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Abstract Bronchopulmonary dysplasia (BPD) is the predominant chronic lung disease in preterm infants, linked with various adverse long-term outcomes. Multiple prenatal and postnatal risk factors can impede lung development, leading to BPD. Current management of BPD relies heavily on pharmacotherapies and alterations in ventilatory strategies. However, these interventions only mitigate BPD symptoms without addressing underlying alveolar, vascular, structural, and functional deficiencies. Given the retarded lung development in infants with BPD and the limitations of existing modalities, new therapeutic approaches are imperative. The induced differentiation of stem/progenitor cells and the spatiotemporal expression patterns of growth factors associated with lung developmental processes are critical for lung development reactivation in BPD, which focuses on stimulating pulmonary vasculogenesis and alveolarization. This review summarizes the process of lung development and offers a comprehensive overview of advancements in therapies designed to reinitiate lung development in BPD. Furthermore, we assessed the potential of these therapies for maintaining lung homeostasis and effectively restoring pulmonary structure and function through stem/progenitor cells and growth factors, which have been widely researched.

Abstract Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in infants and the most frequent adverse outcome of premature birth, despite major efforts to minimize injury. It is thought to result from aberrant repair response triggered by either prenatal or recurrent postnatal injury to the lungs during development. Intrauterine inflammation is an important risk factor for prenatal lung injury, which is also increasingly linked to BPD. However, the specific mechanisms remain unclear. This review summarizes clinical and animal research linking intrauterine inflammation to BPD. We assess how intrauterine inflammation affects lung alveolarization and vascular development. In addition, we discuss prenatal therapeutic strategies targeting intrauterine inflammation to prevent or treat BPD.

The endometrium is essential to the development of embryos and pregnancy. Human umbilical cord mesenchymal stem cells (HUCMSCs) are promising stem cell sources. HUCMSCs self-renew quickly and are painless to collect. Spermidine is an inherent polyamine needed for cellular and molecular processes that regulate physiology and function. HUCMSCs and spermidine (SN) may heal intrauterine adhesions. HUCMSCs were investigated for endometrial repair in rats. Composite hydrogels are used for medical exosome implantation, including their materials, properties, and embedding procedures. This study examined whether bioengineered hydrogel-loaded exosomes from HUCMSCs and spermidine prenatally improved conception rates in mice with poor endometrial lining. The data show that HUCMSC and SN provide a good experimental base for HUCMSC safety and intrauterine treatment in rats. Western blots, exosome structural analysis, pregnancy outcomes, flow cytometry, H&E staining, immunohistochemistry, and immunofluorescence labelling found and recovered the aberrant area. HUCM-derived stem cells and spermidine-derived exosomes biophysically match. These traits strengthen and prolong endometrial function. Pregnant rats with HUCMSC and SN had thinner endometrium. Hydrogel-incorporated HEHUCMSC and SN exosomes may improve IUI in rats with thin endometrium.

Abstract Background Buyang Huanwu Decoction (BYHWD) is a traditional Chinese medicine to treat the syndrome of qi deficiency and blood stasis. Platelets play an important role in regulating thrombus and inflammation after ischemic injury, studies have shown that BYHWD regulate myocardial fibrosis and exert anti-inflammatory effects through IL-17 and TLR4 pathways, but the mechanism of platelet activation by BYHWD in stable coronary heart disease is still unknown. In the present study, model of left anterior descending coronary artery ligation was applied to investigate the mechanisms of BYHWD on modulating platelets hyperreactivity and heart function after fibrosis of ischemic myocardial infarction (MI). Methods Myocardial infarction model was constructed by ligation of the left anterior descending coronary artery. The rats were randomly divided into five groups: sham, model, MI with aspirin (positive), MI with a low dosage of BYHWD (BYHWD-ld) and MI with a high dosage of BYHWD (BYHWD-hd) for 28 days. Results Coronary artery ligation prominently induced left ventricle dysfunction, increased cardiomyocyte fibrosis, which was accompanied by platelets with hyperreactivity, and high levels of inflammatory factors. BYHWD obviously reversed cardiac dysfunction and fibrosis, increased the thickness of the left ventricular wall, and inhibited aggregation ratio and CD62p expression. BYHWD restored the mitochondrial respiration of platelets after MI, concomitant with an increased telomere expression and decreased inflammation. According to the result of transcriptome sequencing, we found that 106 differentially expressed genes compared model with BYHWD treatment. Enrichment analysis screened out the Ras-related protein Rap-1 (Rap1) signaling pathway and platelet activation biological function. Quantitative real-time PCR and Western blotting were applied to found that BYHWD reduced the expression of Rap1/PI3K-Akt/Src-CDC42 genes and attenuated the overactivity of PI3 kinase/Rap1/integrin α(IIb)β(3) pathway. Conclusion BYHWD reduced inflammation and platelet activation via the PI3 kinase/Rap1/integrin α(IIb)β(3) pathway and improved heart function after MI. Graphical Abstract

Abstract Background Antibiotic resistance is a serious global public health issue. However, there are few reports on trends in antimicrobial susceptibility in Chinese neonates, and most of the existing evidence has been derived from adult studies. We aimed to assess the trends in antimicrobial susceptibility of common pathogens in full-term neonates with invasive bacterial infections (IBIs) in China. Methods This cross-sectional survey study analyzed the antimicrobial susceptibility in Chinese neonates with IBIs from 17 hospitals, spanning from January 2012 to December 2021. Joinpoint regression model was applied to illustrate the trends and calculate the average annual percentage change (AAPC). Using Mantel-Haenszel linear-by-linear association chi-square test, we further compared the antibiotic minimum inhibitory concentrations (MICs) by pathogens between 2019 and 2021 to provide precise estimates of changes. Results The proportion of Escherichia coli with extended-spectrum-beta-lactamase-negative strains increased from 0.0 to 88.5% (AAPC = 62.4%, 95% confidence interval (CI): 44.3%, 82.9%), with two breakpoints in 2014 and 2018 (p-trend

DNA plays an indispensable role in ensuring the perpetuation of life and safeguarding the genetic stability of living organisms. The emergence of diseases linked to a wide spectrum of responses to DNA damage has garnered increasing attention within the scientific community. There is growing evidence that patterns of DNA damage response in the lungs are associated with the onset, progression, and treatment of chronic lung diseases such as chronic obstructive pulmonary disease (COPD), asthma, and bronchopulmonary dysplasia (BPD). Currently, some studies have analyzed the mechanisms by which environmental factors induce lung DNA damage. In this article, we summarize inducible factors of lung DNA damage, current indicators, and methods for diagnosing DNA damage in chronic lung diseases and explore repair mechanisms after DNA damage including nonhomologous end-joining and homology-directed repair end joining pathways. Additionally, drug treatments that may reduce DNA damage or promote repair after it occurs in the lungs are briefly described. In general, more accurate assessment of the degree of lung DNA damage caused by various factors is needed to further elucidate the mechanism of lung DNA damage and repair after damage, so as to search for potential therapeutic targets.

Cervical cancer (CC) is a malignant tumor of the female reproductive system that typically occurs in cervical cells and has high incidence and mortality rates, strong metastatic ability, and poor prognosis. Asiatic acid (AA) exhibits anti-inflammatory, anti-depressant, and anti-tumor effects. However, the molecular targets and mechanisms underlying AA-mediated inhibition of CC metastasis remain unclear. AA affects the proliferation, metastasis, and epithelial-mesenchymal transition (EMT) process of CC cell lines. MTT experiments verified that AA inhibited the proliferation ability of CC cells, and the effect of AA on the lateral and longitudinal migration ability of CC was evaluated through wound healing and Transwell assays. Western blotting was used to explore whether AA inhibits EMT process in HeLa and C33a cells. Currently, targeting the PI3K/AKT/mTOR pathway as a strategy for cancer treatment remains an evolving field. However, the molecular mechanism by which AA inhibits CC via the PI3K/AKT/mTOR pathway remains unclear and requires further investigation.

Anthracyclines represent a highly efficacious class of chemotherapeutic agents employed extensively in antitumor therapy. They are universally recognized for their potency in treating diverse malignancies, encompassing breast cancer, gastrointestinal tumors, and lymphomas. Nevertheless, the accumulation of anthracyclines within the body can lead to significant cardiac toxicity, adversely impacting both the survival rates and quality of life for tumor patients. This limitation somewhat restricts their clinical utilization. Determining how to monitor and mitigate their cardiotoxicity at an early stage has become an urgent clinical problem to be solved. Therefore, this paper reviews the mechanism of action, early monitoring, and strategies for the prevention of anthracycline-induced cardiotoxicity for clinical reference.

The role of cellular senescence in age-related diseases has been fully recognized. In various age-related-chronic lung diseases, the function of alveolar epithelial cells (AECs) is impaired and alveolar regeneration disorders, especially in bronchopulmonary dysplasia，pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD), cancer, etc. Except for age-related-chronic lung diseases, an increasing number of studies are exploring the role of cellular senescence in developmental chronic lung diseases, which typically originate in childhood and even in the neonatal period. This review provides an overview of cellular senescence and lung diseases from newborns to the elderly, attempting to draw attention to the relationship between cellular senescence and developmental lung diseases.

Abstract Background Myocardial ischemia/reperfusion injury (MI/RI) is involved in a variety of pathological states for which there is no effective treatment exists. Shuangshen Ningxin (SSNX) capsule which is developed by Xiyuan Hospital, Chinese Academy of Traditional Chinese Medicine has been demonstrated to alleviate MI/RI, but its mechanism remains to be further elucidated. Methods The MI/RI miniature pigs model was constructed to assess the pharmacodynamics of SSNX by blocking the proximal blood flow of the left anterior descending branch of the cardiac coronary artery through an interventional balloon. The principal chemical compounds and potential targets of SSNX were screened by HPLC–MS and SwissTargetPrediction. The targets of MI/RI were identified based on Online Mendelian Inheritance in Man (OMIM) and GeneCards. Cytoscape 3.9.0 was applied to construct a protein–protein interaction (PPI) network, and Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed using metascape. To further validate the mechanism of SSNX, Molecular docking, Transmission electron microscopy, and Western blot analysis were used to test the effectiveness of targets in related pathways. Results Our results indicated that SSNX significantly improved cardiac function, attenuated myocardial I/R injury. Through network analysis, a total of 15 active components and 201 targets were obtained from SSNX, 75 of which are potential targets for the treatment of MI/RI. KEGG and MCODE analysis showed that SSNX is involved in the mitophagy signaling pathway, and ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rb2 are key components associated with the mitophagy. Further experimental results proved that SSNX protected mitochondrial structure and function, and significantly reduced the expression of mitophagy-related proteins PTEN-induced putative kinase 1 (PINK1), Parkin, FUN14 domain containing 1 (FUNDC1) and Bcl-2/E1B-19 kDa interacting protein 3 (BNIP3) in MI/RI miniature pigs. Conclusion In our study, the integration of network pharmacology and experiments in vivo demonstrated that SSNX interfered with MI/RI by inhibiting mitophagy.

Background: Whether minimally invasive esophagectomy (MIE) is superior to open esophagectomy (OE) in the treatment of esophageal squamous cell carcinoma (ESCC) is still uncertain. Therefore, this multicenter prospective study aimed to compare MIE with OE in postoperative parameters and long-term survival. Methods: All hospitalized patients with cT1b-3N0–1M0 thoracic ESCC treated by MIE or OE were enrolled from 19 selected centers from April 1, 2015 to December 31, 2018. The propensity score matching (PSM) was performed to minimize the selection bias. The basic clinicopathological characteristics and 3-year overall survival (OS) as well as disease-free survival (DFS) of two groups were compared by R version 3.6.2. Results: MIE were performed in 1,387 patients and OE in 335 patients. 335 cases in each group were finally matched by PSM, and no significant differences in the essential demographic characteristics were observed between the MIE and OE groups after PSM. Compared with OE, MIE had significantly less intraoperative bleeding, less total drainage volume, shorter postoperative hospital stay, and harvested significantly more lymph nodes (LNs) (all P < 0.001). There were no significant differences in the major postoperative complications and death rates between MIE and OE. The 3-year OS and DFS were 77.0% and 68.1% in the MIE group versus 69.3% and 60.9% in the OE group (OS: P = 0.03; DFS: P = 0.09), and the rates were 75.1% and 66.5% in the MIE group versus 66.9% and 58.6% in the OE group for stage cII patients (OS: P = 0.04, DFS: P = 0.09), respectively. Conclusions: Compared with OE, MIE is a safe and effective treatment approach with similar mortality and morbidity. It has the advantages in harvesting more LNs, improving postoperative recovery and survival of stage cII ESCC patients.

Abstract Background Bronchopulmonary dysplasia (BPD) is the most common and serious chronic lung disease in preterm infants with pathological characteristics of arrested lung development. DNA double-strand breaks (DSBs) are a serious manifestation of oxidative stress damage, but little is known about the role of DSBs in BPD. The current study set out to detect DSB accumulation and cell cycle arrest in BPD and study the expression of genes related to DNA damage and repair in BPD through DNA damage signaling pathway-based PCR array to determine a suitable target to improve arrested lung development associated with BPD. Methods DSB accumulation and cell cycle arrest were detected in a BPD animal model and primary cells, then a DNA damage signaling pathway-based PCR array was used to identify the target of DSB repair in BPD. Results DSB accumulation and cell cycle arrest were shown in BPD animal model, primary type II alveolar epithelial cells (AECII) and cultured cells after exposure to hyperoxia. Of the 84 genes in the DNA damage-signaling pathway PCR array, eight genes were overexpressed and 11 genes were repressed. Rad1, an important protein for DSB repair, was repressed in the model group. Real-time PCR and western blots were used to verify the microarray results. Next, we confirmed that silencing Rad1 expression aggravated the accumulation of DSBs and cell cycle arrest in AECII cells, whereas its overexpression alleviated DSB accumulation and cell cycle arrest. Conclusions The accumulation of DSBs in AECII might be an important cause of alveolar growth arrest associated with BPD. Rad1 could be an effective target for intervention to improve this arrest in lung development associated with BPD.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that disrupts cognitive function and severely affects the quality of life. Existing drugs only improve cognitive function and provide temporary relief of symptoms but do not stop or delay disease progression. Recently, natural medicines, especially Chinese herbal medicines, have gained attention in the treatment of AD due to their antioxidant, anti-inflammatory, and neuroprotective effects. However, conventional oral dosage forms lack brain specificity and have side effects that lead to poor patient compliance. Utilizing nanomedicine is a promising approach to improve brain specificity, bioavailability, and patient compliance. This review evaluates recent advances in the treatment of AD with nanoparticles containing various natural medicines. This review highlights that nanoparticles containing natural medicines are a promising strategy for the treatment of AD. It is believed that this technology can be translated into the clinic, thereby providing opportunities for AD patients to participate in social activities.

Oxygen therapy is common during the neonatal period to improve survival, but it can increase the risk of oxygen toxicity. Hyperoxia can damage multiple organs and systems in newborns, commonly causing lung conditions such as bronchopulmonary dysplasia and pulmonary hypertension, as well as damage to other organs, including the brain, gut, and eyes. These conditions are collectively referred to as newborn oxygen radical disease to indicate the multi-system damage caused by hyperoxia. Hyperoxia can also lead to changes in metabolic pathways and the production of abnormal metabolites through a process called metabolic reprogramming. Currently, some studies have analyzed the mechanism of metabolic reprogramming induced by hyperoxia. The focus has been on mitochondrial oxidative stress, mitochondrial dynamics, and multi-organ interactions, such as the lung–gut, lung–brain, and brain–gut axes. In this article, we provide an overview of the major metabolic pathway changes reported in hyperoxia-associated neonatal diseases and explore the potential mechanisms of metabolic reprogramming. Metabolic reprogramming induced by hyperoxia can cause multi-organ metabolic disorders in newborns, including abnormal glucose, lipid, and amino acid metabolism. Moreover, abnormal metabolites may predict the occurrence of disease, suggesting their potential as therapeutic targets. Although the mechanism of metabolic reprogramming caused by hyperoxia requires further elucidation, mitochondria and the gut–lung–brain axis may play a key role in metabolic reprogramming.

Abstract Background The role of adjuvant chemotherapy in patients with pathological lymph node‐positive (pN+) resectable esophageal squamous cell carcinoma (ESCC) remains unclear. We aimed to explore whether adjuvant chemotherapy could improve the overall survival (OS) of patients with pN+ ESCC and whether oral chemotherapy could be used as an alternative to intravenous chemotherapy. Methods The patients were divided into two groups: a surgery plus chemotherapy group (S + CT group, 400 patients) and a surgery alone group (S group, 582 patients). Propensity score matching (PSM) was used to create patient groups that were balanced across several covariates (n = 331 in each group). The survival rates of patients receiving oral chemotherapy (69 patients with S‐1 and 68 patients with tegafur tablets) and intravenous chemotherapy (263 patients) were compared using the Kaplan–Meier method. Results In the overall study cohort, the 3‐year OS was significantly higher in the S + CT group than in the S group (66.3% vs. 49.9%, p

Abstract Background The high false‐positive rate for pulmonary nodules (PNs) from using low‐dose computed tomography (LDCT) screening can lead to overuse of invasive procedures, overtreatment, and patient anxiety. Therefore, it is very important to develop new diagnostic methods. Methods A negative enrichment‐fluorescence in situ hybridization (NE‐FISH) approach was used to detect circulating tumor cells (CTCs) in patients with PNs. We evaluated whether or not the combination of CTC counts with serum tumor marker levels (CEA, CA 125, CYFRA 21‐1, SCC) could improve the diagnostic ability for distinguishing patients with malignant pulmonary nodules (MPNs) from those with benign pulmonary nodules (BPNs). Moreover, the potential clinical application of this combination for the diagnosis of solitary pulmonary nodules (SPNs) with a diameter ≤2 cm was also investigated. Results The combination of CTC counts and tumor marker levels had a sensitivity of 80.12% and the area under the receiver operating characteristics curve (AUCROC) of 0.853 (95% confidence interval [CI]: 0.800–0.897, p

Summary: Background: To evaluate the efficacy and safety of toripalimab combined with neoadjuvant chemoradiotherapy (NCRT) for locally advanced esophageal squamous cell carcinoma (ESCC). Methods: In this single arm, phase II trial, 44 ESCC patients were enrolled from December 2019 to July 2021 at Sun Yat-sen University Cancer Center (Guangzhou, China). All patients received concurrent radiotherapy (44 Gy in 20 fractions), chemotherapy (paclitaxel 50 mg/m2 and cisplatin 25 mg/m2 on days 1, 8, 15, and 22), and toripalimab (240 mg on days 1 and 22). Within 6–8 weeks of neoadjuvant treatment, patients underwent surgery. The results of the study patients were compared with those of 86 matched patients between July 2015 and March 2022. The primary endpoint was pathological complete response (pCR) rate, and the secondary endpoints were treatment-related adverse events and R0 rates. This trail was registered with ClinicalTrails.gov, NCT04006041. Findings: All patients received neoadjuvant treatment, and 42 completed esophagectomy. Of the 42 patients, 21 (50%; 95% CI 35–65) achieved pCR and 2 (5%) patients were ypT0N+. The R0 resection rate was 98% (41/42). Nine (20%) of 44 patients had grade 3/4 adverse events. Among the perioperative complications (n = 42), anastomotic leakage occurred in five cases (12%), tracheal fistula in three cases (7%), and postoperative death in one case (2%) due to tracheal fistula. Compared with the control cohort, the pCR rate of the study group was higher but without significant difference (50% vs. 36%, P = 0.19). Interpretation: Toripalimab combined with NCRT failed to show significantly better pCR rate than historical data. Nevertheless, considering the signs of efficacy and acceptable safety of this regimen, further evaluation in phase III randomized trials might be warranted. Funding: National Natural Science Foundation of China.

Despite remarkable breakthroughs in diagnosis and treatment, the prevalence of bronchopulmonary dysplasia (BPD) in preterm infants and the consequent mortality have remained high over the last half-century. The pathophysiology of BPD is complicated, with several causes. In addition, infants with severe BPD are predisposed to a variety of complications that need multidisciplinary collaboration during hospitalisation and post-discharge home treatment. Consequently, early prediction, precise prevention and individualised management have become the cornerstones of therapeutic care of preterm infants with BPD, thereby improving patient survival and prognosis. BPD has an operational clinical description; however, it has various clinical phenotypes and endotypes, making accurate prediction challenging. Currently, most approaches for predicting BPD in preterm infants include invasive collection of biofluids, which is inappropriate in fragile neonates. Consequently, researchers and clinicians are becoming more interested in noninvasive monitoring for BPD prediction. Comprehensive assessments of pertinent research, however, remain scarce. In this review, we compared many noninvasive monitoring techniques that contribute to early prediction of BPD development in premature infants.

Telomere wear and dysfunction may lead to aging-related diseases. Moreover, increasing evidence show that the occurrence, development, and prognosis of some pediatric diseases are also related to telomere dysfunction. In this review, we systematically analyzed the relationship between telomere biology and some pediatric congenital and growth-related diseases and proposed new theoretical basis and therapeutic targets for the treatment of these diseases.

Background: Chemosensory disorders associated with COVID-19 have been widely discussed during the pandemic. We performed a meta-analysis to assess the risk factors for olfactory and gustatory dysfunction in patients with COVID-19. Methods: Three databases (PubMed, Embase, and Cochrane Library) were searched for studies published between December 1, 2019, and August 31, 2021. We selected random-effects model or fixed-effects model to pool data based on heterogeneity. The results were reported as odds ratios (ORs) or standardized mean differences (SMDs) and the corresponding 95% confidence intervals (CIs). Heterogeneity was reported as I2. Results: Twenty-six studies with a total of 13,813 patients were included. The pooled data indicated that sex (OR 1.47; 95% CI 0.93–2.31), age (SMD −5.80; 95% CI −13.35 to 1.75), smoking (OR 2.04; 95% CI 0.72–5.79), and comorbidity (OR 1.21; 95% CI 0.58–2.53) of patients with COVID-19 had no effect on gustatory dysfunction. Olfactory dysfunction was more likely to occur in older patients with COVID-19 (SMD, −5.22; 95% CI, −8.28 to −2.16). Patients with COVID-19 with nasal congestion (OR 3.41; 95% CI 2.30–5.06) and rhinorrhea (OR 2.35; 95% CI 1.60–3.45) were more prone to olfactory dysfunction. Conclusion: These findings emphasize that older patients with COVID-19 are more likely to experience olfactory dysfunction. Symptoms of nasal congestion and rhinorrhea may affect the recognition of olfactory dysfunction.

Abstract Background The survival benefits of recurrent laryngeal nerve lymph node dissection (RLNLD) in esophageal squamous cell carcinoma (ESCC) are still under debate, and the prognostic value of unilateral RLNLD has been rarely studied. Therefore, the aim of the present study was to investigate the clinical significance and outcomes of RLNLD in ESCC in a large‐scale cohort study, to shed light on the outcomes of unilateral RLNLD, and to identify the factors that affect the prognostic outcome of RLNLD. Methods We retrospectively reviewed 1153 patients with thoracic ESCC who underwent right thoracotomy with lymphadenectomy. The impact of RLNLD on disease‐free survival (DFS) and overall survival (OS) was estimated using the Kaplan–Meier method and Cox proportional hazard models. Inverse probability of treatment weighting (IPTW) was performed to adjust for differences in baseline variables in pairwise comparisons. Subgroup analysis of survival and postoperative complications was conducted for selective RLNLD. Results RLN lymph node (LN) metastasis was independently associated with tumor location and most other LN station metastases. RLNLD was an independent prognostic factor for DFS and OS. Both patients who underwent unilateral and bilateral RLNLD had significantly better DFS and OS than the non‐RLNLD patients. Furthermore, pairwise comparisons with IPTW confirmed these results, and we found that patients who underwent bilateral RLNLD had better survival than those who underwent unilateral RLNLD. However, subgroup analysis showed that there was no survival benefit and higher morbidity after bilateral RLNLD for patients with cancer in the lower thoracic esophagus, and elderly and female patients. Conclusion RLN LN metastasis is very frequent in ESCC, and both unilateral and bilateral RLNLD have considerable survival benefits. Selective RLNLD with better survival and lower morbidity was recommend for some defined subgroups.

Based on the relationship between rockburst and microseismic event indicators, this study proposes that the risk of rockburst in mine working faces, roadways, and even the entire mine should be studied through the “double high” risk evaluation of microseismic events. The 43 evaluation indexes of rockburst were optimized into eight indexes by using the expert scoring method. Considering the eight indexes as the basic events and the “double high” risk of microseismic events as the top event, the “double high” accident tree of microseismic events was established. According to the qualitative analysis results of the accident tree, the microseismic activity evaluation index was determined, and the “double high” risk evaluation index system was constructed for microseismic events. The system included three first-level indicators and eight second-level indicators. The fuzzy hierarchical comprehensive evaluation model was used to evaluate the “double high” risk of microseismic events in the Yanbei Coal Mine. In this paper, a microseismic monitoring and evaluation index model is constructed to simplify the existing evaluation system, which is convenient to effectively establish the connection between microseismic monitoring data and rockburst index and provide important theoretical support for underground monitoring and rockburst prevention.

White matter damage (WMD) is a primary cause of cerebral palsy and cognitive impairment in preterm infants, and no effective treatments are available. Microglia are a major component of the innate immune system. When activated, they form typical pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes and regulate myelin development and synapse formation. Therefore, they may play a pivotal role in hypoxic–ischemic (HI) WMD. Herein, we investigated neural inflammation and long-term microglia phenotypic polarization in a neonatal rat model of hypoxia-ischemia-induced WMD and elucidated the underlying pathophysiological processes. We exposed 3-day-old (P3) Sprague−Dawley rats to hypoxia (8% oxygen) for 2.5 hr after unilateral common carotid artery ligation. The activation of NLRP3 inflammatory bodies, microglia M1/M2 polarization, myelination, and synaptic development in our model were monitored 7, 14, and 21 days after birth. In addition, the Morris water maze test was performed on postnatal Day 28. We confirmed myelination disturbance in the periventricular white matter, abnormal synaptic development, and behavioral changes in the periventricular area during the development of HI WMD. In addition, we found an association between the occurrence and development of HI WMD and activation of the NLRP3 inflammasome, microglial M1/M2 polarization, and the release of inflammatory factors. NLRP3 inhibition can play an anti-inflammatory role by inhibiting the differentiation of microglia into the M1 phenotype, thereby improving myelination and synapse formation. In conclusion, microglia are key mediators of the inflammatory response and exhibit continuous phenotypic polarization 7–21 days after HI-induced WMD. This finding can potentially lead to a new treatment regimen targeting the phenotypic polarization of microglia early after HI-induced brain injury.

Summary: Background: Neoadjuvant chemoradiotherapy (neoCRT) followed by surgery is the most common approach for locally advanced resectable esophageal squamous cell carcinoma (ESCC) patients. How neoCRT impacts ESCC tumor immune microenvironment (TIME) has not been fully understood. Methods: Single-cell RNA sequencing (scRNA-seq) was conducted to examine the neoCRT-driven cellular and molecular dynamics in 8 pre- and 7 post-neoCRT ESCC samples from 8 male patients. Findings: scRNA-seq data of about 112,000 cells were obtained. Expression programs of cell cycle, epithelium development, immune response, and extracellular structure in pre-treatment tumor cells were related to neoCRT response. Spearman correlation between CD8+ T cells' cytotoxicity and expression of checkpoint molecules was prominent in pre-neoCRT intermediate activated/exhausted CD8+ T cells. NeoCRT increased CD8+ T cells’ infiltration but promoted their exhaustion in both major and minor responders. NeoCRT promoted differentiation of Th but demoted that of Treg cells in major responders. Maturation of cDC1s and expression of M2 macrophage markers increased while the number of cDC2s decreased after neoCRT. Higher activities of immune-related pathways in pre-neoCRT CD8+ T cells and macrophages, as well as a pronounced decrease of them after neoCRT, correlated with better neoCRT response. Interactions between intermediate activated/exhausted CD8+ T and macrophages, cDC1s, and LAMP3+ cDCs decreased after neoCRT. Interpretation: Our comprehensive picture of the neoCRT-related immune changes provides deeper insights into immunological mechanisms associated with ESCC response to neoCRT, which may aid in future development of immune-strategies for improving ESCC treatment. Funding: This work was supported by the National Natural Science Foundation of China (82072607).

Multi-region sequencing of small cell lung cancers (SCLC) can improve our understanding of the disease. Here the authors analyse 120 multi-region samples from 40 SCLC patients with whole exome sequencing and characterise their mutational burden, evolution, heterogeneity, and potential prognostic biomarkers.

BackgroundBronchopulmonary dysplasia (BPD) is the most common neonatal chronic lung disease. However, its exact molecular pathogenesis is not understood. We aimed to identify relevant gene modules that may play crucial roles in the occurrence and development of BPD by weighted gene co-expression network analysis (WGCNA).MethodsWe used RNA-Seq data of BPD and healthy control rats from our previous studies, wherein data from 30 samples was collected at days 1, 3, 7, 10, and 14. Data for preprocessing analysis included 17,613 differentially expressed genes (DEGs) with false discovery rate

Abstract Background Tertiary lymphoid structures (TLSs) play key roles in tumour adaptive immunity. However, the prognostic value and molecular properties of TLSs in oesophageal squamous cell carcinoma (ESCC) patients have not been studied. Methods The prognostic values of the presence and maturation status of tumour‐associated TLSs were determined in 394 and 256 ESCC patients from Sun Yat‐sen University Cancer Center (Centre A) and the Cancer Hospital of Shantou University Medical College (Centre B), respectively. A deep‐learning (DL) TLS classifier was established with haematoxylin and eosin (H&E)‐stained slides using an inception‐resnet‐v2 neural network. Digital spatial profiling was performed to determine the cellular and molecular properties of TLSs in ESCC tissues. Results TLSs were observed in 73.1% of ESCCs from Centre A via pathological examination of H&E‐stained primary tumour slides, among which 42.9% were TLS‐mature and 30.2% were TLS‐immature tumours. The established DL TLS classifier yielded favourable sensitivities and specificities for patient TLS identification and maturation evaluation, with which 55.1%, 39.5% and 5.5% of ESCCs from Centre B were identified as TLS‐mature, TLS‐immature and TLS‐negative tumours. Multivariate analyses proved that the presence of mature TLSs was an independent prognostic factor in both the Centre A and Centre B cohorts (p < .05). Increased proportions of proliferative B, plasma and CD4+ T helper (Th) cells and increased B memory and Th17 signatures were observed in mature TLSs compared to immature ones. Intratumoural CD8+ T infiltration was increased in TLS‐mature ESCC tissues compared to mature TLS‐absent tissues. The combination of mature TLS presence and high CD8+ T infiltration was associated with the best survival in ESCC patients. Conclusions Mature TLSs improve the prognosis of ESCC patients who underwent complete resection. The use of the DL TLS classifier would facilitate precise and efficient evaluation of TLS maturation status and offer a novel probability of ESCC treatment individualization.

A honeycomb rotary wheel fabricated from sheet adsorbent of silica gel is a competitive drying facility for air dehumidification in modern drying and air conditioning industries due to its large contacting area (3,000 m2/m3) and the rapid diffusion of the adsorbate compared to silica gel pellets. The delicate preparation procedure of hygroscopic silica gel is paramount for improved adsorption capacity by optimizing the surface area, pore size, and pore volume of silica gel. In this article, silica gel adsorbent in a honeycomb rotary wheel was fabricated by neutralizing the impregnated water glass solution with a modulus of 3.3 on the glass fiber sheet of the honeycomb matrix using CO2 at different pressure at room temperature instead of corrosive acids. The as-obtained silica gel absorbent was characterized by XRD, scanning electron microscopy (SEM), specific surface area and pore size analysis, and dynamic vapor/gas sorption analysis. The results showed that the as-obtained silica gel adsorbent is uniform in size and tunable in terms of specific surface area, pore size, pore volume, and adsorption capacity by CO2 pressure. The typical silica gel fabricated by CO2 of 0.25 MPa with a specific surface area of 764.86 m2/g, an average micropore size with a diameter of 2.94 nm, and a pore volume of 0.45 ml/g delivers a saturated adsorption capacity of as high as 287.24 mg/g at RH 50%, which is the best in adsorption performance compared to the previously reported results. This provides a new strategy for environment-friendly manufacturing of silica gel adsorbent in honeycomb rotary wheels for air dehumidification.

Identification of molecular subtypes that reflect different prognoses and treatment responses, especially immune checkpoint inhibitors (ICIs) in esophageal squamous cell carcinoma (ESCC), is essential for treatment decisions. We performed targeted sequencing in 201 patients with ESCC to discover genetic subtypes and validate our findings via multiple data sets. We identified 3 driver genes (FCGBP, GRIN2B, and FRY), and recurrent truncating mutations in FRY impaired its tumor-suppressive function and promoted tumor proliferation. A 3-gene mutation signature (FAT1, FAT3, and FRY) recognized a molecular subtype named “FAT/FRY” with frequent Hippo pathway–related mutations. In multiple ESCC cohorts, the patients with the FAT/FRY subtype had poorer prognosis than did patients in the WT group. Transcriptome analysis indicated that the FAT/FRY subtype was characterized by inactivation of the Hippo pathway, hypoxia, chemoresistance, higher infiltration of CD8+ T cells and activated DCs, and a transcriptome similar to that of cancer responders. Furthermore, the 3-gene signature predicted better survival for patients treated with ICIs, partially explained by its positive correlation with the tumor mutation burden and neoantigen burden. The 3-gene signature is a biomarker to recognize the FAT/FRY molecular subtype, evaluate prognosis, and select potential beneficiaries of ICIs in ESCC.

Background and objectiveThere remains controversy regarding vitamin D deficiency and bronchopulmonary dysplasia (BPD) in very low birth weight (VLBW) and extremely low birth weight (ELBW) preterm infants. This study aimed to determine the prevalence of vitamin D deficiency assessed by umbilical cord blood 25-hydroxyvitamin D [25(OH)D] in preterm infants in northeast China and to evaluate the ability and optimal threshold of 25(OH)D for predicting BPD.MethodsThe clinical data of VLBW and ELBW preterm infants with known cord-blood 25(OH)D levels were analyzed retrospectively. Infants were divided into groups based on their cord-blood 25(OH)D levels and BPD diagnosis. Logistic regression was performed to assess the risk factors for BPD and a nomogram was established. Receiver operating characteristic (ROC) curve analysis was used to evaluate the optimal threshold of cord-blood 25(OH)D concentration for predicting BPD.ResultsA total of 267 preterm infants were included, of which 225 (84.3%) exhibited vitamin D deficiency and 134 (50.2%) were diagnosed with BPD. The incidence of BPD was lower in the group with a 25(OH)D level of >20 ng/ml than in the other groups (P = 0.024). Infants with BPD had lower cord-blood 25(OH)D levels than those without BPD (11.6 vs. 13.6 ng/ml, P = 0.016). The multivariate logistic regression model revealed that 25(OH)D levels (odds ratio [OR] = 0.933, 95% confidence interval [95% CI]: 0.891–0.977), gestational age (OR = 0.561, 95% CI: 0.425–0.740), respiratory distress syndrome (OR = 2.989, 95% CI: 1.455–6.142), and pneumonia (OR = 2.546, 95% CI: 1.398–4.639) were independent risk factors for BPD. A predictive nomogram containing these four risk factors was established, which had a C-index of 0.814. ROC curve analysis revealed that the optimal cutoff value of 25(OH)D for predicting BPD was 15.7 ng/ml (area under the curve = 0.585, 95% CI: 0.523–0.645, P = 0.016), with a sensitivity of 75.4% and a specificity of 42.9%.ConclusionsA cord-blood 25(OH)D level of

BackgroundThis study investigated whether 8-hydroxy-2’-deoxyguanosine (8-OHdG) and N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations in the urine could predict bronchopulmonary dysplasia (BPD) in preterm infants.MethodsThis prospective cohort study enrolled 165 preterm infants, of whom 70 developed BPD. We measured urinary 8-OHdG and NT-proBNP concentrations from day of life (DOL) 7 to 28. Then, we evaluated the prediction efficiency by receiver operating characteristic curves and assessed correlations between the two biomarkers. Finally, we identified the predictive risk factors for BPD by multivariable logistic regression.Results8-OHdG and NT-proBNP levels were significantly higher from DOL 7 to 28 in the BPD group than in the control group (P < 0.05). Additionally, the 8-OHdG level was positively correlated with the NT-proBNP level (r: 0.655–0.789, P < 0.001), and the 8-OHdG and NT-proBNP levels were positively correlated with mechanical ventilation duration and oxygen exposure time (r: 0.175–0.505, P < 0.05) from DOL 7 to 28. Furthermore, the 8-OHdG (DOL 14–28) and NT-proBNP (DOL 7–28) levels were significantly associated with BPD development (P < 0.05).ConclusionThe urine 8-OHdG concentrations from DOL 14 to 28 and NT-proBNP concentrations from DOL 7 to 28 may be practical non-invasive predictors of BPD development in preterm infants.

BackgroundEsophageal squamous cell carcinoma (ESCC) is characterized clinically by frequent recurrence, leading to a poor prognosis after radical surgery. The aim of this study was to identify a prognostic nomogram to predict the post-progression survival (PPS) of ESCC patients based on the features of primary tumor and recurrence.MethodsA total of 234 ESCC patients who underwent recurrence after radical surgery were enrolled in this study. The independent prognostic factors screened by the univariate and multivariate Cox regression analysis were subsequently used to construct a nomogram. The predictive performance of the nomogram was evaluated with the concordance index (C-index), decision curve, and the area under the receiver operating characteristic curve (AUC) and validated in two validation cohorts. The Kaplan-Meier curves of different recurrence patterns were analyzed.ResultsThe prognostic nomogram of PPS was established by integrating independent prognostic factors, including age, body mass index, number of lymph node dissection, recurrence pattern, and recurrence treatment. The nomogram demonstrated good performance, with C-index values of 0.756, 0.817, and 0.730 for the training and two validation cohorts. The 1-year AUC values were 0.773, 0.798, and 0.735 and 3-year AUC values were 0.832, 0.871, and 0.791, respectively. Furthermore, we found that patients with bone metastasis displayed the worst PPS compared to other isolated recurrence patterns.ConclusionWe constructed a nomogram to reliably predict PPS, which would be valuable to provide individual managements for ESCC patients after radical surgery.

Bronchopulmonary dysplasia (BPD) is a chronic respiratory complication commonly seen in premature infants. Following continuous advances in neonatal intensive care diagnosis and treatment technology, an increasing number of premature babies are being treated successfully. Despite these remarkable improvements, there has been no significant decline in the incidence of BPD; in fact, its incidence has increased as more extremely preterm infants survive. Therefore, in view of the impact of BPD on the physical and mental health of children and the increased familial and social burden on these children, early prevention of BPD is emphasized. In recent decades, the clinical application of caffeine in treating primary apnea in premature infants was shown not only to stimulate the respiratory center but also to confer obvious protection to the nervous and respiratory systems. Numerous clinical cross-sectional and longitudinal studies have shown that caffeine plays a significant role in the prevention and treatment of BPD, but there is a lack of overall understanding of its potential molecular mechanisms. In this review, we summarize the possible molecular mechanisms of caffeine in the prevention or treatment of BPD, aiming to better guide its clinical application.

Abstract Background Glutathione S-transferase mu 3 (GSTM3) plays a crucial role in tumor progression in various cancers. However, the relationship between GSTM3 expression and the clinical prognosis of esophageal squamous cell carcinoma (ESCC) has not been studied to date. We aimed to characterize the role of GSTM3 in predicting postoperative prognosis of ESCC patients. Methods In the retrospective study, GSTM3 mRNA levels in 184 ESCC tissues and matched 43 adjacent nontumorous tissues were measured by quantitative real-time PCR. GSTM3 protein levels in 247 ESCC tissues were measured by immunohistochemistry. Results Downregulation of GSTM3 occurred in 62.8 % of primary ESCC tissues compared with their nontumor counterparts. Patients with low GSTM3 expression tended to exhibit an increased rate of poor differentiation in both the mRNA cohort (p = 0.024) and protein cohort (p = 0.004). In the mRNA cohort, low GSTM3 expression was associated with unfavorable 3-year disease-free survival (DFS) (39.2 % vs. 57.4 %) and 5-year DFS (26.8 % vs. 45.1 %) (p = 0.023). The result was confirmed in the protein cohort. Patients with low GSTM3 expression had unfavorable 3-year disease-free survival (DFS) (18.7 % vs. 33.5 %) and 5-year DFS (5.3 % vs. 30.5 %) (p = 0.006). Cox multivariate analysis revealed that GSTM3 expression was an independent prognostic factor. Conclusions The findings of the present study provide evidence that GSTM3 may function as a tumor suppressor in ESCC and represents a potential novel prognostic biomarker for disease-free survival for resected ESCC patients.

The No. 21 coal seam in the Zhengzhou mining area is a soft, three-layer, low-permeability coal seam prone to outbursts. The three-layer structure includes the coal seam and the roof and floor layers, which exhibit high gas contents and poor permeability. The dynamic hazards caused by coal and gas outbursts are very serious. A new permeability-increasing fracturing technique that combines hydraulic perforation and hydraulic fracturing was developed specifically for the geologic conditions of the gas-bearing No. 21 coal seam. Numerical simulations were developed to study the influence of the technique on the stress distribution and permeability of the coal around the borehole. In addition, the extracted borehole gas concentrations and extraction amounts at multiple sites were investigated before and after using the technique. The study shows that the permeability-increasing fracturing technique destroys the concentrated stress coal pillars via the development of fractures between boreholes in exposed hydraulically perforated coal. The coal stress within the zone with an effective increase in permeability decreased by 30%. Furthermore, the permeability in this zone increased by three times, and the average extracted gas concentration increased by over six times. The gas pressure in the No. 21 coal seam decreased from 1.1 MPa to 0.4 MPa, and the gas content decreased from 15.96 m3/t to 5.6 m3/t. All outburst prediction indexes measured on site did not exceed their respective limits. The technique not only effectively eliminated the dynamic hazards caused by coal and gas outbursts but also achieved efficient gas extraction in the Zhengzhou mining area.

Objective: To analyze the clinical characteristics of intrauterine Ureaplasma urealyticum (UU) infection in premature infants.Method: In this single-center retrospective case-control study, 291 preterm infants born in our hospital and hospitalized in our department and gestational age no more than 32 weeks, birth weight no more than 2000 g were included from January 2019 to January 2021. Lower respiratory tract secretion, gastric fluid and urine were collected for UU RNA detection within 48 h after birth. Intrauterine UU infection is defined by at least one positive UU-PCR test of secreta or excreta of preterm infants after birth. The UU infection group included 86 preterm infants and the non-UU infection group included 205 preterm infants. We compared their clinical features, hemogram changes and disease outcomes using statistical analyses.Results: The clinical characteristics of premature infants such as the duration of oxygen use and ventilator use in hospital were significantly prolonged in the UU infection group (P < 0.05). The levels of leukocytes, platelet and procalcitonin in the UU infection group were significantly higher than in the non-UU infection group (P < 0.05). In terms of preterm complications, only the incidences of bronchopulmonary dysplasia, retinopathy of prematurity and metabolic bone disease in premature infants in the UU infection group were significantly higher than those in the non-UU infection group (P < 0.05). The mode of delivery, maternal premature rupture of membranes, and postnatal leukocyte level were independent risk factors for UU infection, while gestational hypertension was a protective factor for UU infection. The level of leukocytes in postnatal hemogram of premature infants could be used as a diagnostic index of UU infection, but the diagnostic accuracy was poor.Conclusion: In our study, UU infection can increase the incidence of bronchopulmonary dysplasia, retinopathy of prematurity and metabolic bone disease in preterm infants, but have no effect on the incidence of necrotizing enterocolitis, intracranial hemorrhage, white matter damage and other diseases in preterm infants. For high-risk premature infants, UU should be detected as soon as possible after birth, early intervention and drug treatment necessarily can improve the prognosis as much as possible.

Bronchopulmonary dysplasia (BPD) is a severe respiratory complication in preterm infants. Although the etiology and pathogenesis of BPD are complex and remain to be clarified, recent studies have reported a certain correlation between the microecological environment of the respiratory tract and BPD. Changes in respiratory tract microecology, such as abnormal microbial diversity and altered evolutional patterns, are observed prior to the development of BPD in premature infants. Therefore, research on the colonization and evolution of neonatal respiratory tract microecology and its relationship with BPD is expected to provide new ideas for its prevention and treatment. In this paper, we review microecological changes in the respiratory tract and the mechanisms by which they can lead to BPD in preterm infants.

Background: Multiple systematic reviews (SRs) have been conducted to evaluate the efficacy and safety of Chinese herbal medicine (CHM) in patients with Alzheimer’s disease (AD). Here, we aim to perform an overview to assess the methodological quality and quality of evidence of the SRs to provide convincing data on the treatment of AD with CHM.Method: Six electronic databases including Chinese and English were searched, until April 31, 2021. Two researchers independently screen documents and extract data according to the predesigned rules. A Measure Tool to Assessment System Reviews 2 (AMSTAR-2) was used to investigate the methodological quality, and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) was used to determine the quality of evidence for outcomes.Results: Twelve qualified SRs including 163 randomized controlled trials were reviewed. The methodological quality of the included SRs was considered extremely low assessed through AMSTAR-2. Compared with western medicines (WM) alone, CHM as an adjuvant treatment has shown significant effects in improving Mini-mental State Examination, Alzheimer’s Disease Assessment Scale-Cognitive, and Clinical Dementia Rating scores. The same is true for CHM alone. Regarding the effect on Activities Daily Living, neither the single CHM nor the combination with WM has an obvious effect. For the total effective rate, both single CHM and the combination with WM shown significant effects. Nine SRs suggested that CHM as adjuvant therapy or single-use had fewer adverse events than WM. Additionally, the quality of evidence for the main outcome was reviewed as low or extremely low according to GRADE profiler data.Conclusion: Current evidence suggests that CHM may be beneficial in improving the cognitive function of AD patients. However, we should be cautious about the evidence due to methodological flaws and low quality. High-quality RCTs are further needed to confirm the efficacy and safety of CHM for AD.

With the improvement in neonatal rescue technology, the survival rate of critically ill preterm infants has substantially increased; however, the incidence of brain injury and sequelae in surviving preterm infants has concomitantly increased. Although the etiology and pathogenesis of preterm brain injury, and its prevention and treatment have been investigated in recent years, powerful and effective neuroprotective strategies are lacking. Caffeine is an emerging neuroprotective drug, and its benefits have been widely recognized; however, its effects depend on the dose of caffeine administered, the neurodevelopmental stage at the time of administration, and the duration of exposure. The main mechanisms of caffeine involve adenosine receptor antagonism, phosphodiesterase inhibition, calcium ion activation, and γ-aminobutyric acid receptor antagonism. Studies have shown that there are both direct and indirect beneficial effects of caffeine on the immature brain. Accordingly, this article briefly reviews the pharmacological characteristics of caffeine, its mechanism of action in the context of encephalopathy in premature infants, and its use in the neuroprotection of encephalopathy in this patient population.

Objectives: Whether there is a link between assisted reproductive technology (ART) and brain damage in premature infants remains unclear. The aim of this study was to determine whether premature infants conceived by ART are at a greater risk of developing white matter injury (WMI), as detected by magnetic resonance imaging (MRI) or diffusion-weighted imaging (DWI) within 14 days, than those naturally conceived (NC).Methods: A retrospective case-control study was conducted on singleton premature infants with a gestational age of ≥28 weeks and

Abstract Background Preterm infants have immature gastrointestinal tracts and poor immunity. In this study, the effects of Lactobacillus reuteri DSM 17938 first on early feeding tolerance, growth, and second on infection prevention in preterm infants were evaluated. Methods One hundred fourteen formula-fed preterm infants with a gestational age between 30 weeks and 37 weeks, and a birth weight between 1500 and 2000 g were enrolled; 57 in the intervention and 57 in the control group:the intervention group was given a dose of 1 × 108 colony-forming units (5 drops) of L. reuteri DSM 17938 once daily, beginning with the first feeding until discharge. The control group did not receive probiotics. Early feeding tolerance (as time to full enterla feeding and number of reflux), growth, incidences of sepsis, localized infection, NEC, and adverse effects were recorded for both groups. Results The number of Daily reflux episodes (times/d) was lower (2.18 ± 0.83 vs. 3.77 ± 0.66, P 0.05). The number of daily defecations (times/d) in the intervention group was higher (3.08 ± 0.33 vs. 2.29 ± 0.20, P

Objective: The clinical symptoms of neonatal Prader-Willi syndrome (PWS) are not typical and are easy to miss. The aim of the study was to investigate the clinical features and genetic characteristics of seven cases of neonatal PWS from northern China, and to improve the understanding of PWS in neonates.Methods: We retrospectively analyzed seven infants diagnosed by methylation specific multiplex ligation probe amplification technology (MS-MLPA) in the Neonatology Unit of Shengjing Hospital of China Medical University from September 2016 to July 2020.Results: All seven cases involved full term or nearly full-term infants born to mothers without a history of abnormal pregnancy or delivery. Difficulty in feeding occurred immediately after birth in infants with decreased hypotonia. Five patients had characteristic craniofacial morphology, such as a prominent forehead, narrow face, almond-shaped eyes, small mouth, and downturned mouth. Further, three of the seven infants had patent ductus arteriosus (PDA). In addition, three neonates had hyperammonemia, hypoglycemia, and idiopathic edema, respectively. PWS could be effectively diagnosed and genotyped by MS-MLPA.Conclusion: Neonates with PWS have hypotonia and feeding difficulty. Characteristic facial features and genital hypoplasia are common in neonatal PWS. Infants with PWS may be predisposed to PDA, hypoglycemia, hyperammonemia, and edema.

The tumor microenvironment (TME) of esophageal squamous cell carcinoma (ESCC) impacts tumor progression but is poorly understood. We obtained tumor tissues from 279 patients after esophagectomy and characterized the TME in intraepithelial and stromal regions using multiplex fluorescent immunohistochemistry (mfIHC). A heterogeneous immune population infiltrating tumor and the uninvolved esophageal tissue were observed. The infiltration of intraepithelial programmed death ligand 1 (PD-L1)-positive tumor-associated macrophages (TAMs) and stromal granzyme B+ activated cytotoxic T cells (aCTLs) correlated with both prolonged overall survival (OS) and disease-free survival (DFS). The intraepithelial memory T cell infiltration predicted longer OS, while intraepithelial and stromal regulatory T cell (Treg) infiltration was associated with shortened OS and DFS, respectively. Multivariate models combining immune infiltrates and clinicopathological factors outperformed tumor-node-metastasis (TNM) stage in predicting OS and DFS at 3 and 5 years. The infiltration of Treg inversely correlated with that of the antitumor effectors including CTLs, aCTLs, and natural killer (NK) cells. Intraepithelial memory T cell infiltration also negatively correlated with PD-L1 expression. In spatial analysis, intraepithelial dendritic cell (DC)-memory T cell engagement increased in high PD-L1+ TAM infiltration group. The characterization of the TME revealed a complex interplay between immune populations and may be employed to stratify patient for prognosis prediction and immunotherapy.

Myocardial ischemia/reperfusion (MI/R) injury is a serious threat to human health. Hydroxysafflor yellow A (HSYA), the main water-soluble ingredient extracted from Carthami flos (Carthamus tinctorius L.), has therapeutic potential for treating MI/R injury. However, the mechanisms of HSYA−mediated protection from MI/R injury are incompletely understood. In the present study, we investigated the effects and the underlying mechanisms of HSYA during MI/R. Adult Sprague-Dawley rats were subjected to left anterior descending artery ligation for 30 min followed by 24 h of reperfusion with or without HSYA treatment. The protective effect of HSYA was detected by 2,3,5-triphenyl tetrazolium chloride (TTC) staining, hematoxylin eosin (HE) staining, and myocardial enzymes detections. Serum levels of inflammatory factors such as TNF-α, interleukin (IL)-1β, and IL-18, were detected using ELISA kits. The expression of NLRP3 and other related proteins in the myocardium was detected by western blot and immunohistochemistry. The expression of autophagy-related proteins, including Atg5, BECN1, P62, and LC3B, was detected by western blot to evaluate the effect of HSYA on autophagy. Results showed that HSYA decreased the myocardial infarct size and attenuated the cardiac dysfunction in rats after I/R. In addition, HSYA inhibited myocardial apoptosis compared with the I/R group, decreased the levels of inflammatory cytokines in rat serum, reduced NLRP3 inflammasome expression, and induced autophagy. Mechanistically, our results demonstrated that HSYA can activate AMPK to improve autophagy and inhibit NLRP3 inflammasome by inhibiting the mTOR pathway. This work provides strong data supporting for the clinical applications of HSYA in MI/R injury.

Background: Although pericardial effusion/cardiac tamponade (PCE/CT) is a rare complication of peripherally inserted central catheters (PICCs), with an incidence of 0. 07–2%, it is associated with high mortality and is often life threatening. We sought to improve understanding of PICC-induced PCE/CT among pediatricians.Case presentation: The clinical data of PICC-associated PCE/CT in a very low birth weight (VLBW) infant were summarized, and the relevant literature was also reviewed.Conclusions: In VLBW infants with a PICC, if unstable respiratory circulatory system states are observed that cannot be explained, such as tachycardia, bradycardia, apnea, hypotension, and metabolic acidosis, PICC-induced PCE/CT should be considered. Early diagnosis and pericardial puncture are key to saving infants' lives.

To understand the effects of thermal shock on microcrack propagation and permeability in coal, thermal shock tests were conducted on coal specimens by using a constant temperature drying oven (105 °C) and a SLX program controlled cryogenic tank. The growth and propagation of microcracks were measured with computer tomography (CT) scanning and scanning electron microscope (SEM) tests. Results showed that thermal shocks improved the permeability of coal significantly. Notably, the permeability of coal after thermal shocks increased from 211.31% to 368.99% and was positively correlated with temperature difference. CT scanning images revealed that thermal shocks increased the crack number, crack volume and crack width as well as smoothened and widened the gas flow paths, thereby enhancing coal permeability. Moreover, SEM images showed that heating-cooling shocks created more new microcracks, forming more complex crack propagation paths and better connectivity among microcracks in coal compared to cooling shocks. We proposed a crack propagation criterion for coal to explain the mechanism of crack failure and propagation during thermal shocks. Our experiment results and theoretical analysis indicate that the heating-cooling shock is more effective in damaging and breaking coal than the cooling shock. Thus, it can be used as an alternative approach to enhance coal permeability in the production of coalbed methane (CBM).

Background: Dysregulation of the cell cycle has been implicated in esophageal squamous cell carcinoma (ESCC) progression. This study aimed to evaluate the role of miR-424 in cell cycle regulation and ESCC proliferation. Methods: The role of miR-424 in cell proliferation was evaluated in vitro and in vivo. Transcriptional activation of miR-424 was determined using chromatin immunoprecipitation, and binding of miR-424 to targets was verified using miRNA ribonucleoprotein complex immunoprecipitation. Findings: miR-424 was upregulated and correlated with poor survival in ESCC patients. Repression or overexpression of miR-424 respectively decreased or increased ESCC cell proliferation in vitro and in vivo. miR-424 expression is transcriptionally regulated by E2F1 and increased during G1/S transition. Knockdown or overexpression of miR-424 respectively inhibited or promoted both G1/S and G2/M cell cycle transitions in ESCC cells, and these effects were mediated by two newly identified miR-424 targets, PRKCD and WEE1, respectively. Consequently, elevation of PRKCD by miR-424 knockdown led to enhanced stability of the p21Cip1 protein via increased activation of PRKCD and downstream p38 MAPK and JNK signaling to block CDK2 activation and G1/S transition, while elevated WEE1 maintained CDC2 in an inactive state to block G2/M transition. However, circLARP4 could sponge the binding of miR-424 to PRKCD, thus compromising the regulation of G1/S progression by miR-424. Interpretation: miR-424 coordinates a previously unknown, multilayered regulation of ESCC cell cycle progression to promote ESCC proliferation, and may be used as a novel prognostic marker and an effective therapeutic target for ESCCs. Fund: National Natural Science Foundation of China. Keywords: miR-424, Esophageal squamous cell carcinoma, Cell cycle, Cell proliferation

Abstract Pulmonary fibrosis, which influences lung function and exacerbates a patient’s condition, is the ultimate stage of many lung diseases. Vitamin D deficiency is associated with pulmonary fibrosis and impaired lung function, but the underlying mechanism has not yet been fully elucidated. Moreover, vitamin D deficiency may cause over-activation of the renin-angiotensin system (RAS), which aggravates extracellular matrix (ECM) deposition and lung fibrosis. This study aims to investigate the effect of chronic vitamin D deficiency on lung fibrosis in otherwise healthy mice and to explore the role of RAS in this process. Mice were depleted of vitamin D through diet control and were compared with healthy subjects. Chronic vitamin D deficiency destructs lung structures, impairs lung development and stimulates ECM deposition. RAS components are also found to increase. These effects seem to worsen with prolonged vitamin D deficiency. By giving RAS blockers, these changes can be largely rescued. However, a smooth muscle relaxant whose regulatory effect on blood pressure is independent of RAS does not show similar effects. This study demonstrated that chronic vitamin D deficiency may induce RAS activation, which subsequently stimulates the expression of profibrotic factors and activates the fibrotic cascade. This profibrotic effect of RAS is independent of elevated blood pressure.