DNMT3A governs tyrosine kinase inhibitors responses through IAPs and in a cell senescence-dependent manner in non-small cell lung cancer.

Patients with non-small cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors (TKIs) inevitably exhibit drug resistance, which diminishes therapeutic effects. Nonetheless, the molecular mechanisms of TKI resistance in NSCLC remain obscure. In this study, data from clinical and TCGA databases revealed an increase in DNMT3A expression, which was correlated with a poor prognosis. Using NSCLC organoid models, we observed that high DNMT3A levels reduced TKI susceptibility of NSCLC cells via upregulating inhibitor of apoptosis proteins (IAPs). Simultaneously, the DNMT3Ahigh subset, which escaped apoptosis, underwent an early senescent-like state in a CDKN1A-dependent manner. Furthermore, the cellular senescence induced by TKIs was observed to be reversible, whereas DNMT3Ahigh cells reacquired their proliferative characteristics in the absence of TKIs, resulting in subsequent tumour recurrence and growth. Notably, the blockade of DNMT3A/IAPs signals enhanced the efficacy of TKIs in DNMT3Ahigh tumour-bearing mice, which represented a promising strategy for the effective treatment of NSCLC.

Temporal genomic heterogeneity guiding individualized therapy in recurrent non-small cell lung cancer.

Introduction: Despite the benefit of adjuvant systemic therapy for patients with resected non-small cell lung cancer (NSCLC), the risk of postoperative recurrence remains high. Our objective was to characterize temporal genetic heterogeneity between primary resected and recurrent tumors, and its impact on treatment outcomes. Methods: In this study, next-generation sequencing (NGS) testing was performed on tissue specimens and circulating tumor DNA (ctDNA) collected at postoperative recurrence, and results were compared to the genotypes of initial surgical specimens. Results: Of forty-five patients with matched primary and post-operative recurrent tumors, EGFR status switched in 17 patients (37.8%) at post-operative recurrence and 28 patients (62.2%) had no genotype change (17 mutant, 11 wild-type). Based on the changes of EGFR status, patients were divided into 4 groups. Following subsequent treatment with EGFR TKI o chemotherapy: In group A, with sustained sensitive mutation, the percentage achieving partial response (PR) was the highest, at 72.2%, the median progression-free survival (PFS) was 17 months, and the median overall survival (OS) was 44.0 months respectively; In group B, with genotype changed from wild-type to mutant, 50% achieved PR, PFS was 10 months, and OS was 35 months; In group C, in which mutant status shifted to wild-type or new co-mutation emerged, the percentage achieving PR was 30%, PFS was 9 months, and OS was 35 months. In group D, with sustained wild type, the percentage achieving PR was 27.3%, PFS was 8 months, and OS was 22 months. Discussion: Genotypic shift between paired primary and post-operative recurrent tumors was not infrequent, and this temporal genomic heterogeneity substantially impacted subsequent treatment outcomes.

Programmable DNA Circuit-Facilitated Determination of Circulating Extracellular Vesicle PD-L1 for Lung Cancer Diagnosis and Immunotherapy Response Prediction.

Circulating extracellular vesicle (EV) PD-L1 is correlated with the occurrence and progression of lung cancer and has great potential as a valuable diagnostic and immunotherapy predictive biomarker. In this work, we propose a fluorescent biosensing method for the sensitive and accurate determination of circulating EV PD-L1. Specifically, after the phosphatidylserine-targeting peptide-assisted magnetic enrichment, a programmable DNA circuit is designed to translate the presence of PD-L1 to the appearance of numerous duplex DNA probes on the circulating EV surface. Upon fructose treatment, these newly formed duplex DNA probes are released from the EV surface to activate the trans-cleavage activity of CRISPR/Cas12a system, which finally produces a significant fluorescence signal. Experimental results reveal that the method not only enables sensitive determination of EV PD-L1 with a detection limit of 67 particles/mL but also demonstrates the potential use in the diagnosis and immunotherapy response prediction of lung cancer in a principle-of-proof study. Therefore, the method may provide a useful tool for EV PD-L1 determination, which may provide valuable information for the precise diagnosis and personalized treatment of lung cancer patients.

The effectiveness of an internet-based support program on maternal self-efficacy, postpartum depression and social support for primiparous women during the COVID-19 pandemic: Randomized controlled trial.

Background: Many primiparous women usually encounter various parenting and mental health issues after childbirth. The effects of intervention based on internet platform on parenting and mental health outcomes for Chinese first-time mothers remain unknown during the COVID-19 pandemic. Therefore, our research aimed to evaluate the effectiveness of an internet-based support program (ISP) on maternal self-efficacy (MSE), postpartum depression (PPD) and social support for primiparous women amid the pandemic. Methods: A multicenter randomized controlled trial (RCT) was conducted. From May 2020 to March 2021, 242 primiparous women were recruited in the maternity wards of two hospitals in Shenzhen City, China and randomly assigned to the intervention group and the control group. Women in control group (n = 118) received the routine postpartum care, and women in intervention group (n = 118) accessed to the ISP intervention (expert education and peer support) and routine postpartum care. Intervention outcomes were measured at baseline before randomization (T0), post-intervention (T1), and three-month follow up (T2) through questionnaires. The chi-square (χ2), the independent sample t-test and the repeated measures multivariate analysis of covariance were performed, and the two-tailed p-value <0.05 was regarded as statistically significant. Results: In comparison with women in the control group, women in the intervention group had a significantly higher score of MSE at T1 (mean: 73.53, standard deviation [SD]: 6.21) and at T2 (mean: 72.90, SD: 6.73); and a lower score of PPD at T1(mean: 6.03, SD: 2.50) and T2 (mean: 5.70, SD: 2.23); and a higher score of social support at T1 (mean: 45.70, SD: 3.73), but no significant difference at T2 (mean: 42.90, SD: 3.29). Conclusions: The effect of ISP was evaluated to significantly increase the levels of MSE, social support, and to alleviate PPD symptoms for Chinese first-time mothers. As an effective and easily accessible intervention, ISP could become a significant source for health professionals to support primiparous women on parenting and mental health during the COVID-19 pandemic. Trial registration: The trial is registered at the Chinese Clinical Trials Registry (ChiCTR2000033154).

Prognostic value of inflammatory and nutritional indexes among advanced NSCLC patients receiving PD-1 inhibitor therapy.

Though immunotherapy has to some extent improved the prognosis of patients with advanced non-small cell lung cancer (NSCLC), only a few patients benefit. Furthermore, immunotherapy efficacy is affected by inflammatory and nutritional status of patients. To investigate whether dynamics of inflammatory and nutritional indexes were associated with prognosis, 223 patients were analysed retrospectively. The inflammatory indexes of interest were neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) while prognostic nutritional index (PNI) and the haemoglobin, albumin, lymphocyte and platelet (HALP) score were considered as nutritional indexes. Patients were divided into high and low groups or into 'increase' and 'decrease' groups based on pre-treatment cut-off values and index dynamics after 6-week follow-up respectively. High pre-treatment PLR (OR = 2.612) and increase in NLR during follow-up (OR = 2.516) were significantly associated with lower objective response rates. Using multivariable analysis, high pre-treatment PLR (HR, 2.319) and increase in SII (HR, 1.731) predicted shorter progression-free survival, while high pre-treatment NLR (HR, 1.635), increase in NLR (HR, 1.663) and PLR (HR, 1.691) and decrease in PNI (HR, 0.611) predicted worse overall survival. The nomogram's C-index in inside validation was 0.718 (95% CI: 0.670-0.766). Our results indicated both nutritional and inflammatory indexes are associated with survival outcomes. Inflammatory indexes were additionally linked to treatment response. Index dynamics are better predictors than baseline values in predicting survival in advanced NSCLC patients receiving PD-1 inhibitor combined with chemotherapy as first-line.

Group-Based Trajectory Analysis for Postpartum Depression Symptoms among Chinese Primiparous Women.

BACKGROUND: Subgroups of individuals sharing similar patterns of postpartum depression (PPD) among Chinese women are unknown thus far. Using a group-based trajectory model, this study aimed to explore the subgroups of Chinese primiparous women that share similar patterns of PPD and to explore the predictors of PPD trajectory membership over the course of the first six months postpartum. METHODS: In total, 674 first-time Chinese mothers were recruited, and their depression status was assessed using the Edinburgh Postnatal Depression Scale (EPDS) at four time points. FINDINGS: Around 18.0% of participants belonging to Group 1 labeled as "few or no symptoms" remained stable, with an EPDS score of less than 5 during a six-month postpartum period. Almost one-third of subjects fell within the second trajectory, labeled "subclinical but present symptoms", and peaked into the range of mild PPD but mostly stayed in the minimal range and had few or no PPD symptoms. Group 3 included 31.2% of women labeled "minor PPD status", and their mean EPDS scores increased to a peak of 14.66 at six weeks postpartum. Group 4, with "major PPD status", comprised 19.2% of the population, and the mean EPDS scores dramatically increased, reaching a peak of 19.59 at 12 weeks postpartum. Fewer types of support and not attending parenting training were associated with membership in the minor and major PPD status trajectories. CONCLUSIONS: Almost half of the Chinese new mothers in the study were found to fall into the two groups with minor or major PPD status trajectories, who should be given more attention and awareness from health professionals and researchers. Understanding predictors of group membership could help health providers to identify folks to prioritize getting connected to care as well as forming targeted interventions. Less degree of received support and not attending parenting training were identified to predict PPD trajectory membership. The regular, routine screening of PPD should be conducted at least 12 weeks postpartum, especially for new mothers in the major PPD status trajectory.

Combination of Baseline and Variation of Prognostic Nutritional Index Enhances the Survival Predictive Value of Patients With Advanced Non-Small Cell Lung Cancer Treated With Programmed Cell Death Protein 1 Inhibitor.

Background: Low baseline prognostic nutritional index (PNI) scores are associated with poor survival for various malignancies; however, they vary based on the cohort and time resulting in inaccurate results. We determined the predictive value of the PNI score variations in addition to the baseline PNI scores for patients with advanced non-small cell lung cancer (NSCLC) who received programmed cell death protein 1 (PD-1) inhibitor. Methods: We retrospectively analysed 115 patients with advanced NSCLC who received PD-1 inhibitor. The median follow-up period was 28 months. Patients were clustered into four groups based on the combined PNI scores (combination of baseline and variation of PNI scores): ΔPNI-L-L, ΔPNI-L-H, ΔPNI-H-L, and ΔPNI-H-H subgroups. For instance, if PNI scores of patients with high baseline PNI score increased from baseline to 6 weeks after treatment, they were included in the ΔPNI-H-H subgroup. Cox regression models were used to identify the factors associated with survival. Results: The baseline PNI score was only related to the overall survival (OS) (P = .026), and not to the overall response rate (ORR) (P = .299) and progression-free survival (PFS) (P = .207). The ORR was associated with the combined PNI scores (P = .017). A multivariable Cox regression analysis confirmed that the combined PNI scores were independent factors for PFS (ΔPNI-L-H, 12 months, hazard ratio [HR] = 0.449, P = .009; ΔPNI-H-L, 14 months, HR = 0.500, P = .019; and ΔPNI-H-H, 17 months, HR = 0.390, P = .012; vs ΔPNI-L-L, 8 months) and OS (ΔPNI-L-H, 27 months, HR = 0.403, P = .019; ΔPNI-H-L, 28 months, HR = 0.369, P = .010; and ΔPNI-H-H, not reached, HR = 0.087, P = .002; vs ΔPNI-L-L, 15 months). Conclusions: Patients with high baseline PNI and increased PNI score had the better survival outcome. On dynamic monitoring and comprehensive assessment, the combined PNI scores significantly enhanced the survival predictive ability of patients with NSCLC treated with PD-1 inhibitor.

Association of Sleep Duration and Self-Reported Insomnia Symptoms with Metabolic Syndrome Components among Middle-Aged and Older Adults.

The study aimed to explore the association between sleep duration, insomnia symptoms and the components of metabolic syndrome (MetS) among middle-aged and older adults. A cross-sectional study was conducted in five community health centers and physical check-up centers of two comprehensive hospitals in Guangdong. We recruited 1252 participants (658 female), aged 40-96 years and with a body mass index (BMI) of 16.26-35.56 kg/m2. MetS was assessed based on the guidelines of the International Diabetes Federation. Self-reported sleep duration was evaluated by a simplified questionnaire. Compared with the participants who slept 6-8 h/day, those who slept shorter (<6 h/day) or longer (>8 h/day) periods of time with or without insomnia symptoms had significantly increased odds ratios (ORs) of high blood pressure (except for the SBP in model 2) and high triglycerides (TGs) in all models (p < 0.05), whereas the participants who slept longer (>8 h/day) or shorter (<6 h/day) periods of time with insomnia symptoms had significantly increased ORs of low HDL-C in all models (p < 0.05), but non-significant in those without insomnia symptoms. BMI is significant for insomnia symptoms but not for sleep duration. Our study indicated that the association of sleep duration with MetS components was partially associated with insomnia symptoms. These findings have significant implications to explore the appropriate sleep duration for adults.

Online and Offline Intervention for the Prevention of Postpartum Depression among Rural-to-Urban Floating Women: Study Protocol for a Randomized Control Trial.

BACKGROUND: As a higher-risk group of postpartum depression (PPD), rural to urban floating women urgently require effective and accessible mental health care after childbirth to prevent PPD. Even though there were various interventions, only a small number of women have sought professional help to reduce their depressive symptoms after childbirth, suggesting the need for an innovative intervention delivery to overcome women's help-seeking barriers. Online and offline (OTO) interventions, which combine face-to-face and internet-based interventions, provide apparent benefits. As a result, the protocol for a randomized controlled study (RCT) was designed to examine the effectiveness and acceptability of OTO intervention on psychosocial outcomes for Chinese rural-to-urban floating women including the reduction of PPD symptoms and PPD stigma, and the improvement of social support and quality of life. METHODS: A double blind, multicenter, RCT will be used and a total of 226 participants will be recruited. The OTO intervention called the "Hi, Mom" program will integrate two face-to-face consulting sessions with online sessions comprising an information module, a communication module, an ask-the-expert module, and a peer story module over a period of three months. The control group will receive routine postpartum care. Outcome measures including PPD symptoms, PPD stigma, social support, quality of life, mother-child bonding, and satisfaction with health care received will be conducted at baseline, postintervention, and three-month follow-up. RESULTS AND DISCUSSION: If the intervention is effective, it will provide a convenient and effective intervention program on postpartum mental well-being for rural-to-urban floating women. As the first study to test the effects of an OTO intervention for the prevention of PPD in China, the outcomes gained from this study will provide evidence-based knowledge for clinical practice on PPD prevention based on online and offline health technologies. Moreover, it could be used to plan a culturally appropriate OTO intervention for migrant mothers from different countries.

Microbes in lung cancer initiation, treatment, and outcome: Boon or bane?

Lung cancer is the top reason for cancer-related deaths worldwide. The 5-year overall survival rate of lung cancer is approximately 20 % due to the delayed diagnosis and low response rate to regular treatments. Microbiota, both host-microbiota and alien pathogenic microbiota, have been investigated to be involved in a complicated and contradictory relationship with lung cancer initiation, treatments, and prognosis. Disorders of certain host-microbiota and pathogen infection are associated with the risk of lung cancers based on epidemiological evidence, and antibiotics (ATBs) could dramatically impair anti-cancer treatment efficacy, including chemotherapy and immunotherapy. Moreover, probiotics and microbe-mediated drugs are potential approaches to enhance regular anti-tumor treatments. Therefore, the knowledge of the complex dual effect of microbes on lung cancer is beneficial to take their essence and remove their dross. This review offers insight into the current trends and advancements in microbiota or microbial components related to lung cancer.

Surveillance of Parenting Outcomes, Mental Health and Social Support for Primiparous Women among the Rural-to-Urban Floating Population.

China has the largest population of floating rural-to-urban women worldwide, most of whom are of childbearing age. However, few studies have been conducted to monitor the changing trends in parenting outcomes, mental health and social support for these women in the early postpartum period. In this quantitative longitudinal study, 680 primiparous women among the floating population were recruited in Shenzhen, China. Face-to-face collection of socio-demographic questionnaires was completed by researchers in maternity wards on the third postnatal day. Follow-up electronic questionnaires were dispatched to women via email or WeChat at 6 weeks and 12 weeks following childbirth, including the Self-efficacy in Infant Care Scale (SICS), Edinburgh Postnatal Depression Scale (EPDS) and Postnatal Social Support Scale (PSSS), to measure maternal self-efficacy (MSE), postpartum depression (PPD) and social support, respectively. The mean scores of MSE for these floating women were 67.16 (14.35) at 6 weeks postpartum and slightly increased to 68.71 (15.00) at 12 weeks postpartum. The mean scores of EPDS remained almost stable, from 11.19 (4.89) to 11.18 (5.34) at the two time points. The prevalence of mild and severe PPD among floating women at 6 and 12 weeks after childbirth decreased from 54.4% to 40.1% and from 50.6% to 35.4%, respectively. The mean score of social support was 37.04 (10.15) at 6 weeks postpartum and slightly improved to 38.68 (10.46) at 12 weeks postpartum. Primiparous women among the rural-to-urban migrant population had an obviously negative status of parenting outcomes and mental health; and there was a lack of social support after childbirth. In future, tailored evidence-based interventions are highly needed to promote floating women's parenting outcomes, mental wellbeing and social support in the early stages of motherhood. As a higher-risk group of PPD, primiparous women among the floating population require effective and accessible mental health care after childbirth, such as early PPD screening and timely therapeutic methods.

A narrative review of tumor heterogeneity and challenges to tumor drug therapy.

OBJECTIVE: To accurately evaluate tumor heterogeneity, make multidimensional diagnosis according to the causes and phenotypes of tumor heterogeneity, and assist in the individualized treatment of tumors. BACKGROUND: Tumor heterogeneity is one of the most essential characteristics of malignant tumors. In tumor recurrence, development, and evolution, tumor heterogeneity can lead to the formation of different cell groups with other molecular characteristics. Tumor heterogeneity can be characterized by the uneven distribution of tumor cell subsets of other genes between and within the disease site (spatial heterogeneity) or the time change of cancer cell molecular composition (temporal heterogeneity). The discovery of tumor targeting drugs has dramatically promoted tumor therapy. However, the existence of heterogeneity seriously affects the effect of tumor treatment and the prognosis of patients. METHODS: The literature discussing tumor heterogeneity and its resistance to tumor therapy was broadly searched to analyze tumor heterogeneity as well as the challenges and solutions for gene detection and tumor drug therapy. CONCLUSIONS: Tumor heterogeneity is affected by many factors consist of internal cell factors and cell microenvironment. Tumor heterogeneity greatly hinders effective and individualized tumor treatment. Understanding the fickle of tumors in multiple dimensions and flexibly using a variety of detection methods to capture the changes of tumors can help to improve the design of diagnosis and treatment plans for cancer and benefit millions of patients.

Risk-score model to predict prognosis of malignant airway obstruction after interventional bronchoscopy.

BACKGROUND: Interventional bronchoscopy exhibits substantial effects for patients with malignant airway obstruction (MAO), while little information is available regarding the potential prognostic factors for these patients. METHODS: Between October 31, 2016, and July 31, 2019, a total of 150 patients undergoing interventional bronchoscopy and histologically-confirmed MAO were collected, in which 112 eligible participants formed the cohort for survival study. External validation cohort from another independent institution comprised 33 MAO patients with therapeutic bronchoscopy. The least absolute shrinkage and selection operator regression (LASSO) was applied to the model development dataset for selecting features correlated with MAO survival for inclusion in the Cox regression from which we elaborated the risk score system. A nomogram algorithm was also utilized. RESULTS: In our study, we observed a significant decline of stenosis rate after interventional bronchoscopy from 71.7%±2.1% to 36.6%±2.7% (P<0.001) and interventional bronchoscopy dilated airway effectively. Patients in our study undergoing interventional bronchoscopy had a median survival time of 614.000 days (95% CI: 269.876-958.124). Patients receiving distinct therapeutic methods of interventional bronchoscopy had different prognosis (P=0.022), and patients receiving treatment of electrocoagulation in combination with stenting and electrosurgical snare had worse survival than those receiving other options. Multivariate Cox analysis revealed that nonsmoking status, adenoid cystic carcinoma, and low preoperative stenosis length, as independent predictive factors for better overall survival (OS) of MAO patients. Then, the nomogram based on Cox regression and risk score system based on results from LASSO regression were elaborated respectively. Importantly, this risk score system was proved to have better performance than the nomogram and other single biomarkers such as traditional staging system (area under the curve 0.855 vs. 0.392-0.739). Survival curves showed that patients with the higher risk-score had poorer prognosis than those with lower risk-score (third quantile of OS: 126.000 days, 95% CI: 73.588-178.412 vs. 532.000 days, 95% CI: 0.000-1,110.372; P<0.001). CONCLUSIONS: Nonsmoking status, adenoid cystic carcinoma, and low preoperative stenosis length, were independent predictive factors for better OS of MAO patients. We proposed a nomogram and risk score system for survival prediction of MAO patients undergoing interventional bronchoscopy with good performance.

Artificial intelligence-based analysis for immunohistochemistry staining of immune checkpoints to predict resected non-small cell lung cancer survival and relapse.

BACKGROUND: Conventional analysis of single-plex chromogenic immunohistochemistry (IHC) focused on quantitative but spatial analysis. How immune checkpoints localization related to non-small cell lung cancer (NSCLC) prognosis remained unclear. METHODS: Here, we analyzed ten immune checkpoints on 1,859 tumor microarrays (TMAs) from 121 NSCLC patients and recruited an external cohort of 30 NSCLC patients with 214 whole-slide IHC. EfficientUnet was applied to segment tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs), while ResNet was performed to extract prognostic features from IHC images. RESULTS: The features of galectin-9, OX40, OX40L, KIR2D, and KIR3D played an un-negatable contribution to overall survival (OS) and relapse-free survival (RFS) in the internal cohort, validated in public databases (GEPIA, HPA, and STRING). The IC-Score and Res-Score were two predictive models established by EfficientUnet and ResNet. Based on the IC-Score, Res-Score, and clinical features, the integrated score presented the highest AUC for OS and RFS, which could achieve 0.9 and 0.85 in the internal testing cohort. The robustness of Res-Score was validated in the external cohort (AUC: 0.80-0.87 for OS, and 0.83-0.94 for RFS). Additionally, the neutrophil-to-lymphocyte ratio (NLR) combined with the PD-1/PD-L1 signature established by EfficientUnet can be a predictor for RFS in the external cohort. CONCLUSIONS: Overall, we established a reliable model to risk-stratify relapse and death in NSCLC with a generalization ability, which provided a convenient approach to spatial analysis of single-plex chromogenic IHC.

States Transitions Inference of Postpartum Depression Based on Multi-State Markov Model.

Background: Postpartum depression (PPD) has been recognized as a severe public health problem worldwide due to its high incidence and the detrimental consequences not only for the mother but for the infant and the family. However, the pattern of natural transition trajectories of PPD has rarely been explored. Methods: In this research, a quantitative longitudinal study was conducted to explore the PPD progression process, providing information on the transition probability, hazard ratio, and the mean sojourn time in the three postnatal mental states, namely normal state, mild PPD, and severe PPD. The multi-state Markov model was built based on 912 depression status assessments in 304 Chinese primiparous women over multiple time points of six weeks postpartum, three months postpartum, and six months postpartum. Results: Among the 608 PPD status transitions from one visit to the next visit, 6.2% (38/608) showed deterioration of mental status from the level at the previous visit; while 40.0% (243/608) showed improvement at the next visit. A subject in normal state who does transition then has a probability of 49.8% of worsening to mild PPD, and 50.2% to severe PPD. A subject with mild PPD who does transition has a 20.0% chance of worsening to severe PPD. A subject with severe PPD is more likely to improve to mild PPD than developing to the normal state. On average, the sojourn time in the normal state, mild PPD, and severe PPD was 64.12, 6.29, and 9.37 weeks, respectively. Women in normal state had 6.0%, 8.5%, 8.7%, and 8.8% chances of progress to severe PPD within three months, nine months, one year, and three years, respectively. Increased all kinds of supports were associated with decreased risk of deterioration from normal state to severe PPD (hazard ratio, HR: 0.42-0.65); and increased informational supports, evaluation of support, and maternal age were associated with alleviation from severe PPD to normal state (HR: 1.46-2.27). Conclusions: The PPD state transition probabilities caused more attention and awareness about the regular PPD screening for postnatal women and the timely intervention for women with mild or severe PPD. The preventive actions on PPD should be conducted at the early stages, and three yearly; at least one yearly screening is strongly recommended. Emotional support, material support, informational support, and evaluation of support had significant positive associations with the prevention of PPD progression transitions. The derived transition probabilities and sojourn time can serve as an importance reference for health professionals to make proactive plans and target interventions for PPD.

Tumor Mutation Burden and Differentially Mutated Genes Among Immune Phenotypes in Patients with Lung Adenocarcinoma.

INTRODUCTION: Nowadays, immune checkpoint blockades (ICBs) have been extensively applied in non-small cell lung cancer (NSCLC) treatment. However, the outcome of anti-program death-1/program death ligand-1 (anti-PD-1/PD-L1) therapy is not satisfying in EGFR-mutant lung adenocarcinoma (LUAD) patients and its exact mechanisms have not been fully understood. Since tumor mutation burden (TMB) and tumor immune phenotype had been thought as potential predictors for efficacy of ICBs, we further studied the TMB and immune phenotype in LUAD patients to explore potential mechanisms for poor efficacy of ICBs in EGFR positive mutated patients and to find possible factors that could impact the tumor immune phenotype which might uncover some new therapeutic strategies or combination therapies. METHODS: We enrolled 223 LUAD patients who underwent surgery in our hospital. We evaluated TMB through targeted panel sequencing. The tumor immune phenotype, which could be divided into non-inflamed, intermediate and inflamed, was determined through immunohistochemistry using formalin-fixed paraffin-embedded samples. Enumeration data were analyzed by Chi-square test or Fisher exact test and shown as number (proportion). Logistic regression model was employed for univariate and multivariate analysis of the association between TMB levels and clinical characteristics. RESULTS: The median TMB level was 4.0445 mutations/Mb. Multivariate analysis showed the TMB level was significantly associated with age (P=0.026), gender (P=0.041) and EGFR mutation status (P=0.015), and in EGFR-mutant patients we found a lower proportion of patients with mutated KRAS and BRCA2. Furthermore, we found patients with or without metastatic lesions would have different immune phenotype (P=0.007). And the mutational frequencies of ALK, CDKN2A, MAP2K1, IDH2 and PTEN were significantly different among three immune phenotypes. CONCLUSION: Low TMB level could be the reason for the poor efficacy of ICBs in patients having EGFR mutation. And mutational frequencies of KRAS and BRCA2 were lower in EGFR-mutant patients. Furthermore, ALK, CDKN2A, MAP2K1, IDH2 and PTEN might involve in the formation of immune phenotypes.

FOXP3-based immune risk model for recurrence prediction in small-cell lung cancer at stages I-III.

BACKGROUND: Immunotherapies may prolong the survival of patients with small-cell lung cancer (SCLC) to some extent. The role of forkhead box protein P3 (FOXP3) in tumor microenvironment (TME) remains controversial. We aimed to examine FOXP3-related expression characteristics and prognostic values and to develop a clinically relevant predictive system for SCLC. METHODS: We enrolled 102 patients with histologically confirmed SCLC at stages I-III. Through immunohistochemistry, we determined the expression pattern of FOXP3 and its association with other immune biomarkers. By machine learning and statistical analysis, we constructed effective immune risk score models. Furthermore, we examined FOXP3-related enrichment pathways and TME traits in distinct cohorts. RESULTS: In SCLC, FOXP3 level was significantly associated with status of programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), CD4, CD8, and CD3 (p=0.002, p=0.001, p=0.002, p=0.030, and p<0.001). High FOXP3 expression showed longer relapse-free survival (RFS) than the low-level group (41.200 months, 95% CI 26.937 to 55.463, vs 14.000 months, 95% CI 8.133 to 19.867; p=0.008). For tumor-infiltrating lymphocytes (TILs), subgroup analysis demonstrated FOXP3 and PD-1, PD-L1, lymphocyte activation gene-3, CD3, CD4, or CD8 double positive were significantly correlated with longer RFS. We further performed importance evaluation for immune biomarkers, constructed an immune risk score incorporating the top three important biomarkers, FOXP3, TIL PD-L1, and CD8, and found their independently prognostic role to predict SCLC relapse. Better predictive performance was achieved in this immune risk model compared with single-indicator-based or two-indicator-based prediction systems (area under the curve 0.715 vs 0.312-0.711). Then, relapse prediction system integrating clinical staging and immune risk score was established, which performed well in different cohorts. High FOXP3-related genes were enriched in several immune-related pathways, and the close relationships of interleukin-2, CD28, basic excision repair genes MUTYH, POLD1, POLD2, and oxidative phosphorylation related gene cytochrome c oxidase subunit 8A with FOXP3 expression were revealed. Moreover, we found low-immune risk score group had statistically higher activated CD4+ memory T cells (p=0.014) and plasma cells (p=0.049) than the high-risk group. The heterogeneity of tumor-infiltrating immune cells might represent a promising feature for risk prediction in SCLC. CONCLUSION: FOXP3 interacts closely with immune biomarkers on tumor-infiltrating cells in TME. This study highlighted the crucial prognostic value and promising clinical applications of FOXP3 in SCLC.

Effects of Internet-Based Support Program on Parenting Outcomes for Primiparous Women: A Pilot Study.

(1) Background: Some primiparous women are usually confronted with many parenting problems after childbirth, which can negatively influence the wellbeing of some mothers and infants. Evidence identified that internet interventions can include more tailored information, reach a larger research group, and supply more anonymity than face-to-face traditional interventions. Therefore, the internet-based support program (ISP) was designed to improve the parenting outcomes for Chinese first-time mothers. (2) Methods: A multicenter, single-blinded, pilot randomized controlled trial was conducted. From May to October 2020, a total of 44 participants were recruited in the obstetrical wards of two tertiary hospitals in China. Eighteen women in the control group received routine postnatal care; while eighteen women in the intervention group accessed to the ISP and routine postnatal care. The duration of intervention was not less than three months. Intervention outcomes were assessed through questionnaires before randomization (T0), immediately after intervention (T1), and three months after intervention (T2). The Self-efficacy in Infant Care Scale (SICS), Edinburgh Postnatal Depression Scale (EPDS), and Postpartum Social Support Scale (PSSS) were included to measure MSE, postpartum depression (PPD), and social support, respectively. (3) Results: No significant difference between the two groups were found in terms of the baseline social-demographic characteristics; and the scores of SICS, EPDS and PSSS at T0 (p > 0.05). Repeated measures multivariate analysis of covariance found that women in the intervention group had a higher MSE score at T1 (6.63, p = 0.007), and T2 (5.75, p = 0.020); a lower EPDS score at T1 (3.11, p = 0.003), and T2 (2.50, p = 0.005); and a higher PSSS score at T1 (4.30, p = 0.001); and no significant difference at T2 (0.35, p = 0.743), compared with women in the control group. (4) Conclusion: The effect of ISP was evaluated to significantly increase primiparous women's MSE, social support, and to alleviate their PPD symptoms. However, the small sample in pilot study restricted the research results. Therefore, the ISP should be further investigated with a larger, diverse sample to confirm whether it should be adopted as routine postnatal care to support primiparous women on parenting outcomes and mental wellbeing in the early stage of motherhood.

Single-Cell Sequencing, an Advanced Technology in Lung Cancer Research.

Single-cell sequencing (SCS) which has an unprecedentedly high resolution is an advanced technique for cancer research. Lung cancer still has a high mortality and morbidity. For further understanding the lung cancer, SCS is also been applied to lung cancer research to investigate its heterogeneity, metastasis, drug resistance, tumor microenvironment and many other issues. In this review, we summarized lung cancer research using SCS and their research achievements.

Internet-based support program on parenting outcomes for Chinese primiparous women: Study protocol for a randomized controlled trial.

AIM: To evaluate the effects of internet-based support program for primiparous women in terms of improving the levels of maternal self-efficacy, social support, and satisfaction; and reducing their postpartum depression symptoms. DESIGN: A single-blinded, multicentre, randomized, controlled, parallel-group pre-test and repeated post-test design. METHODS: Based on the self-efficacy theory and the social exchange theory, the internet-based support program has five modules: (a) learning forum of parenting knowledge and skills; (b) communication forum; (c) ask-the-expert forum; (d) baby home forum; and (e) reminder forum. Primiparous women will be recruited in the obstetric wards of two university-affiliated hospitals in China. The participants (N = 258) will be randomly allocated to the intervention group that receive routine care and access to the internet-based support program and the control group that receive routine care during the 3 months postpartum. Maternal self-efficacy, social support, and postpartum depression symptoms will be measured at baseline, immediately after the intervention (post-test 1) and 3 months after the intervention (post-test 2). The study was funded in January 2018 and was ethically approved in May 2020. DISCUSSION: If the internet-based support program has positive outcomes, it will contribute to the scientific and practical knowledge of nursing interventions to support primiparous women on parenting; and could become the routine health care for health professionals to enhance parenting ability and mental well-being of new mothers. IMPACT: As the first RCT study on parenting outcomes using a rigorous research design and a theoretical framework in China, this research will contribute to evidence on the effectiveness of using internet platform to support women after childbirth. The results could help to advance research about the use of internet-based intervention methods to improve women's maternal self-efficacy, social support, satisfaction, and to alleviate depression symptoms. Chinese Clinical Trial Registry: ChiCTR2000033154.