Hippo pathway in non-small cell lung cancer: mechanisms, potential targets, and biomarkers.

Lung cancer is the primary contributor to cancer-related deaths globally, and non-small cell lung cancer (NSCLC) constitutes around 85% of all lung cancer cases. Recently, the emergence of targeted therapy and immunotherapy revolutionized the treatment of NSCLC and greatly improved patients' survival. However, drug resistance is inevitable, and extensive research has demonstrated that the Hippo pathway plays a crucial role in the development of drug resistance in NSCLC. The Hippo pathway is a highly conserved signaling pathway that is essential for various biological processes, including organ development, maintenance of epithelial balance, tissue regeneration, wound healing, and immune regulation. This pathway exerts its effects through two key transcription factors, namely Yes-associated protein (YAP) and transcriptional co-activator PDZ-binding motif (TAZ). They regulate gene expression by interacting with the transcriptional-enhanced associate domain (TEAD) family. In recent years, this pathway has been extensively studied in NSCLC. The review summarizes a comprehensive overview of the involvement of this pathway in NSCLC, and discusses the mechanisms of drug resistance, potential targets, and biomarkers associated with this pathway in NSCLC.

Enhancement of sweetpotato tolerance to chromium stress through melatonin and glutathione: Insights into photosynthetic efficiency, oxidative defense, and growth parameters.

Melatonin (MT) and reduced glutathione (GSH) roles in mitigating chromium (Cr) toxicity in sweetpotato were explored. Plants, pre-treated with varying MT and GSH doses, were exposed to Cr (40 µM). Cr severely hampered growth by disrupting leaf photosynthesis, root system, and oxidative processes and increased Cr absorption. However, the exogenous application of 1 µM of MT and 2 mM of GSH substantially improved growth parameters by enhancing chlorophyll content, gas exchange (Pn, Tr, Gs, and Ci), and chlorophyll fluorescence (Fv/Fm, ETR, qP, and Y(II)). Furthermore, malondialdehyde (MDA), hydrogen peroxide (H2O2), superoxide ion (O2•-), electrolyte leakage (EL), and Cr uptake by roots (21.6 and 27.3%) and its translocation to shoots were markedly reduced by MT and GSH application, protecting the cell membrane from oxidative damage of Cr-toxicity. Microscopic analysis demonstrated that MT and GSH maintained chloroplast structure and integrity of mesophyll cells; they also enhanced stomatal length, width, and density, strengthening the photosynthetic system and plant growth and biomass. MT and GSH improved osmo-protectants (proline and soluble sugars), gene expression, and enzymatic and non-enzymatic antioxidant activities, mitigating osmotic stress and strengthening plant defenses under Cr stress. Importantly, the efficiency of GSH pre-treatment in reducing Cr-toxicity surpassed that of MT. The findings indicate that MT and GSH alleviate Cr detrimental effects by enhancing photosynthetic organ stability, component accumulation, and resistance to oxidative stress. This study is a valuable resource for plants confronting Cr stress in contaminated soils, but further field validation and detailed molecular exploration are necessary.

First-line penpulimab combined with paclitaxel and carboplatin for metastatic squamous non-small-cell lung cancer in China (AK105-302): a multicentre, randomised, double-blind, placebo-controlled phase 3 clinical trial.

BACKGROUND: Penpulimab is a novel programmed death (PD)-1 inhibitor. This study aimed to establish the efficacy and safety of first line penpulimab plus chemotherapy for advanced squamous non-small-cell lung cancer. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 clinical trial enrolled patients with locally advanced or metastatic squamous non-small-cell lung cancer from 74 hospitals in China. Eligible participants were aged 18-75 years, had histologically or cytologically confirmed locally advanced (stage IIIb or IIIc) or metastatic (stage IV) squamous non-small-cell lung cancer, were ineligible to complete surgical resection and concurrent or sequential chemoradiotherapy, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, did not have previous systemic chemotherapy for locally advanced or metastatic non-small-cell lung cancer, and had one or more measurable lesions according to RECIST (version 1.1). Participants were randomly assigned (1:1) to receive intravenous penpulimab 200 mg or placebo (excipient of penpulimab injection), plus paclitaxel 175 mg/m2 and carboplatin AUC of 5 intravenously on day 1 every 3 weeks for four cycles, followed by penpulimab or placebo as maintenance therapy. Stratification was done according to the PD-L1 tumour proportion score (<1% vs 1-49% vs ≥50%) and sex (male vs female). The participants, investigators, and other research staff were masked to group assignment. The primary outcome was progression-free survival assessed by the masked Independent Radiology Review Committee in the intention-to-treat population and patients with a PD-L1 tumour proportion score of 1% or more (PD-L1-positive subgroup). The primary analysis was based on the intention-to-treat analysis set (ie, all randomly assigned participants) and the PD-L1-positive subgroup. The safety analysis included all participants who received at least one dose of study drug after enrolment. This trial was registered with ClinicalTrials.gov (NCT03866993). FINDINGS: Between Dec 20, 2018, and Oct 10, 2020, 485 patients were screened, and 350 participants were randomly assigned (175 in the penpulimab group and 175 in the placebo group). Of 350 participants, 324 (93%) were male and 26 (7%) were female, and 347 (99%) were of Han ethnicity. In the final analysis (June 1, 2022; median follow-up, 24·7 months [IQR 0-41·4]), the penpulimab group showed an improved progression-free survival compared with the placebo group, both in the intention-to-treat population (median 7·6 months, 95% CI 6·8--9·6 vs 4·2 months, 95% CI 4·2-4·3; HR 0·43, 95% CI 0·33-0·56; p<0·0001) and in the PD-L1-positive subgroup (8·1 months, 5·7-9·7 vs 4·2 months, 4·1-4·3; HR 0·37, 0·27-0·52, p<0·0001). Grade 3 or worse treatment-emergent adverse events occurred in 120 (69%) 173 patients in the penpulimab group and 119 (68%) of 175 in the placebo group. INTERPRETATION: Penpulimab plus chemotherapy significantly improved progression-free survival in patients with advanced squamous non-small-cell lung cancer compared with chemotherapy alone. The treatment was safe and tolerable. Penpulimab combined with paclitaxel and carboplatin is a new option for first-line treatment in patients with this advanced disease. FUNDING: The National Natural Science Foundation of China, Shanghai Municipal Health Commission, Chia Tai Tianqing Pharmaceutical, Akeso.

Nivolumab Plus Chemotherapy in Epidermal Growth Factor Receptor-Mutated Metastatic Non-Small-Cell Lung Cancer After Disease Progression on Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: Final Results of CheckMate 722.

PURPOSE: The phase III CheckMate 722 trial (ClinicalTrials.gov identifier: NCT02864251) evaluated nivolumab plus chemotherapy versus chemotherapy in patients with epidermal growth factor receptor (EGFR)-mutated metastatic non-small-cell lung cancer (NSCLC) after disease progression on EGFR tyrosine kinase inhibitors (TKIs). METHODS: Patients with disease progression after first- or second-generation EGFR TKI therapy (without EGFR T790M mutation) or osimertinib (with/without T790M mutation) were randomly assigned 1:1 to nivolumab (360 mg once every 3 weeks) plus platinum-doublet chemotherapy (once every 3 weeks) or platinum-doublet chemotherapy alone (once every 3 weeks) for four cycles. Primary end point was progression-free survival (PFS). Secondary end points included 9- and 12-month PFS rates, overall survival (OS), objective response rate (ORR), and duration of response (DOR). RESULTS: Overall, 294 patients were randomly assigned. At final analysis (median follow-up, 38.1 months), PFS was not significantly improved with nivolumab plus chemotherapy versus chemotherapy (median, 5.6 v 5.4 months; hazard ratio [HR], 0.75 [95% CI, 0.56 to 1.00]; P = .0528), with 9- and 12-month PFS rates of 25.9% versus 19.8%, and 21.2% versus 15.9%, respectively. Post hoc PFS subgroup analyses showed a trend favoring nivolumab plus chemotherapy in patients with tumors harboring sensitizing EGFR mutations (HR, 0.72 [95% CI, 0.54 to 0.97]), one line of previous EGFR TKI (0.72 [95% CI, 0.54 to 0.97]), or both (0.64 [95% CI, 0.47 to 0.88]). Median OS was 19.4 months with nivolumab plus chemotherapy versus 15.9 months with chemotherapy, while ORR was 31.3% versus 26.7%, and median DOR was 6.7 versus 5.6 months, respectively. Grade 3/4 treatment-related adverse events occurred in 44.7% and 29.4% of patients treated with nivolumab plus chemotherapy and chemotherapy alone, respectively. CONCLUSION: Nivolumab plus chemotherapy did not significantly improve PFS versus chemotherapy in patients with EGFR-mutated metastatic NSCLC previously treated with EGFR TKIs. No new safety signals were identified.

The Clinical Analysis of Checkpoint Inhibitor Pneumonitis with Different Severities in Lung Cancer Patients: A Retrospective Study.

Immune-related adverse events (irAEs) of immunotherapy would lead to the temporary or permanent discontinuation of immune checkpoint inhibitors (ICIs). Among them, checkpoint inhibitor pneumonitis (CIP) is a potentially life-threatening irAE. This study aimed to identify the differences between patients with low-grade CIPs (grades 1-2) and high-grade CIPs (grades 3-5) and to explore the prognostic factors. We retrospectively reviewed the medical records of 916 lung cancer patients who were treated with ICIs. Patients with CIPs were identified after multidisciplinary discussion, and their clinical, laboratory, radiological, and follow-up data were analyzed. Among the 74 enrolled CIP patients, there were 31 low-grade CIPs and 43 high-grade CIPs. Compared with low-grade CIP patients, patients with high-grade CIPs were older (65.8 years vs. 61.5 years) and had lower serum albumin (35.2 g/L vs. 37.9 g/L), higher D-dimer (5.1 mg/L vs. 1.7 mg/L), and more pulmonary infectious diseases (32.6% vs. 6.5%) during follow-up. In addition, complication with pulmonary infectious diseases, management with intravenous immunoglobulin, tocilizumab, and longer duration of large dosage corticosteroids might be associated with worse outcomes for patients with CIPs. This study highlights potential risk factors for high-grade CIP and poor prognosis among lung cancer patients who were treated with anti-cancer ICIs.

Efficacy and safety of azvudine in symptomatic adult COVID-19 participants who are at increased risk of progressing to critical illness: a study protocol for a multicentre randomized double-blind placebo-controlled phase III trial.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 will coexist with humans for a long time, and it is therefore important to develop effective treatments for coronavirus disease 2019 (COVID-19). Recent studies have demonstrated that antiviral therapy is a key factor in preventing patients from progressing to severe disease, even death. Effective and affordable antiviral medications are essential for disease treatment and are urgently needed. Azvudine, a nucleoside analogue, is a potential low-cost candidate with few drug interactions. However, validation of high-quality clinical studies is still limited. METHODS: This is a multicentre, randomized, double-blind, placebo-controlled phase III clinical trial involving 1096 adult patients with mild-to-moderate symptoms of COVID-19 who are at high risk for progression to severe COVID-19. Patients will be randomized to (1) receive azvudine tablets 5 mg daily for a maximum of 7 days or (2) receive placebo five tablets daily. All participants will be permitted to use a standard treatment strategy except antiviral therapy beyond the investigational medications. The primary outcome will be the ratio of COVID-19-related critical illness and all-cause mortality among the two groups within 28 days. DISCUSSION: The purpose of this clinical trial is to determine whether azvudine can prevent patients at risk of severe disease from progressing to critical illness and death, and the results will identify whether azvudine is an effective and affordable antiviral treatment option for COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT05689034. Registered on 18 January 2023.

The outcomes of different regimens depend on the molecular subtypes of pulmonary large-cell neuroendocrine carcinoma: A retrospective study in China.

BACKGROUND: The optimal systemic treatment for pulmonary large-cell neuroendocrine carcinoma (LCNEC) remains controversial, and recent advances in LCNEC molecular subtype classification have provided potential strategies for assisting in treatment decisions. Our study aimed to investigate the impact of treatment regimens, molecular subtypes and their concordance on clinical outcomes of patients diagnosed with LCNEC. PATIENTS AND METHODS: All patients diagnosed with advanced pulmonary LCNEC in Peking Union Medical College Hospital (PUMCH) between January 2000 and October 2021 were enrolled in this retrospective study. The tumor samples were collected and sequenced using a tumor-specific gene panel, while clinical information was retrieved from the medical records system. The survival and therapeutic response were analyzed and compared between different subgroups classified by treatment regimen (SCLC or NSCLC-based), molecular subtype (type I or II) or the combination. RESULTS: In univariate subgroup analysis categorized only by treatment regimen or molecular subtype, there were no differences identified in DCR, ORR, PFS, or OS. Nevertheless, the group with consistent treatment regimen and molecular subtype exhibited significantly longer OS than that of the inconsistent group (median OS 37.7 vs. 8.3 months; p = 0.046). Particularly, the OS of patients with type II LCNEC treated with SCLC-based regimen was significantly prolonged than that of others (median 37.7 vs. 10.5 months; p = 0.039). CONCLUSIONS: Collectively, our study revealed the clinical outcomes of different treatment regimens for LCNEC patients highly depend on their molecular subtypes, highlighting the need for sequencing-guided therapy.

Alleviating sweetpotato salt tolerance through exogenous glutathione and melatonin: A profound mechanism for active oxygen detoxification and preservation of photosynthetic organs.

Salt stress profoundly impacts sweetpotato production. Exogenous glutathione (GSH) and melatonin (MT) promoted plant growth under stress, but their specific roles and mechanisms in sweetpotato salt tolerance need exploration. This study investigated GSH and MT's regulatory mechanisms in sweetpotato under salt stress. Salt stress significantly reduces both growth and biomass by hindering photosynthesis, root traits, K+ content, and K+/Na+ balance, leading to oxidative stress and excessive hydrogen peroxide (H2O2), superoxide ion (O2•-), and malondialdehyde (MDA) production and Na+ accumulation. Nevertheless, GSH (2 mM) and MT (25 µM) pre-treatments effectively mitigated salt-induced oxidative damage and protected the plasma membrane. They reduced osmotic pressure by enhancing K+ uptake, K+/Na+ regulation, osmolyte accumulation, and reducing Na+ accumulation. Improved stomatal traits, chloroplast and grana lamella preservation, and maintenance of mesophyll cells, cell wall, and mitochondrial structure were observed with GSH and MT pre-treatments under salt stress, therefore boosting the photosynthetic system and enhancing plant growth and biomass. Moreover, the findings also indicate that the positive outcomes of GSH and MT pre-treatments result from elevated antioxidant levels, enhanced enzymatic activity, and upregulated expression of sodium hydrogen exchanger 2 (NHX2), K+transporter 1 (AKT1), and cation/H+exchanger (CHX), CBL-interacting protein kinase 1 (CIPK1), and antioxidant enzyme genes. These mechanisms enhance structural stability in photosynthesis and reduce salt stress. Evidently, MT pre-treatment exhibited superior effects compared to GSH. These findings provide a firm theoretical basis for employing GSH and MT to enhance salt tolerance in sweetpotato cultivation.

Sunvozertinib for patients in China with platinum-pretreated locally advanced or metastatic non-small-cell lung cancer and EGFR exon 20 insertion mutation (WU-KONG6): single-arm, open-label, multicentre, phase 2 trial.

BACKGROUND: Sunvozertinib is an oral, irreversible, and selective tyrosine kinase inhibitor that has a favourable safety profile and encouraging antitumour activity, as shown in phase 1 studies of patients with heavily pretreated non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutation (exon20ins). We aimed to assess the antitumour efficacy of sunvozertinib in patients with platinum-pretreated locally advanced or metastatic NSCLC with EGFR exon20ins. METHODS: WU-KONG6 is a single-group, open-label, multicentre phase 2 trial of sunvozertinib monotherapy, conducted across 37 medical centres in China. We enrolled adult patients with pathologically or cytologically confirmed locally advanced or metastatic NSCLC whose tumour tissue carried an EGFR exon20ins mutation. All patients had received at least one line of previous systemic therapy, with at least one line containing platinum-based chemotherapy. The primary endpoint was objective response rate (ORR), as assessed by the independent review committee. The ORR was defined as the percentage of patients who achieved complete or partial response, confirmed by two separate assessments with at least 4-week time interval, until disease progression or initiation of any new anti-cancer therapy. Enrolled patients received sunvozertinib 300 mg once daily until meeting discontinuation criteria per the protocol. Patients who received at least one dose of treatment and were evaluable for efficacy analysis were included in the primary analysis, and all patients who received at least one dose of treatment were included in the safety analysis. This study is registered with ChinaDrugTrials.org, CTR20211009, and ClinicalTrials.gov, NCT05712902, and efficacy and safety follow-up are ongoing. FINDINGS: Between July 19, 2021, and May 6, 2022, 104 patients were enrolled. At data cutoff (Oct 17, 2022), the last enrolled patient had been followed up for about 6 months. Among 97 patients evaluable for efficacy analysis, 59 (61%) patients achieved tumour response, with a confirmed ORR of 61% (95% CI 50-71). All tumour responses were partial responses. Tumour responses were observed irrespective of age, sex, smoking history, EGFR exon20ins subtypes, brain metastasis at baseline, previous lines of therapy, and history of onco-immunotherapy. In total, 19 death events occurred over a median follow-up period of 7·6 months (IQR 6·1-9·4). Sunvozertinib was well tolerated at 300 mg once daily. The most common grade 3 or worse treatment-related adverse events were blood creatine phosphokinase increased (18 [17%] of 104), diarrhoea (eight [8%]), and anaemia (six [6%]). The most common serious treatment-related adverse events were interstitial lung disease (five [5%] of 104), anaemia (three [3%]), vomiting (two [2%]), nausea (two [2%]) and pneumonia (two [2%]). INTERPRETATION: In this phase 2 study, sunvozertinib demonstrated antitumour efficacy in patients with platinum-based chemotherapy pretreated NSCLC with EGFR exon20ins, with a manageable safety profile. A multinational randomised, phase 3 study of sunvozertinib versus platinum-doublet chemotherapy in EGFR exon20ins NSCLC is ongoing (NCT05668988). FUNDING: Dizal Pharmaceutical.

Osimertinib versus comparator first-generation epidermal growth factor receptor tyrosine kinase inhibitors as first-line treatment in patients with advanced EGFR-mutated non-small cell lung cancer: a Chinese, multicenter, real-world cohort study.

Background: In the phase 3 FLAURA trial, osimertinib was compared with first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) as a first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). Osimertinib showed longer progression-free survival (PFS), overall survival (OS), and a similar safety profile. However, more studies demonstrating the effectiveness and safety of osimertinib as a first-line strategy are needed in real-world populations. Methods: We enrolled 1,556 patients with EGFR-mutated stage IIIc-IV NSCLC from the CAPTRA-Lung database. All patients received either osimertinib (n=202) or a first-generation EGFR-TKI (n=1,354) as their initial treatment. To adjust for differences in baseline characteristics between two groups, 1:2 propensity score matching (PSM) was performed. Propensity scores included gender, age, Eastern Cooperative Oncology Group performance status score, smoking history, family history of tumor, pathology, EGFR mutations, and central nervous system (CNS) metastases. The standardized mean differences (SMD) before and after PSM were calculated to examine the balance of covariate distributions between two groups. Results: After PSM, 202 patients receiving osimertinib and 404 patients receiving first-generation EGFR-TKIs were finally identified. SMD of each matched variable is less than 0.10. The median PFS was 19.4 months [95% confidence interval (CI): 14.3-24.4] in the osimertinib arm and 10.9 months (95% CI: 9.3-12.5) in the comparator arm [hazard ratio (HR) for progression, 0.47; 95% CI: 0.38-0.59; P<0.001). The median OS was 40.5 months (95% CI: 27.1-54.0) vs. 34.3 months (95% CI: 30.6-38.0) in two groups, respectively (HR for death, 0.76; 95% CI: 0.58-1.00; P=0.045). The incidence of grade 3 adverse events (AEs) between the two groups was 1% and 4.2%, respectively. No grade 4 AEs and treatment-related deaths were reported in both groups. Conclusions: In real-world settings, osimertinib demonstrates longer PFS and OS, with a similar safety profile to that of comparator EGFR-TKIs when used as a first-line strategy in NSCLC patients.

[Immune Checkpoint Inhibitors Related Cystoureteritis:
A Case Report and Literature Review].

A patient with advanced lung adenocarcinoma developed symptoms of frequent urination and urgent urination after 14 cycles of Pembrolizumab combined with chemotherapy. After making comprehensive analysis of the results of urine routine test, renal function, cystoscope and computed tomography (CT) examination, immune checkpoint inhibitors related cystoureteritis and acute kidney injury were considered. The patient's symptoms were relieved after discontinuation of Pembrolizumab combined with chemotherapy. However, the symptoms of urinary irritation worsened significantly after rechallenging Pembrolizumab combined with chemotherapy, and the symptoms was relieved after corticosteroids treatment. If patients develop urinary symptoms during immune checkpoint inhibitors treatment, immune checkpoint inhibitors related cystoureteritis should be considered for early differential diagnosis in order to implement appropriate treatment.
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Divergent tumor and immune cell reprogramming underlying immunotherapy response and immune-related adverse events in lung squamous cell carcinoma.

BACKGROUND: Lung squamous cell carcinoma (LUSC) remains a leading cause of cancer-related deaths with few therapeutic strategies. Immune checkpoint inhibitors (ICIs) have demonstrated promising efficacy in patients with LUSC. However, ICIs could also lead to a unique spectrum of immune-related adverse events (irAEs), which dampen the clinical outcome. In-depth characterization of the immune hallmarks of antitumor responses and irAEs remains an unmet need to maximize ICI-treatment benefits of patients. METHODS: We performed single-cell RNA sequencing (scRNA-seq) on pre-ICI and on-ICI treatment tumor biopsies. We used bulk RNA-seq data of matched pretreatment/on-treatment tumors and irAE affected organs to validate observations from scRNA-seq analysis. Two independent patient cohorts were collected to determine circulating tumor necrosis factor (TNF) protein expression levels. RESULTS: We found that increased proportions of a macrophage subcluster with highly expressed secreted phosphoprotein 1 (SPP1) and two tumor cell subclusters in irAE patients, whereas proportions of two cytotoxic CD8+ T cell subclusters were higher in patients with partial response (PR). TNF signaling pathway was conversely associated with treatment efficacy and irAE development in most macrophage and tumor cell subclusters. Cell-cell communications for TNF ligand-receptor pairs between macrophage/T cells and tumor cells were also bidirectionally remodeled in responders versus non-responders and irAE versus non-irAE patients. Bulk RNA-seq analysis on matched pretreatment/on-treatment tumors and irAE affected organs revealed remarkably enhanced macrophage abundance and TNF signaling pathway in on-treatment tumors and organs developed irAEs. Furthermore, we observed significantly increased circulating TNF protein in plasma or serum of irAE patients but not ICI responders, based on analysis of two independent LUSC patient cohorts and one published ICI patient cohort. CONCLUSIONS: Our data depicts specific reprogramming of macrophage, T cells and tumor cells associated with ICI response and irAEs, elucidates divergent roles of TNF signaling in antitumor immunity and irAEs, and highlights the significance of TNF expression in irAE development in the LUSC setting.

Risk factors associated with COVID-19 pneumonia in Chinese patients with pre-existing interstitial lung disease during the SARS-CoV-2 pandemic.

In China, the emergence of a nationally widespread epidemic infection of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has appeared within a month since December 7, 2022. To evaluate the risk factors for suffering from coronavirus disease 2019 (COVID-19) pneumonia due to infection with SARS-CoV-2 in different kinds of interstitial lung disease (ILD) patients with diverse immunizations, we conducted this retrospective study on 525 patients with ILDs who underwent regular follow-up in our ILD clinic. Among them, 128 ILD patients (24.4%) suffered from COVID-19 pneumonia after SARS-CoV-2 infection. Patients were older with a male predominance in the pneumonia group than in the nonpneumonia group (65.0 ± 10.0 years vs. 56.4 ± 11.7 years, p < 0.001, 55.5% vs. 39.5%, p = 0.002, respectively). Connective tissue disease-associated ILD (CTD-ILD) (25%), idiopathic pulmonary fibrosis (23.4%), and interstitial pneumonia with autoimmune features (21.1%) were the main pre-existing ILDs in the pneumonia group. In Cox multivariable analysis, only male sex and corticosteroid use were risk factors for COVID-19 pneumonia after infection. Two or three doses of vaccination were a protective factor for pre-existing ILD patients suffering from COVID-19 pneumonia. More than two doses of vaccination were strongly recommended for pre-existing ILD patients, particularly for males who were administered corticosteroids.

Effects of mind-body exercise on cognitive performance in middle-aged and older adults with mild cognitive impairment: A meta-analysis study.

BACKGROUND: To systematically evaluate the clinical efficacy of physical and mental exercise on cognitive performance in middle-aged people with mild cognitive impairment (MCI). METHODS: Computer searches of PubMed, Web of science, Embase, Cochrane Library, China Biomedical Literature Service, Wanfang database, China Knowledge Network, and VIP full-text database of Veep journals were conducted to obtain clinical randomized controlled trials on physical and mental exercise interventions in middle-aged and elderly people with MCI. The literature was screened according to inclusion and exclusion criteria, and the final included literature was subjected to data extraction and risk of bias assessment. Meta-analysis was performed using Review Manager 5.4.1 software, and publication bias test was performed using stata17.0 software. RESULTS: A total of 27 publications with a total of 2565 cases of elderly people with MCI were included. The control group was conventional care, health education, or blank control, and the physical and mental exercise group was exercises including Tai Chi, dance, orthopraxia, and qigong for 30 to 90 minutes each time, 3 to 6 times per week, for a total duration of 8 to 36 weeks. Meta-analysis results showed that Montreal cognitive assessment scores (mean difference [MD] = 2.33, 95% CI [1.55, 3.10], P < .00001), the mini-mental state examination score (MD = 1.73, 95% CI [0.60, 2.86], P = .003), trail making test-A score (MD = -4.00, 95% CI [-6.75, -1.25], P = .004), trail making test-B score (MD = -18.46, 95% CI [-23.87, -13.06], P < .00001), global deterioration scale score (MD = -0.72, 95% CI [-1.09, -0.34], P = .0002), Wechsler Logical Memory Scale score (MD = 2.07, 95% CI [0.03, 4.10], P = .05), berg score (MD = -0.70, 95% CI [0.32, 1.07], P < .0003), cerebrospinal fluid Tau protein level (MD = -166.69, 95% CI [-196.93, -136.45], P < .00001), and cerebrospinal fluid levels of αß1-42 protein (MD = 180.39, 95% CI [134.24, 226.55], P < .00001). CONCLUSION: Mind-body exercise can improve cognitive performance, depressive status, and balance as well as increase αß1-42 protein levels and decrease Tau protein levels in middle-aged and older adults with mild cognitive impairment.

Molecular subtypes and prognostic models for predicting prognosis of lung adenocarcinoma based on miRNA-related genes.

BACKGROUND: MicroRNAs (miRNAs) are crucial in cancer development and progression, and therapies targeting miRNAs demonstrate great therapeutic promise. AIM: We sought to predict the prognosis and therapeutic response of lung adenocarcinoma (LUAD) by classifying molecular subtypes and constructing a prognostic model based on miRNA-related genes. METHOD: This study was based on miRNA-mRNA action pairs and ceRNA networks in the Cancer Genome Atlas (TCGA) database. Three molecular subtypes were determined based on 64 miRNA-associated target genes identified in the ceRNA network. The S3 subtype had the best prognosis, and the S2 subtype had the worst prognosis. The S2 subtype had a higher tumor mutational load (TMB) and a lower immune score. The S2 subtype was more suitable for immunotherapy and sensitive to chemotherapy. The least absolute shrinkage and selection operator (LASSO) algorithm was performed to determine eight miRNA-associated target genes for the construction of prognostic models. RESULT: High-risk patients had a poorer prognosis, lower immune score, and lower response to immunotherapy. Robustness was confirmed in the Gene-Expression Omnibus (GEO) database cohort (GSE31210, GSE50081, and GSE37745 datasets). Overall, our study deepened the understanding of the mechanism of miRNA-related target genes in LUAD and provided new ideas for classification. CONCLUSION: Such miRNA-associated target gene characterization could be useful for prognostic prediction and contribute to therapeutic decision-making in LUAD.

Clinical significance of DNA damage response mutations in stage I and stage IIIa NSCLC.

BACKGROUND: DNA damage response (DDR) pathways are essential to sustain genomic stability and play a critical role in cancer development and progression. Here, we investigated the profile of DDR gene mutations in early-stage non-small cell lung cancer (NSCLC) and their prognostic values. METHODS: We first examined 74 DDR genes involved in seven DDR pathways and then focused on six specific genes: ATM, BRCA1, BRCA2, CHEK1, BARD1, and BRIP1. A total of 179 stage I and IIIa NSCLC patients who received curative resection in Peking Union Medical College Hospital and their corresponding samples were collected for DNA sequencing, immunohistochemistry and survival analysis. RESULTS: A total of 167 eligible patients were finally analyzed. Mutation frequencies were 82% and 26.3% for the selected 74 genes and six genes, respectively. Mismatch repair (MMR) and nucleotide excision repair (NER) alterations were observed more frequently in lung squamous cell carcinoma (LUSC) and smokers were more likely to develop the selected six DDR gene mutations than those who never smoked. Deleterious mutations in the six genes were independent prognostic indicators of significantly longer disease-free survival and overall survival. No association was found between DDR gene status and PD-L1 expression, CD8 positive lymphocyte and tumor-associated macrophage infiltration in tumor area. However, numbers of mutations were significantly increased among patients with DDR alterations. CONCLUSIONS: Deleterious mutations of these six genes were common in resected NSCLC and could serve as prognostic biomarkers.

The Presence of Lung Cancer Affects SARS-CoV-2 Vaccine Uptake and Attitude in Chinese Patients: A Clinical Cross-Sectional Investigation.

With the SARS-CoV-2 mutations evolving and prompt of SARS-CoV-2 vaccines, no information is available on SARS-CoV-2 vaccination status in Chinese patients with lung cancer. An electronic questionnaire including sociodemographic characteristics, vaccine status, side effect post-vaccination, and attitude towards a fourth dose of vaccine was conducted within 1018 Chinese patients with lung cancer from October 18th, 2022, to November 25th, 2022. Among 1018 patients, a total of 75 (13.7%) patients reported acceptable systemic adverse events in those had received the SARS-CoV-2 vaccine (549, 54%), the most common of which was fever (39, 7%). Factors including females (OR, 1.512; 95% CI, 1.076-2.124), residents in the municipality (OR, 2.048; 95% CI, 1.238-3.389), undergoing therapy (OR, 2.897; 95% CI, 1.348-6.226), disagree to vaccines is safe for patients with lung cancer (OR, 3.816; 95% CI, 2.198-6.626) contributed to hesitancy. Among 373 patients had received three doses, half respondents (206, 55.2%) were hesitant to receive a fourth dose due to the safety concern and efficacy towards the variants. In conclusion, low vaccine uptake rates in patients with lung cancer could be improved by increasing confidence in vaccine safety, particularly for those with negative beliefs. Appropriate guidance and individualized vaccination plans that meet the healthcare needs of patients with lung cancer were needed during the constantly evolving pandemic.

Effects of aerobic exercises in prediabetes patients: a systematic review and meta-analysis.

Aims: To evaluate the effects of different durations of continuous aerobic exercise on prediabetic patients. Materials and methods: The research encompassed randomized controlled trials that examined how various durations of aerobic exercise training affected outcomes related to Body Mass Index (BMI), Fasting blood glucose (FBG), 2-hour plasma glucose (2hPG), and glycated hemoglobin (HbA1c) in individuals diagnosed with prediabetes. PubMed, Embase, Web of Science, and the Cochrane Library were searched as of January 7, 2023. The Cochrane Risk of Bias, version 2 (ROB 2) tool was used to assess the risk of bias. Results: A total of 10 RCTs with 815 prediabetic patients were included. The average age of the participants was 56.1 years, with a standard deviation of 5.1 years. Among the participants, 39.2% were male. The interventions consisted of aerobic dance, treadmill running, walking, and a combination of aerobic exercises. The training sessions occurred three or four times per week. In prediabetic patients, aerobic exercise demonstrated a significant reduction in BMI compared to the control group, with a weighted mean difference (WMD) of -1.44 kg/m2 (95% confidence interval [CI] -1.89, -0.98). There was a decrease in FBG levels, with WMD of -0.51 mmol/L (95% CI -0.70, -0.32). Additionally, aerobic training led to significant improvements in 2hPG levels, with a WMD of -0.76 mmol/L (95% CI -1.14, -0.38). Furthermore, prediabetic patients showed a decrease in HbA1c levels after engaging in aerobic training compared to the control group, with a WMD of -0.34% (95% CI -0.45, -0.23). Conclusion: In summary, engaging in aerobic exercise can have a significant positive impact on glycemic levels in individuals with prediabetes. It can also lead to reductions in BMI, FBG, 2hPG, HbA1c, and other relevant indicators. The extent of these improvements may vary slightly depending on the duration of the aerobic exercise intervention. Systematic review registration: PROSPERO https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023395515.

Analysis of cytokines in bronchoalveolar lavage fluid in patients with checkpoint inhibitor pneumonitis and pulmonary infection: A case-control study.

BACKGROUND: The discovery of immune checkpoint inhibitors (ICIs) is a breakthrough in the field of cancer therapy. However, ICIs may cause immune-related adverse reactions, including checkpoint inhibitor-related pneumonitis (CIP). The aim of this study was to investigate cytokines in bronchoalveolar lavage fluid (BALF) of patients with CIP compared with patients with pulmonary infection and patients with cancer. METHODS: We retrospectively analyzed 34 cytokine levels and T cell subsets in BALF supernatant samples from ICI-treated patients with CIP (n = 13), pulmonary infection (n = 10), and progressive cancer (n = 12). Cytokine levels and T cell subsets were compared among the three groups of patients. RESULTS: We observed significantly higher levels of IFN-γ-induced protein 10(IP-10) (p = 0.002), and percentage of CD3 + CD8 + T cells (p = 0.020) in BALF of patients with CIP compared with the other two groups. However, we found significantly lower levels of interleukin-21 (p = 0.008) in BALF of patients with progressive disease compared with the other two groups. CONCLUSIONS: Cytokine profile and character of cell subsets in BALF was helpful for the differential diagnosis of CIP. IP-10 may play an important role in pathophysiology for CIP and also be a potential therapeutic target.