T-cell Intracellular Antigen-1 Research Articles

TIA1-Mediated Stress Granules Promote the Neuroinflammation and Demyelination in Experimental Autoimmune Encephalomyelitis through Upregulating IL-31RA Signaling.

The dysfunction of stress granules (SGs) plays a crucial role in the pathogenesis of various neurological disorders, with T cell intracellular antigen 1 (TIA1) being a key component of SGs. However, the role and mechanism of TIA1-mediated SGs in experimental autoimmune encephalomyelitis (EAE) remain unclear. In this study, upregulation of TIA1, its translocation from the nucleus to the cytoplasm, and co-localization with G3BP1 (a marker of SGs) are observed in the spinal cord neurons of EAE mice. Deletion of TIA1 in the CNS alleviates neuroinflammation, suppresses demyelination and axonal damage, and reduces neuronal loss in EAE mice. Furthermore, alleviation of autophagy dysfunction and reduction of chronic persistent SGs are observed in Tia1Nestin-CKO EAE mice. Mechanistically, IL-31RA levels are decreased in Tia1Nestin-CKO EAE mice, which inhibit the downstream PI3K/AKT signaling pathway associated with IL-31RA, thereby enhancing autophagy and suppressing the NF-κB signaling pathway, further alleviating EAE symptoms. Knockdown of TIA1 in primary neurons and N2a cells treated with sodium arsenite also reduces the formation of SGs. These findings reveal an unrecognized role of TIA1-mediated SGs in promoting neuroinflammation and demyelination, offering novel therapeutic targets for MS.

Decoding the Molecular Grammar of TIA1-Dependent Stress Granules in Proteostasis and Welander Distal Myopathy Under Oxidative Stress.

T-cell intracellular antigen 1 (TIA1) is an RNA-binding protein (RBP) that plays a multifunctional role in RNA metabolism. TIA1 has three RNA-Recognition Motifs (RRMs) and a prion-like carboxyl C-terminal domain (LCD) with intrinsically disordered regions (IDR) implicated in the dynamics (i.e., formation, assembly, and disassembly) of transient RNA-protein aggregates known as stress granules (SGs). A protein related to TIA1 is its paralog TIA1-related/like protein (TIAR/TIAL1), whose amino acid sequence, structural organisation, and molecular and cellular functions are highly conserved with TIA1. Both proteins are the main components of SGs, which are non-membranous RNA-protein condensates formed under stress to promote cell survival. Welander distal myopathy (WDM) is a late-onset muscular dystrophy that has been linked to a single-nucleotide substitution (c.1362G>A; p.E384K) in the gene encoding the TIA1 protein, which impacts TIA1-dependent SGs dynamics. Herein, we have analysed cellular and molecular aspects by targeting mutagenesis to position 384 to understand its molecular grammar in an amino acid/proteinogenic-dependent or -independent manner under oxidative stress. The observations suggest differential, even opposing, behaviours between TIA1 and TIAR in the presence of specific amino acids with negative and positive charges, and also uncharged acids, at equivalent positions of TIA1 and TIAR, respectively. Collectively, these findings illustrate a characteristic molecular grammar of TIAR- and TIA1-dependent SGs under oxidative conditions, suggesting a gain of versatility between two structurally and functionally highly conserved/related proteins.

Unravelling stress granules in the deep cold: Characterisation of TIA-1 gene sequence in Antarctic fish species

Stress granules (SGs) are cytoplasmic foci lacking membranes, comprising non-translating messenger ribonucleoproteins, translational initiation factors, and additional proteins. Their formation is crucial for rapidly modulating gene expression in response to adverse environmental conditions, such as pollution and infections. Limited research has focused on investigating the molecular components of SGs in fish, with minimal exploration in Antarctic fish. This study characterises for the first time the transcript sequences of one key protein component of SGs, TIA-1 (T-cell intracellular antigen 1), in two Antarctic endemic fish species, i.e. Trematomus bernacchii and Chionodraco hamatus. The mRNA-binding protein TIA-1 acts as a post-transcriptional regulator of gene expression and its aggregation leads to the formation of SGs in response to cellular damage. The in vitro and bioinformatic analyses of the TIA-1 gene sequences of these two species highlighted interesting peculiarities, which include the transcription of alternatively spliced isoforms unique to the notothenioid lineage, potentially unlocking further insights into their unique adaptations to extreme environmental conditions. This is the first study to analyze tia-1 expression levels in different tissues of Antarctic fish species. Our key findings indicate that the TIA-1 gene is expressed at particularly high levels in the liver and spleen of C. hamatus, as well as in the heart and skeletal muscle of T. bernacchii. This suggests that those tissues play a significant role in the stress response mechanisms of the studied species. This study provides novel insights into the molecular adaptations of Antarctic fish, highlighting the potential importance of TIA-1 in their response to environmental stressors. The unique features of TIA-1 identified in these species may offer broader implications for understanding how Antarctic fish regulate gene transcriptions in their extreme environments.

Diverse Phenotypic Presentation of the Welander Distal Myopathy Founder Mutation, With Myopathy and Amyotrophic Lateral Sclerosis in the Same Family.

Welander distal myopathy is a rare myopathy with prominent and early involvement of distal upper extremity muscles, prevalent in individuals of Scandinavian origin, and caused by a founder mutation in the cytotoxic granule-associated RNA-binding protein (T-cell intracellular antigen-1; TIA1), E384K. Different pathogenic variants in the TIA1 gene, distinct from the founder 1, have recently been associated with frontotemporal dementia and amyotrophic lateral sclerosis (ALS), suggesting that TIA1-related disorders belong to the group of multisystem proteinopathies. We describe the first case of a two-generation family with the founder E384K TIA1 mutation demonstrating phenotypic variability; the mother manifested as Welander myopathy, whereas 2 daughters manifested as ALS. No other genetic cause of ALS was found in 1 of the affected daughters. We also discuss the possible mechanisms explaining this pleotropic presentation of the founder mutation.

Inhibition of inflammation and apoptosis through the cyclic GMP-AMP synthase-stimulator of interferon genes pathway by stress granules after ALKBH5 demethylase activation during diabetic myocardial ischaemia-reperfusion injury.

Post-transcriptional modifications and their specific mechanisms are the focus of research on the regulation of myocardial damage. Stress granules (SGs) can inhibit the inflammatory response by inhibiting the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. This study investigated whether alkylation repair homologue protein 5 (ALKBH5) could affect myocardial inflammation and apoptosis during diabetic myocardial ischaemia-reperfusion injury (IRI) through the cGAS-STING pathway via SGs. A diabetes ischaemia-reperfusion rat model and a high glucose hypoxia/reoxygenation cell model were established. Adeno-associated virus (AAV) and lentivirus (LV) were used to overexpress ALKBH5, while the SG agonist arsenite (Ars) and the SG inhibitor anisomycin were used as interventions. Then, the levels of apoptosis and related indicators in the cell and rat models were measured. In the in vivo experiment, compared with the normal sham group, the degree of myocardial tissue damage, creatine kinase-MB and cardiac troponin I in serum, and myocardial apoptosis, the infarcted area of myocardium, and the level of B-cell lymphoma 2 associated X protein, cGAS-STING pathway and inflammatory factors in the diabetes ischaemia-reperfusion group were significantly increased. However, the expression of SGs and the levels of ALKBH5, rat sarcoma-GTPase-activating protein-binding protein 1, T-cell intracellular antigen-1 and Bcl2 were significantly decreased. After AAV-ALKBH5 intervention, the degree of myocardial tissue damage, degree of myocardial apoptosis, and extent of myocardial infarction in myocardial tissue were significantly decreased. In the in vitro experiment, compared with those in the normal control group, the levels of lactate dehydrogenase, inflammation and apoptosis were significantly greater, and cell viability and the levels of ALKBH5 and SGs were decreased in the high glucose and hypoxia/reoxygenation groups. In the high glucose hypoxia/reoxygenation cell model, the degree of cell damage, inflammation, and apoptosis was greater than those in the high glucose and hypoxia/reoxygenation models, and the levels of ALKBH5 and SGs were further decreased. LV-ALKBH5 and Ars alleviated the degree of cell damage and inhibited inflammation and cell apoptosis. The inhibition of SGs could partly reverse the protective effect of LV-ALKBH5. The cGAS agonist G140 antagonized the inhibitory effects of the SG agonist Ars on cardiomyocyte apoptosis, inflammation and the cGAS-STING pathway. Both ALKBH5 and SGs inhibited myocardial inflammation and apoptosis during diabetic myocardial ischaemia-reperfusion. Mechanistically, ALKBH5 might inhibit the apoptosis of cardiomyocytes by promoting the expression of SGs through the cGAS-STING pathway.

Immunophenotyping and viral studies in pityriasis lichenoides et varioliformis acuta lesions.

The underlying pathogenesis of pityriasis lichenoides et varioliformis acuta (PLEVA) remains unclear, although immunologic injury and viral etiology have been suggested. To evaluate and expand the immunophenotype of PLEVA and to search for possible viral pathogens. Formalin-fixed, paraffin-embedded specimens of 20 patients with PLEVA and 9 patients with common inflammatory dermatoses (ID) were studied for immunophenotyping and for human herpesvirus (HHV) 1 and 2, cytomegalovirus (CMV), HHV-8, parvovirus B19, and Epstein-Barr virus (EBV) immunohistochemistry. The presence of HHV-6, HHV-7, and enteroviruses was assayed molecularly. The numbers of CD8+ T cells and T-cell intracellular antigen-1 (TIA-1)+ cells were statistically significantly higher in PLEVA compared to the ID group. Immunohistochemistry for human HHV-1 and HHV-2, CMV and HHV-8, parvovirus B19, and in situ hybridization for EBV were all negative. There was molecular evidence for HHV-7 in only one PLEVA case (5%). Molecular studies for HHV-6 and enterovirus involvement were negative in all the PLEVA specimens. The predominant T-cell infiltrate in PLEVA is dominated by CD8+ cells, and by increased numbers of TIA1+ cells, which may indicate a cytotoxic T-cell damage to the epidermis. Viral presence was not detected.

A guide to selecting high-performing antibodies for RNA-binding protein TIA1 for use in Western Blot, immunoprecipitation and immunofluorescence.

A member of the RNA-binding protein family, T-cell intracellular antigen-1 (TIA1) regulates mRNA translation and splicing as well as cellular stress by promoting stress granule formation. Variants of the TIA1 gene have implications in neurogenerative disorders including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Reproducible research on TIA1 would be enhanced with the availability of high-quality anti-TIA1 antibodies. In this study, we characterized twelve TIA1 commercial antibodies for Western Blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.

Bibliometric Overview on T-Cell Intracellular Antigens and Their Pathological Implications.

T-cell intracellular antigen 1 (TIA1) and TIA1-like/related protein (TIAL1/TIAR) are two members of the classical family of RNA binding proteins. Through their selective interactions with distinct RNAs and proteins, these multifunctional regulators are involved in chromatin remodeling, RNA splicing and processing and translation regulation, linking them to a wide range of diseases including neuronal disorders, cancer and other pathologies. From their discovery to the present day, many studies have focused on the behavior of these proteins in order to understand their impact on molecular and cellular processes and to understand their relationship to human pathologies. The volume of research on these proteins in various fields, including molecular biology, biochemistry, cell biology, immunology and cancer, has steadily increased, indicating a growing interest in these gene expression regulators among researchers. This information can be used to know the most productive institutions working in the field, understand the focus of research, identify key areas of involvement, delve deeper into their relationship and impact on different diseases, and to establish the level of study associated with them.

Primary Nodal Epstein-Barr Virus-Positive T-Cell/NK-Cell Lymphoma: Real-World Experience

Introduction: Primary nodal Epstein-Barr virus-positive T-cell/NK-cell lymphoma (PTCL-EBV) is a disease entity newly recognized in the World Health Organization’s classification of hematolymphoid tumors, 5th edition (WHO-HAEMS5) and the International Consensus Classification of Mature Lymphoid Neoplasms (ICC). Previously, it was classified as a subtype within peripheral T-cell lymphoma, not otherwise specified, and was known to have a poor prognosis. However, the clinical features and treatment outcomes are not well known. Methods: This retrospective observational study was conducted on patients diagnosed with PTCL-EBV at Samsung Medical Center through a pathology review from 2000 to 2020. We analyzed the clinical data from 14 patients, immunohistochemistry, and survival outcomes including overall survival (OS) and progression-free survival (PFS) for each treatment regimen. PFS was defined as the time from the start of chemotherapy to the confirmation of disease progression on imaging, and hematopoietic stem-cell transplantation (HSCT) was considered a consolidation treatment. OS was defined as the time from diagnosis to the time of death. Results: 25% (1 out of 4) were beta-F1 positive, and 67% (4 out of 6) were T-cell receptor gamma (TCRγ) positive. T-cell intracellular antigen (TIA-1) and granzyme B exhibited positive results in all cases (3 out of 3), whereas the NK-cell marker CD56 was positive in only 11% of patients (1 out of 9). CD3 was observed in all of the patients (11 out of 11). The CD4 was 43% positive (3 out of 7). The CD8 was investigated in 8 patients, with 37.5% positive (3 out of 8). Hepatosplenomegaly was observed in 55% of patients (6 out of 11), and 70% (7 out of 10) of patients displayed B symptoms at the time of diagnosis. Patients who received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or CVP (cyclophosphamide, vincristine, prednisolone) treatment had a median PFS of 2.2 months (95% CI: 1.9–2.5 months), and patients who received other treatments had a median PFS of 5.1 months (NA). The objective response rate (ORR) for ICE/dexa (ifosfamide, carboplatin, etoposide, dexamethasone) as the first- or second-line treatment was 100% (3 out of 3). But ORR of CHOP or CVP as the first-line treatment was 33.3% (3 out of 9). The median OS for the group that received HSCT (3 out of 11) after achieving a response was 34.6 months (95% CI: 0–74.6 months), and the median OS for the group that did not receive HSCT (8 out of 11) was 5.0 months (95% CI: 2.1–7.9 months) (p = 0.04). Conclusions: In conclusion, in the context of PTCL-EBV, despite a limited sample size, the ICE/Dexa regimen shows potential benefits in terms of ORR and PFS. Furthermore, the application of HSCT following the attainment of a complete response may prove advantageous.

Deciphering the role of Zn2+-binding histidines from TIA-1 on the assembly and dynamics of stress granules.

T-cell intracellular antigen-1 (TIA-1) is a key RNA-binding protein that participates in translation regulation and RNA splicing. TIA-1 undergoes liquid-liquid phase separation as a fundamental mechanism that enables the condensation of RNA and proteins into membraneless organelles called stress granules (SGs). However, this dynamic behavior can lead to aberrant fibril formation, implicated in neurodegenerative disorders, and must be tightly regulated. In this study, we investigated the role in the cell of histidine residues His94 and His96, responsible for Zn2+ binding. Using fluorescence microscopy, we found that the specific binding site formed by these residues is critical for SG assembly. Furthermore, it also plays a role maintaining the dynamic behavior of SG-assembled TIA-1. Collectively, our findings confirm the physiological relevance of TIA-1 His94 and His96 in the Zn2+-mediated regulatory mechanism for protection against fibril formation in SGs.

Muscone alleviates neuronal injury via increasing stress granules formation and reducing apoptosis in acute ischemic stroke

As the main bioactive component of musk, muscone has been reported to have marked protective effects in treating acute ischemic stroke (AIS). However, the specific anti-stroke mechanism of muscone still needs further research. In the current investigation, the PC12 cells OGD/R and the rat transient MCAO/R models were utilized as the AIS models. Serum hepatic and renal functional indexes (ALT, AST, BUN, and Cr) and cell viability were determined to select the appropriate muscone concentrations for in vitro and in vivo experiments. TTC, Hematoxylin and eosin (H&E), and Live/Dead staining were utilized to evaluate the protective effects of muscone in injured tissues and cells. Western blotting analysis, TUNEL staining, propidium iodide, and annexin V staining were applied to detect the anti-apoptotic effect of muscone. Double-label immunofluorescence staining of T-cell intracellular antigen-1 (TIA1) and Ras-GAP SH3 domain-binding protein 1 (G3BP1) was performed to observe whether muscone regulated the SG formation level. Molecular docking, TIA1 silencing and TIA1 overexpression experiments were employed to investigate the molecular mechanism underlying the regulation of SG formation by muscone. The 2, 3, 5-Triphenyl-tetrazolium chloride (TTC) staining and live/dead staining showed the AIS injury level of MCAO/R rat and the OGD/R PC12 cells were attenuated by muscone administration. The muscone significantly minimized the apoptosis rate in MCAO/R rats and OGD/R PC12 cells following flow cytometry analysis, western blotting analysis, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The double-label immunofluorescence staining data revealed that muscone promoted the SG formation level in OGD/R PC12 cells and the cortex MCAO/R rats. The results of molecular docking, TIA1 silencing and TIA1 overexpression experiments revealed that muscone could bind to TIA1 protein and regulate its expression level, thereby promoting the formation of stress granules and exerting a protective effect against AIS injury. This study indicated that the significant protective effect of muscone in reducing apoptosis levels might be via promoting SG formation under AIS conditions. This study further explores the therapeutic effect and anti-apoptosis mechanism of muscone in AIS, which may provide a potential candidate drug for the clinical treatment of AIS injury.

RAMP2-AS1 stabilized RAPM2 mRNA through TIA1 to inhibit the progression of non-small cell lung cancer.

As the most common subtype of lung cancer, non-small cell lung cancer (NSCLC)is responsible for a large proportion of global cancer-caused deaths. The implication of long non-coding RNAs (lncRNAs) as tumor-suppressor or carcinogenic genes in NSCLC has been widely documented. Our study sought to investigate the performance of lncRNA RAMP2 antisense RNA1 (RAMP2-AS1) in NSCLC. GEPIA bioinformatics tool and RT-qPCR were applied for assessing the expression of RAMP2-AS1 and its neighboring gene receptor activity-modifying protein 2 (RAMP2) in NSCLC. Functional assays including CCK-8 assay, colony formation assay as well as caspase-3 activity analysis and Transwell invasion assays were applied for detecting the biological phenotypes of NSCLC cells. Interaction among RAMP2-AS1, RAMP2 and T-cell intracellular antigen 1cytotoxic granule associated RNA binding protein (TIA1) was evaluated by RNA immunoprecipitation and pulldown assays. We found that RAMP2-AS1 and RAMP2 were downregulated in NSCLC. Overexpression of RAMP2-AS1 hampered proliferation and invasion, whereas induced apoptosis of NSCLC cells. Mechanistically, RAMP2-AS1 interacted with TIA1 to stabilize the mRNA of RAMP2. In conclusion, we first uncovered that RAMP2-AS1 stabilized RAPM2 mRNA through TIA1 to inhibit the progression of NSCLC, providing new insight to improve the treatment efficacy of NSCLC.

The identification of high-performing antibodies for RNA-binding protein TIA1 for use in Western Blot, immunoprecipitation and immunofluorescence

A member of the RNA-binding protein family, T-cell intracellular antigen-1 (TIA1) regulates mRNA translation and splicing as well as cellular stress by promoting stress granule formation. Variants of the TIA1 gene have implications in neurogenerative disorders including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Reproducible research on TIA1 would be enhanced with the availability of high-quality anti-TIA1 antibodies. In this study, we characterized twelve TIA1 commercial antibodies for Western Blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.

Disseminated Extranodal NK/T-Cell lymphoma, Presenting as an Orbital Mass.

An 84-year-old male patient presented with decreased vision of 20/300 in the right eye, with additional painless upper eyelid fullness, hypoglobus, severe limitation of ocular motility, and conjunctival chemosis of the right eye for several months duration (panel A). He was referred after failing to respond to a trial of oral corticosteroids for presumed orbital myositis. MRI revealed an enlarged enhancing lacrimal gland (arrow), extraocular muscles, and mucosal thickening of the ethmoid sinus (arrowhead) on the right side (panel B). Lacrimal gland biopsy demonstrated medium-sized atypical lymphocytes with irregular nuclear contours, scant-to-moderate amounts of cytoplasm, and brisk mitotic figures (arrow) (panel C, hematoxylin-eosin, ×630), which expressed cytotoxic and natural killer-cell markers CD56 (panel D, ×400), perforin, and T-cell intracellular antigen 1, and were CD4-positive and CD8-negative. Neoplastic cells were positive for Epstein–Barr virus-encoded RNA by in situ hybridization (panel E, ×400). Clinical, morphologic, and immunophenotypic findings were compatible with extranodal natural killer/T-cell lymphoma (natural killer/T-cell lymphoma, nasal type). Optical coherence tomography revealed diffuse choroidal thickening with an undulating anterior border (sea-sick choroid) (arrow), compatible with choroidal involvement by lymphoma (panel F). Positron emission tomography scan showed significantly increased activity in the regional and distal lymph nodes and in multiple bones, compatible with disseminated disease. The patient succumbed to disease shortly after diagnosis. This case highlights the importance of prompt and accurate diagnosis of natural killer/T-cell lymphoma, nasal type, which can present with orbital and ocular involvement simulating an inflammatory process.FIG

Clinical analysis of 20 cases of cutaneous extranodal NK/T-Cell lymphoma.

Background To investigate the clinical features, pathological features and prognostic factors of cutaneous extranodal natural killer/T-cell lymphoma (CENKTL). Methods A total of 20 cases with CENKTL from February 2013 to November 2021 were analysed retrospectively. Results The patients included 15 men and five women, and their ages ranged from 19 to 92 (median age of 61) years. The most common lesions were on the extremities, followed by the trunk. Histopathological examination showed atypical lymphocyte infiltrate in dermis and subcutaneous fat. The tumour tissue showed vascular proliferation, vascular occlusion, and coagulation necrosis. In situ hybridisation revealed that 20 patients were positive for Epstein-Barr virus-coding ribonucleic acid. Immunohistochemistry showed that the tumour cells were positive for CD3 (18/20 and 90%), CD56 (19/20 and 95%), T-cell intracellular antigen (TIA-1) (13/14 and 92.9%) and CD20 (5/20, 25%). About 20 patients were positive for Ki-67 with values of 30-90%. A total of 11 of the 20 patients died, and two patients were lost to follow-up. The 2-year overall survival was 24%, and the median overall survival was 17 months. Univariate analysis revealed that involvement of lymph nodes (P = 0.042) correlated with worse survival. Limitation This is a retrospective study design and has a limited number of patients. Conclusion CENKTL is rare and has a poor prognosis. Diagnosis is challenging due to non-specific clinical symptoms and histopathology results. A comprehensive judgement should be made based on related clinical manifestations and histopathological and molecular examination. Lymph node involvement is an independent prognostic factor for CENKTL.

Comparative Transcriptional Signature Analysis of Peripheral Blood Mononuclear Cells in Early Stage of Hepatitis B-related Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is a prevalent and life-threatening tumor with high morbidity and mortality. Proper prediction and prognosis are incredibly stressed to diagnose HCC and increase patient survival. Objectives: This research aims to evaluate gene expression levels of pre-differentiated transcripts for those suffering from chronic hepatitis B (CHB) and HCC. Methods: To examine the previously analyzed peripheral blood mononuclear cells (PBMCs) transcriptomic array data, we selected seven differentially expressed genes (DEGs) in normal versus CHB and CHB versus HCC (CD44, SP3, USP8, E2F2, UFM1, IFN regulative factor binding protein 2 (IRF2BP2), and T-cell intracellular antigen 1 (TIA1)). The study included individuals with treatment-naïve CHB (n = 30) and primary HCC (n = 25) and healthy controls (n = 15). Subsequently, the expression of genes was assayed using qRT-PCR. A phylogenetic evaluation was performed using direct sequencing of HBsAg. Results: In HCC patients, 60% (n = 15) were HBeAg-positive. HBeAg was negative in all CHB patients, but all were anti-HBe-positive. The hepatitis B virus (HBV) load of HCC patients was more than that of CHB subjects. All patients were of the Iranian race and HBV D genotype. The expression of five transcriptional markers (CD44, SP3, USP8, E2F2, and UFM1) was higher in HCC patients than in CHB and healthy subjects, which was similar to the initial microarray data analysis. Conclusions: Transcriptional signatures may be related to the pathogenesis of HCC and used as diagnostic biological markers for the initial monitoring and prediction of HCC.

Hamster polyomavirus-associated T-cell lymphomas in Syrian hamsters (Mesocricetus auratus).

Hamster polyomavirus (HaPyV) infection has been associated with lymphomas in Syrian hamsters. In the present study, 14 cases of lymphoma in pet Syrian hamsters were pathologically examined and the involvement of HaPyV was investigated. Among 14 cases, 11 were abdominal and 3 were cutaneous lymphomas. The average ages of hamsters with abdominal lymphoma and cutaneous lymphoma were 7 months (range: 4-12 months) and 14 months (range: 6-23 months), respectively. Histologically, abdominal lymphomas were characterized by the diffuse growth of tumor cells with intermediate or large nuclei, low mitotic rates, the presence of tingible body macrophages, and the T-cell immunophenotype. Furthermore, 4/11 abdominal lymphomas were immunopositive for T-cell intracellular antigen-1, suggesting cytotoxic T-cell lymphomas. Cutaneous lymphomas were diagnosed as nonepitheliotropic T-cell lymphoma. Polymerase chain reaction (PCR) detected HaPyV DNA in 12/14 samples, and a sequence analysis of PCR amplicons confirmed >99% nucleotide identity to the published HaPyV sequences. In situ hybridization (ISH) for HaPyV DNA resulted in diffuse nuclear signals within tumor cells in 10/14 cases. Consistent with previous findings, all HaPyV-associated lymphomas were observed in the abdominal cavity of young hamsters. Polymerase chain reaction and ISH were useful for identifying the involvement of HaPyV in lymphomas, and ISH results indicated the presence of episomal HaPyV in neoplastic lymphocytes. The present study suggests that HaPyV infection is highly involved in abdominal lymphomas in young pet Syrian hamsters in Japan and provides diagnostic information on HaPyV-associated lymphoma.

The splicing regulators TIA1 and TIAL1 are required for the expression of the DNA damage repair machinery during B cell lymphopoiesis.

B cell lymphopoiesis requires dynamic modulation of the B cell transcriptome for timely coordination of somatic mutagenesis and DNA repair in progenitor B (pro-B) cells. Here, we show that, in pro-B cells, the RNA-binding proteins Tcell intracellular antigen 1 (TIA1) and TIA1-like protein (TIAL1) act redundantly to enable developmental progression. They are global splicing regulators that control the expression of hundreds of mRNAs, including those involved in DNA damage repair. Mechanistically, TIA1 and TIAL1 bind to 5' splice sites for exon definition, splicing, and expression of DNA damage sensors, such as Chek2 and Rif1. In their absence, pro-B cells show exacerbated DNA damage, altered P53 expression, and increased cell death. Our study uncovers the importance of tight regulation of RNA splicing by TIA1 and TIAL1 for the expression of integrative transcriptional programs that control DNA damage sensing and repair during B cell development.

ALS mutations in the TIA-1 prion-like domain trigger highly condensed pathogenic structures

T cell intracellular antigen-1 (TIA-1) plays a central role in stress granule (SG) formation by self-assembly via the prion-like domain (PLD). In the TIA-1 PLD, amino acid mutations associated with neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) or Welander distal myopathy (WDM), have been identified. However, how these mutations affect PLD self-assembly properties has remained elusive. In this study, we uncovered the implicit pathogenic structures caused by the mutations. NMR analysis indicated that the dynamic structures of the PLD are synergistically determined by the physicochemical properties of amino acids in units of five residues. Molecular dynamics simulations and three-dimensional electron crystallography, together with biochemical assays, revealed that the WDM mutation E384K attenuated the sticky properties, whereas the ALS mutations P362L and A381T enhanced the self-assembly by inducing β-sheet interactions and highly condensed assembly, respectively. These results suggest that the P362L and A381T mutations increase the likelihood of irreversible amyloid fibrillization after phase-separated droplet formation, and this process may lead to pathogenicity.

Intraepithelial cytotoxic lymphocytes are associated with a poor prognosis in feline intestinal T-cell lymphoma.

The expression of cytotoxic molecules in feline intestinal T-cell lymphoma cells was examined immunohistochemically using endoscopic samples of 50 cases. Cases included 14 large-cell lymphomas (LCLs) and 36 small-cell lymphomas (SCLs). Most LCL and some SCL exhibited marked erosion and villous atrophy. Clonal T-cell receptor (TCR) gene rearrangement was detected in 10/14 (71%) LCL cases and 33/36 (92%) SCL cases. No clonal immunoglobulin heavy chain (IgH) gene rearrangement was detected. Immunohistochemically, all cases were positive for CD3 and negative for CD79α, CD30, CD56, and Foxp3. LCLs were positive for CD8 in 13/14 cases (93%), T-cell intracellular antigen 1 (TIA1) in 14/14 cases (100%), and granzyme B in 6/14 cases (43%). SCLs were positive for CD8 in 28/36 cases (78%), TIA1 in 33/36 cases (92%), and granzyme B in 2/36 cases (6%). TIA1- and granzyme B-positive neoplastic lymphocytes were predominantly observed in the mucosal epithelium of 10/50 cases (20%) and 6/50 cases (12%), respectively. No significant differences in survival time were found based on cell size or epitheliotropism. However, cases with TIA1+ and/or granzyme B+ neoplastic lymphocytes predominantly in the mucosal epithelium had significantly shorter survival times (P < .05), suggesting that mucosal epithelium infiltration of neoplastic cells with a cytotoxic immunophenotype is a negative prognostic factor. Therefore, intraepithelial cytotoxic lymphocytes may be associated with mucosal injury and impaired intestinal function, leading to a poor prognosis in cats with intestinal T-cell lymphoma.