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Background: The efficacy and safety of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) hydrogel in adults with deep partial-thickness burns have been confirmed. However, the clinical safety and efficacy analysis of rhGM-CSF in pediatrics is lacking, and the results are questionable. Therefore, a meta-analysis was conducted to evaluate the efficacy and safety of rhGM-CSF hydrogel in children with second- or third-degree burn injury to provide evidence-based medicine for clinical application. Methods: Articles on rhGM-CSF hydrogel for the treatment of pediatric burn wounds were retrieved from PubMed, Embase, WOS, Cochrane Central Registry of Controlled Trials, Chinese Biomedical Literature Database (CBM), China Science and Technology Journal Database (CSTJ), China National Knowledge Infrastructure (CNKI) and Wanfang from the inception of the databases to March 2024. Two reviewers screened articles and extracted the following data: general characteristics, intervention and treatment course, outcome measure. The meta-analysis was conducted using Revman 5.4 software. Results: Eight reports (336 patients: experimental 175, control 161) were ultimately included in the meta-analysis, which showed that the experimental group (rhGM-CSF hydrogel ± other therapy) was superior to the control group (treatments without rhGM-CSF hydrogel) in terms of the wound healing rates at day 7 [mean difference (MD) =13.63, 95% confidence interval (CI): 7.25 to 20.00, P<0.001], day 14 (MD =15.59, 95% CI: 12.50 to 18.69, P<0.001), and day 21 (MD =7.47, 95% CI: 7.36 to 7.58, P<0.001), and the wound healing time (MD =-3.10, 95% CI: -3.50 to -2.71, P<0.001), and the differences were statistically significant. For the risks of bias, one study had a "high risk" in allocation sequence concealment, and the others were classified as "low risk" and "unclear risk". Conclusions: rhGM-CSF hydrogel is significantly effective in improving the wound healing rate and shortening the wound healing time in children with second- or third-degree burns.
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Hypertension (HTN) impacts almost half of adults, predisposing them to cardiovascular disease and renal damage. Salt-sensitive HTN (SSHTN) and angiotensin II (A2)-induced HTN (A2HTN) both involve immune system activation and renal innate immune cell infiltration. Subpopulations of activated [Cluster of differentiation 38 (CD38)] innate immune cells, such as macrophages and dendritic cells (DCs), play distinct roles in modulating renal function and blood pressure. It is unknown how these cells become CD38+ or which subtypes are pro-hypertensive. When bone marrow-derived monocytes (BMDMs) were grown in granulocyte-macrophage colony stimulating factor (GM-CSF) and treated with salt or A2, CD38+ macrophages and CD38+ DCs increased. The adoptive transfer of GM-CSF-primed BMDMs into mice with either SSHTN or A2HTN increased renal CD38+ macrophages and CD38+ DCs. Flow cytometry revealed increased renal M1 macrophages and type-2 conventional DCs (cDC2s), along with their CD38+ counterparts, in mice with either SSHTN or A2HTN. These results were replicable in vitro. Either salt or A2 treatment of GM-CSF-primed BMDMs significantly increased bone marrow-derived (BMD)-M1 macrophages, CD38+ BMD-M1 macrophages, BMD-cDC2s, and CD38+ BMD-cDC2s. Overall, these data suggest that GM-CSF is necessary for the salt or A2 induction of CD38+ innate immune cells, and that CD38 distinguishes pro-hypertensive immune cells. Further investigation of CD38+ M1 macrophages and CD38+ cDC2s could provide new therapeutic targets for both SSHTN and A2HTN.
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Angiotensina II , Células Dendríticas , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Imunidade Inata , Macrófagos , Animais , Angiotensina II/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Camundongos , Imunidade Inata/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Hipertensão/imunologia , Camundongos Endogâmicos C57BL , ADP-Ribosil Ciclase 1/metabolismo , Masculino , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Monócitos/imunologia , Rim/imunologia , Rim/efeitos dos fármacosRESUMO
BACKGROUND: Cryptococcosis is a life-threatening disease caused by Cryptococcus neoformans or C. gattii. Neutralizing autoantibodies (auto-Abs) against granulocyte-macrophage colony-stimulating factor (GM-CSF) in otherwise healthy adults with cryptococcal meningitis have been described since 2013. We searched for neutralizing auto-Abs in sera collected from Colombian patients with non-HIV-associated cryptococcosis in a retrospective national cohort from 1997 to 2016. METHODS: We reviewed clinical and laboratory records and assessed the presence of neutralizing auto-Abs against GM-CSF in 30 HIV negative adults with cryptococcosis (13 caused by C. gattii and 17 caused by C. neoformans). RESULTS: We detected neutralizing auto-Abs against GM-CSF in the sera of 10 out of 13 (77%) patients infected with C. gattii and one out of 17 (6%) patients infected with C. neoformans. CONCLUSIONS: We report eleven Colombian patients diagnosed with cryptococcosis who had auto-Abs that neutralize GM-CSF. Among these patients, ten were infected with C. gattii and only one with C. neoformans.
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Anticorpos Neutralizantes , Autoanticorpos , Criptococose , Cryptococcus gattii , Cryptococcus neoformans , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Humanos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Masculino , Colômbia , Feminino , Adulto , Cryptococcus gattii/imunologia , Pessoa de Meia-Idade , Cryptococcus neoformans/imunologia , Criptococose/imunologia , Criptococose/diagnóstico , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Estudos Retrospectivos , Soronegatividade para HIV/imunologia , Adulto Jovem , IdosoRESUMO
BACKGROUND: Mesenchymal stromal cells (MSCs) tropism for tumours allows their use as carriers of antitumoural factors and in vitro transcribed mRNA (IVT mRNA) is a promising tool for effective transient expression without insertional mutagenesis risk. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine with antitumor properties by stimulating the specific immune response. The aim of this work was to generate modified MSCs by IVT mRNA transfection to overexpress GM-CSF and determine their therapeutic effect alone or in combination with doxorubicin (Dox) in a murine model of hepatocellular carcinoma (HCC). METHODS: DsRed or GM-CSF IVT mRNAs were generated from a cDNA template designed with specific primers followed by reverse transcription. Lipofectamine was used to transfect MSCs with DsRed (MSC/DsRed) or GM-CSF IVT mRNA (MSC/GM-CSF). Gene expression and cell surface markers were determined by flow cytometry. GM-CSF secretion was determined by ELISA. For in vitro experiments, the J774 macrophage line and bone marrow monocytes from mice were used to test GM-CSF function. An HCC model was developed by subcutaneous inoculation (s.c.) of Hepa129 cells into C3H/HeN mice. After s.c. injection of MSC/GM-CSF, Dox, or their combination, tumour size and mouse survival were evaluated. Tumour samples were collected for mRNA analysis and flow cytometry. RESULTS: DsRed expression by MSCs was observed from 2 h to 15 days after IVT mRNA transfection. Tumour growth remained unaltered after the administration of DsRed-expressing MSCs in a murine model of HCC and MSCs expressing GM-CSF maintained their phenotypic characteristic and migration capability. GM-CSF secreted by modified MSCs induced the differentiation of murine monocytes to dendritic cells and promoted a proinflammatory phenotype in the J774 macrophage cell line. In vivo, MSC/GM-CSF in combination with Dox strongly reduced HCC tumour growth in C3H/HeN mice and extended mouse survival in comparison with individual treatments. In addition, the tumours in the MSC/GM-CSF + Dox treated group exhibited elevated expression of proinflammatory genes and increased infiltration of CD8 + T cells and macrophages. CONCLUSIONS: Our results showed that IVT mRNA transfection is a suitable strategy for obtaining modified MSCs for therapeutic purposes. MSC/GM-CSF in combination with low doses of Dox led to a synergistic effect by increasing the proinflammatory tumour microenvironment, enhancing the antitumoural response in HCC.
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Carcinoma Hepatocelular , Doxorrubicina , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Neoplasias Hepáticas , Células-Tronco Mesenquimais , RNA Mensageiro , Animais , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Células-Tronco Mesenquimais/metabolismo , Camundongos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Linhagem Celular Tumoral , Transplante de Células-Tronco Mesenquimais/métodos , Humanos , Camundongos Endogâmicos C3H , TransfecçãoRESUMO
In general, ensuring safety is the top priority of a new modality. Although oncolytic virus armed with an immune stimulatory transgene (OVI) showed some promise, the strategic concept of simultaneously achieving maximum effectiveness and minimizing side effects has not been fully explored. We generated a variety of survivin-responsive "conditionally replicating adenoviruses that can target and treat cancer cells with multiple factors (m-CRAs)" (Surv.m-CRAs) armed with the granulocyte-macrophage colony-stimulating factor (GM-CSF) transgene downstream of various promoters using our m-CRA platform technology. We carefully analyzed both therapeutic and adverse effects of them in the in vivo syngeneic Syrian hamster cancer models. Surprisingly, an intratumor injection of a conventional OVI, which expresses the GM-CSF gene under the constitutively and strongly active "cytomegalovirus enhancer and ß-actin promoter", provoked systemic and lethal GM-CSF circulation and shortened overall survival (OS). In contrast, a new conceptual type of OVI, which expressed GM-CSF under the cancer-predominant and mildly active E2F promoter or the moderately active "Rous sarcoma virus long terminal repeat", not only abolished lethal adverse events but also prolonged OS and systemic anti-cancer immunity. Our study revealed a novel concept that optimal expression levels of an immune stimulatory transgene regulated by a suitable upstream promoter is crucial for achieving high safety and maximal therapeutic effects simultaneously in OVI therapy. These results pave the way for successful development of the next-generation OVI and alert researchers about possible problems with ongoing clinical trials.
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Secondary pulmonary alveolar proteinosis (SPAP) is one of the diffuse parenchymal lung diseases, and the utility and safety of transbronchial lung cryobiopsy (TBLC) for diagnosing SPAP are unknown. A case of SPAP diagnosed by TBLC is presented. Specimens that were useful for diagnosis were collected, and there was no adverse event following TBLC. The usefulness of TBLC for interstitial lung disease has been widely reported, but there are few reports of SPAP. We present the clinical course of TBLC in the diagnosis of SPAP.
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BACKGROUND: Lysinuric protein intolerance (LPI) is a multi-organ metabolic disorder characterized by the imbalance in absorption and excretion of cationic amino acids like lysine, ornithine and arginine. Infants with LPI typically present with recurrent vomiting, poor growth, interstitial lung disease or renal impairment. The early onset of pulmonary alveolar proteinosis (PAP) has been reported to be associated with a severe form of LPI. Treatment of PAP most commonly consists of whole-lung lavage (WLL) and in autoimmune PAP, granulocyte-macrophage colony stimulating factor (GM-CSF) administration. Nevertheless, GM-CSF therapy in LPI-associated PAP has not been scientifically justified. CASE PRESENTATION: We describe the case of an 8-month-old infant presenting with respiratory failure due to LPI associated with PAP, who was twice treated with WLL; firstly, while on veno-venous ECMO assistance and then by the use of a selective bronchial blocker. After the two treatments with WLL, she was weaned from daytime respiratory support while on initially subcutaneous, then on inhaled GM-CSF therapy. CONCLUSIONS: This case supports the notion that GM-CSF therapy might be of benefit in patients with LPI-associated PAP. Further studies are needed to clarify the exact mechanism of GM-CSF in patients with LPI-associated PAP.
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Erros Inatos do Metabolismo dos Aminoácidos , Lavagem Broncoalveolar , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Proteinose Alveolar Pulmonar , Humanos , Proteinose Alveolar Pulmonar/terapia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Lactente , Feminino , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Erros Inatos do Metabolismo dos Aminoácidos/complicaçõesRESUMO
Background: Diabetic lower extremity ulcer, including diabetic foot ulcer (DFU) and leg ulcer, is one of the refractory complications of diabetes, the treatment of which is challenging, expensive, and lengthy. Recombinant Human Granulocyte/Macrophage Colony-stimulating Factor (rhGM-CSF) is an immunomodulatory cytokine that has been mainly applied in the treatment of hematological diseases. Clinical evidence regarding GM-CSF in the treatment of diabetic lower extremity ulcers is limited. This study is the first case series that investigates the repurpose effects of rhGM-CSF on diabetic ulcer healing in real clinical practice. Methods: Nine patients diagnosed with diabetes and refractory lower extremity ulcer (ulcer duration ≥2 weeks) were included from September 2021 to February 2023 in the Division of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Patients with Wagner grade ≥4 and SINDAD ≥5 were excluded. The included subjects were treated with rhGM-CSF plus standard of care (SOC) including glycemic control, foot care education, debridement of necrotic tissues, topical wound dressings, offloading, and infection control when necessary. The observation endpoint was complete epithelialization. Their clinical manifestations, laboratory tests, and therapeutic effects were extracted and analyzed. Results: The case series included 9 cases aged from 29 to 80 years and all the patients were male. Seven of 9 patients presented neuropathic ulcer. Only one case showed non-infected ulcer from tissue samples and one case presented ankle brachial index (ABI) <0.9. It was observed that the ulcer areas among these 9 patients gradually declined throughout the whole treatment period with the average healing velocity 0.32 ± 013 cm2/day and the mean time to complete healing 16.0 ± 3.7 days. The relative area (percentage of initial ulcer area) decreased to 66.7 ± 13.0% on average after the first treatment. Ulcers in all the 9 patients achieved complete epithelialization after 4-8 times treatments. Conclusion: The case series suggests rhGM-CSF as a promising therapeutic strategy for the treatment of diabetic ulceration. More robust data from randomized controlled trials are required to further evaluate its clinical efficacy.
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BACKGROUND: Despite advances in medical therapy, many children and adults with ileal Crohn's disease (CD) progress to fibrostenosis requiring surgery. We aimed to identify MRI and circulating biomarkers associated with the need for surgical management. METHODS: This prospective, multicenter study included pediatric and adult CD cases undergoing ileal resection and CD controls receiving medical therapy. Noncontrast research MRI examinations measured bowel wall 3-dimensional magnetization transfer ratio normalized to skeletal muscle (normalized 3D MTR), modified Look-Locker inversion recovery (MOLLI) T1 relaxation, intravoxel incoherent motion (IVIM) diffusion-weighted imaging metrics, and the simplified magnetic resonance index of activity (sMaRIA). Circulating biomarkers were measured on the same day as the research MRI and included CD64, extracellular matrix protein 1 (ECM1), and granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies (Ab). Associations between MRI and circulating biomarkers and need for ileal resection were tested using univariate and multivariable LASSO regression. RESULTS: Our study sample included 50 patients with CD undergoing ileal resection and 83 patients with CD receiving medical therapy; mean participant age was 23.9â ±â 13.1 years. Disease duration and treatment exposures did not vary between the groups. Univariate biomarker associations with ileal resection included log GM-CSF Ab (odds ratio [OR],â 2.87; Pâ =â .0009), normalized 3D MTR (OR, 1.05; Pâ =â .002), log MOLLI T1 (OR, 0.01; Pâ =â .02), log IVIM perfusion fraction (f; OR, 0.38; Pâ =â .04), and IVIM apparent diffusion coefficient (ADC; OR, 0.3; Pâ =â .001). The multivariable model for surgery based upon corrected Akaike information criterion included age (OR, 1.03; Pâ =â .29), BMI (OR, 0.91; Pâ =â .09), log GM-CSF Ab (OR, 3.37; Pâ =â .01), normalized 3D MTR (OR, 1.07; Pâ =â .007), sMaRIA (OR, 1.14; Pâ =â .61), luminal narrowing (OR, 10.19; Pâ =â .003), log C-reactive protein (normalized; OR, 2.75; Pâ =â .10), and hematocrit (OR, 0.90; Pâ =â .13). CONCLUSION: After accounting for clinical and MRI measures of severity, normalized 3D MTR and GM-CSF Ab are associated with the need for surgery in ileal CD.
Despite advances in medical therapy, many patients with ileal Crohn's disease progress to fibrostenosis requiring surgery. Our study has shown that GM-CSF autoantibodies and MRI biomarker sequences are associated with the need for ileal resection and may help guide management decisions.
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This case report describes the use of smooth endoplasmic reticulum aggregates-positive (SERa+) oocytes along with intracytoplasmic sperm injection (ICSI), supplemented with granulocyte-macrophage colony-stimulating factor (GM-CSF), aiming to enhance fertilization rates and reproductive outcomes. A 39-year-old woman, facing primary infertility for the past seven years, received assisted reproductive treatment (ART), which included adding GM-CSF to the culture medium and culture SERa+ oocytes before ICSI. Clinical results, embryo quality, fertilization rates, and other fertility parameters were used to track the patient's progress toward this individualized approach that led to a positive twin pregnancy and healthy twin babies.
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BACKGROUND: Autoimmune pulmonary alveolar proteinosis (APAP) is a diffuse lung disease that causes abnormal accumulation of lipoproteins in the alveoli; however, its pathogenesis remains unclear. Recently, APAP cases have been reported during the course of dermatomyositis. The combination of these two diseases may be coincidental; however, it may have been overlooked because differentiating APAP from a flare-up of interstitial pneumonia associated with dermatomyositis is challenging. This didactic case demonstrates the need for early APAP scrutiny. CASE PRESENTATION: A 50-year-old woman was diagnosed with anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive dermatitis and interstitial pneumonia in April 2021. The patient was treated with corticosteroids, tacrolimus, and cyclophosphamide pulse therapy for interstitial pneumonia complicated by MDA5 antibody-positive dermatitis, which improved the symptoms and interstitial pneumonia. Eight months after the start of treatment, a new interstitial shadow appeared that worsened. Therefore, three additional courses of cyclophosphamide pulse therapy were administered; however, the respiratory symptoms and interstitial shadows did not improve. Respiratory failure progressed, and 14 months after treatment initiation, bronchoscopy revealed turbid alveolar lavage fluid, numerous foamy macrophages, and numerous periodic acid-Schiff-positive unstructured materials. Blood test results revealed high anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody levels, leading to a diagnosis of APAP. The patient underwent whole-lung lavage, and the respiratory disturbance promptly improved. Anti-GM-CSF antibodies were measured from the cryopreserved serum samples collected at the time of diagnosis of anti-MDA5 antibody-positive dermatitis, and 10 months later, both values were significantly higher than normal. CONCLUSIONS: This is the first report of anti-MDA5 antibody-positive dermatomyositis complicated by interstitial pneumonia with APAP, which may develop during immunosuppressive therapy and be misdiagnosed as a re-exacerbation of interstitial pneumonia. In anti-MDA5 antibody-positive dermatomyositis, APAP comorbidity may have been overlooked, and early evaluation with bronchoalveolar lavage fluid and anti-GM-CSF antibody measurements should be considered, keeping the development of APAP in mind.
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Doenças Autoimunes , Dermatite , Dermatomiosite , Doenças Pulmonares Intersticiais , Proteinose Alveolar Pulmonar , Feminino , Humanos , Pessoa de Meia-Idade , Proteinose Alveolar Pulmonar/complicações , Proteinose Alveolar Pulmonar/diagnóstico , Proteinose Alveolar Pulmonar/tratamento farmacológico , Dermatomiosite/complicações , Dermatomiosite/tratamento farmacológico , Autoanticorpos , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Dermatite/complicações , Helicase IFIH1 Induzida por InterferonRESUMO
T cells contribute to the pathogenesis of atherosclerosis. However, the presence and function of granulocyte-macrophage-colony-stimulating factor (GM-CSF)-producing T helper (ThGM) cells in atherosclerosis development is unknown. This study aims to characterize the phenotype and function of ThGM cells in experimental atherosclerosis. Atherosclerosis was induced by feeding apolipoprotein E knockout (ApoE-/-) mice with a high-fat diet. Aortic ThGM cells were detected and sorted by flow cytometry. The effect of oxidized low-density lipoprotein (oxLDL) on ThGM cells and the impact of ThGM cells on macrophages were evaluated by flow cytometry, quantitative RT-PCR, oxLDL binding/uptake assay, immunoblotting and foam cell formation assay. We found that GM-CSF+IFN-γ- ThGM cells existed in atherosclerotic aortas. Live ThGM cells were enriched in aortic CD4+CCR6-CCR8-CXCR3-CCR10+ T cells. Aortic ThGM cells triggered the expression of interleukin-1ß (IL-1ß), tumour necrosis factor (TNF), interleukin-6 (IL-6) and C-C motif chemokine ligand 2 (CCL2) in macrophages. Besides, aortic ThGM cells expressed higher CD69 than other T cells and bound to oxLDL. oxLDL suppressed the cytokine expression in ThGM cells probably via inhibiting the signal transducer and activator of transcription 5 (STAT5) signalling. Furthermore, oxLDL alleviated the effect of ThGM cells on inducing macrophages to produce pro-inflammatory cytokines and generate foam cells. The nuclear receptor subfamily 4 group A (NR4A) members NR4A1 and NR4A2 were involved in the suppressive effect of oxLDL on ThGM cells. Collectively, oxLDL suppressed the supportive effect of ThGM cells on pro-atherosclerotic macrophages.
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Aterosclerose , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Lipoproteínas LDL , Macrófagos , Linfócitos T Auxiliares-Indutores , Animais , Camundongos , Aterosclerose/genética , Citocinas/metabolismo , Células Espumosas/patologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Interleucina-6/metabolismo , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismoRESUMO
Uveal melanoma is the most common primary intraocular tumor in adults. Approximately 50% of patients develop metastatic disease despite successful treatment of the primary eye tumor. The liver is the most common site of metastatic disease occurring in more than 90% of patients. Clinical prognosis is dependent on the ability to control the growth of liver tumors. Locoregional therapies play an important role in stabilizing liver metastases, prolonging survival for patients with metastatic uveal melanoma. As overall survival is prolonged, the development of extrahepatic disease becomes more common. Immunoembolization, a form of liver-directed therapy, not only focuses on treating hepatic metastases by stimulating the local immune system to suppress the growth of liver tumors, but it potentially generates a systemic immune response delaying the growth of extrahepatic metastases as well. The following article discusses immunoembolization for the treatment of metastatic uveal melanoma including the rationale, mechanism of action, indications, contraindications, outcomes, and associated toxicities.
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Recurrent or metastatic cervical cancer carries a bleak prognosis and presents a formidable challenge in terms of treatment. Granulocyte-macrophage colony-stimulating factor (GM-CSF) increases the body's immune response by enhancing antigen presentation, which has been rarely reported in recurrent or metastatic cervical cancer. A 44-year-old woman presented to the hospital with vaginal bleeding four years after radical hysterectomy for stage IB2 squamous cell carcinoma (SCC) of the cervix (grade II-III). Gynecological examination and imaging revealed a vaginal mass, and the biopsy confirmed the recurrence of grade III SCC. The patient was treated with chemoradiation (CRT) combined with immunoadjuvant GM-CSF and achieved complete remission and a progression-free survival of two years.
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Autologous tooth grafting is a dental restorative modality based on periodontal ligament healing.Human periodontal ligament stem cells(PDLSCs) are involved in the formation and remodeling of periodontal tissue.Based on previous findings, the proliferation and differentiation of processing cryopreserved periodontal ligament stem cells (PDLSCs) exhibit similarities to those of fresh cells. However, there is evident absorption in the transplanted frozen tooth's roots and bones, with the underlying cause remaining unknown. Granulocyte macrophage colony-stimulating factor(GM-CSF) is named for its produce granulocyte and macrophage precursors from bone marrow precursors, and it also serves as one of the regulatory factors in inflammatory and osteoclast formation. This study aimed to investigate changes in GM-CSF expression in frozen PDLSCs (fhPDLSCs) and evaluate the impact of GM-CSF on PDLSCs with respect to cellular activity and osteogenic ability. The role of GM-CSF in periodontal absorption was further speculated by comparing with IL-1ß. The results revealed a significant increase in GM-CSF levels from fhPDLSCs compared to fresh cells, which exhibited an equivalent inflammatory stimulation effect as 1 ng/ml IL-1ß. Cell viability also increased with increasing concentrations of GM-CSF; however, the GM-CSF from fhPDLSCs was not sufficient to significantly trigger osteoclastic factors. Considering its interaction with IL-1ß and positive feedback mechanism, environments with high doses of GM-CSF derived from fhPDLSCs are more likely to activate osteoclastic responses.Therefore, for frozen tooth replantation, great attention should be paid to anti-inflammation and anti-infection.GM-CSF may serve as a potential therapeutic target for inhibiting periodontal resorption in delayed grafts.
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Perda do Osso Alveolar , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Dente , Humanos , Perda do Osso Alveolar/metabolismo , Perda do Osso Alveolar/terapia , Diferenciação Celular , Células Cultivadas , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Macrófagos , Osteoclastos , Dente/transplante , Transplante AutólogoRESUMO
A 31-year-old Japanese man presented with cerebral and pulmonary cryptococcosis. Cryptococcus gattii (C. gattii) genotype VGIIb was detected in the patient's sputum and cerebrospinal fluid specimens. The serum levels of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies were elevated in this patient, which has been associated with pulmonary alveolar proteinosis and is considered a risk factor for C. gattii infection. After undergoing >12 months of antifungal treatments, the patient showed improvements in symptoms and findings on brain and lung imaging. Several Japanese patients who develop C. gattii infection have also been reported; however, most of these patients have been infected outside Japan, as C. gattii infection is rare in Japan. Only one patient with C. gattii genotype VGIIb infection has been reported in Japan, and it is believed that this patient contracted the infection in China. In the present case, our patient has never been outside Japan, indicating that the infection originated in Japan. Our findings suggest that C. gattii might be spreading in Japan. Therefore, patients with positive serum anti-GM-CSF antibodies should be thoroughly monitored for C. gattii infection, even those living in Japan.
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Criptococose , Cryptococcus gattii , Genótipo , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Humanos , Masculino , Adulto , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Cryptococcus gattii/genética , Cryptococcus gattii/imunologia , Cryptococcus gattii/isolamento & purificação , Criptococose/microbiologia , Criptococose/imunologia , Criptococose/diagnóstico , Criptococose/tratamento farmacológico , Criptococose/sangue , Japão , Antifúngicos/uso terapêutico , Pneumopatias Fúngicas/microbiologia , Pneumopatias Fúngicas/imunologia , Pneumopatias Fúngicas/diagnóstico , População do Leste AsiáticoRESUMO
Immune checkpoint inhibitor (ICI) therapy improves outcomes in several cancers. Unfortunately, many patients experience grade 3-4 treatment-related adverse events, including gastrointestinal (GI) toxicities which are common. These GI immune-related adverse events (irAEs) induced by ICIs present significant clinical challenges, require prompt intervention, and result in treatment delays or discontinuations. The treatment for these potentially severe and even fatal GI irAEs which include enterocolitis, severe diarrhea, and hepatitis may interfere with the anti-cancer approach. Sargramostim (glycosylated, yeast-derived, recombinant human GM-CSF) is an agent that has been used in clinical practice for more than 30 years with a well-recognized safety profile and has been studied in many therapeutic areas. The mechanism of action of sargramostim may treat moderate-to-severe GI irAEs without impairing the anti-cancer therapy. Some early data also suggest a potential survival benefit. Through the differentiation/maturation of monocytes, macrophages, and neutrophils and induction of anti-inflammatory T cell responses, GM-CSF aids in GI homeostasis, mucosal healing, and mucosal immunity. GM-CSF knockout mice are susceptible to severe colitis which was prevented with murine GM-CSF administration. For some patients with GI mucosa and immune cell function impairment, e.g., Crohn's disease, sargramostim reduces disease severity. In a prospective, randomized study (ECOG 1608), advanced melanoma patients had a reduction in grade 3-5 GI irAEs and less frequent colonic perforation in the sargramostim plus ipilimumab arm compared to ipilimumab alone. Sargramostim continues to be studied with ICIs for the prophylactic management of irAEs while also potentially providing a survival benefit.
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Interleukin-6 (IL-6) superfamily cytokines play critical roles during human pregnancy by promoting trophoblast differentiation, invasion, and endocrine function, and maintaining embryo immunotolerance and protection. In contrast, the unbalanced activity of pro-inflammatory factors such as interferon gamma (IFNγ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) at the maternal-fetal interface have detrimental effects on trophoblast function and differentiation. This study demonstrates how the IL-6 cytokine family member oncostatin M (OSM) and STAT3 activation regulate trophoblast fusion and endocrine function in response to pro-inflammatory stress induced by IFNγ and GM-CSF. Using human cytotrophoblast-like BeWo (CT/BW) cells, differentiated in villous syncytiotrophoblast (VST/BW) cells, we show that beta-human chorionic gonadotrophin (ßhCG) production and cell fusion process are affected in response to IFNγ or GM-CSF. However, those effects are abrogated with OSM by modulating the activation of IFNγ-STAT1 and GM-CSF-STAT5 signaling pathways. OSM stimulation enhances the expression of STAT3, the phosphorylation of STAT3 and SMAD2, and the induction of negative regulators of inflammation (e.g., IL-10 and TGFß1) and cytokine signaling (e.g., SOCS1 and SOCS3). Using STAT3-deficient VST/BW cells, we show that STAT3 expression is required for OSM to regulate the effects of IFNγ in ßhCG and E-cadherin expression. In contrast, OSM retains its modulatory effect on GM-CSF-STAT5 pathway activation even in STAT3-deficient VST/BW cells, suggesting that OSM uses STAT3-dependent and -independent mechanisms to modulate the activation of pro-inflammatory pathways IFNγ-STAT1 and GM-CSF-STAT5. Moreover, STAT3 deficiency in VST/BW cells leads to the production of both a large amount of ßhCG and an enhanced expression of activated STAT5 induced by GM-CSF, independently of OSM, suggesting a key role for STAT3 in ßhCG production and trophoblast differentiation through STAT5 modulation. In conclusion, our study describes for the first time the critical role played by OSM and STAT3 signaling pathways to preserve and regulate trophoblast biological functions during inflammatory stress.
Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos , Interferon gama , Gravidez , Feminino , Humanos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Interferon gama/farmacologia , Interferon gama/metabolismo , Oncostatina M/farmacologia , Oncostatina M/metabolismo , Fator de Transcrição STAT5/metabolismo , Interleucina-6/metabolismo , Transdução de Sinais , Trofoblastos/metabolismo , Fator de Transcrição STAT3/metabolismoRESUMO
This study aimed to measure the duration and replication level of oncolytic herpes simplex virus type 2 (oHSV2) at the tumor injection site in BALB/c mice. Additionally, the expression level of human granulocyte macrophage colony-stimulating factor (hGM-CSF) and HSV-2 antibody in the serum was also measured. High and low doses of oHSV2-Fluc (firefly luciferin, Fluc) were injected into the mice's tumors to track the change and duration of fluorescence expression. The copy number of oHSV2 gene in tumor tissues was determined using quantitative real-time polymerase chain reaction (qPCR). Enzyme linked immunosorbent assay (ELISA) was used to detect the expression of hGM-CSF and HSV-2 antibody in the serum. The tumor volume in the high-dose group was significantly lower than that in the control group (P < 0.01). Intratumor injection of oHSV2-Fluc showed that the carried Fluc could continue to express in the tumor, with fluorescence still detectable at day 11 and declining to undetectable level by day 18. The mRNA expression of oHSV2 was detected in tumor tissues of both high and low dose groups on day 9 using qPCR. ELISA results showed that the levels of HSV2 antibody and hGM-CSF in both high and low dose groups were significantly increased compared to the control group (P < 0.05) after collecting orbital blood. These findings suggest that oHSV2 can replicate in the tumor and sustainably express exogenous factors, thus effectively targeting and killing the tumor. Furthermore, intratumoral injection of oHSV2 resulted in higher levels of hGM-CSF and HSV-2 antibodies found in the mice's serum.
Assuntos
Herpesvirus Humano 2 , Neoplasias , Camundongos , Animais , Humanos , Herpesvirus Humano 2/genéticaRESUMO
Background: Cryptococcosis is a life-threatening disease caused by Cryptococcus neoformans or C. gattii. Autoantibodies (auto-Abs) neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) in otherwise healthy adults with cryptococcal meningitis have been described since 2013. We searched for neutralizing auto-Abs in sera from Colombian patients with non-HIV related cryptococcosis in a retrospective national cohort collected from 1997 to 2016. Methods: We reviewed clinical and laboratory records and assessed the presence of neutralizing auto-Abs in 30 HIV (-) adults presenting cryptococcosis (13 by C. gattii, and 17 by C. neoformans). Results: We detected auto-Abs neutralizing GM-CSF in the plasma of 9 out of 13 (69%) patients infected with C. gattii and 1 out of 17 (6%) patients with C. neoformans. Conclusions: We report ten Colombian patients with cryptococcosis due to auto-Abs neutralizing GM-CSF. Nine of the ten patients were infected with C. gattii, and only one with C. neoformans.