Foxq1 Promotes Alveolar Epithelial Cell Death through Tle1-mediated Inhibition of the NFκB Signaling Pathway.

Acute lung injury is a common respiratory disease characterized by diffuse alveolar injury and interstitial edema, as well as a hyperinflammatory response, lung cell damage and oxidative stress. Foxq1, a member of the FOX family of transcription factors, is expressed in various tissues, such as the lungs, liver, and kidneys, and contributes to various biological processes, such as stress, metabolism, cell cycle arrest, and aging-related apoptosis. However, the role of Foxq1 in acute lung injury is unknown. We constructed ex vivo and in vivo acute lung injury models by lipopolysaccharide tracheal perfusion of ICR mice and conditioned medium stimulation of injured MLE-12 cells. Foxq1 expression was increased, and its localization was altered in our acute lung injury model. In normal or injured MLE-12 cells, knockdown of Foxq1 promoted cell survival, and overexpression had the opposite effect. This regulatory effect was likely mediated by Tle1 and the NFκB/Bcl2/Bax signaling pathway. These data suggest a potential link between Foxq1 and acute lung injury, indicating that Foxq1 can be used as a biomarker for the diagnosis of acute lung injury. Targeted inhibition of Foxq1 expression could promote alveolar epithelial cell survival and may provide a strategy for mitigating acute lung injury.

Establishment and verification of a prediction model based on clinical characteristics and computed tomography radiomics parameters for distinguishing benign and malignant pulmonary nodules.

Background: The radiographic classification of pulmonary nodules into benign versus malignant categories is a pivotal component of early lung cancer diagnosis. The present study aimed to investigate clinical and computed tomography (CT) clinical-radiomics nomogram for preoperative differentiation of benign and malignant pulmonary nodules. Methods: This retrospective study included 342 patients with pulmonary nodules who underwent high-resolution CT (HRCT) examination. We assigned them to a training dataset (n=239) and a validation dataset (n=103). There are 1781 tumor characteristics quantified by extracted features from the lesion segmented from patients' CT images. The features with poor reproducibility and high redundancy were removed. Then a least absolute shrinkage and selection operator (LASSO) logistic regression model with 10-fold cross-validation was used to further select features and build radiomics signatures. The independent predictive factors were identified by multivariate logistic regression. A radiomics nomogram was developed to predict the malignant probability. The performance and clinical utility of the clinical-radiomics nomogram was evaluated by receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). Results: After dimension reduction by the LASSO algorithm and multivariate logistic regression, four radiomic features were selected, including original_shape_Sphericity, exponential_glcm_Maximum Probability, log_sigma_2_0_mm_3D_glcm_Maximum Probability, and ogarithm_firstorder_90Percentile. Multivariate logistic regression showed that carcinoembryonic antigen (CEA) [odds ratio (OR) 95% confidence interval (CI): 1.40 (1.09-1.88)], CT rad score [OR (95% CI): 2.74 (2.03-3.85)], and cytokeratin-19-fragment (CYFRA21-1) [OR (95% CI): 1.80 (1.14-2.94)] were independent influencing factors of malignant pulmonary nodule (all P<0.05). The clinical-radiomics nomogram combining CEA, CYFRA21-1 and radiomics features achieved an area of curve (AUC) of 0.85 and 0.76 in the training group and verification group for the prediction of malignant pulmonary nodules. The clinical-radiomics nomogram demonstrated excellent agreement and practicality, as evidenced by the calibration curve and DCA. Conclusions: The clinical-radiomics nomogram combined of CT-based radiomics signature, along with CYFRA21-1 and CEA, demonstrated strong predictive ability, calibration, and clinical usefulness in distinguishing between benign and malignant pulmonary nodules. The use of CT-based radiomics has the potential to assist clinicians in making informed decisions prior to biopsy or surgery while avoiding unnecessary treatment for non-cancerous lesions.

Protective effect of FKBP12 on dextran sulfate sodium-induced ulcerative colitis in mice as a tacrolimus receptor.

Ulcerative colitis (UC) is a multifactorial intestinal disease with a high incidence. In recent years, there has been an urgent need for pleiotropic drugs with a clear biosafety profile. Tacrolimus (TAC) is an immunosuppressant with stronger in vivo effects and better gastrointestinal absorption and is considered a potential treatment for UC. FKBP12 is a mediator of TAC immunosuppression; however, it is unclear whether it can participate in the development of UC in combination with TAC. The purpose of this study is to preliminarily validate the function of FKBP12 by establishing dextran sulfate sodium (DSS)-induced UC model and TAC treatment. The results revealed that TAC was effective in alleviating DSS-induced UC symptoms such as body weight and disease activity index (DAI). TAC significantly protects colonic tissue and attenuates DSS-induced histomorphological changes. In addition, FKBP12 is down-regulated in the intestinal tissue of DSS-induced UC mice and in serum samples of UC patients. In conclusion, our study revealed that FKBP12 may act as a TAC receptor to have anti-inflammatory and protective effects on DSS-induced UC in mice, which will provide a new option for the treatment of UC.

Whole-Genome Sequencing of 502 Individuals from Latvia: The First Step towards a Population-Specific Reference of Genetic Variation.

Despite rapid improvements in the accessibility of whole-genome sequencing (WGS), understanding the extent of human genetic variation is limited by the scarce availability of genome sequences from underrepresented populations. Developing the population-scale reference database of Latvian genetic variation may fill the gap in European genomes and improve human genomics research. In this study, we analysed a high-coverage WGS dataset comprising 502 individuals selected from the Genome Database of the Latvian Population. An assessment of variant type, location in the genome, function, medical relevance, and novelty was performed, and a population-specific imputation reference panel (IRP) was developed. We identified more than 18.2 million variants in total, of which 3.3% so far are not represented in gnomAD and dbSNP databases. Moreover, we observed a notable though distinct clustering of the Latvian cohort within the European subpopulations. Finally, our findings demonstrate the improved performance of imputation of variants using the Latvian population-specific reference panel in the Latvian population compared to established IRPs. In summary, our study provides the first WGS data for a regional reference genome that will serve as a resource for the development of precision medicine and complement the global genome dataset, improving the understanding of human genetic variation.

Patient-Reported Quality of Recovery after Local Anesthesia versus Brachial Plexus Block in Hand Surgery: A Randomized Controlled Study.

BACKGROUND: Both local anesthesia (LA) and brachial plexus (BP) anesthesia are commonly used in hand surgery. LA has increased efficiency and reduced costs, but BP is often favored for more complex hand surgery, despite requiring greater time and resources. The primary objective of this study was to assess the quality of recovery of patients who received LA or BP block for hand surgery. Secondary objectives were to compare postoperative pain and opioid use. METHODS: This randomized, controlled, noninferiority study enrolled patients undergoing surgery distal to the carpal bones. Patients were randomized to either LA (wrist or digital block) or BP block (infraclavicular block) before surgery. Patients completed the Quality of Recovery-15 questionnaire on postoperative day (POD) 1. Pain level was assessed with a numeric pain rating scale, and narcotic consumption was recorded on POD1 and POD3. RESULTS: A total of 76 patients completed the study (LA, n = 46, BP, n = 30). No statistically significant difference was found for median Quality of Recovery-15 score between LA [127.5 (interquartile range, 28)] and BP block [123.5 (interquartile range, 31)]. The inferiority margin of LA to BP block at the 95% confidence interval was less than the minimal clinically important difference of 8, demonstrating noninferiority of LA compared with BP block. There was no statistically significant difference between LA and BP block for numeric pain rating scale scores or narcotic consumption on POD1 and POD3 ( P > 0.05). CONCLUSION: LA is noninferior to BP block for hand surgery with regard to patient-reported quality of recovery, postoperative pain, and narcotic use. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Transcriptional adaptor 3 influences the proliferative and invasive phenotypes of non-small cell lung cancer cells via regulating EMT.

Transcriptional adaptor 3 (TADA3/ADA3) is a conserved transcriptional co-activator and is dysregulated in many aggressive tumors. However, the role of TADA3 in non-small cell lung cancer (NSCLC) remains unknown. It was previously demonstrated that TADA3 expression correlates with poor prognosis in patients with NSCLC. In the present study, the expression and function of TADA3 were investigated in cells in vitro and in vivo. TADA3 expression was evaluated in clinical specimens and cell lines using reverse transcription-quantitative PCR and western blot analysis. The TADA3 protein level was significantly higher in human NSCLC specimens compared with matched normal tissues. In human NSCLC cell lines, short hairpin RNA-mediated silencing of TADA3 suppressed their proliferative, migratory and invasive abilities in vitro, and delayed G1 to S phase progression through the cell cycle. Consistent with this, TADA3 silencing increased expression of the epithelial marker E-cadherin and reduced expression of the mesenchymal markers, N-cadherin, Vimentin, Snail, and Slug. To verify the effect of TADA3 on tumor formation and growth in vivo, a mouse tumor xenograft model was established. TADA3 silencing slowed the growth of NSCLC tumor xenografts in nude mice, and excised tumors showed a similarly altered pattern of epithelial-mesenchymal transition (EMT) marker expression. The present results demonstrated the significance of TADA3 in regulating the growth and metastasis of NSCLC and may provide a theoretical basis for early diagnosis and targeted therapy of NSCLC.

Pulmonary neuroendocrine tumors: study of 266 cases focusing on clinicopathological characteristics, immunophenotype, and prognosis.

OBJECTIVE: Pulmonary neuroendocrine tumors (PNETs) consist of small-cell lung cancer (SCLC), large-cell neuroendocrine carcinoma (LCNEC), typical carcinoid (TC), and atypical carcinoid (AC). We aimed to analyze the immunophenotypic, metastatic, and prognostic risk factors for PNETs. MATERIALS AND METHODS: A total of 266 patients with PNETs were enrolled, including 219 patients with SCLC, 18 patients with LCNEC, 11 patients with TC, and 18 patients with AC. Clinicopathological characteristics and immunophenotypes were compared among the subtypes of PNETs. Risk factors for metastasis, progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: Thyroid transcription factor-1 (TTF-1) and the Ki-67 index were significantly different among subtypes of PNETs (all P < 0.05). Smoking (OR, 2.633; P = 0.031), high pretreatment carcinoembryonic antigen (CEA > 5 ng/ml: OR, 3.084; P = 0.014), and poorly differentiated pathotypes (P = 0.001) were independent risk factors for lymph-node metastasis. Smoking (OR, 2.071; P = 0.027) and high pretreatment CEA (OR, 2.260; P = 0.007) were independent risk factors for distant metastasis. Results of the multivariate Cox regression model showed pretreatment CEA (HR, 1.674; P = 0.008) and lymphocyte-monocyte ratio (LMR) (HR = 0.478, P = 0.007) were significantly associated with PFS; BMI (P = 0.031), lymph-node metastasis (HR = 4.534, P = 0.001), poorly differentiated pathotypes (P = 0.015), platelet-lymphocyte ratio (PLR) (HR = 2.305, P = 0.004), and LMR (HR = 0.524, P = 0.045) were significantly associated with OS. CONCLUSIONS: PNETs are a group of highly heterogeneous tumors with different clinical manifestations, pathological features, and prognoses. Knowing clinicopathological characteristics and immunophenotypes of PNETs is significant for diagnosis. Pretreatment PLR, LMR, and CEA have certain value in the prognosis of PNETs.

Development of the dipeptidyl peptidase 4 family and its association with lung diseases: a narrative review.

Background and Objective: Dipeptidyl peptidase (DPP)4 is a member of a subfamily of serine peptidase S9. DPP4, expressed as a type II transmembrane protein, has a wide tissue distribution and is most active in the lung and small intestine. Many substrates of DPP4 have been identified, including neuropeptides, chemokines, and glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptides (GIPs). DPP4 inhibitors are clinically useful in the treatment of type 2 diabetes mellitus. DPP9, an N-terminal dipeptide targeting enzyme with proline or alanine, may have DPP4-like activity. DPP9 is ubiquitously expressed at human and rodent messenger RNA (mRNA) levels and therefore may play a role in the immune system and epithelial cells. It has been shown that DPP9 plays an important signaling role in the regulation of survival and proliferation pathways and is also involved in cell migration, apoptosis, and cell adhesion. In recent years, there has been further progress in DPP9 inhibition through activation of apoptosis by the inflammasome sensor protein Nlrp1b. This study aims to investigate the association of DPP4 family members and DPP9 with lung disease. Methods: The literature search was initiated using the PubMed database. We searched for the content (DPP4) AND (Lung Diseases), (DPP9) AND (Lung Diseases), from which we filtered the literature we needed. Key Content and Findings: Given the high biological activity of the DPP4 family, their involvement in various lung diseases is highly relevant. There is growing evidence for the importance of DPP4 and DPP9 of the DPP4 family in lung diseases, which are closely associated with diseases such as asthma, lung infections, pulmonary fibrosis (PF), and lung cancer. Conclusions: This review summarizes most of the current evidence that DPP4/9 is associated with lung disease. Within the DPP4 family, the role of DPP4 in particular in respiratory disease is important.

Spatially resolved gene regulatory and disease-related vulnerability map of the adult Macaque cortex.

Single cell approaches have increased our knowledge about the cell type composition of the non-human primate (NHP), but a detailed characterization of area-specific regulatory features remains outstanding. We generated single-cell transcriptomic and chromatin accessibility (single-cell ATAC) data of 358,237 cells from prefrontal cortex (PFC), primary motor cortex (M1) and primary visual cortex (V1) of adult female cynomolgus monkey brain, and integrated this dataset with Stereo-seq (spatial enhanced resolution omics-sequencing) of the corresponding cortical areas to assign topographic information to molecular states. We identified area-specific chromatin accessible sites and their targeted genes, including the cell type-specific transcriptional regulatory network associated with excitatory neurons heterogeneity. We reveal calcium ion transport and axon guidance genes related to specialized functions of PFC and M1, identified the similarities and differences between adult macaque and human oligodendrocyte trajectories, and mapped the genetic variants and gene perturbations of human diseases to NHP cortical cells. This resource establishes a transcriptomic and chromatin accessibility combinatory regulatory landscape at a single-cell and spatially resolved resolution in NHP cortex.

Genomic and microbial factors affect the prognosis of anti-pd-1 immunotherapy in nasopharyngeal carcinoma.

Antibodies targeting the programmed cell death protein-1 (PD-1) molecule have been reported to hold promising antitumor activities in patients with nasopharyngeal carcinoma (NPC). However, only a small subset of NPC patients benefits from the anti-PD-1 monotherapy and factors that affect the treatment response need further investigation. This study aimed to examine the impact of multiple genetic and environmental factors on outcome of anti-PD-1 immunotherapy by identifying tumor size, tumor mutation burden (TMB) based on whole exon sequencing, human leukocyte antigen class I (HLA-I) homo-/heterozygosity and supertypes, blood Epstein-Barr virus (EBV) DNA load, T cell proportions, and interferon-γ(IFN-γ) levels in a cohort of 57 NPC patients that received Nivolumab or Camrelizumab treatment. Moreover, we profiled the longitudinal changes in gut microbiota composition using shotgun metagenomics sequencing. We observed that high TMB combined with HLA-I heterozygosity was associated with improved clinical outcomes. In agreement with previous studies, we found that patients with higher plasma EBV DNA load showed worse progression-free survival. We found no evidence for an effect of gut bacterial diversity on the treatment response, but identified a higher abundance of seven specific gut bacteria at baseline of non-responders, including Blautia wexlera and Blautia obeum, as well as four other bacteria belonging to the Clostridiales order, and one Erysipelatoclostridium. Combined, this study provides insight into the influence of several genetic and environmental factors on anti-PD-1 immunotherapy responses in NPC patients.

Distinct Functional Metagenomic Markers Predict the Responsiveness to Anti-PD-1 Therapy in Chinese Non-Small Cell Lung Cancer Patients.

Background: Programmed death 1 (PD-1) and the ligand of PD-1 (PD-L1) are central targets for immune-checkpoint therapy (ICT) blocking immune evasion-related pathways elicited by tumor cells. A number of PD-1 inhibitors have been developed, but the efficacy of these inhibitors varies considerably and is typically below 50%. The efficacy of ICT has been shown to be dependent on the gut microbiota, and experiments using mouse models have even demonstrated that modulation of the gut microbiota may improve efficacy of ICT. Methods: We followed a Han Chinese cohort of 85 advanced non-small cell lung cancer (NSCLC) patients, who received anti-PD-1 antibodies. Tumor biopsies were collected before treatment initiation for whole exon sequencing and variant detection. Fecal samples collected biweekly during the period of anti-PD-1 antibody administration were used for metagenomic sequencing. We established gut microbiome abundance profiles for identification of significant associations between specific microbial taxa, potential functionality, and treatment responses. A prediction model based on random forest was trained using selected markers discriminating between the different response groups. Results: NSCLC patients treated with antibiotics exhibited the shortest survival time. Low level of tumor-mutation burden and high expression level of HLA-E significantly reduced progression-free survival. We identified metagenomic species and functional pathways that differed in abundance in relation to responses to ICT. Data on differential enrichment of taxa and predicted microbial functions in NSCLC patients responding or non-responding to ICT allowed the establishment of random forest algorithm-adopted models robustly predicting the probability of whether or not a given patient would benefit from ICT. Conclusions: Overall, our results identified links between gut microbial composition and immunotherapy efficacy in Chinese NSCLC patients indicating the potential for such analyses to predict outcome prior to ICT.

A H9N2 Human Case and Surveillance of Avian Influenza Viruses in Live Poultry Markets - Huizhou City, Guangdong Province, China, 2021.

What is already known about this topic?: An increasing number of human infected avian influenza A (H9N2) cases have been reported. In 2021, 11 human infections with influenza A virus subtype H9N2 (A/H9N2) have been reported in China. What is added by this report?: A new case of H9N2 that occurred in April 2021 in Huizhou City, Guangdong Province, China, was reported in this study. Epidemiological and laboratory information of the case and routine influenza surveillance data of avian influenza A were presented in this report. What are the implications for public health practice?: The emergence of a human infected with Avian Influenza Virus H9N2 demonstrates that there is an urgent need to strengthen the surveillance of influenza-like illness and live poultry market.

STAT3 Promotes Cell Proliferation by Potentiating the CCL4 Transcriptional Activity in Diffuse Large B-Cell Lymphoma.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor and a candidate therapeutic option for human cancers. However, the underlying mechanism of STAT3 in the pathogenesis of diffuse large B-cell lymphoma (DLBCL) is yet to be established. We studied here whether STAT3 contributes to C-C motif chemokine ligand (CCL4) transcription elevation in DLBCL. Our established protein-protein interactions network revealed the overexpression of STAT3 and CCL4 in DLBCL. Mechanistically, STAT3 activated CCL4 transcription to induce the Wnt/ß-catenin pathway. The prognostic analysis exhibited that the overall survival of patients with high STAT3 and CCL4 were poorer than those with low STAT3 and CCL4 expression. In addition, silencing of STAT3 reverted the malignant phenotype in DLBCL cells. CCL4 overexpression partly weakened the si-STAT3-mediated antitumor effects on DLBCL cells. Tumor xenograft models showed that si-STAT3 inhibited tumor growth in vivo and decreased proliferative and mitogenic activities in tumor tissues, which was consistent with the in vitro data. Hence, this study provides new evidence that STAT3 and CCL4 may be new prognostic biomarkers and therapeutic targets for treating DLBCL.

Cytotoxic lanostane triterpenoids from the ethanol extract of Schisandra viridis.

Three new lanostane triterpenoids, designated as 6-hydroxyl schiglausin A (1), 29-hydroxyl schiglausin D (2), and 6-hydroxyl schiglausin G (3), were isolated from the ethanol extract of the stems of Schisandra viridis. Structural elucidation of all the compounds were performed by spectral methods such as 1D and 2D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. The isolated compounds were tested in vitro for cytotoxic activities. As a result, compound 1 exhibited cytotoxic activities for all six tested human lung cancer cell lines with IC50 values less than 10 µM.

Chronic Pain Causes Peripheral and Central Responses in MIA-Induced TMJOA Rats.

Chronic pain is the predominant symptom that drives temporomandibular joint osteoarthritis (TMJOA) patients to seek medical care; however, currently used treatment modalities remain less effective. This study aimed to investigate chronic pain and the peripheral and central responses in monoiodoacetate (MIA)-induced TMJOA rats. First, the appropriate dose of MIA was determined based on pain behavior assessment in rats. Alterations of the condylar structure in TMJOA rats were evaluated by histological staining and micro-computed tomography (micro-CT). Second, the period of TMJOA chronic pain was further explored by assessing the numbers of glial fibrillary acidic protein (GFAP)-positive astrocytes and ionized calcium-binding adaptor molecule 1 (IBA-1)-positive microglia in the trigeminal spinal nucleus (TSN) and performing nonsteroidal anti-inflammatory drug (NSAID) efficacy experiments. Finally, the expression of neurofilament 200 (NF200), calcitonin gene-related peptide (CGRP), and isolectin B4 (IB4) in the trigeminal ganglion (TG) and TSN was assessed by immunofluorescence. MIA at 4 mg/kg was considered an appropriate dose. Gradual MIA-induced alterations of the condylar structure were correlated with temporomandibular joint (TMJ) pain. The numbers of GFAP- and IBA-1-positive cells were increased at 2, 3, and 4 weeks after MIA injection. NSAIDs failed to alleviate pain behavior 10 days after MIA injection. CGRP and IB4 levels in the TG and TSN were upregulated at 2 and 4 weeks. These results suggest that TMJOA-related chronic pain emerged 2 weeks after MIA injection. CGRP- and IB4-positive afferents in both the peripheral and central nervous systems may be involved in MIA-induced TMJOA-related chronic pain in rats.

Bone Healing and Inflammation: Principles of Fracture and Repair.

Bones comprise a significant percentage of human weight and have important physiologic and structural roles. Bone remodeling occurs when healthy bone is renewed to maintain bone strength and maintain calcium and phosphate homeostasis. It proceeds through four phases: (1) cell activation, (2) resorption, (3) reversal, and (4) bone formation. Bone healing, on the other hand, involves rebuilding bone following a fracture. There are two main types of bone healing, primary and secondary. Inflammation plays an integral role in both bone remodeling and healing. Therefore, a tightly regulated inflammatory response helps achieve these two processes, and levels of inflammation can have detrimental effects on bone healing. Other factors that significantly affect bone healing are inadequate blood supply, biomechanical instability, immunosuppression, and smoking. By understanding the different mechanisms of bone healing and the factors that affect them, we may have a better understanding of the underlying principles of bony fixation and thereby improve patient care.

Peripheral Nerve Healing: So Near and Yet So Far.

Peripheral nerve injuries represent a considerable portion of chronic disability that especially affects the younger population. Prerequisites of proper peripheral nerve injury treatment include in-depth knowledge of the anatomy, pathophysiology, and options in surgical reconstruction. Our greater appreciation of nerve healing mechanisms and the development of different microsurgical techniques have significantly refined the outcomes in treatment for the past four decades. This work reviews the peripheral nerve regeneration process after an injury, provides an overview of various coaptation methods, and compares other available treatments such as autologous nerve graft, acellular nerve allograft, and synthetic nerve conduits. Furthermore, the formation of neuromas as well as their latest treatment options are discussed.

Tendon: Principles of Healing and Repair.

Tendon stores, releases, and dissipates energy to efficiently transmit contractile forces from muscle to bone. Tendon injury is exceedingly common, with the spectrum ranging from chronic tendinopathy to acute tendon rupture. Tendon generally develops according to three main steps: collagen fibrillogenesis, linear growth, and lateral growth. In the setting of injury, it also repairs and regenerates in three overlapping steps (inflammation, proliferation, and remodeling) with tendon-specific durations. Acute injury to the flexor and extensor tendons of the hand are of particular clinical importance to plastic surgeons, with tendon-specific treatment guided by the general principle of minimum protective immobilization followed by hand therapy to overcome potential adhesions. Thorough knowledge of the underlying biomechanical principles of tendon healing is required to provide optimal care to patients presenting with tendon injury.