GM-CSF Research Articles

Peculiarities of granulocyte-macrophage and macrophage colony-stimulating factors receptors expression in subpopulations of peripheral blood monocytes of patients with chronic obstructive pulmonary disease

Introduction. To analyze of the severity of respiratory symptoms in patients with chronic obstructive pulmonary disease (COPD), depending on the presence of an exacerbation or novel coronavirus infection (NCVI), taking into account the activity of acute phase blood parameters.Materials and methods. The medical documentation of 162 patients with COPD was studied, which were divided into 3 groups: group 1 (n=61) ‒ COPD and NCVI, group 2 (n=53) – stable COPD, group 3 (n=48) ‒ COPD exacerbation. The severity of respiratory symptoms was assessed using points. To assess the activity of inflammation the following biochemical indicators were used ‒ C-reactive protein (CRP) and fibrinogen (g/L).Results. According to the severity of cough and the intensity of dyspnea on the mMRC scale, the first, second and third groups did not differ statistically (p=0.07). Patients of the first group (82.5%) characterized by the absence of classical criteria for exacerbation of COPD. In terms of the severity of sputum production, the first, second and third groups are statistically different (p=0.0001). The first, second and third groups differ significantly in the level of serum CRP (p=0.0001) and fibrinogen (p=0.009). According to the results of the correlation analysis, some relationships found between respiratory symptoms and the level of CRP and fibrinogen.Conclusion. The clinical feature of the associated course of stable COPD and NCVI is the presence of severe dyspnea and the absence of classic criteria for exacerbation of COPD. Systemic inflammation in NCVI and stable COPD are more pronounced than in isolated stable COPD or exacerbation and correlates with cough and dyspnea. Practitioners for the differential diagnosis of NCVI in stable COPD can use the data obtained.

Role of lamin A/C on dendritic cell function in antiviral immunity

Dendritic cells (DCs) play a crucial role in orchestrating immune responses, particularly in promoting IFNγ-producing-CD8 cytotoxic T lymphocytes (CTLs) and IFNγ-producing-CD4 T helper 1 (Th1) cells, which are essential for defending against viral infections. Additionally, the nuclear envelope protein lamin A/C has been implicated in T cell immunity. Nevertheless, the intricate interplay between innate and adaptive immunity in response to viral infections, particularly the role of lamin A/C in DC functions within this context, remains poorly understood. In this study, we demonstrate that mice lacking lamin A/C in myeloid LysM promoter-expressing cells exhibit a reduced capacity to induce Th1 and CD8 CTL responses, leading to impaired clearance of acute primary Vaccinia virus (VACV) infection. Remarkably, in vitro-generated granulocyte macrophage colony-stimulating factor bone marrow-derived DCs (GM-CSF BMDCs) show high levels of lamin A/C. Lamin A/C absence on GM-CSF BMDCs does not affect the expression of costimulatory molecules on the cell membrane but it reduces the cellular ability to form immunological synapses with naïve CD4 T cells. Lamin A/C deletion induces alterations in NFκB nuclear localization, thereby influencing NF-κB-dependent transcription. Furthermore, lamin A/C ablation modifies the gene accessibility of BMDCs, predisposing these cells to mount a less effective antiviral response upon TLR stimulation. This study highlights the critical role of DCs in interacting with CD4 T cells during antiviral responses and proposes some mechanisms through which lamin A/C may modulate DC function via gene accessibility and transcriptional regulation.

Spatiotemporal Control of Immune Responses with Nucleic Acid Cocktail Vaccine

AbstractNucleic acid vaccines play important roles in the prevention and treatment of diseases. However, limited immunogenicity remains a major obstacle for DNA vaccine applications in the clinic. To address the issue, the present study investigates a cocktail approach to DNA vaccination. In this proof‐of‐the‐concept study, the cocktail consists of two DNAs encoding viral hemagglutinin (HA) and granulocyte‐macrophage colony stimulatory factor (GM‐CSF), respectively. Data from the study demonstrate that recruitment and activation of antigen‐presenting cells (APCs) can be substantially improved by spatiotemporal regulation of GM‐CSF and HA expressions at the site of vaccination. The types of recruited APCs and their phenotypes are also controllable by adjusting the cocktail compositions. Compared to the mono‐ingredient vaccine, the optimized cocktail vaccine is able to enhance the anti‐viral humoral and T cell immune responses. No significant systemic inflammation is detected after either prime or boost immunization using the cocktail vaccine. Data in the study suggest that the DNA cocktail is a safe, effective, and controllable platform for improving vaccine efficacy.

Differential expression of plasma cytokines in sepsis patients and their clinical implications.

Sepsis, which is characterized by acute systemic inflammation and is associated with high rates of morbidity and mortality, presents a significant challenge in health care. Some scholars have found that the sequential organ failure assessment (SOFA) and quick SOFA scores are not ideal for predicting severe sepsis and mortality. Microbial culture takes a long time (2-3 d) and provides no information for early diagnosis and treatment. Therefore, new diagnostic methods for sepsis need to be explored. To assess cytokine levels in the plasma of sepsis patients and identify potential biomarkers for diagnosing sepsis. Ten sepsis patients admitted to the emergency department within 24 h of onset were enrolled as the observation group, whereas ten noninfected patients served as the control group. Of the 10 noninfected patients, 9 hypertension combined with cerebral infarction, 1 patients with vertiginous syndrome. Plasma Cytokines were measured using the Bio-Plex Pro™ Human Chemokine Panel 40-plex. Differentially expressed cytokines in plasma of sepsis and nonsepsis patients were analyzed using Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Interleukin (IL)-16, granulocyte-macrophage granulocyte-macrophage colony-stimulating factor (GM-CSF), CX3CL1, CXCL9, CXCL16, CCL25, and CCL23 plasma levels were significantly increased in sepsis patients. GO analysis revealed that these cytokines were mainly associated with cellular structures such as intermediates, nuclear plaques, adhesion plaques, lateral plasma membranes, and cell matrix junctions. These genes were involved in various molecular functions, such as cytokine activity, receptor ligand activity, and signal receptor activator activity, contributing to various biological functions, such as leukocyte chemotaxis, migration, and chemotaxis. KEGG analysis indicated involvement in cytokine cytokine receptor interactions, chemokine signaling pathways, virus-protein interactions with cytokines and cytokine receptors, and the tumor necrosis factor signaling pathway. Elevated serum levels of IL-16, GM-CSF, CX3CL1, CXCL9, CXCL16, CCL25, and CCL23 in sepsis patients suggest their potential as diagnostic biomarkers for sepsis.

Profiling migration of human monocytes in response to chemotactic and barotactic guidance cues

Monocytes are critical to innate immunity, participating in chemotaxis during tissue injury, infection, and inflammatory conditions. However, the migration dynamics of human monocytes under different guidance cues are not well characterized. Here, we developed a microfluidic device to profile the migration characteristics of human monocytes under chemotactic and barotactic guidance cues while also assessing the effects of age and cytokine stimulation. Human monocytes preferentially migrated toward the CCL2 gradient through confined microchannels, regardless of donor age and migration pathway. Stimulation with interferon (IFN)-γ, but not granulocyte-macrophage colony-stimulating factor (GM-CSF), disrupted monocyte navigation through complex paths and decreased monocyte CCL2 chemotaxis, velocity, and CCR2 expression. Additionally, monocytes exhibited a bias toward low-hydraulic-resistance pathways in asymmetric environments, which remained consistent across donor ages, cytokine stimulation, and chemoattractants. This microfluidic system provides insights into the unique migratory behaviors of human monocytes and is a valuable tool for studying peripheral immune cell migration in health and disease.

Deciphering the role of endothelial granulocyte macrophage-CSF in chronic inflammation associated with HIV

People with HIV (PWH) experience endothelial dysfunction (ED) that is aggravated by chronic inflammation and microbial translocation across a damaged gut barrier. Although this paradigm is well-described, downstream pathways that terminate in endothelial dysfunction are only partially understood. This study found increased expression of granulocyte macrophage colony stimulating factor (GM-CSF), toll-like receptor-4 (TLR4), and myeloperoxidase in the aortic endothelium of PWH compared to those without HIV. Bacteria-derived lipopolysaccharide (LPS) heightened glucose uptake and induced GM-CSF expression in primary human endothelial cells. Exposure to sodium-glucose cotransporter-2 (SGLT2) inhibitors reduced glucose uptake, GM-CSF release, and ED in LPS-activated endothelial cells exvivo, and PWH treated with SGLT2 inhibitors for diabetes had significantly lower plasma GM-CSF levels than non-diabetic PWH not on this medication. The findings suggest that microbial products trigger glucose uptake and GM-CSF expression in the endothelium, contributing to localized inflammation in PWH. Modifying this altered state could offer therapeutic benefits.

Tuberculosis in otherwise healthy adults with inherited TNF deficiency

Severe defects in human IFNγ immunity predispose individuals to both Bacillus Calmette–Guérin disease and tuberculosis, whereas milder defects predispose only to tuberculosis1. Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant. Neither has any other clinical phenotype and both mount normal clinical and biological inflammatory responses. Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFNγ. Blood leukocyte subset development is normal in these patients. However, an impairment in the respiratory burst was observed in granulocyte–macrophage colony-stimulating factor (GM-CSF)-matured MDMs and alveolar macrophage-like (AML) cells2 from both patients with TNF deficiency, TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages, and healthy control MDMs and AML cells differentiated with TNF blockers in vitro, and in lung macrophages treated with TNF blockers ex vivo. The stimulation of TNF-deficient iPS-cell-derived macrophages with TNF rescued the respiratory burst. These findings contrast with those for patients with inherited complete deficiency of the respiratory burst across all phagocytes, who are prone to multiple infections, including both Bacillus Calmette–Guérin disease and tuberculosis3. Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents.

Regulatory effect of rapamycin on recruitment and function of myeloid-derived suppressor cells in heart failure

BackgroundImmune response and inflammation play important roles in the physiological and pathophysiological processes of heart failure (HF). In our previous study, myeloid-derived suppressor cells (MDSCs), a heterogeneous group of immature myeloid cells with anti-inflammatory and immunosuppressive functions, were shown to exert cardioprotective effects in HF. The pharmacological targeting of MDSCs using rapamycin may emerge as a promising strategy for the prevention and treatment of HF. However, the specific mechanisms underlying rapamycin-induced MDSC accumulation remain unclear. Our study aimed to clarify the effects of rapamycin on the recruitment and function of MDSCs in HF, exploring new therapeutic options for the prevention and treatment of HF. MethodsWe used transverse aortic constriction surgery and isoproterenol injection to establish HF models. Flow cytometry, reverse transcription polymerase chain reaction, transcriptomics and western blot were used to explore the regulation of rapamycin on recruitment and function of MDSCs in HF. Furthermore, rapamycin and granulocyte–macrophage colony-stimulating factor (GM-CSF) were combined to induce exogenous MDSCs from bone marrow cells. ResultsRapamycin promotes the recruitment of MDSCs by inhibiting their maturation and differentiation via suppression of the Wnt signaling in HF mice and enhanced the immunosuppressive function of MDSCs via the NF-κB signaling. Furthermore, exogenous MDSCs induced by rapamycin and GM-CSF can significantly alleviate transverse aortic constriction-induced cardiac dysfunction. ConclusionsThe pharmacological targeting of MDSCs using rapamycin is a promising strategy for the prevention and treatment of HF.

Macrophage colony-stimulating factor receptor/CD115+ non-classical monocytes are expanded in systemic lupus erythematosus and associated with lupus nephritis

Objective In systemic lupus erythematosus (SLE), the non-classical monocyte compartment is expanded, but its phenotype and association with clinical disease manifestations have not been explored. Method Monocyte subsets from 39 SLE patients, 32 healthy age-matched controls, and 16 patients from a disease control (autoimmune connective tissue disease other than SLE) were determined based on CD14 and CD16 surface expression. Cell surface expression of the receptors for macrophage colony-stimulating factor (M-CSF) (CD115) and granulocyte–macrophage colony-stimulating factor (GM-CSF) (CD116), as well as 6-Sulpho LacNAc (slan), were analysed by flow cytometry. The association of monocyte populations with disease manifestations, disease activity markers, and current medication of each patient was analysed by chart review. Results Non-classical monocytes displayed a cell-type specific signature of high M-CSF receptor CD115 and low GM-CSF receptor CD116 expression that separated them from the other two monocyte subsets. In healthy individuals, the M-CSF receptor on non-classical monocytes was an age-dependent surface marker, with lower expression in young adults. However, SLE monocytes were characterized by a marked expansion of M-CSF receptor/CD115+ non-classical monocytes in patients of all ages. The expanded population of M-CSF receptor/CD115+ non-classical monocytes was associated with lupus nephritis but not with disease activity, and coexpressed slan. Conclusion The non-classical monocyte subset in SLE is characterized by an expansion of M-CSF receptor/CD115+ cells that are associated with lupus nephritis and coexpress slan.

PD-1 inhibitor combined with SBRT, GM-CSF, and thymosin alpha-1 in metastatic breast cancer: A case report and literature review.

Triple-negative breast cancer is characterized by a worse prognosis compared with other breast cancer subtypes, especially in the case of pretreated metastatic triple-negative breast cancer (mTNBC). Because of the limited treatment options and suboptimal response rates, there is a pressing need to explore novel treatment protocols. A 48-year-old female patient diagnosed with mTNBC who had not responded to multiple lines of therapy (including surgery, chemotherapy, and radiotherapy) but demonstrated significant efficacy and abscopal effects after enrolling in our clinical trial. Triple-negative breast cancer with lung metastases. The clinical trial combined stereotactic body radiotherapy, immunotherapy, granulocyte-macrophage colony-stimulating factor, and thymosin alpha-1 to treat previously treated metastatic solid cancers. This combined treatment regimen implemented in this clinical trial yielded the patient's notable efficacy, accompanied by abscopal effects. The target lesion and the 3 observed lesions achieved a partial response according to the RECIST v1.1 criteria. reevaluation scans after 2 cycles of immunotherapy indicated a regression rate of -78.97% for the target lesion and -56.73% for the observed lesions. Hematological indexes were stable, and there was no apparent myelosuppression. Also, the tumor marker CA-199 exhibited a downward trend. During the course of treatment, the patient experienced a grade 2 skin reaction, which improved after receiving antiallergic treatment. No further adverse effects were observed. This treatment regimen may offer a promising treatment strategy for patients with mTNBC and other metastatic solid cancers.

Paracrine Activation of STAT3 Drives GM-CSF Expression in Breast Carcinoma Cells, Generating a Symbiotic Signaling Network with Breast Carcinoma-Associated Fibroblasts.

This study evaluated the paracrine signaling between breast carcinoma-associated fibroblasts (CAFs) and breast cancer (BCa) cells. Resolving cell-cell communication in the BCa tumor microenvironment (TME) will aid the development of new therapeutics. Here, we utilized our patented TAME (tissue architecture and microenvironment engineering) 3D culture microphysiological system, which is a suitable pathomimetic avatar for the study of the BCa TME. We cultured in 3D BCa cells and CAFs either alone or together in cocultures and found that when cocultured, CAFs enhanced the invasive characteristics of tumor cells, as shown by increased proliferation and spread of tumor cells into the surrounding matrix. Secretome analysis from 3D cultures revealed a relatively high secretion of IL-6 by CAFs. A marked increase in the secretion of granulocyte macrophage-colony stimulating factor (GM-CSF) when carcinoma cells and CAFs were in coculture was also observed. We theorized that the CAF-secreted IL-6 functions in a paracrine manner to induce GM-CSF expression and secretion from carcinoma cells. This was confirmed by evaluating the activation of STAT3 and gene expression of GM-CSF in carcinoma cells exposed to CAF-conditioned media (CAF-CM). In addition, the treatment of CAFs with BCa cell-CM yielded a brief upregulation of GM-CSF followed by a marked decrease, indicating a tightly regulated control of GM-CSF in CAFs. Secretion of IL-6 from CAFs drives the activation of STAT3 in BCa cells, which in turn drives the expression and secretion of GM-CSF. As a result, CAFs exposed to BCa cell-secreted GM-CSF upregulate inflammation-associated genes such as IL-6, IL-6R and IL-8, thereby forming a positive feedback loop. We propose that the tight regulation of GM-CSF in CAFs may be a novel regulatory pathway to target for disrupting the CAF:BCa cell symbiotic relationship. These data provide yet another piece of the cell-cell communication network governing the BCa TME.

Sintilimab in combination with stereotactic body radiotherapy and granulocyte-macrophage colony-stimulating factor in metastatic non-small cell lung cancer: The multicenter SWORD phase 2 trial

This single-arm, multicenter, phase 2 trial (NCT04106180) investigated the triple combination of sintilimab (anti-PD1 antibody), stereotactic body radiotherapy (SBRT) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in metastatic non-small cell lung cancer (NSCLC). With a median follow-up of 32.1 months, 18 (36.7%, 90% CI 25.3%–49.5%) of the 49 evaluable patients had an objective response, meeting the primary endpoint. Secondary endpoints included out-of-field (abscopal) response rate (ASR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). The ASR was 30.6% (95% CI 18.3%–45.4%). The median PFS and OS were 5.9 (95% CI 2.5–9.3) and 18.4 (95% CI 9.7–27.1) months, respectively. Any grade and grade 3 TRAEs occurred in 44 (86.3%) and 6 (11.8%) patients, without grade 4–5 TRAEs. Moreover, in pre-specified biomarker analyses, SBRT-induced increase of follicular helper T cells (Tfh) in unirradiated tumor lesions and patient’s blood, as well as of circulating IL-21 levels, was found associated with improved prognosis. Taken together, the triple combination therapy was well tolerated with promising efficacy and Tfh may play a critical role in SBRT-triggered anti-tumor immunity in metastatic NSCLC.

Microglia-mediated neuroimmune suppression in PTSD is associated with anhedonia

Dynamic brain immune function in individuals with posttraumatic stress disorder is rarely studied, despite evidence of peripheral immune dysfunction. Positron emission tomography brain imaging using the radiotracer [11C]PBR28 was used to measure the 18-kDa translocator protein (TSPO), a microglial marker, at baseline and 3 h after administration of lipopolysaccharide (LPS), a potent immune activator. Data were acquired in 15 individuals with PTSD and 15 age-matched controls. The PTSD group exhibited a significantly lower magnitude LPS-induced increase in TSPO availability in an a priori prefrontal-limbic circuit compared to controls. Greater anhedonic symptoms in the PTSD group were associated with a more suppressed neuroimmune response. In addition, while a reduced granulocyte-macrophage colony-stimulating factor response to LPS was observed in the PTSD group, other measured cytokine responses and self-reported sickness symptoms did not differ between groups; these findings highlight group differences in central-peripheral immune system relationships. The results of this study provide evidence of a suppressed microglia-mediated neuroimmune response to a direct immune system insult in individuals with PTSD that is associated with the severity of symptoms. They also provide further support to an emerging literature challenging traditional concepts of microglial and immune function in psychiatric disease.

Immunologic Crosstalk and Host-Specific Immune Signature Associated with Dengue.

In tropical and subtropical regions, dengue fever is a common febrile illness that is mostly spread by Aedes mosquitoes. Urban population migration, inadequate water storage facilities, and high mosquito density are features associated with this disease. The severity of the illness ranges from mild to deadly dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), often with severe cases causing profound shock from extensive plasma leakage, and may result in demise. The symptoms of the illness include headache, myalgia, retro-orbital pain, and hemorrhagic signs. There may also be an intermittent shift in blood vessel integrity and coagulation, but recovery is typically complete and rapid. In this review, we emphasize the immunological aspects of this illness. The intricate interactions among the virus, host genes, and host immune systems impact the pathophysiology of dengue. Postinfection antibody-dependent enhancement is prominent, which significantly influences the etiology and virulence of the disease. Whereas the severe form only manifests when the host immune system is actively working to eradicate the infection by secreting several inflammatory cytokines, chemokines, and lipid mediators, for example, early dengue virus infection (DVI) resulted in the production of Interleukin 2 (IL-2), IL-6, and later infection, IL-4, IL-5, and IL-10. Higher concentrations of interferons gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage migration inhibitory factor (MIF), IL-1, IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, and IL-13 were found in DHF patients. These are significantly more prevalent in severe infections than in mild ones. Numerous immunopathogenic processes involving both virus and host variables influence the severity of dengue. There is growing evidence that a compromised immune system limits viral clearance and causes severe inflammation, which in turn causes dengue hemorrhagic fever and dengue shock syndrome. Furthermore, the capacity of DENV to infect a broad range of immune cells, such as macrophages, dendritic cells, mast cells, T and B cells, and monocytes, further dysregulates these cells' antiviral activities, leading to the spread of the virus. Even though a number of risk factors linked to the advancement of the disease have been suggested, further research and evaluation of novel technologies are necessary to understand the complicated etiology and develop reliable and effective vaccines to fight against this febrile illness.

Results of a phase I/IIa trial of SV-BR-1-GM inoculation with low-dose cyclophosphamide and interferon alpha (Bria-IMT) in metastatic breast cancer

ABSTRACT This Phase I/IIa open-label, single-arm clinical trial addressing advanced, refractory, metastatic breast cancer was conducted at six medical centers in the United States. We repeated inoculations with irradiated SV-BR-1-GM, a breast cancer cell line with antigen-presenting activity engineered to release granulocyte-macrophage colony-stimulating factor (GM-CSF), with pre-dose low-dose cyclophosphamide and post-dose local interferon alpha. Twenty-six patients were enrolled; 23 (88.5%) were inoculated, receiving a total of 79 inoculations. There were six Grade 4 and one Grade 5 adverse events noted (judged unrelated to SV-BR-1-GM). Disease control (stable disease [SD]) occurred in 8 of 16 evaluable patients; 4 showed objective regression of metastases, including 1 patient with near-complete regressions in 20 of 20 pulmonary lesions. All patients with regressions had human leukocyte antigen (HLA) matches with SV-BR-1-GM; non-responders were equally divided between matching and nonmatching (p = .01, Chi-squared), and having ≥2 HLA matches with SV-BR-1-GM (n = 6) correlated with clinical benefit. Delayed-type hypersensitivity (DTH) testing to candida antigen and SV-BR-1-GM generated positive responses (≥5 mm) in 11 (42.3%) and 13 (50%) patients, respectively. Quantifying peripheral circulating tumor cells (CTCs) and cancer-associated macrophage-like cells (CAMLs) showed that a drop in CAMLs was significantly correlated with an improvement in progression-free survival (PFS; 4.1 months vs. 1.8 months, p = .0058). Eight of 10 patients significantly upregulated programmed cell death ligand 1 (PD-L1) on CTCs/CAMLs with treatment (p = .0012). These observations support the safety of the Bria-IMT regimen, demonstrate clinical regressions, imply a role for HLA matching, and identify a possible value for monitoring CAMLs in peripheral blood.

A phase II randomized trial of talimogene laherparepvec oncolytic immunotherapy with or without radiotherapy for patients with cutaneous metastases from solid tumors

BackgroundCutaneous metastases (CMs) are a manifestation of advanced cancer and can be treated with oncolytic immunotherapy. Laboratory studies suggest radiotherapy (RT) may facilitate response to immunotherapy. We hypothesized that oncolytic immunotherapy with talimogene lapherparepvec (T-VEC, an oncolytic immunotherapy that expresses granulocyte–macrophage colony stimulating factor) and RT would produce response in non-targeted metastases. MethodsA randomized phase 2 trial of T-VEC+/-RT was conducted. Eligible patients had ≥1 CM from a solid tumor amenable to T-VEC and RT and another measurable metastasis. Tumor and overall response was assessed using modified World Health Organization (mWHO) criteria. Adverse events (AEs) and quality of life (QOL) were characterized using CTCAE v4.0 and Skindex-16, respectively. Correlative analyses of tumor genomics and the immune system were performed. Results19 patients were randomized to receive T-VEC (n = 9) or T-VEC+RT (n = 10). One patient in each arm demonstrated complete response in the largest non-targeted metastasis. The trial was closed after the first stage of enrollment because of no overall mWHO responses, slow accrual and the COVID-19 pandemic. AEs were consistent with prior reports of T-VEC. Skin related QOL was poor before and after treatment. Median progression free survival was 1.2 and 2.5 months in the T-VEC and T-VEC+RT arms; median overall survival was 4.9 and 17.3 months in the T-VEC and T-VEC+RT arms. Analyses of peripheral blood cells and cytokines demonstrated responders exhibited several outlying lymphocyte and cytokine parameters. ConclusionsLow overall response rate, slow accrual, and the COVID-19 pandemic led to closure of this trial. Responses in non-injected and non-irradiated metastases were infrequent.

European Respiratory Society guidelines for the Diagnosis and Management of Pulmonary Alveolar Proteinosis.

Pulmonary alveolar proteinosis (PAP) is a rare syndrome caused by several distinct diseases leading to progressive dyspnoea, hypoxemia, risk of respiratory failure and early death due to accumulation of proteinaceous material in the lungs. Diagnostic strategies may include computed tomography (CT) of the lungs, bronchoalveolar lavage, evaluation of antibodies against granulocyte macrophage colony stimulating factor (GM-CSF), genetic testing, and, eventually, lung biopsy. The management options are focused at removing the proteinaceous material by whole lung lavage (WLL), augmentation therapy with GM-CSF, rituximab, plasmapheresis, and lung transplantation. The presented diagnostic and management guideline aim to provide guidance to physicians managing patients with PAP. A European Respiratory Society Task Force committee composed of clinicians, methodologists, and patients with experience in PAP developed recommendations in accordance with the ERS Handbook for Clinical Practice Guidelines and the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach. This included a systematic review of the literature and application of the GRADE approach to assess the certainty of the evidence and strength of recommendations. The committee formulated five PICO (Patients, Intervention, Comparison, Outcomes) questions, and two narrative questions to develop specific evidence-based recommendations. The Task Force committee developed recommendations for five PICOs. These included management of PAP with WLL, GM-CSF augmentation therapy, rituximab, plasmapheresis, and lung transplantation. Also, the committee made recommendations regarding the use of GM-CSF antibody testing, diagnostic bronchoalveolar lavage (BAL) and biopsy based on narrative questions.In addition to the recommendations, the committee provided information on the hierarchy of diagnostic interventions and therapy. The diagnosis of PAP is based on CT and BAL cytology or lung histology, whereas diagnosis of specific PAP-causing diseases requires GM-CSF antibody testing or genetic analysis. There are several therapies including WLL and augmentation therapy with GM-CSF available to treat PAP, but supporting evidence is still limited.

GC-MS Analysis and In-silico Molecular Docking of Phytoconstituents of Sansevieria roxburghiana against IL-1β and TNF-α for Anti-Rheumatic Activity

Background: Rheumatoid arthritis (RA) is recognized as a long-term inflammatory form of arthritis. This inflammation becomes long-lasting, and the synovial tissue thickens as a result of increased cell activity, protein production, and other variables in the joint, causing discomfort, redness, and warmth. It can also harm the joints of the hands, wrists, fingers, elbows, shoulders, toes, spinal column, and knees. Due to the autoimmune response, there is an aberrant production of inflammatory mediators such as Tumour necrosis factor- alpha (TNF-a), Interleukins (IL-1, IL-6, IL-7, IL-15, IL-17, IL-18, and IL-23), Granulocyte-macrophage colony-stimulating factor (GM-CSF), and Interferon (IFN)-ϒ. By inhibiting their production, those inflammatory mediators will play a pivotal role in the therapy of RA. Purpose of the Study: The goal of the current study was to explore the anti-rheumatic activity of Sansevieria roxburghiana using the computational docking method. Research Rationale: Administration of Non-steroidal anti-inflammatory drugs, steroidal medicaments, and Disease-modifying anti-rheumatoid therapies creates substantial adverse effects in people suffering with RA. To overcome the burdens and toxicity of drug products herbal medicines were taken into the field of research. Materials and Methods: For this, 14 bioactive compounds from ethanolic extract of S. roxburghiana leaves were identified using the GC-MS (Gas chromatography-mass spectrometry) study and utilized as a binding compound (ligand) for biological target interactions. The crystallographic geometries of two targeted molecules, Interleukin-1β (IL-1β) and Tumour necrosis factor-alpha (TNF-α), have been retrieved from the PDB database. Methotrexate, a well-known medication for IL-1β and TNF-α inhibitors, was chosen as the reference for the comparative analysis. Computational docking was performed using the Autodock4 (version 1.5.6) choice based on the score functions. Results: The results displayed the binding energy as follow -10.13, -9.77, -8.98 and -8.67 Kcal/mol of 2-isopropyl-5 methyl cyclohexyl 3-(1-(4-chlorophenyl)-3-oxobutyl)-C, 3-chloro-5-cholestene, stigmasterol, and cycloartanol against IL-1 β (PDB ID: 4GAI) and standard methotrexate was -8.14 Kcal/mol. For TNF-α (PDB ID: 5M2J) the binding energy is -8.94, -8.85, -8.46, and -8.24 Kcal/mol of cycloartanol, stigmasterol, 2-isopropyl-5 methyl cyclohexyl 3-(1-(4-chlorophenyl)-3-oxobutyl)-C and 3-chloro-5-cholestene by with comparing methotrexate (-8.89 Kcal/mol). Conclusion: Hence, it was indicated that the phytoconstituents of S. roxburghiana could serve as a potential approach for designing future antirheumatic drugs.

Perfused In Vitro Intestine Tissue Model to Evaluate the Role of Stromal and Immune Cells in Epithelial Response to Inflammatory Cues and Drug Therapies.

We establish an in vitro perfusion intestinal tissue bioreactor system tailored to study drug responses related to inflammatory bowel disease (IBD). The system includes key components including multiple human intestinal cell types (colonoids, myofibroblasts, and macrophages), a three-dimensional (3D) intestinal architecture, and fluid flow. Inclusion of myofibroblasts resulted in increased secretion of cytokines such as glypican-1 (GCP-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin 1-α (IL-1α), whereas inclusion of macrophages resulted in increased secretion of monocyte chemoattractant proteins (MCPs) demonstrating a significant role of both stromal and immune cell types in intestinal inflammation. The system is responsive to drug treatments, as reflected in the reduction of pro-inflammatory cytokine production in tissue in some treatment scenarios. While future studies are needed to evaluate more nuanced responses in an IBD context, the present study demonstrates the ability to establish a 3D intestinal model with multiple relevant cell types and flow that is responsive to both inflammatory cues and various drug treatment options.

Rheumatoid Arthritis Treatment: Harnessing Novel Molecular Targets and Therapeutics for Improved Patient Outcomes

Rheumatoid arthritis (RA) is a chronic autoimmune disease that has significant unmet needs for improved treatment outcomes. This review provides an overview of emerging molecular targets and potential new therapies for managing RA. The discussed targets, such as CD40-CD40 ligand, programmed death protein 1 (PD-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 receptor-associated kinases (IRAKs), tyrosine kinase 2 (TYK2), bradykinin receptor 1 (B1R), and OX40-OX40 ligand, have shown promising results in preclinical studies and clinical trials. These findings stimulate continued efforts to develop more effective and safer therapeutic options, encouraging stakeholders to contribute to improving RA management.