Levels of Circulating PD-L1 Are Decreased in Patients with Resectable Cholangiocarcinoma

Tumor resection represents the only curative treatment option for patients with biliary tract cancers (BTCs), including intrahepatic cholangiocarcinoma (CCA), perihilar and extrahepatic CCA and gallbladder cancer. However, many patients develop early tumor recurrence and are unlikely to benefit from surgery. Therefore, markers to identify ideal surgical candidates are urgently needed. Circulating programmed cell death 1 ligand 1 (PD-L1) has recently been associated with different malignancies, including pancreatic cancer which closely resembles BTC in terms of patients’ prognosis and tumor biology. Here, we aim at evaluating a potential role of circulating PD-L1 as a novel biomarker for resectable BTC. Methods: Serum levels of PD-L1 were analyzed by ELISA in 73 BTC patients and 42 healthy controls. Results: Circulating levels of preoperative PD-L1 were significantly lower in patients with BTC compared to controls. Patients with low PD-L1 levels displayed a strong trend towards an impaired prognosis, and circulating PD-L1 was negatively correlated with experimental markers of promalignant tumor characteristics such as CCL1, CCL21, CCL25 and CCL26. For 37 out of 73 patients, postoperative PD-L1 levels were available. Interestingly, after tumor resection, circulating PD-L1 raised to almost normal levels. Notably, patients with further decreasing PD-L1 concentrations after surgery showed a trend towards an impaired postoperative outcome. Conclusion: Circulating PD-L1 levels were decreased in patients with resectable BTC. Lack of normalization of PD-L1 levels after surgery might identify patients at high risk for tumor recurrence or adverse outcome.

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The possible role of Interleukin-6 as a regulator of insulin sensitivity in patients with neuromyelitis optica spectrum disorder

BMC Neurology ◽

10.1186/s12883-021-02198-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Zhila Maghbooli ◽

Abdorreza Naser Moghadasi ◽

Nasim Rezaeimanesh ◽

Abolfazl Omidifar ◽

Tarlan Varzandi ◽

...

Keyword(s):

Insulin Sensitivity ◽

Neuromyelitis Optica ◽

Serum Levels ◽

Spectrum Disorder ◽

Control Group ◽

Neuromyelitis Optica Spectrum Disorder ◽

Downstream Signaling ◽

Reduce Insulin Sensitivity ◽

Circulating Levels

Abstract Background Neuromyelitis optica spectrum disorder (NMOSD) is associated with inflammatory mediators that may also trigger downstream signaling pathways leading to reduce insulin sensitivity. Methods We aimed to determine the risk association of hyperinsulinemia in NMOSD patients with seropositive AQP4-IgG and the serum levels of interleukin (IL)-6 and IL-17A compared with the control group. Serum levels of metabolic (Insulin, Fasting Blood Sugar (FBS), lipid profile) and inflammatory (IL-6 and IL-17) markers were assessed in 56 NMOSD patients and 100 controls. Results Hyperinsulinemia was more prevalent in NMOSD patients independent of age, sex and body mass index (BMI) (48.2% vs. 26%, p = 0.005) compared to control group. After adjusting age, sex and BMI, there was significant association between lower insulin sensitivity (IS) and NMOSD risk (95% CI: Beta = 0.73, 0.62 to 0.86, p = 0.0001). Circulating levels of IL-6 and IL-17 were higher in NMOSD patients, and only IL-6 had an effect modifier for the association between lower insulin sensitivity and NMOSD risk. Conclusions Our data suggests that inflammatory pathogenesis of NMOSD leads to hyperinsulinemia and increases the risk of insulin resistance.

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Soluble urokinase plasminogen activator receptor (suPAR) as a novel biomarker in patients undergoing resection of pancreatic adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.248 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 248-248

Author(s):

Sven H Loosen ◽

Marcel Binnebösel ◽

Thomas Longerich ◽

Christoph Roderburg ◽

Christian Trautwein ◽

...

Keyword(s):

Plasminogen Activator ◽

Pancreatic Adenocarcinoma ◽

Tumor Resection ◽

Serum Levels ◽

Healthy Controls ◽

Urokinase Plasminogen Activator Receptor ◽

Tissue Samples ◽

Pdac Tissue ◽

Plasminogen Activator Receptor

248 Background: Surgical resection represents the only potentially curative therapy for patients with pancreatic adenocarcinoma (PDAC), an aggressive malignancy with a very limited 5-year survival rate. However, even after successful R0 tumor resection, some patients are still facing an unfavourable prognosis underlining the need for better preoperative stratification algorithms. The soluble urokinase plasminogen activator receptor (suPAR) was recently described as a promising new biomarker for different clinical conditions including cancer. Here, we evaluated the potential role of circulating suPAR as a biomarker in patients undergoing resection of PDAC. Methods: Expression levels of uPAR, the membrane-bound source of circulating suPAR, were analysed in PDAC tissue samples using IHC. Serum levels of suPAR were measured by ELISA in an exploratory as well as a validation cohort comprising a total of 127 PDAC patients and 75 healthy controls. Results were correlated with clinical data. Results: Correlating with a high immunohistochemical expression of uPAR in PDAC tissue samples, serum levels of suPAR were significantly elevated in PDAC patients compared to healthy controls. Importantly, patients with high preoperative suPAR levels above a calculated cut-off value of 5.956 ng/ml showed a significantly reduced overall survival after tumor resection. The prognostic role of suPAR was further corroborated by uni- and multivariate Cox-regression analyses including parameters of systemic inflammation, liver and kidney function as well as clinico-pathological patients’ characteristics. Moreover, high baseline suPAR levels identified those patients particularly susceptible to acute kidney injury after surgery. Conclusions: Our data suggest that circulating suPAR represents a novel prognostic marker in PDAC patients undergoing tumor resection that might be a useful addition to existing preoperative stratification algorithms for identifying patients that particularly benefit from extended tumor resection.

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Seizure burden pre- and postresection of low-grade gliomas as a predictor of tumor progression in low-grade gliomas

Neuro-Oncology Practice ◽

10.1093/nop/npy022 ◽

2018 ◽

Vol 6 (3) ◽

pp. 209-217 ◽

Cited By ~ 2

Author(s):

Fernando Santos-Pinheiro ◽

Mingjeong Park ◽

Diane Liu ◽

Lawrence N Kwong ◽

Savannah Cruz ◽

...

Keyword(s):

Seizure Frequency ◽

Tumor Recurrence ◽

Surgical Intervention ◽

Tumor Resection ◽

Frequency Change ◽

Low Grade ◽

Low Grade Gliomas ◽

Before And After ◽

Early Tumor ◽

Early Tumor Recurrence

Abstract Background Low-grade gliomas (LGGs) are slow-growing, infiltrative tumors frequently associated with seizures. Predicting which patients will develop early tumor recurrence based on clinical indicators following initial surgical intervention remains a challenge. Seizure recurrence following surgery may be an early indicator of tumor recurrence, especially in patients presenting with increase in seizure frequency. Methods This study analyzed 148 patients meeting inclusion criteria (age >18 years, LGG diagnosis, at least 1 seizure event recorded before and after initial surgical intervention). All patients were treated at the Brain and Spine Center at The University of Texas MD Anderson Cancer Center from January 2000 to March 2013. Seizure frequency in a 6-month period before and after tumor resection was categorized as none, 1, few (2 to 3 seizures) or several (>3 seizures). Immediately postoperative seizures (up to 48 hours from surgery) were not included in the analysis. Results A total of 116 (78.4%) patients had seizures at initial presentation and most (95%) were started on antiepileptic drugs (AEDs). We found 2 clinical variables with a significant impact on progression-free survival (PFS): Higher seizure frequency during the 6-month postoperative period and seizure frequency increase between the 6-month pre- and the 6-month postoperative periods were both correlated to higher risk of early tumor recurrence (P = .007 and P = .004, respectively). Conclusion Seizure frequency following surgical resection of LGGs and the seizure frequency change between the 6-month preoperative and postoperative periods may serve as clinical predictors of early tumor recurrence in patients with LGGs who are also afflicted by seizures.

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Elevated circulating levels of interferon-γ and interferon-γ-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2015-209020 ◽

2016 ◽

Vol 76 (1) ◽

pp. 166-172 ◽

Cited By ~ 98

Author(s):

Claudia Bracaglia ◽

Kathy de Graaf ◽

Denise Pires Marafon ◽

Florence Guilhot ◽

Walter Ferlin ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Systemic Juvenile Idiopathic Arthritis ◽

Serum Levels ◽

Interferon Γ ◽

Mrna Levels ◽

Circulating Levels ◽

Activation Syndrome

ObjectivesInterferon-γ (IFNγ) is the pivotal mediator in murine models of primary haemophagocytic lymphohistiocytosis (pHLH). Given the similarities between primary and secondary HLH (sec-HLH), including macrophage activation syndrome (MAS), we investigate the involvement of the IFNγ pathway in MAS by evaluating levels of IFNγ and of the induced chemokines, and their relation with laboratory parameters of MAS in systemic juvenile idiopathic arthritis (sJIA) patients with MAS and in a murine MAS model.MethodsThe Luminex multiplexing assay was used to assess serum levels of interleukin (IL)-1β, IL-6, IFNγ and of the IFNγ-induced chemokines CXCL9, CXCL10 and CXCL11 in patients with sec-HLH (n=11) and in patients with sJIA (n=54), of whom 20 had active MAS at sampling. Expression of IFNγ-induced chemokines was assessed in IL-6 transgenic mice in which MAS is induced by TLR4 stimulation with lipopolysaccharide.ResultsLevels of IFNγ and of IFNγ-induced chemokines were markedly elevated during active MAS and sec-HLH and were significantly higher in patients with MAS compared with active sJIA without MAS. Levels in patients with active sJIA without MAS were comparable to those of patients with clinically inactive sJIA. During MAS, ferritin and alanine transferase levels and neutrophil and platelet counts were significantly correlated with serum levels of IFNγ and CXCL9. In murine MAS, serum levels of ferritin were significantly correlated with mRNA levels of Cxcl9 in liver and spleen.ConclusionsThe high levels of IFNγ and of IFNγ-induced chemokines and their correlation with the severity of laboratory abnormalities of MAS suggest a pivotal role of IFNγ in MAS.

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Circulating Levels of Endothelin-1 and Big Endothelin-1 in Patients with Essential Hypertension

Pathophysiology ◽

10.3390/pathophysiology28040031 ◽

2021 ◽

Vol 28 (4) ◽

pp. 489-495

Author(s):

Krasimir Kostov ◽

Alexander Blazhev

Keyword(s):

Essential Hypertension ◽

Serum Levels ◽

Control Group ◽

Consistent Finding ◽

Endothelin 1 ◽

The Mean ◽

Circulating Levels

The role of endothelin-1 (ET-1) in the pathogenesis of hypertension (HTN) is not clearly established. There is evidence that its circulating levels are elevated in some forms of experimental and human HTN, but this was not a consistent finding. Based on these controversial data, we tested serum levels of ET-1 and Big ET-1 (the precursor of ET-1) in patients with essential HTN, comparing the results with those of healthy normotensive controls. The levels of ET-1 and Big ET-1 were measured by ELISA. Our results in patients with essential HTN showed that the mean levels of ET-1 (5.01 ± 2.1 pg/mL) were significantly higher (F = 6.34, p = 0.0144) than the mean levels in the control group (3.2 ± 1.0 pg/mL). The levels of Big ET-1 in patients with essential HTN (0.377 ± 0.1 pmol/L) were similar to those in the control group (0.378 ± 0.07 pmol/L) and did not differ significantly (F = 0.00, p = 0.9531). These data suggest that ET-1, but not Big ET-1, may play an important role in the pathogenesis of primary HTN.

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Involvement of Eotaxins (CCL11, CCL24, CCL26) in Pathogenesis of Osteopenia and Osteoporosis

Iranian Journal of Public Health ◽

10.18502/ijph.v49i9.4098 ◽

2020 ◽

Author(s):

Hadis AHMADI ◽

Hossein KHORRAMDELAZAD ◽

Gholamhossein HASSANSHAHI ◽

Mitra ABBASI FARD ◽

Zahra AHMADI ◽

...

Keyword(s):

Healthy Subjects ◽

Serum Levels ◽

Dual Energy ◽

Enzyme Linked Immunosorbent Assay ◽

Mineral Density ◽

X Ray ◽

Significant Difference ◽

Elisa Technique ◽

Circulating Levels

Background: The purpose of this study was to investigate the role of eotaxin family members including C-C motif chemokine 11 (CCL11), C-C motif chemokine 24 (CCL24), and C-C motif chemokine 26 (CCL26) as the subgroups of CC-chemokine in patients affected with osteoporosis and osteopenia. Methods: Overall, 19 osteoporotic patients, 18 osteopenic individuals, and 20 healthy subjects were recruited in this study. The bone mineral density (BMD) was then measured at the lumbar spine (L1-L4) and the hip (femoral neck and total hip) using dual-energy X-ray absorptiometry for diagnosis of bone density and related disorders. Additionally, enzyme-linked immunosorbent assay (ELISA) technique was employed to measure the serum levels of CCL11, CCL24, and CCL26. Results: The circulating levels of CCL11, CCL24, and CCL26 had been increased in both groups of patients with osteopenia and osteoporosis compared to those in healthy subjects (P<0.05); while no significant difference was observed between serum levels of these chemokines in such patients. Conclusion: Eotaxins can play a role in the pathogenesis of osteoporosis and osteopenia; however, further studies are needed to clarify various roles of eotaxins in the pathophysiology of osteoporosis and osteopenia.

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High baseline soluble urokinase plasminogen activator receptor (suPAR) serum levels indicate adverse outcome after resection of pancreatic adenocarcinoma

Carcinogenesis ◽

10.1093/carcin/bgz033 ◽

2019 ◽

Vol 40 (8) ◽

pp. 947-955 ◽

Cited By ~ 4

Author(s):

Sven H Loosen ◽

Frank Tacke ◽

Niklas Püthe ◽

Marcel Binneboesel ◽

Georg Wiltberger ◽

...

Keyword(s):

Plasminogen Activator ◽

Pancreatic Adenocarcinoma ◽

Tumor Resection ◽

Serum Levels ◽

Urokinase Plasminogen Activator ◽

Healthy Controls ◽

Urokinase Plasminogen Activator Receptor ◽

High Baseline ◽

Plasminogen Activator Receptor

Abstract Surgical resection represents the only potentially curative therapy for patients with pancreatic adenocarcinoma (PDAC), an aggressive malignancy with a very limited 5-year survival rate. However, even after complete tumor resection, many patients are still facing an unfavorable prognosis underlining the need for better preoperative stratification algorithms. Here, we explored the role of the secreted glycoprotein soluble urokinase plasminogen activator receptor (suPAR) as a novel circulating biomarker for patients undergoing resection of PDAC. Serum levels of suPAR were measured by enzyme-linked immunosorbent assay (ELISA) in an exploratory as well as a validation cohort comprising a total of 127 PDAC patients and 75 healthy controls. Correlating with a cytoplasmic immunohistochemical expression of uPAR in PDAC tumor cells, serum levels of suPAR were significantly elevated in PDAC patients compared to healthy controls and patient with PDAC precursor lesions. Importantly, patients with high preoperative suPAR levels above a calculated cutoff value of 5.956 ng/ml showed a significantly reduced overall survival after tumor resection. The prognostic role of suPAR was further corroborated by uni- and multivariate Cox-regression analyses including parameters of systemic inflammation, liver and kidney function as well as clinico-pathological patients’ characteristics. Moreover, high baseline suPAR levels identified those patients particularly susceptible to acute kidney injury and surgical complications after surgery. In conclusion, our data suggest that circulating suPAR represents a novel prognostic marker in PDAC patients undergoing tumor resection that might be a useful addition to existing preoperative stratification algorithms for identifying patients that particularly benefit from extended tumor resection.

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Serum levels of circulating microRNA-107 are elevated in patients with early-stage HCC

PLoS ONE ◽

10.1371/journal.pone.0247917 ◽

2021 ◽

Vol 16 (3) ◽

pp. e0247917

Author(s):

Sven H. Loosen ◽

Mirco Castoldi ◽

Markus S. Jördens ◽

Sanchary Roy ◽

Mihael Vucur ◽

...

Keyword(s):

Overall Survival ◽

Early Stage ◽

Tumor Resection ◽

Serum Levels ◽

Circulating Microrna ◽

Liver Malignancy ◽

Clear Trend ◽

Disease Etiology ◽

Expression Levels

Background Early detection of hepatocellular carcinoma (HCC), the most common primary liver malignancy, is crucial to offer patients a potentially curative treatment strategy such as surgical resection or liver transplantation (LT). However, easily accessible biomarkers facilitating an early diagnosis of HCC as well as a reliable risk prediction are currently missing. The microRNA(miR)-107 has recently been described as a driver of HCC in both murine and human HCC but data on circulating miR-107 in HCC patients are scarce. In the present study, we evaluated a potential diagnostic and/or prognostic role of circulating miR-107 in patients undergoing tumor resection or LT for early-stage HCC. Methods The Kmplot bioinformatic tool was used to query publicly available databases (including TCGA, GEO and EGA) in order to analyse the prognostic value of tumoral miR-107 expression in HCC patients (n = 372). Serum levels of miR-107 were measured by qPCR in n = 45 HCC patients undergoing surgical tumor resection (n = 37) or LT (n = 8) as well as n = 18 healthy control samples. Results were correlated with clinical data. Results A high tumoral expression of miR-107 was associated with a significantly better overall survival compared to patients with low miR-107 expression levels (HR 0.69, 95% CI 0.48–0.99, p = 0.041). In addition, serum levels of miR-107 were significantly higher in HCC patients when compared to healthy controls. However, miR-107 serum levels in HCC patients were independent of different disease etiology, tumor stage or tumor grading. HCC patients with baseline miR-107 expression levels above a calculated ideal prognostic cut-off value (9.82) showed a clear trend towards an impaired overall survival (p = 0.119). Conclusion Tumoral miR-107 expression levels are a potential prognostic marker in early stage HCC. Furthermore, we describe a potential role of circulating miR-107 levels as a diagnostic biomarker in patients with early-stage HCC.

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Serum Levels of Kisspeptin Are Elevated in Patients with Pancreatic Cancer

Disease Markers ◽

10.1155/2019/5603474 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Sven H. Loosen ◽

Mark Luedde ◽

Georg Lurje ◽

Martina Spehlmann ◽

Pia Paffenholz ◽

...

Keyword(s):

Performance Status ◽

Treatment Options ◽

Tumor Resection ◽

Serum Levels ◽

Ecog Performance Status ◽

Related Factors ◽

Suitable Treatment ◽

Novel Biomarkers ◽

Selection Of

Pancreatic adenocarcinoma (PDAC) still represents a devastating disease associated with a very limited survival. Novel biomarkers allowing an early diagnosis as well as an optimal selection of suitable treatment options for individual patients are urgently needed to improve the dismal outcome of PDAC patients. Recently, alterations of Kisspeptin serum levels, a member of the adipokine family, were described in various types of cancers. However, the role of circulating Kisspeptin as a biomarker in PDAC patients is poorly defined. In this study, we measured Kisspeptin serum levels in a cohort of 128 prospectively enrolled PDAC patients undergoing surgical resection as well as 36 healthy controls. Kisspeptin concentrations were elevated in PDAC patients compared to control samples. Nevertheless, Kisspeptin serum levels were independent of tumor-related factors such as the tumor grading, TNM stage, or clinical features such as the ECOG performance status. Finally, in our analysis, neither preoperative nor postoperative Kisspeptin levels turned out as a significant predictor of overall survival after tumor resection. In conclusion, our data suggest that Kisspeptin concentrations are altered in PDAC patients but do not allow to predict patients’ outcome after resection of PDAC.

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Interactions between kisspeptin and neurokinin B in the control of GnRH secretion in the female rat

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00517.2010 ◽

2011 ◽

Vol 300 (1) ◽

pp. E202-E210 ◽

Cited By ~ 160

Author(s):

Víctor M. Navarro ◽

Juan M. Castellano ◽

Sarah M. McConkey ◽

Rafael Pineda ◽

Francisco Ruiz-Pino ◽

...

Keyword(s):

Critical Role ◽

Fold Increase ◽

Serum Levels ◽

Female Rat ◽

Neurokinin B ◽

Hypothalamic Nuclei ◽

Lh Secretion ◽

Circulating Levels ◽

Lateral Cerebral Ventricle

Neurokinin B (NKB) and its cognate receptor neurokinin 3 (NK3R) play a critical role in reproduction. NKB and NK3R are coexpressed with dynorphin ( Dyn) and kisspeptin ( Kiss1) genes in neurons of the arcuate nucleus (Arc). However, the mechanisms of action of NKB as a cotransmitter with kisspeptin and dynorphin remain poorly understood. We explored the role of NKB in the control of LH secretion in the female rat as follows. 1) We examined the effect of an NKB agonist (senktide, 600 pmol, administered into the lateral cerebral ventricle) on luteinizing hormone (LH) secretion. In the presence of physiological levels of estradiol (E2), senktide induced a profound increase in serum levels of LH and a 10-fold increase in the number of Kiss1 neurons expressing c -fos in the Arc ( P < 0.01 for both). 2) We mapped the distribution of NKB and NK3R mRNAs in the central forebrain and found that both are widely expressed, with intense expression in several hypothalamic nuclei that control reproduction, including the Arc. 3) We studied the effect of E2 on the expression of NKB and NK3R mRNAs in the Arc and found that E2 inhibits the expression of both genes ( P < 0.01) and that the expression of NKB and NK3R reaches its nadir on the afternoon of proestrus (when circulating levels of E2 are high). These observations suggest that NKB/NK3R signaling in Kiss1/NKB/Dyn-producing neurons in the Arc has a pivotal role in the control of gonadotropin-releasing hormone (GnRH)/LH secretion and its regulation by E2-dependent negative feedback in the rat.

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