Search Results (747)

Patients with Relapsed/Refractory Diffuse Large B-cell Lymphoma (R/R DLBCL) harbor a poor prognosis. Novel therapies, such as bispecific antibodies (BsAbs), provide an effective therapeutic option for such patients. BsAbs are studied both as monotherapy and combination therapy for patients with R/R DLBCL with promising results. Unlike cellular therapies, such as autologous stem cell transplant (ASCT) or chimeric antigen receptor therapy (CAR-T), BsAbs are more amenable to administration in a community setting, given the lower incidence and severity of key toxicities, such as cytokine release syndrome (CRS) and immune effector cell-associated neurologic syndrome (ICANS). Deployment of BsAbs in the community setting requires operational considerations and a multidisciplinary team approach. This review will discuss the currently approved BsAb treatment regimens and our community institution’s experience in implementing BsAbs. Full article

Ischemia–reperfusion injury (IRI) is a mechanism based on inflammatory mediators’ release and activation of effectors of damage. Studies showed a correlation between cytokine, severity of damage, and post-operative outcomes. Ex situ perfusion may work as a platform for the treatment of IRI mechanisms, such as the removal of cytokines using cytokine adsorption (CA). We assessed the safety and benefits of an integrated CA during ex situ dual-oxygenated hypothermic (D-HOPE) and normothermic perfusion (NMP). During the period of July 2021–December 2023, 84 octogenarian liver grafts, suitable for transplantation, were considered: 12 were randomized to D-HOPE or NMP with or without CA (D-HOPE + CA, D-HOPE, NMP + CA, NMP groups, n = 3 each) and compared to 72 performed using grafts preserved in static cold storage (SCS). IL-1, IL-6, IL-10, and TNF-a perfusate concentrations were evaluated together with perfusion parameters and post-operative outcomes. Perfusion procedures were unaffected by CA integration. In NMP, cytokine levels were 10–40 times higher than in healthy subjects and 20–50 times higher than D-HOPE. Cytokines were removed both in D-HOPE and NMP, but the concentration-dependent mechanisms of action of CA led to more remarkable removal in NMP. IL-10 and TNF-a concentrations were significantly lower in NMP + CA than in NMP. The application of CA was associated with significantly higher arterial flows both in D-HOPE and NMP, and reduced neutrophil infiltration in NMP. No differences in post-operative outcomes were found among groups. In conclusion, cytokine adsorption during ex situ machine perfusion of liver grafts from elderly donors is safe and feasible and is associated with modulation of inflammatory mediators and perfusion dynamics. These findings are hypothesis-generating, and larger studies are required to determine the clinical impact of this strategy. Full article

Cisplatin (CDDP) is a cornerstone chemotherapeutic drug, yet its efficacy is frequently compromised by renal toxicity, primarily manifesting as acute kidney injury (AKI). Magnolol (MG) is a polyphenol from Magnolia officinalis and has been widely documented for its pronounced antioxidant and anti-inflammatory properties. This study evaluated the renoprotective effects of MG in a murine model of CDDP-induced AKI. Male C57BL/6 mice received MG (20 mg/kg) via daily intraperitoneal injection for four consecutive days, starting one day before a single CDDP injection. MG significantly reduced the serum concentrations of blood urea nitrogen and creatinine. Histopathological assessment revealed attenuated tubular damage and reduced expression of tubular injury markers. MG inhibited pro-inflammatory cytokines at both systemic and renal levels, alleviated endoplasmic reticulum stress, and suppressed activation of mitogen-activated protein kinase signaling pathways. Apoptotic damage was mitigated, as shown by the fewer TUNEL-positive cells and lowered expression of pro-apoptotic markers. In parallel, ferroptotic processes were alleviated through downregulation of pro-ferroptotic proteins and preservation of key antioxidant regulators. Importantly, MG restored nuclear factor erythroid 2-related factor 2 activity and upregulated downstream antioxidant effectors. These findings highlight the multi-targeted renoprotective actions of MG and support its possible utility as a therapeutic agent to prevent CDDP-induced renal injury. Full article

Chimeric antigen receptor (CAR) T cell therapy has demonstrated clinical success in hematologic malignancies but has limited efficacy in solid tumors due to tumor microenvironment (TME) barriers that impede CAR T cell recognition, infiltration, and sustained function. Traditional 2D assays inadequately recapitulate these constraints, necessitating improved in vitro models. This study validated a 3D tumor spheroid platform using an agarose microwell system to generate uniform B7-H3-positive spheroids from multiple solid tumor cell lines, enabling the evaluation of CAR T cell activity. TME-relevant immune modulation under 3D conditions was analyzed by flow cytometry for B7-H3, MHC I/II, and antigen processing machinery (APM), followed by co-culture with B7-H3 CAR T cells to assess cytotoxicity, spheroid integrity, tumor viability, and CAR T cell activation, exhaustion, and cytokine production. Two human cancer-cell-line-derived spheroids, DU 145 (prostate cancer) and SUM159 (breast cancer), retained B7-H3 expression, while MC38 (mouse colon cancer)-derived spheroids served as a B7-H3 negative control. Under 3D culture conditions, DU 145 and SUM159 spheroids acquire TME-like immune evasion characteristics and specifically downregulated MHC-I and APM (TAP1, TAP2, LMP7) with concurrent upregulation of MHC-II and calreticulin. Co-culture showed effective spheroid infiltration, cytotoxicity, and structural disruption, with infiltrating CAR T cells displaying higher CD4⁺ fraction, activation, exhaustion, effector/terminal differentiation, and IFN-γ/TNF-α production. This 3D platform recapitulates critical TME constraints and provides a cost-effective, feasible preclinical tool to assess CAR T therapies beyond conventional 2D assays. Full article

Breast cancer is a heterogeneous disease that exists in multiple subtypes, some of which still lack targeted and effective therapy. A major challenge is to unravel their underlying molecular mechanisms and bring to light novel therapeutic targets. In this study, we investigated the role of WNT-inducible signaling pathway protein 1 (WISP1) matricellular protein in the acquirement of an invasive phenotype by breast cancer cells. To this aim, we treated non-invasive MCF7 cells with WISP1 and assessed the expression levels of macrophage migration inhibitory factor (MIF) and its cellular receptor CD74. Next, we examined the expression of epithelial-to-mesenchymal transition (EMT) markers as well as molecular effectors of the tumor microenvironment, such as CD44, the main hyaluronan receptor that also acts as a co-receptor for MIF, the hyaluronan oncogenic network, and specific matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs). The results showed that WISP1 potently induces the expression of MIF cytokine and affects the expression of specific extracellular matrix molecules with established roles in the promotion of malignant properties. Notably, Src kinases and MIF are critically involved in these processes. Collectively, the present study demonstrates for first time a WISP1/Src/MIF axis as well as its ability to induce an invasive phenotype in MCF7 cells and highlights novel cellular and molecular processes involved in the epithelial-to-mesenchymal transition and the development of invasive breast cancer. This suggests that specific cues from the tumor microenvironment can activate a migratory/invasive phenotype in a subpopulation of cells residing within the heterogeneous breast tumor. Full article

Tumor tissue is surrounded by mast cells (MCs), which participate in the inflammatory immune response by producing cytokines, proteases, and other molecules. MCs are involved in both innate and acquired immunity and are associated with the IgE response through the FcεRI receptor. MCs mediate inflammation in several immune reactions, including acute hyperreactivity, leukocyte recruitment, acute tissue swelling, anaphylaxis, and pro-inflammatory cytokine production. They not only function as pro-inflammatory effector cells but may also contribute to the regulation of the acquired immune response in tumor tissue. Therefore, MCs may mediate immunity in breast cancer by promoting remodelling and counteracting cancer growth. They also produce anti-inflammatory substances, such as histamine, transforming growth factor-β (TGF-β)1, IL-10, and IL-4, which inhibit the acquired immune response and reduce the inflammatory state. IL-37 and IL-38 are novel natural regulators of inflammation and are anti-inflammatory members of the IL-1 family. IL-1, generated by immune cells such as macrophages and lymphocytes, is released downstream of oncogenes in breast cancer, triggering an inflammatory response by stimulating other pro-inflammatory cytokines such as IL-6, tumor necrosis factor (TNF), and IL-33 (an early warning cytokine). Therefore, blocking IL-1 with IL-37 or IL-38 could represent a novel therapeutic strategy that, when combined with other treatments, could be beneficial in breast cancer. This review focuses on the new discoveries and insights into the role of MCs in breast cancer. We also analyzed molecules that can promote tumor growth and those that can inhibit cancer development and metastasis. This review aims to study the role of MCs accumulated in the stroma of breast adenocarcinoma in relation to secreted anti-inflammatory cytokines, such as IL-37 and IL-38. Full article

RNA methyltransferases are key regulators of bacterial physiology, yet their specific roles in virulence remain poorly defined. In this study, we characterize PA3840, a putative RNA methyltransferase in Pseudomonas aeruginosa (P. aeruginosa). Deletion of PA3840 specifically impaired twitching motility without affecting bacterial growth, swimming, or swarming. Notably, PA3840 was found to suppress the expression of Type III Secretion System (T3SS) genes, thereby reducing cytotoxicity and host cell rounding. Consistent with these observations, PA3840 expression attenuated pro-inflammatory cytokine production in epithelial cells by inhibiting NF-κB activation. Mechanistic analysis revealed that PA3840 is translocated into host cells in a Type VI Secretion System (T6SS)-dependent manner. This translocation was reduced by hcp1 deletion and nearly abolished by a double deletion of pscF and hcp3, suggesting the involvement of multiple T6SS components and potential interplay with T3SS machinery. However, direct transfection of PA3840 into host cells failed to suppress cytokine expression, indicating that its immunomodulatory function is mediated by a bacterium-intrinsic mechanism rather than direct intracellular action. Collectively, these findings identify PA3840 as a translocated effector that modulates twitching motility and dampens host inflammation by repressing T3SS and NF-κB signaling, revealing a novel layer of post-transcriptional virulence regulation in P. aeruginosa. Full article

Autoantibodies have long been regarded as passive reflections of immune dysregulation in connective tissue diseases (CTDs). Recent advances in systems immunology and molecular pathology have fundamentally redefined them as active molecular fingerprints that delineate distinct disease endophenotypes with predictive power for clinical trajectories and therapeutic responses. Rather than mere epiphenomena, autoantibodies encode precise information about dominant immune pathways, organ tropism, and pathogenic mechanisms. This review synthesizes emerging evidence that autoantibody repertoires—defined by specificity, structural properties, and functional characteristics—stratify patients beyond traditional clinical taxonomy into discrete pathobiological subsets. Specific signatures such as anti-MDA5 in rapidly progressive interstitial lung disease, anti-RNA polymerase III in scleroderma renal crisis, and anti-Ro52/TRIM21 in systemic overlap syndromes illustrate how serological profiles predict outcomes with remarkable precision. Mechanistically, autoantibody pathogenicity is modulated by immunoglobulin isotype distribution, Fc glycosylation patterns, and tissue-specific receptor expression—variables that determine whether an antibody functions as a biomarker or pathogenic effector. The structural heterogeneity of autoantibodies, shaped by cytokine microenvironments and B-cell subset imprinting, creates a dynamic continuum between pro-inflammatory and regulatory states. The integration of serological, transcriptomic, and imaging data establishes a precision medicine framework: autoantibodies function simultaneously as disease classifiers and therapeutic guides. This endophenotype-driven approach is already influencing trial design and patient stratification in systemic lupus erythematosus, systemic sclerosis, and inflammatory myopathies, and is reshaping both clinical practice and scientific taxonomy in CTDs. Recognizing autoantibodies as endophenotypic determinants aligns disease classification with pathogenic mechanism and supports the transition towards immunologically informed therapeutic strategies. Full article

Background: Liver X receptors (LXRs) are critical regulators of cholesterol homeostasis that modulate T cell function with anti-inflammatory effects. LXR downregulation has been implicated in the pathogenesis of inflammatory bowel disease (IBD), although its underlying mechanisms remain to be fully elucidated. Recent evidence has confirmed the link between T cell senescence and autoimmune diseases. Here, we sought to investigate whether and how LXRs regulate T cell senescence in controlling intestinal inflammation. Methods and Results: We found that LXRβ expression was decreased in the colons of mice with experimental colitis, and LXRβ deficiency (Lxrβ^−/−) significantly aggravated their colitis. Intriguingly, this finding was accompanied by enhanced CD4⁺ T cell senescence both in the colons and spleens of Lxrβ^−/− mice, evidenced by upregulation of SA-β-gal levels and the remarkable expansion of effector memory subclusters in CD4⁺ T cells. Moreover, senescent Lxrβ^−/− CD4⁺ T cells secreted elevated levels of proinflammatory cytokines, especially in effector memory populations, exhibiting a pronounced proinflammatory phenotype. RNA-sequencing further confirmed the role of LXRβ in restricting CD4⁺ T cell senescence. Mechanistically, the absence of LXRβ in CD4⁺ T cells directly enhanced senescence by promoting the cGAS/STING pathway. Blocking STING signaling with a targeted inhibitor significantly alleviated senescence in Lxrβ^−/− CD4⁺ T cells. Conclusions: Our findings demonstrate the role of LXRβ in regulating intestinal CD4⁺ T cell senescence to inhibit colitis development, identifying LXRβ as a potential therapeutic target for treating IBD. Full article

Acute Appendicitis (AA) is the commonest abdominal digestive surgical emergency, but its etiology is not clarified. Based on histologic observations, an allergic cause has been proposed. In a type I hypersensitivity allergic reaction, there is a Th2 immune response characterized by Th2 cells, eosinophils, basophils, IgE, IL-4, IL-5, and IL-13 serum elevation. Recent studies showed a local appendicular endoluminal and parietal Th2 immune response in acute phlegmonous appendicitis. We performed a prospective single-center study where we evaluated the Th2 blood immune response in 38 patients with acute phlegmonous appendicitis, 27 patients with acute gangrenous appendicitis, and 18 patients with the clinical picture of AA, who underwent appendectomy but had negative histology for AA (negative appendectomy group). Higher levels of basophils were found in phlegmonous appendicitis (p = 0.03), and higher levels of eosinophils were found in the control group (p = 0.003). Effector memory CD4 T cells re-expressing CD45RA were higher in gangrenous (p = 0.020) and central memory CD4 T cells in phlegmonous appendicitis (p = 0.004). The number of Th2 circulating cells was higher in gangrenous appendicitis (p = 0.037), while Th1 circulating cells were higher in phlegmonous appendicitis (p = 0.028). IL-4 blood concentrations were elevated in acute gangrenous appendicitis (p = 0.029). No significant differences were found in the levels of IgE, IL-5, or IL-13 in any of the groups. Thus, a Th2 response was not detected in patients’ serum with phlegmonous appendicitis. Serum levels of IgE, IL-5, and IL-13 were not different among patients with acute phlegmonous appendicitis, acute gangrenous appendicitis, and the negative appendectomy group. These findings are in contrast to our previous work in which we evaluated the Th2 response at the local level, at the appendicular luminal aspect and appendicular wall, in phlegmonous appendicitis and control groups, and we unequivocally showed a Th2 response in phlegmonous appendicitis. Thus, in patients with phlegmonous appendicitis, the local Th2 response is not reflected in the serum levels of immune cells and cytokines. Full article

Bispecific antibodies (BsAbs) have emerged as an important new class drugs for the treatment of multiple myeloma (MM) over the last few years. Currently, BsAbs are only licensed for use as monotherapy in patients with relapsed/refractory MM who have had at least three prior lines of treatment and are triple class-exposed (patients who have received an anti-CD38 monoclonal antibody, an immunodulatory drug, and a proteasome inhibitor). However, their use in earlier lines, including in the upfront setting, is being explored in multiple ongoing clinical trials with promising early results. The BsAbs have specific toxicities, including a high rate of low-grade cytokine release syndrome and, less commonly, immune effector cell-associated neurotoxicity syndrome. These immune-related toxicities occur almost exclusively during the initiation phase of the BsAbs. This has led to frequent hospitalization of patients for the duration of the initial step-up dosing phase. Strategies that could facilitate outpatient step-up dosing, such as tocilizumab prophylaxis, will become even more critical if BsAbs move into earlier lines of treatment and are used in larger numbers of patients. Optimizing infection prophylaxis is critical for ensuring the safe delivery of BsAbs as infection is the leading cause of non-relapse mortality in patients being treated with BsAbs. Multiple strategies to minimize the infection risk, including antimicrobial prophylaxis, immunoglobulin replacement, vaccination and reduced dosing frequency, have been evaluated. The clinical data on the efficacy of these supportive measures are described in this review article alongside the available strategies for mitigating and managing CRS and ICANS. Full article

The concept of united airway disease (UAD) highlights the bidirectional relationship between inflammatory disorders of the upper airways—such as allergic rhinitis and chronic rhinosinusitis with or without nasal polyps (CRSwNP/CRSsNP)—and lower airway diseases, most notably asthma. This paradigm is supported by epidemiological, embryological, and immunological evidence demonstrating that airway inflammation represents a single, interconnected process rather than isolated compartmental pathology. Central to many UAD phenotypes is type 2 (T2) inflammation, driven by cytokines including IL-4, IL-5, and IL-13, and mediated by effector cells such as eosinophils and group 2 innate lymphoid cells (ILC2s). Epithelial barrier dysfunction often serves as the initiating trigger for this shared inflammatory cascade by production of TSLP, IL-25 and IL-33. Optimal diagnosis and management of UAD require an integrated, multidisciplinary framework. Clinical evaluation remains essential for patient characterization but must be complemented by pheno-endotypic assessment using imaging (CT), allergy testing, biomarker profiling (FeNO, blood eosinophils, IgE), and pulmonary function testing (spirometry, impulse oscillometry). Therapeutic strategies are layered, targeting both symptom control and inflammation across airway compartments. Standard approaches include intranasal and inhaled corticosteroids as well as saline irrigations, while severe T2-high disease increasingly benefits from biologic therapies (anti-IL-5/IL-5R, anti-IL-4R, anti-TSLP), which reduce dependence on systemic corticosteroids and surgical interventions such as endoscopic sinus surgery (ESS). Emerging precision-medicine models, particularly the “treatable traits” approach, further underscore the need to view the airway as a unified system. Collectively, these insights reinforce the clinical imperative of addressing upper and lower airway disease as a continuum, ensuring that inflammation in one district is neither overlooked nor treated in isolation. Full article

Chimeric antigen receptor (CAR) cell therapies have revolutionized cancer immunotherapy by enabling targeted and potent antitumor immune responses. However, clinical challenges such as limited efficacy in solid tumors, severe toxicities including cytokine release syndrome (CRS), and manufacturing complexities restrict their broader use. Recently, CAR cell-derived exosomes (CAR-Exos) have emerged as promising cell-free therapeutic alternatives that retain the key antitumor functionalities of their parent cells while potentially overcoming the limitations of live cellular therapies. These nanoscale vesicles can deliver bioactive CAR molecules, cytotoxic proteins, and immunomodulatory cargo, enabling targeted tumor cell killing with reduced systemic toxicity and offering “off-the-shelf” applicability. This review comprehensively explores the biology, engineering, and therapeutic potential of CAR-Exos derived from T cells, natural killer (NK) cells, and other immune effectors. We discuss advances in isolation, characterization, and cargo profiling techniques, as well as preclinical and early clinical data supporting their application. Further, we address translational challenges including large-scale production, biodistribution, and immune evasion in tumor microenvironments. Combining cellular and exosomal CAR platforms holds promise to enhance efficacy and safety in cancer treatment, representing a frontier in targeted immunotherapy. Full article

Chimeric antigen receptor (CAR)-based immunotherapy has shown considerable promise in cancer treatment by redirecting immune effector cells to recognize and eliminate tumor cells in an antigen-specific manner. While CAR-T cells bearing tumor-specific CARs have shown remarkable success in treating some hematological malignancies, their clinical application is limited by cytokine release syndrome, neurotoxicity, and graft-versus-host disease. In contrast, CAR–natural killer (NK) cells retain their multiple forms of natural anti-tumor capabilities without the pathological side effects and are compatible with allogeneic “off-the-shelf” application by not requiring prior activation signaling. Despite CAR-NK therapies showing promising results in hematological malignancies, they remain limited as effector cells against solid tumors. This is primarily due to the complex, immunosuppressive tumor microenvironment (TME), characterized by hypoxia, nutrient depletion, lactate-induced acidosis, and inhibitory soluble factors. Collectively, these significantly impair NK cell functionality. This review examines challenges faced by CAR-NK therapy in combating solid tumors and outlines strategies to reduce them. Barriers include tumor antigen heterogeneity, immune escape, trogocytosis-mediated fratricide, rigid structural and metabolic barriers in the TME, immunosuppressive factors, and defective homing and cell persistence of CAR-NK cells. We also emphasize the impact of combining other complementary immunotherapies (e.g., multi-specific immune engagers and immunomodulatory agents) that further strengthen CAR-NK efficacy. Finally, we highlight critical research gaps in CAR-NK therapy and propose that cutting-edge technologies are required for successful clinical translation in solid tumor treatment. Full article

The functional landscape of the skin microbiome is largely defined by dominant genera such as Cutibacterium and Staphylococcus, whereas rare commensals remain poorly understood. In this study, we identified Rothia kristinae BF00107, a skin-resident strain with a complete pantothenate biosynthesis pathway, as a novel postbiotic candidate with distinct dermatological benefits. BF00107 fermentation filtrate suppressed pro-inflammatory cytokines (IL-1β and TNF-α) in keratinocytes and restored extracellular matrix homeostasis in UVB-irradiated fibroblasts by upregulating COL1A1 expression and reducing MMP-1 levels. Consistent with the observed phenotypes, transcriptomic profiling revealed a strain-specific signature characterized by downregulation and upregulation of the expression of inflammatory mediators and barrier- and ECM-associated genes, respectively. Comparative genomics and metabolite profiling confirmed BF00107 as a unique high-pantothenate producer. Supplementation with pantothenic acid reproduced the anti-inflammatory and barrier-supporting effects of the strain, confirming its role as a key effector metabolite. Furthermore, BF00107 passed standard safety assessments, including the Human Repeat Insult Patch Test (HRIPT), Ames, and irritation tests, supporting its suitability for human applications. These findings establish the pantothenate-producing R. kristinae BF00107 as the first functionally validated Rothia strain with anti-inflammatory and photoaging-protective properties. This study expands the functional scope of the skin microbiome and highlights rare commensals as valuable reservoirs for safe, strain-specific postbiotic development. Full article