The impact of minimal invasive extracorporeal circulation on postoperative kidney function.

INTRODUCTION: Acute kidney injury following cardiac surgery is a frequent complication associated with increased mortality and morbidity. Minimal invasive extracorporeal circulation is suggested to preserve postoperative renal function. The aim of this study was to assess the impact of minimal invasive versus conventional extracorporeal circulation on early postoperative kidney function. METHODS: Randomized controlled trail including 60 patients undergoing elective stand-alone coronary artery bypass graft surgery and allocated in a 1:1 ratio to either minimal invasive (n = 30) or conventional extracorporeal circulation (n = 30). Postoperative kidney injury was assessed by elevation of plasma neutrophil gelatinase-associated lipocalin (NGAL), a sensitive tubular injury biomarker. In addition, we assessed changes in estimated glomerular filtration rate (eGFR), and the incidence of acute kidney injury according to the Acute Kidney Injury Network (AKIN) classification. RESULTS: We observed no differences between groups regarding increase of plasma NGAL (p = 0.31) or decline of eGFR (p = 0.82). In both groups, 6/30 patients developed acute kidney injury according to the AKIN classification, all regaining preoperative renal function within 30 days. CONCLUSION: Our findings challenge the superiority of minimal invasive compared to conventional extracorporeal circulation in terms of preservation of renal function following low-risk coronary surgery.

Influence of Microgravity on Apoptosis in Cells, Tissues, and Other Systems In Vivo and In Vitro.

All life forms have evolved under the constant force of gravity on Earth and developed ways to counterbalance acceleration load. In space, shear forces, buoyance-driven convection, and hydrostatic pressure are nullified or strongly reduced. When subjected to microgravity in space, the equilibrium between cell architecture and the external force is disturbed, resulting in changes at the cellular and sub-cellular levels (e.g., cytoskeleton, signal transduction, membrane permeability, etc.). Cosmic radiation also poses great health risks to astronauts because it has high linear energy transfer values that evoke complex DNA and other cellular damage. Space environmental conditions have been shown to influence apoptosis in various cell types. Apoptosis has important functions in morphogenesis, organ development, and wound healing. This review provides an overview of microgravity research platforms and apoptosis. The sections summarize the current knowledge of the impact of microgravity and cosmic radiation on cells with respect to apoptosis. Apoptosis-related microgravity experiments conducted with different mammalian model systems are presented. Recent findings in cells of the immune system, cardiovascular system, brain, eyes, cartilage, bone, gastrointestinal tract, liver, and pancreas, as well as cancer cells investigated under real and simulated microgravity conditions, are discussed. This comprehensive review indicates the potential of the space environment in biomedical research.

Simulated Microgravity Influences VEGF, MAPK, and PAM Signaling in Prostate Cancer Cells.

Prostate cancer is one of the leading causes of cancer mortality in men worldwide. An unusual but unique environment for studying tumor cell processes is provided by microgravity, either in space or simulated by ground-based devices like a random positioning machine (RPM). In this study, prostate adenocarcinoma-derived PC-3 cells were cultivated on an RPM for time periods of 3 and 5 days. We investigated the genes associated with the cytoskeleton, focal adhesions, extracellular matrix, growth, survival, angiogenesis, and metastasis. The gene expression of signaling factors of the vascular endothelial growth factor (VEGF), mitogen-activated protein kinase (MAPK), and PI3K/AKT/mTOR (PAM) pathways was investigated using qPCR. We performed immunofluorescence to study the cytoskeleton, histological staining to examine the morphology, and a time-resolved immunofluorometric assay to analyze the cell culture supernatants. When PC-3 cells were exposed to simulated microgravity (s-µg), some cells remained growing as adherent cells (AD), while most cells detached from the cell culture flask bottom and formed multicellular spheroids (MCS). After 3-day RPM exposure, PC-3 cells revealed significant downregulation of the VEGF, SRC1, AKT, MTOR, and COL1A1 gene expression in MCS, whereas FLT1, RAF1, MEK1, ERK1, FAK1, RICTOR, ACTB, TUBB, and TLN1 mRNAs were not significantly changed. ERK2 and TLN1 were elevated in AD, and FLK1, LAMA3, COL4A5, FN1, VCL, CDH1, and NGAL mRNAs were significantly upregulated in AD and MCS after 3 days. After a 5-day culture in s-µg, the PC-3 cells showed significant downregulations of VEGF mRNA in AD and MCS, and FN1, CDH1, and LAMA3 in AD and SCR1 in MCS. In addition, we measured significant upregulations in FLT1, AKT, ERK1, ERK2, LCN2, COL1A1, TUBB, and VCL mRNAs in AD and MCS, and increases in FLK1, FN1, and COL4A5 in MCS as well as LAMB2, CDH1, RAF1, MEK1, SRC1, and MTOR mRNAs in AD. FAK1 and RICTOR were not altered by s-µg. In parallel, the secretion rate of VEGFA and NGAL proteins decreased. Cytoskeletal alterations (F-actin) were visible, as well as a deposition of collagen in the MCS. In conclusion, RPM-exposure of PC-3 cells induced changes in their morphology, cytoskeleton, and extracellular matrix protein synthesis, as well as in their focal adhesion complex and growth behavior. The significant upregulation of genes belonging to the PAM pathway indicated their involvement in the cellular changes occurring in microgravity.

Drug-Induced Hypertension Caused by Multikinase Inhibitors (Sorafenib, Sunitinib, Lenvatinib and Axitinib) in Renal Cell Carcinoma Treatment.

This paper reviews current treatments for renal cell carcinoma/cancer (RCC) with the multikinase inhibitors (MKIs) sorafenib, sunitinib, lenvatinib and axitinib. Furthermore, it compares these drugs regarding progression-free survival, overall survival and adverse effects (AE), with a focus on hypertension. Sorafenib and sunitinib, which are included in international clinical guidelines as first- and second-line therapy in metastatic RCC, are now being challenged by new-generation drugs like lenvatinib and axitinib. These drugs have shown significant clinical benefits for patients with RCC, but all four induce a variety of AEs. Hypertension is one of the most common AEs related to MKI treatment. Comparing sorafenib, sunitinib and lenvatinib revealed that sorafenib and sunitinib had the same efficacy, but sorafenib was safer to use. Lenvatinib showed better efficacy than sorafenib but worse safety. No trials have yet been completed that compare lenvatinib with sunitinib. Although axitinib promotes slightly higher hypertension rates compared to sunitinib, the overall discontinuation rate and cardiovascular complications are favourable. Although the mean rate of patients who develop hypertension is similar for each drug, some trials have shown large differences, which could indicate that lifestyle and/or genetic factors play an additional role.

Key Proteins Involved in Spheroid Formation and Angiogenesis in Endothelial Cells After Long-Term Exposure to Simulated Microgravity.

BACKGROUND/AIMS: Cardiovascular complications are common in astronauts returning from a prolonged spaceflight. These health problems might be driven by complex modulations of gene expression and protein synthesis in endothelial cells (ECs). Studies on the influence of microgravity on phenotype, growth pattern and biological processes of ECs can help to understand these complications. METHODS: We exposed ECs (EA.hy926) to a Random Positioning Machine (RPM). Proteins associated with cell structure, angiogenesis and endothelial dysfunction were investigated in distinct pools of multicellular spheroids (MCS), adherent cells (AD) and tubular structures (TS) formed after a 35-day RPM-exposure. RESULTS: Combining morphological and molecular approaches, we found AD, MCS and TS with changes in the synthesis and release of proteins involved in three-dimensional growth. Fibronectin and monocyte chemoattractant protein-1 (MCP-1) mRNAs and protein contents were elevated along with an increased secretion of vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-8, MCP-1, intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), neutrophil gelatinase-associated lipocalin (NGAL) and regulated on activation, normal T cell expressed and secreted (RANTES) proteins in the culture supernatant as determined by multianalyte profiling technology. Together they form a network of interaction. CONCLUSIONS: These results show that a prolonged RPM-exposure of ECs induced TS and MCS formation. The factors VEGF, NGAL, IL-6, IL-8, MCP-1, VCAM-1, ICAM-1, fibronectin and RANTES seem to be affected when gravity is omitted.

Neutrophil gelatinase-associated lipocalin (NGAL) and cardiovascular events in patients with stable coronary artery disease.

Inflammation is an important mediator in the pathogenesis of atherosclerosis. Neutrophil gelatinase-associated lipocalin (NGAL) is a small glycoprotein secreted by neutrophils. NGAL regulates the activity of matrix metalloproteinase-9, which plays a role in plaque instability. It has therefore been hypothesised that NGAL may modulate inflammation and promote the development and progression of atherosclerosis. Our aim was to assess the predictive value of plasma NGAL in a prospective cohort study of 876 high-risk patients with stable coronary artery disease (CAD). NGAL levels were measured using the NGAL TestTM from BioPorto Diagnostics. Clinical follow-up was performed after a median of 3.1 years. The endpoint was a combination of non-fatal acute myocardial infarction (MI), cardiovascular death (CVD), or ischaemic stroke. The NGAL concentration was (median [25;75%]: 64.3 µg/L [51.3;81.4]). The area under the receiver operating characteristic curve (AUC) was 0.56 (95% confidence interval (CI): 0.49;0.64) for the diagnosis of the composite endpoint and 0.66 (95% CI: 0.56;0.75) after adding NGAL to high-sensitive C-reactive protein (hs-CRP), leucocyte count, interleukin-6 (IL-6), calprotectin, age, sex, body mass index (BMI), diabetes mellitus, smoking and creatinine. However, the AUC for hs-CRP, leucocyte count, IL-6, calprotectin, age, sex, BMI, diabetes mellitus, smoking and creatinine without NGAL was similar at 0.66 (95% CI: 0.56;0.76). NGAL alone had no predictive value with respect to the composite endpoint of non-fatal AMI, ischaemic stroke, or CVD in stable CAD patients. NGAL did not add any predictive value to the endpoint compared with existing inflammatory biomarkers and cardiovascular risk factors.

Long-Term Ethanol Exposure Decreases the Endotoxin-Induced Hepatic Acute Phase Response in Rats.

BACKGROUND: Long-term excessive alcohol intake predisposes to infectious diseases. The hepatic acute-phase response is a component of the innate immune system and is part of the first line of defense against invading pathogens, which may be compromised by alcohol. We aimed to investigate whether an induced acute-phase response is impaired in long-term ethanol (EtOH)-fed rats. METHODS: For 6 weeks, rats were either fed a Lieber-DeCarli EtOH-containing (36% as calories) liquid diet ad libitum or calorically pair-fed. Then, the rats were injected intraperitoneally with a low dose of lipopolysaccharide (LPS) (0.5 mg/kg) to induce an acute-phase response. Two hours after LPS, we measured the plasma concentrations of an array of inflammatory cytokines. Twenty-four hours after LPS, we measured the hepatic mRNA expression and serum concentrations of prominent rat acute-phase proteins. RESULTS: EtOH-fed rats showed either no liver histopathological changes or varying degrees of steatosis. EtOH feeding decreased the spontaneous liver mRNA expression of the prevailing acute-phase protein alpha-2-macroglobulin (α2M) by 30% (p < 0.01). LPS immediately increased plasma tumor necrosis factor-alpha and interleukin-6 more than 100-fold in both feeding groups (p < 0.001, all) and approximately twice as much in the EtOH-fed rats (p < 0.05 and p = 0.08, respectively). LPS also induced a variable but marked amplification of (α2M), haptoglobin, alpha-1-acid glycoprotein, and lipocalin-2 liver mRNA expression levels and serum concentrations in both feeding groups (p ≤ 0.01 to 0.001). However, the LPS-induced increases in serum (α2M) and haptoglobin were less pronounced in the EtOH-fed rats, averaging approximately 60% of the concentrations in the pair-fed rats (p < 0.01 and p < 0.001, respectively). CONCLUSIONS: Long-term EtOH exposure in rats reduces the spontaneous hepatic mRNA expression of (α2M) and markedly impairs the hepatic acute-phase response to endotoxin, despite higher pro-inflammatory cytokine release. The same phenomenon may contribute to the increased susceptibility to infections observed in humans with long-term excessive alcohol intake.

Neutrophil gelatinase-associated lipocalin as a risk marker in cardiovascular disease.

Neutrophil gelatinase-associated lipocalin (NGAL) is a promising diagnostic biomarker of early acute kidney injury. Increasing evidence suggests that NGAL may also be involved in inflammatory processes in cardiovascular disease. NGAL modulates the enzymatic activity of matrix metalloproteinase-9 (MMP-9), which is an important mediator of plaque instability in atherosclerosis. The complex formation between NGAL and MMP-9 therefore suggests that NGAL might play a role in progression of atherothrombotic disease. This review summarises current data on NGAL in atherosclerosis, acute myocardial infarction, and heart failure.

Effects and Side Effects of Using Sorafenib and Sunitinib in the Treatment of Metastatic Renal Cell Carcinoma.

In recent years, targeted therapies have proven beneficial in terms of progression-free survival (PFS) and overall survival (OS) in the treatment of metastatic renal cell carcinoma (mRCC). The tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib are included in international clinical guidelines as first-line and second-line therapy in mRCC. Hypertension is an adverse effect of these drugs and the degree of hypertension associates with the anti-tumour effect. Studies have compared newer targeted drugs to sorafenib and sunitinib in terms of PFS, OS, quality of life and safety profiles. Phase III studies presented promising response rates and acceptable safety profiles of axitinib and tivozanib compared to sorafenib, and a phase II study reported greater efficacy using a combination of bevacizumab and IFN-α compared to sunitinib. Treatment with nintedanib exhibited a notably low prevalence of hypertension compared to sunitinib. The use of sorafenib and sunitinib are challenged by new drugs, but do not appear likely to be substituted in the near future. To clarify whether newer targeted drugs should replace sorafenib and sunitinib, more research is needed. This manuscript reviews the current utility and adverse effects of sorafenib and sunitinib and newer targeted therapies in the treatment of mRCC.

Hypertension Caused by Lenvatinib and Everolimus in the Treatment of Metastatic Renal Cell Carcinoma.

Multikinase inhibitors (MKI) and mammalian target of rapamycin (mTOR) inhibitors prolong progression-free (PFS) and overall survival (OS) in the treatment of metastatic renal cell carcinoma (mRCC) by reducing angiogenesis and tumor growth. In this regard, the MKI lenvatinib and the mTOR inhibitor everolimus proved effective when applied alone, but more effective when they were administered combined. Recently, both drugs were included in clinical trials, resulting in international clinical guidelines for the treatment of mRCC. In May 2016, lenvatinib was approved by the American Food and Drug Administration (FDA) for the use in combination with everolimus, as treatment of advanced renal cell carcinoma following one prior antiangiogenic therapy. A major problem of treating mRCC with lenvatinib and everolimus is the serious adverse event (AE) of arterial hypertension. During the treatment with everolimus and lenvatinib combined, 42% of the patients developed hypertension, while 10% of the patients treated with everolimus alone and 48% of the of the lenvatinib only treated patients developed hypertension. Lenvatinib carries warnings and precautions for hypertension, cardiac failure, and other adverse events. Therefore, careful monitoring of the patients is necessary.

Reduced Expression of Cytoskeletal and Extracellular Matrix Genes in Human Adult Retinal Pigment Epithelium Cells Exposed to Simulated Microgravity.

BACKGROUND/AIMS: Microgravity (µg) has adverse effects on the eye of humans in space. The risk of visual impairment is therefore one of the leading health concerns for NASA. The impact of µg on human adult retinal epithelium (ARPE-19) cells is unknown. METHODS: In this study we investigated the influence of simulated µg (s-µg; 5 and 10 days (d)), using a Random Positioning Machine (RPM), on ARPE-19 cells. We performed phase-contrast/fluorescent microscopy, qRT-PCR, Western blotting and pathway analysis. RESULTS: Following RPM-exposure a subset of ARPE-19 cells formed multicellular spheroids (MCS), whereas the majority of the cells remained adherent (AD). After 5d, alterations of F-actin and fibronectin were observed which reverted after 10d-exposure, suggesting a time-dependent adaptation to s-µg. Gene expression analysis of 12 genes involved in cell structure, shape, adhesion, migration, and angiogenesis suggested significant changes after a 10d-RPM-exposure. 11 genes were down-regulated in AD and MCS 10d-RPM-samples compared to 1g, whereas FLK1 was up-regulated in 5d- and 10d-RPM-MCS-samples. Similarly, TIMP1 was up-regulated in 5d-RPM-samples, whereas the remaining genes were down-regulated in 5d-RPM-samples. Western blotting revealed similar changes in VEGF, ß-actin, laminin and fibronectin of 5d-RPM-samples compared to 10d, whereas different alterations of ß-tubulin and vimentin were observed. The pathway analysis showed complementing effects of VEGF and integrin ß-1. CONCLUSIONS: These findings clearly show that s-µg induces significant alterations in the F-actin-cytoskeleton and cytoskeleton-related proteins of ARPE-19, in addition to changes in cell growth behavior and gene expression patterns involved in cell structure, growth, shape, migration, adhesion and angiogenesis.

Pathways Regulating Spheroid Formation of Human Follicular Thyroid Cancer Cells under Simulated Microgravity Conditions: A Genetic Approach.

Microgravity induces three-dimensional (3D) growth in numerous cell types. Despite substantial efforts to clarify the underlying mechanisms for spheroid formation, the precise molecular pathways are still not known. The principal aim of this paper is to compare static 1g-control cells with spheroid forming (MCS) and spheroid non-forming (AD) thyroid cancer cells cultured in the same flask under simulated microgravity conditions. We investigated the morphology and gene expression patterns in human follicular thyroid cancer cells (UCLA RO82-W-1 cell line) after a 24 h-exposure on the Random Positioning Machine (RPM) and focused on 3D growth signaling processes. After 24 h, spheroid formation was observed in RPM-cultures together with alterations in the F-actin cytoskeleton. qPCR indicated more changes in gene expression in MCS than in AD cells. Of the 24 genes analyzed VEGFA, VEGFD, MSN, and MMP3 were upregulated in MCS compared to 1g-controls, whereas ACTB, ACTA2, KRT8, TUBB, EZR, RDX, PRKCA, CAV1, MMP9, PAI1, CTGF, MCP1 were downregulated. A pathway analysis revealed that the upregulated genes code for proteins, which promote 3D growth (angiogenesis) and prevent excessive accumulation of extracellular proteins, while genes coding for structural proteins are downregulated. Pathways regulating the strength/rigidity of cytoskeletal proteins, the amount of extracellular proteins, and 3D growth may be involved in MCS formation.

Plasma neutrophil gelatinase-associated lipocalinin in the general population: association with inflammation and prognosis.

OBJECTIVE: Neutrophil gelatinase-associated lipocalin (NGAL) is a glycoprotein stored in granules of neutrophil leukocytes participating in inflammatory and atherosclerotic processes and possibly plaque rupture. Despite the putative role of NGAL in atherosclerosis and acute myocardial infarction, human studies of plasma NGAL are still limited. APPROACH AND RESULTS: We prospectively followed 5599 randomly selected men and women from the community in the fourth Copenhagen Heart Study. Plasma NGAL was measured at study entry. Participants were followed for 10 years. During follow-up, 20% died (n=1120) and 15% (n=884) developed a major adverse cardiovascular event. Plasma NGAL associated strongly with all inflammatory markers (high-sensitivity C-reactive protein, total leukocyte count, neutrophil count) and inversely with estimated glomerular filtration rate (all, P<0.001). Multivariate analysis identified neutrophil leukocyte count as the main determinant of plasma NGAL. During follow-up, participants with increasing NGAL had increased risk of all-cause mortality and major adverse cardiovascular event (both, P<0.001). Even after adjustment for confounding risk factors by Cox regression analysis, NGAL remained an independent predictor of both all-cause mortality and major adverse cardiovascular event. When added to the Framingham risk score, NGAL improved c-statistics and correctly reclassified ≈15% into more appropriate risk groups. In comparison with high-sensitivity C-reactive protein, when both markers were added to the Framingham risk score, NGAL conferred 3× to 4× the risk. CONCLUSIONS: Plasma NGAL is strongly associated with inflammation in the general population. NGAL independently associated with 10-year outcome, and when added to the Framingham risk score, NGAL both improves c-statistics and correctly reclassifies participants into more accurate risk categories.

Mechanisms of apoptosis in irradiated and sunitinib-treated follicular thyroid cancer cells.

The multikinase inhibitor sunitinib (S) seems to have promising potential in the treatment of thyroid cancer. We focused on the impact of S and/or irradiation (R) on mechanisms of apoptosis in follicular thyroid cancer cells. The effects of R, S and their combination were evaluated 2 and 4 days after treatment, using the human thyroid cancer cell line CGTH W-1. The transcription of genes involved in the regulation of apoptosis was investigated using quantitative real-time PCR. Western blot analyses of caspases and survivin were also performed. S elevated BAX (day 4), CASP9, CASP3, BIRC5 (day 4) and PRKACA (day 4) gene expression, whereas the mRNAs of BCL2, CASP8, PRKCA, ERK1, and ERK2 were not significantly changed. S, R and R+S clearly induced caspase-9 protein and elevated caspase-3 activity. Survivin was down-regulated at day 4 in control cells and the expression was blunted by S treatment. R+S induced survivin expression at day 2 followed by a reduction at day 4 of treatment. Sunitinib and the combined application with radiation induced apoptosis in follicular thyroid cancer cells via the intrinsic pathway of apoptosis. In addition, sunitinib might induce apoptosis via decreased expression of the anti-apoptotic protein survivin. These findings suggest the potential use of sunitinib for the treatment of poorly differentiated follicular thyroid carcinomas.

The impact of microgravity-based proteomics research.

Proteomics is performed in microgravity research in order to determine protein alterations occurring qualitatively and quantitatively, when single cells or whole organisms are exposed to real or simulated microgravity. To this purpose, antibody-dependent (Western blotting, flow cytometry, Luminex(®) technology) and antibody-independent (mass spectrometry, gene array) techniques are applied. The anticipated findings will help to understand microgravity-specific behavior, which has been observed in bacteria, as well as in plant, animal and human cells. To date, the analyses revealed that cell cultures are more sensitive to microgravity than cells embedded in organisms and that proteins changing under microgravity are highly interactive. Furthermore, one has to distinguish between primary gravity-induced and subsequent interaction-dependent changes of proteins, as well as between direct microgravity-related effects and indirect stress responses. Progress in this field will impact on tissue engineering and medicine and will uncover possibilities of counteracting alterations of protein expression at lowered gravity.

Anti-vascular endothelial growth factor therapy in breast cancer.

Neo-angiogenesis is a critical process for tumor growth and invasion and has become a promising target in cancer therapy. This manuscript reviews three currently relevant anti-angiogenic agents targeting the vascular endothelial growth factor system: bevacizumab, ramucirumab and sorafenib. The efficacy of anti-angiogenic drugs in adjuvant therapy or as neo-adjuvant treatment has been estimated in clinical trials of advanced breast cancer. To date, the overall observed clinical improvements are unconvincing, and further research is required to demonstrate the efficacy of anti-angiogenic drugs in breast cancer treatments. The outcomes of anti-angiogenic therapy have been highly variable in terms of tumor response. New methods are needed to identify patients who will benefit from this regimen. The development of biomarkers and molecular profiling are relevant research areas that may strengthen the ability to focus anti-angiogenic therapy towards suitable patients, thereby increase the cost-effectiveness, currently estimated to be inadequate.

Early neutrophil gelatinase-associated lipocalin (NGAL) measurement could rule out future acute kidney injury in patients with acute coronary syndrome-Prospective observational study.

Background and Aims: The diagnosis of acute kidney injury (AKI) is of importance among patients with ST segment elevation (STEMI) undergoing primary coronary intervention (PCI). It is often delayed given the need in serial measurements of creatinine or other serum markers. Neutrophil gelatinase-associated lipocalin (NGAL) is a proven marker for AKI, although its role as an early predictor in this setting was scarcely addressed before and was the aim of our study. Methods: Prospective observational study including 133 patients with STEMI treated with PCI. Plasma NGAL was drawn immediately before PCI (NGAL-0) and 24 h after (NGAL-24). Similar analysis of C-reactive protein (CRP) was performed for additional comparison. Results: Mean age was 62 ± 13 years, 78% were men, and 20 (15%) developed AKI after admission. Patients with AKI after admission demonstrated higher levels of NGAL-0 (164 vs. 95 ng/mL; p < 0.001) and NGAL-24 (142 vs. 93 ng/mL; p < 0.001). Levels of NGAL-0 and NGAL-24 were similar within the AKI and non-AKI groups. Using ROC curve analysis, NGAL-0 had best predictive ability for AKI development (AUC 0.841, 95% CI 0.80-0.96), compared with NGAL-24 (0.783, 95% CI 0.74-0.85), CRP-0 (0.701, 95% CI 0.58-0.83), and CRP-24 (0.781, 95% CI 0.66-0.90). The optimal NGAL-0 cutoff for AKI prediction was 125 ng/mL, with 70% sensitivity, 84% specificity, and 94% negative predictive value. Conclusions: Among STEMI patients, NGAL measurement upon admission are associated with AKI and may serve as a reliable marker for early AKI detection. Future studies may direct risk stratification using this single test can direct personalized evaluations during the admission, and focused interventions to prevent AKI.

Cognitive dysfunction in early experimental metabolic dysfunction-associated steatotic liver disease is associated with systemic inflammation and neuroinflammation.

Background & Aims: Cognitive dysfunction is an increasingly recognised manifestation of metabolic dysfunction-associated steatotic liver disease (MASLD), but the mechanistic link remains unclear. The aim of this study was to investigate the hypothesis that experimental MASLD leads to cognitive dysfunction via systemic inflammation and neuroinflammation. Methods: Twenty male Sprague Dawley rats were randomised to a high-fat high-cholesterol (HFHC) diet to induce MASLD, or a standard diet (n = 10/group), for 16 weeks. Assessments included: MASLD severity (histology), neurobehaviour, inflammation (liver, plasma and cerebrospinal fluid), brain microglia and astrocyte activation, and synaptic density. Results: The HFHC diet induced MASLD with extensive steatosis and lobular inflammation without fibrosis. Several plasma cytokines were elevated (CXCL1, IL-6, IL-17, MIP-1α, MCP-1, IL-10; all p <0.05) and correlated with increases in hepatic chemokine gene expression. Cerebrospinal fluid concentrations of CXCL1 were elevated (p = 0.04). In the prefrontal brain cortex, we observed a 19% increase in microglial activation confirmed by Iba1 immunohistochemistry (p = 0.03) and 3H-PK11195 autoradiography (p <0.01). In parallel, synaptic density was reduced to 92%, assessed by 3H-UCB-J autoradiography (p <0.01). MASLD animals exhibited impaired memory to previously encountered objects in the novel object recognition test (p = 0.047) and showed depression-like behaviour evidenced by increased immobility time (p <0.01) and reduced swimming time (p = 0.03) in the forced swim test. Conclusions: Experimental non-fibrotic MASLD, as a model to reflect the early stage of human disease, results in cognitive impairment and depression-like behaviour. This is associated with an inflammatory phenotype not only in the liver but also in the plasma and brain, which together with diminished synaptic density, provides a pathophysiological link between liver disease and cognitive dysfunction in MASLD. Impact and implications: Cognitive dysfunction is an increasingly recognised comorbidity in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), yet the underlying mechanisms remain unclear. This study provides evidence of impaired memory and depression-like symptoms in early experimental MASLD and indicates that hepatic inflammation may drive a systemic inflammatory response, resulting in neuroinflammation and reduced brain synaptic density. The evidence of impaired memory in MASLD and establishing its underlying pathophysiological link provides insights that could guide the development of potential new treatments for this increasingly common condition in people of working age. The study also emphasises the need to develop better tools for clinical cognitive testing, which will enable physicians to assess and manage brain dysfunction early in MASLD.

Impact of sunitinib on human thyroid cancer cells.

BACKGROUND/AIMS: Thyroid cancer accounts for about 1% of all cancer cases. Multikinase inhibitors like sunitinib (S) have a promising potential in thyroid cancer therapy. Therefore, the principal aim of this study was to investigate the impact of sunitinib on the secretion of cytokines of follicular thyroid cancer cells. METHOD: The effects of irradiation (R), S, and their combination (R+S) on cytokine secretion by the human thyroid cancer cell lines ML-1 and CGTH W-1 were evaluated after two (d2) and four days (d4) of treatment. RESULTS: Multi-Analyte Profiling of cytokine release showed a decrease after S treatment (CGTH W-1: IFN-γ, IL-4, IL-8 d2, MIP-1a, MMP-2, TNF-α and TNF-ß; ML-1: IFN-γ, IL-4, IL-6, IL-7, IL-8; MIP-1α, MMP-2, MCP-1, TNF-α and TNF-ß). R elevated significantly the release of cytokines (exception ML-1: MCP-1, MMP-2; CGTH W-1: IL-4, TNF-ß). In contrast, R+S treatment resulted in a reduction of IFN-γ, IL-4, and MMP-2 in both cell lines. IL-6, IL-8 and MCP-1 proteins in the supernatant correlated with the data obtained by quantitative RT-PCR. VEGFD mRNAs were significantly elevated by R+S. CONCLUSION: A target-based therapy with R+S changed VEGFD, IL-6 and IL-8 in follicular thyroid cancer cells. These in vitro-experiments suggest IL-6, IL-8, VEGFD and TNF-α as interesting biomarkers to be investigated in vivo. Different reactions of the cell lines under equal treatment might be due to their different origin and characteristics.

Biomarkers for anti-angiogenic therapy in cancer.

Angiogenesis, the development of new vessels from existing vasculature, plays a central role in tumor growth, survival, and progression. On the molecular level it is controlled by a number of pro- and anti-angiogenic cytokines, among which the vascular endothelial growth factors (VEGFs), together with their related VEGF-receptors, have an exceptional position. Therefore, the blockade of VEGF signaling in order to inhibit angiogenesis was deemed an attractive approach for cancer therapy and drugs interfering with the VEGF-ligands, the VEGF receptors, and the intracellular VEGF-mediated signal transduction were developed. Although promising in pre-clinical trials, VEGF-inhibition proved to be problematic in the clinical context. One major drawback was the generally high variability in patient response to anti-angiogenic drugs and the rapid development of therapy resistance, so that, in total, only moderate effects on progression-free and overall survival were observed. Biomarkers predicting the response to VEGF-inhibition might attenuate this problem and help to further individualize drug and dosage determination. Although up to now no definitive biomarker has been identified for this purpose, several candidates are currently under investigation. This review aims to give an overview of the recent developments in this field, focusing on the most prevalent tumor species.