Correlation of inflammation-related markers with MDSC and IL-17, and use as prognostic indicators in patients with advanced gastric and colorectal cancers.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14204-e14204
Author(s):  
Masahiko Shibata ◽  
Daisuke Ujiie ◽  
Mai Ashizawa ◽  
Tomohiro Kikuchi ◽  
Hirokazu Okayama ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Markers ◽  
Mononuclear Cells ◽  
Suppressor Cells ◽  
Prognostic Indicators ◽  
Peripheral Blood Mononuclear ◽  
Patients With Cancer ◽  
Kaplan Meier ◽  
Th 17 ◽  
Advanced Stages

e14204 Background: Although a causal relationship for inflammation and immunity of cancer is more widely accepted today, the precise cell mechanisms mediating this relationship have not been elucidated. Accumulating evidence suggests that myeloid-derived suppressor cells (MDSC), may contribute to the negative regulation of immune responses during cancer and inflammation. IL-17 is a pro-inflammatory cytokine that is primarily secreted by T helper (Th)17 cells and we have reported that IL-17 correlates with immunosuppressive conditions in patients with cancer. Methods: PBMC (peripheral blood mononuclear cells) were harvested from 106 patients including 43 with gastric and 63 with colorectal cancer. PBMC were stimulated with PHA (phytohemagglutinin) and the production of IL-17 was measured by ELISA. MDSC were detected by flow cytometry (CD11b+,CD14-,CD33+). The levels of CRP (C-reacting protein) and NLR (neutrophil to lymphocyte ratio) were used as inflammatory markers. Results: Both of MDSC and IL-17 production were increased in patients with advanced stages, and correlated with each other, inflammatory markers and immune suppression. The patients were divided with average levels of MDSC and IL-17 production and the prognosis were analyzed with Kaplan-Meier method. The overall survival of patients with high MDSC or high IL-17 production were significantly worse than those with low MDSC or low IL-17 production, respectively, in patients with stages III and IV, although the differences were not significant in patients with stages I and II. Conclusions: Thus these inflammatory markers are closely related with systemic inflammation involving IL-17 and with immunosuppression driven by MDSC, and are effective prognostic indicators in patients with stages III and IV gastric and colorectal cancer.

Correlation of IL-17 with immune suppression involving MDSC, malnutrition, and prognosis in patients with gastric and colorectal cancer.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 83-83 ◽  
Author(s):  
Kenji Gonda ◽  
Masahiko Shibata ◽  
Daisuke Ujiie ◽  
Mai Ashizawa ◽  
Tomohiro Kikuchi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Immune Suppression ◽  
Stimulation Index ◽  
Suppressor Cells ◽  
Retinol Binding Protein ◽  
Reactive Protein ◽  
Th 17 ◽  
Cell Mediated Immune Response ◽  
Inflammatory Processes ◽  
Advanced Stages

83 Background: Although a causal relationship linking inflammation and cancer immunity is more widely accepted today, precise cell mechanisms mediating this relationship have not been elucidated. IL-17, a pro-inflammatory cytokine primarily secreted by T helper (Th)17 cells, has previously been associated with inflammatory processes in autoimmune disease. The presence of IL-17 and Th17 cells has been confirmed in various invasive cancers and recently linked to immunosuppression in cancer patients. We investigated systemic inflammation, immune suppression, malnutrition, and prognosis associated with IL-17 in patients with gastric and colorectal cancer. Methods: We measured IL-17 in 106 patients, including 43 with gastric and 63 with colorectal cancer, Production of IL-17 stimulated by PHA was measured by ELISA. MDSC (myeloid-derived suppressor cells), which significantly contribute to immunosuppression, were measured by flow cytometry (CD11b+CD14-CD33+). Neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) were used as inflammatory markers. Production of IL-12 and the SI (stimulation index) of lymphocytes’ blastogenic response were used as markers of cell-mediated immune response. Results: Production of IL-17 increased in advanced stages of gastric and colorectal cancer. IL-17 positively correlated with levels of MDSC, serum concentrations of VEGF, NLR, and levels of CRP, and was inversely correlated with IL-12 production, SI, and nutritional markers including prealbumin and retinol binding protein. Patient cohorts were divided into two groups with IL-17 level (540 pg/ml) and OS (overall survival) of patients with stages III and IV gastric or colorectal cancer both significantly worse in patients with high production of IL-17 than in those with low IL-17, although the differences were not significant in patients at stages I and II. Conclusions: The present study suggests that IL-17 may reflect an inflammatory impact on the advancement and progression of cancer, and it may serve as useful marker of immune suppression involving MDSC, malnutrition, and poor prognosis in patients with gastric and colorectal cancer.

Blood myeloid derived suppressor cells (MDSC) in metastatic urothelial carcinoma (mUC) are correlated with neutrophil-to-lymphocyte ratio (NLR) and overall survival (OS).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 436-436
Author(s):  
Iris Yeong- Fung Sheng ◽  
C. Marcela Diaz-Montero ◽  
Patricia A. Rayman ◽  
Wei (Auston) Wei ◽  
Jaleh Fallah ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Dynamic Assessment ◽  
Suppressor Cells ◽  
Intravesical Therapy ◽  
Rank Test ◽  
Peripheral Blood Mononuclear ◽  
Inflammatory Microenvironment ◽  
Inflammatory Biomarker ◽  
Kaplan Meier

436 Background: MDSC have been linked to the chronic inflammatory microenvironment of tumor cells and pathologic outcomes in UC patients (pts) undergoing cystectomy. NLR is an established inflammatory biomarker with prognostic properties in mUC. We hypothesized that MDSCs correlate with NLR and OS in mUC. Methods: MDSCs were measured in blood samples from mUC patients by fresh unfractionated whole blood (WB) and peripheral blood mononuclear cells (PBMC). MDSCs were identified by flow cytometry in WB and defined as LinloCD33+/HLADR- (Total MDSC). MDSC subsets were defined as polymorphonuclear (PMN-MDSC: CD15+/CD14-), monocytic (M-MDSC: CD15-/CD14+), and uncommitted (UC-MDSC: CD15-/CD14-). MDSC populations were presented as % of live nucleated blood cells from PB and absolute numbers from WB. Spearman’s correlation assessed correlations between MDSC & NLR. Kaplan Meier curves and log rank test estimated OS from the time of MDSC collection to last follow up or date of death. Results: Of 79 pts, 77% were men and 42% were never smokers with a median age of 69 (31-83). Overall, 71% had pure UC and 81% had lower tract UC. Prior therapies include intravesical therapy (22%), neoadjuvant chemotherapy (31%), and cystectomy/nephroureterectomy (61%). Median follow up was 12 months (range: 0.6-36.5). PMN-MDSC was the predominant subset in WB and PBMC. There was significant correlation between individual MDSC subsets in WB and PBMC (p≤0.001). Negative correlation was noted between NLR and WB UC-MDSC:PMN-MDSC ratios (rho = -0.27, p = 0.03), as well as NLR and PB UC-MDSC:PMN-MDSC (rho = -0.28, p = 0.02). Median survival was 17.7 months (95% CI: 11.0-NA months). Overall 1-yr and 3-yr survival were 0.60 (95% CI: 0.49-0.73) and 0.15 (95% CI: 0.03-0.67), respectively. Higher WB UC-MDSC levels were associated with shorter OS (HR 2.85, 95% CI: 1.43-5.65, p = 0.003). Conclusions: Specific MDSC subsets correlate with NLR. Higher WB UC-MDSC levels have negative prognostic roles for OS. Given the feasibility of serial blood draws, dynamic assessment of MDSC over time and further validation with longer follow up are needed.

Relationship of myeloid-derived suppressor cells (MDSC) and immune suppression, nutritional impairment, and inflammatory markers in patients with gastrointestinal cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 675-675 ◽  
Author(s):  
Masahiko Shibata ◽  
Kenji Gonda ◽  
Izumi Nakamura ◽  
Shinji Ohki ◽  
Kenichi Sakurai ◽  
...  
Keyword(s):  
Chronic Inflammation ◽  
Gastrointestinal Cancer ◽  
Peripheral Blood ◽  
Inflammatory Markers ◽  
Mononuclear Cells ◽  
Suppressor Cells ◽  
Cell Mediated Immunity ◽  
Myeloid Derived Suppressor Cells ◽  
Peripheral Blood Mononuclear ◽  
Immune Suppressor Cells

675 Background: A suppression of cell mediated immunity and malnutrition are commonly seen in patients with advanced cancer and it has been reported that chronic inflammation plays a key role in induction of these conditions. MDSC: myeloid-derived suppressor cells, found as a new type of immune suppressor cells that is closely related to chronic inflammation, have reported to be present in blood circulation in patients with cancer. MDSC have been reported to suppress immune function through several pathways. Methods: Peripheral blood mononuclear cells (PBMC) were collected from 18 normal healthy volunteers, and 53 patients with gastrointestinal cancer including 5 patients with esophageal, 16 with gastric, 26 with colorectal, 3 with bile duct, 1 with pancreatic and 1 with hepatocellular carcinomas, and these cells were used for the detection of MDSC (CD11b+CD14-CD33+) by flow cytometry. PBMC was also used for the PHA-blastogenesis of lymphocytes which is a marker of cell mediated immunity (stimulation indices: SI). Results: MDSC(%PBMC) of whole patients with gastrointestinal cancer, those with gastric cancer and those with colorectal cancer were higher than those of healthy volunteer (3.76+4.90%, 5.18+1.86%, 4.21+1.43% vs 1.59+1.08%, p<0.05, p<0.05, p<0.10, respectively). MDSC of patients with gastrointestinal cancer were also inversely correlated to the SI (r=−0.271, p<0.05) and to the serum concentrations of total protein (r=−0.490, p<0.005). It also tended to correlate to neutrophil counts (r=0.287, p<0.10) and neutrophil/lymphocyte ratios (NLR, r=0.623, p=0.10), and inversely did to lymphocyte counts (r=−0.251, p<0.10).Thus MDSC was successfully detected in peripheral blood and was significantly higher in patients with gastrointestinal cancer. It was related to the inhibition of cell-mediated immunity, hypoaproteinemia and inflammatory markers such as NLR. Conclusions: MDSC seemed to work in the mechanisms of suppression of immune reaction and malnutrition, typically seen in cancer cachexia, in patients with gastrointestinal cancer and may be important as a marker of advancement of malignant diseases.

scholarly journals 686 Characterization of a novel compound that inhibits peroxynitrite generation by myeloid derived suppressor cells

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A714-A714
Author(s):  
Gabriella Lapurga ◽  
Steven Sun ◽  
Erick Carlson ◽  
Himanshu Savardekar ◽  
Kari Kendra ◽  
...  
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Human Peripheral Blood ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Peripheral Blood Mononuclear ◽  
Patients With Cancer ◽  
Blood Mononuclear Cells

BackgroundMyeloid-derived suppressor cells (MDSC) are immature immune cells that suppress immunity and mediate resistance to immune–based cancer therapies. MDSC exert their immunosuppressive effects partly through the production of reactive nitrogen and oxygen species, which combine to form peroxynitrite (PNT). PNT reacts with the tyrosine residues of key immune cell signaling proteins and inactivates them via nitration. Targeting MDSC via PNT inhibitors is an attractive avenue to improve the response to immunotherapy. The Peterson and Carson Labs have collaborated to develop a novel inhibitor of PNT and have explored its use in murine tumor models and human patients with cancer.MethodsSplenocytes (comprised of 12% MDSC) were isolated from mice bearing tumors derived from the EMT6 breast cancer cell line and cultured with 10 µm beads labelled with polyclonal antibodies (immunoglobulin-G or IgG). Fluorescence emitted upon MDSC recognition and reaction with IgG was detected with a previously reported fluorescent sensor compound termed PS3. Cells were mixed with PS3 and IgG beads (or controls: IgG without beads and beads without IgG) and treated for 4 hours with the following agents: (1) BRP0112233, a novel biaryl furan discovered via high-throughput screening using PNT depletion as the readout (6 or 12 µM); (2) Ibrutinib, an FDA-approved Bruton's tyrosine kinase inhibitor shown by the Carson Lab to inhibit the activity of nitric oxide synthase in MDSC, (2, 10 µM); and (3) PBS control. Fluorescence produced by reaction of PS3 with PNT was measured in triplicate wells using a Clariostar plate reader.ResultsSplenocytes from tumor-bearing mice produced significantly greater levels of PNT than normal splenocytes (24-fold vs 8-fold increase over plain beads, p<0.0001). Differences in fluorescence were confirmed via confocal microscopy. BRP0112233 inhibited PNT levels by 40% and 85% for the 6 and 12 µM doses, respectively. Ibrutinib inhibited PNT output by 90% and 100% at 2 and 10 µM. Cell viability was >90% except for the higher BRP dose (60% viability). In humans, peripheral blood mononuclear cells (PBMC) isolated from patients with cancer produced more PNT than healthy donor PBMC.ConclusionsPNT output could be reproducibly quantified via this assay and BRP0112233 and ibrutinib greatly inhibited MDSC PNT production. Using the EMT6 model, these compounds are being tested in combination with anti-PD-1 antibodies approved for patients with cancer. This assay has shown similar results in human peripheral blood mononuclear cells isolated from patients with cancer.AcknowledgementsWe thank the NIH (NCI UM1 CA186712, R01CA211720), a OSUCCC Translational Therapeutics Seed Grant, and the Pelotonia Fellowship Program for financial support.

scholarly journals Blood functional assay for rapid clinical interpretation of germline TP53 variants

2020 ◽  
pp. jmedgenet-2020-107059 ◽  
Author(s):  
Sabine Raad ◽  
Marion Rolain ◽  
Sophie Coutant ◽  
Céline Derambure ◽  
Raphael Lanos ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Transcriptional Response ◽  
Functional Assay ◽  
Mrna Levels ◽  
Peripheral Blood Mononuclear ◽  
Patients With Cancer ◽  
Pathogenic Variants ◽  
Functional Variants ◽  
Multiplex Ligation Probe Amplification ◽  
P53 Mrna

BackgroundThe interpretation of germline TP53 variants is critical to ensure appropriate medical management of patients with cancer and follow-up of variant carriers. This interpretation remains complex and is becoming a growing challenge considering the exponential increase in TP53 tests. We developed a functional assay directly performed on patients’ blood.MethodsPeripheral blood mononuclear cells were cultured, activated, exposed to doxorubicin and the p53-mediated transcriptional response was quantified using reverse transcription–multiplex ligation probe amplification and RT-QMPSF assays, including 10 p53 targets selected from transcriptome analysis, and two amplicons to measure p53 mRNA levels. We applied this blood functional assay to 77 patients addressed for TP53 analysis.ResultsIn 51 wild-type TP53 individuals, the mean p53 functionality score was 12.7 (range 7.5–22.8). Among eight individuals harbouring likely pathogenic or pathogenic variants, the scores were reduced (mean 4.8, range 3.1–7.1), and p53 mRNA levels were reduced in patients harbouring truncating variants. We tested 14 rare unclassified variants (p.(Pro72His), p.(Gly105Asp), p.(Arg110His), p.(Phe134Leu), p.(Arg158Cys), p.(Pro191Arg), p.(Pro278Arg), p.(Arg283Cys), p.(Leu348Ser), p.(Asp352Tyr), p.(Gly108_Phe109delinsVal), p.(Asn131del), p.(Leu265del), c.-117G>T) and 12 yielded functionally abnormal scores. Remarkably, the assay revealed that the c.*1175A>C polymorphic variant within TP53 poly-adenylation site can impact p53 function with the same magnitude as a null variant, when present on both alleles, and may act as a modifying factor in pathogenic variant carriers.ConclusionThis blood p53 assay should therefore be a useful tool for the rapid clinical classification of germline TP53 variants and detection of non-coding functional variants.

scholarly journals Depression, GABA, and Age Correlate with Plasma Levels of Inflammatory Markers

2019 ◽  
Vol 20 (24) ◽  
pp. 6172
Author(s):  
Amol K. Bhandage ◽  
Janet L. Cunningham ◽  
Zhe Jin ◽  
Qiujin Shen ◽  
Santiago Bongiovanni ◽  
...  
Keyword(s):  
Inflammatory Markers ◽  
Major Depressive Episode ◽  
Mononuclear Cells ◽  
Gamma Aminobutyric Acid ◽  
Protein Markers ◽  
Major Depressive ◽  
Peripheral Blood Mononuclear ◽  
Inhibitory Neurotransmitter ◽  
Mental Diseases ◽  
And Control

Immunomodulation is increasingly being recognised as a part of mental diseases. Here, we examined whether levels of immunological protein markers changed with depression, age, or the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). An analysis of plasma samples from patients with a major depressive episode and control blood donors (CBD) revealed the expression of 67 inflammatory markers. Thirteen of these markers displayed augmented levels in patients compared to CBD. Twenty-one markers correlated with the age of the patients, whereas 10 markers correlated with the age of CBD. Interestingly, CST5 and CDCP1 showed the strongest correlation with age in the patients and CBD, respectively. IL-18 was the only marker that correlated with the MADRS-S scores of the patients. Neuronal growth factors (NGFs) were significantly enhanced in plasma from the patients, as was the average plasma GABA concentration. GABA modulated the release of seven cytokines in anti-CD3-stimulated peripheral blood mononuclear cells (PBMCs) from the patients. The study reveals significant changes in the plasma composition of small molecules during depression and identifies potential peripheral biomarkers of the disease.

scholarly journals Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 71 ◽  
Author(s):  
Varun Sasidharan Nair ◽  
Salman M Toor ◽  
Rowaida Z Taha ◽  
Ayman A Ahmed ◽  
Mohamed A Kurer ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
T Regulatory Cell ◽  
Peripheral Blood Mononuclear ◽  
Functional Studies ◽  
Normal Tissues ◽  
Pathway Analyses ◽  
Colorectal Cancer Patients

T cell immunoglobulin mucin-3 (TIM-3) is an immune checkpoint identified as one of the key players in regulating T-cell responses. Studies have shown that TIM-3 is upregulated in the tumor microenvironment (TME). However, the precise role of TIM-3 in colorectal cancer (CRC) TME is yet to be elucidated. We performed phenotypic and molecular characterization of TIM-3+ T cells in the TME and circulation of CRC patients by analyzing tumor tissues (TT, TILs), normal tissues (NT, NILs), and peripheral blood mononuclear cells (PBMC). TIM-3 was upregulated on both CD4+ and CD3+CD4− (CD8+) TILs. CD4+TIM-3+ TILs expressed higher levels of T regulatory cell (Tregs)-signature genes, including FoxP3 and Helios, compared with their TIM-3− counterparts. Transcriptomic and ingenuity pathway analyses showed that TIM-3 potentially activates inflammatory and tumor metastatic pathways. Moreover, NF-κB-mediated transcription factors were upregulated in CD4+TIM-3+ TILs, which could favor proliferation/invasion and induce inflammatory and T-cell exhaustion pathways. In addition, we found that CD4+TIM-3+ TILs potentially support tumor invasion and metastasis, compared with conventional CD4+CD25+ Tregs in the CRC TME. However, functional studies are warranted to support these findings. In conclusion, this study discloses some of the functional pathways of TIM-3+ TILs, which could improve their targeting in more specific therapeutic approaches in CRC patients.

scholarly journals Anti-lymphocyte globulin stimulates normal human T cells to proliferate and to release lymphokines in vitro. A study at the clonal level

Blood ◽  
1988 ◽  
Vol 72 (3) ◽  
pp. 956-963
Author(s):  
GC Barbano ◽  
A Schenone ◽  
S Roncella ◽  
R Ghio ◽  
A Corcione ◽  
...  
Keyword(s):  
T Cells ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Interleukin 2 ◽  
Suppressor Cells ◽  
Peripheral Blood Mononuclear ◽  
Gm Csf ◽  
Recombinant Interleukin 2 ◽  
Macrophage Colony

Abstract Human peripheral blood mononuclear cells (PBMC) were stimulated in vitro with anti-lymphocyte globulin (ALG), and the phenotypic and functional properties of the blasts obtained were investigated. When stained with monoclonal antibodies (MoAbs), all of the blasts were identified as T cells that expressed predominantly the CD4 phenotype (70% of the cells). The remaining blasts were CD8+. These findings demonstrate that ALG stimulates both helper-inducer and cytotoxic- suppressor cells at random since the CD4 to CD8 ratio in the stimulated blasts was the same as in resting PBMC. This ratio is different from that observed in short-term cultures of T cells stimulated with phytohemagglutinin (PHA) under the same conditions (CD4 to CD8 ratio less than 1). ALG-stimulated T cells were cloned by limiting dilution in the presence of recombinant Interleukin-2 (rIL-2). The clones obtained were expanded and maintained in long term cultures with rIL-2. Thirty-two clones were tested for their capacity of producing colony stimulating activity (CSA) or burst promoting activity (BPA). Twenty- eight of them produced CSA and 12 produced BPA. No correlation was found between the surface phenotype and the ability of the clones to produce CSA or BPA (ie, both the CD4+ and CD8+ clones released the cytokines). When 16 of the same clones were tested for II-2 and gamma interferon (gamma IFN) production, 12 were found to be gamma INF and IL- 2 producers. All of the gamma IFN producers also released IL-2, whereas in the single clones no correlation was found with the capacity of releasing BPA and CSA. Supernatants from selected T-cell clones were also tested for hematopoietic growth factor activities in the presence of neutralizing antisera to human granulocyte-macrophage colony stimulating factor (GM-CSF) or to Interleukin-3 (IL-3). It was found that most CSA was attributable to GM-CSF, whereas BPA was mainly related to the presence of IL-3.

scholarly journals DDAH2 mRNA Expression Is Inversely Associated with Some Cardiovascular Risk-Related Features in Healthy Young Adults

2009 ◽  
Vol 27 (1) ◽  
pp. 37-44 ◽  
Author(s):  
Blanca Puchau ◽  
Helen Hermana M. Hermsdorff ◽  
M. Ángeles Zulet ◽  
J. Alfredo Martínez
Keyword(s):  
Young Adults ◽  
Cardiovascular Risk ◽  
Mrna Expression ◽  
Inflammatory Markers ◽  
Mononuclear Cells ◽  
Expression Profiles ◽  
Peripheral Blood Mononuclear ◽  
Disease Marker ◽  
Reduced Risk ◽  
Apparently Healthy

The purpose of this study was to evaluate whether the mRNA expression profiles of three genes (PRMT1, DDAH2 and NOS3) are related to ADMA metabolism and signalling, and the potential relationships with anthropometrical, biochemical, lifestyle and inflammatory indicators in healthy young adults. An emphasis on the putative effect of different mRNA expression on cardiovascular risk-related features was paid. Anthropometrical measurements as well as lifestyle features were analyzed in 120 healthy young adults. Fasting blood samples were collected for the measurement of glucose and lipid profiles as well as the concentrations of selected inflammatory markers. Profiles of mRNA expression were assessed for PRMT1, DDAH2 and NOS3 genes from peripheral blood mononuclear cells. Regarding inflammatory biomarkers, DDAH2 was inversely associated with IL-6 and TNF-α. Moreover, subjects in the highest quintile of DDAH2 mRNA expression showed a reduced risk to have higher values of waist circumference, and to be more prone to show higher values of HDL-c. Interestingly, DDAH2 gene expression seemed to be related with some anthropometrical, biochemical, lifestyle and inflammatory indicators linked to cardiovascular risk in apparently healthy young adults, emerging as a potential disease marker.

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