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BACKGROUND Recent studies have revealed that the nasal microbiota in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) is profoundly altered and is correlated with systemic inflammation. However, little is known regarding whether the microbiota can be utilized to predict nasal polyp recurrence. This study is aimed to determine whether altered nasal microbiota constituents could be used as biomarkers to predict CRSwNP recurrence. METHODS Nasal microbiota constituents were quantified and characterized using bacterial 16S ribosomal RNA gene sequencing. Selected features for least absolute shrinkage and selection operator regression-based predictors were the nasal microbiota community composition and CRSwNP patient clinical characteristics. The primary outcome was recurrence, which was determined post-admission. RESULTS By distinguishing recurrence-associated nasal microbiota taxa and exploiting the distinct nasal microbiota abundance between patients with recurrent and non-recurrent CRSwNP, we developed a predictive classifier for the diagnosis of nasal polyps' recurrence with 91.4% accuracy. CONCLUSIONS Key taxonomical features of the nasal microbiome could predict recurrence in CRSwNP patients. The nasal microbiome is an understudied source of clinical variation in CRSwNP and represents a novel therapeutic target for future prevention and treatment.

Background: Fine particulate matter (PM) (PM with an aerodynamic diameter Objective: We sought to investigate the effect of PM2.5 exposure on mucociliary function in primary human nasal epithelial cells (HNECs) and the underlying mechanism. Methods: HNECs derived from control subjects and patients with chronic rhinosinusitis with nasal polyps were established as air-liquid interface cultures. Confluent cultures were exposed to 100 or 200 μg/mL PM2.5 for 24 h and assessed for expression of specific mucociliary-associated factors, the percentage of β-tubulin IV-positive and MUC5AC-positive cells, expression of epidermal growth factor receptor (EGFR) ligand and activation of phosphoinositide 3-kinase (PI3K)-AKT/ERK. In addition, cultures pretreated for 30 min with AG1478 (an EGFR inhibitor) or LY294002 (a PI3K inhibitor) following PM2.5 exposure were assessed for MUC5AC mRNA and protein expression. Results: PM2.5 exposure at 100 or 200 μg/mL for 24 h did not affect geminin coiled-coil domain containing, multiciliate differentiation and DNA synthesis associated cell cycle protein, FOXJ1, or DNAI2 mRNA expression or the percentage of β-tubulin IV-positive cells. However, 200 μg/mL PM2.5 exposure significantly increased mRNA expression of SAM-pointed domain-containing ETS transcription factor and MUC5AC and the percentage of MUC5AC-positive cells. PM2.5 also increased expression of EGFR ligands, including heparin-binding EGF-like growth factor and amphiregulin. Furthermore, PM2.5induced activation of PI3K, AKT, and ERK, and pretreatment of HNECs with AG1478 or LY294002 attenuated PM2.5-induced MUC5AC mRNA and protein expression. Conclusions and Clinical Relevance: This study demonstrates that short-term PM2.5 exposure increases MUC5AC expression in HNECs. Furthermore, this study shows that PM2.5-induced MUC5AC expression is likely mediated through the EGFR-PI3K pathway.

miRNAs in circulating extracellular vesicles (EVs) are promising biomarkers for cancer. However, their diagnostic ability for early‐stage non‐small‐cell lung cancer (NSCLC) is not well known. In this study, the circulating EV miRNAs profiling was initially performed in 36 untreated NSCLC patients and 36 healthy controls by TaqMan Low Density Array (TLDA). Subsequently, we performed quantitative reverse‐transcription PCR assay (RT‐qPCR) validation in several independent cohorts that included 159 NSCLC patients, 120 age/sex‐matched healthy controls and 31 benign nodule patients enrolled from three different clinical centres. In addition, 38 cases of NSCLC were analysed before and after surgery. We demonstrated that miR‐520c‐3p and miR‐1274b were significantly and steadily increased in NSCLC patients in comparison with healthy controls and benign nodule patients (P, Sensitive and specific biomarkers for the detection of non‐small‐cell lung cancer (NSCLC) are urgently needed. Here, we investigated the diagnostic potential of extracellular vesicle (EV) miRNAs as biomarkers for NSCLC in a multiphase case–control study. We report that EV‐miR‐520c‐3p and miR‐1274b hold potential as novel diagnostic biomarkers for early‐stage NSCLC.

Little is known about the transcriptomic plasticity and adaptive mechanisms of circulating tumor cells (CTCs) during hematogeneous dissemination. Here we interrogate the transcriptome of 113 single CTCs from 4 different vascular sites, including hepatic vein (HV), peripheral artery (PA), peripheral vein (PV) and portal vein (PoV) using single-cell full-length RNA sequencing in hepatocellular carcinoma (HCC) patients. We reveal that the transcriptional dynamics of CTCs were associated with stress response, cell cycle and immune-evasion signaling during hematogeneous transportation. Besides, we identify chemokine CCL5 as an important mediator for CTC immune evasion. Mechanistically, overexpression of CCL5 in CTCs is transcriptionally regulated by p38-MAX signaling, which recruites regulatory T cells (Tregs) to facilitate immune escape and metastatic seeding of CTCs. Collectively, our results reveal a previously unappreciated spatial heterogeneity and an immune-escape mechanism of CTC, which may aid in designing new anti-metastasis therapeutic strategies in HCC., Circulating tumour cells can be useful for monitoring disease progression but how they survive in the circulatory system is unclear. Here, the authors use single-cell sequencing of circulating tumour cells from multiple vascular sites in liver cancer patients and identify genes that may help the cells survive.

BackgroundEpidemiological evidence on Urine metals and cognitive impairment in older individuals is sparse and limited. The goal of this study was to analyze if there was a link between urinary metal levels and cognitive performance in U.S. people aged 60 and up.MethodsThe National Health and Nutrition Examination Survey (NHANES) data from 2011 to 2014 were utilized in this cross-sectional analysis. Memory function was quantified using the following methods: Established Consortium for Word Learning in Alzheimer's Disease (CERAD-WL) (immediate learning and recall and delayed recall), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). An inductively coupled plasma mass spectrometry (ICP-MS) was used to estimate urine metal concentrations. The connection of Urine metals level with cognitive function was investigated employing binary logistic regression and restricted cubic spline models.ResultsA total of 840 participants aged 60 years and over were enrolled in this study. After controlling for confounders, the association between cadmium, barium, cobalt, cesium, manganese, and thallium and poor cognitive performance showed significance in multiple logistic regression compared to the lowest quartile of metals. In the DSST test, the weighted multivariate adjusted ORs (95% CI) for cadmium in the highest quartile, barium and cesium in the third quartile were 2.444 (1.310–4.560), 0.412 (0.180–0.942) and 0.440 (0.198–0.979), respectively. There were L-shaped associations between urine cesium, barium, or manganese and low cognitive performance in DSST. Urine lead, molybdenum and uranium did not show any significant relationships with cognitive impairment, respectively, compared to the respective lowest quartile concentrations.ConclusionThe levels of barium (Ba), cobalt (Co), cesium (Cs), manganese (Mn), and thallium (Tl) in urine were found to be negatively related to the prevalence of impaired cognitive performance in our cross-sectional investigation. Higher cadmium (Cd) levels were associated with cognitive impairment.

Background We have looked at antimony (Sb) as a new neurotoxin which causes neuronal apoptosis in animal studies. At the population level, however, there is no direct evidence for a relationship between Sb exposure and cognitive performance. Method The study comprehensively assessed the correlation between urinary antimony levels and cognitive test scores in 631 creatinine-corrected older persons using data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014. Results Using logistic regression, the study looked at the prevalence of cognitive impairment at different levels of urine antimony concentrations and found that, after controlling for covariates, higher doses of urinary antimony were positively associated with cognitive function compared to controls, odds ratio (ORs) with 95% confidence interval (CI) were 0.409 (0.185–0.906) and 0.402 (0.186–0.871) respectively. Restricted cubic spline curves showed a non-linear and dose-specific correlation between urinary antimony and cognitive performance, with lower doses associated with better cognitive performance, while higher doses may be associated with cognitive impairment. Conclusions Our data provide evidence for a correlation between Sb and cognitive function at the population level, although the specific mechanisms need to be investigated further.

BackgroundImmune microenvironment is well recognized as a critical regulator across cancer types, despite its complex roles in different disease conditions. Intrahepatic cholangiocarcinoma (iCCA) is characterized by a tumor-reactive milieu, emphasizing a deep insight into its immunogenomic profile to provide prognostic and therapeutic implications.MethodsWe performed genomic, transcriptomic, and proteomic characterization of 255 paired iCCA and adjacent liver tissues. We validated our findings through H&E staining (n=177), multiplex immunostaining (n=188), single-cell RNA sequencing (scRNA-seq) (n=10), in vitro functional studies, and in vivo transposon-based mouse models.ResultsIntegrated multimodule data identified three immune subgroups with distinct clinical, genetic, and molecular features, designated as IG1 (immune-suppressive, 25.1%), IG2 (immune-exclusion, 42.7%), and IG3 (immune-activated, 32.2%). IG1 was characterized by excessive infiltration of neutrophils and immature dendritic cells (DCs). The hallmark of IG2 was the relatively higher tumor-proliferative activity and tumor purity. IG3 exhibited an enrichment of adaptive immune cells, natural killer cells, and activated DCs. These immune subgroups were significantly associated with prognosis and validated in two independent cohorts. Tumors with KRAS mutations were enriched in IG1 and associated with myeloid inflammation-dominated immunosuppression. Although tumor mutation burden was relatively higher in IG2, loss of heterozygosity in human leucocyte antigen and defects in antigen presentation undermined the recognition of neoantigens, contributing to immune-exclusion behavior. Pathological analysis confirmed that tumor-infiltrating lymphocytes and tertiary lymphoid structures were both predominant in IG3. Hepatitis B virus (HBV)-related samples tended to be under-represented in IG1, and scRNA-seq analyses implied that HBV infection indeed alleviated myeloid inflammation and reinvigorated antitumor immunity.ConclusionsOur study elucidates that the immunogenomic traits of iCCA are intrinsically heterogeneous among patients, posing great challenge and opportunity for the application of personalized immunotherapy.

BACKGROUND: Sinonasal symptoms were usually reported to appear initially, yielding the symptoms important for the early detection of coronavirus disease 2019 (COVID-19). This study was conducted retrospectively to investigate the detailed sinonasal manifestations and dynamic profile of real-time reverse transcription polymerase chain reaction (RT-PCR) results for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in COVID-19 patients longitudinally. METHODS: This retrospective study included 11 consecutive patients. The prevalence, timing and severity of sinonasal manifestations were analyzed. Oropharyngeal, nasal, sputum and stool specimens were collected to detect RT-PCR for SARS-CoV-2 over COVID-19 period. RESULTS: Among the 11 patients, 6 (54.5%) were female, and the median age was 51 (IQR, 36-62) years. Seven patients (63.6%) experienced sinonasal symptoms, with 6 (54.5%) exhibiting sinonasal symptoms on the onset day. Seven patients (63.6%) demonstrated nasal obstruction, 5 (45.5%) had rhinorrhea, and 4 (36.4%) exhibited olfactory dysfunction. All six patients with sinonasal symptoms on the onset day had non-severe infections. Most patients (85.7%) with sinonasal symptoms had non-severe infections. Sinonasal symptoms commonly appeared early. The positive RT-PCR rate for SARS-CoV-2 in various specimens was highest in the first week (73.3%), then gradually decreased over the disease course, but 3 patients (27.3%) had experienced a long-lasting fluctuated positive RT-PCR results since 29 days of illness in both groups, especially for two patients with airway comorbidities. CONCLUSIONS: Sinonasal symptoms were more prevalent in patients with mild or moderate COVID-19 and usually appeared early. In addition, regular nucleic acid testing for SARS-CoV-2 should be considered for COVID-19 patients with certain airway comorbidities.

Background The conventional belief that glucocorticosteroid (GC) acts through a single brand glucocorticoid receptor (GR)α protein has changed dramatically with the discovery of multiple GR isoforms. We aimed to evaluate whether multiple GR protein isoforms are expressed in chronic rhinosinusitis with nasal polyps (CRSwNP) and whether GR protein isoform expression profiles differ between different endotypes of CRSwNP. Methods Thirty-eight patients with CRSwNP and ten healthy volunteers were included. The protein expression of multiple GR isoforms in nasal polyps (NPs) tissue and control mucosae was examined by western blot analysis with different GR antibodies. Results Five bands, including three bands for known proteins (GRα-A/B, GRα-C, and GRα-D) and two bands for unidentified proteins at 67 kilodaltons (kDa) and 60 kDa, were identified with both total GR antibody (PA1-511A) and GRα-specific antibody (PA1-516). GRα-D intensity, which was abundant in nasal mucosa, was significantly increased in the CRSwNP group and was especially elevated in the noneosinophilic CRSwNP (NE-CRSwNP) group (PA1-511A: P P = 0.0018; PA1-516: P P = 0.006, respectively). Additionally, the intensities of the newly recognized 67 kDa and 60 kDa bands were much greater in the NE-CRSwNP subgroup than in the eosinophilic CRSwNP (E-CRSwNP) subgroup; in the E-CRSwNP subgroup, the median intensities were even lower than those in the control group. Conclusions This study provides evidence that nasal tissues express multiple GR protein isoforms. GR protein isoforms presented disease and tissue-specific expression profiles that differed between the CRSwNP and control groups and between the E-CRSwNP and NE-CRSwNP subgroups. Graphical abstract

Predictors of prognosis in patients with coronary chronic total occlusion (CTO) undergoing elective percutaneous coronary intervention (PCI) have remained lacking. Lipidomic profiling enables researchers to associate lipid species with disease progression and may improve the prediction of cardiovascular events.In the present study, 781 lipids were measured by targeted lipidomic profiling in 350 individuals (50 healthy controls, 50 patients with coronary artery disease and 250 patients with CTO). L1-regularized logistic regression was used to identify lipid species associated with adverse cardiovascular events and create predicting models, which were verified by 10-fold cross-validation (200 repeats). Comparisons were made between a traditional model constructed with clinical characteristics alone and a combined model built with both lipidomic data and traditional factors.Twenty-four lipid species were dysregulated exclusively in patients with CTO, most of which belonged to sphingomyelin (SM) and triacylglycerol (TAG). Compared with traditional risk factors, new model combining lipids and traditional factors had significantly improved performance in predicting adverse cardiovascular events in CTO patients after PCI (area under the curve, 0.870 vs. 0.726, p .05; Akaike information criterion, 129 versus 156; net reclassification improvement, 0.312, p .001; integrated discrimination improvement, 0.244, p .001). Nomogram was built based on the incorporated model and proved efficient by Kaplan-Meier method.Lipidomic profiling revealed lipid species which may participate in the formation of CTO and could contribute to the risk stratification in CTO patients undergoing PCI.

Hypercholesterolemia is found in patients with chronic lung inflammation, during which airway epithelial cells play important roles in maintenance of inflammatory responses to pathogens. The present study aims at molecular mechanisms by which cholesterol changes airway epithelial sensitivity in response to smoking.Human bronchial epithelial cells (HBEs) were stimulated with cigarette smoke extract (CSE) and mice were exposed to CS/lipopolysaccharide (LPS) as models in vitro and in vivo. Severe COPD patients and healthy volunteers were also enrolled and the level of cholesterol in plasma was detected by metabolomics. Filipin III and elisa kits were used to stain free cholesterol. Mitochondrial function was detected by mitotracker green, mitotracker green, and Seahorse. Mitochondrial morphology was detected by high content screening and electron microscopy. The mRNA and protein levels of mitochondrial dynamics-related proteins were detected by RT-qPCR and Western blot,respectively. BODIPY 493/503 was used to stain lipid droplets. Lipidomics was used to detect intracellular lipid components. The mRNA level of interleukin (IL)-6 and IL-8 were detected by RT-qPCR.We found that the cholesterol overload was associated with chronic obstructive pulmonary disease (COPD) and airway epithelia-driven inflammation, evidenced by hypercholesterolemia in patients with COPD and preclinical models, alteration of lipid metabolism-associated genes in CSE-induced airway epithelia and production of ILs. External cholesterol altered airway epithelial sensitivity of inflammation in response to CSE, through the regulation of STARD3-MFN2 pathway, cholesterol re-distribution, altered transport and accumulation of cholesterol, activities of lipid transport regulators and disorder of mitochondrial function and dynamics. MFN2 down-regulation increased airway epithelial sensitivity and production of ILs after smoking, at least partially by injuring fatty acid oxidation and activating mTOR phosphorylation.Our data provide new insights for understanding molecular mechanisms of cholesterol-altered airway epithelial inflammation and for developing diagnostic biomarkers and therapeutic targets to improve patient outcomes.

Nuclear lipid metabolism and metabolites play important roles in regulation of lipid-lipid, lipid-gene, lipid-chromatin, lipid-membrane and lipid-protein interactions to maintain the nuclear microenvironment, three-dimensional chromatin architecture, gene expression and transcription and biological function. This Editorial highlights the value of lipid-gene interaction in the identification and development of biomarkers and targets and emphasizes the significance of inter-regulation between lipids and genes in innovation and application of precise therapies for patients. Regulatory functions of nuclear lipid dynamics and biophysics modify transcriptomic expression, and modification (lipotranscriptome) can be a new approach for discovery and development of disease-specific diagnoses and therapies, although there are several challenges to be overcome. Better understanding of how lipid-based changes of nuclear functions and transcriptomic profiles modify clinical phenomes will provide new insights to understand molecular mechanisms of diseases and to develop spatiotemporal molecular medicine diagnostics and therapeutics.

BackgroundN6-methyladenosine (m6A) is the most abundant internal mRNA modification in eukaryotic cells. There is accumulating evidence that m6A methylation can play a significant role in the early diagnosis and treatment of cancers. However, the mechanism underlying the involvement of m6A in cervical cancer remains unclear.MethodsHere, we examined the m6A modification patterns of immune cells in the tumour microenvironments (TMEs) of 306 patients with cervical cancer from The Cancer Genome Atlas dataset and analysed the relations between them according to 32 m6A regulators. Immune infiltration in the TME of cervical cancer was analysed using the CIBERSORT algorithm and single-sample gene set enrichment analysis. The m6Ascore was structured though principal component analysis.ResultsTwo different m6A modification patterns were detected in 306 patients with cervical cancer, designated as m6Acluster A and B. The immune cell infiltration characteristics and biological behaviour differed between the two patterns, with m6Acluster A showing a higher level of immune infiltration. The samples were also divided into two genomic subtypes according to 114 m6A regulatory genes shown to be closely correlated with prognosis on univariate Cox regression analysis. Survival analysis showed that gene cluster B was related to better survival than gene cluster A. Most of the m6A regulators showed higher expression in gene cluster B than in gene cluster A. Single-sample gene set enrichment analysis indicated a higher level of immune cell infiltration in gene cluster A. The m6Ascore signature was examined to determine the m6A modification patterns in cervical cancer. Patients with a high m6Ascore showed better survival, while the low m6Ascore group had a higher mutation frequency and better response to treatment.ConclusionsThis study showed that m6A modification patterns play important roles in cervical cancer. Analysis of m6A modification patterns will yield an improved understanding of the TME in cervical cancer, and facilitate the development of better immunotherapy strategies.

Single-cell RNA sequencing (scRNA-seq) is considered an important approach to understand the molecular mechanisms of cancer microenvironmental functions and has the potential for clinical and translational discovery and development. The recent concerns on the impact of scRNA-seq for clinical practice are whether scRNA can be applied as a routine measurement of clinical biochemistry to assist in clinical decision-making for diagnosis and therapy. Pushing single-cell sequencing into clinical application is one of the important missions for clinical and translational medicine (CTM), although there still are a large number of challenges to be overcome. The present Editorial as one of serials aims at overviewing the history of scRNA-seq publications in CTM, sharing the understanding and consideration of the cancer microenvironment at the single-cell solution and emphasising the objective of translating scRNA-seq into clinical application. The dynamic characteristics and patterns of single-cell identity, regulatory networks, and intercellular communication play decisive roles in the properties of the microenvironment, malignancy and migrative capacity of cancer cells, and defensive capacity of immune cells. The microenvironmental single-cell transcriptomic profiles and cell clusters defined by scRNA-seq have great value for exploring the molecular mechanisms of diseases and predicting cell sensitivities to therapy and patient prognosis.

No study has evaluated the diagnostic value of SpyGlass by comparing SpyGlass results and non-SpyGlass results. In this retrospective study, we aimed to compare the diagnostic value of EUS-guided fine-needle aspiration (EUS-FNA) and EUS-FNA combined with SpyGlass to evaluate whether SpyGlass is valuable for increasing the diagnostic yield of EUS-FNA. From April 2015 to April 2020, 251 patients suspected of having pancreatic cystic lesions (PCLs) by imaging techniques who then underwent EUS-FNA were retrospectively enrolled. Only 98 patients who underwent surgical resection with a pathological diagnosis of pancreatic cystic lesion (PCL) were studied. The diagnostic performance outcomes were compared between the EUS-FNA group (EUS-FNA alone, n = 40) and the SpyGlass group (EUS-FNA combined with SpyGlass, n = 58) to assess the value of SpyGlass in diagnosing PCLs. There were 71 females and 27 males with an overall mean age of 47.6 years. The median diameter of the PCLs was 42.2 mm (range, 11.4–100.0 mm). Approximately 37 cysts were localized in the head/neck of the pancreas, while 61 in the body/tail. The sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of the EUS-FNA group were 96.4% (27/28), 83.3% (10/12), 93.1% (27/29), 90.9% (10/11) and 92.5% (37/40), while those in the SpyGlass group were 100% (54/54), 75% (3/4), 98.2% (54/55), 100% (3/3) and 98.3% (57/58), respectively. The diagnostic accuracy rate in the SpyGlass group was higher than that in the EUS-FNA group; however, no significant difference was found between the two groups (P = 0.368). The diagnostic accuracy of evaluating specific cyst types in the EUS-FNA group was 85% (34/40), similar to that in the SpyGlass group (85.0% vs 84.5%, P = 0.944). SpyGlass seems less valuable for the diagnosis of PCLs when EUS and EUS-FNA have been performed by experienced endoscopists.

Background In this study we compared intraoperative bleeding and regional cerebral oxygenation in patients with different degrees of the reverse Trendelenburg position (RTP) during endoscopic sinus surgery (ESS). Methods In total, 120 patients with chronic rhinosinusitis treated by ESS were randomly assigned to the following 4 groups: a horizontal position (HP) group, and 5°, 10°, and 15° RTP (5-RTP, 10-RTP, and 15-RTP, respectively) groups. The primary outcome was the Boezaart grading scale (BS). The cerebral oxygen saturation (ScO2 ), total blood loss, numerical rating scale (NRS) scores, and complications were also recorded. Results The median BS values in the HP, 5-RTP, 10-RTP, and 15-RTP groups were 2.0, 2.0, 2.1, and 1.7, respectively. Multiple pairwise comparisons of the BS showed significant differences between the 15-RTP group and the other 3 groups (HP, 5-RTP, and 10-RTP). Regarding the NRS and bleeding rate, significant differences were found between the HP and 15-RTP groups. No difference was found in ScO2 among the 4 groups, and no cerebral desaturation events occurred in any group. No complications, including vital organ (heart, brain, and kidney) dysfunction problems, were reported in this study during hospitalization. Conclusion Compared with HP, 5-RTP, and 10-RTP, 15-RTP can improve visual clarity during ESS, and ScO2 is not affected by the degree of RTP. No cerebral deoxygenation or vital organ dysfunction was observed in this study. Therefore, we recommend 15-RTP with moderate deliberate hypotension for ESS.

Background Endoscopic drainage of walled-off necrosis (WON) is still a challenge due to stent-associated problems. We explored endoscopic gastric fenestration (EGF) as an innovative alternative intervention. Aim To assess the feasibility, efficacy and safety of EGF for WON. Methods Between March 2019 and March 2020, five patients with symptomatic WON in close contact with the stomach wall were treated by EGF. Endoscopic ultrasound (EUS) was used to select appropriate sites for gastric fenestration, which then proceeded layer by layer as in endoscopic submucosal dissection. Both the stomach muscularis propria and pseudocyst capsule were penetrated. Fenestrations were expanded up to 1.5-3 cm for drainage or subsequent necrosectomy. Results EGF failed in Case 1 due to nonadherence of WON to the gastric wall. EGF was successfully implemented in the other four cases by further refinement of fenestration site selection according to computed tomography, endoscopy and EUS features. The average procedure time for EGF was 124 min (EUS assessment, 32.3 min; initial fenestration, 28.8 min; expanded fenestration, 33 min), and tended to decrease as experience gradually increased. The diameter of the fenestration site was 1.5-3 cm, beyond the caliber of a lumen-apposing metal stent (LAMS), to ensure effective drainage or subsequent necrosectomy. Fenestration sites showed surprising capacity for postoperative self-healing within 1-3 wk. No EGF-related complications were seen. WON disappeared within 3 wk after EGF. In Case 3, another separate WON, treated by endoscopic LAMS drainage, recurred within 4 d after LAMS removal due to stent-related hemorrhage, and resolved slowly over almost 3 mo. No recurrences were observed in the five patients. Conclusion EGF is an innovative and promising alternative intervention for WON adherent to the gastric wall. The challenge resides in the gauging of actual adherence and in selecting appropriate fenestration sites.

Gliomas grow and invade along white matter fiber tracts. This study assessed the effects of motor cortex gliomas on the cerebral white matter fiber bundle skeleton. The motor cortex glioma group included 21 patients, and the control group comprised 14 healthy volunteers. Both groups underwent magnetic resonance imaging-based 3.0 T diffusion tensor imaging. We used tract-based spatial statistics to analyze the characteristics of white matter fiber bundles. The left and right motor cortex glioma groups were analyzed separately from the control group. Results were statistically corrected by the family-wise error rate. Compared with the controls, patients with left motor cortex gliomas exhibited significantly reduced fractional anisotropy and an increased radial diffusivity in the corpus callosum. The alterations in mean diffusivity (MD) and the axial diffusivity (AD) were widely distributed throughout the brain. Furthermore, atlas-based analysis showed elevated MD and AD in the contralateral superior fronto-occipital fasciculus. Motor cortex gliomas significantly affect white matter fiber microstructure proximal to the tumor. The range of affected white matter fibers may extend beyond the tumor-affected area. These changes are primarily related to early stage tumor invasion.

During pregnancy, mother-child interactions trigger a variety of subtle changes in the maternal body, which may be reflected in the status of peripheral blood mononuclear cells (PBMCs). Although these cells are easy to access and monitor, a PBMC atlas for pregnant women has not yet been constructed.We applied single-cell RNA sequencing (scRNA-seq) to profile 198,356 PBMCs derived from 136 pregnant women (gestation weeks 6 to 40) and a control cohort. We also used scRNA-seq data to establish a transcriptomic clock and thereby predicted the gestational age of normal pregnancy.We identified reconfiguration of the peripheral immune cell phenotype during pregnancy, including interferon-stimulated gene upregulation, activation of RNA splicing-related pathways and immune activity of cell subpopulations. We also developed a cell-type-specific model to predict gestational age of normal pregnancy.We constructed a single-cell atlas of PBMCs in pregnant women spanning the entire gestation period, which should help improve our understanding of PBMC composition turnover in pregnant women.

Recent studies show that myeloid-derived suppressor cells (MDSCs) and M2-like macrophages are involved in the treatment of tumors; however, their therapeutic response role is rarely known in non-small cell lung cancer (NSCLC) during radiotherapy. We aim to explore the dynamic alteration of the circulating MDSCs and M2-like macrophages, to examine their relationship, and to evaluate their therapeutic response value for NSCLC patients in radiotherapy.Peripheral blood mononuclear cells from healthy controls and NSCLC patients with different radiotherapy phases were isolated to examine the circulating MDSCs and M2-like macrophages by flow cytometry. 40 plasma inflammatory cytokines were measured by multiplex ELISA.In comparison with healthy controls, the percentages of MDSCs and CD68MDSCs and CD68

Spatial transcriptomics is considered as an important part of spatiotemporal molecular images to bridge molecular information with clinical images. Of those potentials and opportunities, the excellent quality of human sample preparation and handling will ensure the precise and reliable information generated from clinical spatial transcriptome. The present study aims at defining potential factors that might influence the quality of spatial transcriptomics in lung cancer, para‐cancer, or normal tissues, pathological images of sections and the RNA integrity before spatial transcriptome sequencing. We categorised potential influencing factors from clinical aspects, including patient selection, pathological definition, surgical types, sample harvest, temporary preservation conditions and solutions, frozen approaches, transport and storage conditions and duration. We emphasis on the relationship between the combination of histological scores with RNA integrity number (RIN) and the unique molecular identifier (UMI), which is determines the quality of of spatial transcriptomics; however, we did not find significantly relevance between them. Our results showed that isolated times and dry conditions of sample are critical for the UMI and the quality of spatial transcriptomic samples. Thus, clinical procedures of sample preparation should be furthermore optimised and standardised as new standards of operation performance for clinical spatial transcriptome. Our data suggested that the temporary preservation time and condition of samples at operation room should be within 30 min and in ‘dry’ status. The direct cryo‐preservation within OCT media for human lung sample is recommended. Thus, we believe that clinical spatial transcriptome will be a decisive approach and bridge in the development of spatiotemporal molecular images and provide new insights for understanding molecular mechanisms of diseases at multi‐orientations., Processes and workflow of clinical spatial transcriptome from sample harvest to transcriptomic imprints.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is considered a nasal sinus inflammatory disease that can be dominated by immune cells and cytokines. IL-10 family cytokines exert essential functions in immune responses during infection and inflammation. Recently, the understanding of the roles of the IL-10 family in CRSwNP is being reconsidered. IL-10 family members are now considered complex cytokines that are capable of affecting epithelial function and involved in allergies and infections. Furthermore, the IL-10 family responds to glucocorticoid treatment, and there have been clinical trials of therapies manipulating these cytokines to remedy airway inflammatory diseases. Here, we summarize the recent progress in the understanding of IL-10 family cytokines in CRSwNP and suggest more specific strategies to exploit these cytokines for the effective treatment of CRSwNP.

Background Immune cells play important roles in mediating immune response and host defense against invading pathogens. However, insights into the molecular mechanisms governing circulating immune cell diversity among multiple species are limited. Methods In this study, we compared the single‐cell transcriptomes of immune cells from 12 species. Distinct molecular profiles were characterized for different immune cell types, including T cells, B cells, natural killer cells, monocytes, and dendritic cells. Results Our data revealed the heterogeneity and compositions of circulating immune cells among 12 different species. Additionally, we explored the conserved and divergent cellular crosstalks and genetic regulatory networks among vertebrate immune cells. Notably, the ligand and receptor pair VIM‐CD44 was highly conserved among the immune cells. Conclusions This study is the first to provide a comprehensive analysis of the cross‐species single‐cell transcriptome atlas for peripheral blood mononuclear cells (PBMCs). This research should advance our understanding of the cellular taxonomy and fundamental functions of PBMCs, with important implications in evolutionary biology, developmental biology, and immune system disorders., Our study compared the single‐cell transcriptomes of immune cells from 12 species. The results revealed the heterogeneity and compositions of circulating immune cells. We explored the conserved and divergent cellular crosstalks and genetic regulatory networks among vertebrate immune cells.

Background. Members of the formin-like gene (FMNL) family are required for cytoskeleton-related processes, and their expressions are implicated to the progression of a multitude of malignancies. However, there are insufficient studies on transcription factors and promising prognosis benefit of FMNLs during the genesis of breast cancer (BrCa). Methods. The transcriptional levels of FMNL family members in primary BrCa tissues and their association with intrinsic subclasses were analyzed using the UALCAN database. Then, the prognostic values of FMNLs in BrCa patients were investigated via the Kaplan-Meier plotter. Moreover, the correlations between FMNL expression levels and immune infiltrations were analyzed using the TIMER database. In addition, the expression patterns of FMNLs in BrCa were investigated by single-cell RNA-sequencing (scRNA-seq) analysis and were validated by immunohistochemistry (IHC) staining. Results. The transcriptional level of FMNL1 was shown to be considerably increased in BrCa. It is surprising that the transcriptional quantities of FMNL2 and FMNL3 were substantially reduced. In addition, during the comparison of several BrCa subclasses, FMNL1 and FMNL2 mRNA levels of patients with HER2-positive and triple-negative BrCa subclasses increased, while FMNL3 mRNA levels reduced. With the processions of experimentation, high FMNL1 expression was hopefully linked to well clinical outcome, while high FMNL2 expression predicted poor prognosis. Moreover, FMNL1 was highly expressed in tumor-infiltrating immune cells (TIICs) in tumor tissues. Last but not least, FMNL1 was highly expressed in TIICs and served as a gene marker for TIICs. Conclusions. The fact and result which we analyzed demonstrate FMNL1 as a diagnostic marker for TIICs by comprehensively elucidating the expression patterns and changeable prognostic implications of FMNLs in BrCa clinical applications.

Cisplatin-based therapy is a widely used chemotherapeutic regimen for non-small cell lung cancer (NSCLC); however, drug resistance limits its efficacy. Acetyl-11-keto-β-boswellic acid (AKBA), a bioactive compound from frankincense, has been shown to exert anti-cancer effects. The aim of this study is to explore the potential of AKBA in combination with cisplatin as a new regimen for NSCLC. CCK8 assay and clone formation assay were used to determine the effects of AKBA in combination with cisplatin on cell viability of NSCLC cell lines. A three-dimensional spherification assay was used to simulate in vivo tumor formation. Flow cytometry was performed to examine cell cycle distribution and the percentages of apoptotic cells. The associated proteins and mRNA of cell cycle, apoptosis, and autophagy were measured by western blotting and real-time fluorescence quantitative PCR. Immunofluorescence assay was used to test apoptotic nuclei and autolysosome. Small interfering RNA experiments were used to silence the expression of p21. Combination treatment of AKBA and cisplatin inhibited cell viability, clone formation, and three-dimensional spherification, enhanced G0/G1 phase arrest, increased the percentages of apoptotic cells, and decreased the ratio of positive autolysosomes, compared with cisplatin alone. AKBA in combination with cisplatin suppressed the protein expressions of cyclin A2, cyclin E1, p-cdc2, CDK4, Bcl-xl, Atg5, and LC3A/B, and upregulated p27 and p21 mRNA levels in A549 cells. Downregulation of p21 decreased G0/G1 phase arrest and the percentages of apoptotic cells, and promoted autophagy in NSCLC A549 cells. Our study demonstrates that AKBA enhances the cisplatin sensitivity of NSCLC cells and that the mechanisms involve G0/G1 phase arrest, apoptosis induction, and autophagy suppression via targeting p21-dependent signaling pathway.

The mutation rates of tumor suppressor protein p53 gene (TP53) are high in lung adenocarcinoma and promote the development of acquired drug resistance. The present study evaluated the p53-dependent role in lung cancer cell sensitivity to PI3K-specific inhibitors, PI3K-associated inhibitors, PI3K-non-related inhibitors, and protein-based stimuli using designed p53 mutation. We found that the deletion of p53 key regions from amino acid 96 to 393 with the CRISPR-Cas9 altered multi-dimensional structure and sequencing of p53, probably leading the secondary changes in chemical structures and properties of PI3K subunit proteins or in interactions between p53 and PI3K isoform genes. The p53-dependent cell sensitivity varied among target specificities, drug chemical properties, mechanism-specific signal pathways, and drug efficacies, independently upon the size of molecules. The effects of the designed p53 mutation highly depend upon p53-involved molecular mechanisms in the cell. Our results indicate that lung cancer cell resistance to drug can develop with dynamic formations of p53 mutations changing the cell sensitivity. This may explain the real-time occurrence of cancer cell resistance to drug treatment, during which drugs may induce the new mutations of p53. Thus, it is important to dynamically monitor the formation of new mutations during the therapy and discover new drug resistance-specific targets.

Background Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase produces reactive oxygen species (ROS) involved in oxidative stress and signal transduction. Recent studies have suggested that NADPH oxidase is associated with the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). The aim of this study was to detect the expression of NADPH oxidase subunits and 4-hydroxynonenal (4-HNE) in nasal polyp tissue and normal nasal mucosa, in order to explore the possible role played by NADPH oxidase in the pathogenesis of CRSwNP. Methods Thirteen patients with CRSwNP and 9 normal control subjects were selected to participate in this study, in which we evaluated the expression of different NADPH oxidase subunits (gp91phox , p67phox , p47phox , and p22phox ) in nasal polyp (NP) tissue and control mucosa by Western blotting and real-time polymerase chain reaction (PCR). Immunohistochemistry and immunofluorescence staining were used to detect expression of the p67phox subunit and 4-HNE in NP tissue and normal nasal mucosa. Results Western blot and real-time PCR results showed that p67phox expression was significantly increased in NP tissue when compared with its expression in control mucosa (p = 0.004). p67phox was expressed in the eosinophils and neutrophils found in NP tissue, but not in the macrophages. Additionally, the levels of 4-HNE expression were also significantly increased in NP tissue when compared with control mucosa (p = 0.001). Conclusion The levels of p67phox messenger RNA (mRNA) and protein as well as 4-HNE were both upregulated in NP tissue, suggesting that p67phox and oxidative stress play roles in the pathogenesis of CRSwNP.

Disordered lipid metabolisms have been evidenced in lung cancer as well as its subtypes. Lipidomics with in-depth mining is considered as a critical member of the multiple omics family and a lipid-specific tool to understand disease-associated lipid metabolism and disease-specific dysfunctions of lipid species, discover biomarkers and targets for monitoring therapeutic strategies, and provide insights into lipid profiling and pathophysiological mechanisms in lung cancer. The present review describes the characters and patterns of lipidomic profiles in patients with different lung cancer subtypes, important values of comprehensive lipidomic profiles in understanding of lung cancer heterogeneity, urgent needs of standardized methodologies, potential mechanisms by lipid-associated enzymes and proteins, and the importance of integration between clinical phenomes and lipidomic profiles. The characteristics of lipidomic profiles in different lung cancer subtypes are extremely varied among study designs, objects, methods, and analyses. Preliminary data from recent studies demonstrate the specificity of lipidomic profiles specific for lung cancer stage, severity, subtype, and response to drugs. The heterogeneity of lipidomic profiles and lipid metabolism may be part of systems heterogeneity in lung cancer and be responsible for the development of drug resistance, although there are needs for direct evidence to show the existence of intra- or inter-lung cancer heterogeneity of lipidomic profiles. With an increasing understanding of expression profiles of genes and proteins, lipidomic profiles should be associated with activities of enzymes and proteins involved in the processes of lipid metabolism, which can be profiled with genomics and proteomics, and to provide the opportunity for the integration of lipidomic profiles with gene and protein expression profiles. The concept of clinical trans-omics should be emphasized to integrate data of lipidomics with clinical phenomics to identify disease-specific and phenome-specific biomarkers and targets, although there are still a large number of challenges to be overcome in the integration between clinical phenomes and lipidomic profiles.

Background Eosinophilic (Eos) and non-eosinophilic (non-Eos) chronic rhinosinusitis with nasal polyps (CRSwNP) react differently to clinical treatment, with eosinophilic chronic rhinosinusitis with nasal polyps (Eos CRSwNP) being more likely to recur after surgery. Objective To explore the clinical value of the visual analog scale (VAS), nasal endoscopy score (Lund–Kennedy, L–K), computed tomography (CT) score (Lund–Mackay scoring system, L–M), and blood Eos percentage in the differential diagnosis of Eos CRSwNP and non-Eos CRSwNP. Methods Ninety-nine patients with CRSwNP were enrolled in this study and assigned to 2 groups (Eos CRSwNP and non-Eos CRSwNP). The blood Eos percentage and VAS, L–K, and L–M scores in the 2 groups of patients were compared. A receiver operating characteristic (ROC) was used to assess the usefulness of VAS, L–K, and L–M scores for differentiating Eos CRSwNP and non-Eos CRSwNP. Results There were significantly differences between the Eos CRSwNP group and non-Eos CRSwNP group in the following scores: blood Eos percentage, mean VAS score, olfaction/VAS, general discomfort/L–K, edema score/L–K, olfactory cleft (OC) score via endoscopy, mean L–M score, anteriorethmoid sinus score, posterior ethmoid sinus score, sphenoid sinus score, frontal sinus score, and OC score via CT. An ROC analysis showed that blood Eos percentage had the highest area under the ROC curve (AUC) value (0.749); however, several other scores (olfaction score/VAS, edema score/L–K, and mean L–M score) also had high AUC values. The combination of olfaction score/VAS and blood Eos percentage had the highest clinical convenience score as well as high sensitivity and specificity. A combination of cutoff values for the 2 predictors (blood Eos percentage ≥3.85%, olfaction score/VAS score ≥3) showed a sensitivity of 75.5% and a specificity of 78.0%. Conclusion The olfaction score/VAS score and the blood Eos percentage can be combined to differentiate Eos CRSwNP from non-Eos CRSwNP in a Chinese population.

Rationale: Particulate matter with an aerodynamic diameter equal or less than 2.5 µm (PM2.5) represents a main constituent of polluted air with a potential detrimental impact on human health. Objec...

Omicron variants are part of the “Coronavirus disease 2019 [COVID‐19] Variants of Concerns” and has the potential to spread around the world rapidly and can harm human life. We can anticipate that the endemic state of COVID‐19 will be characterized by the development of new strains with surges that will predominate in unvaccinated and immunodeficient populations. Thus, there will be an important role in promoting vaccinations, boosters and accessible testing to prevent disease transmission and to rapidly detect surges. There is an urgent need to explore the virology and biology of Omicron variants, define clinical phenomes and therapies, monitor dynamics of genetic changes, and translate the knowledge of COVID‐19 into new variants. Clinical and translational medicine will be impactful in addressing these challenges by providing new insights for understanding and predicting new variants‐associated transmissibility, disease severity, immune escape, diagnostic or therapeutic failure.

scRNA‐seq is on track for use as a routine measurement of clinical biochemistry and to assist in clinical decision‐making and guide the performance of molecular medicine, but there are still a large number of challenges to be overcome. In conclusion, scRNA‐seq‐based clusters and differentiation of circulating blood cells have been examined and informative in patients with various diseases, although the information generated from scRNA‐seq varies between different conditions, technologies, and diseases. Most of the clinical studies published have focused on the landscape of circulating immune cells, disease‐specific patterns of new clusters, understanding of potential mechanisms, and potential correlation between cell clusters, differentiations, cell interactions, and circulating and migrated cells. It is clear that the information from scRNA‐seq advances the understanding of the disease, identifies disease‐specific target panels, and suggests new therapeutic strategies. The adaptation of scRNA‐seq as a routine clinical measurement will require standardization and normalization of scRNA‐seq‐based comprehensive information and validation in a large population of healthy and diseased patients. The integration of public databases on human circulating cell clusters and differentiations with an application of artificial intelligence and computational science will accelerate the application of scRNA‐seq for clinical practice. Thus, we call special attention from scientists and clinicians to the clinical and translational discovery, validation, and medicine opportunities of scRNA‐seq development.

Increasing evidence supports a central role of the immune system in lung diseases. Understanding how immunological alterations between lung diseases provide opportunities for immunotherapy. Exhausted T cells play a key role of immune suppression in lung cancer and chronic obstructive pulmonary disease was proved in our previous study. The present study aims to furthermore define molecular landscapes and heterogeneity of systemic immune cell target proteomic and transcriptomic profiles and interactions between circulating immune cells and lung residential cells in various lung diseases. We firstly measured target proteomic profiles of circulating immune cells from healthy volunteers and patients with stable pneumonia, stable asthma, acute asthma, acute exacerbation of chronic obstructive pulmonary disease, chronic obstructive pulmonary disease and lung cancer, using single‐cell analysis by cytometry by time‐of‐flight with 42 antibodies. The nine immune cells landscape was mapped among those respiratory system diseases, including CD4+ T cells, CD8+ T cells, dendritic cells, B cells, eosinophil, γδT cells, monocytes, neutrophil and natural killer cells. The double‐negative T cells and exhausted CD4+ central memory T cells subset were identified in patients with acute pneumonia. This T subset expressed higher levels of T‐cell immunoglobulin and mucin domain‐containing protein 3 (Tim3) and T‐cell immunoreceptor with Ig and ITIM domains (TIGIT) in patients with acute pneumonia and stable pneumonia. Biological processes and pathways of immune cells including immune response activation, regulation of cell cycle and pathways in cancer in peripheral blood immune cells were defined by bulk RNA sequencing (RNA‐seq). The heterogeneity among immune cells including CD4+, CD8+ T cells and NK T cells by single immune cell RNA‐seq with significant difference was found by single‐cell sequencing. The effect of interstitial telocytes on the immune cell types and immune function was finally studied and the expressions of CD8a and chemokine C–C motif receptor 7 (CCR7) were increased significantly in co‐cultured groups. Our data indicate that proteomic and transcriptomic profiles and heterogeneity of circulating immune cells provides new insights for understanding new molecular mechanisms of immune cell function, interaction and modulation as a source to identify and develop biomarkers and targets for lung diseases., 1. New clusters and functions of circulating immune cells can be an important source to understand molecular mechanisms, identify disease‐specific biomarkers, and develop new target therapies. 2. The difference of biological processes and pathways of PBICs by single‐cell sequencing and RNAseq varies among diseases. 3. The interstitial cells could alter the differentiation and development of the immune cell types and immune function.

The communication between endoplasmic reticulum (ER) and mitochondria (Mt) plays important roles in maintenance of intra‐ and extra‐cellular microenvironment, metabolisms, signaling activities and cell‐cell communication. The present review aims to overview the advanced understanding about roles of ER‐Mt structural contacts, molecular interactions and chemical exchanges, signal transmissions and inter‐organelle regulations in ER‐Mt communication. We address how the ER‐Mt communication contributes to the regulation of lipid, amino acid and glucose metabolisms by enzymes, transporters and regulators in the process of biosynthesis. We specially emphasize the importance of deep understanding about molecular mechanisms of ER‐Mt communication for identification and development of biology‐specific, disease‐specific and metabolism‐specific biomarkers and therapeutic targets for human diseases. The inhibitors and modulators of the ER‐Mt communication are categorized according to therapeutic targets. Rapid development of biotechnologies will provide new insights for spatiotemporally understanding the molecular mechanisms of ER‐Mt communication., Highlights 1. The ER‐Mt interactions are the important part of intracellular communication responsible for cell metabolism, development and death in the biological processes. 2. The ER‐Mt regulations contribute to molecular mechanisms of diseases and vary among diseases, severities, stages and sensitivities to therapies. 3. The molecular signals during ER‐Mt communication can be potential sources to discover and develop biology‐, disease‐ and therapy‐specific biomarkers and targets.

The combination of spatial transcriptomics (ST) and single cell RNA sequencing (scRNA-seq) acts as a pivotal component to bridge the pathological phenomes of human tissues with molecular alterations, defining in situ intercellular molecular communications and knowledge on spatiotemporal molecular medicine. The present article overviews the development of ST and aims to evaluate clinical and translational values for understanding molecular pathogenesis and uncovering disease-specific biomarkers. We compare the advantages and disadvantages of sequencing- and imaging-based technologies and highlight opportunities and challenges of ST. We also describe the bioinformatics tools necessary on dissecting spatial patterns of gene expression and cellular interactions and the potential applications of ST in human diseases for clinical practice as one of important issues in clinical and translational medicine, including neurology, embryo development, oncology, and inflammation. Thus, clear clinical objectives, designs, optimizations of sampling procedure and protocol, repeatability of ST, as well as simplifications of analysis and interpretation are the key to translate ST from bench to clinic.

Cardiac voltage‐gated ion channels (VGICs) play critical roles in mediating cardiac electrophysiological signals, such as action potentials, to maintain normal heart excitability and contraction. Inherited or acquired alterations in the structure, expression, or function of VGICs, as well as VGIC‐related side effects of pharmaceutical drug delivery can result in abnormal cellular electrophysiological processes that induce life‐threatening cardiac arrhythmias or even sudden cardiac death. Hence, to reduce possible heart‐related risks, VGICs must be acknowledged as important targets in drug discovery and safety studies related to cardiac disease. In this review, we first summarize the development and application of electrophysiological techniques that are employed in cardiac VGIC studies alone or in combination with other techniques such as cryoelectron microscopy, optical imaging and optogenetics. Subsequently, we describe the characteristics, structure, mechanisms, and functions of various well‐studied VGICs in ventricular myocytes and analyze their roles in and contributions to both physiological cardiac excitability and inherited cardiac diseases. Finally, we address the implications of the structure and function of ventricular VGICs for drug safety evaluation. In summary, multidisciplinary studies on VGICs help researchers discover potential targets of VGICs and novel VGICs in heart, enrich their knowledge of the properties and functions, determine the operation mechanisms of pathological VGICs, and introduce groundbreaking trends in drug therapy strategies, and drug safety evaluation., The structure, distribution, interaction and function of voltage‐gated ion channels (VGICs) maintains a physiological balance of the ionic currents, normal action potential (AP), excitation‐contraction coupling, and synchronization in cardiomyocytes.Various genetic mutations and molecular dysregulation of the VGICs could result in ionic imbalance, abnormal AP waveform, and even cardiac arrhythmia.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal pathogen of the ongoing global pandemic of coronavirus disease 2019 (COVID-19). Loss of smell and taste are symptoms of COVID-19, and may be related to cilia dysfunction. Here, we found that the SARS-CoV-2 ORF10 increases the overall E3 ligase activity of the CUL2ZYG11B complex by interacting with ZYG11B. Enhanced CUL2ZYG11B activity by ORF10 causes increased ubiquitination and subsequent proteasome-mediated degradation of an intraflagellar transport (IFT) complex B protein, IFT46, thereby impairing both cilia biogenesis and maintenance. Further, we show that exposure of the respiratory tract of hACE2 mice to SARS-CoV-2 or SARS-CoV-2 ORF10 alone results in cilia-dysfunction-related phenotypes, and the ORF10 expression in primary human nasal epithelial cells (HNECs) also caused a rapid loss of the ciliary layer. Our study demonstrates how SARS-CoV-2 ORF10 hijacks CUL2ZYG11B to eliminate IFT46 and leads to cilia dysfunction, thereby offering a powerful etiopathological explanation for how SARS-CoV-2 causes multiple cilia-dysfunction-related symptoms specific to COVID-19.

Mitochondrial dysfunction contributes to the imbalance of cellular homeostasis and the development of diseases, which is regulated by mitochondria‐associated factors. The present review aims to explore the process of the mitochondrial quality control system as a new source of the potential diagnostic biomarkers and/or therapeutic targets for diseases, including mitophagy, mitochondrial dynamics, interactions between mitochondria and other organelles (lipid droplets, endoplasmic reticulum, endosomes, and lysosomes), as well as the regulation and posttranscriptional modifications of mitochondrial DNA/RNA (mtDNA/mtRNA). The direct and indirect influencing factors were especially illustrated in understanding the interactions among regulators of mitochondrial dynamics. In addition, mtDNA/mtRNAs and proteomic profiles of mitochondria in various lung diseases were also discussed as an example. Thus, alternations of mitochondria‐associated regulators can be a new category of biomarkers and targets for disease diagnosis and therapy., 1. The mitochondria quality control system includes mitochondrial dynamics and mitophagy, which is closely related to cellular mesenchymal activations and metabolism reprogramming. 2. Mitochondria can contact with other organelles by the predominant interface of the outer membrane of mitochondria with endoplasmic reticulum, lysosomes, and lipid droplets. 3. The regulation of mitochondrial DNA/RNA transcription and post‐transcriptional modifications are closely related to physiological and pathological processes in various diseases.

Interleukin (IL)-25 is a T helper (Th) type-2 cytokine implicated in the pathogenesis of asthma. Fibrocytes are progenitor cells that can migrate into circulation and inflamed bronchial epithelium.We aim to test the hypothesis that circulating fibrocytes may be the novel cellular targets of IL-25 and the recruitment of IL-25RBy using flow cytometry analysis, IL-25RWe found the percentage of total and IL-25RWe concluded that circulating fibrocytes are the novel potential cellular targets of IL-25. IL-25R

The rapid development of technologies provides the potential to perform real‐time visualization of transcriptional bursting patterns, superenhancer formation and sensitivity to perturbation, and interactions between enhancers, promoters, and regulators during the burst. The transcriptional bursting‐induced fluctuation can modify cell capacities, cell–cell communications, cell responses to microenvironmental changes, and forms of cell death. A large number of clinical and translational studies describe the existence of heterogeneity among cells, tissues, and organs but mechanism‐based understanding of how and why the heterogeneity exists and how it is formed. The transcriptional bursting, fluctuation, and control determine the development of heterogeneity and optimize cell functions in the cell development and differentiation, contribute to the initiation of cell dysfunction and tumorigenesis in response to environments, and development/evolvement of hyper/hyposensitivity to drugs. Spatiotemporal monitoring of transcriptional bursting and control provides a new insight and deeper understanding of spatiotemporal molecular medicine by integrating the transcriptional positioning and function with cell phenotypes, cell–cell communication, and clinical phenomes.

Background As a typical “united airway” disease, asthma-chronic rhinosinusitis (CRS) overlap has recently drawn more attention. Bronchiectasis is a heterogeneous disease related to a variety of diseases. Whether bronchiectasis exists and correlates with asthma-CRS patients has not been fully elucidated. The purpose of the study was to explore the presence and characteristics of bronchiectasis in patients with overlapping asthma and CRS. Methods This report describes a prospective study with consecutive asthma-CRS patients. The diagnosis and severity of bronchiectasis were obtained by thorax high-resolution computed tomography (HRCT), the Smith radiology scale and the Bhalla scoring system. CRS severity was evaluated by paranasal sinus CT and the Lund-Mackay (LM) scoring system. The correlations between bronchiectasis and clinical data, fraction of exhaled nitric oxide, peripheral blood eosinophil counts and lung function were analyzed. Results Seventy-two (40.91%) of 176 asthma-CRS patients were diagnosed with bronchiectasis. Asthma-CRS patients with overlapping bronchiectasis had a higher incidence rate of nasal polyps (NPs) (P = 0.004), higher LM scores (P = 0.044), higher proportion of ≥ 1 severe exacerbation of asthma in the last 12 months (P = 0.003), lower postbronchodilator forced expiratory volume in one second (FEV1) % predicted (P = 0.006), and elevated peripheral blood eosinophil counts (P = 0.022). Smith and Bhalla scores were shown to correlate positively with NPs and negatively with FEV1% predicted and body mass index. Cutoff values of FEV1% predicted ≤ 71.40%, peripheral blood eosinophil counts > 0.60 × 109/L, presence of NPs, and ≥ 1 severe exacerbation of asthma in the last 12 months were shown to differentiate bronchiectasis in asthma-CRS patients. Conclusions Bronchiectasis commonly overlaps in asthma-CRS patients. The coexistence of bronchiectasis predicts a more severe disease subset in terms of asthma and CRS. We suggest that asthma-CRS patients with NPs, severe airflow obstruction, eosinophilic inflammation, and poor asthma control should receive HRCT for the early diagnosis of bronchiectasis.

Intervertebral disc degeneration (IDD) is a common orthopedic multifactorial disease associated with spine-related disorders, such as low back pain. Recent studies have shown that both platelet-rich plasma (PRP) and exosomes could be used to treat IDD, but the effects and mechanism of PRP-derived exosomes in the treatment of IDD are still unclear. This study showed that PRP-derived exosomes inhibited the polarization of M1 macrophages by regulating the NF-κB and MAPK pathways and affected the polarization of M2 macrophages by regulating STAT6 phosphorylation. Additionally, PRP-derived exosomes promoted the autophagic degradation of NLRP3 by increasing NLRP3 ubiquitination and reducing IL-1β and Caspase-1 production. Moreover, PRP-derived exosomes could reduce IL-1β-induced apoptosis of nucleus pulposus cells. Lastly, in vivo experiments confirmed that PRP-derived exosomes reduced the expression of inflammatory mediators and apoptotic factors, which could thereby alleviate the progression of IDD. Taken together, these data showed that PRP-derived exosomes could alleviate the IDD-associated inflammation by regulating the ubiquitination and autophagic degradation of NLRP3 inflammasome, providing new insights into the treatment of IDD.

Background Lung cancer is still the main cause of death in patients with cancer, due to poor understanding of intracellular regulations. Of those, osteopontin (OPN) may induce the epithelial‐to‐mesenchymal transition (EMT) to promote tumor cell metastasis. The present study aims to evaluate the regulatory mechanism of internal and external OPN in the development of lung cancer. Methods We evaluated genetic variations and different bioinformatics of genes in chromosome 4 among subtypes of lung cancer using global databases. We validated the expression of OPN and EMT‐related proteins (e.g., E‐cadherin, vimentin) in 208 non‐small‐cell lung cancer (NSCLC) tumors and the adjacent nontumorous tissues, further to explore the function of OPN in the progression of lung cancer, with a focus on a potential communication between OPN and EMT in the lung cancer. Results We found that OPN might act as a target molecule in lung cancer, which is associated with lymph node metastasis, postresection recurrence/metastasis, and prognosis of patients with lung cancer. Biological behaviors and pathological responses of OPN varied among diseases, challenges, and severities. Overexpression of OPN was correlated with the existence of EMT in lung cancer tissues. Internal and external OPN plays the decisive roles in lung cancer cell movement, proliferation, and EMT formation, through the upregulation of OPN‐PI3K and OPN‐MEK pathways. PI3K and MEK inhibitors downregulated the process of EMT and biological behaviors of lung cancer cells, probably through altering vimentin‐associated cytoskeletons. Conclusion OPN can be a metastasis‐associated or specific biomarker for lung cancer and a potential target for antimetastatic treatment., OPN can be a metastasis‐associated or specific biomarker for lung cancer.OPN over‐expressed in lung cancer was correlated with cell movement, proliferation and the existence of EMT.OPN plays the decisive roles in lung cancer biological behaviors and EMT formation, through PI3K/Akt and MAPK/Erk1/2 pathways.

Gliomas typically grow along white matter fiber tracts, yet their invasion patterns remain unclear. This study assessed the effect of insular glioma on large white matter fiber tracts and the microstructural subcortical changes associated with clinical outcomes in patients with insular glioma. Twenty-five patients with insular glioma were enrolled and divided into left and right groups according to tumor lateralization. The control group comprised 14 healthy volunteers. Subjects in both the glioma and control groups underwent diffusion tensor magnetic resonance imaging at 3.0 T. The characteristics of white matter fiber bundles were analyzed using tract-based spatial statistics and automatic fiber quantification. Both Automatic Fiber Quantification and Tract-Based Spatial Statistics revealed that patients with insular glioma had significantly lower fractional anisotropy (FA) values in the inferior frontal-occipital fasciculus and uncinate fasciculus ipsilateral to the tumor, than the controls. Fractional anisotropy associated with mean diffusivity values several large fiber tracts showed potential on tumor-grade distinguishing. Diffusion metrics can sensitively detect microstructural changes in tumor progression. Insular glioma significantly affects the microstructure of white matter fibers proximal to the tumor. The range of white matter fiber bundles affected differs according to the grade of the glioma. These changes are mainly associated with early-stage tumor invasion.

Single-cell biomedicine, a new merging discipline of cell biology and medicine to improve the life quality of patients, gains high priority in cell biology and toxicology. Single-cell nuclear elements are specially focused and headlined to understand regulatory mechanisms by which transcriptional factors, DNA elements, and genome organization interact with each other and contribute to the developmental evolution and dynamic formation of genotoxicity. Cell molecular phenomics, clonal genotypes, and structural metamorphoses during the cell cycle at single-cell level provide deep insights to understanding mechanism-based bridges between cell biology and toxicology, between cell sensitive and resistance, and between chronic diseases and cancer.