Search Results (292)

Cutaneous malignant melanoma is an extraordinarily aggressive and heterogeneous cancer that contains a small subpopulation of tumor stem cells (CSCs) responsible for tumor initiation, metastasis, and recurrence. Identification and characterization of CSCs in melanoma is challenging due to tumor heterogeneity and the lack of specific markers (CD271, ABCB5, ALDH, Nanog) and the ability of cells to dynamically change their phenotype. Phenotype-maintaining signaling pathways (Wnt/β-catenin, Notch, Hedgehog, HIF-1) promote self-renewal, treatment resistance, and epithelial–mesenchymal transitions. Tumor plasticity reflects the ability of differentiated cells to acquire stem-like traits and phenotypic flexibility under stress conditions. The interaction of CSCs with the tumor microenvironment accelerates disease progression: they induce the formation of cancer-associated fibroblasts (CAFs) and neo-angiogenesis, extracellular matrix remodeling, and recruitment of immunosuppressive cells, facilitating immune evasion. Emerging therapeutic strategies include immunotherapy (immune checkpoint inhibitors), epigenetic inhibitors, and nanotechnologies (targeted nanoparticles) for delivery of chemotherapeutic agents. Understanding the role of CSCs and tumor plasticity paves the way for more effective innovative therapies against melanoma. Full article

Protein-losing nephropathy (PLN) involves a heterogeneous group of pathologies leading to selective glomerular damage and development of renal disease. ICGN, the main cause of PLN, requires immunosuppressive treatment. However, the scientific evidence in veterinary medicine on immunosuppressive therapeutic schemes in this condition is limited. The aim of this study is to describe the clinical and paraclinical evolution of five dogs with PLN, presumably associated with ICGN, treated with chlorambucil as immunosuppressive monotherapy. Suspected IGCN was established by the presence of a urine protein–creatinine ratio (UPC) ≥ 3 without response to standard therapy, hypoalbuminemia < 2, or progressive azotemia. Patients were treated with a dosage range of chlorambucil from 0.16 to 0.4 mg/kg (mean 0.25 mg/kg) every 24 h as the sole immunosuppressant. In the end, 4/5 patients showed significant clinical improvement, 3/3 had resolution of the nephrotic syndrome, 5/5 had a sustained decrease in UPC values during follow-up and no relevant adverse effects were observed. In this report, chlorambucil proved to be a well-tolerated and potentially effective monotherapy for immune-mediated PLN in dogs. Full article

Hypomagnesemia is a frequent and often underrecognized electrolyte disturbance with important clinical consequences, especially in hospitalized and critically ill patients. This multifactorial condition arises from impaired intestinal absorption, renal magnesium wasting, and the effects of various medications. Magnesium, the second most abundant intracellular cation, is crucial in enzymatic and physiological processes; its deficiency is associated with neuromuscular, cardiovascular, and metabolic complications. This narrative review focuses on the mechanisms and clinical consequences of drug-induced hypomagnesemia, highlighting the major drug classes involved such as diuretics, antibiotics, antineoplastic agents, and immunosuppressants. Management strategies include magnesium supplementation and adjunctive therapies like amiloride and SGLT2 inhibitors to reduce renal magnesium losses. Recognizing and addressing drug-induced hypomagnesemia is essential to improve patient outcomes and prevent long-term complications. Full article

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by venous and arterial thrombosis and obstetric complications, driven by antiphospholipid antibodies (APLAs). This review synthesizes the latest advancements and current understanding, diagnosis, and treatment of APS. APLAs, including lupus anticoagulant (LAC), anticardiolipin (aCL), and anti-β2-glycoprotein I (aβ2-GPI), interfere with coagulation and endothelial function, as well as with placental health. APS can be primary or secondary; it is often associated with systemic autoimmune diseases like lupus. The pathogenesis of APS remains only partially understood. APLAs promote thrombosis through endothelial damage, platelet activation, and inflammatory signaling pathways. Laboratory diagnosis relies on persistent positivity for APLAs and LAC through tests like ELISA and clotting assays, following a three-step confirmation process. New integrated test systems have been introduced to improve standardization. Classification criteria have evolved, with the 2023 EULAR-ACR criteria providing a weighted, domain-based scoring system, enhancing diagnostic precision. Catastrophic APS (CAPS) is a severe, rare manifestation of APS, characterized by multi-organ failure due to rapid, widespread microthrombosis and systemic inflammation, which requires urgent anticoagulation. Seronegative APS is proposed for patients with clinical features of APS but negative standard antibody tests, possibly due to non-criteria antibodies or transient immunosuppression. Treatment primarily involves long-term anticoagulation with vitamin K antagonists; direct oral anticoagulants are generally not recommended. APS diagnosis and management remain complex due to clinical heterogeneity and laboratory challenges. Continued refinement of diagnostic tools and criteria is essential for improving outcomes in this life-threatening condition. Full article

Background and Clinical Significance: Antisynthetase syndrome (ASyS) is a rare autoimmune entity defined by the presence of anti-aminoacyl-t ribonucleic acid (RNA) synthetase autoantibodies and classically associated with a triad of interstitial lung disease (ILD), inflammatory myopathy, and arthritis. Additional clinical features may include Raynaud’s phenomenon and “mechanic’s hands”. Among antisynthetase antibodies, anti-PL-12 is notably associated with predominant or isolated ILD and may occur in the absence of clinically evident myositis, thereby complicating timely diagnosis. Case Presentation: We are presenting a 45-year-old non-smoking female patient with a prior diagnosis of seronegative rheumatoid arthritis (RA) who developed progressive dyspnea, dry cough, and sicca symptoms. High-resolution computed tomography revealed a nonspecific interstitial pneumonia (NSIP) pattern. Despite normal creatine kinase and lactate dehydrogenase levels, serological work-up revealed positive anti-PL-12 and anti-Ro52 antibodies, supporting a diagnosis of antisynthetase syndrome without myositis, fulfilling the diagnostic criteria for ASyS per Connors and Solomon. Treatment with corticosteroids and cyclophosphamide induced clinical and functional respiratory improvement, while azathioprine was initiated for maintenance. Conclusions: This case underscores the clinical heterogeneity of antisynthetase syndrome and highlights the diagnostic challenge posed by anti-PL-12–associated ILD in the absence of myositis. Importantly, it demonstrates that in patients with pre-existing rheumatologic diagnoses, the emergence of atypical pulmonary manifestations warrants repeat serologic evaluation to assess ASyS and other autoimmune conditions. Early diagnosis and immunosuppressive treatment are essential to optimize outcomes. Full article

Individuals with immunosuppressive conditions are at a higher risk of developing malignancies than those in the general population. Immunosuppression weakens tumor immunity, hinders the detection of pro-oncogenic cells, and activates oncogenic viruses. Malignancies arising in immunosuppressed patients tend to be aggressive, have a high incidence of virus-associated cancers, and are reversible in some cases. Notably, immunosuppressive agents influence the frequency and type of malignancies, as well as their clinicopathological features. Organ transplant recipients receive long-term immunosuppressants to prevent acute rejection. Post-transplant malignancies vary depending on the type of drug administered before the onset of these diseases. Patients with rheumatoid arthritis (RA) are treated with long-term immunosuppressive medications, such as methotrexate (MTX). MTX is widely recognized as being associated with a specific type of lymphoproliferative disorder (LPD), known as MTX-associated LPD. Our recent report indicated that the clinicopathological features of rheumatoid arthritis-associated lymphoproliferative disorder (RA-LPD) also vary based on the other anti-RA agents used, such as tacrolimus and tumor necrosis factor inhibitors. Therefore, the clinicopathological characteristics of post-transplant LPD and RA-LPD evolve alongside the changes in the immunosuppressants/immunomodulators administered. Understanding the various characteristics and time trends of immunosuppressive neoplasms, particularly LPDs, in relation to different immunosuppressant/immunomodulator medications is highly valuable in clinical practice. Full article

Inhaled corticosteroids (ICSs) are widely used to manage chronic respiratory conditions such as asthma, chronic obstructive pulmonary disease (COPD), and human immunodeficiency virus (HIV). However, prolonged use of ICS is associated with the development of oropharyngeal candidiasis, a fungal infection primarily caused by Candida albicans, due to local immunosuppression in the oral cavity. The incidence of oropharyngeal candidiasis varies depending on geographic region, patient age, and comorbidities, with immunocompromised individuals, those with diabetes, and the elderly being particularly vulnerable. Key risk factors include high ICS doses, poor oral hygiene, and improper use of inhalers. Prevention is the cornerstone of managing oropharyngeal candidiasis associated with the chronic use of inhaled corticosteroids. Patient education on proper inhaler technique and oral hygiene is essential to reduce the risk of fungal overgrowth in the oral cavity. Additional preventive strategies include the use of spacers, mouth rinsing after inhalation, and proper denture care. In cases where these measures fail to prevent the infection, prompt detection and early intervention are crucial to prevent progression or recurrence. This narrative review aims to analyze the most effective prophylactic measures to prevent oropharyngeal candidiasis associated with the chronic use of inhaled corticosteroids, emphasizing patient education, oral hygiene, and proper use of inhalation devices. Full article

Macrophages are a heterogenous population of cells that adopt specific phenotypes in response to signals from their dynamic microenvironment. Apart from being key players in innate immunity and in the maintenance of tissue homeostasis, macrophages are also important drivers of low-grade inflammation, which is associated with different chronic conditions including stress and cancer. The activation of macrophages during chronic stress and cancer results in their multifaceted pathogenic roles. Macrophages residing in the tumor microenvironment are commonly known as tumor-associated macrophages and favor or inhibit tumor growth depending on the microenvironmental cues and their activation state. Activated macrophages display a continuum of properties rather than a distinct proinflammatory or anti-inflammatory dichotomy. Emerging evidence suggests that prolonged tissue residency restricts the plasticity of macrophages, while recruited monocytes are more plastic and their differentiation into tumor-associated macrophages during stress can result in a dual imprinting from both the existing stress-induced inflammation and the tumor microenvironment. In addition, the immunomodulation of the tumor microenvironment and reprogramming of tumor-associated macrophages toward the anti-tumor phenotypes have emerged as promising therapeutic approaches. In this review, we will focus on how the persistent inflammatory state underlying chronic stress affects macrophages as well as the macrophages’ contribution to various aspects of tumor growth and progression, highlighting a therapeutic potential of modulation of the macrophage-mediated immunosuppressive tumor microenvironment. Full article

Background: TNBC patients respond poorly to chemotherapy, leading to high mortality rates and a worsening prognosis. Here, we investigated the effect of M-I on TNBC tumor growth suppression and its potential mechanisms. Methods: Signaling pathways were analyzed to study the effect of M-I on TNBC cells (human MDA-MB-231 and mouse 4T1). We used orthotopic mouse models to examine the anti-tumor efficacy of M-I. Tumor volume and the status of tumor-associated macrophages (TAMs) were assessed by qRT-PCR or FACS analysis. Results: We found a significant dose- and time-dependent inhibition of TNBC cell proliferation following treatment with M-I. Cell cycle analysis revealed a shortened S phase in M-I-treated cells and downregulation of AURKA, PLK1, CDC25c, CDK1, and cyclinB1. Furthermore, M-I treatment reduced the expression of pSTAT3, cyclinD1, and c-Myc in TNBC cells. To evaluate the anti-tumor efficacy of M-I, we employed orthotopic TNBC mouse models and observed a significant reduction in tumor growth without measurable toxicity. Next, we analyzed RNA from control and M-I-treated tumors to further assess the status of TAMs and observed a significant decrease in M2-like macrophages in the M-I-treated group. Immortalized bone marrow-derived mouse macrophages (iMacs) exposed to conditioned media (CM) of TNBC cells with or without M-I treatment indicated that the M-I treated CM of TNBC cells significantly reduce the M2phenotype in iMacs. Mechanistically, we found that M-I specifically targets the IL-4/MAPK signaling axis to reduce immunosuppressive M2 macrophage polarization. Conclusions: Our study reveals a novel mechanism by which M-I inhibits TNBC cell proliferation by regulating intracellular signaling and altering TAMs in the tumor microenvironment and highlights its potential as a promising candidate for TNBC therapy. Full article

Background/Objectives: Tuberculous meningitis is the most severe form of tuberculosis in children, with a high mortality and morbidity rate if it is not diagnosed and treated in a timely manner. The aim of this study is to highlight the challenges associated with establishing a diagnosis of tuberculous meningitis in a child with immunosuppression, given the presence of nonspecific clinical manifestations. Methods: We present the case of a 15-year-old adolescent with systemic lupus erythematosus, on immunosuppressive therapy, who is diagnosed with tuberculous meningoencephalitis presenting the clinical, diagnostic and imaging characteristics, as well as the diagnostic traps and limitations associated with this condition. Antituberculosis therapy was started empirically, because there was no improvement in the clinical status with conventional antibiotic therapy; the diagnosis was established 7 days after the start of the antituberculosis treatment, with the help of an acid-fast bacilli culture from the cerebrospinal fluid. Results: The course of the tuberculous meningoencephalitis was slowly favorable, despite the superimposed COVID-19 infection. Delay in administering immunosuppressive therapy led to the onset of renal and joint manifestations. Conclusions: Tuberculous meningitis is a highly lethal, often underdiagnosed disease with nonspecific clinical and imaging manifestations, which can have a favorable outcome if the diagnosis is established early on and treatment is started promptly. Full article

Glioblastoma is a highly aggressive brain tumor with an overall poor prognosis due to its immunosuppressive tumor microenvironment (TME). Microglia and tumor-associated macrophages (TAMs) with pro-tumorigenic properties are dominant populations of immune cells in the glioblastoma TME. To date, several studies targeting TAMs to fight tumor progression in different tumor entities have been initiated. However, the impact of standard therapy schemes of glioblastoma cells on macrophage polarization, activation, and phagocytosis remains controversial. The same applies to the relevance of PD-1/PD-L1 blockade in the interaction between macrophages and tumor cells. Our study, therefore, investigated patient-oriented treatment of GLIOBLASTOMA by examining the phagocytic capacity of polarized M1- and M2-like macrophages using GL261-luc2 tumor cells as a preclinical model system. Additionally, we analyzed the expression of activation and immune checkpoint markers on these macrophage subtypes following contact with tumor cells and their microenvironment. These factors were also determined after PD-1 blockade was initiated. The analyses revealed that the immunoregulatory M2-like macrophages generally exhibited a higher phagocytosis rate than the pro-inflammatory M1-like macrophages; however, this was not influenced by the pretreatment of glioblastoma cells with chemo- or radiotherapy. This could not be improved by blocking the PD-1 receptor. Furthermore, there were no modulations in the expression of differentiation, activation, or immune checkpoint molecules of M1- and M2-like macrophages after cell-to-cell contact with glioblastoma cells. But the medium conditioned by tumor cells strongly altered M1-like macrophages toward a more activated state, whereas M2-like cells were only mildly influenced. This was further enhanced by tumor cell treatment, with the most prominent effect after irradiation. These results suggest that conventional GLIOBLASTOMA tumor cell treatment affects the immunogenic status of macrophage subtypes, which is relevant for enhancing the anti-tumor immune response in brain tumors. Full article

The tumor microenvironment (TME) is crucial for the onset, development, and resistance to treatment of lung cancer. The tumor microenvironment consisting of a complex array of immune cells, fibroblasts, endothelial cells, extracellular matrix elements, and signaling molecules, facilitates tumor growth and spread while inhibiting the body’s antitumor immune response. In lung cancer, tumor-associated macrophages, cancer-associated fibroblasts, mast cells, and dendritic cells interact through cytokines, chemokines, growth factors, and matrix metalloproteinases to create an immunosuppressive and proangiogenic milieu. Hypoxic conditions within the TME further enhance cancer cell adaptability through hypoxia-inducible factors (HIFs), promoting epithelial–mesenchymal transition, immune evasion, and metastasis. Moreover, miRNAs have emerged as key regulators of gene expression within the TME, offering novel insights into tumor behavior and potential therapeutic targets. Targeting dynamic interactions within the TME, particularly through the modulation of immune responses, angiogenesis, and stromal remodeling, offers promising avenues for precision pharmacological approaches. This review covers the current understanding of the lung TME, highlighting its impact on cancer pathophysiology and treatment strategies. Understanding and therapeutically reprogramming the TME may pave the way for personalized and more effective interventions for lung cancer treatment. Full article

Background: Ulcerative colitis (UC) is a chronic inflammatory condition associated with the colon and rectum, often predisposing individuals to inflammatory bowel disease-related colorectal cancer (IBD-CRC). Current therapeutic options for UC, including corticosteroids and immunosuppressive drugs, pose significant side effects. Punica granatum peel powder (PPPG), a traditional herbal remedy in Ayurveda medicine for colitis, exhibits promising therapeutic effects with a favorable safety profile. Objectives: This study aims to explore the therapeutic potential and mechanism of action of a modified PPPG formulation in UC treatment. Methods: Using NCM460 cells and an acetic acid-induced UC murine model, the efficacy of modified PPPG was evaluated. Results: Therapy with modified PPPG significantly improved UC-associated symptoms, such as improvements in body weight, colon length, and disease activity index, as validated by histological examination. Transcriptomic sequencing identified downregulation of the IL-6/STAT3 signaling pathway and reduced inflammatory markers like p-NF-κB, IL-1β, and NLRP3 on PPPG therapy. Conclusions: These findings suggest that modified PPPG holds promise as a novel therapeutic strategy for UC intervention, targeting key inflammatory pathways implicated in UC pathogenesis and potentially mitigating the risk of IBD-CRC. Full article

Background/Objectives: The SARS-CoV-2 pandemic challenged patients with inflammatory bowel disease (IBD) under immunosuppressive therapies. We used data from the RisCoin cohort to investigate factors associated with a poor immune response to mRNA vaccination in these patients. Methods: From 4115 RisCoin participants, we matched 110 IBD patients by age and time interval since the second mRNA vaccination with 306 healthcare workers (HCW) without comorbidities (HCW-healthy) and 292 with medical conditions (HCW-plus); all were SARS-CoV-2 infection naïve. Basic questionnaires collected data on medication, COVID-19 vaccinations and side-effects, dietary patterns, lifestyle factors, and self-perceived stress. Main outcomes included anti-spike immunoglobulin levels and antibody-mediated live-virus neutralization immunity (NT) to the Omicron BA.1 variant (threshold NT ≥ 10 defined as IC50 values ≥1:10 serum dilution) after the second (baseline) and third vaccinations. Results: At baseline, IBD patients treated with anti-TNF but not those under vedolizumab or ustekinumab therapy had lower anti-spike levels compared to HCW-healthy and HCW-plus (166 versus 1384 and 1258 BAU/mL, respectively; p < 0.0001). Anti-TNF compared to vedolizumab/ustekinumab-treated patients reached NT titers above threshold in 17% versus 64%, respectively, and HCW-subgroups in 73% and 79% (all p < 0.0001). Current smokers showed a four to five times increased risk for non-neutralizing immunity compared to non-smokers. After the third vaccination, NT titers did not reach threshold in 15% anti-TNF compared to 5% vedolizumab/ustekinumab-treated patients and none of HCW (p < 0.01). Patients with IBD reported fewer clinical symptoms after vaccination. Perceived stress was not increased. Conclusions: Our findings support individualized schedules for mRNA-based vaccines in IBD patients with different immunosuppressive therapies and enforcement of non-smoking. Full article

Background/Objectives: Autoimmune inner ear disease (AIED) causes sensorineural hearing loss that classically presents as fluctuating, asymmetric loss of hearing. Associated vestibular and other ear symptoms can be present in many patients. First-line treatment of AIED is high-dose corticosteroids. AIED can present either as a primary condition limited to ear involvement or secondary, as part of an underlying systemic autoimmune rheumatic disease, the most common of which include vasculitis and relapsing polychondritis. We described our cohort of primary AIED, including demographics, treatment, and outcomes. We excluded from this review sensorineural hearing loss in the context of vasculitis and relapsing polychondritis. Methods: We performed a chart review of patients with the diagnosis of AIED at Mayo Clinic and compared the cohort by sex. Results: Thirty-one patients met the inclusion criteria. The mean age was 48.5 years, and 17 were men. Patients were initially evaluated at the Department of Otorhinolaryngology or Internal Medicine, and 29 patients were subsequently referred to the Department of Rheumatology, with a mean of 12.2 weeks after the first evaluation. Treatment with corticosteroids showed improvement in hearing and vestibular symptoms during the first month but no further improvement by the end of the third month. Other immunosuppressive medications were used with various degrees of response. Methotrexate was the second most used therapy, with 11 of 17 patients reporting an improvement in symptoms. Conclusions: Corticosteroid therapy is an effective initial treatment for AIED and should be followed with corticosteroid-sparing agents to prevent further damage to the cochlea. Full article