Mapping brain activity and neurotransmitters pre-cigarette smoking evolution: A study of male subjects.

BACKGROUND: The impact of tobacco smoking on global health persists and it is essential to understand the progression of addiction and the involvement of neurotransmitters. METHODS: This study assessed 47 participants with tobacco use disorder (TUD) categorized based on changes in Fagerström Test for Nicotine Dependence (FTND) scores over 6 years: progressive TUD (pTUD), regressive TUD (rTUD), and stable TUD (sTUD). Additionally, 35 healthy controls were included. Resting-state functional magnetic resonance imaging was used to evaluate brain regional homogeneity (ReHo) and correlations with neurotransmitter distributions using JuSpace. RESULTS: Significant differences in ReHo were observed among pTUD, rTUD, sTUD, and controls. After strict Bonferroni correction, rTUD exhibited increased ReHo in the dorsolateral superior frontal gyrus compared to sTUD (p < 0.001) and controls (p < 0.001). Both pTUD (p < 0.001) and rTUD (p < 0.001) showed decreased ReHo in the superior temporal gyrus compared to sTUD. sTUD had increased ReHo in the supramarginal gyrus compared to all other groups (p < 0.001, p < 0.001, p = 0.002, separately). The strongest association, which survived rigorous Bonferroni correction, was between the ReHo changes in rTUD compared to sTUD and neurotransmitter distribution. This includes 5-hydroxytryptamine receptor 2A (p = 0.001), gamma-aminobutyric acid type A receptor (p < 0.001), norepinephrine transporter (p < 0.001), and N-Methyl-D-Aspartate (p = 0.002). CONCLUSIONS: This study provides insights into how smoking behaviors correlate with alterations in brain activity and neurotransmitter function. By elucidating these neural links to tobacco use disorder progression, our findings contribute to a deeper understanding of smoking's neurological impact and potentially inform more targeted therapeutic strategies.

Polymeric nanocarrier via metabolism regulation mediates immunogenic cell death with spatiotemporal orchestration for cancer immunotherapy.

The limited efficacy of cancer immunotherapy occurs due to the lack of spatiotemporal orchestration of adaptive immune response stimulation and immunosuppressive tumor microenvironment modulation. Herein, we report a nanoplatform fabricated using a pH-sensitive triblock copolymer synthesized by reversible addition-fragmentation chain transfer polymerization enabling in situ tumor vaccination and tumor-associated macrophages (TAMs) polarization. The nanocarrier itself can induce melanoma immunogenic cell death (ICD) via tertiary amines and thioethers concentrating on mitochondria to regulate metabolism in triggering endoplasmic reticulum stress and upregulating gasdermin D for pyroptosis as well as some features of ferroptosis and apoptosis. After the addition of ligand cyclic arginine-glycine-aspartic acid (cRGD) and mannose, the mixed nanocarrier with immune adjuvant resiquimod encapsulation can target B16F10 cells for in situ tumor vaccination and TAMs for M1 phenotype polarization. In vivo studies indicate that the mixed targeting nanoplatform elicits tumor ICD, dendritic cell maturation, TAM polarization, and cytotoxic T lymphocyte infiltration and inhibits melanoma volume growth. In combination with immune checkpoint blockade, the survival time of mice is markedly prolonged. This study provides a strategy for utilizing immunoactive materials in the innate and adaptive immune responses to augment cancer therapy.

Altered functional connectivity within the primary visual networks and neurotransmitter activity in male smokers: A group ICA study.

Smoking puts patients at high risk for cognitive and psychiatric disorders. The aim of this study was to explore the effects of nicotine use on primary visual network (PVN) and its association with neurotransmitters. A total of 59 tobacco use disorder (TUD) patients and 51 healthy controls (HC) participated in this study and underwent resting state functional magnetic resonance imaging scans. Functional connectivity (FC) within the network was explored using independent component analysis. In addition, the spatial correlations of PVN changes with neurotransmitters and their correlations with clinical characteristics of patients were evaluated using the JuSpace toolbox and SPSS. We found reduced FC within the PVN in patients with TUD compared with HC. In terms of relevant analysis, there is a spatial correlation between FC changes in the patient's PVN and a higher distribution of dopamine receptor and gamma-aminobutyric acid receptor. This study revealed changes in the FC and neurotransmitters of the PVN in patients with TUD, expanding the potential neural mechanisms underlying sensory perception and psychiatric disorders.

Alternations voxel-wise interhemispheric and intrahemipheric functional connectivity dynamics in internet gaming disorder.

BACKGROUND: Currently, numerous studies have indicated that individuals with internet gaming disorder (IGDs) have aberrant functional connection patterns between multiple brain regions and networks. However, temporal variability in the intra- and interhemispheric dynamic functional connectivity in IGDs remains unknown. METHODS: This study investigated resting-state functional magnetic resonance data from 55 IGDs and 50 demographically matched healthy controls (HCs). Functional connectivity density (FCD) combined with sliding window analysis is employed to calculate the temporal variability of global functional connectivity. The temporal variability of dynamic functional connectivity further quantified utilizing the standard deviations of global, intra-, and interhemispheric FCD. Finally, correlation analyses were performed between dynamic FCD varience (dFCD) in differential brain regions and clinical behaviors. RESULT: IGDs showed decreased intra- and interhemispheric dFCD variance in the visual attention network (precuneus and calcarine) and also demonstrated hemispheric-level dFCD variance abnormalities in the posterior cingulate cortex (PCC) compared to HCs. Moreover, abnormal global dFCD variability of the calcarine and ipsilateral dFCD variability of the PCC were negatively correlated with the severity of IGDs in the IGD group. CONCLUSION: Our results demonstrate abberant intra- and interhemispheric dynamic functional connectivity in the visual attention network, which emphasizes the neurobiological basis for impaired concentration in IGDs.

Exploring clinical factors to predict the survival of patients with resectable non-small cell lung cancer with neoadjuvant immunotherapy.

OBJECTIVES: The goal was to explore clinical factors and build a predictive model for the disease-free and overall survival of patients with non-small cell lung cancer (NSCLC) receiving neoadjuvant chemotherapy combined with immune checkpoint inhibitors. METHODS: Inclusion criteria for patients in this multicentre study were as follows: (i) Patients who were diagnosed with stages I-III NSCLC after a bronchoscopy biopsy or puncture; (ii) patients who were examined with computed tomography/positron emission tomography-computed tomography before treatment and surgery; (iii) patients who received neoadjuvant chemotherapy combined with immune checkpoint inhibitors for 2 to 6 cycles preoperatively; (iv) patients whose peripheral blood indicators and tumour markers were assessed before treatment and preoperatively; (v) patients who underwent radical lung cancer surgery after neoadjuvant therapy. Cases were divided into high- and low-risk groups according to 78 clinical indicators based on a 10-fold Least Absolute Shrinkage and Selection Operator selection. We used Cox proportional hazards models to predict disease-free and overall survival. Then, we used time-dependent area under the curve and decision curve analyses to examine the accuracy of the results. RESULTS: Data were collected continuously, and 212 and 85 cases were randomly assigned to training and testing sets, respectively. The area under the curve for the prediction of disease-free survival (training: 1 year, 0.83; 2 years, 0.81; 3 years, 0.83 versus testing: 1 year, 0.65; 2 years, 0.66; 3 years, 0.70), overall survival (training: 1 year, 0.86; 2 years, 0.85; 3 years, 0.86 versus testing: 1 year, 0.66; 2 years, 0.57; 3 years, 0.70) were determined. The coefficient factors including pathological response; preoperative tumour maximum diameter; preoperative lymph shorter diameter; preoperative tumour and lymph maximum standardized uptake value; change in tumour standardized uptake value preoperatively; and blood-related risk factors were favourably associated with prognosis (P < 0.001). CONCLUSIONS: Our prediction model, which integrated data from preoperative positron emission tomography-CT, preoperative blood parameters and pathological response, was able to make highly accurate predictions for disease-free and overall survival in patients with NSCLC receiving neoadjuvant immunity with chemical therapy.

Altered local intrinsic neural activity and molecular architecture in internet use disorders.

BACKGROUND: Internet gaming disorder (IGD) is mainly characterized by its core dysfunction in higher-order brain cortices involved in inhibitory control, whose neurobiological basis remains unclear. Then, we will investigate local intrinsic neural activity (INA) alterations in IGD, ascertain whether these potential alterations are related to clinical characteristics, and further explore the underlying molecular architecture. METHOD: In this study, we performed the fractional amplitude of low-frequency fluctuation (fALFF) and regional homogeneity (ReHo) derived from resting-state functional magnetic resonance imaging (rs-fMRI) to explore the impact of IGD on local INA. Correlation analysis revealed the relationship between ReHo and fALFF in terms of group differences and clinical characteristics. Moreover, correlations between fALFF, ReHo, and PET- and SPECT-driven maps were investigated to elucidate the specific molecular architecture alternations in IGD. Finally, receiver operating characteristic curve (ROC) analysis was used to show the potential abilities of fALFF and ReHo in distinguishing individuals with IGD (IGDs) from healthy controls (HCs). RESULT: Compared with HCs, IGDs revealed increased ReHo and fALFF in the prefrontal cortex. Significantly decreased ReHo was observed in the temporal lobe, occipital lobe, and cerebellum. In addition, the ReHo values in the cerebellum_7b_R were positively correlated with internet addiction severity. ROC curve analysis showed that ReHo and fALFF-altered brain regions could effectively distinguish IGDs from HCs. More importantly, cross-modal correlations revealed local INA changes in brain regions associated with the monoamine neurotransmitter system and the less studied cholinergic/GABAergic system. CONCLUSION: These results suggest that local functional impairments are shown in the audiovisual and inhibitory control circuits in IGDs. This may be associated with underlying neurotransmitter system alterations. Therefore, this study provides the possibility of GABAergic receptor agonists and cholinergic receptor inhibitors for the treatment of IGD.

Assessment of image quality and diagnostic accuracy for cervical spondylosis using T2w-STIR sequence with a deep learning-based reconstruction approach.

OBJECTIVES: To investigate potential of enhancing image quality, maintaining interobserver consensus, and elevating disease diagnostic efficacy through the implementation of deep learning-based reconstruction (DLR) processing in 3.0 T cervical spine fast magnetic resonance imaging (MRI) images, compared with conventional images. METHODS: The 3.0 T cervical spine MRI images of 71 volunteers were categorized into two groups: sagittal T2-weighted short T1 inversion recovery without DLR (Sag T2w-STIR) and with DLR (Sag T2w-STIR-DLR). The assessment covered artifacts, perceptual signal-to-noise ratio, clearness of tissue interfaces, fat suppression, overall image quality, and the delineation of spinal cord, vertebrae, discs, dopamine, and joints. Spanning canal stenosis, neural foraminal stenosis, herniated discs, annular fissures, hypertrophy of the ligamentum flavum or vertebral facet joints, and intervertebral disc degeneration were evaluated by three impartial readers. RESULTS: Sag T2w-STIR-DLR images exhibited markedly superior performance across quality indicators (median = 4 or 5) compared to Sag T2w-STIR sequences (median = 3 or 4) (p < 0.001). No statistically significant differences were observed between the two sequences in terms of diagnosis and grading (p > 0.05). The interobserver agreement for Sag T2w-STIR-DLR images (0.604-0.931) was higher than the other (0.545-0.853), Sag T2w-STIR-DLR (0.747-1.000) demonstrated increased concordance between reader 1 and reader 3 in comparison to Sag T2w-STIR (0.508-1.000). Acquisition time diminished from 364 to 197 s through the DLR scheme. CONCLUSIONS: Our investigation establishes that 3.0 T fast MRI images subjected to DLR processing present heightened image quality, bolstered diagnostic performance, and reduced scanning durations for cervical spine MRI compared with conventional sequences.

Abnormalities in static and dynamic intrinsic neural activity and neurotransmitters in first-episode OCD.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a disabling disorder in which the temporal variability of regional brain connectivity is not well understood. The aim of this study was to investigate alterations in static and dynamic intrinsic neural activity (INA) in first-episode OCD and whether these changes have the potential to reflect neurotransmitters. METHODS: A total of 95 first-episode OCD patients and 106 matched healthy controls (HCs) were included in this study. Based on resting-state functional magnetic resonance imaging (rs-fMRI), the static and dynamic local connectivity coherence (calculated by static and dynamic regional homogeneity, sReHo and dReHo) were compared between the two groups. Furthermore, correlations between abnormal INA and PET- and SPECT-derived maps were performed to examine specific neurotransmitter system changes underlying INA abnormalities in OCD. RESULTS: Compared with HCs, OCD showed decreased sReHo and dReHo values in left superior, middle temporal gyrus (STG/MTG), left Heschl gyrus (HES), left putamen, left insula, bilateral paracentral lobular (PCL), right postcentral gyrus (PoCG), right precentral gyrus (PreCG), left precuneus and right supplementary motor area (SMA). Decreased dReHo values were also found in left PoCG, left PreCG, left SMA and left middle cingulate cortex (MCC). Meanwhile, alterations in INA present in brain regions were correlated with dopamine system (D2, FDOPA), norepinephrine transporter (NAT) and the vesicular acetylcholine transporter (VAChT) maps. CONCLUSION: Static and dynamic INA abnormalities exist in first-episode OCD, having the potential to reveal the molecular characteristics. The results help to further understand the pathophysiological mechanism and provide alternative therapeutic targets of OCD.

Meta-analysis of structural and functional abnormalities in behavioral addictions.

BACKGROUND: The incidence of behavioral addictions (BAs) associated with scientific and technological advances has been increasing steadily. Unfortunately, a large number of studies on the structural and functional abnormalities have shown poor reproducibility, and it remains unclear whether different addictive behaviors share common underlying abnormalities. Therefore, our objective was to conduct a quantitative meta-analysis of different behavioral addictions to provide evidence-based evidence of common structural and functional changes. METHODS: We conducted systematic searches in PubMed, Web of Science and Scopus from January 2010 to December 2023, supplementing reference lists of high-quality relevant meta-analyses and reviews, to identify eligible voxel-based morphometry (VBM) and functional magnetic resonance imaging (fMRI) studies. Using anisotropic seed-based D-Mapping (AES-SDM) meta-analysis methods, we compared brain abnormalities between BAs and healthy controls (HCs). RESULTS: There were 11 GMV studies (287 BAs and 292 HCs) and 26 fMRI studies (577 BAs and 545 HCs) that met inclusion criteria. Compared with HCs, BAs demonstrated significant reductions in gray matter volume (GMV) in (1) right anterior cingulate gyri extending into the adjacent superior frontal gyrus, as well as in the left inferior frontal gyrus and right striatum. (2) the bilateral precuneus, right supramarginal gyrus, and right fusiform gyrus were hyperfunction; (3) the left medial cingulate gyrus extended to the superior frontal gyrus, the left inferior frontal gyrus, and right middle temporal gyrus had hypofunction. CONCLUSIONS: Our study identified structural and functional impairments in brain regions involved in executive control, cognitive function, visual memory, and reward-driven behavior in BAs. Notably, fronto-cingulate regions may serve as common biomarkers of BAs.

Altered intrinsic neural timescales and neurotransmitter activity in males with tobacco use disorder.

Previous researches of tobacco use disorder (TUD) has overlooked the hierarchy of cortical functions and single modality design separated the relationship between macroscopic neuroimaging aberrance and microscopic molecular basis. At present, intrinsic timescale gradient of TUD and its molecular features are not fully understood. Our study recruited 146 male subjects, including 44 heavy smokers, 50 light smokers and 52 non-smokers, then obtained their rs-fMRI data and clinical scales related to smoking. Intrinsic neural timescale (INT) method was performed to describe how long neural information was stored in a brain region by calculating the autocorrelation function (ACF) of each voxel to examine the difference in the ability of information integration among the three groups. Then, correlation analyses were conducted to explore the relationship between INT abnormalities and clinical scales of smokers. Finally, cross-modal JuSpace toolbox was used to investigate the association between INT aberrance and the expression of specific receptor/transporters. Compared to healthy controls, TUD subjects displayed decreased INT in control network (CN), default mode network (DMN), sensorimotor areas and visual cortex, and such trend of decreasing INT was more pronounced in heavy smokers. Moreover, various neurotransmitters (including dopaminergic, acetylcholine and µ-opioid receptors) were involved in the molecular mechanism of timescale decreasing and differed in heavy and light smokers. These findings supplied novel insights into the brain functional aberrance in TUD from an intrinsic neural dynamic perspective and confirm INT was a potential neurobiological marker. And also established the connection between macroscopic imaging aberrance and microscopic molecular changes in TUD.

Leveraging existing 16S rRNA gene surveys to decipher microbial signatures and dysbiosis in cervical carcinogenesis.

The presence of dysbiotic cervicovaginal microbiota has been observed to be linked to the persistent development of cervical carcinogenesis mediated by the human papillomavirus (HPV). Nevertheless, the characteristics of the cervical microbiome in individuals diagnosed with cervical cancer (CC) are still not well understood. Comprehensive analysis was conducted by re-analyzing the cervical 16S rRNA sequencing datasets of a total of 507 samples from six previously published studies. We observed significant alpha and beta diversity differences in between CC, cervical intraepithelial neoplasia (CIN) and normal controls (NC), but not between HPV and NC in the combined dataset. Meta-analysis revealed that opportunistic pernicious microbes Streptococcus, Fusobacterium, Pseudomonas and Anaerococcus were enriched in CC, while Lactobacillus was depleted compared to NC. Members of Gardnerella, Sneathia, Pseudomonas, and Fannyhessea have significantly increased relative abundance compared to other bacteria in the CIN group. Five newly identified bacterial genera were found to differentiate CC from NC, with an area under the curve (AUC) of 0.8947. Moreover, co-occurrence network analysis showed that the most commonly encountered Lactobacillus was strongly negatively correlated with Prevotella. Overall, our study identified a set of potential biomarkers for CC from samples across different geographic regions. Our meta-analysis provided significant insights into the characteristics of dysbiotic cervicovaginal microbiota undergoing CC, which may lead to the development of noninvasive CC diagnostic tools and therapeutic interventions.

Purine metabolism in lung adenocarcinoma: A single-cell analysis revealing prognostic and immunotherapeutic insights.

Lung adenocarcinoma (LUAD) is a prevalent subtype of lung cancer, yet the contribution of purine metabolism (PM) to its pathogenesis remains poorly elucidated. PM, a critical component of intracellular nucleotide synthesis and energy metabolism, is hypothesized to exert a significant influence on LUAD development. Herein, we employed single-cell analysis to investigate the role of PM within the tumour microenvironment (TME) of LUAD. PM scoring (PMS) across distinct cell types was determined using AUCell, UCell, singscore and AddModuleScore algorithms. Subsequently, we explored communication networks among cells within high- and low-PMS groups, establishing a robust PM-associated signature (PAS) utilizing a comprehensive dataset comprising LUAD samples from TCGA and five GEO datasets. Our findings revealed that the high-PMS group exhibited intensified cell interactions, while the PAS, constructed using PM-related genes, demonstrated precise prognostic predictive capability. Notably, analysis across the TCGA dataset and five GEO datasets indicated that low-PAS patients exhibited a superior prognosis. Furthermore, the low-PAS group displayed increased immune cell infiltration and elevated CD8A expression, coupled with reduced PD-L1 expression. Moreover, data from eight publicly available immunotherapy cohorts suggested enhanced immunotherapy outcomes in the low-PAS group. These results underscore a close association between PAS and tumour immunity, offering predictive insights into genomic alterations, chemotherapy drug sensitivity and immunotherapy responses in LUAD. The newly established PAS holds promise as a valuable tool for selecting LUAD populations likely to benefit from future clinical stratification efforts.

Integrated analysis highlights the significance role of ITGAL in lung adenocarcinoma.

Integrin alpha L (ITGAL), a member of the integrin family, is associated with carcinogenesis and immune regulation. However, the biological functions of ITGAL in lung adenocarcinoma (LUAD) remain poorly understood. In this study, we utilized the TCGA dataset to analyse ITGAL mRNA expression in LUAD and examined its correlation with clinical prognosis. Three-dimensional (3D) Matrigel culture, 5-bromodeoxyuridine (BrdU) ELISA, wound-healing migration and cell adherence assays were used to demonstrate the potential role of ITGAL in LUAD progression. Additionally, we analysed single-cell sequencing data of LUAD to determine the expression and biological function of ITGAL. Our research revealed that the expression of ITGAL in LUAD samples is an independent predictor of prognosis. Patients with high expression of ITGAL had significantly better overall survival (OS), progression-free survival (PFS) and disease-specific survival (DSS) compared to the low-expression group. Meanwhile, the expression of ITGAL suppressed malignant progression in LUAD cells. Functional enrichment analyses showed that ITGAL was significantly correlated with cell immune response and immune checkpoint, consistent with the analysis of single-cell sequencing in paired samples of normal and tumour. Furthermore, we confirmed that ITGAL expression affect the tumour microenvironment (TME) through regulation of the expression of cytokines in NK cells of LUAD. In summary, ITGAL is a prognostic biomarker for LUAD patients, and it repressed malignant progression in LUAD cells. Moreover, ITGAL expression also enhanced the effect of immunotherapy and may be an important target in LUAD therapy.

Single-cell and bulk RNA-sequencing reveal SPP1 and CXCL12 as cell-to-cell communication markers to predict prognosis in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) generally presents as an immunosuppressive microenvironment. The characteristics of cell-to-cell communication in the LUAD microenvironment has been unclear. In this study, the LUAD bulk RNA-seq data and single-cell RNA-seq data were retrieved from public dataset. Differential expression genes (DEGs) between LUAD tumor and adjacent non-tumor tissues were calculated by limma algorithm, and then detected by PPI, KEGG, and GO analysis. Cell-cell interactions were explored using the single-cell RNA-seq data. Finally, the first 15 CytoHubba genes were used to establish related pathways and these pathways were used to characterize the immune-related ligands and their receptors in LUAD. Our analyses showed that monocytes or macrophages interact with tissue stem cells and NK cells via SPP1 signaling pathway and tissue stem cells interact with T and B cells via CXCL signaling pathway in different states. Hub genes of SPP1 participated in SPP1 signaling pathway, which was negatively correlated with CD4+ T cell and CD8+ T cell. The expression of SPP1 in LUAD tumor tissues was negatively correlated with the prognosis. While CXCL12 participated in CXCL signaling pathway, which was positively correlated with CD4+ T cell and CD8+ T cell. The role of CXCL12 in LUAD tumor tissues exhibits an opposite effect to that of SPP1. This study reveals that tumor-associated monocytes or macrophages may affect tumor progression. Moreover, the SPP1 and CXCL12 may be the critic genes of cell-to-cell communication in LUAD, and targeting these pathways may provide a new molecular mechanism for the treatment of LUAD.

Unraveling the role of low-density lipoprotein-related genes in lung adenocarcinoma: Insights into tumor microenvironment and clinical prognosis.

BACKGROUND: The hypothesized link between low-density lipoprotein (LDL) and oncogenesis has garnered significant interest, yet its explicit impact on lung adenocarcinoma (LUAD) remains to be elucidated. This investigation aims to demystify the function of LDL-related genes (LRGs) within LUAD, endeavoring to shed light on the complex interplay between LDL and carcinogenesis. METHODS: Leveraging single-cell transcriptomics, we examined the role of LRGs within the tumor microenvironment (TME). The expression patterns of LRGs across diverse cellular phenotypes were delineated using an array of computational methodologies, including AUCell, UCell, singscore, ssGSEA, and AddModuleScore. CellChat facilitated the exploration of distinct cellular interactions within LDL_low and LDL_high groups. The findmarker utility, coupled with Pearson correlation analysis, facilitated the identification of pivotal genes correlated with LDL indices. An integrative approach to transcriptomic data analysis was adopted, utilizing a machine learning framework to devise an LDL-associated signature (LAS). This enabled the delineation of genomic disparities, pathway enrichments, immune cell dynamics, and pharmacological sensitivities between LAS stratifications. RESULTS: Enhanced cellular crosstalk was observed in the LDL_high group, with the CoxBoost+Ridge algorithm achieving the apex c-index for LAS formulation. Benchmarking against 144 extant LUAD models underscored the superior prognostic acuity of LAS. Elevated LAS indices were synonymous with adverse outcomes, diminished immune surveillance, and an upsurge in pathways conducive to neoplastic proliferation. Notably, a pronounced susceptibility to paclitaxel and gemcitabine was discerned within the high-LAS cohort, delineating prospective therapeutic corridors. CONCLUSION: This study elucidates the significance of LRGs within the TME and introduces an LAS for prognostication in LUAD patients. Our findings accentuate putative therapeutic targets and elucidate the clinical ramifications of LAS deployment.

Evaluation of the diagnostic performance of colposcopy in the detection of cervical high-grade squamous intraepithelial lesions among women with transformation zone type 3.

BACKGROUND: Inaccurate colposcopy diagnosis may lead to inappropriate management and increase the incidence of cervical cancer. This study aimed to evaluate the diagnostic accuracy of colposcopy in the detection of histologic cervical intraepithelial neoplasia grade 2 or worse (CIN2+) in women with transformation zone type 3 (TZ3). METHODS: Records from 764 patients with TZ3 who underwent colposcopy-directed biopsy and/or endocervical curettage in Putuo Hospital China between February 2020 and March 2023 were retrospectively collected. Colposcopy was carried out based on 2011 International Federation of Cervical Pathology and Colposcopy (IFCPC) and Colposcopy nomenclature. The diagnostic performance of colposcopy for identifying CIN2 + was evaluated compared with biopsies. The Kappa and McNemar tests were used to perform statistical analyses. RESULTS: Among the study population, 11.0% had pathologic CIN2+. The relative sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of colposcopy for histologic CIN2 + were 51.2%, 96.5%, 64.2% and 94.1%, respectively. The senior colposcopists (80.6%) had a higher colposcopic accuracy to diagnose histologic CIN2 + than junior colposcopists (68.6%). In subgroup analyses, age group ≥ 60 years (70.3%) showed lowest diagnostic accuracy when compared with age groups of < 45 years (84.4%) and 45-59 years (74.9%). CONCLUSION: Our findings suggest an increased risk of diagnostic inaccuracy of colposcopy in identifying CIN2 + in those ≥ 60 years of age with TZ3, and the accuracy of colposcopy is required to be further improved.

Characteristics of lymphocyte subsets and inflammatory factors in patients with COVID-19.

Objective: This research aims to examine the involvement of lymphocyte subsets and inflammatory cytokines in the development and progression of COVID-19. Methods: 164 COVID-19 patients were admitted to hospital between December 2022 and January 2023. Based on lung CT scans and whether it is necessary for intensive care unit (ICU) admission, they were categorized into: severe groups (84) and mild disease groups (80). Peripheral blood were also collected from 101 healthy examinees and 164 patients. Flow cytometry (FCM) was used to measure the absolute and relative counts of lymphocyte subsets, while chemiluminescence was used to detect the level of inflammatory cytokines. Results: The COVID-19 patient group exhibited lower count of lymphocytes subsets than healthy control group. Moreover, COVID-19 patient case presented higher content of cytokines (IL-6, IL-4, IL-8, IL-10, and TNF-α) expression compared to healthy control case. Within the COVID-19 patient group, individuals with severe disease showed lower counts of lymphocytes subsets than the mild disease case. Furthermore, IL-6 levels in severe case were higher than the mild disease patients case. Multi-variate logistic regression analysis confirmed IL-6 (odds ratio: 0.985 [0.977-0.993]), CD3+ T cells (odds ratio:1.007 [1.004-1.010]), CD8+ T cells (odds ratio:1.016 [1.009-1.023]), and CD19+ B cells (odds ratio:1.011 [1.002-1.020]) independently predicted severe progression. ROC curve results indicated AUC for lymphocytes in patients with severe COVID-19 was 0.8686 (0.8112-0.9260), CD3+ T cells was 0.8762 (0.8237-0.9287), CD8+ T cells was 0.7963 (0.7287-0.8638), CD4+ T cells was 0.8600 (0.8036-0.9164), CD19+ B cells was 0.7217 (0.6434-0.8001), NK cells was 0.6492 (0.5627-0.7357), age was 0.6699 (0.5877-0.7521), diabetes was 0.5991 (0.5125-0.6857), and IL-6 was 0.7241 (0.6479-0.8003). Furthermore, the ROC curves for different factors (CD3+ T cells, age, IL-6) yielded an AUC of 0.9031 (0.8580-0.9483). Conclusions: The research indicated that COVID-19 patients experience a decrease in lymphocytes subset and an increase in the inflammatory factor IL-6, particularly in the severe case group. As a result, the count of lymphocyte subset (CD3+ T cells) and the content of inflammatory cytokine (IL-6) can serve as predictive markers for assessing the severity of COVID-19 and developing treatment plans efficacy.

A Triple-Responsive Polymeric Prodrug Nanoplatform with Extracellular ROS Consumption and Intracellular H2O2 Self-Generation for Imaging-Guided Tumor Chemo-Ferroptosis-Immunotherapy.

High reactive oxygen species (ROS) levels in tumor microenvironment (TME) impair both immunogenic cell death (ICD) efficacy and T cell activity. Furthermore, tumor escapes immunosurveillance via programmed death-1/programmed death ligand-1 (PD-L1) signal, and the insufficient intracellular hydrogen peroxide weakens ferroptosis efficacy. To tackle the above issues, a glutathione (GSH)/ROS/pH triple-responsive prodrug nanomedicine that encapsulates Fe2O3 nanoparticle via electrostatic interaction is constructed for magnetic resonance imaging (MRI)-guided multi-mode theranostics with chemotherapy/ferroptosis/immunotherapy. The diselenide bond consumes ROS in TME to increase T cells and ICD efficacy, the cleavage of which facilitates PD-L1 antagonist D peptide release to block immune checkpoint. After intracellular internalization, Fe2O3 nanoparticle is released in the acidic endosome for MRI simultaneously with lipid peroxides generation for tumor ferroptosis. Doxorubicin is cleaved from polymers in the condition of high intracellular GSH level accompanied by tumor ICD, which simultaneously potentiates ferroptosis by NADPH oxidase mediated H2O2 self-generation. In vivo results indicate that the nanoplatform strengthens tumor ICD, induces cytotoxic T lymphocytes proliferation, inhibits 4T1 tumor regression and metastasis, and prolongs survival median. In all, a new strategy is proposed in strengthening ICD and T cells activity cascade with ferroptosis as well as immune checkpoint blockade for effective tumor immunotherapy.

Study of miRNA and lymphocyte subsets as potential biomarkers for the diagnosis and prognosis of gastric cancer.

Objective: The aim of this study was to identify the expression of miRNA and lymphocyte subsets in the blood of gastric cancer (GC) patients, elucidate their clinical significance in GC, and establish novel biomarkers for the early diagnosis and prognosis of GC. Methods: The expression of miRNAs in the serum of GC patients was screened using second-generation sequencing and detected using qRT-PCR. The correlation between miRNA expression and clinicopathological characteristics of GC patients was analyzed, and molecular markers for predicting cancer were identified. Additionally, flow cytometry was used to detect the proportion of lymphocyte subsets in GC patients compared to healthy individuals. The correlations between differential lymphocyte subsets, clinicopathological features of GC patients, and their prognosis were analyzed statistically. Results: The study revealed that hsa-miR-1306-5p, hsa-miR-3173-5p, and hsa-miR-296-5p were expressed at lower levels in the blood of GC patients, which is consistent with miRNA-seq findings. The AUC values of hsa-miR-1306-5p, hsa-miR-3173-5p, and hsa-miR-296-5p were found to be effective predictors of GC occurrence. Additionally, hsa-miR-296-5p was found to be negatively correlated with CA724. Furthermore, hsa-miR-1306-5p, hsa-miR-3173-5p, and hsa-miR-296-5p were found to be associated with the stage of the disease and were closely linked to the clinical pathology of GC. The lower the levels of these miRNAs, the greater the clinical stage of the tumor and the worse the prognosis of gastric cancer patients. Finally, the study found that patients with GC had lower absolute numbers of CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ B cells, and lymphocytes compared to healthy individuals. The quantity of CD4+ T lymphocytes and the level of the tumor marker CEA were shown to be negatively correlated. The ROC curve and multivariate logistic regression analysis demonstrated that lymphocyte subsets can effectively predict gastric carcinogenesis and prognosis. Conclusion: These miRNAs such as hsa-miR-1306-5p, hsa-miR-3173-5p, hsa-miR-296-5p and lymphocyte subsets such as the absolute numbers of CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ B cells, lymphocytes are down-regulated in GC and are closely related to the clinicopathological characteristics and prognosis of GC patients. They may serve as new molecular markers for predicting the early diagnosis and prognosis of GC patients.

Clinical prognostication and immunotherapy response prediction in esophageal squamous cell carcinoma using the DNA damage repair-associated signature.

BACKGROUND: The relationship between DNA damage repair (DDR) and cancer is intricately intertwined; however, its specific role in esophageal squamous cell carcinoma (ESCC) remains enigmatic. METHODS: Employing single-cell analysis, we delineated the functionality of DDR-related genes within the tumor microenvironment (TME). A diverse array of scoring mechanisms, including AUCell, UCell, singscore, ssgsea, and AddModuleScore, were harnessed to scrutinize the activity of DDR-related genes across different cell types. Differential pathway alterations between high-and low-DDR activity cell clusters were compared. Furthermore, leveraging multiple RNA-seq datasets, we constructed a robust DDR-associated signature (DAS), and through integrative multiomics analysis, we explored differences in prognosis, pathways, mutational landscapes, and immunotherapy predictions among distinct DAS groups. RESULTS: Notably, high-DDR activity cell subpopulations exhibited markedly enhanced cellular communication. The DAS demonstrated uniformity across multiple datasets. The low-DAS group exhibited improved prognoses, accompanied by heightened immune infiltration and elevated immune checkpoint expression. SubMap analysis of multiple immunotherapy datasets suggested that low-DAS group may experience enhanced immunotherapy responses. The "oncopredict" R package analyzed and screened sensitive drugs for different DAS groups. CONCLUSION: Through the integration of single-cell and bulk RNA-seq data, we have developed a DAS associated with prognosis and immunotherapy response. This signature holds promise for the future stratification and personalized treatment of ESCC patients in clinical settings.