Search Results (32,047)

T-cell non-Hodgkin lymphomas, which arise from post-thymic mature T cells, constitute approximately 10–15% of all non-Hodgkin lymphomas. Their leukemic presentations, referred to here as mature T-cell leukemias, are relatively uncommon and present significant diagnostic and therapeutic challenges requiring an informed approach to diagnosis and management. The initial presentation is often persistent T-cell lymphocytosis that must be distinguished from reactive (non-malignant) causes. Unlike B-cell lymphocytosis, where clonality usually indicates malignancy, T-cell clonality can be detected in benign conditions such as autoimmune disorders and viral infections. Thus, establishing clonality is helpful but not sufficient, and a systematic diagnostic approach integrating clinical features, morphology, immunophenotype, and molecular findings is critical. This review outlines our approach to the diagnosis and treatment of four major subtypes of mature T-cell leukemias: T-cell prolymphocytic leukemia (T-PLL), adult T-cell leukemia/lymphoma (ATLL), T-large granular lymphocytic leukemia (T-LGL), and Sézary syndrome (SS). Each section includes a discussion of clinical features, workup, and treatment options. Full article

A novel HIV-1 vaccine candidate under development targeting the highly conserved protease cleavage regions reduced viral acquisition and delayed disease progression in a macaque SIV-challenge model. Breakthrough virus isolated from vaccinees and control animals were sequenced in the regions surrounding the SIV protease cleavages. We identified unique viral mutations that were associated with alterations in viral load and maintenance of CD4+ T cell counts in vaccinees. To evaluate whether the vaccine-elicited mutations were detrimental to virus fitness, we produced 11 mutant constructs and transfection-derived viral stocks harboring mutations in both PCS2 (in CA/p2) and PCS12 (in Nef) that had emerged at high frequency during breakthrough viremia. Virus preparations harboring mutations displayed impaired proteolytic Gag processing, reduced viral RNA incorporation and p27-CA content. These mutants were also compromised in their ability to replicate in primary cells and cell lines. Interestingly, we observed only partial compensation of these PCS2 defects by downstream mutation at PCS12. In sum, we demonstrate that vaccine-elicited immunity directed to viral protease cleavage regions impair viral escape, and breakthrough virus cannot easily restore replicative fitness. Full article

The appearance of antibiotic-resistant strains of Helicobacter pylori (H. pylori) is leading to a decreased eradication rate of H. pylori infection. There is an urgent need to find new agents with antimicrobial mechanisms different from those of antibiotics, with therapeutic potential to clear colonization of H. pylori in the stomach. Some antimicrobial peptides (AMPs) possess bactericidal activity by enhancing the permeability of the outer membrane and damaging the integrity of the cell membrane. Bacteria are not susceptible to drug resistance through this antimicrobial mechanism. In this study, 28 short peptides containing 12 amino acid residues were designed based on nine amino acid fragments (KRIVQRIKD) from human cathelicidin LL-37, which is stable in gastric juice, and 3 amino acids were added at the C-terminus of the peptide. These designed peptides were not digested and degraded by pepsin at low pH values. The peptides were predicted using the online tool platform. Then, the strongest antimicrobial peptide, named SAMP-12aa (KRIVQRIKDVIR), was screened from 28 short peptides. Further studies found that SAMP-12aa retained anti-H. pylori activity after incubation in simulated gastric juice. The MIC and MBC of SAMP-12aa were 8 μg/mL and 32 μg/mL, respectively. SAMP-12aa showed good bactericidal kinetics. SAMP-12aa was found to have cell selectivity, penetrating and damaging bacterial cell membranes and exhibiting almost no toxicity to human cells at a relatively high concentration (128 μg/mL). Regulatory T (Treg) cells express CD25^High with immunosuppressive activity that induces immune tolerance in response to H. pylori. Molecular docking prediction revealed that SAMP-12aa could target the active center of Foxp3. Flow cytometry analysis revealed that SAMP-12aa can inhibit Foxp3 activity and downregulate CD25 protein expression on CD4⁺ T cells, thereby reducing the development and differentiation of CD4⁺Foxp3⁺CD25^High Treg cells with immunosuppressive effects. Further research revealed that the levels of the cytokine interferon-γ (IFN-γ), which activates CD8⁺ T-cell activity, were significantly elevated, and the levels of transforming growth factor-β (TGF-β), which inhibits CD8⁺ T-cell activity, were significantly reduced. The results of this study reveal that SAMP-12aa not only possesses antibacterial activity but also has immunomodulatory effects. Full article

We prospectively evaluated whether cytotoxic T-lymphocyte (CTL) activation and T-cell receptor (TCR) Vβ clonality predict treatment-free remission (TFR) after tyrosine kinase inhibitor (TKI) cessation in chronic-phase chronic myeloid leukemia (CML). Forty-five patients with sustained deep molecular response (DMR) were enrolled (On-TKI, n = 38; Off-TKI, n = 7) and underwent one-year immuno-monitoring from consent. The primary endpoint was 12-month TFR, defined as retention of MR4. Overall, 32/45 patients (71%) maintained TFR at 12 months. Longer TKI exposure and stable DMR were associated with TFR; notably, patients fulfilling “≥7 years of TKI plus ≥1 year of DMR” and exhibiting CTL activation features—CD8 > CD4, memory > effector, and/or highly activated CTL clones on TCR Vβ repertoire—showed the highest likelihood of durable TFR. By contrast, NK cells, effector Tregs, and G-/M-MDSCs did not discriminate TFR status in this cohort. Although antigen specificity against CML stem cells was not directly tested, the memory-dominant CTL phenotype is consistent with immune control after antigen reduction. These findings suggest that a simple, clinically accessible strategy based on flow cytometric CTL profiling and TCR Vβ clonality may help inform TKI discontinuation decisions in CML. External validation is warranted to confirm transportability and refine clinical thresholds. Full article

Background: Clinical outcomes for multiple myeloma are highly variable. Inherited genetic variants of immune regulatory genes can modulate disease susceptibility and clinical outcomes. The germline variant CTLA4 rs231775 polymorphism may alter T-cell function and affect clinical outcomes. Methods: We conducted a retrospective single-center study including 156 consecutive myeloma patients who underwent first-line ASCT. The patients were stratified according to the CTLA4 rs231775 genotype and disease stage (ISS I–III). Results: The CTLA4 rs231775 AA genotype was associated with inferior PFS in ISS I–II and superior PFS in ISS III. In the multivariate analysis, the CTLA4 rs231775 AA genotype emerged as a potential risk factor in ISS I-II and a potential protective factor in ISS III. Conclusions: This germline CTLA4 polymorphism may serve as biomarker to refine post-transplant risk stratification and enable personalized treatment management. Full article

Background: Hyperuricemia (HUA) is a metabolic disorder that severely threatens human health. Chronic uric acid (UA) overload promotes the progression of tubulointerstitial fibrosis (TIF), leading to impaired UA excretion. Our previous studies identified HIPK2 inhibitor XRF-1021, which exhibits robust anti-TIF activity and lowers UA levels in vivo. This study aimed to elucidate its UA-lowering mechanism and therapeutic potential for HUA. Methods: Uricase and xanthine oxidase (XOD) assays were performed to assess effects on UA degradation/production. HEK293T cells transiently expressing UA transporters and gene-knockdown rats were used to evaluate transporter inhibition, while HK-2 cells were analyzed by Western blot. Pharmacokinetics were characterized in rats. Efficacy was tested in potassium oxonate-induced acute HUA rats, diet/adenine-induced chronic HUA quails, and adenine-induced mice with HUA secondary to TIF. Maximum tolerated dose and long-term toxicity were assessed in rats. Results: XRF-1021 neither activated uricase nor inhibited XOD, indicating no direct effect on UA catabolism or synthesis. Instead, XRF-1021 inhibited URAT1 and GLUT9, reducing renal UA reabsorption, while sparing OAT3, OAT4, and ABCG2 activity and upregulating OAT3 and NPT4, suggesting minimal risk of disrupting drug or uremic toxin handling. XRF-1021 showed dose-dependent systemic exposure in rats, lowered serum UA, and provided renal protection in vivo. LD₅₀ values were 2345.4 mg/kg (male) and 1078.9 mg/kg (female), with no obvious toxicity after long-term dosing. Conclusions: XRF-1021 lowers UA by inhibiting URAT1 and GLUT9 to enhance renal UA excretion and provides kidney protection, supporting XRF-1021 as a promising candidate for HUA therapy. Full article

Immunosenescence is characterized by an age-associated decline in immune function, particularly involving T-cell dysfunction, which increases susceptibility to infections and chronic diseases. This study investigated the anti-aging and immunomodulatory effects of American ginseng extract (G1899) using in vitro and in vivo models of aging. Cellular senescence was induced in HepG2 cells by D-galactose treatment, followed by exposure to G1899 (20 and 100 μg/mL). Senescence-associated markers were assessed to evaluate cellular aging. An aging mouse model was established in male C57BL/6 mice through intraperitoneal administration of D-galactose (500 mg/kg) and tert-butyl hydroperoxide (0.4 mmol/kg), and G1899 was orally administered at 400 mg/kg. Thymic immune cell subsets and aging-related protein expression were analyzed using flow cytometry and Western blotting. G1899 significantly reduced p21 expression and senescence-associated β-galactosidase activity in senescent HepG2 cells. In aging-induced mice, G1899 restored CD4⁺ and CD8⁺ T-cell populations, normalized naïve T-cell levels, and reduced anergic CD28-negative T cells. Furthermore, G1899 regulated the expression of key aging-related proteins, including FOXO1, Sirt1, p53, and CD38. These findings demonstrate that G1899 attenuates age-related immune alterations by restoring thymic T-cell homeostasis and regulating aging-associated molecular pathways. Full article

Background/Objectives: Eliciting robust immune responses against the hepatitis B virus (HBV) through therapeutic vaccination holds promise for curing chronic hepatitis B. We previously developed the heterologous protein prime/viral vector boost clinical vaccine candidate, TherVacB. Here, we evaluated a replication-competent chimeric vesicular stomatitis virus vector (VSV-GP) as an alternative viral vector boost vaccine. Methods: A recombinant VSV-GP vector co-expressing HBV surface and core antigens (VSV-GP-HBs/c) was generated and characterized for antigen expression. Its immunogenicity, antiviral efficacy, and durability were assessed in HBV-naïve and HBV-carrier mice, using protein primed, viral vector-primed, and multi-viral vector boost regimens. Results: VSV-GP-HBs/c efficiently expressed both HBV antigens in vitro. A single immunization with VSV-GP-HBs/c induced only weak HBV-specific immune responses in vivo. Replacing protein priming with VSV-GP-HBs/c resulted in modest immune activation and limited antiviral effects in HBV-carrier mice. In contrast, substituting the modified vaccinia virus Ankara (MVA)-HBs/c boost in the TherVacB regimen with VSV-GP-HBs/c elicited robust HBV-specific antibody responses and strong CD4 and CD8 T-cell immunity, assessed by intracellular IFN-γ staining after peptide stimulation. This regimen achieved a substantial reduction in serum HBsAg levels, numbers of HBV-positive hepatocytes, and intrahepatic HBV-DNA, with antiviral efficacy comparable to that of the classical TherVacB regimen. Notably, a second viral vector boost did not enhance HBV-specific immunity or antiviral efficacy; instead, it promoted dominant vector-specific CD8 T-cell responses. Long-term analyses performed 10 weeks after the last vaccination further demonstrated that a single protein-prime/VSV-GP-HBs/c boost was sufficient to achieve sustained antiviral control. Conclusions: These findings identify VSV-GP-HBs/c as an effective boost vector for therapeutic hepatitis B vaccination and establish protein priming followed by a single viral vector boost as an optimal strategy for sustained antiviral immunity. Full article

Herpes simplex virus type 2 (HSV-2) is the primary pathogen responsible for genital herpes. Predominantly transmitted via sexual contact, HSV-2 not only poses significant physical and psychological burdens on infected individuals but also substantially elevates the risk of HIV acquisition and represents a potentially fatal threat to newborns. Following primary infection, HSV-2 establishes lifelong latent infection within the sacral ganglia. Currently, there are no vaccines or therapeutics capable of eradicating this latent virus reservoir or effectively preventing initial infection. The core impediment to developing such interventions lies in the incomplete elucidation of the protective immune mechanisms against HSV-2 and its precise molecular pathogenesis. The host immune response against HSV-2 hinges critically on the coordinated interplay between innate and adaptive immunity. The innate immune system, serving as the first line of defense, acts to curtail early viral replication and initiate adaptive responses. This is achieved through mechanisms, including the genital mucosal barrier, activation of Toll-like receptors (TLRs), the cGAS-STING signaling pathway, interferon (IFN)-mediated antiviral effector functions, and activation of innate immune cells such as natural killer (NK) cells and dendritic cells (DCs). Crucially, however, HSV-2 counteracts these host defenses by expressing immune modulatory proteins (e.g., ICP0, ICP27, ICP35) that target key host antiviral signaling pathways, thereby affecting immune evasion. Within the adaptive immune response, neutralizing antibodies generated by the humoral immunity can provide localized protection at mucosal sites, but their protective efficacy is limited due to sophisticated viral immune evasion mechanisms. Cellular immunity, particularly mediated by CD4+ T cells, constitutes the core mechanism for viral clearance and suppression of recurrent outbreaks. Notably, tissue-resident memory T cells (TRMs) play a pivotal role in controlling the reactivation of latent HSV-2 within the ganglia. This review integrates current research advances to delineate the innate and adaptive immune mechanisms engaged during HSV-2 infection from the perspective of the dynamic host–virus interplay, with an ultimate aim to provide a theoretical foundation informing the rational development of preventive vaccines and therapeutic agents against HSV-2. Full article

Human papillomavirus (HPV), especially high-risk HPV types, is a significant public health concern due to its association with various cancers and increased risk of acquiring other sexually transmitted infections (STIs). In most cases, host immunity rapidly responds to and clears HPV infections, but persistent or latent infections can increase susceptibility to cancer. A better understanding of how HPV interacts with and evades the immune response is vital to understanding disease progression and guiding the next generation of vaccines and immunotherapies. This review article provides a comprehensive overview of the immune mechanisms involved in HPV infection, highlighting the roles of T cells and other immune subsets. We discuss the immune evasion strategies employed by HPV and subsequent modulation of the immune microenvironment. Additionally, we explore the current therapeutic landscape and emerging immunotherapeutic approaches under investigation. By unveiling the intricacies of the immune response to HPV, we may inform improved strategies for the treatment of HPV-related diseases. Full article

Renal cell carcinomas (RCCs) driven by TFE3 rearrangement or TFEB alteration (MiT-RCC) account for up to 40% of pediatric RCCs but are rare in adults. MiT-RCC includes fusion-driven tumors with TFE3 or TFEB rearrangements (translocation RCC, tRCC) and TFEB-amplified RCC. Morphologic heterogeneity and historical exclusion from trials have limited evidence-based management. We reviewed the literature through January 2026 to summarize molecular biology, pathology, clinical behavior, and systemic therapy. MiT-RCC comprises biologically distinct entities: TFEB-rearranged tumors are often indolent in younger patients, whereas TFEB-amplified RCC, frequently co-amplifying VEGFA, behaves aggressively in older adults. In TFE3-rearranged RCC, fusion partner influences prognosis. Paradoxically, ASPSCR1::TFE3 fusions have the poorest natural history, yet fusion-annotated cohorts suggest these tumors may derive particular benefit from immune checkpoint inhibitor (ICI) plus VEGF receptor tyrosine kinase inhibitor (VEGFR-TKI) combinations. Diagnostic advances including GPNMB immunohistochemistry, TRIM63 RNA in situ hybridization, and sequencing-based fusion panels improve detection of cryptic alterations. First-line ICI + VEGFR-TKI combinations are increasingly favored for metastatic tRCC in eligible patients, while optimal management of TFEB-amplified RCC remains uncertain. Full article

This study compared the effectiveness of alkaline protease, neutral protease, trypsin, and papain in hydrolyzing oyster proteins and evaluated the antioxidant activities of the resulting hydrolysates. Alkaline protease achieved the highest degree of hydrolysis (30.96%) and the highest proportion of peptides ≤1 kDa (64.23%). Papain showed the lowest hydrolysis degree (18.29%). After separation by Sephadex G-15 gel filtration chromatography, the resulting low-molecular-weight peptide fractions (≤1 kDa) from each hydrolysate exhibited higher in vitro antioxidant activity than the higher-molecular-weight fractions (>1 kDa). Notably, trypsin and papain-derived low-molecular-weight fractions (OPP-T2 and OPP-P2) demonstrated stronger DPPH radical scavenging and inhibition of linoleic acid autoxidation than those from alkaline and neutral proteases. Cell experiments revealed that all low-molecular-weight fractions effectively alleviated H₂O₂-induced oxidative damage in LO2 cells. OPP-T2 and OPP-P2 exhibited significantly stronger protection of cell membrane integrity and enhancement of superoxide dismutase (SOD) activity than OPP-A2 and OPP-N2 (p < 0.05). OPP-T2 also showed the most pronounced increase in glutathione peroxidase (GSH-Px) activity (p < 0.05). These findings demonstrate that protease selection critically influences hydrolysis efficiency and antioxidant activity, with molecular weight being a key determinant of peptide antioxidant capacity. This work provides a reference for the development and application of oyster peptides. Full article

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by epidermal barrier dysfunction and dysregulated immune responses, particularly an imbalance between T helper type 1 (Th1) and type 2 (Th2) cytokines. Natural products with immunomodulatory activity have attracted increasing attention as potential strategies for regulating allergic inflammation. In this study, we investigated the immunomodulatory effects of bioprocessed black rice bran (BRB-F) and bioprocessed balloon flower root (BFR-F). In vitro assays using human B cells, mast cells, and keratinocytes were conducted to evaluate IgE production, mast cell degranulation, and epithelial inflammatory mediator release. The efficacy of the BRB-F:BFR-F mixture was further evaluated in BALB/c mice with 2,4-dinitrochlorobenzene (DNCB)/Dermatophagoides farinae extract (DFE)-induced AD-like dermatitis. BRB-F and BFR-F suppressed IgE production, attenuated mast cell degranulation and thymic stromal lymphopoietin (TSLP) release, and reduced keratinocyte-derived inflammatory mediators (thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC), and IL-6). In mice, dietary supplementation with the BRB-F:BFR-F mixture (10–80 mg/kg/day) dose-dependently improved clinical skin lesions and histopathological changes, with serum IgE reduced by up to 87.1% at the highest dose. The treatment significantly suppressed Th2 cytokine mRNA expression in ear tissue (IL-4, IL-5, and IL-13) by 37.2%, 32.7%, and 34.0%, respectively, compared with the positive control. In contrast, splenic Th1 cytokine mRNA expression (IL-2, IL-12, and IFN-γ) was partially restored by 37.1%, 22.5%, and 18.7%, respectively. These findings indicate that BRB-F and BFR-F modulate multiple immune pathways and help restore Th1/Th2 immune balance, suggesting their potential as functional materials for regulating immune dysregulation associated with AD. Full article

The efficacy of immunotherapy in colorectal cancer (CRC) has long been considered to be closely associated with microsatellite instability (MSI) status. Patients with microsatellite stable (MSS) tumors typically exhibit poor responses to PD-1/PD-L1 inhibitors and a poor prognosis, often being categorized as immunologically ‘cold’ tumors. However, some MSS patients can still achieve favorable therapeutic responses, sometimes even surpassing those of certain MSI patients. Immune-cold and immune-hot tumor phenotypes are largely determined by the abundance, clonal expansion, and functional states of tumor-infiltrating T cells. This suggests that immunotherapy responses are driven by dynamic remodeling of T-cell clonality rather than by MSI status alone. To elucidate the underlying T cell clonal dynamics, integrated single-cell transcriptome (scRNA-seq) and T cell receptor sequencing (scTCR-seq) data analyses from 43 blood and tissue samples of MSI and MSS colorectal cancer patients before and after anti-PD-1 therapy were performed. Using our developed TCR reconstruction pipeline (TORBiT), we systematically analyzed the clonal architecture of the TCR repertoire, inter-tissue migration, and its association with T-cell functional state transitions. From a TCR clonal kinetic perspective, we revealed two distinct modes of immune Coercion that may further affect the immune response: a “high-fluctuation, deep-exhaustion” pattern in MSI tumors and a “high-baseline, strong-suppression” pattern in MSS tumors. These findings provide a novel theoretical foundation and research perspective for understanding the responsiveness and resistance mechanisms to immune checkpoint inhibitors. Full article