the validation set. CONCLUSION The radiomics algorithm could distinguish GISTs with the KIT exon 11 mutation based on CE-CT images and could potentially be used for selective genetic analysis to support the precision medicine of GISTs.

Radiomics Nomogram Based on Contrast-enhanced CT to Predict the Malignant Potential of Gastrointestinal Stromal Tumor: A Two-center Study.

RATIONALE AND OBJECTIVES: Contrast-enhanced computed tomography (CE-CT) was used to establish radiomics nomogram to evaluate the malignant potential of gastrointestinal stromal tumors (GISTs). MATERIALS AND METHODS: A total of 500 GIST patients were enrolled in this study and divided into training cohort (n = 346, our center) and validation cohort (n = 154, another center). Minimum redundancy maximum relevance (mRMR) and least absolute shrinkage and selection operator (LASSO) algorithms were used to select the feature subset with the best discriminant features from the three phases image, and five classifiers were used to establish four radiomics signatures. Preoperative radiomics nomogram was constructed by adding the clinical features determined by multivariate logistic regression analysis. The performance of radiomics signatures and nomogram were evaluated by area under the curve (AUC) of the receiver operating characteristic (ROC). The calibration of nomogram was appraised by calibration curve. RESULTS: A total of 13 radiomic features were extracted from tri-phase combined CE-CT images. Tri-phase combined CE-CT features + Support Vector Machine (SVM) was the best combination at predicting the malignant potential of GIST, with an AUC of 0.895 (95% CI 0.858-0.931) in the training cohort and 0.847 (95% CI 0.778-0.917) in the validation cohort. The nomogram also had good calibration. In the training cohort and the validation cohort, preoperative radiomics nomogram reached AUCs of 0.927 and 0.905, respectively, which were higher than clinical. CONCLUSION: The radiomics nomogram had a good predictive effect and generalization on the malignant potential of GIST, which could effectively help guide preoperative clinical decision.

Prognostic value of HPV 16/18 genotyping and geminin mRNA quantification in low-grade cervical squamous intraepithelial lesion.

Low-grade cervical squamous intraepithelial lesion is a precancerous neoplasia that has appreciable probability to evolve into malignancy. To explore the prognostic value of HPV 16/18 genotyping and geminin mRNA quantification in predicting the progressiveness of LSIL. We recruited 212 participants who were negative for intraepithelial lesion or malignancy (NILM 76), low-grade squamous intraepithelial lesion (LSIL 85), high-grade squamous intraepithelial lesion (HSIL 36) and cervical intraepithelial neoplasia grade cervical cancer grade 3, (CIN3 15) patients. Tissues were obtained during excisional treatment. HPV 16/18 genotyping and geminin mRNA qRT-PCR were performed. HPV 16/18 positivity rate and geminin mRNA level were integrated with the clinical parameters into a multivariate logistic model. Area under curve was yielded based on receiver operation curve derived from this multivariate logistic model. Follow-up visits were performed to LSIL patients with progression. HSIL patients have higher HPV 16/18 positivity rate and geminin mRNA levels than LSIL. Among HSIL, CIN3 have higher HPV 16/18 positivity rate and geminin mRNA levels. Multivariate logistic analysis showed that HPV 16/18 positivity and geminin mRNA expression status are independent factors for differentiating HSIL and LSIL. The baseline HPV 16/18 positivity rate and geminin mRNA levels of 18 LSIL patients who developed HSIL are significantly higher than non-progressive LSIL patients. The values examined at follow-up timepoints were also higher than baseline. These results suggest that geminin is implicated in the progression of LSIL and combining HPV 16/18 genotyping and geminin mRNA qRT-PCR could potentially differentiating the progressive LSIL and improve the efficacy of clinical intervention.

Combined associations of obesity and metabolic health with subclinical left ventricular dysfunctions: Danyang study.

AIMS: The association of strictly defined metabolic healthy obese (MHO) with subclinical cardiac function was unclear. Our study aims to examine the role of MHO in subclinical cardiac dysfunction in a Chinese population. METHODS AND RESULTS: The study subjects were recruited from Danyang from 2017 to 2019. Obesity was defined by body mass index (BMI) categories (normal weight, overweight and obesity). Metabolic health was strictly defined as having neither any of the guidelines recommended metabolic syndrome components nor insulin resistance. Thus, subjects were grouped by BMI categories and metabolic health status as six groups. Preclinical systolic (global longitudinal strain [GLS]) and diastolic function were assessed by 2D speckle tracking, and transmitral and tissue Doppler imaging, respectively. The 2757 participants (mean age ± standard deviation, 52.7 ± 11.7 years) included 1613 (58.5%) women, 999 (36.2%) obese, 2080 (75.4%) metabolically unhealthy and 93 (3.4%) MHO participants. After adjustment for covariates, the trend was similar for left ventricular (LV) ejection fraction (Ptrend  ≥ 0.07) but significantly worse for GLS, e' and E/e' (Ptrend  ≤ 0.02) across the six groups or passing from normal weight to obese individuals irrespective of metabolic status. MHO participants had lower GLS (20.4 vs. 21.4%) and e' (9.6 vs. 10.6 cm/s) compared with controls (P < 0.0001) but had similar GLS (P = 0.47) compared with metabolically unhealthy obese (MUO). Regardless of obesity status, metabolically unhealthy participants had worse diastolic function compared with their metabolically healthy counterparts (P ≤ 0.0004). Compared with controls, MHO individuals were at higher risk of subclinical LV systolic dysfunction (OR = 3.44, 95% CI = 1.25-9.49, P = 0.02). These results were robust to sensitivity analysis. CONCLUSIONS: MHO was substantially associated with worse subclinical systolic function although early diastolic dysfunction seemed to be more accentuated in MUO.

Downregulation of DEC1 inhibits proliferation, migration and invasion, and induces apoptosis in ovarian cancer cells via regulation of Wnt/ß-catenin signaling pathway.

DEC1 has been reported to regulate the expression of multiple target genes, participate in cell differentiation, apoptosis, aging and the development and progression of numerous tumors, but the detailed effects and possible mechanisms of DEC1 in ovarian cancer (OC) remain unknown. The present study aimed to investigate the expression and mechanism of function of DEC1 in OC. The present results demonstrated that DEC1 was highly expressed in OC tissues and cell lines using reverse transcription-quantitative PCR, western blotting and immunohistochemistry, and high expression of DEC1 was negatively associated with the prognosis of patients with OC. In addition, knockdown of DEC1 significantly inhibited proliferation in SKOV3 and OVCAR3 cells compared with control. DEC1 knockdown also induced apoptosis and increased the expression of apoptosis-related proteins in OC cells. The results suggested that knockdown of DEC1 inhibited OC cell migration and invasion via regulation of epithelial-mesenchymal transition-related protein. It was also found that DEC1 knockdown significantly inhibited the Wnt/ß-catenin pathway. Collectively, the current results indicated that knockdown of DEC1 inhibited proliferation, migration and invasion, and induced apoptosis in OC cells via modulating the Wnt/ß-catenin signaling pathway. Thus, DEC1 may participate in malignant progression of OC, and may be a target for treatment and diagnosis of OC.

Bioinformatic analysis of potential hub genes in gastric adenocarcinoma.

Gastric adenocarcinoma is the most common histologic type of gastric cancer; however, the pathogenic mechanisms remain unclear. To improve mechanistic understanding and identify new treatment targets or diagnostic biomarkers, we used bioinformatic tools to predict the hub genes related to the process of gastric adenocarcinoma development from public datasets, and explored their prognostic significance. We screened differentially expressed genes between gastric adenocarcinoma and normal gastric tissues in Gene Expression Omnibus datasets (GSE79973, GSE118916, and GSE29998) using the GEO2R tool, and their functions were annotated with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes signaling pathway enrichment analyses in the DAVID database. Hub genes were identified based on the protein-protein network constructed in the STRING database with Cytoscape software. A total of 10 hub genes were selected for further analysis, and their expression patterns in gastric adenocarcinoma patients were investigated using the Oncomine GEPIA database. The expression levels of ATP4A, CA9, FGA, ALDH1A1, and GHRL were reduced, whereas those of TIMP1, SPP1, CXCL8, THY1, and COL1A1 were increased in gastric adenocarcinoma. The Kaplan-Meier online plotter tool showed associations of all hub genes except for CA9 with prognosis in gastric adenocarcinoma patients; CXCL8 and ALDH1A1 were positively correlated with survival, and the other genes were negatively correlated with survival. These 10 hub genes may be involved in important processes in gastric adenocarcinoma development, providing new directions for research to clarify the role of these genes and offer insight for improved treatment.

Construction of a clinical survival prognostic model for middle-aged and elderly patients with stage III rectal adenocarcinoma.

BACKGROUND: Nomograms for prognosis prediction in colorectal cancer patients are few, and prognostic indicators differ with age. AIM: To construct a new nomogram survival prediction tool for middle-aged and elderly patients with stage III rectal adenocarcinoma. METHODS: A total of 2773 eligible patients were divided into the training cohort (70%) and the validation cohort (30%). Optimal cutoff values were calculated using the X-tile software for continuous variables. Univariate and multivariate Cox proportional hazards regression analyses were used to determine overall survival (OS) and cancer-specific survival (CSS)-related prognostic factors. Two nomograms were successfully constructed. The discriminant and predictive ability and clinical usefulness of the model were also assessed by multiple methods of analysis. RESULTS: The 95%CI in the training group was 0.719 (0.690-0.749) and 0.733 (0.702-0.74), while that in the validation group was 0.739 (0.696-0.782) and 0.750 (0.701-0.800) for the OS and CSS nomogram prediction models, respectively. In the validation group, the AUC of the three-year survival rate was 0.762 and 0.770, while the AUC of the five-year survival rate was 0.722 and 0.744 for the OS and CSS nomograms, respectively. The nomogram distinguishes all-cause mortality from cancer-specific mortality in patients with different risk grades. The time-dependent AUC and decision curve analysis showed that the nomogram had good clinical predictive ability and decision efficacy and was significantly better than the tumor-node-metastases staging system. CONCLUSION: The survival prediction model constructed in this study is helpful in evaluating the prognosis of patients and can aid physicians in clinical diagnosis and treatment.

Application of three-dimensional reconstruction with a Hisense computer-assisted system in upper pancreatic lymph node dissection during laparoscopic-assisted radical gastrectomy.

BACKGROUND/OBJECTIVE: To investigate the feasibility of three-dimensional (3D) reconstruction with an interactive Hisense computer-assisted system (CAS) for preoperative planning and intraoperative guidance during laparoscopic-assisted upper pancreatic lymph node dissection in distal gastrectomy for gastric cancer. METHODS: This study included 28 patients who underwent preoperative 3D reconstruction of the upper border of the pancreas using Hisense CAS (3D reconstruction group) for preoperative planning and intraoperative navigation. To determine its efficacy, the clinical data of these patients were compared with those of 28 patients who did not undergo 3D reconstruction (control group). RESULTS: Fifty-six cases of laparoscopic-assisted distal gastrectomy were performed. Three-dimensional reconstruction was successful in all the patients in the 3D reconstruction group, and real-time navigation was performed during the operation. The rate of correspondence between the 3D reconstruction images and intraoperative findings was 100%. The time taken for upper pancreatic lymph node dissection, number of upper pancreatic lymph node dissections, and number of unnecessary injuries during surgery were superior in the 3D reconstruction group than in the control group. The results of the remaining parameters were not statistically significant. CONCLUSION: Preoperative planning with interactive Hisense CAS 3D reconstruction technology can improve surgeons' understanding of each patient's individual anatomy and can reveal anatomical variations, which is helpful for accurate preoperative planning and intraoperative navigation. This technique is helpful for the implementation of the precise dissection of lymph nodes at the upper edge of the pancreas and improves the quality and safety of the surgery.