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BACKGROUND/OBJECTIVES: The phase 3 REGAIN study and its open-label extension demonstrated the efficacy of the complement C5 inhibitor eculizumab in patients with treatment-refractory, acetylcholine receptor antibody-positive generalized myasthenia gravis (gMG). The aim of the ELEVATE study was to assess the effectiveness of eculizumab in clinical practice in adults with MG in the United States. METHODS: A retrospective chart review was conducted in adults with MG who initiated eculizumab treatment between October 23, 2017 and December 31, 2019. Outcomes assessed before and during eculizumab treatment using a pre- versus post-treatment study design included Myasthenia Gravis-Activities of Daily Living (MG-ADL) total scores; minimal symptom expression (MSE); physician impression of clinical change; minimal manifestation status (MMS); and concomitant medication use. RESULTS: In total, 119 patients were included in the study. A significant reduction was observed in mean MG-ADL total score, from 8.0 before eculizumab initiation to 5.4 at 3 months and to 4.7 at 24 months after eculizumab initiation (both p

Immune checkpoint blockade (ICB) with PD-1/PD-L1 inhibition has revolutionized the treatment of non-small cell lung cancer (NSCLC). Durable responses, however, are observed only in a subpopulation of patients. Defective antigen presentation and an immunosuppressive tumor microenvironment (TME) can lead to deficient T cell recruitment and ICB resistance. We evaluate intratumoral (IT) vaccination with CXCL9- and CXCL10-engineered dendritic cells (CXCL9/10-DC) as a strategy to overcome resistance. IT CXCL9/10-DC leads to enhanced T cell infiltration and activation in the TME and tumor inhibition in murine NSCLC models. The antitumor efficacy of IT CXCL9/10-DC is dependent on CD4+ and CD8+ T cells, as well as CXCR3-dependent T cell trafficking from the lymph node. IT CXCL9/10-DC, in combination with ICB, overcomes resistance and establishes systemic tumor-specific immunity in murine models. These studies provide a mechanistic understanding of CXCL9/10-DC-mediated host immune activation and support clinical translation of IT CXCL9/10-DC to augment ICB efficacy in NSCLC.

Aim: To investigate the association between physical activity and immunogenicity among SARS-CoV-2 seropositive patients with autoimmune rheumatic diseases prior to and following a 2-dose schedule of CoronaVac (Sinovac inactivated vaccine). Methods: This was a prospective cohort study within an open-label, single-arm, phase 4 vaccination trial conducted in Sao Paulo, Brazil. In this substudy, only SARS-CoV-2 seropositive patients were included. Immunogenicity was assessed by seroconversion rates of total anti-SARS-CoV-2 S1/S2 immunoglobulin G (IgG), geometric mean titers of anti-S1/S2 IgG, frequency of positive neutralizing antibodies, and neutralizing activity before and after vaccination. Physical activity was assessed through a questionnaire. Model-based analyses were performed controlling for age (<60 or ≥60 y), sex, body mass index (<25, 25–30, and >30 kg/m2), and use of prednisone, immunosuppressants, and biologics. Results: A total of 180 seropositive autoimmune rheumatic disease patients were included. There was no association between physical activity and immunogenicity before and after vaccination. Conclusions: This study suggests that the positive association between physical activity and greater antibody responses seen in immunocompromised individuals following vaccination is overridden by previous SARS-CoV-2 infection, and does not extend to natural immunity. [ABSTRACT FROM AUTHOR]

Electronic cigarettes (e-cigarettes) are thought to pose low risk of cancer because the components of e-cigarette liquid are not carcinogens. We analyzed the effects of the two major components, PG/VG and nicotine, on tumor development in preclinical models. We found that PG/VG promoted tumor cell migration in migration assays and contributed to more aggressive, metastatic, and immunosuppressive tumors in vivo, aggravated by the presence of nicotine. Whole body exposure of mice to PG/VG and nicotine rendered animals more susceptible to developing tumors with high frequencies of infiltrating proinflammatory macrophages expressing IL-6 and TNFα. Moreover, tumor-infiltrating and circulating T cells in e-cigarette exposed mice showed increased levels of immune checkpoints including CTLA4 and PD-1. Treatment with anti-CTLA4 antibody was able to abrogate metastasis with no detrimental effects on its ability to induce tumor regression in exposed mice. These findings suggest that the major components used in e-cigarette fluid can impact tumor development through induced immunosuppression.

Background: Long‐term renal function and survival after kidney transplantation rely on appropriate immunosuppressive treatment to prevent the risk of rejection. New biomarkers are needed to accurately assess the degree of immunosuppression in renal transplant recipients in order to avoid organ rejection and the development of opportunistic infections. Highly prevalent in humans, torque teno virus (TTV), which belongs to the family Anelloviridae, is a small, nonenveloped, single‐stranded DNA virus which has not been linked with any specific human illness, but which constitutes a major component of the human virome. Host antiviral responses allow TTV levels to be controlled; however, viral persistence remains, explaining the high prevalence in human populations, including healthy individuals. Important confounders of TTV load include time since transplantation, age, gender, obesity, and smoking status. Aims: TTV‐based guidance of immunosuppressive drug dosing could help with risk stratification, reducing the risk of infection, graft rejection and oncologic disease on an individual level, enabling long‐term patient and graft survival. Methods: Original studies were accessed by a systematic search from electronic databases including PubMed, ScienceDirect and Wiley Online Library. Results: The presented data mainly derive from adult transplant recipients showing an association between TTV plasma levels and the immune status of the host: High‐TTV load and high immunosuppression are associated with a risk of infection, and low‐TTV load and low immunosuppression indicate a risk of rejection. However, there is minimal information on pediatric transplant recipients with further research required in this cohort. To date, it has been demonstrated that longer posttransplant times are significantly associated with lower TTV levels in children with renal transplant. Meanwhile, an association between lower TTV loads and increased risk of graft reject during the first year of transplantation was also reported. More recently, Eibensteiner et al. revealed a robust, independent association between TTV plasma load and the onset of Cytomegalovirus and BK virus infections. Conclusion: Data from randomized controlled trials are still missing, even in adults, but a multicenter randomized controlled trial for TTV‐guided immunosuppression in adult kidney recipients (TTVguideIT) began in 2022. There is, therefore, great promise for TTV levels to be used as a biomarker that could potentially improve both graft and patient survival in transplantation. [ABSTRACT FROM AUTHOR]

Objective: This review sought to answer the following research question: What are the characteristics of pediatric necrotizing otitis externa (NOE)? Moreover, we wanted to highlight the clinical importance of the current limitations in the literature. Methods: A scoping review was performed to determine what is known about NOE in the pediatric population. Four databases (COCHRANE Library, CINAHL, PubMed, and Scopus) were queried for articles published in English between 1976 to 2022. Variables extracted included comorbidities, demographics, outcomes, and treatment. Results: A total of 20 studies (N = 439) reported sufficient measures to be included in the review. Patients with NOE had a mean age of 10.0 years (range 2 months to 14 years) with a male-to-female gender ratio of 1.1:1. Mean length of hospital stay was 2.9 days (95%CI: 2.7-3.0). Demographics included 45.4% Caucasian, 6.0% African American, and 2.7% Asian/Pacific Islander. Less than 5% of patients had diabetes, while other reported comorbidities included neutropenia (n = 6), anemia (n = 5), dehydration/malnutrition (n = 4), Stevens Johnson Syndrome (n = 2), some form of immunosuppression/organ transplantation (n = 2), thrombocytopenia (n = 2), and leukopenia (n = 2). There have been no reported deaths from NOE in children. Conclusions: In the adult population NOE most commonly affects patients with diabetes, but our review reveals that diabetes does not appear to play as big a role in children. The disease seems to commonly affect patients with immunosuppression or severe health conditions. Complications such as cranial nerve palsies appear to be more common in the pediatric population. Specifically, the role of biopsy and culture in the treatment of pediatric NOE is stressed as they are important in treatment decisions. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy, as an emerging cancer treatment approach, harnesses the patient's own immune system to effectively prevent tumor recurrence or metastasis. However, its clinical application has been significantly hindered by relatively low immune response rates. In recent years, metal-based biomaterials have been extensively studied as effective immunomodulators and potential tools for enhancing anti-tumor immune responses, enabling the reversal of immune suppression without inducing toxic side effects. This review introduces the classification of bioactive metal elements and summarizes their immune regulatory mechanisms. In addition, we discuss the immunomodulatory roles of biomaterials constructed from various metals, including aluminum, manganese, gold, calcium, zinc, iron, magnesium, and copper. More importantly, a systematic overview of their applications in enhancing immunotherapy is provided. Finally, the prospects and challenges of metal-based biomaterials with immunomodulatory functions in cancer immunotherapy are outlined. Cancer immunotherapy, as an emerging cancer treatment approach, harnesses the patient's own immune system to effectively prevent tumor recurrence or metastasis. However, its clinical application has been significantly hindered by relatively low immune response rates. In recent years, metal-based biomaterials have been extensively studied as effective immunomodulators and potential tools for enhancing anti-tumor immune responses, enabling the reversal of immune suppression without inducing toxic side effects. This review introduces the classification of bioactive metal elements and summarizes their immune regulatory mechanisms. In addition, we discuss the immunomodulatory roles of biomaterials constructed from various metals, including aluminum, manganese, gold, calcium, zinc, iron, magnesium, and copper. More importantly, a systematic overview of their applications in enhancing immunotherapy is provided. Finally, the prospects and challenges of metal-based biomaterials with immunomodulatory functions in cancer immunotherapy are outlined. [Display omitted] [ABSTRACT FROM AUTHOR]

Exposure to temperatures outside of a fish's optimal range results in suppression of the immune system, ultimately leaving aquaculture stocks susceptible to disease outbreaks. This effect is exacerbated in triploid fishes, which demonstrate greater susceptibility to stress than their diploid counterparts. This study investigates the impacts of acute heat stress on the abundance of immune transcripts and proteins in diploid and triploid Chinook salmon (Oncorhynchus tshawytscha), an important finfish crop. This study also demonstrates that acute heat stress induces significant increases in the abundance hsp70, hsp90 and il1b transcripts in the head kidneys, gills and heart ventricles of both diploid and triploid Chinook salmon. Widespread dysregulation of antigen‐presentation transcripts was also observed in fish of both ploidies. These results suggest that acute heat stress activates acute‐phase responses in Chinook salmon and dysregulates antigen presentation, potentially leaving fish more susceptible to infection. At the protein level, IL‐1β was differentially expressed in the head kidney and ventricles of diploid and triploid salmon following heat shock. Differential expression of two tapasin‐like proteins in diploid and triploid salmon subjected to heat shock was also observed. Altogether, these data indicate that diploid and triploid Chinook salmon respond differently to acute thermal stressors. [ABSTRACT FROM AUTHOR]

Immunosuppression after solid organ transplantation is associated with an increased risk of keratinocyte carcinoma (KC). Despite its established morbidity, KC risk in liver transplant (LT) recipients is understudied, including the contribution of immunosuppression regimen and latitude. A retrospective cohort of 9,966 adult first LT alone recipients alive with their native allograft at 1-year post-LT without prior KC between 2007 and 2016 were identified using linked data from the Organ Procurement and Transplantation Network and Medicare administrative claims. The primary exposures were immunosuppression regimen and latitude of residence. The primary outcome was incident, de novo KC occurring at least 1-year after LT. Adjusted Cox regression analysis stratified by transplant center was used in all analyses. The cohort was 63.4% male, 70.2% White and with median age 61 years (interquartile range, IQR, 54–66) at transplant. Calcineurin inhibitor (CNI) with anti-metabolite combination was independently associated with incident KC when measured as intention-to-treat (adjusted hazard ratio (aHR) 1.21 vs. CNI monotherapy, 95% CI 1.02–1.43, p = 0.026), in a time-updating as-treated analysis (aHR 1.61, 95% CI 1.34–1.93; p < 0.001) and when measured as cumulative exposure (aHR 1.13 per 6-month increase, 95% CI: 1.02–1.33; p = 0.027). More southern latitude of residence was also independently associated with incident KC with an aHR of 1.26 per 5°N decrease towards the Equator (95% CI: 1.08–1.47, p = 0.003). We demonstrate independent effects of CNI with antiM immunosuppression regimen and latitude of residence on the risk of post-LT KC, which will better inform screening practices and immunosuppression management. [ABSTRACT FROM AUTHOR]

To look for the spectrum of infections and the factors predisposing to infection in patients with systemic sclerosis (SSc). In this retrospective study, demographic, clinical features, details of infections, immunosuppressive therapy, and outcomes of patients with SSc attending clinics at department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India from 1990 to 2022 were captured. Multivariable-adjusted logistic regression was applied to identify independent predictors of infection. Data of 880 patients, mean age 35.5 ± 12 years, and female: male ratio 7.7:1, were analyzed. One hundred and fifty-three patients had at least 1 infection with a total of 233 infectious episodes. Infections were most common in lung followed by skin and soft tissue. Tuberculosis was diagnosed in 45 patients (29.4%). Klebsiella was the commonest non-tubercular organism in lung and Escherichia coli in urinary tract infections. In comparison to matched control group, patients with infection had a greater number of admissions due to active disease, odds ratio (OR) 6.27 (CI 3.23–12.18), were receiving immunosuppressive medication OR, 5.05 (CI 2.55–10.00), and had more digital ulcers OR, 2.53 (CI 1.17–5.45). Patients who had infection had more likelihood for death OR, 13.63 (CI 4.75 -39.18). Tuberculosis is the commonest infection and lung remains the major site of infection in patients with SSc. Number of hospital admissions, digital ulcers and immunosuppressive therapy are predictors of serious infection in patients with SSc. Patients with infections had more likelihood of death. [ABSTRACT FROM AUTHOR]

Ultraviolet B narrow band (UVB-NB) phototherapy is the gold standard treatment for vitiligo, primarily due to its immunomodulatory effects. Additionally, it may influence circadian melatonin balance, that may indirectly induce sleep regulation, which in turn could potentially contribute to vitiligo improvement. The association between melatonin, vitiligo and phototherapy has been little investigated. The aim of this study was to evaluate the current evidence regarding the effects of circadian melatonin regulation and sleep, particularly during vitiligo treatment with phototherapy. We undertook a narrative review to synthetize the evidence on this association through the MEDLINE/PubMed database, using combined search terms: melatonin, vitiligo, phototherapy, and circadian rhythm (sleep). A total of 56 articles were included. There are few studies on this relationship, and conflicting findings. Some studies have suggested that UV exposure and phototherapy might benefit vitiligo by stimulating melanocytes, which have melatonin receptors, and this could potentially synchronize the circadian regulation of melatonin. This improved melatonin balance could result in better sleep quality further enhancing the antiinflammatory properties of melatonin and contributing to vitiligo improvement. Less is known about the possible effects of the use of topical melatonin, with or without phototherapy, to treat vitiligo lesions. In conclusion, there is some evidence that circadian melatonin regulation plays an important role in the course of vitiligo, both through sleep regulation and its anti-inflammatory properties. The evidence suggests that the systemic and physiological properties of melatonin, especially its circadian behavior regulated by phototherapy, may be more effective in respect of vitiligo improvement than the use of topical melatonin. However, the effects of the oral intake of melatonin are less clear. Phototherapy, as a potential modulator of circadian melatonin rhythm, that influences sleep and clinical improvement of vitiligo, needs further examination, as does the use of melatonin as an adjuvant treatment to UVB phototherapy in vitiligo. [ABSTRACT FROM AUTHOR]

An editorial is presented that discusses the significance of timely diagnosis and treatment for anti-factor H antibody-associated aHUS, highlighting the effectiveness of eculizumab and the need for standardization in anti-FH antibody testing. It notes that while some studies advocate for its use as a primary treatment, further multicenter research is necessary to refine management strategies and establish effective treatment protocols.

A 14-year-old patient presents with hematuria and proteinuria. Clinical evaluation reveals a positive anti-nuclear antibody titer, positive anti-double stranded DNA antibody and hypocomplementemia. Systemic lupus erythematosus (SLE) is diagnosed based on the 2019 EULAR/ACR (European League Against Rheumatism/American College of Rheumatology) classification criteria (Aringer et al. Arthritis Rheumatol 71:1400–1412, 2019). A kidney biopsy is performed that confirms the presence of immune complex glomerulonephritis, ISN-RPS (International Society of Nephrology/Renal Pathology Society) class IV (Bajema et al. Kidney Int 93:789–796, 2018). According to the latest clinical practice guidelines (Rovin et al. Kidney Int 100:753–779, 2021; Fanouriakis et al. Ann Rheum Dis 83:15–29, 2023), there are alternatives to treating this patient with cyclophosphamide. But what if this patient also presented with oliguria and volume overload requiring intensive care and dialysis? What if this patient also presented with altered mental status and seizures, and was diagnosed with neuropsychiatric lupus? What if this patient was also diagnosed with a pulmonary hemorrhage and respiratory failure? The clinical practice guidelines do not address these scenarios that are not uncommon in patients with SLE. Moreover, in some countries worldwide, patients do not have the privilege of access to biologics or more expensive alternatives. The purpose of this review is to evaluate the contemporary options for initial treatment of nephritis in patients with SLE. [ABSTRACT FROM AUTHOR]

Radiation therapy (RT) initiates a local and systemic immune response which can induce antitumor immunity and improve immunotherapy efficacy. Neutrophils are among the first immune cells that infiltrate tumors after RT and are suggested to be essential for the initial antitumor immune response. However, neutrophils in tumors are associated with poor outcomes and RT-induced neutrophil infiltration could also change the composition of the tumor microenvironment (TME) in favor of tumor progression. To improve RT efficacy for patients with cancer it is important to understand the interplay between RT and neutrophils. Here, we review the literature on how RT affects the infiltration and function of neutrophils in the TME of solid tumors, using both patients studies and preclinical murine in vivo models. In general, it was found that neutrophil levels increase and reach maximal levels in the first days after RT and can remain elevated up to 3 weeks. Most studies report an immunosuppressive role of neutrophils in the TME after RT, caused by upregulated expression of neutrophil indoleamine 2,3-dioxygenase 1 and arginase 1, as well as neutrophil extracellular trap formation. RT was also associated with increased reactive oxygen species production by neutrophils, which can both improve and inhibit antitumor immunity. In addition, multiple murine models showed improved RT efficacy when depleting neutrophils, suggesting that neutrophils have a protumor phenotype after RT. We conclude that the role of neutrophils should not be overlooked when developing RT strategies and requires further investigation in specific tumor types. In addition, neutrophils can possibly be exploited to enhance RT efficacy by combining RT with neutrophil-targeting therapies. [ABSTRACT FROM AUTHOR]

A 15-y-old captive-born female bottlenose dolphin (Tursiops truncatus) had slowly progressive lethargy, inappetence, and pallor of the oral mucosa. Serial hemograms and serum biochemistry analysis revealed hemolyzed plasma, gradually severe anemia with reticulocytosis, spherocytosis, pronounced neutrophilia with left shift and toxic change, and indirect hyperbilirubinemia. Urinalysis identified both hemoglobinuria and bilirubinuria. Hyperglobulinemia with polyclonal gammopathy was evident by protein electrophoresis, and the saline agglutination test was positive. Splenomegaly and hyperechogenic liver were also observed on ultrasound. These findings meet the diagnostic criteria established for immune-mediated hemolytic anemia (IMHA) in small animals, which is extremely rare in cetacean species, and, to our knowledge, has not been fully documented. Several potential triggers of a secondary IMHA were ruled out, including the most common cetacean virus, exposure to new drugs, and recent vaccination events. Following recommendations from companion animal medicine, immunosuppressive therapy was implemented and proved effective in this bottlenose dolphin; the CBC returned to normal after 3 mo of treatment. [ABSTRACT FROM AUTHOR]

The document discusses the increased risk of skin cancers, specifically basal-cell carcinomas (BCC) and squamous-cell carcinomas (SCC), in solid organ transplant recipients (SOTR) due to immunosuppression. Treatment primarily involves surgical excision, with adjuvant radiotherapy for aggressive SCC. Immune-checkpoint inhibitors (ICI) are used for advanced SCC in non-immunosuppressed patients, but their use in SOTR requires careful consideration due to the risk of allograft rejection. Prevention strategies include treating precancerous lesions and implementing photoprotection measures. Future perspectives include new immunotherapies, HPV vaccination, and local blockade of tacrolimus for tumor rejection. [Extracted from the article]

Introduction: Cytomegalovirus (CMV) is a common opportunistic infection after solid organ transplantation, with significant impact on morbidity and long-term survival. Despite advances in diagnostics and therapeutics, the management of CMV remains very challenging. Areas Covered: This article reviews emerging data on the clinical utility of laboratory assays that quantify cell-mediated immune responses to CMV. Observational studies have consistently demonstrated that a deficiency in pathogen-specific cell-mediated immunity is correlated with a heightened risk of primary, reactivation or recurrent CMV after transplantation. A limited number of interventional studies have recently investigated cell-mediated immune assays in guiding the prevention and treatment of CMV infection after solid organ transplantation. Expert Opinion: The pathogenesis and outcome of CMV after solid organ transplantion reflect the interplay between viral replication and CMV-specific immune reconstitution. Research in CMV-specific cell-mediated immunity paved way for the development of several laboratory assays that may assist clinicians in predicting the risk of CMV after transplantation, individualize the approach to CMV disease prevention, guide the need and duration of treatment of CMV infection, and predict the risk of relapse after treatment. More interventional studies are needed to further solidify the role of cell-mediated immune assays in various clinical situations after transplantation. [ABSTRACT FROM AUTHOR]

Microplastics (MPs) and glyphosate‐based herbicides (GBH) are among the most common contaminants in aquatic environments. In Brazilian rivers, both contaminants were found in elevated levels, leading to a high probability of their association, which can alter their individual effects and potentially intensify their toxicity. This study evaluated the isolated and combined effects of polyethylene microplastics (PE‐MPs) and GBH on Oreochromis niloticus using multi‐biomarkers of toxicity. The fish were subjected to a 96‐h exposure period, with concentrations set based either isolated, PE‐MPs group (5 mg L−1), GBH group (5 mg L−1), or in a group of associated contaminants (GAC), PE‐MP + GBH (5 mg L−1 + 5 mg L−1). Toxicity effects were evaluated using biochemical, cytogenetic, hematological, and histopathological biomarkers. We observed change in erythrocyte parameters leading to macrocytic normochromic anemia in GAC. Leukocyte parameters indicate a nonspecific immunosuppression caused by the exposure of associated contaminants, besides the attempts to repair damage caused by PE‐MPs. Histopathological markers indicate damage to tissues exposed to contaminants. Besides, there were morphophysiological adjustments on gills, with proliferation and hypertrophy of mitochondria‐rich cells on GBH and GAC, besides epithelium ruptures, which were mostly present in the exposed groups. Therefore, this study indicates that PE‐MPs and GBHs present toxic effects in O. niloticus with the used concentrations, intensified by the association of contaminants. Thus, multi‐biomarkers were useful key to verify toxicity, providing data to the investigation of high levels of contaminant's mixture toxicity present in aquatic environments. [ABSTRACT FROM AUTHOR]

T helper (Th) 17 cells, a distinct subset of Th lymphocytes, are known for their prominent interleukin (IL)-17 production and other pro-inflammatory cytokines. These cells exhibit remarkable plasticity, allowing them to exhibit different phenotypes in the cancer microenvironment. This adaptability enables Th17 cells to promote tumor progression by immunosuppressive activities and angiogenesis, but also mediate anti-tumor immune responses through employing immune cells in tumor setting or even by directly converting toward Th1 phenotype and producing interferon-gamma (IFN-γ). This dual role of Th17 cells in cancer makes it a double-edged sword in encountering cancer. In this review, we aim to elucidate the complexities of Th17 cell function in cancer by summarizing recent studies and, ultimately, to design novel therapeutic strategies, especially targeting Th17 cells in the tumor milieu, which could pave the way for more effective cancer treatments. [ABSTRACT FROM AUTHOR]

Background: Sepsis, a severe inflammatory response to infection, is a global health priority due to its high mortality and long-term disability rates. Its pathophysiology involves both inflammation and immune suppression. Managing sepsis requires significant healthcare resources and expenditure, with sepsis being a leading cause of hospital costs. Gut microbiotas play a crucial role in sepsis, and probiotics show promise in managing it by restoring microbial balance. Despite advances, targeted therapies for sepsis remain elusive, necessitating innovative approaches such as probiotic therapy. Method: Fifty-four eligible patients with sepsis will be randomly assigned to either the synbiotic or placebo group. The synbiotic supplement, KidiLact, comprises ten probiotic strains and prebiotic fructooligosaccharides. Participants will receive two sachets daily for 7 days, mixed with sterile water and administered orally or via gavage. Inflammatory factors including interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) will be evaluated. Anthropometric measurements, nutritional assessment, biochemical analysis, and clinical evaluation will be conducted to assess treatment outcomes. Statistical analysis will be performed to compare results between the two groups, employing SPSS version 19 with a significance level of P <.05. Conclusion: This randomized clinical trial aims to evaluate synbiotic supplementation effects on inflammatory markers and clinical outcomes in pediatric sepsis patients in the pediatric intensive care unit (PICU). Probiotics have shown promise in reducing proinflammatory cytokines like IL-6, TNF-α, and CRP, which are vital in the inflammatory response. Synbiotics can enhance gut integrity, preventing pathogen translocation and reducing inflammation. If our expectations regarding the effects of probiotics are correct, we can use them as a cost-effective supplement to improve the condition of pediatric sepsis in hospitals. Trial registration: IRCT,IRCT20230523058266N1 Registered 30 October 2023, https://irct.behdasht.gov.ir/trial/71397. [ABSTRACT FROM AUTHOR]

Background Objective Animals Methods Results Conclusion and Clinical Importance Limited information is available regarding the clinical features, treatment, and prognosis of neosporosis in adult dogs.Describe the clinical signs, laboratory findings, magnetic resonance imaging (MRI) findings, treatment and outcome in adult dogs (>6 months) diagnosed with neosporosis based on consistent clinical signs and positive serology (titer ≥1 : 800) at a referral hospital in Sydney, Australia.Twenty‐one client‐owned dogs.Retrospective case series of affected dogs between 2010 and 2023. Survival times were determined from onset of clinical signs to date of death or censoring.Clinical signs varied, and were indicative of generalized myopathy (6 dogs), multifocal intracranial disease (7 dogs), myelopathy (4 dogs), polyneuropathy (2 dogs) and single cases of focal myopathy and cerebellar disease. Serum creatine kinase activity was markedly increased (median, 3369 U/L) in most dogs. The most common MRI abnormalities were multifocal intracranial abnormalities (7/13 dogs) and muscle changes (5/13 dogs) whereas T2‐weighted cerebellar abnormalities (2/13 dogs) and cerebellar atrophy (1/13) were less common. Treatment response was complete (resolution to normal) in 8 dogs, incomplete (persistent neurological deficits) in 6 dogs, but there was minimal response in 7 dogs. Thirteen dogs (62%) were alive after 6 months and 12 dogs (57%) alive after 1 year. Relapse was common, with 4 dogs experiencing at least 1 relapse event during the follow‐up period.Adult‐onset neosporosis is uncommon and has variable clinical presentations. Treatment response also is variable, and relapse can occur, even among patients that respond completely to initial treatment. [ABSTRACT FROM AUTHOR]

Introduction: Patients with chronic HBV infection (CHI) exhibit defective antiviral immune-response whose underlying causes still remain unclear. Monocytes act as immune sentinels for pathogens and can regulate immunity via interaction with other immune-cells, apart from differentiating into macrophages. Immunecheckpoint molecules (ICMs) expressed by immune-cells, including monocytes are known to negatively regulate immune-responses. Here, we evaluated the expression of ICMs, namely, Gal-9, PD-L1, and CTLA-4 on monocytes in different phases of CHI, identified the viral and the host factors causing their aberrant expression and investigated their impact during interaction of monocytes with Tcells, B-cells and NK-cells and also on monocyte to macrophage differentiation. Influence of Tenofovir therapy on the expression of monocytic ICMs was also studied. Methods: Collection of blood and liver-tissue samples from HBV infected patients and controls, flow-cytometry, cell sorting, cell culture and immunefluorescence were performed for this study. Results: Gal-9+ and PD-L1+-monocytes were significantly increased in HBeAgpositive as well as HBeAg-negative chronic hepatitis B (CHB) patients than healthy controls (HC). In immune-tolerant (IT) subjects, only Gal-9+- monocytes and in inactive carriers (IC), PD-L1+-monocytes were higher than HC while CTLA-4+-monocytes remained comparable among groups. High serum Hepatitis B surface antigen (HBsAg) concentration in CHB as well as IT and TNF-α in CHB triggered monocytic Gal-9-expression whereas, PD-L1 was induced by elevated TNF-α and IL-4 in CHB and IL-1β in CHB and IC. Purified monocytes from CHB and IT having high Gal-9 expression led to expansion of CD4+CD25+FOXP3+-Tregs, CD19+IL-10+-Bregs and CD19+CD27-CD21- atypical memory B-cells and these monocytes also preferentially differentiated into M2-macrophages. These phenomena were reversed by anti-Gal-9- antibody. Parallelly, PD-L1+-monocytes in CHB and IC reduced IL-2/IFN-γ and IL-6 production by HBV-specific T- and B-cells respectively, which were restored by anti-PD-L1-antibody. Both Gal-9+- and PD-L1+ -monocytes caused decline in IFN-γ+-NK-cells but enhanced IL-10-expressing HBVspecific-T-cells and NK-cells. Increased intrahepatic CD14+Gal-9+ and CD14+PD-L1+-monocytes were noted in CHB patients than HC. One-year tenofovir therapy failed to reduce monocytic Gal-9 and PD-L1 along with the levels of HBsAg, TNF-α, IL-1β and IL-4. Conclusions: Monocytic Gal-9 and PD-L1, expressed heterogeneously in different phases of CHI, exert diverse inhibitory effects on immune-responses and their therapeutic targeting could boost anti-HBV immunity. [ABSTRACT FROM AUTHOR]

Background: Infusion of mesenchymal stromal cells (MSCs) has been proposed as immune-modulatory therapy in solid organ transplantation. The use of allogenic MSCs could improve standardization and allow for direct availability of the product. Method: The nonrandomized phase Ib Neptune clinical trial provided safety and feasibility data on the use of allogenic bone-marrow-derived MSCs, infused in 10 patients at week 25 and 26 post kidney transplantation. Here, we performed detailed analysis on the peripheral blood immune cell composition of these patients up to 52 weeks post transplantation. We used a 40 marker antibody panel with mass cytometry to assess potential effects of MSC therapy on the immune system. Results: We showed minor changes in major immune lineages at week 27, 34 and 52 post kidney transplantation after MSC infusion at week 25 and week 26, confirming previous data with regular flow cytometry. However, in a direct comparison between pre- and post MSC infusion, as soon as 4 hours after MSC infusion, we observed a significant increase in cell numbers of B cell and T cell subsets that shared a unique expression of CD11b, CD11c, CD38, CD39, and Ki-67. Conclusion: Exploring these CD11b+CD11c+CD38+CD39+Ki-67+ B cells and T cells in the context of MSC infusion after kidney transplantation may be a promising avenue to better understand the immunological effects of MSC therapy. [ABSTRACT FROM AUTHOR]

The editorial in Frontiers in Immunology discusses immune system disorders, focusing on molecular mechanisms and clinical implications. The research highlights the pathogenic consequences of immune system dysfunction, including immunodeficiencies, inflammatory, and autoimmune disorders. Various review articles explore autoimmune diseases, treatments, and potential biomarkers for rheumatic diseases. The research aims to enhance understanding of immune dysregulation and its impact on diseases, paving the way for targeted therapies. [Extracted from the article]

Introduction: Lactate is a pivotal molecule with diverse functions in the metabolic reprogramming of cancer cells. Beyond its role in metabolism, lactate exerts a modulatory effect within the tumor microenvironment; it is utilized by stromal cells and has been implicated in the suppression of the immune response against the tumor. Methods: Using in vitro assays (including flow cytometry, live-cell imaging and metabolic analyses), the impact of lactate dehydrogenase inhibitors (LDHIs) on melanoma cells were assessed. The therapeutic potential of LDHIs with immune checkpoint inhibitors (ICIs) were tested in vivo in murine models of melanoma tumors. Results: A potent anti-proliferative effect (via both cell cycle alterations and enhanced apoptosis) of LDHIs, Oxamate (Oxa) and methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate (NHI-2), was found upon treatment of melanoma cell lines. Using a combination of Oxa and NHI-2, a synergistic effect to inhibit proliferation, glycolysis, and ATP production was observed. Metabolic analysis revealed significant alteration in glycolysis and oxidative phosphorylation, while metabolite profiling emphasized consequential effects on lactate metabolism and induced energy depletion by LDHIs. Detection of increased RANTES and MCP-1, with Oxa and NHI-2 treatment, prompted the consideration of combining LDHIs with ICIs. In vivo studies using a murine B78 melanoma tumor model revealed a significant improvement in treatment efficacy when LDHIs were combined with ICIs. Conclusions: These findings propose the potential of targeting lactate metabolism to enhance the efficacy of ICI treatments in patients with melanoma. [ABSTRACT FROM AUTHOR]

Nanocatalytic immunotherapy holds excellent potential for future cancer therapy due to its rapid activation of the immune system to attack tumor cells. However, a high level of N-glycosylation can protect tumor cells, compromising the anticancer immunity of nanocatalytic immunotherapy. Here, we show a 2-deoxyglucose (2-DG) and bismuth ferrite co-loaded gel (DBG) scaffold for enhanced cancer piezocatalytic immunotherapy. After the implantation in the tumor, DBG generates both reactive oxygen species (ROS) and piezoelectric signals when excited with ultrasound irradiation, significantly promoting the activation of anticancer immunity. Meanwhile, 2-DG released from ROS-sensitive DBG disrupts the N-glycans synthesis, further overcoming the immunosuppressive microenvironment of tumors. The synergy effects of ultrasound-triggered and glycosylation inhibition enhanced tumor piezocatalytic immunotherapy are demonstrated on four mouse cancer models. A "hot" tumor-immunity niche is produced to inhibit tumor progress and lung metastasis and elicit strong immune memory effects. This work provides a promising piezocatalytic immunotherapy for malignant solid tumors featuring both low immunogenicity and high levels of N-glycosylation. N-glycosylation has a significant role in immunosuppressive tumor microenvironment (TME). Here, the authors design an injectable ROS-sensitive hydrogel scaffold co-delivering piezocatalyst BiFeO3 and glucose/mannose analog 2-deoxy-d-glucose alleviating N-glycosylation inhibition and thereby effectively stimulating immune responses within TME. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) provides essential conditions for the occurrence, invasion, and spread of cancer cells. Initial research has uncovered immunosuppressive properties of the TME, which include low oxygen levels (hypoxia), acidic conditions (low pH), increased interstitial pressure, heightened permeability of tumor vasculature, and an inflammatory microenvironment. The presence of various immunosuppressive components leads to immune evasion and affects immunotherapy efficacy. This indicates the potential value of targeting the TME in cancer immunotherapy. Therefore, TME remodeling has become an effective method for enhancing host immune responses against tumors. In this study, we elaborate on the characteristics and composition of the TME and how it weakens immune surveillance and summarize targeted therapeutic strategies for regulating the TME. [ABSTRACT FROM AUTHOR]

Background Hospital-acquired (HAP) and ventilator-associated pneumonia (VAP) are important complications early (<30 days) after lung transplantation (LT). However, current incidence, associated factors, and outcomes are not well reported. Methods LT recipients transplanted at our institution (July 2019–January 2020 and October 2021–November 2022) were prospectively included. We assessed incidence and presentation of pneumonia and evaluated the impact of associated factors using regression models. We also evaluated molecular relatedness of respiratory pathogens collected peri-transplant and at pneumonia occurrence using pulsed-field gel electrophoresis (PFGE). Results In the first 30 days post-LT, 25/270 (9.3%) recipients were diagnosed with pneumonia (68% [17/25] VAP; 32% [8/25] HAP). Median time to pneumonia was 11 days (IQR, 7–13); 49% (132/270) of donor and 16% (44/270) of recipient respiratory peri-transplant cultures were positive. However, pathogens associated with pneumonia were not genetically related to either donor or recipient cultures at transplant, as determined by PFGE. Diagnosed pulmonary hypertension (HR, 4.42; 95% CI, 1.62–12.08) and immunosuppression use (HR, 2.87; 95% CI, 1.30–6.56) were pre-transplant factors associated with pneumonia. Pneumonia occurrence was associated with longer hospital stay (HR, 5.44; 95% CI, 2.22–13.37) and VAP with longer ICU stay (HR, 4.31; 95% CI, 1.73–10.75) within the first 30 days post-transplantation; 30- and 90-day mortality were similar. Conclusions Prospectively assessed early pneumonia incidence occurred in ∼10% of LT. Populations at increased risk for pneumonia occurrence include LT with pre-transplant pulmonary hypertension and pre-transplant immunosuppression. Pneumonia was associated with increased healthcare use, highlighting the need for further improvements by preferentially targeting higher-risk patients. [ABSTRACT FROM AUTHOR]

Introduction: Mesenchymal stromal cell (MSC)-based cell therapy is a promising approach for various inflammatory disorders based on their immunosuppressive capacity. Osteopontin (OPN) regulates several cellular functions including tissue repair, bone metabolism and immune reaction. However, the biological function of OPN in regulating the immunosuppressive capacity of MSCs remains elusive. Objectives: This study aims to highlight the underlying mechanism of the proinflammatory cytokines affect the therapeutic ability of MSCs through OPN. Methods: MSCs in response to the proinflammatory cytokines were collected to determine the expression profile of OPN. In vitro T-cell proliferation assays and gene editing were performed to check the role and mechanisms of OPN in regulating the immunosuppressive capacity of MSCs. Inflammatory disease mouse models were established to evaluate the effect of OPN on improving MSC-based immunotherapy. Results: We observed that OPN, including its two isoforms iOPN and sOPN, was downregulated in MSCs upon proinflammatory cytokine stimulation. Interestingly, iOPN, but not sOPN, greatly enhanced the immunosuppressive activity of MSCs on T-cell proliferation and thus alleviated the inflammatory pathologies of hepatitis and colitis. Mechanistically, iOPN interacted with STAT1 and mediated its deubiquitination, thereby inducing the master immunosuppressive mediator inducible nitric oxide synthase (iNOS) in MSCs. In addition, iOPN expression was directly downregulated by activated STAT1, which formed a negative feedback loop to restrain MSC immunosuppressive capacity. Conclusion: Our findings demonstrated that iOPN expression modulation in MSCs is a novel strategy to improve MSC-based immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Tumor cells develop multiple mechanisms to facilitate their immune evasion. Identifying tumor-intrinsic factors that support immune evasion may provide new strategies for cancer immunotherapy. We aimed to explore the function and the mechanism of the tumor-intrinsic factor NPM1, a multifunctional nucleolar phosphoprotein, in cancer immune evasion and progression. Methods: The roles of NPM1 in tumor progression and tumor microenvironment (TME) reprogramming were examined by subcutaneous inoculation of Npm1-deficient tumor cells into syngeneic mice, and then explored by CyTOF, flow cytometry, immunohistochemistry staining, and RNA-seq. The in-vitro T-cell killing of OVA-presenting tumor cells by OT-1 transgenic T cells was observed. The interaction of NPM1 and IRF1 was verified by Co-IP. The regulation of NPM1 in IRF1 DNA binding to Nlrc5, Ciita promoter was determined by dual-luciferase reporter assay and ChIP-qPCR. Results: High levels of NPM1 expression predict low survival rates in various human tumors. Loss of NPM1 inhibited tumor progression and enhanced the survival of tumor-bearing mice. Npm1-deficient tumors showed increased CD8+ T cell infiltration and activation alongside the reduced presence of immunosuppressive cells. Npm1 deficiency increased MHC-I and MHC-II molecules and specific T-cell killing. Mechanistically, NPM1 associates with the transcription factor IRF1 and then sequesters IRF1 from binding to the Nlrc5 and Ciita promoters to suppress IRF1-mediated expression of MHC-I and MHC-II molecules in tumor cells. Conclusions: Tumor-intrinsic NPM1 promotes tumor immune evasion via suppressing IRF1-mediated antigen presentation to impair tumor immunogenicity and reprogram the immunosuppressive TME. Our study identifies NPM1 as a potential target for improving cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Sepsis is a life-threatening organ malfunction induced by an imbalanced immunological reaction to infection in the host. Many studies have utilized traditional RNA sequencing (RNA-seq) data to identify important biological targets to predict sepsis prognosis. However, alterations in core cells and functional status cannot be effectively detected in sepsis patients. The goal of this study was to identify key cells through single-cell RNA-seq (scRNA-seq), and combine bulk RNA-seq data and multiple algorithm analysis to construct a stable prognostic model for sepsis. The scRNA-seq and bulk RNA-seq data from sepsis patients were collected from the Gene Expression Omnibus (GEO) database. The R package "Seurat" was used to process the scRNA-seq data. Cell communication was investigated using the R package "CellChat". The pseudo-time of the cells was calculated using the R package "monocle". The R package "limma" was used to identify differentially expressed genes (DEGs) between the sepsis group and the control group. Weighted gene correlation network analysis (WGCNA) was used to identify critical modules. Eight kinds of machine learning and 90 algorithm combinations were used to construct the prognostic model for sepsis. Quantitative real-time PCR (qRT‒PCR) was performed to determine the expression of key genes in the cecal ligation and puncture (CLP)-induced sepsis mouse model. The immunological status and related properties of DEGs were then investigated in the high- and low-risk groups delineated by the model. By combining the scRNA-seq data from nine samples, 13 clusters and 9 cell types were identified. CellChat analysis revealed that the number and strength of interactions between platelets and a variety of cells increased. We identified key platelet genes from the scRNA-seq data and combined these genes and the results of differential analysis and WGCNA of the bulk RNA-seq data. After univariate Cox regression analysis, we calculated the Cindex of the model constructed by the combination of 90 algorithms, and we finally determined the "CoxBoost + Lasso" combination. Multivariate Cox regression was used to construct the final prognostic model. The qRT-PCR results revealed significant differences in five key prognostic genes between the CLP and sham groups. The data was classified into high- and low-risk groups based on the model score. The high-risk group had a poorer survival rate and less immune infiltration. We identified the importance of platelets in sepsis patients through scRNA-seq, and established prognostic models with key genes that were identified via scRNA-seq combined with bulk RNA-seq analysis. The results of this model were closely associated with patient survival rates and immunological status and this model is useful for the prognostic management of sepsis. [ABSTRACT FROM AUTHOR]

Background Aims The European Union encompasses 30 outermost and overseas countries and territories (OCTs). Despite a recent increasing activity of renal transplantation in these territories, many patients still undergo transplantation in continental Europe, with follow‐up care coordinated between health professionals from both their transplant center and their home region. Each territory has its unique infectious epidemiology which must be known to ensure appropriate care for kidney transplant recipients (KTRs).This paper proposes a pragmatic approach to optimize pre‐transplant check‐up and to provide an overview of the specific epidemiological features of each region. It offers practical algorithms to help practitioners in managing infected KTR living in these territories. This work advocates for increased collaborative research among European OCTs. [ABSTRACT FROM AUTHOR]

Obejectives: This study explored the immunomodulatory effects of a prebiotic formula consisting of 2′-fucosyllactose (2′-FL), galacto-oligosaccharides (GOSs), and fructo-oligosaccharides (FOSs) (hereinafter referred to as 2FGF) in cyclophosphamide (CTX)-induced immunosuppressed BALB/c mice and its underlying mechanisms. Methods: Sixty healthy female BALB/c mice were randomly divided into the following groups: normal control (NC) group; CTX treatment (CTX) group; 2FGF low-dose (2FGF-L) group; 2FGF medium-dose (2FGF-M) group; and 2FGF high-dose (2FGF-H) group. An immunosuppressed model was established in the 2FGF-H group by intraperitoneal injection of 80 mg/kg CTX. After 30 days of 2FGF intervention, peripheral blood, spleen tissue, thymus tissue, and intestinal tissue from the mice were collected and analyzed. The changes in weight and food intake of the mice were recorded weekly. Hematoxylin-eosin (HE) staining was used to observe the histological change of the spleen tissue. Enzyme-linked immunosorbent assay (ELISA) was employed to detect cytokine levels in peripheral blood. Flow cytometry was used to analyze T lymphocyte subgroup ratio of splenic lymphocytes. Western blot analysis was conducted on intestinal tissues to assess the expression of proteins involved in the tight junction, toll-like receptor 4 (TLR4), mitogen-activated protein kinase (MAPK), and nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling pathways. Additionally, molecular techniques were used to analyze the intestinal microbiota. Results: The results showed that 2FGF restored CTX-induced splenic injury, increased the number of splenic T lymphocytes, and elevated serum cytokines such as interleukin-4 (IL-4) and IL-10. In the intestine, 2FGF upregulated the expression of intestinal epithelial tight junction proteins such as Claudin-1 and zonula occludens 1 (ZO-1), thereby enhancing intestinal barrier function and activating the MAPK and NF-κB pathways via TLR4. Furthermore, 2FGF elevated the α-diversity (Shannon and Simpson indices) of the gut microbiota in CTX-induced immunosuppressed mice, enriching bacteria species positively correlated with anti-inflammatory cytokines (e.g., IL-4) such as g_Streptomyces and g_Bacillus and negatively correlated with pro-inflammatory cytokines (e.g., IL-1β) such as g_Saccharomyces. The results suggest that 2FGF may enhance immunity via the gut–immune axis. Conclusions: The 2FGF prebiotic formula showed an immunomodulatory effect in CTX-induced immunosuppressed mice, and the mechanism of which might involve optimizing the gut flora, enhancing intestinal homeostasis, strengthening the intestinal barrier, and promoting the expression of immune factors by regulating the TLR-4/MAPK/NF-κB pathway. [ABSTRACT FROM AUTHOR]

Mutualistic relationships with photosynthetic organisms are common in cnidarians, which form an intracellular symbiosis with dinoflagellates in the family Symbiodiniaceae. The establishment and maintenance of these symbionts are associated with the suppression of key host immune factors. Because of this, there are potential trade-offs between the nutrition that cnidarian hosts gain from their symbionts and their ability to successfully defend themselves from pathogens. To investigate these potential trade-offs, we utilized the facultatively symbiotic polyps of the upside-down jellyfish Cassiopea xamachana and exposed aposymbiotic and symbiotic polyps to the pathogen Serratia marcescens. Symbiotic polyps had a lower probability of survival following S. marcescens exposure. Gene expression analyses 24 hours following pathogen exposure indicate that symbiotic animals mounted a more damaging immune response, with higher levels of inflammation and oxidative stress likely resulting in more severe disruptions to cellular homeostasis. Underlying this more damaging immune response may be differences in constitutive and pathogen-induced expression of immune transcription factors between aposymbiotic and symbiotic polyps rather than broadscale immune suppression during symbiosis. Our findings indicate that in facultatively symbiotic polyps, hosting symbionts limits C. xamachana's ability to survive pathogen exposure, indicating a trade-off between symbiosis and immunity that has potential implications for coral disease research. [ABSTRACT FROM AUTHOR]

Background: Head and neck squamous cell carcinoma (HNSCC) is a major tumor that seriously threatens the health of the head and neck or mucosal system. It is manifested as a malignant phenotype of high metastasis and invasion caused by squamous cell transformation in the tissue area. Therefore, it is necessary to search for a biomarker that can systematically correlate and reflect the prognosis of HNSCC based on the characteristics of head and neck tumors. Methods: Based on TCGA-HNSCC data, R software was used to analyze gene expression, correlation, Venn diagram, immune invasive and immunosuppressive phenotypes respectively. The intrinsic effect of ITGA5 on the malignant phenotype of HNSCC cells was verified by cell experiments. Immunohistochemical images from The Human Protein Atlas (THPA) database display the differences in the expression of related proteins in HNSCC tissues. Based on functional enrichment and correlation analysis, the prognostic value of ITGA5 for HNSCC was explored, and the expression level of ITGA5 may affect the chemotherapy of targeting the PI3K-AKT. Results: In this study, the target gene ITGA5 may be identified as a valuable prognostic marker for HNSCC. The results of enrichment analysis showed that ITGA5 was mainly involved in the dynamic process of extracellular matrix, which may affect the migration or metastasis of tumor cells. Meanwhile, ITGA5 may be closely related to the infiltration of M2 macrophages, and its secretory phenotypes TGFB1, PDGFA and PDGFB may affect the immunosuppressive phenotypes of tumor cells, which reflects the systemic influence of ITGA5 in HNSCC. In addition, the expression levels of ITGA5 were negatively correlated with the efficacy of targeting PI3K-AKT chemotherapy. Conclusion: ITGA5 can be used as a potential marker to systematically associate with prognosis of HNSCC, which may be associated with HNSCC malignant phenotype, immunosuppression and chemotherapy resistance. [ABSTRACT FROM AUTHOR]

Background: N4-Acetylcytidine (ac4C), a highly conserved post-transcriptional mechanism, plays a pivotal role in RNA modification and tumor progression. However, the molecular mechanism by which ac4C modification mediates tumor immunosuppression remains elusive in triple-negative breast cancer (TNBC). Methods: NAT10 expression was analyzed in TNBC samples in the level of mRNA and protein, and compared with the corresponding normal tissues. ac4C modification levels also measured in the TNBC samples. The effects of NAT10 on immune microenvironment and tumor metabolism were investigated. NAT10-mediated ac4C and its downstream regulatory mechanisms were determined in vitro and in vivo. The combination therapy of targeting NAT10 in TNBC was further explored. Results: The results revealed that the loss of NAT10 inhibited TNBC development and promoted T cell activation. Mechanistically, NAT10 upregulated JunB expression by increasing ac4C modification levels on its mRNA. Moreover, JunB further up-regulated LDHA expression and facilitated glycolysis. By deeply digging, remodelin, a NAT10 inhibitor, elevated the surface expression of CTLA-4 on T cells. The combination of remodelin and CTLA-4 mAb can further activate T cells and inhibite tumor progression. Conclusion: Taken together, our study demonstrated that the NAT10-ac4C-JunB-LDHA pathway increases glycolysis levels and creates an immunosuppressive tumor microenvironment (TME). Consequently, targeting this pathway may assist in the identification of novel therapeutic strategies to improve the efficacy of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Pulmonary pseudoaneurysm (PAP) is a fatal complication of severe acute respiratory syndrome caused by coronavirus 2 infections in the lungs. Other causative agent such as fungal and tubercular also responsible for this entity. Early detection and treatment can save a patient's life. Case presentation: Here we describe a case of a left pulmonary artery pseudo aneurysm in a 54-year-old patient with COVID-19 pneumonia who presented with massive hemoptysis and which was treated with endovascular embolization. Conclusion: It is caused by vasculopathy due to immunosuppression /immune dysregulation in COVID-19. Minimally invasive endovascular embolization of pseudoaneurysm carries less mortality and morbidity. [ABSTRACT FROM AUTHOR]

Lactate significantly impacts immune cell function in sepsis and septic shock, transcending its traditional view as just a metabolic byproduct. This review summarizes the role of lactate as a biomarker and its influence on immune cell dynamics, emphasizing its critical role in modulating immune responses during sepsis. Mechanistically, key lactate transporters like MCT1, MCT4, and the receptor GPR81 are crucial in mediating these effects. HIF-1a also plays a significant role in lactate-driven immune modulation. Additionally, lactate affects immune cell function through post-translational modifications such as lactylation, acetylation, and phosphorylation, which alter enzyme activities and protein functions. These interactions between lactate and immune cells are central to understanding sepsis-associated immune dysregulation, offering insights that can guide future research and improve therapeutic strategies to enhance patient outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Immunotherapy has revolutionized cancer treatment, and Chimeric Antigen Receptor T cell therapy (CAR-T) is a groundbreaking approach. Traditional second-generation CAR-T therapies have achieved remarkable success in hematological malignancies, but there is still room for improvement, particularly in developing new targeting strategies. To address this limitation, engineering T cells with multi-target universal CARs (UniCARs) based on monomeric streptavidin has emerged as a versatile approach in the field of anti-tumor immunotherapy. However, no studies have been conducted on the importance of the intracellular signaling domains of such CARs and their impact on efficiency and specificity Method: Here, we developed second-generation and third-generation UniCARs based on an extracellular domain comprising an affinity-enhanced monomeric streptavidin, in addition to CD28 and 4-1BB co-stimulatory intracellular domains. These UniCAR structures rely on a biotinylated intermediary, such as an antibody, for recognizing target antigens. In co-culture assays, we performed a functional comparison between the third-generation UniCAR construct and two second-generation UniCAR variants, each incorporating either the CD28 or 4-1BB as costimulatory domain Results: We observed that components in culture media could inhibit the binding of biotinylated antibodies to monomeric streptavidin-CARs, potentially compromising their efficacy. Furthermore, third-generation UniCAR-T cells showed robust cytolytic activity against cancer cell lines upon exposure to specific biotinylated antibodies like anti-CD19 and anti-CD20, underscoring their capability for multi-targeting. Importantly, when assessing engineered UniCAR-T cell activation upon encountering their target cells, third-generation UniCAR-T cells exhibited significantly enhanced specificity compared to second-generation CAR-T cells Discussion: First, optimizing culture conditions would be essential before deploying UniCAR-T cells clinically. Moreover, we propose that third-generation UniCAR-T cells are excellent candidates for preclinical research due to their high specificity and multi-target anti-tumor cytotoxicity [ABSTRACT FROM AUTHOR]

With the rapid development of intensive livestock and poultry farms, the diseases are spreading fast, easy to form epidemic disease, and the phenomenon of immunosuppression is widespread, which makes the prevention and control of animal and poultry epidemics face greater pressure in China. Caused by many negative factors. Therefore, the prevention and control of in China is facing unprecedented pressure. Baizhu (Atractylodes macrocephala Koidz.), the dried rhizome of the compositae plants, is a commonly used in traditional Chinese medicine for tonic. Modern pharmacological studies on Rhizama atrac‐ tylodis Koidz. indicate that the polysaccharide of Atractylodes macrocephala Koidz. (PAMK) is one of the main active ingredient. This paper reviews the progress of the study of PAMK in animal immunization in recent years, and provides reference for the in-depth research and clinical development of Rhizama atractylodis macrocephalae Koidz. [ABSTRACT FROM AUTHOR]

The French Society of Pediatric Neurology and the FILNEMUS network created a working group on corticosteroid therapy in children with Duchenne muscular dystrophy in order to analyze the literature review and current French practices. The aim of this work was to produce guidelines regarding treatment initiation, pre-therapeutic interventions, choice between available compounds, and treatment monitoring (dosage, duration, and discontinuation). The treatment side effects and their management are also detailed: osteoporosis, endocrinological anomaly (growth delay, weight gain, pubertal delay), cataract, arterial hypertension, behavioral disorders, management of immunosuppression and vaccines, and management of gastrointestinal and metabolic complications. [ABSTRACT FROM AUTHOR]

Purpose: Despite advances in extremity trauma care and reconstructive microsurgery, management of the traumatic amputations remains a challenge. The majority of patients will forever experience some level of disability even with replantation or advanced prosthetics. The goal of this article is to familiarize hand and reconstructive surgeons with the current state of upper extremity transplantation, so they better can educate their amputee patients regarding this as an option following limb loss. Methods: Current literature, in addition to the international registry on hand and composite tissue transplantation, was reviewed to assemble a summary of outcomes in upper extremity replantation and transplantation. Results: Sensory and functional outcomes of replantation and transplantation are comparable. Reported complications of immunosuppression are similar to those of other solid organ transplants. The financial cost of hand transplantation is high, but comparable to the lifetime cost of prosthesis use. Conclusion: While the risk of immunosuppression is a serious consideration for patients pursuing hand transplantation, in the well-selected and informed patient, hand transplantation can dramatically improve patient reported to outcomes and quality of life. [ABSTRACT FROM AUTHOR]

Background: The tumor microenvironment (TME) plays a critical role in cancer progression and response to immunotherapy. Immunotherapy targeting the immune system has emerged as a promising treatment modality, but challenges in understanding the TME limit its efficacy. Optical imaging strategies offer noninvasive, real‐time insights into the interactions between immune cells and the TME. Objective: This review assesses the progress of optical imaging technologies in monitoring immunotherapy within the TME and explores their potential applications in clinical trials and personalized cancer treatment. Methods: This is a comprehensive literature review based on the advances in optical imaging modalities including fluorescence imaging (FLI), bioluminescence imaging (BLI), and photoacoustic imaging (PAI). These modalities were analyzed for their capacity to provide high‐resolution, real‐time imaging of immune cell dynamics, tumor vasculature, and other critical components of the TME. Results: Optical imaging techniques have shown significant potential in tracking immune cell infiltration, assessing immune checkpoint inhibitors, and visualizing drug delivery within the TME. Technologies like FLI and BLI are pivotal in tracking immune responses in preclinical models, while PAI provides functional imaging with deeper tissue penetration. The integration of these modalities with immunotherapy holds promise for improving treatment monitoring and outcomes. Conclusion: Optical imaging is a powerful tool for understanding the complexities of the TME and optimizing immunotherapy. Further advancements in imaging technologies, combined with nanomaterial‐based approaches, could pave the way for enhanced diagnostic accuracy and therapeutic efficacy in cancer treatment. [ABSTRACT FROM AUTHOR]

Corticosteroids play a crucial role as anti-inflammatory and immunomodulatory agents in dermatology and other medical specialties; however, their therapeutic benefits are accompanied by significant risks, especially in older adults. This review examines the broad spectrum of adverse effects (AEs) associated with oral corticosteroid therapy and offers strategies to prevent, monitor, and manage these issues effectively in older adults. AEs associated with systemic corticosteroids include immune suppression, gastrointestinal problems, hyperglycemia, insulin resistance, weight gain, cardiovascular complications, ocular issues, osteoporosis, osteonecrosis, muscle weakness, collagen impairment, psychiatric symptoms, and adrenal suppression. To minimize these AEs, tailored dosing and duration, frequent monitoring, and additional preventative measures can be employed to optimize corticosteroid treatment. By customizing management plans to the specific needs and risk factors associated with each patient, clinicians can promote the safe and effective use of oral corticosteroids, ultimately improving outcomes and quality of life in patients with inflammatory dermatologic disorders. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is a challenging subtype of breast cancer characterized by the absence of estrogen and progesterone receptors and HER2 expression, leading to limited treatment options and a poorer prognosis. TNBC is particularly prevalent in premenopausal African-descent women and is associated with aggressive tumor behavior and higher metastatic potential. Tumor-associated macrophages (TAMs) are abundantly present within the TNBC microenvironment and play pivotal roles in promoting tumor growth, progression, and metastasis through various mechanisms, including immune suppression and enhancement of angiogenesis. This review provides an in-depth overview of TNBC, focusing on its epidemiology, its molecular characteristics, and the critical influence of TAMs. It discusses the pathological and molecular aspects that define TNBC's aggressive nature and reviews current and emerging therapeutic strategies aimed at targeting these dynamics. Special attention is given to the role of TAMs, exploring their potential as therapeutic targets due to their significant impact on tumor behavior and patient outcomes. This review aims to highlight the complexities of the TNBC landscape and to present the innovative approaches that are currently being pursued to improve therapeutic efficacy and patient survival. [ABSTRACT FROM AUTHOR]

Glioblastoma is known to be one of the most aggressive and fatal human cancers, with a poor prognosis and resistance to standard treatments. In the last few years, many solid tumor treatments have been revolutionized with the help of immunotherapy. However, this type of treatment has failed to improve the results in glioblastoma patients. Effective immunotherapeutic strategies may be developed after understanding how glioblastoma achieves tumor-mediated immune suppression in both local and systemic landscapes. Biomarkers may help identify patients most likely to benefit from this type of treatment. In this review, we discuss the use of immunotherapy in glioblastoma, with an emphasis on immune checkpoint inhibitors and the factors that influence clinical response. A Pubmed data search was performed for all existing information regarding immune checkpoint inhibitors used for the treatment of glioblastoma. All data evaluating the ongoing clinical trials involving the use of ICIs either as monotherapy or in combination with other drugs was compiled and analyzed. [ABSTRACT FROM AUTHOR]

Rice false smut, caused by Ustilaginoidea virens, threatens rice production by reducing yields and contaminating grains with harmful ustiloxins. However, studies on resistance genes are scarce. In this study, the resistance level of IR28 (resistant cultivar) to U. virens was validated through artificial inoculation. Notably, a reactivation of resistance genes after transient down-regulation during the first 3 to 5 dpi was observed in IR28 compared to WX98 (susceptible cultivar). Cluster results of a principal component analysis and hierarchical cluster analysis of differentially expressed genes (DEGs) in the transcriptome exhibited longer expression patterns in the early infection phase of IR28, consistent with its sustained resistance response. Results of GO and KEGG enrichment analyses highlighted the suppression of immune pathways when the hyphae first invade stamen filaments at 5 dpi, but sustained up-regulated DEGs were linked to the 'Plant–pathogen interaction' (osa04626) pathway, notably disease-resistant protein RPM1 (K13457, CNLs, coil-coiled NLR). An analysis of CNLs identified 245 proteins containing Rx-CC and NB-ARC domains in the Oryza sativa Indica genome. Partial candidate CNLs were shown to exhibit up-regulation at both 1 and 5 dpi in IR28. This study provides insights into CNLs' responses to U. virens in IR28, potentially informing resistance mechanisms and genetic breeding targets. [ABSTRACT FROM AUTHOR]

Simple Summary: The tumor microenvironment (TME) refers to the area immediately surrounding a cancerous tumor that influences the tumor's behavior and how the immune system reacts to it. Central to the TME environment are special immune cells—tumor-associated macrophages (TAMs)—that, rather than restrict the tumor, actually facilitate tumor growth and metastasis. Thus, targeting these TAMs can help to eliminate cancer. In this article, we review the biology of TAMs and delve into the signaling mechanisms underlying the polarization of macrophage phenotypes, their plasticity, and therapeutic implications. Within the tumor microenvironment, myeloid cells constitute a dynamic immune population characterized by a heterogeneous phenotype and diverse functional activities. In this review, we consider recent literature shedding light on the increasingly complex biology of M2-like immunosuppressive tumor-associated macrophages (TAMs), including their contribution to tumor cell invasion and metastasis, stromal remodeling (fibrosis and matrix degradation), and immune suppressive functions, in the tumor microenvironment (TME). This review also delves into the intricate signaling mechanisms underlying the polarization of diverse macrophage phenotypes, and their plasticity. We also review the development of promising therapeutic approaches to target these populations in cancers. The expanding knowledge of distinct subsets of immunosuppressive TAMs, and their contributions to tumorigenesis and metastasis, has sparked significant interest among researchers regarding the therapeutic potential of TAM depletion or phenotypic modulation. [ABSTRACT FROM AUTHOR]

Simple Summary: Idiopathic granulomatous mastitis (IGM) is a rare breast disease that can be mistaken for inflammatory breast cancer. It requires a tissue biopsy for an accurate diagnosis. Even though it is not cancerous, IGM can cause emotional distress because of severe pain and ensuing breast deformity. It is important to distinguish IGM from other breast inflammations caused by infections. IGM is mostly found in premenopausal women, often after pregnancy or breastfeeding. Smoking and contraceptive use might be risk factors, but the evidence is unclear. The treatment options include NSAIDs, steroids, immunosuppressants, surgery, prolactin suppressants, and antibiotics; many patients relapse, making treatment challenging. This review summarizes current information, which mostly comes from case reports and small studies, and presents GRAMAREG as a registry for IGM initiated by the EUBREAST Study Group, which aims to collect detailed data on IGM to improve the knowledge base for diagnosis and treatment. Background: Idiopathic granulomatous mastitis (IGM) is a rare, benign inflammatory breast condition often mistaken for inflammatory breast cancer and, therefore, requires a biopsy for accurate diagnosis. Although not cancerous, IGM can cause emotional distress because of severe pain and ensuing breast deformity. Differentiating IGM from other breast inflammations caused by infections is essential. IGM mostly affects premenopausal women and is potentially associated with recent pregnancies and breastfeeding. The risk factors, including smoking and contraceptive use, have inconsistent associations. Steroid responses suggest an autoimmune component, though specific markers are lacking. Methods: We performed a narrative review on potential risk factors, diagnostics, and therapy of IGM. Results: Diagnostics and clinical management of IGM are challenging. The treatment options include NSAIDs, steroids, surgery, antibiotics, immunosuppressants, prolactin suppressants, and observation, each with varying effectiveness and side effects. Conclusions: Current IGM treatment evidence is limited, based on case reports and small series. There is no consensus on the optimal management strategy for this disease. The GRAMAREG study by the EUBREAST Study Group aims to collect comprehensive data on IGM to improve diagnostic and treatment guidelines. By enrolling patients with confirmed IGM, the study seeks to develop evidence-based recommendations, enhancing patient care and understanding of this condition. [ABSTRACT FROM AUTHOR]