Striatin plays a major role in angiotensin II-induced cardiomyocyte and cardiac hypertrophy in mice in vivo.

The three striatins (STRN, STRN3, STRN4) form the core of STRiatin-Interacting Phosphatase and Kinase (STRIPAK) complexes. These place protein phosphatase 2A (PP2A) in proximity to protein kinases thereby restraining kinase activity and regulating key cellular processes. Our aim was to establish if striatins play a significant role in cardiac remodelling associated with cardiac hypertrophy and heart failure. All striatins were expressed in control human hearts, with up-regulation of STRN and STRN3 in failing hearts. We used mice with global heterozygote gene deletion to assess the roles of STRN and STRN3 in cardiac remodelling induced by angiotensin II (AngII; 7 days). Using echocardiography, we detected no differences in baseline cardiac function or dimensions in STRN+/- or STRN3+/- male mice (8 weeks) compared with wild-type littermates. Heterozygous gene deletion did not affect cardiac function in mice treated with AngII, but the increase in left ventricle mass induced by AngII was inhibited in STRN+/- (but not STRN3+/-) mice. Histological staining indicated that cardiomyocyte hypertrophy was inhibited. To assess the role of STRN in cardiomyocytes, we converted the STRN knockout line for inducible cardiomyocyte-specific gene deletion. There was no effect of cardiomyocyte STRN knockout on cardiac function or dimensions, but the increase in left ventricle mass induced by AngII was inhibited. This resulted from inhibition of cardiomyocyte hypertrophy and cardiac fibrosis. The data indicate that cardiomyocyte striatin is required for early remodelling of the heart by AngII and identify the striatin-based STRIPAK system as a signalling paradigm in the development of pathological cardiac hypertrophy.

Genome-Wide Identification of Calmodulin-Binding Protein 60 Gene Family and the Function of GhCBP60B in Cotton Growth and Development and Abiotic Stress Response.

The calmodulin-binding protein 60 (CBP60) family is a gene family unique to plants, and its members play a crucial role in plant defense responses to pathogens and growth and development. Considering that cotton is the primary source of natural cotton textile fiber, the functional study of its CBP60 gene family members is critical. In this research, we successfully identified 162 CBP60 members from the genomes of 21 species. Of these, 72 members were found in four cotton species, divided into four clades. To understand the function of GhCBP60B in cotton in depth, we conducted a detailed analysis of its sequence, structure, cis-acting elements, and expression patterns. Research results show that GhCBP60B is located in the nucleus and plays a crucial role in cotton growth and development and response to salt and drought stress. After using VIGS (virus-induced gene silencing) technology to conduct gene silencing experiments, we found that the plants silenced by GhCBP60B showed dwarf plants and shortened stem nodes, and the expression of related immune genes also changed. In further abiotic stress treatment experiments, we found that GhCBP60B-silenced plants were more sensitive to drought and salt stress, and their POD (peroxidase) activity was also significantly reduced. These results imply the vital role of GhCBP60B in cotton, especially in regulating plant responses to drought and salt stress. This study systematically analyzed CBP60 gene family members through bioinformatics methods and explored in depth the biological function of GhCBP60B in cotton. These research results lay a solid foundation for the future use of the GhCBP60B gene to improve cotton plant type and its drought and salt resistance.

Unraveling the mechanism in l-Caldesmon regulating the osteogenic differentiation of PDLSCs: An innovative perspective.

Maxillofacial bone defect is one of the common symptoms in maxillofacial, which affects the function and aesthetics of maxillofacial region. Periodontal ligament stem cells (PDLSCs) are extensively used in bone tissue engineering. The mechanism that regulates the osteogenic differentiation of PDLSCs remains not fully elucidated. Previous studies demonstrated that l-Caldesmon (l-CALD, or CALD1) might be involved in the osteogenic differentiation of PDLSCs. Here, the mechanism by which CALD1 regulates the osteogenic differentiation of PDLSCs is investigated. The osteogenic differentiation of PDLSCs is enhanced with Cald1 knockdown. Whole transcriptome sequencing (RNA-seq) analysis shows that bone morphogenetic proteins (BMP) signaling pathway and Wingless type (Wnt) pathway have significant change with Cald1 knockdown, and the expressions of Wnt-induced secreted protein 1 (WISP1), BMP2, Smad1/5/9, and p-Smad1/5/9 are significantly upregulated, while Glycogen synthase kinase 3ß (GSK3ß) and p-GSK3ß are downregulated. In addition, subcutaneous implantation in nude mice shows that knockdown of Cald1 enhances the osteogenic differentiation of PDLSCs in vivo. Taken together, this study demonstrates that knockdown of Cald1 enhances the osteogenic differentiation of PDLSCs by BMP and Wnt signaling pathways, and provides a novel approach for subsequent clinical treatment.

Reticular Myxoid Odontogenic Neoplasm with Novel STRN::ALK Fusion: Report of 2 Cases in 3-Year-Old Males.

Odontogenic tumors represent a collection of entities ranging from hamartomas to destructive benign and malignant neoplasms. Occasionally, pathologists encounter gnathic lesions which clearly exhibit an odontogenic origin but do not fit within the confines of established diagnoses. Here, we describe two such odontogenic tumors, both affecting 3-year-old males. Each case presented as a destructive, radiolucent mandibular lesion composed of mesenchymal cells, some with unique multi-lobed nuclei, frequently arranged in a reticular pattern and supported by a myxoid stroma with focal laminations. Production of odontogenic hard tissues was also seen. Because of their unique microscopic features, both cases were investigated by next-generation sequencing and found to harbor the same STRN::ALK oncogene fusion. To our knowledge, these cases represent the first report of an odontogenic tumor with a STRN::ALK gene rearrangement. We propose the possibility that this neoplasm could be separate from other known odontogenic tumors. Both patients were treated with surgical resection and reconstruction. The prognosis of patients with this entity is currently uncertain but shall become more apparent over time as more cases are identified and followed.

Construction of a prognostic model with CAFs for predicting the prognosis and immunotherapeutic response of lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) is one of the subtypes of lung cancer (LC) that contributes to approximately 25%-30% of its prevalence. Cancer-associated fibroblasts (CAFs) are key cellular components of the TME, and the large number of CAFs in tumour tissues creates a favourable environment for tumour development. However, the function of CAFs in the LUSC is complex and uncertain. First, we processed the scRNA-seq data and classified distinct types of CAFs. We also identified prognostic CAFRGs using univariate Cox analysis and conducted survival analysis. Additionally, we assessed immune cell infiltration in CAF clusters using ssGSEA. We developed a model with a significant prognostic correlation and verified the prognostic model. Furthermore, we explored the immune landscape of LUSC and further investigated the correlation between malignant features and LUSC. We identified CAFs and classified them into three categories: iCAFs, mCAFs and apCAFs. The survival analysis showed a significant correlation between apCAFs and iCAFs and LUSC patient prognosis. Kaplan-Meier analysis showed that patients in CAF cluster C showed a better survival probability compared to clusters A and B. In addition, we identified nine significant prognostic CAFRGs (CLDN1, TMX4, ALPL, PTX3, BHLHE40, TNFRSF12A, VKORC1, CST3 and ADD3) and subsequently employed multivariate Cox analysis to develop a signature and validate the model. Lastly, the correlation between CAFRG and malignant features indicates the potential role of CAFRG in promoting tumour angiogenesis, EMT and cell cycle alterations. We constructed a CAF prognostic signature for identifying potential prognostic CAFRGs and predicting the prognosis and immunotherapeutic response for LUSC. Our study may provide a more accurate prognostic assessment and immunotherapy targeting strategies for LUSC.

STRN3 promotes tumour growth in hepatocellular carcinoma by inhibiting the hippo pathway.

HCC is a globally high-incidence malignant tumour, and its pathogenesis is still unclear. Recently, STRN3 has been found to be elevated in various tumours, but its expression and biological functions in HCC have not been studied. In the study, clinical correlation analysis was performed on 371 liver cancer patients from TCGA database and liver cancer tissues and normal tissues from the GEO database. qRT-PCR and western blotting were used to detect relevant proteins in cells, and CCK8 and colony formation experiments were performed to analyse cell proliferation ability. Transwell and wound healing experiments were performed to detect cell invasion ability, and flow cytometry was used to detect cell apoptosis. Single-cell sequencing data and multiple immunofluorescence were analysed for the expression abundance and distribution of certain proteins. Immunohistochemistry was used to assess the expression of STRN3 in patients' tumour and adjacent non-cancerous tissues. The results indicated STRN3 was highly expressed in liver tumour tissues and was closely associated with poor prognosis. Knockdown of STRN3 could significantly inhibit cell proliferation and migration ability. At the same time, we found that STRN3 could inhibit the Hippo pathway and promote the entry of YAP protein into the nucleus. Our study first found that STRN3 could promote tumour growth by inhibiting the Hippo pathway. The study of STRN3 can promote the understanding and treatment of the occurrence and development of HCC.

Validating core therapeutic targets for osteoporosis treatment based on integrating network pharmacology and informatics.

OBJECTIVE: Our goal was to find metabolism-related lncRNAs that were associated with osteoporosis (OP) and construct a model for predicting OP progression using these lncRNAs. METHODS: The GEO database was employed to obtain gene expression profiles. The WGCNA technique and differential expression analysis were used to identify hypoxia-related lncRNAs. A Lasso regression model was applied to select 25 hypoxia-related genes, from which a classification model was created. Its robust classification performance was confirmed with an area under the ROC curve close to 1, as verified on the validation set. Concurrently, we constructed a ceRNA network based on these genes to unveil potential regulatory processes. Biologically active compounds of STZYD were identified using the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP) database. BATMAN was used to identify its targets, and we obtained OP-related genes from Malacards and DisGeNET, followed by identifying intersection genes with metabolism-related genes. A pharmacological network was then constructed based on the intersecting genes. The pharmacological network was further integrated with the ceRNA network, resulting in the creation of a comprehensive network that encompasses herb-active components, pathways, lncRNAs, miRNAs, and targets. Expression levels of hypoxia-related lncRNAs in mononuclear cells isolated from peripheral blood of OP and normal patients were subsequently validated using quantitative real-time PCR (qRT-PCR). Protein levels of RUNX2 were determined through a western blot assay. RESULTS: CBFB, GLO1, NFKB2 and PIK3CA were identified as central therapeutic targets, and ADD3-AS1, DTX2P1-UPK3BP1-PMS2P11, TTTY1B, ZNNT1 and LINC00623 were identified as core lncRNAs. CONCLUSIONS: Our work uncovers a possible therapeutic mechanism for STZYD, providing a potential therapeutic target for OP. In addition, a prediction model of metabolism-related lncRNAs of OP progression was constructed to provide a reference for the diagnosis of OP patients.

Upregulation of CALD1 predicted a poor prognosis for platinum-treated ovarian cancer and revealed it as a potential therapeutic resistance target.

BACKGROUND: Ovarian cancer (OC) has the worst prognosis among gynecological malignancies, most of which are found to be in advanced stage. Cell reduction surgery based on platinum-based chemotherapy is the current standard of treatment for OC, but patients are prone to relapse and develop drug resistance. The objective of this study was to identify a specific molecular target responsible for platinum chemotherapy resistance in OC. RESULTS: We screened the protein-coding gene Caldesmon (CALD1), expressed in cisplatin-resistant OC cells in vitro. The prognostic value of CALD1 was evaluated using survival curve analysis in OC patients treated with platinum therapy. The diagnostic value of CALD1 was verified by drawing a Receiver Operating Characteristic (ROC) curve using clinical samples from OC patients. This study analyzed data from various databases including Gene Expression Omnibus (GEO), Human Protein Atlas (HPA), The Cancer Cell Line Encyclopedia (CCLE), The Cancer Genome Atlas (TCGA), GEPIA 2, UALCAN, Kaplan-Meier (KM) plotter, LinkedOmics database, and String. Different expression genes (DEGs) between cisplatin-sensitive and cisplatin-resistant cells were acquired respectively from 5 different datasets of GEO. CALD1 was selected as a common gene from 5 groups DEGs. Online data analysis of HPA and CCLE showed that CALD1 was highly expressed in both normal ovarian tissue and OC. In TCGA database, high expression of CALD1 was associated with disease stage and venous invasion in OC. Patients with high CALD1 expression levels had a worse prognosis under platinum drug intervention, according to Kaplan-Meier (KM) plotter analysis. Analysis of clinical sample data from GEO showed that CALD1 had superior diagnostic value in distinguishing patients with platinum "resistant" and platinum "sensitive" (AUC = 0.816), as well as patients with worse progression-free survival (AUC = 0.741), and those with primary and omental metastases (AUC = 0.811) in ovarian tumor. At last, CYR61 was identified as a potential predictive molecule that may play an important role alongside CALD1 in the development of platinum resistance in OC. CONCLUSIONS: CALD1, as a member of cytoskeletal protein, was associated with poor prognosis of platinum resistance in OC, and could be used as a target protein for mechanism study of platinum resistance in OC.

Conjunctival leiomyosarcoma: A clinico-pathological study with in deep molecular characterization.

BACKGROUND: Primary and metastatic leiomyosarcomas (LMS) involving the orbital region are well known to occur however, the conjunctiva represents an extremely rare site of occurrence. METHODS: A 97-year-old male was referred to the Ocular Oncology Unit due to a rapidly growing painful mass (16×12×20 mm) in the nasal conjunctiva of his left eye. Wide excision followed by radiotherapy was performed. RESULTS: Based on the microscopic features (hypercellular neoplasm composed of spindle cells with cigar shaped and blunt ended nuclei with brightly eosinophilic fibrillary cytoplasm) and immunohistochemical findings (positive staining for Vimentin, Desmin, Caldesmon, and SMA and negative staining for AE1/AE3, EMA, CD117, S100, MelanA, SOX10, HMB45, TLE1, CD99, EMA and AE1 / AE3) the final diagnosis of grade 2 leyomiosarcoma was rendered. Moreover, 'in deep' DNA sequencing (>500 genes analysis) revealed a neoplasm with high TMB: 64 muts/Mb and numerous VUS and several pathogenic/oncogenic molecular alterations, including CNV loss or gain in > 10 genes. At the last follow-up visit, residual disease was observed in the superior fornix, at the nasal limbus and the cornea. At the time of writing, after a follow-up of 2 month the patients is still alive without evidence of metastatic disease. CONCLUSION: An uncommon molecular finding observed in our case was the presence of TSC1 gene mutation usually associated with soft tissue and gynecological PEComas. Our finding may harbor important therapeutic implications since the inactivation of the tumor suppressor genes TSC1 and TSC2 lead to upregulation of mTOR signaling, providing the rationale for target therapy with mTOR inhibitors. Additional studies on larger series are needed to validate our findings.

The gene expression of CALD1, CDH2, and POSTN in fibroblast are related to idiopathic pulmonary fibrosis.

Introduction: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung dysfunction due to excessive collagen production and tissue scarring. Despite recent advancements, the molecular mechanisms remain unclear. Methods: RNA sequencing identified 475 differentially expressed genes (DEGs) in the TGF-ß1-induced primary lung fibrosis model. Gene expression chips GSE101286 and GSE110147 from NCBI gene expression omnibus (GEO) database were analyzed using GEO2R, revealing 94 DEGs in IPF lung tissue samples. The gene ontology (GO) and pathway enrichment, Protein-protein interaction (PPI) network construction, and Maximal Clique Centrality (MCC) scoring were performed. Experimental validation included RT-qPCR, Immunohistochemistry (IHC), and Western Blot, with siRNA used for gene knockdown. A co-expression network was constructed by GeneMANIA. Results: GO enrichment highlighted significant enrichment of DEGs in TGF-ß cellular response, connective tissue development, extracellular matrix components, and signaling pathways such as the AGE-RAGE signaling pathway and ECM-receptor interaction. PPI network analysis identified hub genes, including FN1, COL1A1, POSTN, KIF11, and ECT2. CALD1 (Caldesmon 1), CDH2 (Cadherin 2), and POSTN (Periostin) were identified as dysregulated hub genes in both the RNA sequencing and GEO datasets. Validation experiments confirmed the upregulation of CALD1, CDH2, and POSTN in TGF-ß1-treated fibroblasts and IPF lung tissue samples. IHC experiments probed tissue-level expression patterns of these three molecules. Knockdown of CALD1, CDH2, and POSTN attenuated the expression of fibrotic markers (collagen I and α-SMA) in response to TGF-ß1 stimulation in primary fibroblasts. Co-expression analysis revealed interactions between hub genes and predicted genes involved in actin cytoskeleton regulation and cell-cell junction organization. Conclusions: CALD1, CDH2, and POSTN, identified as potential contributors to pulmonary fibrosis, present promising therapeutic targets for IPF patients.

Identification of Novel/Rare EWSR1 Fusion Partners in Undifferentiated Mesenchymal Neoplasms.

Recurrent gene fusions (GFs) in translocated sarcomas are recognized as major oncogenic drivers of the disease, as well as diagnostic markers whose identification is necessary for differential diagnosis. EWSR1 is a 'promiscuous' gene that can fuse with many different partner genes, defining different entities among a broad range of mesenchymal neoplasms. Molecular testing of EWSR1 translocation traditionally relies on FISH assays with break-apart probes, which are unable to identify the fusion partner. Therefore, other ancillary molecular diagnostic modalities are being increasingly adopted for accurate classification of these neoplasms. Herein, we report three cases with rare GFs involving EWSR1 in undifferentiated mesenchymal neoplasms with uncertain differential diagnoses, using targeted RNA-seq and confirming with RT-PCR and Sanger sequencing. Two GFs involved hormone nuclear receptors as 3' partners, NR4A2 and RORB, which have not been previously reported. NR4A2 may functionally replace NR4A3, the usual 3' partner in extraskeletal myxoid chondrosarcoma. The third GF, EWSR1::BEND2, has previously been reported in a subtype of astroblastoma and other rare entities, including a single case of a soft-tissue tumor that we discuss in this work. In conclusion, our findings indicate that the catalogue of mesenchymal neoplasm-bearing EWSR1 fusions continues to grow, underscoring the value of using molecular ancillary techniques with higher diagnostic abilities in the routine clinical setting.

Comprehensive overview of disease models for Wolfram syndrome: toward effective treatments.

Wolfram syndrome (OMIM 222300) is a rare autosomal recessive disease with a devastating array of symptoms, including diabetes mellitus, optic nerve atrophy, diabetes insipidus, hearing loss, and neurological dysfunction. The discovery of the causative gene, WFS1, has propelled research on this disease. However, a comprehensive understanding of the function of WFS1 remains unknown, making the development of effective treatment a pressing challenge. To bridge these knowledge gaps, disease models for Wolfram syndrome are indispensable, and understanding the characteristics of each model is critical. This review will provide a summary of the current knowledge regarding WFS1 function and offer a comprehensive overview of established disease models for Wolfram syndrome, covering animal models such as mice, rats, flies, and zebrafish, along with induced pluripotent stem cell (iPSC)-derived human cellular models. These models replicate key aspects of Wolfram syndrome, contributing to a deeper understanding of its pathogenesis and providing a platform for discovering potential therapeutic approaches.

The Complex Interplay between Toxic Hallmark Proteins, Calmodulin-Binding Proteins, Ion Channels, and Receptors Involved in Calcium Dyshomeostasis in Neurodegeneration.

Calcium dyshomeostasis is an early critical event in neurodegeneration as exemplified by Alzheimer's (AD), Huntington's (HD) and Parkinson's (PD) diseases. Neuronal calcium homeostasis is maintained by a diversity of ion channels, buffers, calcium-binding protein effectors, and intracellular storage in the endoplasmic reticulum, mitochondria, and lysosomes. The function of these components and compartments is impacted by the toxic hallmark proteins of AD (amyloid beta and Tau), HD (huntingtin) and PD (alpha-synuclein) as well as by interactions with downstream calcium-binding proteins, especially calmodulin. Each of the toxic hallmark proteins (amyloid beta, Tau, huntingtin, and alpha-synuclein) binds to calmodulin. Multiple channels and receptors involved in calcium homeostasis and dysregulation also bind to and are regulated by calmodulin. The primary goal of this review is to show the complexity of these interactions and how they can impact research and the search for therapies. A secondary goal is to suggest that therapeutic targets downstream from calcium dyshomeostasis may offer greater opportunities for success.

Calcineurin inhibition, cardiovascular consequences, vascular resistance, and potential responses.

AIM: To place the consequences of calcineurin inhibition in a cardiovascular context. METHODS: Literature review coupled with personal encounters. RESULTS: Calcineurin is a calcium-binding and calmodulin-binding protein that is conserved across evolution from yeast to mammals. The enzyme functions as a calcium-dependent, calmodulin-stimulated protein phosphatase. Its role in regulating physiology has largely been elucidated by observing calcineurin inhibition. Calcineurin inhibition transformed organ transplantation from an experiment into a therapy and made much of general immunotherapy possible. The function of this phosphatase and how its inhibition leads to toxicity concern us to this date. Initial research from patients and animal models implicated a panoply of factors contributing to hypertension and vasculopathy. Subsequently, the role of calcineurin in regulating the effective fluid volume, sodium reabsorption, and potassium and hydrogen ion excretion was elucidated by investigating calcineurin inhibition. Understanding the regulatory effects of calcineurin on endothelial and vascular smooth muscle cell function has also made substantial progress. However, precisely how the increase in systemic vascular resistance arises requires further mechanistic research. CONCLUSION: Calcineurin inhibition continues to save lives; however, options to counteract the negative effects of calcineurin inhibition should be vigorously pursued.

Oligomerization and aggregation of NAP-22 with several metal ions.

Metal ions participate in various biochemical processes such as electron transport chain, gene transcription, and enzymatic reactions. Furthermore, the aggregation promoting effect of several metal ions on neuronal proteins such as prion, tau, Aß peptide, and α-synuclein, has been reported. NAP-22 (also called BASP1 or CAP-23) is a neuron-enriched calmodulin-binding protein and one of the major proteins in the detergent-resistant membrane microdomain fraction of the neuronal cell membrane. Previously, we showed oligomer formation of NAP-22 in the presence of several phospholipids and fatty acids. In this study, we found the aggregation of NAP-22 by FeCl2, FeCl3, and AlCl3 using native-PAGE. Oligomer or aggregate formation of NAP-22 by ZnCl2 or CuSO4 was shown with SDS-PAGE after cross-linking with glutaraldehyde. Morphological analysis with electron microscopy revealed the formation of large aggregates composed of small annular oligomers in the presence of FeCl3, AlCl3, or CuSO4. In case of FeCl2 or ZnCl2, instead of large aggregates, scattered annular and globular oligomers were observed. Interestingly, metal ion induced aggregation of NAP-22 was inhibited by several coenzymes such as NADP+, NADPH, or thiamine pyrophosphate. Since NAP-22 is highly expressed in the presynaptic region of the synapse, this result suggests the participation of metal ions not only on the protein and membrane dynamics at the presynaptic region, but also on the metabolic regulation though the interaction with coenzymes.

[SRF-rearranged cellular perivascular myoid tumor: a clinicopathological analysis of two cases].

Objective: To investigate the clinicopathological features, immunophenotype, diagnosis and differential diagnosis of SRF-rearranged cellular perivascular myoid tumor. Methods: Two cases of SRF-rearranged cellular perivascular myoid tumor diagnosed in the Department of Pathology, Fudan University Shanghai Cancer Center from October 2021 to March 2022 were collected. Immunohistochemical staining, fluorescence in-situ hybridization (FISH) and next-generation sequencing (NGS) were performed, and the literature was reviewed. Results: Case 1, a 3-month-old boy presented with a painless tumor of the scalp, measuring about 2 cm in diameter. Case 2, a 3-year-old girl complained with a painless tumor of the knee, measuring approximately 1.5 cm in diameter. Microscopically, the tumor had a clear boundary and showed multinodular growth. The tumor was mainly composed of spindle cells arranged in long intersecting fascicles associated with thin, slit-like or branching ectatic vessels, focally forming hemangiopericytoma-like appearance. The tumor cells were abundant, but there was no obvious atypia. Mitotic figures (3-4/10 HPF) were noted. H-caldesmon and SMA were positive in both cases. Case 1 showed diffuse and strong positivity for Desmin, and focally for CKpan. Ki-67 proliferation index was 20% and 30%, respectively. FISH displayed NCOA2 gene translocation in case 1 and the RELA gene translocation in case 2. NGS detected the SRF-NCOA2 gene fusion in case 1 and the SRF-RELA gene fusion in case 2. Both patients underwent local excisions. During the follow-up of 5-14 months, case 1 had no local recurrence, while case 2 developed local recurrence 1 year post operatively. Conclusions: SRF-rearranged cellular perivascular myoid tumor is a novel variant of perivascular cell tumor, which tends to occur in children and adolescents. The tumor forms a broad morphologic spectrum ranging from a pericytic pattern to a myoid pattern, and include hybrid tumors with a mixture of pericytic and myoid patterns. Due to its diffuse hypercellularity and increased mitotic figures and smooth muscle-like immunophenotype, the tumor is easy to be misdiagnosed as myogenic sarcomas. The tumor usually pursues a benign clinical course and rare cases may locally recur.

Prediction significance of autophagy-related genes in survival probability and drug resistance in diffuse large B-cell lymphoma.

BACKGROUND/AIMS: Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, has significant prognostic heterogeneity. This study aimed to generate a prognostic prediction model based on autophagy-related genes for DLBCL patients. METHODS: Utilizing bioinformatics techniques, we analyzed the clinical information and transcriptome data of DLBCL patients from the Gene Expression Omnibus (GEO) database. Through unsupervised clustering, we identified new autophagy-related molecular subtypes and pinpointed differentially expressed genes (DEGs) between these subtypes. Based on these DEGs, a prognostic model was constructed using Cox and Lasso regression. The effectiveness, accuracy, and clinical utility of this prognostic model were assessed using numerous independent validation cohorts, survival analyses, receiver operating characteristic (ROC) curves, multivariate Cox regression analysis, nomograms, and calibration curves. Moreover, functional analysis, immune cell infiltration, and drug sensitivity analysis were performed. RESULTS: DLBCL patients with different clinical characterizations (age, molecular subtypes, ECOG scores, and stages) showed different expression features of autophagy-related genes. The prediction model was constructed based on the eight autophagy-related genes (ADD3, IGFBP3, TPM1, LYZ, AFDN, DNAJC10, GLIS3, and CCDC102A). The prognostic nomogram for overall survival of DLBCL patients incorporated risk level, stage, ECOG scores, and molecular subtypes, showing excellent agreement between observed and predicted outcomes. Differences were noted in the proportions of immune cells (native B cells, Treg cells, CD8+ T cell, CD4+ memory activated T cells, gamma delta T cells, macrophages M1, and resting mast cells) between high-risk and low-risk groups. LYZ and ADD3 exhibited correlations with drug resistance to most chemotherapeutic drugs. CONCLUSIONS: This study established a novel prognostic assessment model based on the expression profile of autophagy-related genes and clinical characteristics of DLBCL patients, explored immune infiltration and predicted drug resistance, which may guide precise and individualized immunochemotherapy regimens.

UBE2A and UBE2B are recruited by an atypical E3 ligase module in UBR4.

UBR4 is a 574 kDa E3 ligase (E3) of the N-degron pathway with roles in neurodevelopment, age-associated muscular atrophy and cancer. The catalytic module that carries out ubiquitin (Ub) transfer remains unknown. Here we identify and characterize a distinct E3 module within human UBR4 consisting of a 'hemiRING' zinc finger, a helical-rich UBR zinc-finger interacting (UZI) subdomain, and an N-terminal region that can serve as an affinity factor for the E2 conjugating enzyme (E2). The structure of an E2-E3 complex provides atomic-level insight into the specificity determinants of the hemiRING toward the cognate E2s UBE2A/UBE2B. Via an allosteric mechanism, the UZI subdomain modestly activates the Ub-loaded E2 (E2∼Ub). We propose attenuated activation is complemented by the intrinsically high lysine reactivity of UBE2A, and their cooperation imparts a reactivity profile important for substrate specificity and optimal degradation kinetics. These findings reveal the mechanistic underpinnings of a neuronal N-degron E3, its specific recruitment of UBE2A, and highlight the underappreciated architectural diversity of cross-brace domains with Ub E3 activity.

Whole genome sequencing for inherited retinal diseases in the Korean National Project of Bio Big Data.

PURPOSE: This study aimed to analyze the genetic results of inherited retinal diseases (IRDs) and evaluate the diagnostic usefulness of whole genome sequencing (WGS) in the Korean National Project of Bio Big Data. METHODS: As part of the Korean National Project of Bio Big Data, WGS was performed on 32 individuals with IRDs with no identified pathogenic variants through whole or targeted exome sequencing. RESULTS: Individuals with retinitis pigmentosa (n = 23), cone dystrophy (n = 2), cone-rod dystrophy (n = 2), familial exudative vitreoretinopathy (n = 2), pigmented paravenous chorioretinal atrophy (n = 1), North Carolina macular dystrophy (n = 1), and bull's-eye macular dystrophy (n = 1) were included. WGS revealed genetic mutations in the IQCB1, PRPF31, USH2A, and GUCY2D genes in five cases (15.6%). Two large structural variations and an intronic variant were newly detected in three cases. Two individuals had biallelic missense mutations that were not identified in previous exome sequencing. CONCLUSION: With WGS, the causative variants in 15.6% of unsolved IRDs from the Korean National Project of Bio Big Data were identified. Further research with a larger cohort might unveil the diagnostic usefulness of WGS in IRDs and other diseases.

LncRNA KTN1-AS1 facilitates esophageal squamous cell carcinoma progression via miR-885-5p/STRN3 axis.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies and frequent cause of cancer-related death worldwide. Long non-coding RNAs (lncRNAs) play regulatory roles and serve as biomarkers of multiple cancers, including ESCC. Our previous studies have confirmed that lncRNA Kinectin 1 antisense RNA 1 (KTN1-AS1) is highly expressed in ESCC and exerts oncogene function through RBBP4/HDAC1 complex. OBJECTIVE: Our present study focused on exploring a novel molecular mechanism of KTN1-AS1 in ESCC. METHODS: In this study, qRT-PCR assay, Western blot assay, Luciferase reporter assay, and RNA immunoprecipitation assay were conducted. RESULTS: We found that KTN1-AS1 could bind to miR-885-5p in ESCC cells, and miR-885-5p was low expressed in ESCC. Overexpression of miR-885-5p inhibited esophageal cancer cells proliferation and invasion in vitro. Mechanistic analysis demonstrated that miR-885-5p specifically targeted striatin 3 (STRN3), and KTN1-AS1/miR-885-5p promoted the EMT process by Hippo pathway in STRN3/YAP1 dependent manner. CONCLUSION: To sum up, KTN1-AS1 facilitates ESCC progression by acting as a ceRNA for miR-885-5p to regulate STRN3 expression and the Hippo pathway, and KTN1-AS1 maybe used as a promising therapeutic target for ESCC.