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Journal of Translational Medicine May 2024The immune microenvironment impacts tumor growth, invasion, metastasis, and patient survival and may provide opportunities for therapeutic intervention in pancreatic...
BACKGROUND
The immune microenvironment impacts tumor growth, invasion, metastasis, and patient survival and may provide opportunities for therapeutic intervention in pancreatic ductal adenocarcinoma (PDAC). Although never studied as a potential modulator of the immune response in most cancers, Keratin 17 (K17), a biomarker of the most aggressive (basal) molecular subtype of PDAC, is intimately involved in the histogenesis of the immune response in psoriasis, basal cell carcinoma, and cervical squamous cell carcinoma. Thus, we hypothesized that K17 expression could also impact the immune cell response in PDAC, and that uncovering this relationship could provide insight to guide the development of immunotherapeutic opportunities to extend patient survival.
METHODS
Multiplex immunohistochemistry (mIHC) and automated image analysis based on novel computational imaging technology were used to decipher the abundance and spatial distribution of T cells, macrophages, and tumor cells, relative to K17 expression in 235 PDACs.
RESULTS
K17 expression had profound effects on the exclusion of intratumoral CD8+ T cells and was also associated with decreased numbers of peritumoral CD8+ T cells, CD16+ macrophages, and CD163+ macrophages (p < 0.0001). The differences in the intratumor and peritumoral CD8+ T cell abundance were not impacted by neoadjuvant therapy, tumor stage, grade, lymph node status, histologic subtype, nor KRAS, p53, SMAD4, or CDKN2A mutations.
CONCLUSIONS
Thus, K17 expression correlates with major differences in the immune microenvironment that are independent of any tested clinicopathologic or tumor intrinsic variables, suggesting that targeting K17-mediated immune effects on the immune system could restore the innate immunologic response to PDAC and might provide novel opportunities to restore immunotherapeutic approaches for this most deadly form of cancer.
Topics: Humans; Keratin-17; Pancreatic Neoplasms; Tumor Microenvironment; Female; Carcinoma, Pancreatic Ductal; Male; CD8-Positive T-Lymphocytes; Macrophages; Middle Aged; Aged; Receptors, Cell Surface; Antigens, Differentiation, Myelomonocytic; Antigens, CD
PubMed: 38730319
DOI: 10.1186/s12967-024-05252-1 -
Experimental and Molecular Pathology Jun 2024Soluble CD163 (sCD163) is a selective marker of macrophages whose circulating levels have been found to be induced in patients with active inflammatory bowel disease...
Soluble CD163 (sCD163) is a selective marker of macrophages whose circulating levels have been found to be induced in patients with active inflammatory bowel disease (IBD). Urinary proteins are emerging as non-invasive diagnostic biomarkers, and here, sCD163 levels were measured in the urine of 18 controls and 63 patients with IBD by enzyme-linked immunosorbent assay. Urinary sCD163 levels did, however, not differentiate IBD patients from controls. Analysis of sCD163 in the serum of 51 of these patients did not show higher levels in IBD. Primary sclerosing cholangitis (PSC) is often associated with IBD, and sCD163 was higher in the urine of the 21 patients and in the serum of the 13 patients with PSC compared to patients with IBD. Of clinical relevance, urinary sCD163 levels were higher in PSC patients compared to those with other chronic liver diseases (n = 16), while serum sCD163 levels were comparable between the two groups. Serum sCD163 of IBD and PSC patients positively correlated with serum C-reactive protein. Serum creatinine and glomerular filtration rate, surrogate markers for renal function, did not significantly correlate with urinary or serum sCD163 levels in IBD or PSC patients. Moreover, urinary sCD163 was not related to fecal calprotectin levels whereas serum sCD163 of IBD patients showed a positive trend. PSC associated with IBD and PSC without underlying IBD had similar levels of urinary sCD163 while serum sCD163 tended to be higher in the latter group. In PSC patients, urinary sCD163 did not correlate with serum aminotransferase levels, gamma glutamyl transferase, alkaline phosphatase, bilirubin or the Model for End Stage Liver Disease score. Ursodeoxycholic acid was prescribed to our PSC patients and fecal levels of ursodeoxycholic acid and its conjugated forms were increased in PSC compared to IBD patients. Otherwise, fecal bile acid levels of IBD and PSC patients were almost identical, and were not correlated with urinary and serum sCD163 in PSC. In summary, our study identified urinary sCD163 as a potential biomarker for PSC.
Topics: Humans; Antigens, Differentiation, Myelomonocytic; Cholangitis, Sclerosing; Antigens, CD; Receptors, Cell Surface; Biomarkers; Male; Female; Middle Aged; Adult; Inflammatory Bowel Diseases; Aged; C-Reactive Protein; Leukocyte L1 Antigen Complex
PubMed: 38729058
DOI: 10.1016/j.yexmp.2024.104900 -
Breast Cancer Research : BCR May 2024Tumor-associated macrophages (TAMs) are a prominent immune subpopulation in the tumor microenvironment that could potentially serve as therapeutic targets for breast...
CD163 macrophages in the triple-negative breast tumor microenvironment are associated with improved survival in the Women's Circle of Health Study and the Women's Circle of Health Follow-Up Study.
BACKGROUND
Tumor-associated macrophages (TAMs) are a prominent immune subpopulation in the tumor microenvironment that could potentially serve as therapeutic targets for breast cancer. Thus, it is important to characterize this cell population across different tumor subtypes including patterns of association with demographic and prognostic factors, and breast cancer outcomes.
METHODS
We investigated CD163 macrophages in relation to clinicopathologic variables and breast cancer outcomes in the Women's Circle of Health Study and Women's Circle of Health Follow-up Study populations of predominantly Black women with breast cancer. We evaluated 611 invasive breast tumor samples (507 from Black women, 104 from White women) with immunohistochemical staining of tissue microarray slides followed by digital image analysis. Multivariable Cox proportional hazards models were used to estimate hazard ratios for overall survival (OS) and breast cancer-specific survival (BCSS) for 546 cases with available survival data (median follow-up time 9.68 years (IQR: 7.43-12.33).
RESULTS
Women with triple-negative breast cancer showed significantly improved OS in relation to increased levels of tumor-infiltrating CD163 macrophages in age-adjusted (Q3 vs. Q1: HR = 0.36; 95% CI 0.16-0.83) and fully adjusted models (Q3 vs. Q1: HR = 0.30; 95% CI 0.12-0.73). A similar, but non-statistically significant, association was observed for BCSS. Macrophage infiltration in luminal and HER2+ tumors was not associated with OS or BCSS. In a multivariate regression model that adjusted for age, subtype, grade, and tumor size, there was no significant difference in CD163 macrophage density between Black and White women (RR = 0.88; 95% CI 0.71-1.10).
CONCLUSIONS
In contrast to previous studies, we observed that higher densities of CD163 macrophages are independently associated with improved OS and BCSS in women with invasive triple-negative breast cancer. Trial registration Not applicable.
Topics: Humans; Female; Tumor Microenvironment; Antigens, Differentiation, Myelomonocytic; Antigens, CD; Middle Aged; Receptors, Cell Surface; Triple Negative Breast Neoplasms; Follow-Up Studies; Prognosis; Adult; Tumor-Associated Macrophages; Macrophages; Aged; Biomarkers, Tumor; Proportional Hazards Models
PubMed: 38720366
DOI: 10.1186/s13058-024-01831-8 -
WMJ : Official Publication of the State... May 2024Acute myelomonocytic leukemia is a type of acute myeloid leukemia with monocytic expansion. Both the disease and its treatment can be immunocompromising....
INTRODUCTION
Acute myelomonocytic leukemia is a type of acute myeloid leukemia with monocytic expansion. Both the disease and its treatment can be immunocompromising. Immunocompromised patients are more susceptible to infections, such as Fournier's gangrene, a rare necrotizing infection of the groin.
CASE PRESENTATION
A 56-year-old male presented to the emergency department with abdominal pain, leukocytosis, and perineal ecchymosis. Overnight, his perineal discoloration and tenderness worsened. He underwent irrigation and debridement for Fournier's gangrene and received broad-spectrum antimicrobial therapy. Subsequent workup revealed acute myeloid leukemia with leukemia cutis and central nervous system involvement, necessitating chemotherapy initiation prior to complete wound healing.
DISCUSSION/CONCLUSIONS
This case highlights the challenges in the diagnosis and management of acute leukemia in the setting of a concomitant life-threatening soft tissue infection, as both the hematologic disease and treatment thereof can exacerbate infectious complications.
Topics: Humans; Fournier Gangrene; Male; Middle Aged; Leukemia, Myelomonocytic, Acute; Diagnosis, Differential; Debridement; Immunocompromised Host
PubMed: 38718243
DOI: No ID Found -
Frontiers in Cellular and Infection... 2024The relationship between macrophages and the gut microbiota in patients with atherosclerosis remains poorly defined, and effective biological markers are lacking. This...
OBJECTIVE
The relationship between macrophages and the gut microbiota in patients with atherosclerosis remains poorly defined, and effective biological markers are lacking. This study aims to elucidate the interplay between gut microbial communities and macrophages, and to identify biomarkers associated with the destabilization of atherosclerotic plaques. The goal is to enhance our understanding of the underlying molecular pathways and to pave new avenues for diagnostic approaches and therapeutic strategies in the disease.
METHODS
This study employed Weighted Gene Co-expression Network Analysis (WGCNA) and differential expression analysis on atherosclerosis datasets to identify macrophage-associated genes and quantify the correlation between these genes and gut microbiota gene sets. The Random Forest algorithm was utilized to pinpoint PLEK, IRF8, BTK, CCR1, and CD68 as gut microbiota-related macrophage genes, and a nomogram was constructed. Based on the top five genes, a Non-negative Matrix Factorization (NMF) algorithm was applied to construct gut microbiota-related macrophage clusters and analyze their potential biological alterations. Subsequent single-cell analyses were conducted to observe the expression patterns of the top five genes and the interactions between immune cells. Finally, the expression profiles of key molecules were validated using clinical samples from atherosclerosis patients.
RESULTS
Utilizing the Random Forest algorithm, we ultimately identified PLEK, IRF8, CD68, CCR1, and BTK as gut microbiota-associated macrophage genes that are upregulated in atherosclerotic plaques. A nomogram based on the expression of these five genes was constructed for use as an auxiliary tool in clinical diagnosis. Single-cell analysis confirmed the specific expression of gut microbiota-associated macrophage genes in macrophages. Clinical samples substantiated the high expression of PLEK in unstable atherosclerotic plaques.
CONCLUSION
Gut microbiota-associated macrophage genes (PLEK, IRF8, CD68, CCR1, and BTK) may be implicated in the pathogenesis of atherosclerotic plaques and could serve as diagnostic markers to aid patients with atherosclerosis.
Topics: Humans; Macrophages; Plaque, Atherosclerotic; Gastrointestinal Microbiome; Biomarkers; Single-Cell Analysis; Algorithms; Machine Learning; Receptors, CCR1; Atherosclerosis; Antigens, Differentiation, Myelomonocytic; Agammaglobulinaemia Tyrosine Kinase; Antigens, CD; Gene Expression Profiling; Gene Regulatory Networks; CD68 Molecule; Interferon Regulatory Factors
PubMed: 38716195
DOI: 10.3389/fcimb.2024.1395716 -
Acta Neuropathologica Communications May 2024Neuroinflammation and Alzheimer's disease (AD) co-pathology may contribute to disease progression and severity in dementia with Lewy bodies (DLB). This study aims to...
BACKGROUND
Neuroinflammation and Alzheimer's disease (AD) co-pathology may contribute to disease progression and severity in dementia with Lewy bodies (DLB). This study aims to clarify whether a different pattern of neuroinflammation, such as alteration in microglial and astroglial morphology and distribution, is present in DLB cases with and without AD co-pathology.
METHODS
The morphology and load (% area of immunopositivity) of total (Iba1) and reactive microglia (CD68 and HLA-DR), reactive astrocytes (GFAP) and proteinopathies of alpha-synuclein (KM51/pser129), amyloid-beta (6 F/3D) and p-tau (AT8) were assessed in a cohort of mixed DLB + AD (n = 35), pure DLB (n = 15), pure AD (n = 16) and control (n = 11) donors in limbic and neocortical brain regions using immunostaining, quantitative image analysis and confocal microscopy. Regional and group differences were estimated using a linear mixed model analysis.
RESULTS
Morphologically, reactive and amoeboid microglia were common in mixed DLB + AD, while homeostatic microglia with a small soma and thin processes were observed in pure DLB cases. A higher density of swollen astrocytes was observed in pure AD cases, but not in mixed DLB + AD or pure DLB cases. Mixed DLB + AD had higher CD68-loads in the amygdala and parahippocampal gyrus than pure DLB cases, but did not differ in astrocytic loads. Pure AD showed higher Iba1-loads in the CA1 and CA2, higher CD68-loads in the CA2 and subiculum, and a higher astrocytic load in the CA1-4 and subiculum than mixed DLB + AD cases. In mixed DLB + AD cases, microglial load associated strongly with amyloid-beta (Iba1, CD68 and HLA-DR), and p-tau (CD68 and HLA-DR), and minimally with alpha-synuclein load (CD68). In addition, the highest microglial activity was found in the amygdala and CA2, and astroglial load in the CA4. Confocal microscopy demonstrated co-localization of large amoeboid microglia with neuritic and classic-cored plaques of amyloid-beta and p-tau in mixed DLB + AD cases.
CONCLUSIONS
In conclusion, microglial activation in DLB was largely associated with AD co-pathology, while astrocytic response in DLB was not. In addition, microglial activity was high in limbic regions, with prevalent AD pathology. Our study provides novel insights into the molecular neuropathology of DLB, highlighting the importance of microglial activation in mixed DLB + AD.
Topics: Humans; Lewy Body Disease; Alzheimer Disease; Female; Male; Aged; Aged, 80 and over; Neuroinflammatory Diseases; Microglia; Astrocytes; alpha-Synuclein; tau Proteins; Antigens, CD; Amyloid beta-Peptides; Middle Aged; Antigens, Differentiation, Myelomonocytic; Brain; CD68 Molecule
PubMed: 38715119
DOI: 10.1186/s40478-024-01786-z -
Journal of Cutaneous Pathology May 2024Traditionally, skin involvement in chronic myelomonocytic leukemia (CMML) has been considered to be either specific (leukemia cutis) or non-specific, with granulomatous...
Traditionally, skin involvement in chronic myelomonocytic leukemia (CMML) has been considered to be either specific (leukemia cutis) or non-specific, with granulomatous dermatitis included in the latter group. More recently, the true nature of the myeloid cells present in the cutaneous infiltrates of this theoretically reactive dermatitis is being clarified with the use of new molecular techniques such as next-generation sequencing. The same mutations in bone marrow (BM) myeloid neoplastic cells and in the cells of cutaneous infiltrates have been found. We present the case of a 77-year-old man who presented with spread and treatment-resistant skin granulomatous lesions previous to the diagnosis of CMML. The same clonal mutations in SRSF2, IDH1, and RUNX1 were found in both skin and BM with resolution of the lesions after the initiation of azacytidine. In conclusion, we report an exceptional case in which specific granulomatous cutaneous lesions have preceded and allowed the earlier diagnosis of an underlying CMML and a review of all previous similar cases in the literature, including molecular alterations.
PubMed: 38711181
DOI: 10.1111/cup.14638 -
Leukemia & Lymphoma May 2024The presence of mutation in hematological malignancies, excluding Hairy cell leukemia, and its significance as a driver mutation in myeloid neoplasms (MNs) remains...
The presence of mutation in hematological malignancies, excluding Hairy cell leukemia, and its significance as a driver mutation in myeloid neoplasms (MNs) remains largely understudied. This research aims to evaluate patient characteristics and outcomes of -mutated MNs. Among a cohort of 6667 patients, 48 (0.7%) had -mutated MNs. Notably, three patients exhibited sole mutation, providing evidence supporting the hypothesis of 's role as a driver mutation in MNs. In acute myeloid leukemia, the majority of patients had secondary acute myeloid leukemia, accompanied by poor-risk cytogenic and RAS pathway mutations. Although the acquisition of mutation during disease progression did not correlate with unfavorable outcomes, its clearance through chemotherapy or stem cell transplant exhibited favorable outcomes (median overall survival of 34.8 months versus 10.4 months, = 0.047). Furthermore, G469A was the most frequently observed mutation, differing from solid tumors and hairy cell leukemia, where V600E mutations were predominant.
PubMed: 38696743
DOI: 10.1080/10428194.2024.2347539 -
World Journal of Gastrointestinal... Apr 2024Chronic myelomonocytic leukemia (CMML) complicated with Sweet syndrome (SS) is a rare hematological neoplasm. However, cases of concomitant development of perianal...
BACKGROUND
Chronic myelomonocytic leukemia (CMML) complicated with Sweet syndrome (SS) is a rare hematological neoplasm. However, cases of concomitant development of perianal necrotizing SS (NSS) have not been reported.
CASE SUMMARY
We report a case of a 49-year-old male patient who underwent sequential procedures for hemorrhoids and perianal abscess. He developed postoperative incision infection and was referred to the department where the authors work. Initially, perianal necrotizing fasciitis secondary to incision infection after perianal abscess surgery was suspected. Despite receiving antibiotic therapy and undergoing surgical debridement, deeper necrotic areas formed in the patient's perianal wounds, accompanied by persistent high fever. Blood and fungal cultures yielded negative results. The final diagnosis was corrected to be CMML with suspected concomitant perianal NSS.
CONCLUSION
CMML with perianal NSS is a rare condition, often misdiagnosed as perianal abscess or perianal necrotizing fasciitis. Conventional antibiotic therapy and surgical debridement are ineffective in managing this condition.
PubMed: 38690058
DOI: 10.4240/wjgs.v16.i4.1176 -
Cardiovascular Diabetology Apr 2024The GLP-1 receptor agonist liraglutide is used to treat hyperglycemia in type 2 diabetes but is also known to induce weight loss, preserve the beta cell and reduce... (Comparative Study)
Comparative Study
BACKGROUND
The GLP-1 receptor agonist liraglutide is used to treat hyperglycemia in type 2 diabetes but is also known to induce weight loss, preserve the beta cell and reduce cardiovascular risk. The mechanisms underlying these effects are however still not completely known. Herein we explore the effect of liraglutide on markers of immune cell activity in a population of obese individuals with prediabetes or newly diagnosed type 2 diabetes mellitus.
METHOD
Plasma levels of the monocyte/macrophage markers, soluble (s)CD163 and sCD14, the neutrophil markers myeloperoxidase (MPO) and neutrophil gelatinase-associated lipocalin (NGAL),the T-cell markers sCD25 and T-cell immunoglobulin mucin domain-3 (sTIM-3) and the inflammatory marker TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) were measured by enzyme-linked immunosorbent assays in obese individuals with prediabetes or diabetes diagnosed within the last 12 months, prior to and after comparable weight loss achieved with lifestyle changes (n = 20) or liraglutide treatment (n = 20), and in healthy subjects (n = 13).
RESULTS
At baseline, plasma levels of the macrophage marker sCD163, and the inflammatory marker LIGHT were higher in cases as compared to controls. Plasma levels of sCD14, NGAL, sTIM-3 and sCD25 did not differ at baseline between patients and controls. After weight reduction following lifestyle intervention or liraglutide treatment, sCD163 decreased significantly in the liraglutide group vs. lifestyle (between-group difference p = 0.023, adjusted for visceral adipose tissue and triglycerides basal values). MPO and LIGHT decreased significantly only in the liraglutide group (between group difference not significant). Plasma levels of MPO and in particular sCD163 correlated with markers of metabolic dysfunction and inflammation. After weight loss, only sCD163 showed a trend for decreased levels during OGTT, both in the whole cohort as in those of liraglutide vs lifestyle group.
CONCLUSION
Weight loss following treatment with liraglutide was associated with reduced circulating levels of sCD163 when compared to the same extent of weight loss after lifestyle changes. This might contribute to reduced cardiometabolic risk in individuals receiving treatment with liraglutide.
Topics: Humans; Liraglutide; Diabetes Mellitus, Type 2; Weight Loss; Male; Middle Aged; Female; Obesity; Biomarkers; Antigens, Differentiation, Myelomonocytic; Prediabetic State; Receptors, Cell Surface; Treatment Outcome; Antigens, CD; Risk Reduction Behavior; Incretins; Adult; Case-Control Studies; Time Factors; Down-Regulation; Hypoglycemic Agents; Aged
PubMed: 38685051
DOI: 10.1186/s12933-024-02237-8