Since November 2021, Omicron has emerged as the dominant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, and its sublineages continue to appear one after another, significantly reducing the effectiveness of existing therapeutic neutralizing antibodies (NAbs). It is urgent to develop effective NAbs against circulating Omicron variants. Here, we isolated receptor binding domain (RBD)-specific single memory B cells via flow cytometry from a COVID-19 convalescent. The antibody variable region genes of the heavy chain (VHs) and light chain (VLs) were amplified and cloned into expression vectors. After antibody expression, ELISA screening and neutralizing activity detection, we obtained an IGHV3-53-encoded RBD-targeting cross-neutralizing antibody D6, whose VL originated from the IGKV1-9*01 germlines. D6 could potently neutralize circulating Omicron variants (BA.1, BA.2, BA.4/5 and BF.7), with IC50 values of less than 0.04 µg/mL, and the neutralizing ability against XBB was reduced but still effective. The KD values of D6 binding with RBD of the prototype and BA.1 were both less than 1.0 × 10-12 M. The protein structure of the D6-RBD model indicates that D6 interacts with the RBD external subdomain and belongs to the RBD-1 community. The sufficient contact and deep interaction of D6 HCDR3 and LCDR3 with RBD may be the crucial reason for its cross-neutralizing activity. The sorting and analysis of mAb D6 will provide important information for the development of anti-COVID-19 reagents.
INTRODUCTION: Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) has been increasingly replaced by bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in the treatment of human immunodeficiency virus (HIV) owing to its more favorable pharmacokinetics and fewer drug-drug interactions. However, the effect of this switch on plasma lipids and lipidomic profiles remains poorly characterized. METHODS: HIV infected patients on an E/C/F/TAF regimen were recruited into the study and followed up every 12 weeks. Participants were divided into E/C/F/TAF and B/F/TAF groups depending on whether they were switched to B/F/TAF during follow-up. Clinical information and blood samples were collected at 0, 12, and 24 weeks, and lipidomic analysis was performed using liquid chromatography mass spectrometry. RESULTS: No significant differences were observed between the groups at baseline. At week 24, patients switched to B/F/TAF had lower triglyceride [mmol/L; 1.23 (0.62) versus 2.03 (0.75), P = 0.001] and very low-density lipoprotein cholesterol [mmol/L; 0.64 (0.26) versus 0.84 (0.32), P = 0.037) compared with patients who continued E/C/F/TAF therapy. Small decrease from baseline in Framingham general cardiovascular risk score (FRS) was observed in the B/F/TAF arm [week (W) 0: 2.59 (1.57) versus W24: 2.18 (1.01), P = 0.043]. Lipidomic analysis indicated that E/C/F/TAF treatment increased the levels of several diglycerides (DGs), triacylglycerols (TAGs), and lyso-phosphatidylcholines (LPCs), whereas switching to B/F/TAF led to increased sphingolipids and glycerophospholipids. After adjusting for demographic and clinical parameters, only DG (16:0/18:2), DG (18:2/22:6), DG (18:3/18:2), DG (20:5/18:2), TAG (18:3/18:2/21:5), TAG (20:5/18:2/22:6), and LPC (22:6) were found to be significantly associated with FRS (regression coefficient of 0.17-6.02, P < 0.05). Most of these FRS associate lipid species were significantly elevated in individuals treated with E/C/F/TAF instead of individuals treated with B/F/TAF. CONCLUSION: E/C/F/TAF promotes the accumulation of lipid species closely associated with cardiovascular disease (CVD) risk among people living with HIV, whereas B/F/TAF has a decreased impact on CVD-related lipid profile and is associated with lower CVD risk. A graphical abstract is available with this article. TRIAL REGISTRATION: ClinicalTrials.gov; identifier, NCT06019273.
Background: Some studies of dual-targeted therapy (DTT) targeting epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET) have shown promising efficacy in non-small-cell lung cancer (NSCLC). Consequently, patient management following DTT resistance has gained significance. However, the underlying resistance mechanisms and clinical outcomes in these patients remain unclear. Objectives: This study aimed to delineate the molecular characteristics and survival outcomes of patients with NSCLC harboring EGFR mutations and acquired MET amplification after developing resistance to DTT. Design: We conducted a retrospective analysis of patients with NSCLC with EGFR mutations and acquired MET amplification who exhibited resistance to EGFR/MET DTT. Methods: Next-generation sequencing (NGS) was performed on patients with available tissue samples before and/or after the development of resistance to DTT. Stratified analyses were carried out based on data sources and subsequent salvage treatments. Univariate/multivariate Cox regression models and survival analyses were employed to explore potential independent prognostic factors. Results: The study included 77 NSCLC patients, with NGS conducted on 19 patients. We observed many resistance mechanisms, including EGFR-dependent pathways (4/19, 21.1%), MET-dependent pathways (2/19, 10.5%), EGFR/MET co-dependent pathways (2/19, 10.5%), and EGFR/MET-independent resistance mechanisms (11/19, 57.9%). Post-progression progression-free survival (pPFS) and post-progression overall survival (pOS) significantly varied among patients who received the best supportive care (BSC), targeted therapy, or chemotherapy (CT), with median pPFS of 1.5, 3.9, and 4.9 months, respectively (p = 0.003). Median pOS were 2.3, 7.7, and 9.2 months, respectively (p < 0.001). The number of treatment lines following DTT resistance and the Eastern Cooperative Oncology Group performance status emerged as the independent prognostic factors. Conclusion: This study revealed a heterogeneous landscape of resistance mechanisms to EGFR/MET DTT, with a similar prevalence of on- and off-target mechanisms. Targeted therapy or CT, as compared to BSC, exhibited the potential to improve survival outcomes for patients with advanced NSCLC following resistance to DTT.
Background: Mesenchymal-epithelial transition (MET) amplification is a crucial oncogenic driver and a resistance mechanism to epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) of non-small-cell lung cancer (NSCLC). Fluorescence in situ hybridization (FISH) is the gold standard for MET amplification detection. However, it is inapplicable when tissue samples are unavailable. Objective: This study assessed the performance of plasma droplet digital polymerase chain reaction (ddPCR) in MET amplification detection in NSCLC patients. Design and methods: A total of 87 NSCLC patients were enrolled, and 94 paired tissue and plasma samples were analyzed for the concordance between FISH and plasma ddPCR/tissue next-generation sequencing (NGS) in detecting MET amplification. In addition, the efficacy of patients with MET amplification using different detection methods who were treated with MET-TKIs was evaluated. Results: Plasma ddPCR showed substantial concordance with FISH (74.1% sensitivity, 92.5% specificity, and 87.2% accuracy with a kappa value of 0.68) and outperformed tissue NGS (kappa value of 0.64) in MET amplification detection. Combined plasma ddPCR and tissue NGS showed substantial concordance with FISH (92.3% sensitivity, 89.2% specificity, and an accuracy of 90.1% with a kappa value of 0.77). The efficacy is comparable in these NSCLC patients with MET amplification detected by FISH and plasma ddPCR who were treated with MET-TKIs. Conclusion: Plasma ddPCR is a potentially reliable method for detecting MET amplification in advanced NSCLC patients. Combined plasma ddPCR and tissue NGS might be an alternative or complementary method to MET amplification detection.
Nano-particles possess desirable attributes such as small particle size, excellent injectivity, and migration performance, making them highly compatible and adaptable for addressing the water flooding requirements of the low-permeability oil reservoir. When selecting an oil displacement agent for enhancing water flooding and improving oil recovery, factors such as injectivity and migration need to be carefully considered. In this study, through a comprehensive analysis of the mechanism and technical characteristics of nano-particle oil displacement agents, the plugging and profile control mechanisms recognized by the mainstream of nano-particles are elucidated. By examining various elements including outcrop fractures, natural micro-fractures, artificial support fractures, and dynamic monitoring data, a reevaluation of the dominant channel scale governing water drive in low permeability reservoirs is conducted, thereby defining the target entities for profile control and flooding operations. Drawing upon Darcy's percolation law and leveraging enhanced oil recovery techniques based on the classical Kozeny equation, a profile control and flooding mechanism is proposed that focuses on increasing the specific surface area of polymer particles while simultaneously reducing reservoir permeability. This innovative approach establishes a novel matching method between nano-polymer particles and the diverse media found within the reservoir. Lastly, the application of nanoparticle flooding technology in Changqing Oilfield is presented, highlighting its practical implementation and benefits.
Pyroptosis is a new form of programmed cell death recognized as crucial in developing sepsis. However, there is limited research on the mechanism of pyroptosis-related genes in sepsis-related from the Gene Expression Omnibus (GEO) database and standardized. The expression levels of pyroptosis-related genes were extracted, and differential expression analysis was conducted. A prediction model was constructed using random forest (RF), support vector machine (SVM), weighted gene co-expression new analysis (WGCNA), and nomogram techniques to assess the risk of sepsis. The relationship between pyroptosis-related subgroups and the immune microenvironment and inflammatory factors was studied using consistent clustering algorithms, principal component analysis (PCA), single-sample genomic enrichment analysis (ssGSEA), and immune infiltration. A risk prediction model based on 3 PRGs has been constructed and can effectively predict the risk of sepsis. Patients with sepsis can be divided into two completely different subtypes of pyroptosis-related clusters. Cluster B is highly correlated with the lower proportion of Th17 celld and has lower levels of expression of inflammatory factors. This study utilizes mechanical learning methods to further investigate the pathogenesis of sepsis, explore potential biomarkers, provide effective molecular targets for its diagnosis and treatment of sepsis.
Pyroptosis , Sepsis , Humans , Pyroptosis/genetics , Sepsis/diagnosis , Sepsis/genetics , Apoptosis , Algorithms , Cluster Analysis
Vaccination has proven to be highly effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the long-term immunogenicity and the functional preserved immune responses of vaccines are needed to inform evolving evidence-based guidelines for boosting schedules. We enrolled 205 healthcare workers into a cohort study; all had received three doses of BBIBP-CorV (China Sinopharm Bio-Beijing Company, Beijing, China) inactivated vaccine. We assessed SARS-CoV-2 specific binding antibodies, neutralizing antibodies, and peripheral T and B cell responses. We demonstrated that more robust antibody responses to SARS-CoV-2 were elicited by booster immunization compared with primary vaccination. Neutralizing antibody titers to SARS-CoV-2 Omicron BA.1 were also efficiently elevated post-homologous vaccine booster despite being in a lower titer compared with the prototype stain. In addition to S-specific humoral and cellular immunity, BBIBP-CorV also induced N-specific antibody and effector T cell responses. The third-dose vaccination led to further expansion of critical polyfunctional T cell responses, likely an essential element for vaccine protection. In particular, a functional role for Tfh cell subsets in immunity was suggested by the correlation between both CD4+ Tfh and CD8+ Tfh with total antibody, IgG, B cell responses, and neutralizing antibodies. Our study details the humoral and cellular responses generated by the BBIBP-CorV booster vaccination in a seven-month follow-up study. There is a clear immunologic boosting value of homologous inactivated SARS-CoV-2 vaccine boosters, a consideration for future vaccine strategies.
Introduction: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been posing a severe threat to global public health. Although broadly neutralizing antibodies have been used to prevent or treat corona virus disease 2019 (COVID-19), new emerging variants have been proven resistant to these antibodies. Methods: In this study, we isolated receptor binding domain (RBD)-specific memory B cells using single-cell sorting method from two COVID-19 convalescents and expressed the antibody to test their neutralizing activity against diverse SARS-CoV-2 variants. Then, we resolved antibody-RBD complex structures of potent RBD-specific neutralizing antibodies by X-ray diffraction method. Finally, we analyzed the whole antibody repertoires of the two donors and studied the evolutionary pathway of potent neutralizing antibodies. Results and discussion: We identified three potent RBD-specific neutralizing antibodies (1D7, 3G10 and 3C11) from two COVID-19 convalescents that neutralized authentic SARS-CoV-2 WH-1 and Delta variant, and one of them, 1D7, presented broadly neutralizing activity against WH-1, Beta, Gamma, Delta and Omicron authentic viruses. The resolved antibody-RBD complex structures of two antibodies, 3G10 and 3C11, indicate that both of them interact with the external subdomain of the RBD and that they belong to the RBD-1 and RBD-4 communities, respectively. From the antibody repertoire analysis, we found that the CDR3 frequencies of the light chain, which shared high degrees of amino acid identity with these three antibodies, were higher than those of the heavy chain. This research will contribute to the development of RBD-specific antibody-based drugs and immunogens against multiple variants.
COVID-19 , SARS-CoV-2 , Humans , Broadly Neutralizing Antibodies , Antibodies, Neutralizing
The low oil recovery rate observed in current oil fields is largely attributed to the presence of remaining oil trapped in the pores of porous media during waterflooding. To improve the recovery rate, it is imperative to gain an understanding of the oil-water flow characteristics and displacement mechanisms during waterflooding, as well as to elucidate the underlying mobilization mechanisms of residual oil at the pore scale. In this paper, we explore these issues in depth by numerically investigating the influence of factors such as water injection velocities, oil-water viscosity ratios, and wettability conditions on pore-scale oil-water flow characteristics and oil recovery rate. To this end, we employ a direct numerical simulation (DNS) method in conjunction with the volume of fluid (VOF) method to study the microscopic displacement mechanisms of waterflooding in a reconstructed two-dimensional digital rock core based on micro-CT technology. In addition, the particle tracing method is adopted to identify the flow path and dominant areas during waterflooding in order to mobilize the residual oil within the pores. The findings indicate that the oil-water flow characteristics in porous media are determined by the interplay between capillary and viscous forces. Furthermore, the oil recovery rate is 10.6% and 24.7% lower under strong water-wet and oil-wet conditions than that (32.36%) under intermediate wettability conditions, and the final oil recovery rate is higher under water-wet conditions than under oil-wet conditions. The seepage path and the dominant areas are directly linked to the capillarity formed during waterflooding. The findings of this study are significant in terms of enhancing the recovery rate of residual oil and provide a novel perspective for understanding the waterflooding process.
BACKGROUND: Patients infected with HIV are at high risk of developing Epstein-Barr Virus (EBV)-related diseases. The genotype and viral biological behavior of EBV infection in patients with human immunodeficiency virus-1 (HIV) in China remain unclear. This study analyzed the characteristics of EBV in patients infected with HIV in southeastern China. METHODS: A total of 162 HIV-infected patients and 52 patients without HIV were enrolled in this study. EBV viral load in blood was determined by fluorescence quantitative PCR. EBV typing was performed using saliva according to polymorphisms in the EBNA3C region. EBV LMP-1 carboxy terminus (C-ter) was sequenced, and compared with the epidemic strains in the world. RESULTS: Among HIV infected patients, the EBV strain variant was mainly EBV-1, while EBV-2 had a higher viral load than EBV-1 (P = 0.001) and EBV-1/2 (P = 0.002). HIV infected patients had higher active virus replication. The EBV LMP-1 variants were mainly the China1 variant. HIV-infected patients had different nucleic acid positions of 30-bp deletion (del30) and had a higher incidence of high 33-bp tandem repeats (rep33) copies than non-HIV-infected patients. There was a difference in the mutations of EBV LMP-1 C-ter del30 and ins15 between HIV infected patients and the control group (P < 0.001). CONCLUSION: In southeastern China, EBV in HIV-infected patients had higher active virus replication; EBV infection was mainly EBV-1, and EBV-2 infection has higher EBV virus load; hotspot mutations of LMP-1 C-ter were different between HIV-infected patients and non-HIV-infected patients. TRIAL REGISTRATION: This study was approved by the ethics committee of the First Affiliated Hospital of Zhejiang University School of Medicine (Approval No. 2018764), and registered in Chinese Clinical Trial Registry on 3 June 2019 (ChiCTR, ChiCTR1900023600, http://www.chictr.org.cn/usercenter.aspx ).
Epstein-Barr Virus Infections , HIV Infections , HIV-1 , Humans , Herpesvirus 4, Human/genetics , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/epidemiology , Epstein-Barr Virus Infections/genetics , Base Sequence , HIV-1/genetics , China/epidemiology , HIV Infections/complications , HIV Infections/epidemiology , DNA, Viral/genetics
BACKGROUND: For patients with lung malignancies with RET rearrangement, the efficacy of immune checkpoint inhibitors is limited. The characteristics of the tumour immune microenvironment (TIME) and molecular pathological features of these patients have not been well elucidated. We aimed to investigate their clinical outcomes and explore characteristics of TIME, using multiplex immunohistochemistry technology (mIHC). PATIENTS AND METHODS: The pathology and TIME characteristics of 29 patients with lung malignancies with RET rearrangement were retrospectively analysed, and their relationships with clinical efficacy and prognosis were investigated. Gene detection relied on high-throughput sequencing, and TIME detection was based on mIHC. RESULTS: Of 29 patients, 25(86%) had adenocarcinoma, and the acinar type accounted for the greatest percentage of patients, followed by the solid type, regardless of whether the disease was early or locally advanced and metastatic. In addition, we report a novel KIF5B-RET(k24:R8) rearrangement in pulmonary sarcoma. The density of CD8+ T cells in tumour stroma in early-stage patients was significantly higher than that in locally advanced and metastatic patients (P = 0.014). The proportion of M2 macrophages in tumour stroma was significantly higher than that in tumour parenchyma (P = 0.046). Although the difference was not statistically significant (P = 0.098), patients positive for M2 macrophage infiltration into the tumour parenchyma (≥5%) may have a better prognosis. Seven patients received immunotherapy and disease control rate was 85.7%. CONCLUSIONS: A novel KIF5B-RET rearrangement variant in pulmonary sarcoma shows similar TIME characteristics to lung cancer. amongst patients with lung malignancies with RET rearrangement, patients with M2 macrophage infiltration into the tumour parenchyma may have a better prognosis, but further studies with larger cohorts are needed.
Adenocarcinoma , Lung Neoplasms , Proto-Oncogene Proteins c-ret , Sarcoma , Humans , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Proto-Oncogene Proteins c-ret/genetics , Retrospective Studies , Sarcoma/genetics , Sarcoma/pathology , Tumor Microenvironment
Hepatocellular carcinoma (HCC) is the most common type of liver cancer with a high morbidity and fatality rate. Traditional diagnostic methods for HCC are primarily based on clinical presentation, imaging features, and histopathology. With the rapid development of artificial intelligence (AI), which is increasingly used in the diagnosis, treatment, and prognosis prediction of HCC, an automated approach to HCC status classification is promising. AI integrates labeled clinical data, trains on new data of the same type, and performs interpretation tasks. Several studies have shown that AI techniques can help clinicians and radiologists be more efficient and reduce the misdiagnosis rate. However, the coverage of AI technologies leads to difficulty in which the type of AI technology is preferred to choose for a given problem and situation. Solving this concern, it can significantly reduce the time required to determine the required healthcare approach and provide more precise and personalized solutions for different problems. In our review of research work, we summarize existing research works, compare and classify the main results of these according to the specified data, information, knowledge, wisdom (DIKW) framework.
OBJECTIVES: De novo mesenchymal-to-epithelial transition (MET) gene fusions in non-small cell lung cancer (NSCLC) are a promising target for MET tyrosine kinase inhibitors (TKIs). We aimed to examine the response to targeted therapy with MET TKIs and resistance mechanisms in de novo MET fusion-positive NSCLC as these have not been comprehensively explored. MATERIALS AND METHODS: We examined the MET fusions in 4,429 patients with advanced-stage NSCLC using targeted next-generation sequencing and validated the results using RT-PCR. We analyzed cellular models harboring MET fusions and established a patient-derived organoid (PDO) model. RESULTS: We identified 13 (0.29 %, 13/4429) patients with de novo MET fusions and found EPHB4, THAP5, TNPO3, and DST as novel MET fusion partners. The most common concomitant gene with MET fusions was TP53 mutations. Among 12 patients receiving MET TKI treatment, two achieved stable disease, six achieved partial response, and four underwent progressive disease. An in vitro study showed that EPHB4-MET is a functional driver gene. MET inhibitors significantly inhibited the proliferation and phosphorylation of downstream STAT3, AKT, and ERK1/2 in EPHB4-MET overexpressing cells. Acquired MET D1228H/N or D1246N mutations were found in patients harboring MET fusions after acquiring resistance to MET TKIs. Tivantinib showed optimal suppression efficacy in a PDO model with an acquired MET D1228N mutation. CONCLUSION: MET fusions occur in a rare subset of patients with NSCLC and represent a promising therapeutic target. MET secondary mutations D1228H/N or D1246N present the potential resistance mechanisms of MET inhibitors in patients with de novo MET fusions.
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , ErbB Receptors/genetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Drug Resistance, Neoplasm/genetics , Mutation , Receptor Protein-Tyrosine Kinases/genetics , beta Karyopherins/genetics
Predicting the clinical response to chemotherapeutic or targeted treatment in patients with locally advanced or metastatic lung cancer requires an accurate and affordable tool. Tumor organoids are a potential approach in precision medicine for predicting the clinical response to treatment. However, their clinical application in lung cancer has rarely been reported because of the difficulty in generating pure tumor organoids. In this study, we have generated 214 cancer organoids from 107 patients, of which 212 are lung cancer organoids (LCOs), primarily derived from malignant serous effusions. LCO-based drug sensitivity tests (LCO-DSTs) for chemotherapy and targeted therapy have been performed in a real-world study to predict the clinical response to the respective treatment. LCO-DSTs accurately predict the clinical response to treatment in this cohort of patients with advanced lung cancer. In conclusion, LCO-DST is a promising precision medicine tool in treating of advanced lung cancer.
Lung Neoplasms , Humans , Lung Neoplasms/drug therapy , Precision Medicine , Organoids/pathology
OBJECTIVES: Transformed small-cell lung cancer (T-SCLC) has an extremely poor prognosis, and no remedies based on immunotherapy have been evaluated among T-SCLC patients. We retrospectively analysed the efficacy and safety of combining atezolizumab with chemotherapy for T-SCLC. METHODS: Forty-seven patients harbouring EGFR mutations who developed T-SCLC were enrolled. Eleven patients who used immunotherapy were defined as the I/O group, and the remaining 36 were defined as the Non-I/O group. Clinical characteristics, pathological data, and survival outcomes were collected. RNA sequencing and whole-exome sequencing (WES) were performed for in-depth analysis. RESULTS: All patients received at least one line of EGFR-TKI before rebiopsy to confirm T-SCLC. Nine patients received atezolizumab-bevacizumab-carboplatin-paclitaxel (albumin-bound) (ABCP), and the remaining 2 received atezolizumab-etoposide-carboplatin (ECT) in the I/O group. The objective response rate was 73 % (8/11). The median progression-free survival (mPFS) of T-SCLC on post-transformation therapy with I/O group and Non-I/O group was 5.1 m and 4.1 m, respectively. The median post-T-SCLC overall survival of the I/O group was significantly longer than that Non-I/O group (20.2 m vs 7.9 m, P ï¼ 0.01). T-SCLC harbouring EGFR L858R tended to be longer than EGFR 19del (mPFS: not reached vs 3.7 m, P = 0.11). Positive PD-L1 status was also associated with PFS benefits (mPFS: 6.0 m vs 3.7 m, P = 0.20). Furthermore, RNA sequencing revealed that expression of SFTPA1 is significantly higher in the durable clinical benefit group. WES showed that STC2 mutation is more frequently observed at the time-point immunotherapy acquired resistance. Combination therapy based on a PD-L1 inhibitor was well tolerated, and the safety profile was consistent with previously reported studies. CONCLUSION: Our study first demonstrated that a PD-L1 inhibitor combined with chemotherapy ± bevacizumab could be a potential safe option for specific SCLC-transformed patients. Subsequent studies with more patients are essential to verify the efficacy and potential biomarkers.
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Carboplatin , Bevacizumab/therapeutic use , Immune Checkpoint Inhibitors/therapeutic use , Retrospective Studies , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/genetics , ErbB Receptors
Backgrounds: Neutrophil extracellular traps (NETs) play an important role in the occurrence, metastasis, and immune escape of cancers. We aim to investigate Long non-coding RNAs (lncRNAs) that are correlated to NETs to find some potentially useful biomarkers for lung adenocarcinoma (LUAD), and to explore their correlations with immunotherapy and chemotherapy, as well as the tumor microenvironment. Methods: Based on the The Cancer Genome Atlas (TCGA) database, we identified the prognosis-related lncRNAs which are associated with NETs using cox regression. The patients were then separated into two clusters based on the expression of NETs-associated lncRNAs to perform tumor microenvironment analysis and immune-checkpoint analysis. Least absolute shrinkage and selection operator (LASSO) regression was then performed to establish a prognostic signature. Furthermore, nomogram analysis, tumor mutation burden analysis, immune infiltration analysis, as well as drug sensitivity analysis were performed to test the signature. Results: Using univariate cox regression, we found 10 NETs-associated lncRNAs that are associated with the outcomes of LUAD patients. Also, further analysis which separated the patients into 2 clusters showed that the 10 lncRNAs had significant correlations with the tumor microenvironment. Using LASSO regression, we finally constructed a signature to predict the outcomes of the patients based on 4 NETs-associated lncRNAs. The 4 NETs-associated lncRNAs were namely SIRLNT, AL365181.3, FAM83A-AS1, and AJ003147.2. Using Kaplan-Meier (K-M) analysis, we found that the risk model was strongly associated with the survival outcomes of the patients both in the training group and in the validation group 1 and 2 (p < 0.001, p = 0.026, and p < 0.01). Using receiver operating characteristic (ROC) curve, we tested the sensitivity combined with the specificity of the model and found that the risk model had a satisfactory level of 1-year, 3-year, and 5-year concordance index (C-index) (C = 0.661 in the training group, C = 0.679 in validation group 1, C = 0.692 in validation group 2). We also explored the immune microenvironment and immune checkpoint correlation of the risk model and found some significant results. Conclusion: We constructed a NETs-associated lncRNA signature to predict the outcome of patients with LUAD, which is associated with immunephenoscores and immune checkpoint-gene expression.
OBJECTIVE: Cervical pregnancy is a rare type of ectopic pregnancy. When the pregnancy is terminated, it will sometimes lead to persistent bleeding. In some cases, hysterectomy is inevitable and the patient loses fertility. Therefore, early diagnosis and targeted management with systemic or local injection of methotrexate is the first-line treatment. Multiple interventions of cervical pregnancy were used to prevent massive hemorrhage, including dilatation and curettage, laparoscopic resection, hysteroscopic resection combined with uterine artery embolization, or uterine artery clip. CASE REPORT: We report a case of cervical pregnancy with a high beta-hCG level accompanied by a visible fetal heartbeat that was successfully treated with hysteroscopic cervical tissue resection and balloon compression combined with systemic administration of methotrexate. CONCLUSION: Efficacy and safety with preserved fertility were important issues in the management of cervical pregnancy. We provide a safe, simple and effective treatment of cervical pregnancy.
Abortifacient Agents, Nonsteroidal , Balloon Occlusion , Pregnancy, Ectopic , Uterine Artery Embolization , Pregnancy , Female , Humans , Methotrexate/therapeutic use , Abortifacient Agents, Nonsteroidal/therapeutic use , Pregnancy, Ectopic/drug therapy , Pregnancy, Ectopic/surgery , Hemorrhage/therapy
Purpose: Cognitive impairment associated with human immunodeficiency virus (HIV)-related cryptococcal meningitis (HCM) in the context of immune reconstitution inflammatory syndrome is difficult to address. This study was a follow-up of lenalidomide treatment outcomes in patients with HCM and cognitive impairment after complete cryptococcal clearance. Patients and Methods: Seven HCM patients with neuroinflammation and cognitive impairment after complete cryptococcal clearance were enrolled in this prospective study. Neurocognitive assessment, clinical examination and cerebrospinal fluid (CSF) assays were performed before and after lenalidomide treatment. Results: After lenalidomide treatment, the Montreal Cognitive Assessment [week (W) 0 (median [interquartile range]: 23.0 (13.0-24.0) vs W24: 26.0 (24.0-28.00), P=0.018] and International HIV Dementia Scale scores [W0: 9.0 (2.5-10.5) vs W24: 11.0 (10.00-12.0), P=0.028] improved significantly, mainly in the domain of memory function. There was no significant difference in the Center for Epidemiological Research Depression scores for anxiety and depression before and after treatment. Further stratified analyses revealed that the patients with cognitive improvement group had higher levels of CSF white blood cells [94.0 (44.0-180.0) vs 0 (0-1.5), P=0.032], CSF protein [4.9 (3.0-6.6) vs 0.6 (0.5-0.7), P=0.034], CSF albumin [318.5 (190.9-346.5) vs 33.5 (30.4-46.2), P=0.034], and CSF IgG [160.5 (73.8-256. 0) vs 4.7 (4.3-7.4), P=0.034] but a lower CSF glucose level [2.4 (2.0-2.7) vs 2.8 (2.8-3.9), P=0.032] than the patients with cognitive non-improvement group before treatment. CSF inflammatory cytokines of the growth-related oncogene, interleukin [IL]-10, granulocyte-colony stimulating factor, IL-6, IL-8, complement factor H, tumor necrosis factor-α, and α-2 macroglobulin were obviously decreased in patients with cognitive improvement group after lenalidomide treatment. Conclusion: Lenalidomide potentially reduces cognitive impairment caused by immune reconstitution inflammatory syndrome in patients with HCM after cryptococcal clearance by inhibiting intracranial inflammation.
