ALKBH5 promotes non-small cell lung cancer progression and susceptibility to anti-PD-L1 therapy by modulating interactions between tumor and macrophages.

BACKGROUND: Understanding the mechanisms that mediate the interaction between tumor and immune cells may provide therapeutic benefit to patients with cancer. The N6-methyladenosine (m6A) demethylase, ALKBH5 (alkB homolog 5), is overexpressed in non-small cell lung cancer. However, its role in the tumor microenvironment is unknown. METHODS: Datasets and tissue samples were used to determine the relationship between ALKBH5 expression and immunotherapy efficacy. Bioinformatic analysis, colorimetric assay to determine m6A RNA methylation, dual luciferase reporter assay, RNA/m6A-modified RNA immunoprecipitation, RNA stability assay, and RNA sequencing were used to investigate the regulatory mechanism of ALKBH5 in non-small cell lung cancer. In vitro and in vivo assays were performed to determine the contribution of ALKBH5 to the development of non-small cell lung cancer. RESULTS: ALKBH5 was upregulated in primary non-small cell lung cancer tissues. ALKBH5 was positively correlated with programmed death-ligand 1 expression and macrophage infiltration and was associated with immunotherapy response. JAK2 was identified as a target of ALKBH5-mediated m6A modification, which activates the JAK2/p-STAT3 pathway to promote non-small cell lung cancer progression. ALKBH5 was found to recruit programmed death-ligand 1-positive tumor-associated macrophages and promote M2 macrophage polarization by inducing the secretion of CCL2 and CXCL10. ALKBH5 and tumor-associated macrophage-secreted IL-6 showed a synergistic effect to activate the JAK2/p-STAT3 pathway in cancer cells. CONCLUSIONS: ALKBH5 promotes non-small cell lung cancer progression by regulating cancer and tumor-associated macrophage behavior through the JAK2/p-STAT3 pathway and the expression of CCL2 and CXCL10, respectively. These findings suggest that targeting ALKBH5 is a promising strategy of enhancing the anti-tumor immune response in patients with NSCLC and that identifying ALKBH5 status could facilitate prediction of clinical response to anti-PD-L1 immunotherapy.

STING mediates LPS-induced acute lung injury by regulating ferroptosis.

The pathogenesis of acute lung injury is not fully understood. Stimulator of interferon genes (STING) and ferroptosis have been implicated in various pathological and physiological processes, including acute lung injury (ALI). However, the relationship between STING and ferroptosis in lipopolysaccharide (LPS)-induced ALI is unclear. We found that LPS stimulation activated STING and ferroptosis. Furthermore, STING knockout and ferroptosis inhibitor alleviated lung inflammation and epithelial cell damage. Also, STING knockout reduced inflammation injury and ferroptosis. Notably, the ferroptosis inducer reversed the alleviation of inflammation caused by STING knockout. These results show that STING participates in the inflammation injury of ALI by regulating ferroptosis. Results also showed that p-STAT3 levels increased after STING knockout, suggesting that STING negatively regulates STAT3 activation. Besides, STAT3 inhibitor aggravated ferroptosis after STING knockout, indicating that STING regulates ferroptosis through STAT3 signaling. In conclusion, STING mediates LPS-induced ALI by regulating ferroptosis, indicating that STING and ferroptosis may be new targets for ALI treatment.

Association between baseline office blood pressure level and the incidence and development of long-term frailty in the community-dwelling very elderly with hypertension.

Frailty is the most important risk factor causing disability in the elderly. Hypertension is one of the most common chronic diseases in the elderly and is closely related to frailty, but there is still controversy about the association between blood pressure and frailty. To explore the association between baseline blood pressure level and the incident and development of long-term frailty in the community-dwelling very elderly (i.e., over 80 years old [1]) with hypertension, in order to provide a basis for scientific blood pressure management of very elderly hypertension. In this study, very elderly hypertensive patients who received comprehensive geriatric assessment from January to June 2019 and with complete data were included, and follow-up was conducted from January 1 to February 14, 2023. A total of 330 very elderly individuals with hypertension were enrolled in this study. FRAIL scale was used to evaluate frailty. Binomial logistic regression analysis was used to calculate the OR and 95%CI between baseline systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP) levels and long-term incident and development of frailty. The dose-response relationship between baseline office SBP, DBP or PP levels and incident frailty and its development was analyzed by Generalized Additive Model (GAM) using smooth curve fitting and threshold effect analysis. Smooth curve fitting and threshold effect analysis showed that the relationship between baseline office SBP level and incident frailty was U-shaped, with the nadir of the U-shaped curve at 135 mmHg after adjustment. Baseline office SBP, PP level and development frailty was U-shaped and the nadir was 140 mmHg and 77 mmHg. In the community-dwelling very elderly with hypertension, baseline office SBP level had a relationship with long-term incident frailty and its development and PP level had a relationship with long-term development of frailty.

E3 ubiquitin ligase RNF6 promotes antiviral immune responses through enhancing the expression of interferon stimulated genes in myeloid cells.

Interferon signaling is closely associated with clearance of viral infections as well as the development of systemic lupus erythematosus (SLE). Therefore, from a clinical perspective, it is important to identify the key regulators involved in interferon signaling pathways. In this study, we identified that RNF6, as an interferon inducible E3 ubiquitin ligase, promoted the interferon-dependent antiviral response. Knock-down of RNF6 greatly attenuated expression of ISGs and the transcriptional activity of ISRE. Specifically, increased RNF6 expression in myeloid cells of patients with SLE correlated with high expression of ISGs. Our results uncover RNF6 as a positive mediator in the antiviral immune responses and suggest that RNF6 may contribute to predict interferon signaling in SLE.

Application of an innovative grid-based surveillance strategy to ensure elimination and prevent reintroduction of malaria in high-risk border communities in China.

Grid management is a grassroots governance strategy widely implemented in China since 2004 to improve the government's efficiency to actively find and solve problems among populated regions. A grid-based strategy surveillancing high-risk groups, including mobile and migrant populations (MMPs), in the China-Myanmar border region has played an indispensable role in promoting and consolidating the malaria elimination efforts by tracking and timely identification of potential importation or re-establishment of malaria among MMPs. A sequential mixed methods was implementated to explore the operational mechanism and best practices of the grid-based strategy including through the focus group discussions (FGDs), comparison of before and after the implementation of a grid-based strategy in the field sites, and data collection from the local health system.This paper distills the implementation mechanism and highlights the role of the grid-based strategy in the elimination and prevention of re-establishment of malaria transmission.

Host stimulator of interferon genes is essential for the efficacy of anti-programmed cell death protein 1 inhibitors in non-small cell lung cancer.

The stimulator of interferon genes (STING) pathway is important for anticancer immune responses. However, the relative contributions of host and tumour STING in anti-programmed cell death protein 1 (anti-PD-1) inhibitor responses in non-small cell lung cancer (NSCLC) are unknown. STING expression in tumour and blood was associated with anti-PD-1 therapy in NSCLC patients; Moreover, loss of PD-1 inhibitor therapeutic potency was demonstrated in STING KO (knock out) splenocytes and STING KO mice. STING knock-down in tumour cells had no effect. STING on CD8+ T cells and host cells, not tumour cells, correlated with clinical effect of anti-PD-1 therapy in NSCLC patients. Finally, adoptive transfer of CD8+ T cells restored PD-1 inhibitor anticancer effects. STING in host cells but not in tumour cells mediates anti-PD-1 inhibitor responses in cancer immunotherapy and could be used to select advantageous NSCLC patients from immunotherapy.

Role of international network on surveillance and response system leading to malaria elimination: China's engagement in global health.

China has accumulated multiple practices and experiences in building and enhancing malaria surveillance and response system. As China's engagement into global health has gathered stronger momentum than ever, China together with the Swiss Tropical and Public Health Institute and WHO has organised five sessions of the International Forum on Surveillance-Response System Leading to Tropical Diseases Elimination during 2012-2020, in which malaria elimination has always been one of the hottest topics. In this study, the roles of international network on the surveillance and response system were explored to achieve a global malaria-free goal. China's approach to malaria elimination has demonstrated significance of global collaboration on taking joint prevention and control, and building a worldwide institutional-based network.

A Case Study on the Disease Burden and Influencing Factors of Imported Malaria Patients in a County-Level Hospital - Guangxi Zhuang Autonomous Region, China, 2016-2019.

WHAT IS ALREADY KNOWN ON THIS TOPIC?: Imported malaria cases endanger people's health and potentially cause local re-transmission, and they may also cause economic loss on patients' families and society as a whole. WHAT IS ADDED BY THIS REPORT?: This is the first report to focus on the disease burden of a case study incurred by the imported malaria. The results indicated that the median direct medical cost was 2,904.4 CNY and the median indirect cost was 242.0 CNY for a patient's hospitalization. The economic cost was related to age, time between onset and diagnosis, and days of stay in hospital. WHAT ARE THE IMPLICATIONS FOR PUBLIC HEALTH PRACTICE?: This study analyzed the main causes based on both direct and indirect economic loss of imported malaria cases to provide general information for the evaluation of the disease burden of imported malaria patients and shed light on the rational allocation of medical resources.

Challenges of Sustaining Malaria Community Case Management in 81 Township Hospitals along the China-Myanmar Border Region - Yunnan Province, China, 2020.

What is already known on this topic? The health workforce at township hospitals in the China-Myanmar border region has played a key role in sustaining Community case management of malaria (CCMm), while few studies have investigated their performance and challenges. What is added by this report? Sustaining CCMm in the region was subject to the following major challenges: insufficient training on malaria diagnosis and testing, lacking necessary and timely treatment for patients, and risks of instability among the malaria workforce. What are the implications for public health practice? These challenges called for the national and provincial authorities to provide regular trainings and intensive supervision to strengthen malaria diagnosis and treatment capacity in the region and to set up incentive mechanisms and individual career development paths to sustain the workforce.

Evaluation of the Lung Immune Prognostic Index in Non-Small Cell Lung Cancer Patients Treated With Systemic Therapy: A Retrospective Study and Meta-Analysis.

The lung immune prognostic index (LIPI) has been shown to be an important prognostic marker for various tumors. However, the prognostic value of LIPI among non-small cell lung cancer (NSCLC) patients treated with systemic therapy remains controversial. We aimed to evaluate survival status according to LIPI among NSCLC patients receiving different forms of systemic therapy at our institution. We also performed a meta-analysis of articles from PubMed and Embase to illustrate this question. For our cohort, we found that good LIPI was associated with better overall survival (OS) among 91 patients on immunotherapy, 329 patients on targeted therapy, and 570 patients on chemotherapy. For the meta-analysis, a total of eight studies with 8,721 patients were included. Pooled results showed that a higher LIPI (those with 1 or 2 factors) was associated with poor overall progression-free survival (PFS) (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.45-1.71) and OS (HR, 2.01; 95% CI, 1.75-2.31). Subgroup analyses showed that a higher LIPI was related to poor survival among patients prescribed different systemic therapies: immunotherapy (OS HR, 2.50; 95% CI, 1.99-3.13; PFS HR, 1.77; 95% CI, 1.56-2.01), chemotherapy (OS HR, 1.58; 95% CI, 1.34-1.86; PFS HR, 1.38; 95% CI, 1.23-1.55), and targeted therapy (OS HR; 2.15, 95% CI, 1.57-2.96; PFS HR, 1.60; 95% CI, 1.25-2.06). The study shows that the LIPI is a clinically significant prognostic factor for NSCLC patients receiving systemic therapy. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420209009.

Deployment of workforce in global health: what should be the priorities for China?

BACKGROUND: China has increasingly emerged as an important player in global health. However, compared to developed countries, China still lacks a sufficient health workforce for global health engagement with the necessary competencies required. The world has recognized that to solve global health issues, the role of China needs to be strengthened. The priorities for the deployment of the Chinese workforce in global health remain unclear. This study aims to identify the priorities of the deployment of Chinese global health workforce by exploring the core competencies for Chinese global health workforce, factors influencing the deployment and the approach of deployment. METHODS: Quantitative descriptive statistical analysis was applied to analyze the quantitative data. A total of 148 key respondents from 10 provinces in China conducting global health projects over the last 3 years were selected as the study subjects. A structured questionnaire was developed to collect the data on four aspects, including general information, core competencies, factors influencing deployment, and mode of deployment. The questionnaire was distributed to the respondents through an online survey. All original data were exported to Microsoft Excel 2010 to calculate the frequencies and percentages of each option. A descriptive analysis was carried out of the priorities of deployment of the Chinese global health workforce. RESULTS: More than half of the respondents (51.4%, 76/148) regarded "communication" as the most important competency of the Chinese global health workforce, while a large proportion of participants from Chinese embassies (50.0%, 6/12) and international organizations (75.0%, 12/16) believed that "professional skills" were paramount. In addition, 58.1% (86/148) of the participants agreed that incentive factors (salary, professional position, etc.) were the main factors that influenced deployment, whereas 75% (12/16) of participants from international organizations emphasized "security" as the most important determinant. In addition, 60.8% (90/148) of the participants thought that the deployment of staff should be based on the needs of the global health project implementation. CONCLUSIONS: This study highlights the deployment priorities of the Chinese global health workforce, including strengthening communication and professional skills, focusing on personal security and incentives, and catering to the project implementation. This study also highlights the importance of Chinese agencies in developing global health mindsets through global health practices and proactive integration within the global community.

Association of MUC19 Mutation With Clinical Benefits of Anti-PD-1 Inhibitors in Non-small Cell Lung Cancer.

Although anti-PD-1 inhibitors exhibit impressive clinical results in non-small cell lung cancer (NSCLC) cases, a substantial percentage of patients do not respond to this treatment. Moreover, the current recommended biomarkers are not perfect. Therefore, it is essential to discover novel molecular determinants of responses to anti-PD-1 inhibitors. We performed Whole Exome Sequencing (WES) in a cohort of 33 Chinese NSCLC patients. Patients were classified into the durable clinical benefit (DCB) and no durable benefit (NDB) groups. Infiltrating CD8+ cells in the tumor microenvironment (TME) were investigated by immunohistochemistry. We also used public datasets to validate our results. In our cohort, good clinical responses to anti-PD-1 inhibitors were more pronounced in younger patients with lower Eastern Cooperative Oncology Group (ECOG) scores and only extra-pulmonary metastasis. More importantly, we identified a novel MUC19 mutation, which was significantly enriched in DCB patients (P = 0.015), and MUC19-mutated patients had a longer progression-free survival (PFS) (hazard ratio = 0.3, 95% CI 0.1-0.9; P = 0.026). Immunohistochemistry results indicated that the MUC19 mutation was associated with increased infiltration by CD8+ T cells in the TME (P = 0.0313). When combining MUC19 mutation with ECOG scores and intra-pulmonary metastasis status, patients with more positive predictors had longer PFS (P = 0.003). Furthermore, MUC19 mutation was involved in immune responses and associated with a longer PFS in the Memorial Sloan-Kettering Cancer Center (MSKCC) cohort. Collectively, we identified that MUC19 mutations were involved in immune responses, and NSCLC tumors harboring mutated MUC19 exhibited good responses to anti-PD-1 inhibitors.

Serum Exosomal miRNA Might Be a Novel Liquid Biopsy to Identify Leptomeningeal Metastasis in Non-Small Cell Lung Cancer.

PURPOSE: The survival time of patients with leptomeningeal metastasis (LM) of lung cancer is very short, and the clinical characteristics of LM are varied, making the clinical diagnosis difficult. At present, a positive CSF fluid (CSF) cytology result remains the gold standard for diagnosing LM in lung cancer; however, the process of collecting CSF is traumatic and far less convenient than blood collection. With the development in technology, an increasing number of studies prefer to use liquid biopsy to diagnose or predict the occurrence of the disease. Therefore, we aimed to explore whether serum exosomal miRNA can replace miRNA from CSF to identify or predict the occurrence of LM. PATIENTS AND METHODS: Herein, four pairs of serum and CSF samples were collected at four different time points from a patient with LM from non-small cell lung cancer (NSCLC). Serum and CSF exosomes were extracted. Western blot (CD63, TSG101) and electron microscope analyses were used to verify exosome extraction, after which exosomal miRNA sequencing was performed. Next, exosomal miRNA from serum and CSF samples from seven patients with LM and 30 patients without LM were collected for validation. RESULTS: Sequencing results of serum exosomal miRNA and CSF exosomal miRNA showed that there were 44 exosomal miRNAs stably co-expressed at four different time points. Then, three common miRNAs related to LM were found (hsa-miR-483-5p, hsa-miR-423-5p, and hsa-miR-342-5p). Subsequently, exosomal miRNA was extracted from serum and CSF samples from seven patients with LM and 30 patients without LM for verification, and the expression of these exosomal miRNA was detected. The results showed that miRNA-483-5p and miRNA-342-5p significantly differed in LM-/+ patients (P = 0.0142 and P = 0.0031, respectively), whereas miRNA-423-5p had no difference (P = 0.0921). Additionally, as the symptoms improved, the expression of these miRNAs decreased or remained stable. CONCLUSION: Serum exosomal miRNA (hsa-miR-483-5p, and hsa-miR-342-5p) may be involved in LM of lung cancer and may replace CSF to predict LM in NSCLC.

Antibiotic exposure windows and the efficacy of immune checkpoint blockers in patients with cancer: a meta-analysis.

BACKGROUND: Immune checkpoint blockers (ICBs) improve the survival of patients with cancer, but primary or acquired drug resistance is inevitable. Intestinal microorganisms play an important role in immunotherapy and antitumor response, and antibiotic use can cause changes in intestinal microbial abundance and diversity. At present, the effects of antibiotic exposure on the anticancer activity of immunotherapy remain controversial. METHODS: We performed a meta-analysis of relevant studies retrieved from electronic databases to assess the effects of the time window of antibiotic exposure on the efficacy of immune checkpoint inhibitors (ICIs). In accordance with the definition of antibiotic use in different articles, the time window of antibiotic exposure was divided into three groups, namely, Groups 1 (antibiotic use within 2 months before or after ICI), 2 (antibiotic use before ICI), and 3 (antibiotic use anytime during ICI). RESULTS: After retrieval from the PubMed and the Embase databases, 39 cohorts were included. In group 1, progression-free survival [PFS; hazard ratio (HR) =1.81, 95% confidence interval (CI): 1.40-2.34] and overall survival (OS; HR =1.81, 95% CI: 1.43-2.28) were prolonged in patients without antibiotic use. In group 2, the subgroup analysis showed that antibiotic use had no effect on PFS (HR =0.90, 95% CI: 0.65-1.26) and OS (HR =1.53, 95% CI: 0.89-2.62) when the exposure window defined as 0-3 months. In Group 3, pooled results indicated that PFS (HR =0.78, 95% CI: 0.65-0.93) was prolonged in patients with antibiotic during immunotherapy, and no difference was observed in the OS data (HR =0.98, 95% CI: 0.78-1.24) between the patients with antibiotic and without antibiotic. CONCLUSIONS: Antibiotic use in shortly time (within before or after 2 months) around the initiation of immunotherapy was remarkably related to the efficacy of ICIs. A different scenario could be observed that during the long-term treatment of ICIs, the effect of antibiotic exposure seems to be eliminated.

Low-dose carboplatin reprograms tumor immune microenvironment through STING signaling pathway and synergizes with PD-1 inhibitors in lung cancer.

Although the combination of chemotherapy and immunotherapy is a hot topic in lung cancer, little is understood regarding the possible mechanisms behind their synergy. Moreover, safety is a major concern for clinicians while performing chemotherapy. Therefore, it is important to determine the appropriate dose and period of chemotherapy for combining it with immunotherapy, and investigate the underlying synergistic mechanism. Here, we showed that carboplatin can induce DNA damage and activate the canonical STING/TBK1/IRF3 pathway and non-canonical STING-NF-κB signaling complex. Further, low-dose carboplatin changed the "cold" tumor into a "hot" tumor via the signaling hub STING, augmenting CD8+ T-cell infiltration, increasing PD-L1 expression, and hence potentiating the anti-tumor effect of PD-1 inhibitors; importantly, there were no adverse effects. Furthermore, knocking down STING in tumor cells effectively reversed PD-L1 upregulation and STING pathway activation, and reduced the anti-tumor effect of low-dose carboplatin and carboplatin-PD-1 inhibitor combination. Our findings collectively reported a previously unexplored role of low-dose carboplatin targeting in the STING pathway and provided an economical, useful and safe option for improving the efficacy of PD-1 inhibitors in lung cancer.