ObjectiveCervical cancer ranks as the fourth most prevalent cancer among women globally; it originates in the cervix and has a significant association with human papillomavirus (HPV) infection. The purpose of this study was to investigate the diagnostic utility of cell block (CB) preparations from liquid-based cytology samples in identifying cervical lesions among Turkish patients with HPV. This approach was intended to supplement conventional Pap smear tests and HPV testing.Material and MethodsA retrospective analysis was conducted on 60 HPV-positive cervical smear samples processed through the ThinPrep Pap test. CBs were prepared from liquid-based residues, stained with hematoxylin and eosin, and analyzed. Cytological diagnoses were compared with histopathological findings from colposcopy-guided biopsies. The relationships between the Pap smear, CB, and biopsy results were statistically analyzed.ResultsPap smear cytology identified 1.6%, 16.6%, 43.3%, and 3.3% as high-grade squamous intraepithelial lesion (HSIL), low-grade squamous intraepithelial lesion (LSIL), atypical squamous cells of undetermined significance, and atypical squamous cells - HSIL cannot be excluded + LSIL, respectively. The CB evaluations classified 6.6% of the samples as cervical intraepithelial neoplasia (CIN)1, 1.6% as CIN2, and 1.6% as squamous cell carcinoma (SCC), with 78.3% deemed negative. Histopathological biopsy revealed CIN1 in 11.7%, CIN2 in 1.7%, and CIN3 in 8.3% of the patients. High concordance was observed between the Pap smear and CB diagnoses for negative and low-grade lesions, although discrepancies occurred in higher-grade lesions. HPV testing revealed 65% high-risk positivity, predominantly for HPV16 and HPV18. Significant correlations were found among HPV subtype positivity, CB, and biopsy diagnosis (P < 0.05).ConclusionCB preparations provide enhanced diagnostic accuracy for high-grade lesions and SCC, thus complementing Pap smear cytology and HPV testing. This approach supports their integration into the routine cervical cancer screening protocols in Türkiye. Further global, multicenter studies are recommended to validate these findings.

ObjectiveThe prognosis of patients with non-small cell lung cancer (NSCLC) is poor, and this malignancy represents a grievous danger to human health due to its high rates of recurrence and metastasis. Previous studies have linked prominin 2 (PROM2) to certain cancers. However, the impact of PROM2 on the biological behavior of NSCLC cells and regulatory pathways has rarely been explored. Therefore, the study aims to elucidate the roles and regulatory mechanisms of PROM2 in the cell function of NSCLC by interfering with PROM2.Material and MethodsPROM2 messenger ribonucleic acid (mRNA) and protein expression levels in NSCLC cells were analyzed by applying quantitative real-time polymerase chain reaction and Western blot analysis. Phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), and phosphorylated-AKT (p-AKT) protein levels were evaluated through Western blot analysis. Cell counting kit-8 and Transwell assays were used to evaluate NSCLC cell proliferation, migration, and invasion.ResultsPROM2 mRNA protein levels drastically increased in NSCLC tissues and cells. High PROM2 mRNA level was related to the poor prognosis of patients with NSCLC. PROM2 silencing remarkably repressed NCI-H520 and A549 cell proliferation, migration, and invasion. Furthermore, PI3K and p-AKT protein levels clearly decreased after PROM2 silencing. Importantly, rescue experiments elucidated that PI3K/AKT pathway activation could reverse the inhibitory effect of PROM2 silencing on the proliferation, migration, and invasion of NCI-H520 and A549 cells.ConclusionThis study verified that PROM2 knockdown inhibits the growth, migration, and invasion of NSCLC by repressing the PI3K/AKT pathway.

ObjectiveThe etiology and specific pathological mechanisms of keloids remain elusive. Array expression profiling has revealed dysregulation of the transcription cofactor ankyrin repeat domain 1 (ANKRD1) in keloid fibroblasts. The present study focused on examining the expression pattern of ANKRD1 in keloids and assessing its function in human keloid fibroblasts (HKFs).Material and MethodsDifferential mRNA expression profiles in keloid fibroblasts were investigated by analyzing data from gene expression omnibus (GEO) datasets. Immunohistochemistry assays were performed to verify the expression patterns of ANKRD1 and claudin 11 (CLDN11) in keloid tissue samples. Functional studies were conducted by transfecting HKFs with either a small interfering RNA (siRNA) targeting ANKRD1 (siANKRD1) or ANKRD1-overexpressing plasmids. The functional impact of ANKRD1 was assessed using cell proliferation, flow cytometry, and Transwell migration assays. mRNA expression was evaluated using reverse transcription polymerase chain reaction, and protein expression was determined using Western blotting.ResultsAnalysis of the GEO series (GSE) GSE44270 revealed eight differentially expressed mRNAs, with ANKRD1 and CLDN11 being the top two downregulated mRNAs. ANKRD1 expression was observed to be lower in keloid tissues than in normal skin tissues, whereas CLDN11 expression showed no significant difference between the two groups. ANKRD1 overexpression suppressed HKF proliferation, migration, and the expression levels of collagen I, fibronectin, matrix metallopeptidase 9, whereas the opposite effects were observed on ANKRD1 knockdown. ANKRD1 did not affect apoptotic cell levels.ConclusionANKRD1 is downregulated in keloids and inhibits the growth, migration, and extracellular matrix deposition of keloid fibroblasts. Thus, ANKRD1 may function as a suppressor in keloid formation.

Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are the primary downstream effectors of the Hippo signaling pathway. This pathway plays a crucial role in regulating organ size, maintaining tissue homeostasis, and controlling cellular processes such as fate determination and tissue development. This review provides an overview of the current understanding of how the transcriptional regulators YAP and TAZ contribute to the physiological and pathological processes in tissues and cells associated with the skeletal motor system. The underlying molecular mechanisms and mechanical transduction were reviewed.

Objective:Soft tissue and bone cancers, collectively known as sarcomas, constitute a diverse array of uncommon tumors originating from connective tissues. Among sarcomas, leiomyosarcoma (LMS) is one of the most frequently encountered subtypes. This study aims to investigate the expression, clinical significance, biological regulation, and dysregulation mechanisms of extra spindle pole bodies like 1 (ESPL1), a gene critical for cell cycle regulation in LMS.Material and Methods:Bioinformatics analysis was performed using the data from The Cancer Genome Atlas-Sarcoma and Genotype-Tissue Expression datasets. Functional experiments to assess cell proliferation and the cell cycle were performed in LMS cells (SK-LMS-1) after ESPL1 knockdown. Bioinformatics analyses were conducted to identify the potential transcriptional regulators of ESPL1. The regulatory relationship between ESPL1 and the E2F transcription factor 1 (E2F1) was validated through the various molecular assays.Results:ESPL1 is significantly overexpressed in LMS compared with normal muscle tissue. High ESPL1 expression is associated with a shorter progression-free interval (PFI) in sarcoma patients, particularly in the LMS subset. ESPL1 expression might be an independent prognostic factor for poor overall survival and PFI in LMS patients. Functional studies in the LMS cell line SK-LMS-1 demonstrated that ESPL1 knockdown slowed cell proliferation and increased G2/M cell cycle arrest, suggesting its crucial role in maintaining LMS cell viability and genomic integrity. Further bioinformatics analysis identified the E2F1 transcription factor as a key regulator of ESPL1 expression in LMS. Mechanistic investigations demonstrated that E2F1 interacts with the ESPL1 promoter, leading to transcriptional activation.Conclusion:These findings highlight the ESPL1-E2F1 axis as a potential prognostic biomarker and therapeutic target in LMS.

Langerhans cell histiocytosis (LCH) and Erdheim–Chester disease (ECD) are exceptionally rare disorders characterized by varied clinical presentations, posing several challenges for clinicians. The concomitant occurrence of LCH and ECD is exceedingly rare and has no known etiology. In this report, we present a rare case of mixed histiocytosis (both ECD and LCH) with multisystem involvement. The patient, a 49-year-old female, initially presented with a rash 2 years ago and progressively developed exophthalmos, fatigue, and shortness of breath. She lacked the mutation in codon 600 of exon 15 of B-Raf proto-oncogene (BRAF-V600E) and subsequently underwent treatment with corticosteroids, interferon-alpha, and chemotherapy, all of which proved ineffective. This work highlights the urgent need to improve treatment outcomes for such patients. Therefore, we discuss the latest advancements in understanding treatment strategies for mixed histiocytic syndromes.

Objective:Macrophages perform vital functions in cardiac remodeling after myocardial infarction (MI). Transglutaminase 2 (TG2) participates in fibrosis. Nevertheless, the role of TG2 in MI and mechanisms underlying macrophage polarization are unclear. This study aimed to discover the functions and possible mechanisms of TG2 in MI.Material and Methods:C57BL/6 mice were classified into three groups (six mice per group): Sham, MI, and MI+GK921 groups. GK921 acts as a TG2 inhibitor. Cardiac function, myocardial cell apoptosis, fibrosis, and macrophage phenotype in mouse experiments were detected through echocardiography, terminal deoxynucleotidyl transferase dUTP nick end labeling, Masson staining, immunofluorescence, and flow cytometry, respectively. The in vitro study involved the treatment of mouse cardiac fibroblasts isolated from mice with transforming growth factor β1 (TGF-β1) and evaluation of fibrosis through the detection of the expressions of fibrosis-associated proteins using Western blot. Bone marrow-derived macrophages (BMDMs) obtained from mice were triggered by interleukin (IL)-4, and the type of macrophages was determined through flow cytometry.Results:In in vivo experiments, GK921 substantially improved cardiac injury and fibrosis, induced M2 macrophage polarization, and suppressed the TGF-β1/small mother against decapentaplegic 3 (Smad3) pathway in MI mice. Moreover, TG2 knockdown considerably decreased the expressions of fibrosis-associated proteins in TGF-β1-triggered mouse cardiac fibroblasts, which indicates the repressive effect of TG2 knockdown on fibrosis. In addition, the inhibition effect of TG2 downregulation on the TGF-β1/Smad3 pathway was proven in TGF-β1-treated mouse cardiac fibroblasts in vitro. Moreover, TG2 inhibition remarkably increased M2 macrophage polarization in IL-4-induced BMDMs.Conclusion:TG2 inhibition facilitated M2 macrophage polarization to provide protection against MI-caused cardiac fibrosis in mice, and these effects may be attained through modulation of the TGF-β1/Smad3 pathway.

Objective:Benign histiocytic proliferation in effusion specimens can be found in a variety of diseases such as rheumatoid arthritis, systemic lupus erythematosus, microorganism infections, trauma, reactive eosinophilic pleuritis, and others. In addition, nodular histiocytic/mesothelial hyperplasia is another well-recognized rare cause. The previous studies have shown that proliferative histiocytes have raisinoid nuclei and abundant eosinophilic granular cytoplasm and can be confused with malignant lesions, especially metastatic carcinomas. In this study, we evaluated the cytomorphology of benign histiocytes, discussed the diagnosis and differential diagnosis, and the clinical significance of histiocytic signet ring cells in effusion cytology.Material and Methods:Seven hundred and fifty-five benign effusion cases (433 pleural effusions and 322 abdominal fluids) were found over 1 year. Among benign cases, 35 cases (28 pleural effusions and seven abdominal fluids) were included with findings of dominantly histiocytic signet ring cell morphology as well as immunohistochemical (IHC) stains. The clinical findings were also correlated.Results:In contrast to the well-documented cytomorphology of raisinoid nuclei and eosinophilic cytoplasm of proliferative histiocytes in previous studies, we find that these cells predominately presented as signet ring cell morphology with clear cytoplasm. The most characteristic findings of benign histiocytes in pleural effusions are: (1) cells are arranged in sheets and/or scattered individual cells, but no two- or three-dimensional cell clusters; (2) cells are intermediate in size and with normal N/C ratio; (3) cells have eccentric located nuclei and abundant clear cytoplasm, giving signet ring cell appearance; (4) nuclei have fine granular chromatin pattern, no hyperchromia or coarse chromatin pattern, no nuclear atypia; and (5) immunohistochemical (IHC) stains demonstrate a strongly positivity for macrophage-histiocyte lineage marker CD68, but negativity for epithelial markers and mesothelial markers. Clinically, these patients do not demonstrate nodularity or lesions in the mesothelial lining of serous cavities.Conclusion:Our study provides a detailed characterization of benign histiocytic signet ring cells in effusion cytology. The differential diagnosis of histiocytic signet ring cells is broad. The most important differential diagnoses are metastatic adenocarcinoma and epithelioid signet ring cell mesothelioma. The accurate diagnosis is critical for the appropriate clinical management of the patient. Cytopathologists should be aware of the diagnostic pitfalls of benign histiocytic signet ring cells in effusion samples in daily practice.

Objective:Studies have shown that chemokines can stimulate the migration and activation of microglia to cause chronic post-surgical pain (CPSP). However, the involvement of C-X-C motif chemokine receptor 2 (CXCR2) as a new chemotactic factor in regulating CPSP and its underlying mechanism remains unclear. This study is to investigate the role of CXCR2 in the development of CPSP and reveal the underlying mechanism.Material and Methods:A rat model of skin/muscle incision and retraction was established, and treated with or without SB225002 (a selective inhibitor of CXCR2). In addition, the primary microglia cells induced by lipopolysaccharide were applied as an in vitro model for CPSP and treated individually with si-negative control (NC), si-CXCR2, si-CXCR2+Interleukin (IL)-6 (an agonist of the janus kinase (JAK)/signal transducers and activators of transcription (STAT)3 signaling pathway), si-CXCR2+IL-6+si-NC, or si-CXCR2+IL-6+si-exchange protein 1 directly activated by cAMP (EPAC1).Results:Results from the database analysis showed that CXCR2 and JAK/STAT3 signaling pathway-related genes, including JAK1, STAT3, and EPAC1, were mainly involved in the development of CPSP. Inhibition of CXCR2 expression not only inhibited the reduction of foot pain threshold in CPSP models but also led to a decreased expression of CXCR2 and the phosphorylation levels of JAK and STAT3 in both animal and cell models. Furthermore, inhibition of EPAC1 expression can hinder the regulatory function of CXCR2.Conclusion:This study indicated that the high expression of CXCR2 activates the JAK1/STAT3 signaling pathway, enhances EPAC1 activation in microglial cells, and exacerbates CPSP.

Orbital inflammatory disease (OID) comprises approximately 6% of orbital conditions, affecting individuals across all ages. The range of the primary orbital inflammation’s differential diagnosis is extensive, encompassing autoimmune disorders such as thyroid diseases, vasculitis, sarcoidosis, connective tissue diseases, immunoglobulin G4-related disease (IgG4-RD), and giant cell myositis, whereas secondary causes span from infections to drug-induced causes. Analyzing histopathological aspects and cell populations could enhance our comprehension of the etiology of orbital inflammatory involvement in systemic diseases such as IgG4-RD. We present a series of four patients from our Rheumatology clinic, each with distinct systemic diseases, illustrating diverse manifestations of OID. This series was conducted to facilitate discussions and diagnoses of challenging cases of OID in a rheumatologic setting. The difficulty in the differential diagnosis arises from the extensive range of structures involved, resulting in a significant variation of clinical manifestations. Furthermore, the lack of definitive diagnostic laboratory tests and, often, histological findings add to the complexity. OID poses diagnostic challenges with variable clinical manifestations and overlapping imaging findings. As a diagnosis of exclusion, a comprehensive evaluation is crucial, often necessitating an orbital biopsy for confirmation. Collaborative efforts among specialists are essential for managing these intricate cases.