Whole Genome Sequencing Highlights the Pathogenic Profile in Nocardia Keratitis.

Purpose: Nocardia keratitis is a serious and sight-threatening condition. This study aims to reveal the virulence and antimicrobial resistance gene profile of Nocardia strains using whole genome sequencing. Methods: Whole-genome sequencing was performed on 23 cornea-derived Nocardia strains. Together with genomic data from the respiratory tract and the environment, 141 genomes were then utilized for phylogenetic and pan-genome analyses, followed by virulence and antibiotic resistance analysis. The correlations between virulence genes and pathogenicity were experimentally validated, including the characteristics of Nocardia colonies and clinical and histopathological evaluations of Nocardia keratitis mice models. Results: Whole-genome sequencing of 141 Nocardia strains revealed a mean of 220 virulence genes contributed to bacterial pathogenesis. The mce gene family analysis led to the categorization of strains from the cornea into groups A, B, and C. The colonies of group C had the largest diameter, height, and fastest growth rate. The size of corneal ulcers and the clinical scores showed a significant increase in mouse models induced by group C. The relative expression levels of pro-inflammatory cytokines (CD4, IFN-γ, IL-6Rα, and TNF-α) in the lesion area exhibited an increasing trend from group A to group C. Antibiotic resistance genes (ARGs) spanned nine distinct drug classes, four resistance mechanisms, and seven primary antimicrobial resistance gene families. Conclusions: Whole genome sequencing highlights the pathogenic role of mce gene family in Nocardia keratitis. Its distribution pattern may contribute to the distinct characteristics of the growth of Nocardia colonies and the clinical severity of the mice models.

Neoadjuvant chemoimmunotherapy confers survival advantage for patients undergoing sleeve lobectomy.

OBJECTIVES: It has been demonstrated that neoadjuvant immune checkpoint inhibitor (ICI) plus chemotherapy was safe and feasible referred to neoadjuvant chemotherapy for patients with non-small cell lung cancer undergoing sleeve lobectomy. Nevertheless, no survival data were reported in the previous researches. Therefore, we conducted this study to compare neoadjuvant ICI plus chemotherapy versus neoadjuvant chemotherapy followed by sleeve lobectomy for long-term survival outcomes. METHODS: Patients who underwent bronchial sleeve lobectomy following neoadjuvant ICI plus chemotherapy or neoadjuvant chemotherapy were retrospectively identified. Treatment response, perioperative outcomes, event-free survival and overall survival were compared between groups in the overall and the inverse probability of treatment weighting-adjusted cohort. RESULTS: A total of 139 patients with 39 lung cancer recurrence and 21 death were included. Among them, 83 (59.7%) and 56 (40.3%) patients received neoadjuvant chemotherapy and neoadjuvant ICI plus chemotherapy, respectively. After inverse probability of treatment weighting, more patients achieved complete pathological response in the neoadjuvant ICI plus chemotherapy group (6.0% vs 26.3%, P < 0.001). There was no significant difference regarding overall postoperative complication (23.8% vs 20.2%, P = 0.624) and specific complications (all P > 0.05). Patients receiving neoadjuvant ICI plus chemotherapy had favourable event-free survival (hazard ratio 0.37, 95% confidence interval 0.16-0.85, P = 0.020) and overall survival (hazard ratio 0.23, 95% confidence interval 0.06-0.80, P = 0.021). Multivariable analysis revealed that neoadjuvant ICI plus chemotherapy was an independent predictor for favourable event-free survival (hazard ratio 0.37, 95% confidence interval 0.15-0.86, P = 0.020, adjusted for clinical TNM stage). CONCLUSIONS: Neoadjuvant ICI plus chemotherapy was correlated with favourable long-term survival in patients with non-small cell lung cancer undergoing sleeve lobectomy.

Cascaded momentum-space polarization filters enabled label-free black-field microscopy for single nanoparticles analysis.

Label-free optical imaging of single-nanometer-scale matter is extremely important for a variety of biomedical, physical, and chemical investigations. One central challenge is that the background intensity is much stronger than the intensity of the scattering light from single nano-objects. Here, we propose an optical module comprising cascaded momentum-space polarization filters that can perform vector field modulation to block most of the background field and result in an almost black background; in contrast, only a small proportion of the scattering field is blocked, leading to obvious imaging contrast enhancement. This module can be installed in various optical microscopies to realize a black-field microscopy. Various single nano-objects with dimensions smaller than 20 nm appear distinctly in the black-field images. The chemical reactions occurring on single nanocrystals with edge lengths of approximately 10 nm are in situ real-time monitored by using the black-field microscopy. This label-free black-field microscopy is highly promising for a wide range of future multidisciplinary science applications.

Ferroptosis as a Potential Therapeutic Target for Reducing Inflammation and Corneal Scarring in Bacterial Keratitis.

Purpose: Bacterial keratitis (BK) is a serious ocular infection that can cause severe inflammation and corneal scarring, leading to vision loss. In this study, we aimed to investigate the involvement of ferroptosis in the pathogenesis of BK. Methods: Transcriptome analysis was performed to evaluate ferroptosis-related gene expression in human BK corneas. Subsequently, the ferroptosis in mouse models of Pseudomonas aeruginosa keratitis and corneal stromal stem cells (CSSCs) were validated. The mice were treated with levofloxacin (LEV) or levofloxacin combined with ferrostatin-1 (LEV+Fer-1). CSSCs were treated with lipopolysaccharide (LPS) or LPS combined Fer-1. Inflammatory cytokines, α-SMA, and ferroptosis-related regulators were evaluated by RT-qPCR, immunostaining, and Western blot. Iron and reactive oxygen species (ROS) were measured. Results: Transcriptome analysis revealed significant alterations in ferroptosis-related genes in human BK corneas. In the BK mouse models, the group treated with LEV+Fer-1 exhibited reduced inflammatory cytokines (MPO, TNF-α, and IFN-γ), decreased corneal scarring and α-SMA expression, and lower Fe3+ compared to the BK and LEV groups. Notably, the LEV+Fer-1 group showed elevated GPX4 and SLC7A11 in contrast to the BK and LEV group. In vitro, Fer-1 treatment effectively restored the alterations of ROS, Fe2+, GPX4, and SLC7A11 induced by LPS in CSSCs. Conclusions: Ferroptosis plays a crucial role in the pathogenesis of BK. The inhibition of ferroptosis holds promise for mitigating inflammation, reducing corneal scarring, and ultimately enhancing the prognosis of BK. Consequently, this study provides a potential target for innovative therapeutic strategies for BK, which holds immense potential to transform the treatment of BK.

Acanthamoeba Keratitis in China: Genotypic and Clinical Correlations.

Purpose: To investigate the relationship between Acanthamoeba genotypes, clinical manifestations, and outcomes in Acanthamoeba keratitis (AK) patients. Methods: This retrospective study included 159 culture-confirmed AK patients. Patients' data were collected, including demographics, initial diagnosis, treatments, and clinical features. The genotype of Acanthamoeba was identified through sequencing the Diagnostic Fragment 3 (DF3) region in the small ribosomal subunit RNA genes. The phylogenetic tree was constructed using the ClustalW model and maximum likelihood method. Cases with "poor outcome" were defined based on specific clinical criteria, including corneal perforation, keratoplasty, other eye surgery, duration of anti-amoebic therapy ≥8.0 months, and final visual acuity ≤20/80. "Better outcome" cases were the remainder. The correlation between T4 subtypes, clinical phenotypes, and clinical prognosis were further analyzed. Results: In this study, AK was primarily attributed to the T4A genotype, with a positive correlation between geographical and genetic distances. The primary clinical associated with T4 subtypes was deep stromal infiltration. Results was also showed a significant association between T4 subtypes and clinical outcomes (P = 0.021). Further analysis revealed that T4C was closely associated with a better prognosis (P = 0.040) and T4D with worse outcomes (P = 0.013). Conclusions: In China, AK was predominantly caused by the T4A subtype. Geographical distance positively correlated with genetic distance. Clinical prognosis varied among different subtypes, notably in T4C and T4D. Translational Relevance: This study demonstrated the association between T4 subtypes and clinical phenotypes, as well as the effects of T4 subtypes on clinical prognosis.

Corneal Epithelial Dendritic Cells: An Objective Indicator for Ocular Surface Inflammation in Patients with Obstructive Meibomian Gland Dysfunction?

PURPOSE: To examine whether corneal epithelial dendritic cells (CEDC) could serve as an indicator to distinguish obstructive meibomian gland dysfunction (MGD) with or without ocular surface inflammation (OSI). METHODS: We performed a case-control study on patients with diagnosed obstructive MGD between August 2017 and November 2019. RESULTS: 30 MGD cases and 25 healthy controls were recruited. The classification of MGD patients with and without OSI was based on the tear pro-inflammatory cytokine levels. Compared with the MGD without OSI and the control group, a higher CEDC density was detected in the MGD with OSI subgroup. The presence of >15.6 cells/mm2 CEDC had a sensitivity of 73% and specificity of 75% for the diagnosis of MGD with OSI. CONCLUSIONS: OSI is not present in all patients with obstructive MGD. Evaluation of CEDC density in the central cornea may help identify whether MGD is concomitant with OSI.

Prognostic Significance of the Proposed Residual Tumor Classification in Patients With NSCLC After Sleeve Lobectomy.

Introduction: To validate the residual tumor (R) classification proposed by the International Association for the Study of Lung Cancer (IASLC) in NSCLC after sleeve lobectomy. Methods: A total of 682 patients were analyzed. The R status, on the basis of the Union for International Cancer Control (UICC) criteria, was recategorized according to the IASLC descriptors. Recurrence-free survival (RFS) and overall survival (OS) among different R classifications were assessed for the entire cohort and pathologic node (pN) subgroups. Results: All in all, 631 (92.5%), 48 (7.1%), and three patients (0.4%) were classified as R0, R1, and R2, respectively, by the UICC criteria, whereas 489 (71.7%), 110 (16.1%), and 83 patients (12.2%), received R0, uncertain resection (R[un]), and R1/2 resection, respectively, according to the IASLC criteria. There were 96 patients (15.2%) with UICC R0 who were reclassified as R(un), mainly because of the positive highest mediastinal node station (82 of 96, 85.4%). A total of 46 patients (7.3%) were reassigned from UICC R0 to IASLC R1/2 owing to extracapsular extension. For the entire cohort, patients with R(un) and R1/2 exhibited worse RFS (R[un], adjusted p = 0.023; R1/2, adjusted p = 0.001) and OS (R[un], adjusted p = 0.040; R1/2, adjusted p = 0.051) compared with R0. No significant differences were observed between R(un) and R1/2 (RFS, adjusted p = 0.586; OS, adjusted p = 0.781). Furthermore, subgroup analysis revealed a distinct prognostic impact of the IASLC R status-with prognostic significances in the pN1 and pN2 subgroups, but not in the pN0 subgroup. Conclusions: The IASLC R descriptors helped to stratify the prognosis of NSCLC after sleeve lobectomy, with its prognostic impact varied among pN stages.

Extracellular Vesicle MicroRNAs From Corneal Stromal Stem Cell Enhance Stemness of Limbal Epithelial Stem Cells by Targeting the Notch Pathway.

Purpose: The limbal niche supports the self-renewal of limbal epithelial stem cells (LESCs). The corneal stromal stem cell (CSSC) is an important component in the niche that regulates the LESC phenotype. However, the intercellular communication between LESCs and CSSCs has yet to be elucidated. Methods: A traditional two-dimensional (2D) system, a direct three-dimensional (3D) system, and an indirect 3D coculture system of LESCs and CSSCs were used to elucidate the paracrine pathway effect of CSSCs on LESCs. To reveal the impact of CSSC derived extracellular vesicles (CSSC-EVs) on LESCs, GW4869 and CSSC-EVs were added separately to the LESC culture medium. The outgrowth rate, cell density, differentiation, and stemness maintenance were compared among these methods. The miRNAs in the CSSC-EVs were sequenced, and the targeted Notch pathway was further confirmed by RT‒qPCR and Western blotting. Results: Compared with 2D culture, both the direct and indirect 3D coculture systems yielded a higher outgrowth rate and expression of stem cell markers of LESCs. The phenotypes of LESCs cultivated using the two coculture approaches were also comparable. Nevertheless, GW4869 inhibited the effect of CSSCs on LESCs, and the addition of CSSC-EVs to the 2D culture system could increase cell density, and the proportion of p63αbright cells, which indicated that CSSC-EVs were crucial in regulating LESCs. Furthermore, the EV-AlixKD with reduced miRNA partly lost its regulating function. The abundant miRNAs in CSSC-EVs, such as hsa-miR-663b, hsa-miR-16-5p, and hsa-miR-1290, target the Notch pathway. The LESCs transfected with miR-663b had higher p63 expression via downregulating of the Notch pathway. Conclusions: CSSC-EV played an important role in promoting LESC proliferation and stemness maintenance by targeting Notch signaling via miRNAs, which will increase our understanding of the limbal niche and provide a potential new approach for LESC culture and the treatment of corneal epithelial disorders.

Treatment options and prognosis of patients with lung squamous cell cancer in situ: a comparative study of lung adenocarcinoma in situ and stage IA lung squamous cell cancer.

Background: Lung squamous cell cancer in situ (LSCIS) is preinvasive squamous tumor and generally overlooked as a potential subtype of pathological and clinical significance, which has seldom been investigated systematically. This study sought to explore the clinical features, prognostic factors, and optimal treatments for LSCIS patients. Methods: Patients diagnosed with LSCIS (n=449), lung adenocarcinoma in situ (LAIS; n=1,132), stage IA lung squamous cell cancer (LSQCC; n=22,289) and stage IA lung adenocarcinoma (LUAD; n=68,523) were identified in the Surveillance Epidemiology and End Results (SEER) database. Additionally, 512 patients from the Shanghai Pulmonary Hospital diagnosed with LSCIS (n=34), LAIS (n=248), stage IA LSQCC (n=118) and stage IA LUAD (n=112) were included in the study. Kaplan-Meier survival curves were constructed, and Cox proportional hazards regression analyses were performed to examine the overall survival (OS), lung cancer-specific survival (LCSS), and progression-free survival (PFS) of the patients. Results: The univariate and multivariate analyses showed the patients with LSCIS had significantly worse survival than those with LAIS. Although, the univariate analysis revealed that the LSCIS patients had significantly worse OS and LCSS than the stage IA LSQCC patients, the multivariate analyses showed that the prognosis of the LSCIS was similar to that of the stage IA LSQCC in the SEER cohort. The prognosis of the LSCIS was similar to that of the stage IA LSQCC in the Shanghai Pulmonary Hospital cohort. The univariate and multivariate analyses showed that age (>70 years) and chemotherapy were negative prognostic factors, and surgery was a favorable prognostic factor for the LSCIS patients. The survival of the LSCIS patients who underwent local tumor destruction or excision was similar to that of those who did not receive surgery. Lobectomy was the surgical procedure associated with the highest OS and LCSS in LSCIS patients. Conclusions: The survivals of the LSCIS were similar to those of the stage IA LSQCC, but significantly worse than those of the LAIS. Surgery was an independent favorable prognostic factor for the LSCIS patients. Lobectomy was a superior choice of surgical procedure, and significantly improved the current outcomes of the LSCIS patients.

Rivaroxaban versus nadroparin for thromboprophylaxis following thoracic surgery for lung cancer: A randomized, noninferiority trial.

The benefit of rivaroxaban in thromboprophylaxis after oncologic lung surgery remains unknown. To evaluate the efficacy and safety of rivaroxaban, patients who underwent thoracic surgery for lung cancer were enrolled, and randomly assigned to rivaroxaban or nadroparin groups in a 1:1 ratio; anticoagulants were initiated 12-24 h after surgery and continued until discharge. Four hundred participants were required according to a noninferiority margin of 2%, assuming venous thromboembolism (VTE) occurrence rates of 6.0% and 12.6% for patients in the rivaroxaban and nadroparin groups, respectively. The primary efficacy outcome was any VTE during the treatment and 30-day follow-up periods. The safety outcome was any on-treatment bleeding event. Finally, 403 patients were randomized (intention-to-treat [ITT] population), with 381 included in per-protocol (PP) population. The primary efficacy outcomes occurred in 12.5% (25/200) of the rivaroxaban group and 17.7% (36/203) of the nadroparin group (absolute risk reduction, -5.2%; 95% confidence interval [CI], [-12.2-1.7]), indicating the noninferiority of rivaroxaban in ITT population. Sensitivity analysis was performed in the PP population and yielded similar results, confirming the noninferiority of rivaroxaban. In the safety analysis population, the incidence of any on-treatment bleeding events did not differ significantly between the groups (12.2% for rivaroxaban vs. 7.0% for nadroparin; relative risk [RR], 1.9; 95% CI, [0.9-3.7]; p = .08), including major bleeding (9.7% vs. 6.5%; RR, 1.6 [95% CI, 0.9-3.7]; p = .24), and nonmajor bleeding (2.6% vs. 0.5%; RR, 5.2 [95% CI, 0.6-45.2]; p = .13). Rivaroxaban for thromboprophylaxis after oncologic lung surgery was shown to be noninferior to nadroparin.

The development and validation of a circulating tumor cells-based integrated model for improving the indeterminate lung solid nodules diagnosis.

Background: There is a risk of over investigation and delayed treatment in the work up of solid nodules. Thus, the aim of our study was to develop and validate an integrated model that estimates the malignant risk for indeterminate pulmonary solid nodules (IPSNs). Methods: Patients included in this study with IPSNs who was diagnosed malignant or benign by histopathology. Univariate and multivariate logistic regression were used to build integrated model based on clinical, circulating tumor cells (CTCs) and radiomics features. The performance of the integrated model was estimated by applying receiver operating characteristic (ROC) analysis, and tested in different nodules size and intermediate risk IPSNs. Net reclassification index (NRI) was applied to quantify the additional benefit derived from the integrated model. Results: The integrated model yielded areas under the ROC curves (AUCs) of 0.83 and 0.76 in internal and external set, respectively, outperforming CTCs (0.70, P=0.001; 0.68, P=0.128), the Mayo clinical model (0.68, P<0.001; 0.55, P=0.007), the and radiomics model (0.72, P=0.002; 0.67, P=0.050) in both validation sets. Robust performance with high sensitivity up to 98% was also maintained in IPSNs with different solid size and intermediate risk probability. The performance of the integrated model was comparable with positron emission tomography/computed tomography (PET-CT) examination (P=0.308) among the participants with established PET-CT records. NRI demonstrated that the integrated model provided net reclassification of at least 10% on the external validation set compared with single CTCs test. Conclusions: The integrated model could complement conventional risk models to improve the diagnosis of IPSNs, which is not inferior to PET-CT and could help to guide clinician's decision-making on clinically specific population.

MicroRNAs of extracellular vesicles derived from mesenchymal stromal cells alleviate inflammation in dry eye disease by targeting the IRAK1/TAB2/NF-κB pathway.

PURPOSE: To investigate the efficacy and mechanisms of human umbilical cord-derived MSC-derived extracellular vesicles (hucMSC-EVs) in a mouse model of desiccation-induced dry eye disease (DED). METHODS: hucMSC-EVs were enriched by ultracentrifugation. The DED model was induced by desiccating environment combined with scopolamine administration. The DED mice were divided into the hucMSC-EVs group, fluorometholone (FML) group, PBS group, and blank control group. Tear secretion, corneal fluorescein staining, the cytokine profiles in tears and goblet cells, TUNEL-positive cell, and CD4+ cells were examined to assess therapeutic efficiency. The miRNAs in the hucMSC-EVs were sequenced, and the top 10 were used for miRNA enrichment analysis and annotation. The targeted DED-related signaling pathway was further verified by using RT‒qPCR and western blotting. RESULTS: Treatment with hucMSC-EVs increased the tear volume and maintained corneal integrity in DED mice. The cytokine profile in the tears of the hucMSC-EVs group presented with a lower level of proinflammatory cytokines than PBS group. Moreover, hucMSC-EVs treatment increased goblet cell density and inhibited cell apoptosis and CD4+ cell infiltration. Functional analysis of the top 10 miRNAs in hucMSC-EVs showed a high correlation with immunity. Among them, miR-125 b, let-7b, and miR-6873 were conserved between humans and mice and were associated with the IRAK1/TAB2/NF-κB pathway that was activated in DED. Furthermore, IRAK1/TAB2/NF-κB pathway activation and the abnormal expression of IL-4, IL-8, IL-10, IL-13, IL-17, and TNF-α were reversed by hucMSC-EVs. CONCLUSIONS: hucMSCs-EVs alleviate DED signs, suppress inflammation and restore homeostasis of the corneal surface by multitargeting the IRAK1/TAB2/NF-κB pathway via certain miRNAs.

Time-Course Transcriptomic Analysis Reveals the Crucial Roles of PANoptosis in Fungal Keratitis.

Purpose: Fungal keratitis (FK) is a serious corneal infection with high morbidity. Host immune responses function as a double-edged sword by eradicating fungal pathogens while also causing corneal damage, dictating the severity, progression, and outcome of FK. However, the underlying immunopathogenesis remains elusive. Methods: Time-course transcriptome was performed to illustrate the dynamic immune landscape in a mouse model of FK. Integrated bioinformatic analyses included identification of differentially expressed genes, time series clustering, Gene Ontology enrichment, and inference of infiltrating immune cells. Gene expression was verified by quantitative polymerase chain reaction (qPCR), Western blot, or immunohistochemistry. Results: FK mice exhibited dynamic immune responses with concerted trends with clinical score, transcriptional alteration, and immune cell infiltration score peaking at 3 days post infection (dpi). Disrupted substrate metabolism, broad immune activation, and corneal wound healing occurred sequentially in early, middle, and late stages of FK. Meanwhile, dynamics of infiltrating innate and adaptive immune cells displayed distinct characteristics. Proportions of dendritic cells showed overall decreasing trend with fungal infection, whereas that of macrophages, monocytes, and neutrophils rose sharply in early stage and then gradually decreased as inflammation resolved. Activation of adaptive immune cells was also observed in late stage of infection. Furthermore, shared immune responses and activation of AIM2-, pyrin-, and ZBP1-mediated PANoptosis were revealed across different time points. Conclusions: Our study profiles the dynamic immune landscape and highlights the crucial roles of PANoptosis in FK pathogenesis. These findings provide novel insights into host responses to fungi and contribute to the development of PANoptosis-targeted therapeutics for patients with FK.

SLAMF7/STAT6 Pathway Inhibits Innate Immune Response in Late-Stage Human Acanthamoeba Keratitis: A Comparative Transcriptome Analysis.

Acanthamoeba keratitis (AK) is a blinding corneal infection caused by the protozoan Acanthamoeba. The long-term course of AK suggests the host immunity could not kill Acanthamoeba rapidly. The immune status is still unclear in the late stage of AK. The comparative transcriptome analysis was made based on the bulk RNA sequencing of cornea tissues from AK patients and donors. Differentially expressed genes and enriched signaling pathways were calculated. CIBERSORT algorithm was used for immune infiltration analysis of cornea tissue between AK and normal controls. A total of 2668 differentially expressed genes, including 1477 upregulated genes and 1191 downregulated genes, were detected. Gene Ontology analysis revealed that the pathways were significantly enriched in leukocyte migration, regulation of T-cell activation, the external side of plasma membrane, collagen-containing extracellular matrix, immune receptor activity, and cytokine binding. The Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the pathways were significantly enriched in the cytokine-cytokine receptor interaction, hematopoietic cell lineage, and Staphylococcus aureus infection pathway. The immune infiltration profiles varied little between AK and normal controls. Compared with normal tissue, cornea tissue of AK contained a higher proportion of M0 macrophages and CD8 T cells, while resting memory CD4 T cells contributed to a relatively lower portion (p < 0.05). Finally, the expression levels of cell markers and SLAMF7/STAT6 pathway were confirmed by histopathology examinations, RT-qPCR, and Western blot.

Single planar photonic chip with tailored angular transmission for multiple-order analog spatial differentiator.

Analog spatial differentiation is used to realize edge-based enhancement, which plays an important role in data compression, microscopy, and computer vision applications. Here, a planar chip made from dielectric multilayers is proposed to operate as both first- and second-order spatial differentiator without any need to change the structural parameters. Third- and fourth-order differentiations that have never been realized before, are also experimentally demonstrated with this chip. A theoretical analysis is proposed to explain the experimental results, which furtherly reveals that more differentiations can be achieved. Taking advantages of its differentiation capability, when this chip is incorporated into conventional imaging systems as a substrate, it enhances the edges of features in optical amplitude and phase images, thus expanding the functions of standard microscopes. This planar chip offers the advantages of a thin form factor and a multifunctional wave-based analogue computing ability, which will bring opportunities in optical imaging and computing.

Clinicopathologic characteristics and prognostic impact of atypical EGFR mutations in completely resected lung adenocarcinoma.

INTRODUCTION: This study evaluated the clinicopathologic characteristics and prognostic impact of atypical epidermal growth factor receptor (EGFR) mutations in patients with completely resected lung adenocarcinoma (LUAD) and investigate whether adjuvant chemotherapy could benefit the survival outcomes for these subjects. MATERIAL AND METHODS: We retrospectively reviewed resected LUAD samples from 8437 patients and identified 5358 EGFR-mutated (EGFRm) cases. Of these, 4847 had classical mutations, while 511 had atypical mutations. For further survival analysis, propensity score matching, Kaplan-Meier curve, and Cox regression analyses were conducted. RESULTS: Of the 511 patients with atypical EGFRm LUAD, 131 patients had compound mutations. The frequency of exon 20 insertion (20-ins), G719X, L861Q, S768I, and de novo T790M were 30.3%, 32.7%, 21.9%, 9.2%, and 11.4%, respectively. These patients included a higher proportion of males than those with classical EGFRm LUAD. Between the 483 matched pairs of the classical and atypical EGFRm patients, no significant difference emerged in disease-free survival (DFS) (p = 0.476). Patients with the L861Q mutation had the poorest DFS among those with atypical EGFRm LUAD (p = 0.005). Cox regression analyses revealed that the L861Q mutation was an independent prognostic factor for DFS in 487 patients with solely atypical EGFRm LUAD. In addition, adjuvant chemotherapy did not improve the DFS for those patients, whether in stage IB (p = 0.638) or II-III (p = 0.505) of the disease. CONCLUSION: The L861Q mutation is an independent prognostic factor for DFS in patients with atypical EGFRm LUAD after complete resection who would not benefit from adjuvant chemotherapy regardless of disease stage.

Significance of the Expression of TC and TG Levels in the Initial Diagnosis and Treatment of SCLC Patients and Their Tie-In with Prognosis.

The article examines the expression of TC and TG levels in the initial diagnosis and treatment of SCLC patients and their tie-in with prognosis. Patients with SCLC are included in the case set, who are initially treated in the tumor center of our hospital from January 2020 to January 2021 and are confirmed by histopathology or cytology as the research subjects. 80 healthy volunteers are included in the control set, who received physical examination. All the enrolled patients received the first-line standard treatment plan, and the clinical data of all SCLC patients are inquired through the medical record file system of the hospital. At the initial diagnosis and treatment, the TG and TC levels of all patients and healthy persons are measured and recorded by blood biochemistry. For SCLC patients, the risk factors affecting the prognosis of patients with progression-free survival include newly diagnosed TC, TG levels, and tumor stage. Combined TC and TG detection can be used as indicators to predict the prognosis of the patients. TC and TG are significantly correlated with the prognosis of the patients with progression-free survival time. It is worthy of clinical application.

Dry Eye Disease in Patients With Schizophrenia: A Case-Control Study.

OBJECTIVE: To evaluate the clinical features and inflammatory cytokines of dry eye disease (DED) in patients with schizophrenia. METHODS: This is a case-control study. The modified self-rating depression scale (M-SDS) and the ocular surface disease index (OSDI) were used to evaluate the symptoms of depression and DED, respectively. Lipid layer thickness (LLT), partial blink rate (PBR), meibomian gland loss (MGL), tear break-up time (TBUT), corneal fluorescein staining, Schirmer I-test, and eyelid margin abnormalities were also measured. A multiplex ELISA Quantibody array was used to detect the inflammatory cytokines in the tears of all participants. RESULTS: Forty schizophrenic patients and 20 control subjects were included. The mean age was 45.0 ± 9.5 years (range, 22-63 years) in schizophrenic patients and 45.4 ± 16.2 years (range, 23-76 years) in controls (P = 0.914). The ratio of male to female was 1.1 in schizophrenic patients and 1.0 in controls (P = 0.914). Ten women (52.6%) with schizophrenia and 2 (20%) in the control group (P = 0.096) were menopausal or post-menopausal. The OSDI [0.0 (0.0-4.2) vs. 7.3 (2.1-14.6)] and TBUT [4.5 (3.0-6.0) vs. 10.0 (3.5-11.0)] were significantly lower in patients with schizophrenia than in controls (P = 0.003 and P = 0.009, respectively). The rate of MGL [36.5 (17.5-47.5) vs. 8.5 (0.0-17.5)] increased in schizophrenic patients (P < 0.001). Among pro-inflammatory cytokines, the levels of interleukin (IL)-1α, IL-6, IL-11, IL-12A, IL-15, IL-17A, and granulocyte colony-stimulating factor (G-CSF) in tears were elevated in the schizophrenia group (all P < 0.01). Most of the chemokines examined were at increased levels in the tears of schizophrenics (all P < 0.05). The levels of matrix metalloproteinases-9 (MMP-9) and intercellular adhesion molecule-1 (ICAM-1) were also higher in the schizophrenic patients (all P < 0.001). The concentrations of IL-1Ra, tissue-inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2 in the schizophrenia group were decreased (all P < 0.001). In schizophrenic patients, the level of CCL2 in tears was positively correlated with OSDI (R = 0.34, P = 0.03). The increasing TIMP-1 and decreasing IL-5 were correlated with increasing LLT (R = 0.33, P = 0.035; R = -0.35, P = 0.027, respectively). The level of ICAM-1 was then positively correlated with partial blink rate (PBR) (R = 0.33, P = 0.035). There was a negative correlation between IL-8 and the Schirmer I-test (R = -0.41, P = 0.009). CONCLUSIONS: Patients with schizophrenia were more likely to experience asymptomatic DED, with mild symptoms and obvious signs. The inflammatory cytokines in the tears of schizophrenic patients differed greatly from that of non-schizophrenic patients.

Prognostic and predictive value of the newly proposed grading system of invasive pulmonary adenocarcinoma in Chinese patients: a retrospective multicohort study.

Our aim was to validate and analyze the prognostic impact of the novel International Association for the Study of Lung Cancer (IASLC) Pathology Committee grading system for invasive pulmonary adenocarcinomas (IPAs) in Chinese patients and to evaluate its utility in predicting a survival benefit from adjuvant chemotherapy (ACT). In this multicenter, retrospective, cohort study, we included 926 Chinese patients with completely resected stage I IPAs and classified them into three groups (Grade 1, n = 119; Grade 2, n = 431; Grade 3, n = 376) according to the new grading system proposed by the IASLC. Recurrence-free survival (RFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and prognostic factors were assessed using univariable and multivariable Cox proportional hazards models. All included cohorts were well stratified in terms of RFS and OS by the novel grading system. Furthermore, the proposed grading system was found to be independently associated with recurrence and death in the multivariable analysis. Among patients with stage IB IPA (N = 490), the proposed grading system identified patients who could benefit from ACT but who were undergraded by the adenocarcinoma (ADC) classification. The novel grading system not only demonstrated prognostic significance in stage I IPA in a multicenter Chinese cohort but also offered clinical value for directing therapeutic decisions regarding adjuvant chemotherapy.

Lymphocyte activation gene-3 is associated with programmed death-ligand 1 and programmed cell death protein 1 in small cell lung cancer.

BACKGROUND: In recent years, immunotherapy has achieved notable success in cancer treatment. Indeed, the novel immune checkpoint lymphocyte activation gene-3 (LAG3) has shown promising therapeutic efficacy in non-small cell lung cancer. However, it is unclear about the role of LAG3 in immunotherapy and survival in small cell lung cancer (SCLC). METHODS: The expression of LAG3 in SCLC was evaluated in four public datasets. The association of LAG3 with programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), and overall survival (OS) was investigated. The LAG3-related biological processes and pathways were identified by functional analyses. RESULTS: LAG3 expression was detected in SCLC tumor tissues. In the cBioPortal dataset with 81 clinical SCLC samples, LAG3 expression was markedly associated with PD-1 and PD-L1 expression (both P<0.050). In addition, Patients with high LAG3 expression had a trend toward a better OS (P=0.073). A similar survival trend was also observed in the GSE60052 dataset. Significantly, LAG3 expression was related to immune-related biological processes, such as immune response, antigen processing and presentation, and T cell co-stimulation (all P<0.001). CONCLUSIONS: This study demonstrated that LAG3 is an important immune checkpoint that is closely associated with PD-1/PD-L1. LAG3 may be a promising novel immunotherapy target for SCLC.