The miR-9-5p/KLF5/IL-1ß Axis Regulates Airway Smooth Muscle Cell Proliferation and Apoptosis to Aggravate Airway Remodeling and Inflammation in Asthma.

The aim of this study was to investigate the underlying mechanism of miR-9-5p in airway smooth muscle cells (ASMCs) of asthmatic mice. An asthmatic mouse model was established through the intraperitoneal injection of ovalbumin. Histopathological changes in lung tissues of asthmatic mice were observed using HE staining. ASMCs was identified using immunofluorescence staining and cell morphology. The mRNA expressions of miR-9-5p, KLF5, and IL-1ß were measured using RT-qPCR. Additionally, CCK8 assay and flow cytometry were applied for ASMC proliferation and apoptosis, respectively. The protein levels of OPN, KLF5, and IL-1ß were assessed using western blotting. The results showed that miR-9-5p was abnormally downregulated in lung tissues and ASMCs of asthmatic mice. Dual-Luciferase Reporter Assay and Chromatin immunoprecipitation confirmed that miR-9-5p targeted KLF5 that bounds to IL-1ß promoter. Besides, miR-9-5p negatively regulated IL-1ß mRNA and protein level via KLF5. Moreover, miR-9-5p was found to positively regulate ASMC apoptosis, negatively regulate ASMC proliferation and OPN protein expression, albeit with partial reversal by KLF5. Mechanistically, the regulation of ASMC proliferation and apoptosis by miR-9-5p is achieved by targeting KLF5/IL-1ß axis.

The co-regulation of the gut microbiome and host genes might play essential roles in metformin gastrointestinal intolerance.

Metformin is commonly used, but approximately 20% of patients experience gastrointestinal intolerance, leading to medication discontinuation for unclear reasons and a lack of effective management strategies. In this study, the 18 fecal and blood samples were analyzed using 16S rRNA and mRNA transcriptome, respectively. These samples included 3 fecal and 4 blood from metformin-tolerant T2D patients before and after metformin treatment (T and Ta), 3 fecal and 5 blood from metformin-intolerant T2D patients before and after treatment (TS and TSa), and 6 fecal samples from healthy controls. The results showed that certain anti-inflammatory gut bacteria and gene, such as Barnesiella (p = 0.046), Parabacteroides goldsteinii (p = 0.016), and the gene JUND (p = 0.0002), exhibited higher levels in metformin-intolerant patients, and which decreased after metformin treatment (p < 0.05). This potentially invalidates patients' anti-inflammatory effect and intestinal mucus barrier protection, which may lead to alterations in intestinal permeability, decreased gut barrier function, and gastrointestinal symptoms, including diarrhea, bloating, and nausea. After metformin treatment, primary bile acids (PBAs) production species: Weissella confusa, Weissella paramesenteroides, Lactobacillus brevis, and Lactobacillus plantarum increased (p < 0.05). The species converting PBAs to secondary bile acids (SBAs): Parabacteroides distasonis decreased (p < 0.05). This might result in accumulation of PBAs, which also may lead to anti-inflammatory gene JUND and SQSTM1 downregulated. In conclusion, this study suggests that metformin intolerance may be attributed to a decrease in anti-inflammatory-related flora and genes, and also alterations in PBAs accumulation-related flora. These findings open up possibilities for future research targeting gut flora and host genes to prevent metformin intolerance.

Cytopathological Features of Extensive Bilateral Pleural Effusions in Metastatic Prostate Cancer: Report of a Rare Case.

We report a rare case of a 59-year-old male with a history of metastatic prostate cancer presenting with acute onset dyspnea due to extensive bilateral pleural effusions. This case highlights the rarity of metastatic prostate cancer with pleural involvement and underscores the importance of accurate diagnosis using cytopathology and immunohistochemical staining.

The antidepressive mechanism of Longya Lilium combined with Fluoxetine in mice with depression-like behaviors.

Traditional Chinese medicine is one of the most commonly used complementary and alternative medicine therapies for depression. Integrated Chinese-western therapies have been extensively applied in numerous diseases due to their superior efficiency in individual treatment. We used the meta-analysis, network pharmacology, and bioinformatics studies to identify the putative role of Longya Lilium combined with Fluoxetine in depression. Depression-like behaviors were mimicked in mice after exposure to the chronic unpredictable mild stress (CUMS). The underlying potential mechanism of this combination therapy was further explored based on in vitro and in vivo experiments to analyze the expression of COX-2, PGE2, and IL-22, activation of microglial cells, and neuron viability and apoptosis in the hippocampus. The antidepressant effect was noted for the combination of Longya Lilium with Fluoxetine in mice compared to a single treatment. COX-2 was mainly expressed in hippocampal CA1 areas. Longya Lilium combined with Fluoxetine reduced the expression of COX-2 and thus alleviated depression-like behavior and neuroinflammation in mice. A decrease of COX-2 curtailed BV-2 microglial cell activation, inflammation, and neuron apoptosis by blunting the PGE2/IL-22 axis. Therefore, a combination of Longya Lilium with Fluoxetine inactivates the COX-2/PGE2/IL-22 axis, consequently relieving the neuroinflammatory response and the resultant depression.

When Lymphoma Strikes the Pancreas: A Rare Presentation of Systemic Anaplastic Lymphoma Kinase-Negative Anaplastic Large Cell Lymphoma in a Human Immunodeficiency Virus-Positive Patient.

Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is an uncommon subtype of non-Hodgkin lymphoma, with pancreatic involvement being exceedingly rare and documented in only a handful of case reports. We present a unique case of a 31-year-old human immunodeficiency virus (HIV)-positive male with multisite ALK-negative ALCL, who initially presented with a buttock ulcer, leading to a suspicion of primary cutaneous ALCL or lymphomatoid papulosis. However, the discovery of multiple extracutaneous sites, including an atypical pancreatic head involvement, confirmed the diagnosis of systemic ALK-negative ALCL with cutaneous manifestation. The patient received six cycles of brentuximab vedotin + cyclophosphamide-doxorubicin-prednisone (BV + CHP) treatment, achieving a substantial reduction in the size of the pancreatic head mass and no detectable fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) scan. This case underscores the diagnostic challenges of ALK-negative ALCL in HIV-positive patients with extranodal presentations and demonstrates the potential effectiveness of targeted therapeutic strategies for such cases.

Unmasking the Silent Invader: A Rare Case of Follicular Thyroid Carcinoma With Skull Metastasis and an Uncommon KRAS Q61R Mutation.

Follicular thyroid carcinoma (FTC) is a noteworthy subtype of thyroid cancer known for its tendency to metastasize through the bloodstream, usually to the lungs and bones. This case report examines an exceptionally rare instance involving an 81-year-old female presenting with an unusual metastatic scalp lesion. Remarkably, this aggressive metastasis originated from a thyroid lesion as small as 0.7 cm. Lab findings, including suppressed TSH and elevated T3 levels, revealed subclinical hyperthyroidism, adding another layer of rarity to this FTC case. Molecular profiling identified a rare KRAS Q61R mutation, providing potential insight into the case's aggressive behavior and underscoring the importance of genetic assessment in FTC. This report emphasizes the critical role of comprehensive diagnostic evaluations, including histopathological assessments, in properly diagnosing and managing FTC, especially when clinical presentations defy conventional paradigms.

Internal energy deposition and ion fragmentation in atmospheric-pressure mid-infrared laser ablation electrospray ionization.

Mid-infrared laser ablation of water-rich targets at the maximum of the 2.94 µm absorption band is a two-step process initiated by phase explosion followed by recoil pressure induced material ejection. Particulates and/or droplets ejected by this high temperature high pressure process can be ionized for mass spectrometry by charged droplets from an electrospray. In order to gauge the internal energy introduced in this laser ablation electrospray ionization (LAESI®) process, we apply the survival yield method and compare the results with electrospray ionization (ESI) and matrix-assisted laser desorption ionization (MALDI). The results indicate that LAESI yields ions with internal energies indistinguishable from those produced by ESI. This finding is consistent with the recoil pressure induced ejection of low micrometre droplets that does not significantly change the internal energy of solute molecules.

Lymphoepithelioma-Like Carcinoma of the Breast: A Case Report of a Rare Type of Invasive Carcinoma.

Lymphoepithelioma carcinoma (LELC) is an extremely rare type of mammary cancer. Based on the histology, it can be misdiagnosed with inflammatory lesions like mastitis and medullary carcinoma or other hematopoietic neoplasms like lymphoma in the breast. Since LELC has a good response to chemotherapy with a good prognosis, t is prognostically important to recognize LELC. We report a rare case of LELC in a 51-year-old pre-menopausal female with a left breast mass, diagnosed with invasive ductal carcinoma (IDC), LELC type, treated with mastectomy, followed by adjuvant chemotherapy and radiotherapy, with a disease-free interval of 10 months. Herein, we present the case with its clinical presentation, radiologic imaging, histopathological features, and immunohistochemistry (IHC) findings. The rarity of this type of breast tumor warrants studying the behavior of these uncommon tumors to avoid misdiagnosis and establish well-defined criteria for diagnosis.

Single-Cell Transcriptomics Uncovers Cellular Heterogeneity, Mechanisms, and Therapeutic Targets for Parkinson's Disease.

Objective: This study aimed to exploit cellular heterogeneity for revealing mechanisms and identifying therapeutic targets for Parkinson's disease (PD) via single-cell transcriptomics. Methods: Single-cell RNA sequencing (scRNA-seq) data on midbrain specimens from PD and healthy individuals were obtained from the GSE157783 dataset. After quality control and preprocessing, the principal component analysis (PCA) was presented. Cells were clustered with the Seurat package. Cell clusters were labeled by matching marker genes and annotations of the brain in the CellMarker database. The ligand-receptor networks were established, and the core cell cluster was selected. Biological functions of differentially expressed genes in core cell clusters were analyzed. Upregulated marker genes were identified between PD and healthy individuals, which were measured in 18 PD patients' and 18 healthy individuals' blood specimens through RT-qPCR and Western blotting. Results: The first nine PCs were determined, which can better represent the overall change. Five cell clusters were identified, including oligodendrocytes, astrocytes, neurons, microglial cells, and endothelial cells. Among them, endothelial cells were the core cell cluster in the ligand-receptor network. Marker genes of endothelial cells possessed various biological functions. Among them, five marker genes (ANGPT2, APOD, HSP90AA1, HSPA1A, and PDE1C) were upregulated in PD patients' than in healthy individuals' endothelial cells, which were confirmed in PD patients' than in healthy individuals' blood specimens. Conclusion: Our findings revealed that the cellular heterogeneity of PD and endothelial cells could play a major role in cell-to-cell communications. Five upregulated marker genes of endothelial cells could be underlying therapeutic targets of PD, which deserve more in-depth clinical research.

Weighted Gene Coexpression Network Analysis Uncovers Critical Genes and Pathways for Multiple Brain Regions in Parkinson's Disease.

OBJECTIVE: In this study, we aimed to identify critical genes and pathways for multiple brain regions in Parkinson's disease (PD) by weighted gene coexpression network analysis (WGCNA). METHODS: From the GEO database, differentially expressed genes (DEGs) were separately identified between the substantia nigra, putamen, prefrontal cortex area, and cingulate gyrus of PD and normal samples with the screening criteria of p value < 0.05 and ∣log2fold change (FC) | >0.585. Then, a coexpression network was presented by the WGCNA package. Gene modules related to PD were constructed. Then, PD-related DEGs were used for construction of PPI networks. Hub genes were determined by the cytoHubba plug-in. Functional enrichment analysis was then performed. RESULTS: DEGs were identified for the substantia nigra (17 upregulated and 52 downregulated genes), putamen (317 upregulated and 317 downregulated genes), prefrontal cortex area (39 upregulated and 72 downregulated genes), and cingulate gyrus (116 upregulated and 292 downregulated genes) of PD compared to normal samples. Gene modules were separately built for the four brain regions of PD. PPI networks revealed hub genes for the substantia nigra (SLC6A3, SLC18A2, and TH), putamen (BMP4 and SNAP25), prefrontal cortex area (SNAP25), and cingulate gyrus (CTGF, CDH1, and COL5A1) of PD. These DEGs in multiple brain regions were involved in distinct biological functions and pathways. GSEA showed that these DEGs were all significantly enriched in electron transport chain, proteasome degradation, and synaptic vesicle pathway. CONCLUSION: Our findings revealed critical genes and pathways for multiple brain regions in PD, which deepened the understanding of PD-related molecular mechanisms.

Multiomics Analysis of Genetics and Epigenetics Reveals Pathogenesis and Therapeutic Targets for Atrial Fibrillation.

OBJECTIVE: This study is aimed at understanding the molecular mechanisms and exploring potential therapeutic targets for atrial fibrillation (AF) by multiomics analysis. METHODS: Transcriptomics and methylation data of AF patients were retrieved from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) and differentially methylated sites between AF and normal samples were screened. Then, highly expressed and hypomethylated and lowly expressed and hypermethylated genes were identified for AF. Weighted gene coexpression network analysis (WGCNA) was presented to construct AF-related coexpression networks. 52 AF blood samples were used for whole exome sequence. The mutation was visualized by the maftools package in R. Key genes were validated in AF using independent datasets. RESULTS: DEGs were identified between AF and controls, which were enriched in neutrophil activation and regulation of actin cytoskeleton. RHOA, CCR2, CASP8, and SYNPO2L exhibited abnormal expression and methylation, which have been confirmed to be related to AF. PCDHA family genes had high methylation and low expression in AF. We constructed two AF-related coexpression modules. Single-nucleotide polymorphism (SNP) was the most common mutation type in AF, especially T > C. MUC4 was the most frequent mutation gene, followed by PHLDA1, AHNAK2, and MAML3. There was no statistical difference in expression of AHNAK2 and MAML3, for AF. PHLDA1 and MUC4 were confirmed to be abnormally expressed in AF. CONCLUSION: Our findings identified DEGs related to DNA methylation and mutation for AF, which may offer possible therapeutic targets and a new insight into the pathogenesis of AF from a multiomics perspective.