Search Results (6,686)

Background/Objectives: Tacrolimus is the most used immunosuppressive agent in solid organ transplantation due to its efficacy in preventing acute rejection, but it has a narrow therapeutic range, and overexposure often leads to toxicities, including neurological side effects like tremors. Tremor affects up to 54% of renal transplant patients under tacrolimus. Extended-release tacrolimus (LCPT) has demonstrated efficacy in reducing tremor severity, as evidenced by studies employing quality of life (QoL) questionnaires, the Fahn–Tolosa–Marin (FTM) scale, and Accelerometer devices. The objectives of this study were to evaluate the benefits of the conversion to LCPT formulation in kidney transplant recipients experiencing tremors on prolonged-release tacrolimus (PR-TAC) treatment and to validate the DyCare device, a wearable wireless sensor for tremors. Results: The DyCare device measured tremor frequencies of 8.74 ± 0.11 Hz and 1.36 ± 0.08° and 17.38 ± 1.16°, as root mean square (RMSx100 for accelerometer and Gyroscope, respectively) in PR-TAC patients. After switching ten patients to LCPT, tremor severity significantly decreased, as confirmed by DyCare and the QoL in the Essential Tremor Questionnaire (QUEST). Additionally, LCPT allowed a 34% reduction in tacrolimus dosage while maintaining therapeutic trough concentrations. Immunological and pharmacodynamic biomarkers (p-miR-210-3p, p-IL10, p-IL12p70, p-IFNγ uCXCL10, NFAT-regulated gene expression) confirmed stable immunosuppression post-conversion. Conclusions: The conversion to the LCPT formulation significantly reduced tremors in kidney transplant recipients without altering their immunological status, as confirmed through a panel of immunologic and pharmacodynamic biomarkers. The DyCare device enables a precise quantification of tremors in transplant recipients, allowing physicians to optimize treatment strategies. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, marked by late diagnosis, limited responsiveness to conventional therapies, and an immunosuppressive tumor microenvironment. While immunotherapy has transformed treatment paradigms in several cancers, its efficacy in PDAC has been minimal. Oncolytic viruses and therapeutic cancer vaccines have emerged as promising immunotherapeutic strategies designed to stimulate robust, tumor-specific immune responses and reshape the immune landscape. However, despite encouraging preclinical data, clinical translation in PDAC has been largely disappointing. This review critically evaluates the design, delivery, and efficacy of oncolytic virotherapy and cancer vaccines in PDAC, examining barriers such as stromal desmoplasia, immune exclusion, and tumor heterogeneity. We also explore combination strategies integrating checkpoint inhibitors, chemotherapy, radiotherapy, and stromal modulation to overcome resistance. Ultimately, the viability of these approaches hinges on a clearer understanding of their mechanistic limitations and the refinement of delivery platforms. These factors will determine whether oncolytic viruses and cancer vaccines can be successfully repositioned within the therapeutic arsenal or warrant reevaluation in the evolving landscape of PDAC treatment. Full article

Human cytomegalovirus (HCMV) establishes lifelong latency following primary infection, residing within myeloid progenitor cells and monocytes. To achieve this, the virus employs multiple immune evasion strategies. It suppresses innate immune signaling by inhibiting Toll-like receptor and cGAS-STING pathways. In addition, the virus suppresses major histocompatibility complex (MHC)-dependent antigen presentation to evade T cell recognition. As the downregulation of MHC molecules may trigger NK cell activation, the virus compensates for this by expressing proteins such as UL40 and IL-10, which engage inhibitory NK cell receptors and block activating signals, thereby suppressing NK cell immune surveillance. Viral proteins like UL36 and UL37 block host cell apoptosis and necroptosis, allowing HCMV to persist undetected and avoid clearance. In settings of profound immunosuppression, such as after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or solid organ transplantation, slow immune reconstitution creates a window for viral reactivation. Likewise, immunosenescence and chronic low-grade inflammation during aging increases the risk of reactivation. Once reactivated, HCMV triggers programmed cell death, releasing viral PAMPs (pathogen-associated molecular patterns) and host-derived DAMPs (damage-associated molecular patterns). This release fuels a potent inflammatory response, promoting further viral reactivation and exacerbating tissue damage, creating a vicious cycle. This cycle of inflammation and reactivation contributes to both transplant-related complications and the decline of antiviral immunity in the elderly. Therefore, understanding the immune regulatory mechanisms that govern the switch from latency to reactivation is critical, especially within the unique immune landscapes of transplantation and aging. Elucidating these pathways is essential for developing strategies to prevent and treat HCMV-related disease in these high-risk populations. Full article

Therapy with chimeric antigen receptor (CAR)-T cells has revolutionized the treatment of hematological malignancies. However, their application in solid tumors remains a formidable challenge due to obstacles such as the immunosuppressive tumor microenvironment, tumor heterogeneity, and limited T cell persistence. Although second- and third-generation CAR-T cells have shown restricted efficacy in clinical trials, next-generation strategies—including cytokine-armored CAR-T cells (e.g., IL-15, IL-7/CCL19), logic-gated systems, and localized delivery approaches—demonstrate promising potential to overcome these limitations. This review examines the major barriers impeding CAR-T cell efficacy in solid tumors, evaluates clinical outcomes from conventional CAR constructs, and highlights innovative strategies being tested in recent clinical trials. Key advances discussed include the use of dominant-negative receptors (e.g., TGFβRII) to combat immunosuppression and the co-expression of bispecific T cell engagers (BiTEs) to address antigen escape. Full article

The lung is increasingly recognized as an organ with dual endocrine and respiratory roles, participating in a complex bidirectional crosstalk with systemic hormones and local/paracrine activity. Endocrine and paracrine pathways regulate lung development, ventilation, immunity, and repair, while pulmonary cells express hormone receptors and secrete mediators with both local and systemic effects, defining the concept of the “endocrine lung”. This narrative review summarizes current evidence on the endocrine–pulmonary axis. Thyroid hormones, glucocorticoids, sex steroids, and metabolic hormones (e.g., insulin, leptin, adiponectin) critically influence alveologenesis, surfactant production, ventilatory drive, airway mechanics, and immune responses. Conversely, the lung produces mediators such as serotonin, calcitonin gene-related peptide, endothelin-1, leptin, and keratinocyte growth factor, which regulate vascular tone, alveolar homeostasis, and immune modulation. We also describe the respiratory manifestations of major endocrine diseases, including obstructive sleep apnea and lung volume alterations in acromegaly, immunosuppression and myopathy in Cushing’s syndrome, hypoventilation in hypothyroidism, restrictive “diabetic lung”, and obesity-related phenotypes. In parallel, chronic pulmonary diseases such as chronic obstructive pulmonary disease, interstitial lung disease, and sleep apnea profoundly affect endocrine axes, promoting insulin resistance, hypogonadism, GH/IGF-1 suppression, and bone metabolism alterations. Pulmonary neuroendocrine tumors further highlight the interface, frequently presenting with paraneoplastic endocrine syndromes. Finally, therapeutic interactions are discussed, including the risks of hypothalamic–pituitary–adrenal axis suppression with inhaled corticosteroids, immunotherapy-induced endocrinopathies, and inhaled insulin. Future perspectives emphasize mapping pulmonary hormone networks, endocrine phenotyping of chronic respiratory diseases, and developing hormone-based interventions. Full article

The progression of pancreatic cancer (PC) is significantly influenced by the immune system. In the United States, PC is the third leading cause of cancer-related mortality. The high lethality of PC is attributed to its immunological advantage, which is facilitated by an immunosuppressive microenvironment, a low mutational burden, and minimal T-cell infiltration. Although immunotherapies, such as checkpoint blockades or genetically engineered T cells, have not yet demonstrated viability, there is a growing body of evidence suggesting that innovative combinations of conventional therapies and various procedures may lead to effective immunotherapy in the treatment of PC. This review focuses on the importance of the tumor microenvironment and the promising role of immunotherapies in PC. Full article

Dendritic cells (DCs) are critical antigen-presenting cells that orchestrate the interface between innate and adaptive immunity, making them attractive approaches for cancer immunotherapy. Recent advances in the characterization of DC subsets, antigen delivery strategies, and adjuvant design have enabled the enhancement of DC-based vaccines for solid tumors. Clinical studies across melanoma, glioblastoma, prostate cancer, and non-small cell lung cancer have demonstrated safety and immunogenicity, with encouraging signals of clinical efficacy, particularly when DC vaccination is combined with immune checkpoint blockade or personalized neoantigen approaches. However, translational barriers remain, including the immunosuppressive tumor microenvironment, inefficient DC migration, and variability in manufacturing protocols. Developing solutions such as in vivo DC targeting, biomaterials-based delivery systems, high-resolution single-cell analyses, and artificial intelligence-driven epitope prediction are controlled to overcome these challenges. Together, these innovations highlight the evolving role of DC immunotherapy as a foundation of precision oncology, offering the potential to integrate personalized vaccination strategies into standard treatment paradigms for solid tumors. Therefore, in this review, we specifically focus on these advances in dendritic cell immunotherapy for solid tumors and their translational implications. Full article

Background/Objectives: Cytomegalovirus (CMV) is an opportunistic pathogen, complicating acute severe ulcerative colitis (ASUC), and its role in ASUC prognosis remains a debate. This study aims to report the rates and identify predictors for colectomy at 12 months, following an episode of ASUC with concomitant CMV colonic infection. Methods: This is a retrospective cohort study of patients with ASUC and CMV colonic infection confirmed by PCR or Immunohistochemistry. Baseline clinical, biochemical, endoscopic and disease-related characteristics were recorded. Patients were followed-up for 12 months to calculate the one-year colectomy rate. Predictors of colectomy were identified via multivariate logistic regression. Results: Forty-five cases of CMV colonic infection in 37 patients with ASUC were recorded [66.7% men, mean age: 47.0 years (SD = 18.5)]. At diagnosis, 20% were on monotherapy with advanced treatment and 37.8% on advanced treatment plus corticosteroids and/or immunomodulators. Twenty-three (51.1%) were receiving corticosteroids, while 17.8% did not receive any immunosuppressive agent. Forty (88.9%) patients were treated with ganciclovir and valganciclovir and one (2.2%) with foscarnet for at least 21 days. Eleven patients (24.4%) required colectomy, two (4.4%) during their initial hospitalization and nine (20%) during the follow-up period. The recurrence of CMV was recorded in nine (20.9%) cases, three of which required colectomy. Patients with hemoglobin < 12 g/dL (p = 0.023) and patients on vedolizumab at diagnosis (p = 0.050) had a higher probability of colectomy. Conclusions: We report a 25% one-year colectomy rate in our cohort with ASUC and superimposed CMV colonic infection. At baseline, anemia and vedolizumab treatment were associated with a higher probability of colectomy. Full article

Interleukin-10 (IL-10), a potent anti-inflammatory cytokine, plays a vital role in regulating immune responses across various infectious and inflammatory conditions. While IL-10 is essential for preventing excessive tissue damage and maintaining immune homeostasis (e.g., respiratory syncytial virus), its elevated levels could result in immunosuppression during viral infections, enabling viruses to evade host defenses (e.g., foot-and-mouth disease virus). This review aims to elucidate the mechanisms through which IL-10 mediates immunosuppression in viral infections and to explore the implications of these mechanisms for therapeutic intervention. The key scientific concepts outlined in this review include the mechanisms of IL-10 production and its varied impacts on the immune response during viral infections. Specifically, we discuss the multifaceted inhibitory effects of IL-10 on innate and adaptive immunity, including its implications for antigen presentation, T cells activation, pro-inflammatory cytokine production, immune cell differentiation, trafficking, apoptosis, and co-inhibitory expression related to T cells exhaustion. Finally, we discuss the therapeutic potential of targeting IL-10, such as monoclonal antibodies and small molecule inhibitors, and their potential to restore effective immune responses. By summarizing current knowledge on IL-10’s role in viral infections, this review offers a thorough insight into its immunosuppressive mechanisms and their therapeutic potential, paving the way for innovative treatment strategies in viral diseases. Full article

Cochlioquinones are a member of meroterpenoids possessing a core 6/6/6/6 tetracyclic ring system, which originate from the polyketide-terpenoid hybrid biosynthesis. Up to date, there are eighty-one analogues with diverse post-modifications isolated from different fungi, most of which exhibit different biological activities, such as phytotoxic, antibacterial, cytotoxic, and immunosuppressive effects. Structurally, cochlioquinones can be mainly categorized into two classes: benzoquinone-type and phenol-type cochlioquinones, respectively. In this review, chemistry and biology of cochlioquinones including the structures, NMR and MS features, bioactivities, and biosynthesis from 1968 to 2024 are systematically summarized, which might provide insights into the exploration and utilization of this group of meroterpenoids in the agricultural or pharmaceutical industry. Full article

Within the glioblastoma (GBM) microenvironment, macrophages are widely implicated in immunosuppression. The neuro-oncology community is interested in modulating this immune suppression to improve therapies for GBM, but this approach poses significant challenges. Non-coding RNAs present an attractive target for therapeutic modulation of the immune system, and they are implicated, broadly, in macrophage polarization and the pathophysiology of GBM. Here, we discuss the extant literature on non-coding RNAs and how they impact the polarization of macrophages with particular emphasis on their impact within glioblastoma. We further discuss the clinical relevance of these non-coding RNAs and macrophage polarization to disease progression and associated therapeutic opportunities. Full article

Today, science and medicine are striving to develop novel techniques for treating deadly diseases, including a wide range of cancers. Efforts are being made to better understand the molecular and biochemical mechanisms of tumor cell functioning, but a particular emphasis has recently been given to investigating immune cells residing in the tumor microenvironment, which may lead to revolutionary benefits in the design of new immunotherapies. Among these cells, tumor-associated macrophages (TAMs) are highly abundant and act as critical regulators of ovarian cancer progression, metastasis, and resistance to therapy. Their dual nature—as drivers of malignancy and as potential therapeutic mediators—has positioned them at the forefront of research into next-generation immunotherapies. As therapeutic targets, approaches include blocking macrophage recruitment (e.g., CSF-1/CSF-1R inhibitors), selectively depleting subsets of TAMs (e.g., via Folate Receptor Beta), or reprogramming immunosuppressive M2-like macrophages toward an anti-tumor M1 phenotype. On the other hand, macrophages can also serve as a therapeutic tool—they may be engineered to enhance anti-tumor immunity, as exemplified by the development of Chimeric Antigen Receptor Macrophages (CAR-Ms), or leveraged as delivery vehicles for targeted drug transport into the tumor microenvironment. A particularly innovative strategy involves Macrophage–Drug Conjugates (MDCs), which employs the transfer of iron-binding proteins (TRAIN) mechanism for precise intracellular delivery of therapeutic agents, thereby enhancing drug efficacy while minimizing systemic toxicity. This review integrates current knowledge of TAM biology, highlights emerging therapeutic approaches, and underscores the promise of macrophage-based interventions in ovarian cancer. By integrating macrophage-targeting strategies with advanced immunotherapeutic platforms, novel treatment paradigms may be determined that could substantially improve outcomes for patients with ovarian cancer and other solid tumors. Our work highlights that macrophages should be a particular area of research interest in the context of cancer treatment. Full article

Background/Objectives: Black hairy tongue syndrome (BHT) is characterized by structural epithelial changes and a dark discoloration on the surface of the tongue, causing a variety of symptoms such as xerostomia, altered taste, and nausea. Methods: Herein, we report a 70-year-old female patient with a history of Sjogren’s syndrome, rheumatoid arthritis, and occasional use of intranasal and inhaled corticosteroids, who presented with BHT exacerbated by consumption of colored beverages and carbohydrates. We also provide a review of the literature on published articles reporting cases of BHT syndrome. Results: Our patient’s condition improved after implementing dietary restrictions in combination with local care. A literature review revealed that the most common reported exposures and underlying conditions in patients with BHT were the recent administration of antibiotics, solid organ or hematologic malignancy, immunosuppressants, smoking, corticosteroids, autoimmune conditions, receipt of antidepressants, local radiation therapy, proton pump inhibitors, and alcohol. The majority of cases were successfully managed with the elimination of implicated factors when possible and local hygiene. Conclusions: Different factors may contribute to the development of BHT. Discontinuation of implicated medications together with measures for topical care constitute the most effective ways to achieve resolution. Full article

Background and Clinical Significance: Granulomatous reactions are rare but clinically significant complications of aesthetic procedures involving dermal fillers, particularly in individuals with underlying immune dysregulation. These reactions present diagnostic and therapeutic challenges, especially when associated with undiagnosed or latent autoimmune diseases. This case illustrates the interaction between filler composition, immune status, and the risk of delayed inflammatory responses, underscoring the need for thorough patient evaluation and individualized management strategies. Case Presentation: A 49-year-old woman developed delayed-onset subcutaneous nodules following midface augmentation with two filler types: a monophasic, cross-linked hyaluronic acid gel (concentration 20 mg/mL, 1.0 mL per side) injected into the deep malar fat pads, and a calcium hydroxyapatite suspension (30% CaHA microspheres in a carboxymethylcellulose carrier, 0.5 mL per side) placed in the subdermal plane along the zygomatic arch. The procedure was performed in a single session using a 22 G blunt cannula, with no immediate adverse events. High-resolution ultrasound demonstrated hypoechoic inflammatory nodules without systemic symptoms. A retrospective review of her medical history revealed a latent, previously undisclosed diagnosis of granulomatosis with polyangiitis (GPA). The immune-adjuvant properties of calcium hydroxyapatite likely triggered a localized pro-inflammatory response in this predisposed patient. A conservative, staged, non-invasive therapeutic protocol—saline infiltration, intradermal polynucleotide injections, and manual lymphatic drainage—achieved complete clinical and radiological resolution without systemic immunosuppression or surgical intervention. Conclusions: This case highlights the critical importance of pre-procedural immunological assessment in aesthetic medicine. Subclinical autoimmune conditions may predispose patients to delayed granulomatous reactions after filler injections. An individualized, conservative management strategy can effectively resolve such complications while minimizing the risks associated with aggressive treatment. Greater awareness of immune-mediated responses to dermal fillers is essential to ensure patient safety and optimize clinical outcomes. Full article

Background/Objectives: The interaction between brain-metastasizing melanoma cells and surrounding microglia shapes the immune tumor microenvironment and influences tumor progression. Gene expression analysis revealed that sphingosine-1-phosphate receptor 1 (S1PR1), encoding the S1P1 receptor, is upregulated in microglia upon interaction with melanoma cells. Here, we investigated the functions of S1P1 in microglia and its contribution to melanoma–microglia crosstalk. Methods: We examined the effects of S1P1 inhibition on microglia and four brain-metastasizing human melanoma cell lines in monocultures and co-cultures using the selective S1P1 antagonist NIBR0213 and S1PR1 gene knockdown. Results: We found that melanoma-secreted IL-6 upregulated S1PR1 expression in microglia. S1P1 inhibition increased expression of CD32, CD150, and CD163 in microglia; however, CD150 and CD163 upregulation was abolished in the presence of melanoma cells. S1P1 inhibition downregulated immunosuppressive and anti-inflammatory factors in microglia, including CD274, SOCS3, TGFBR1, TGFBR2, and JunB, promoting a pro-inflammatory phenotype. It also reduced viability of both melanoma and microglia cells, inducing apoptosis in melanoma-associated microglia, possibly via downregulation of CH25H, an upstream regulator of SREBPs. In co-cultures, melanoma cells were more sensitive than microglia to NIBR0213-induced growth arrest. In 3D spheroid cultures, NIBR0213 delayed melanoma–microglia aggregation. Combined treatment with the BRAF inhibitor Vemurafenib and NIBR0213 enhanced Vemurafenib efficacy in three of four melanoma lines. Conclusions: S1P1 contributes to the immunosuppressive phenotype of microglia. Inhibiting the S1P/S1P1 axis impairs viability and crosstalk between melanoma cells and tumor-activated microglia, offering a potential therapeutic strategy for melanoma brain metastases. Full article