Diffusion barriers imposed by tissue topology shape morphogen gradients.

Animals use a small number of morphogens to pattern tissues, but it is unclear how evolution modulates morphogen signaling range to match tissues of varying sizes. Here, we used single molecule imaging in reconstituted morphogen gradients and in tissue explants to determine that Hedgehog diffused extra-cellularly as a monomer, and rapidly transitioned between membrane-confined and -unconfined states. Unexpectedly, the vertebrate-specific protein SCUBE1 expanded Hedgehog gradients by accelerating the transition rates between states without affecting the relative abundance of molecules in each state. This observation could not be explained under existing models of morphogen diffusion. Instead, we developed a topology-limited diffusion model in which cell-cell gaps create diffusion barriers, and morphogens can only overcome the barrier by passing through a membrane-unconfined state. Under this model, SCUBE1 promotes Hedgehog secretion and diffusion by allowing it to transiently overcome diffusion barriers. This multiscale understanding of morphogen gradient formation unified prior models and discovered novel knobs that nature can use to tune morphogen gradient sizes across tissues and organisms.

LncRNA MIR210HG promotes phenotype switching of pulmonary arterial smooth muscle cells through autophagy-dependent ferroptosis pathway.

Hypoxic pulmonary hypertension (HPH) is a pathophysiological syndrome in which pulmonary vascular pressure increases under hypoxic stimulation and there is an urgent need to develop emerging therapies for the treatment of HPH. LncRNA MIR210HG is a long non-coding RNA closely related to hypoxia and has been widely reported in a variety of tumor diseases. But its mechanism in hypoxic pulmonary hypertension is not clear. In this study, we identified for the first time the potential effect of MIR210HG on disease progression in HPH. Furthermore, we investigated the underlying mechanism through which elevated levels of MIR210HG promotes the transition from a contractile phenotype to a synthetic phenotype in PASMCs under hypoxia via activation of autophagy-dependent ferroptosis pathway. While overexpression of HIF-2α in PASMCs under hypoxia significantly reversed the phenotypic changes induced by MIR210HG knockdown. We further investigated the potential positive regulatory relationship between STAT3 and the transcription of MIR210HG in PASMCs under hypoxic conditions. In addition, we established both in vivo and in vitro models of HPH to validate the differential expression of specific markers associated with hypoxia. Our findings suggest a potential mechanism of LncRNA MIR210HG in the progression of HPH and offer potential targets for disease intervention and treatment.

Safety and efficacy of Paxlovid in the treatment of adults with mild to moderate COVID-19 during the omicron epidemic: a multicentre study from China.

BACKGROUND: Since December 2022, the Omicron variant has led to a widespread pandemic in China. The study was to explore the safety and effectiveness of Paxlovid for the treatment of coronavirus disease 2019 (COVID-19). RESEARCH DESIGN AND METHODS: We included patients at risk of developing severe COVID-19, all of whom exhibited mild to moderate symptoms and were admitted to three hospital centers. Patients were divided into two groups: one received Paxlovid alongside standard care, while the other was given only standard care. We compared clinical characteristics, hospital stay duration, and clinical outcomes between two groups. Multi-factor analysis determined the independent risk factors influencing the duration of hospitalization and disease progression. RESULTS: In the study, those treated with Paxlovid shorter hospital stays than those in the control group (p < 0.001). Multivariate analysis indicated that the absence of Paxlovid treatment was a distinct risk factor for hospitalizations lasting over 7 days (OR: 4.983, 95% CI: 3.828-6.486, p < 0.001) and 14 days (OR: 2.940, 95% CI: 2.402-3.597, p < 0.001). CONCLUSION: Amid the Omicron outbreak, Paxlovid has proven to be a safe and effective treatment for reducing hospitalization durations for patients with mild to moderate COVID-19.

Novel clinical radiomic nomogram method for differentiating malignant from non-malignant pleural effusions.

Objectives: To establish a clinical radiomics nomogram that differentiates malignant and non-malignant pleural effusions. Methods: A total of 146 patients with malignant pleural effusion (MPE) and 93 patients with non-MPE (NMPE) were included. The ROI image features of chest lesions were extracted using CT. Univariate analysis was performed, and least absolute shrinkage selection operator and multivariate logistic analysis were used to screen radiomics features and calculate the radiomics score. A nomogram was constructed by combining clinical factors with radiomics scores. ROC curve and decision curve analysis (DCA) were used to evaluate the prediction effect. Results: After screening, 19 radiomics features and 2 clinical factors were selected as optimal predictors to establish a combined model and construct a nomogram. The AUC of the combined model was 0.968 (95% confidence interval [CI] = 0.944-0.986) in the training cohort and 0.873 (95% CI = 0.796-0.940) in the validation cohort. The AUC value of the combined model was significantly higher than those of the clinical and radiomics models (0.968 vs. 0.874 vs. 0.878, respectively). This was similar in the validation cohort (0.873, 0.764, and 0.808, respectively). DCA confirmed the clinical utility of the radiomics nomogram. Conclusion: CT-based radiomics showed better diagnostic accuracy and model fit than clinical and radiological features in distinguishing MPE from NMPE. The combination of both achieved better diagnostic performance. These findings support the clinical application of the nomogram in diagnosing MPE using chest CT.

Hypoxia-induced long non-coding RNA plasmacytoma variant translocation 1 upregulation aggravates pulmonary arterial smooth muscle cell proliferation by regulating autophagy via miR-186/Srf/Ctgf and miR-26b/Ctgf signaling pathways.

BACKGROUND: The lncRNA PVT1 reportedly functions as a competing endogenous RNA (ceRNA) of miR-186 and miR-26b in different tissue types. In this study, we investigated the possible involvement of the miR-186/Srf/Ctgf and miR-26b/Ctgf signaling pathways in the pathogenesis of hypoxia-induced PAH. METHODS: Expression of PVT1, miR-186, miR-26b, and Srf and Ctgf mRNAs were evaluated by real-time polymerase chain reaction. Protein expression of SRF, CTGF, LC3B-I, LC3B-II, and Beclin-I was evaluated using western blotting. The regulatory relationship between the lncRNA, miRNAs, and target mRNAs was explored using luciferase assays. Immunohistochemistry was used to evaluate the expression of SRF and CTGF in situ. MTT assay was performed to assess the proliferation of PASMCs. RESULTS: Exposure to hypoxia markedly altered the expression of PVT1, Srf, Ctgf, miR-186, and miR-26b in a rat model. MiR-186 binding sites in the sequences of Srf mRNA and PVT1 were confirmed by luciferase assays, indicating that miR-186 may interact with both PVT1 and Srf mRNA. Additionally, miR-26b binding sites were identified in the sequences of Ctgf mRNA and PVT1, suggesting that miR-26b may interact with both PVT1 and Ctgf mRNA. In line with this, we found that overexpression of PVT1 reduced expression of miR-26b and miR-186 but activated expression of Srf, Ctgf, LC3B-II, and Beclin-I. CONCLUSIONS: Upregulation of PVT1 by exposure to hypoxia promoted the expression of CTGF, leading to deregulation of autophagy and abnormal proliferation of PASMCs. Dysregulation of the miR-186/Srf/Ctgf and miR-26b/Ctgf signaling pathways may be involved in the pathogenesis of hypoxia-induced PASMCs.

Lhx2 is a progenitor-intrinsic modulator of Sonic Hedgehog signaling during early retinal neurogenesis.

An important question in organogenesis is how tissue-specific transcription factors interact with signaling pathways. In some cases, transcription factors define the context for how signaling pathways elicit tissue- or cell-specific responses, and in others, they influence signaling through transcriptional regulation of signaling components or accessory factors. We previously showed that during optic vesicle patterning, the Lim-homeodomain transcription factor Lhx2 has a contextual role by linking the Sonic Hedgehog (Shh) pathway to downstream targets without regulating the pathway itself. Here, we show that during early retinal neurogenesis in mice, Lhx2 is a multilevel regulator of Shh signaling. Specifically, Lhx2 acts cell autonomously to control the expression of pathway genes required for efficient activation and maintenance of signaling in retinal progenitor cells. The Shh co-receptors Cdon and Gas1 are candidate direct targets of Lhx2 that mediate pathway activation, whereas Lhx2 directly or indirectly promotes the expression of other pathway components important for activation and sustained signaling. We also provide genetic evidence suggesting that Lhx2 has a contextual role by linking the Shh pathway to downstream targets. Through these interactions, Lhx2 establishes the competence for Shh signaling in retinal progenitors and the context for the pathway to promote early retinal neurogenesis. The temporally distinct interactions between Lhx2 and the Shh pathway in retinal development illustrate how transcription factors and signaling pathways adapt to meet stage-dependent requirements of tissue formation.

High Expression of DEPDC1B Predicts Poor Prognosis in Lung Adenocarcinoma.

Introduction: Lung adenocarcinoma (LUAD) is the most common type of lung cancer. DEP domain-containing 1 B (DEPDC1B) is involved in the development of several cancers; however, its role in LUAD is unknown. Therefore, we aimed to determine the biological function and prognostic value of DEPDC1B in LUAD. Material and Methods: We analyzed the correlation between DEPDC1B expression and the clinical features of LUAD and lung squamous cell carcinoma (LUSC). Survival was evaluated by generating Kaplan-Meier curves, which were used to analyze the relationship between DEPDC1B expression and prognosis in LUAD and LUSC. DEPDC1B expression in tumor and normal tissues from patients with LUAD and LUSC was determined using immunohistochemistry, and its clinical significance was analyzed. Finally, the correlation between the expression and biological function of DEPDC1B in LUAD was examined. Results: Our findings revealed that DEPDC1B expression was higher in tumor tissues than that in normal tissues from patients with LUAD and LUSC (P < 0.001). These results were confirmed in clinical samples from patients using immunohistochemistry. Analysis of a dataset from The Cancer Genome Atlas (TCGA) showed that high DEPDC1B expression was associated with poor prognosis only in patients with LUAD (P < 0.001). Similarly, high DEPDC1B expression was related to shorter overall survival (OS) and progression-free interval (PFI) in patients with LUAD. These associations were not observed in LUSC. Functional enrichment analysis suggested that DEPDC1B promoted tumor development in LUAD by regulating the cell cycle. Conclusion: High DEPDC1B expression predicts poor prognosis in patients with LUAD. Thus, DEPDC1B has potential as a therapeutic target for LUAD.

Mortality and risk factors for COVID-19 in hemodialysis patients: A systematic review and meta-analysis.

Introduction: The present study systematically reviewed the clinical features and risk factors in patients undergoing maintenance hemodialysis (MHD) who also acquired coronavirus disease 2019 (COVID-19). More specifically, clinical manifestations, prognosis, and risk factors for death among this population were explored. Method: A literature search using the PubMed, Web of Science, and Embase databases, for articles involving patients with laboratory-confirmed COVID-19 and undergoing MHD published between January 1, 2020, and March 13, 2022, was performed. Random-effects meta-analyses were performed to calculate the weighted mean prevalence and corresponding 95% confidence interval (CI) or weighted means and 95% CI. Heterogeneity among studies was assessed using I2 statistics. Results: Twenty-two studies including 13,191 patients with COVID-19 undergoing MHD were selected. The most common symptoms included fever (53% [95% CI 41%-65%]) and cough (54% [95% CI 48%-60%]); however, 17% (95% CI 11%-22%) of the cases were asymptomatic. In subgroup analysis, the proportion of male patients (65% [95% CI 58%-71%]), and patients with coronary artery disease (30% [95% CI 17%-44%) and chronic obstructive pulmonary disease (9% [95% CI 4%-15%]) was greater in the non-survivor group compared with the survivor group. Furthermore, patients undergoing MHD, who were also positive for COVID-19, exhibited a high mortality rate (24% [95% CI 19%-28%]). Conclusions: MHD patients with COVID-19 may initially present as asymptomatic or with mild symptoms; nevertheless, in this study, these patients exhibited a higher risk for death compared with COVID-19 patients not undergoing MHD. Moreover, male sex and underlying cardiovascular and respiratory diseases increased the mortality risk.

Efficacy and Safety of Nanoadministration in the Treatment of Non-Small-Cell Lung Cancer Is Good to Some Extent: A Systematic Review and Meta-Analysis.

Purpose: The purpose of this study was to evaluate the efficacy and safety of a nanodrug delivery regimen compared with conventional drug administration for the treatment of lung cancer. Materials and Methods: Studies were retrieved through PubMed, Web of Science, and ScienceDirect. Primary and secondary outcome measures, including overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events, were extracted from the retrieved literature and systematically evaluated. Results: Six trials, including 4806 advanced non-small-cell lung cancer patients, were included in this study. Compared with conventional drug administration in the treatment of lung cancer, the nanodrug delivery regimen improved the ORR (risk ratio = 1.43, 95% confidence interval (CI) = 1.25-1.63, p ≤ 0.001), prolonged PFS (hazard ratio (HR) = 0.83, 95% CI = 0.76-0.92, p ≤ 0.001), and obtained superior OS (HR = 0.91, 95% CI = 0.83-0.99, p ≤ 0.001). Regarding safety, the incidence of neutropenia, alopecia, sensory neuropathy, myalgia, and arthralgia was lower in the nanoadministration group, but the risk of thrombocytopenia, anaemia, and nausea was increased. Conclusion: Nanodrug administration is safe and effective in patients with non-small-cell lung cancer to some extent.

Gestational Psittacosis With Secondary Hemophagocytic Syndrome: A Case Report and Literature Review.

Gestational psittacosis and hemophagocytic syndrome (HPS) are rare clinical diseases. In this article, a case of gestational psittacosis concomitant with secondary HPS was reported. An analysis was performed on the clinical characteristics, signs, laboratory findings, progression, diagnosis, and treatment of a patient with gestational psittacosis concomitant with secondary HPS. Besides, the literature with respect to this disease was reviewed. This patient was definitively diagnosed through metagenomic next-generation sequencing techniques, bone marrow puncture and smear examination, and the determination of sCD25 level and natural killer (NK) cell activity. Anti-infectives such as doxycycline and etoposide combined with hormone chemotherapy achieved significant improvement in cough and expectoration, a return to normal temperature, and a significant improvement in oxygenation index. In addition, chest computed tomography revealed obvious absorption of lung lesions and a return of NK cell activity and sCD25 levels to normal ranges. Chlamydia psittaci pneumonia requires a clear determination of etiology, while HPS requires bone marrow puncture and smear examination, together with the determination of sCD25 level and NK cell activity in the blood. The findings of this study suggest that metagenomic next-generation sequencing is an effective instrument in clearly identifying pathogens that cause lung infection. Clinicians should consider atypical pathogens of lung infection in patients with poor response to empirical anti-infectives, and strive to design an effective treatment strategy as per an accurate diagnosis based on the etiology. As for patients suffering from long-term high fever and poor temperature control after broad-spectrum antibiotic treatment, non-infectious fever should be taken into account. A rapid and clear diagnosis would significantly improve patient prognosis.

ARL14 as a Prognostic Biomarker in Non-Small Cell Lung Cancer.

PURPOSE: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. The mechanisms underlying NSCLC initiation and progression require further investigation. The purpose of this study was to investigate the role of ADP ribosylation factor-like GTPase 14 (ARL14) related to the progression of NSCLC. PATIENTS AND METHODS: We analyzed the correlation between clinical characteristics and ARL14 expression using data from The Cancer Genome Atlas (TCGA). Kaplan-Meier analysis was conducted to evaluate the prognostic value of ARL14 in NSCLC. Functions of ARL14 were identified by enrichment analysis. The relationship between ARL14 expression and immune cell infiltration was also studied. Furthermore, ARL14 expression was examined using immunohistochemistry, and its clinical significance was analyzed in 120 patients with NSCLC. RESULTS: Our study revealed that the expression level of ARL14 in patients with NSCLC was higher than that in normal tissues. Using TCGA data, higher ARL14 expression in lung adenocarcinoma was associated with residual tumor (P = 0.017), while it was associated with age (P = 0.003) and N stage (P = 0.009) in lung squamous cell carcinoma. Similar results were obtained from 120 patients with NSCLC. High ARL14 expression was associated with poor overall survival and progression-free survival in NSCLC. Multivariate analysis revealed that ARL14 was an independent risk factor for patients with NSCLC. Functional enrichment analysis indicated that ARL14 was related to the occurrence and development of tumors. CONCLUSION: Increased ARL14 expression was considerably correlated with poor survival in NSCLC, and it might be a promising prognostic biomarker for NSCLC.

Effect of Methylation Status of lncRNA-MALAT1 and MicroRNA-146a on Pulmonary Function and Expression Level of COX2 in Patients With Chronic Obstructive Pulmonary Disease.

This study aimed to investigate the role of methylation of MALAT1 and miR-146a in the pathogenesis of chronic obstructive pulmonary disease (COPD). COPD patients were grouped according to their methylation status of MALAT1 and miR-146a promoters, and we found that forced vital capacity, volume that has been exhaled at the end of the first second of forced expiration, and diffusion capacity for carbon monoxide were the highest in the MALAT1 HYPO + miR-146a HYPER group and lowest in the MALAT1 HYPER + miR-146a HYPO group, and COPD patients with hypermethylated MALAT1 showed lower expression of MALAT1 than that in the COPD patients with hypomethylated MALAT1. Meanwhile, miR-146a was the most significantly upregulated in the MALAT1 HYPER + miR-146a HYPO group and the most significantly downregulated in the MALAT1 HYPO + miR-146a HYPER group. Both prostaglandin E1 and cyclooxygenase 2 (COX2) expression were the highest in the MALAT1 HYPO + miR-146a HYPER group and the lowest in the MALAT1 HYPER + miR-146a HYPO group. In conclusion, our results established a MALAT1/miR-146a/COX2 signaling axis. The overexpression of MALAT1 could increase the expression of COX2 by inhibiting the expression of miR-146a, thus affecting the pulmonary function of COPD patients.

Integrated analysis of the molecular mechanisms in idiopathic pulmonary fibrosis.

Rationale: Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of idiopathic interstitial pneumonia. Some miRNAs may be associated with IPF and may affect the occurrence and development of IPF in various pathways. Many miRNAs and genes that may be involved in the development of IPF have been discovered using chip and high throughput technologies. Methods: We analyzed one miRNA and four mRNA databases. We identified hub genes and pathways related to IPF using GO, KEGG enrichment analysis, gene set variation analysis (GSVA), PPI network construction, and hub gene analysis. A comprehensive analysis of differentially expressed miRNAs (DEMs), predicted miRNA target genes, and differentially expressed genes (DEGs) led to the creation of a miRNA-mRNA regulatory network in IPF. Results: We found 203 DEGs and 165 DEMs that were associated with IPF. The findings of enrichment analyses showed that these DEGs were mainly involved in antimicrobial humoral response, antimicrobial humoral immune response mediated by antimicrobial peptide, extracellular matrix organization, cell killing, and organ or tissue specific immune response. The VEGFA, CDH5, and WNT3A genes overlapped between hub genes and the miRNA-mRNA regulatory network. The miRNAs including miR-199b-5p, miR-140-5p, miR-199a-5p, miR-125A-5p, and miR-107 that we predicted would regulate the VEGFA, CDH5, and WNT3A genes, which were also associated with IPF or other fibrosis-related diseases. GSVA indicated that metabolic processes of UTP and IMP, immune response, regulation of Th2 cell cytokine production, and positive regulation of NK cell-mediated immunity are associated with the pathogenesis and treatment of IPF. These pathways also interact with VEGFA, CDH5, and WNT3A. Conclusion: These findings provide a new research direction for the diagnosis and treatment of IPF.

Nivolumab monotherapy or combination therapy with ipilimumab for lung cancer: a systemic review and meta-analysis.

BACKGROUND: The high incidence and mortality of lung cancer have seriously affected human life and health. Nivolumab is a monoclonal antibody that can inhibit programmed death 1 (PD-1) and Ipilimumab is a monoclonal antibody against CTLA-4(cytotoxic T lymphocyte-associated antigen 4), both of which can prevent the immune escape of tumor cells. Our goal was to synthesize evidence from published randomized controlled trials involving the safety and efficacy of either Nivolumab alone or in combination for the treatment of unresectable lung cancer. METHODS: We searched the following electronic databases: PubMed, Embase, and Cochrane libraries, and screened the retrieved records for eligibility. We used the Stata16 software for the analyses. The results of the analysis are expressed as hazard ratios (HRs) or risk ratios (RRs) and their corresponding 95% confidence intervals (CI). RESULTS: The final analysis included seven trials involving 3817 patients. Among patients with advanced lung cancer, patients using immunotherapy had better overall survival (OS), progression-free survival (PFS), and an objective response rate (ORR) than patients receiving chemotherapy. The HR of Nivolumab monotherapy or combination therapy with OS was compared with that of chemotherapy (HR: 0.73, 95% CI 0.64-0.83; HR: 0.67, 95% CI 0.55-0.81), and the HR of PFS was (HR: 0.81, 95% CI 0.69-0.94; HR: 0.67, 95% CI 0.55-0.82). CONCLUSIONS: Immunotherapy has been shown to have more clinically meaningful survival benefits for patients with lung cancer, whether monotherapy or combination immunotherapy. CRD42020213440.

Association Between NAT2 Polymorphism and Lung Cancer Risk: A Systematic Review and Meta-Analysis.

Lung cancer is the leading cause of cancer-related death worldwide and has a high incidence rate. N-Acetyltransferase 2 (NAT2) is a polymorphic xenobiotic enzyme, which can catalyze N-acetylation and O-acetylation of various carcinogens such as aromatic, heterocyclic amines and hydrazines. At present, many studies have explored the effects of NAT2 polymorphism on lung cancer, but we found inconsistent results. We researched 18 published studies, involving 4,016 patients and 5,469 controls, to more accurately assess the effects of NAT2 polymorphism on lung cancer risk and to investigate whether smoking is associated. We used STATA software to analyze the extracted data and used STATA for subgroup analysis, sensitivity analysis, and to perform publication bias tests. To determine the correlation, we used the crude odds ratio (ORs) with 95% confidence interval (CIs). Our study was prospectively registered in PROSPERO (CRD42020159737). The odds ratio was 1.53 (95% CI: 1.21-1.95, I² = 45.2%, P=0.104) for the NAT2 slow + intermediate phenotype versus rapid phenotype. The results suggested that people with NAT2 non-rapid (slow + intermediate) phenotype have a significantly increased risk of lung cancer. In addition, NAT2 rapid phenotype was significantly associated with reduced risk of lung cancer, compared with slow phenotype or intermediate phenotype (slow phenotype vs . rapid phenotype: OR: 1.61, 95% CI: 1.07-2.42, I²= 50%, P= 0.075; intermediate phenotype vs . rapid phenotype: OR: 1.47, 95% CI: 1.15-1.88, I²= 40.3%, P= 0.137).

Reconstitution of Morphogen Signaling Gradients in Cultured Cells.

Development of multicellular organisms depends on the proper establishment of signaling information in space and time. Secreted molecules called morphogens form concentration gradients in space and provide positional information to differentiating cells within the organism. Although the key molecular components of morphogen pathways have been identified, how the architectures and key parameters of morphogen pathways control the properties of signaling gradients, such as their size, speed, and robustness to perturbations, remains challenging to study in developing embryos. Reconstituting morphogen gradients in cell culture provides an alternative approach to address this question. Here we describe the methodology for reconstituting Sonic Hedgehog (SHH) signaling gradients in mouse fibroblast cells. The protocol includes the design of morphogen sending and receiving cell lines, the setup of radial and linear gradients, the quantitative time-lapse imaging, and the data analysis. Similar approaches could potentially be applied to other cell-cell communication pathways.

Synthetic Developmental Biology: Understanding Through Reconstitution.

Reconstitution is an experimental strategy that seeks to recapitulate biological events outside their natural contexts using a reduced set of components. Classically, biochemical reconstitution has been extensively applied to identify the minimal set of molecules sufficient for recreating the basic chemistry of life. By analogy, reconstitution approaches to developmental biology recapitulate aspects of developmental events outside an embryo, with the goal of revealing the basic genetic circuits or physical cues sufficient for recreating developmental decisions. The rapidly growing repertoire of genetic, molecular, microscopic, and bioengineering tools is expanding the complexity and precision of reconstitution experiments. We review the emerging field of synthetic developmental biology, with a focus on the ways in which reconstitution strategies and new biological tools have enhanced our modern understanding of fundamental questions in developmental biology.

Author Correction: Epoxyeicosatrienoic acids enhance embryonic haematopoiesis and adult marrow engraftment.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.