Alveolar epithelial cells shape lipopolysaccharide-induced inflammatory responses and reprogramming of alveolar macrophages.

Alveolar macrophages (AMs) are sentinels in the airways, where they sense and respond to invading microbes and other stimuli. Unlike macrophages in other locations, AMs can remain responsive to Gram-negative lipopolysaccharides (LPS) after they have responded to LPS in vivo (they do not develop "endotoxin tolerance"), suggesting that the alveolar microenvironment may influence their responses. Although alveolar epithelial cells (AECs) normally limit AMs' innate responses, preventing inflammation induced by harmless antigens in the lung, how AECs influence the innate responses of AMs to infectious agents has been uncertain. Here we report that (1) after exposure to aspirated (intranasal instillation) LPS, AMs increase their responses to TLR agonists and elevate their phagocytic and bactericidal activities in mice; (2) Aspirated LPS pre-exposure increases host resistance to pulmonary infection caused by Gram-negative bacteria and the protection effect lasts for at least 35 days; (3) LPS stimulation of AECs both increases AMs' innate immune responses and prevents AMs from developing tolerance in vitro; (4) Upon LPS stimulation, AMs secreted TNF-α induces AECs to release GM-CSF, which potentiates AMs' response. These experiments have revealed a previously unappreciated role that AECs may play in boosting the innate responses of AMs and promoting resistance to pulmonary infections.

Efficacy of nebulized GM-CSF inhalation in preventing oral mucositis in patients undergoing hematopoietic stem cell transplantation: A retrospective study.

Objective: To study the efficacy of oxygen atomization inhalation of granulocyte-macrophage colony-stimulating factor (GM-CSF) for preventing oral mucositis in patients following hematopoietic stem cell transplantation. Methods: Data from patients who received hematopoietic stem cell transplantation and were treated with GM-CSF for the prevention/treatment of oral mucositis in our hospital from June 2021 to June 2023 were collected. The enrolled patients were divided into an observation group and a control group according to the use of GM-CSF. The WHO Mucositis Scale Assessment Criteria were utilized to evaluate the characteristics of patients with oral mucositis (OM) from the beginning of the pretreatment period until they were discharged from the hospital. The general data, preconditioning protocol, transplantation method, overall grade and duration of oral mucositis, pain score, nutritional score and number of days of parenteral nutrition use, oral mucosal infection status and antibiotic use intensity, the granulocyte and megakaryocyte reconstruction time, and adverse reaction reports of the patients were collected and summarized through the medical records system. Results: A total of 143 patients were included in this study, including 75 patients in the observation group. In the observation group, there were 36 males and 39 females aged 22-67 years. There were 45 patients who received autologous transplantation and 30 patients who received allogeneic transplantation. In terms of the disease distribution, there were 33 cases of leukemia, 24 cases of lymphoma, 11 cases of multiple myeloma, and 8 other cases (3 cases of aplastic anemia, 2 cases of myelodysplastic syndrome, 2 cases of myelofibrosis, 1 case of POEMS syndrome). There were 68 patients in the control group, including 33 males and 35 females; the control group patients were aged 25-74years. Forty-one patients received autologous transplantation, and 27 patients received allogeneic transplantation. The disease distribution included 29 cases of leukemia, 17 cases of lymphoma, 12 cases of multiple myeloma, and 7 other cases (3 cases of aplastic anemia, 2 cases of myelodysplastic syndrome, 1 case of myelofibrosis, 1 case of POEMS syndrome). There were no significant differences between the two groups concerning age, sex, disease distribution or the transplantation method (P > 0.05). In the observation group, 13 cases did not develop oral mucositis, and 32 cases developed oral mucositis (16 cases of Grade I, 14 cases of Grade II, 2 cases of Grade III, and 0 cases of Grade IV). In the control group, there were 5 cases without mucositis and 36 cases with oral mucositis (6 cases of Grade Ⅰ, 16 cases of Grade Ⅱ, 8 cases of Grade Ⅲ, and 6 cases of Grade Ⅳ), the difference was statistically significant (P < 0.05). The pain score and duration of mucositis in the observation group were significantly lower than those in the control group (P < 0.05). In addition, the oral infection rate, antibiotic use intensity, nutritional score, per capita number of days of parenteral nutrition use and hematopoietic reconstruction time in the observation group were significantly lower than those in the control group (P < 0.05). In the observation group, 8 patients did not develop oral mucositis, and 22 patients developed oral mucositis (13 cases of Grade I, 7 cases of Grade II, 1 case of Grade III, and 1 case of Grade IV). In the control group, 1 case did not develop mucositis, and 26 cases developed oral mucositis (3 cases of Grade Ⅰ, 10 cases of Grade Ⅱ, 9 cases of Grade Ⅲ, and 4 cases of Grade Ⅳ). The difference was statistically significant (P < 0.05). The pain score and duration of mucositis in the observation group were significantly lower than those in the control group (P < 0.05). In addition, the oral mucosal infection rate, antibiotic use intensity, nutritional score, per capita number of days of parenteral nutrition use and hematopoietic reconstruction time in the observation group were significantly lower than those in the control group (P < 0.05). No adverse reactions were reported in either group. Conclusion: In both autologous transplantation and allogeneic transplantation patients, GM-CSF atomized inhalation can improve the prevention and treatment of oral mucositis in stem cell transplantation patients, reduce the incidence of oral infection, reduce the intensity of antibiotic use and the number of days of parenteral nutrition use, and thus promote the process of hematopoietic reconstruction.

Effect of colony­stimulating factor in the mechanism of bone metastasis development (Review).

Bone metastasis (BM) is a common complication of cancer and contributes to a higher mortality rate in patients with cancer. The treatment of BM remains a significant challenge for oncologists worldwide. The colony­stimulating factor (CSF) has an important effect on the metastasis of multiple cancers. In vitro studies have shown that CSF acts as a cytokine, promoting the colony formation of hematopoietic cells by activating granulocytes and macrophages. Other studies have shown that CSF not only promotes cancer aggressiveness but also correlates with the development and prognosis of various types of cancer. In recent years, the effect of CSF on BM has been primarily investigated using cellular and animal models, with limited clinical studies available. The present review discussed the composition and function of CSF, as well as its role in the progression of BM across various types of cancer. The mechanisms by which osteoclast­ and osteoblast­mediated BM occur are comprehensively described. In addition, the mechanisms of action of emerging therapeutic agents are explored for their potential clinical applications. However, further clinical studies are required to validate these findings.

Inhibition of CEACAM1 expression in cytokine-activated neutrophils using JAK inhibitors.

OBJECTIVES: Carcinoembryonic-antigen-related cell-adhesion molecule 1 (CEACAM1) is an adhesion molecule that acts as a coinhibitory receptor in the immune system. We previously demonstrated that CEACAM1 is predominantly expressed on peripheral blood neutrophils in patients with RA. The aim of the present study was to investigate the effects of Janus kinase inhibitors (JAKi) on cytokine-activated human neutrophils and CEACAM1 expression. METHODS: Peripheral blood neutrophils were obtained from healthy subjects. Isolated neutrophils were stimulated with tumor necrosis factor-alpha (TNF-α) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in the presence or absence of JAKi. The expression of CEACAM1 in peripheral blood neutrophils was analyzed by flow cytometry. Protein phosphorylation of signal transducer and activator of transcription (STAT)1, STAT3, and STAT5 was assessed by western blot using phospho-specific antibodies. RESULTS: We found that TNF-α-induced CEACAM1 expression was marginally suppressed after pretreatment with pan-JAK inhibitor, tofacitinib. Moreover, TNF-α induced STAT1 and STAT3 phosphorylation at the late stimulation phase (4 to 16 h). The expressions of CEACAM1 on neutrophils were markedly up-regulated by GM-CSF not by interleukin (IL)-6 stimulation. All JAKi inhibited GM-CSF-induced CEACAM1 expressions on neutrophils, however, the inhibitory effects of baricitinib were larger compared to those of tofacitinib or filgotinib. Moreover, CEACAM1 was marginally upregulated in interferon (IFN)-γ stimulated neutrophils. Similarly, JAKi inhibited IFN-γ-induced CEACAM1 expressions on neutrophils. CONCLUSIONS: We demonstrated that JAKi prevent GM-CSF-induced CEACAM1 expression in neutrophils, and JAKi-induced inhibition depends on their selectivity against JAK isoforms. These findings suggest that JAKi can modulate the expression of CEACAM1 in cytokine-activated neutrophils, thereby limiting their activation.

Pulmonary alveolar proteinosis complicated by lung cancer with favorable prognosis: a case report and literature review.

With the increasing incidence of lung cancer, the coexistence of pulmonary alveolar proteinosis (PAP) and lung cancer is becoming more common. However, the standard treatment protocols for patients with both conditions are still being explored. The conflict between the rapidly evolving therapeutic approaches for tumors and the limited treatment options for PAP presents a significant challenge for clinicians. Determining the optimal timing of treatment for both conditions to maximize patient benefit is a clinical conundrum. Here, we report a rare case of PAP complicated by lung adenocarcinoma, where interstitial lung changes worsened after neoadjuvant therapy but improved significantly following surgical resection of the lung adenocarcinoma. This case highlights the importance of prioritizing tumor treatment in patients with lung cancer complicated by PAP and examines the interplay between the two conditions, as well as potential therapeutic strategies.

Denovo granulocyte-macrophage colony-stimulating factor antibody production has been linked to acute graft-versus-host disease following hematopoietic stem cell transplantation from an HLA-matched, unrelated donor.

The role of non-HLA antibodies in hematopoietic stem cell transplantation (HSCT) and acute graft-versus-host disease (aGVHD) is not established. Serum samples collected from 58 adult patients before and after HSCT were examined for non-HLA antibodies. Following HSCT, 47 out of 58 patients (81.0 %) had various antibody patterns, with 23 of them (39.7 %) producing denovo antibodies. The most prevalent antibodies were directed against granulocyte-macrophage colony-stimulating factor (GM-CSF). The Fisher exact test revealed a statistically significant correlation between the incidence of acute graft-versus-host disease and denovo production of GM-CSF antibodies in patients fully HLA-matched with their donors (p = 0.001). There were no cases of denovo GM-CSF antibody production seen in non-permissively HLA-mismatched patients. Consequently, we hypothesize that the development of aGVHD after HLA-matched HSCT may differ from that following HLA-mismatched HSCT.

Elevated Salt or Angiotensin II Levels Induce CD38+ Innate Immune Cells in the Presence of Granulocyte-Macrophage Colony Stimulating Factor.

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.

Efficacy and safety of recombinant human granulocyte-macrophage colony-stimulating factor hydrogel in treating second- or third-degree burn wounds in children: a systematic review and meta-analysis.

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.

An optimal promoter regulating cytokine transgene expression is crucial for safe and effective oncolytic virus immunotherapy.

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.

Modified mesenchymal stromal cells by in vitro transcribed mRNA: a therapeutic strategy for hepatocellular carcinoma.

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.

Autoantibodies Neutralizing GM-CSF in HIV-Negative Colombian Patients Infected with Cryptococcus gattii and C. neoformans.

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.

Whole lung lavage and GM-CSF use for pulmonary alveolar proteinosis in an infant with lysinuric protein intolerance: a case report.

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.

Cryobiopsy for Secondary Pulmonary Alveolar Proteinosis.

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.

Effects of Recombinant Human Granulocyte/Macrophage Colony-Stimulating Factor on Diabetic Lower Extremity Ulcers: Case Series of Nine Patients.

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.

SERa-Positive Oocyte Intracytoplasmic Injection and Its Outcome: A Case Report.

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.

MRI and Blood-based Biomarkers Are Associated With Surgery in Children and Adults With Ileal Crohn's Disease.

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 23.9 ±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], 2.87; P = .0009), normalized 3D MTR (OR, 1.05; P = .002), log MOLLI T1 (OR, 0.01; P = .02), log IVIM perfusion fraction (f; OR, 0.38; P = .04), and IVIM apparent diffusion coefficient (ADC; OR, 0.3; P = .001). The multivariable model for surgery based upon corrected Akaike information criterion included age (OR, 1.03; P = .29), BMI (OR, 0.91; P = .09), log GM-CSF Ab (OR, 3.37; P = .01), normalized 3D MTR (OR, 1.07; P = .007), sMaRIA (OR, 1.14; P = .61), luminal narrowing (OR, 10.19; P = .003), log C-reactive protein (normalized; OR, 2.75; P = .10), and hematocrit (OR, 0.90; P = .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.

Oxidized low-density lipoproteins impair the pro-atherosclerotic effect of granulocyte-macrophage-colony-stimulating factor-producing T helper cells on macrophages.

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.

A case of autoimmune pulmonary alveolar proteinosis during the course of treatment of rapidly progressive interstitial pneumonia associated with anti-MDA5 antibody-positive dermatomyositis.

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.

Granulocyte-Macrophage Colony-Stimulating Factor in Combination With Chemoradiation for Recurrent or Metastatic Cervical Cancer.

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.

Immunoembolization for the Treatment of Uveal Melanoma Hepatic Metastases.

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.