CD90 (Thy-1) is a glycophosphatidylinositol-anchored glycoprotein considered as a surrogate marker for a variety of stem cells, including glioblastoma (GBM) stem cells (GSC). However, the molecular ...and cellular functions of CD90 remain unclear.
The function of CD90 in GBM was addressed using cellular models from immortalized and primary GBM lines,
orthotopic mouse models, and GBM specimens' transcriptome associated with MRI features from GBM patients. CD90 expression was silenced in U251 and GBM primary cells and complemented in CD90-negative U87 cells.
We showed that CD90 is not only expressed on GSCs but also on more differentiated GBM cancer cells. In GBM patients, CD90 expression was associated with an adhesion/migration gene signature and with invasive tumor features. Modulation of CD90 expression in GBM cells dramatically affected their adhesion and migration properties. Moreover, orthotopic xenografts revealed that CD90 expression induced invasive phenotypes
Indeed, CD90 expression led to enhanced SRC and FAK signaling in our GBM cellular models and GBM patients' specimens. Pharmacologic inhibition of these signaling nodes blunted adhesion and migration in CD90-positive cells. Remarkably, dasatinib blunted CD90-dependent GBM cell invasion
and killed CD90
primary GSC lines.
Our data demonstrate that CD90 is an actor of GBM invasiveness through SRC-dependent mechanisms and could be used as a predictive factor for dasatinib response in CD90
GBM patients.
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OBJECTIVEDexamethasone, a known regulator of mesenchymal programming in glioblastoma (GBM), is routinely used to manage edema in GBM patients. Dexamethasone also activates the expression of genes, ...such as CEBPB, in GBM stem cells (GSCs). However, the drug's impact on invasion, proliferation, and angiogenesis in GBM remains unclear. To determine whether dexamethasone induces invasion, proliferation, and angiogenesis in GBM, the authors investigated the drug's impact in vitro, in vivo, and in clinical information derived from The Cancer Genome Atlas (TCGA) cohort.METHODSExpression profiles of patients from the TCGA cohort with mesenchymal GBM (n = 155) were compared with patients with proneural GBM by comparative marker selection. To obtain robust data, GSCs with IDH1 wild-type (GSC3) and with IDH1 mutant (GSC6) status were exposed to dexamethasone in vitro and in vivo and analyzed for invasion (Boyden chamber, human-specific nucleolin), proliferation (Ki-67), and angiogenesis (CD31). Ex vivo tumor cells from dexamethasone-treated and control mice were isolated by fluorescence activated cell sorting and profiled using Affymetrix chips for mRNA (HTA 2.0) and microRNAs (miRNA 4.0). A pathway analysis was performed to identify a dexamethasone-regulated gene signature, and its relationship with overall survival (OS) was assessed using Kaplan-Meier analysis in the entire GBM TCGA cohort (n = 520).RESULTSThe mesenchymal subgroup, when compared with the proneural subgroup, had significant upregulation of a dexamethasone-regulated gene network, as well as canonical pathways of proliferation, invasion, and angiogenesis. Dexamethasone-treated GSC3 demonstrated a significant increase in invasion, both in vitro and in vivo, whereas GSC6 demonstrated a modest increase. Furthermore, dexamethasone treatment of both GSC3 and GSC6 lines resulted in significantly elevated cell proliferation and angiogenesis in vivo. Patients with mesenchymal GBM had significant upregulation of dexamethasone-regulated pathways when compared with patients with proneural GBM. A prognostic (p = 0.0007) 33-gene signature was derived from the ex vivo expression profile analyses and used to dichotomize the entire TCGA cohort by high (median OS 12.65 months) or low (median OS 14.91 months) dexamethasone signature.CONCLUSIONSThe authors present evidence that furthers the understanding of the complex effects of dexamethasone on biological characteristics of GBM. The results suggest that the drug increases invasion, proliferation, and angiogenesis in human GSC-derived orthotopic tumors, potentially worsening GBM patients' prognoses. The authors believe that careful investigation is needed to determine how to minimize these deleterious dexamethasone-associated side effects in GBM.
Dyslipidemia is a risk factor for incident type 2 diabetes; however, no study has specifically assessed the lipid ratios (i.e. total cholesterol (TC)/high density lipoprotein cholesterol (HDL-C) and ...triglyceride (TG)/HDL-C) as predictors of diabetes. We aimed to compare the independent association between the different lipid measures with incident diabetes over a median follow up of 6.4 years in Iranian men and women.
The study population consisted of 5201 non diabetic (men = 2173, women = 3028) subjects, aged > or =20 years. The risk factor adjusted odds ratios (ORs) for diabetes were calculated for every 1 standard deviation (SD) change in TC, log-transformed TG, HDL-C, non-HDL-C, TC/HDL-C and log-transformed TG/HDL-C using multivariate logistic regression analysis. Receiver operator characteristic (ROC) curve analysis was used to define the points of the maximum sum of sensitivity and specificity (MAXss) of each lipid measure as a predictor of diabetes.
We found 366 (146 men and 220 women) new diabetes cases during follow-up. The risk-factor-adjusted ORs for a 1 SD increase in TG, TC/HDL-C and TG/HDL-C were 1.23, 1.27 and 1.25 in men; the corresponding risks in females were 1.36, 1.14, 1.39 respectively (all p < 0.05, except TC/HDL-C in females which was marginally significant, p = 0.07). A 1 SD increase of HDL-C only in women decreased the risk of diabetes by 25% 0.75(0.64-0.89). In both genders, there was no difference in the discriminatory power of different lipid measures to predict incident diabetes in the risk factor adjusted models (ROC approximately 82%). TG cutoff values of 1.98 and 1.66 mmol/l; TG/HDL-C cutoff values of 4.7 and 3.7, in men and women, respectively, TC/HDL-C cutoff value of 5.3 in both genders and HDL-C cutoff value of 1.18 mmol/l in women yielded the MAXss for defining the incidence of diabetes.
TC/HDL-C and TG/HDL-C showed similar performance for diabetes prediction in men population however; among women TG/HDL-C highlighted higher risk than did TC/HDL-C, although there was no difference in discriminatory power. Importantly, HDL-C had a protective effect for incident diabetes only among women.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
We compared systolic (SBP) and diastolic blood pressure (DBP), mean arterial pressure (MAP) and pulse pressure (PP) as independent predictors of cardiovascular disease (CVD), total and CVD ...mortality among an Iranian population. The study conducted among 5991 subjects aged ≥ 30 years without baseline CVD and antihypertensive medication. The mean of two measurements of SBP and DBP, in sitting position, was considered the subject's blood pressure. During a median follow-up of 8.7 years, 346 CVD and 157 deaths, 63 attributed to CVD, occurred. Hazard ratios (HRs) of each outcome were calculated for a one standard deviation (SD) increase in each blood pressure (BP) measures. In multivariate models, all BP measures were associated with increased risk of CVD regardless of age. In those aged < 60 years, SBP, DBP, PP and MAP were associated with total mortality (p < 0.05), but in subjects aged ≥ 60 years, only SBP and PP increased risk of total mortality significantly. In multivariate analyses, a 1SD increase in SBP, PP and MAP were associated with 35%, 31% and 28% increased risk of CVD mortality (p < 0.05). In terms of fitness and discrimination of models, DBP, PP and MAP were not superior to SBP. In conclusion, our findings provided further evidence from a Middle Eastern population, in support of SBP predictability for CVD events and CVD and all-cause mortality compared with other BP measures.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Diabetes is a strong risk factor for cardiovascular disease (CVD).The relative role of various lipid measures in determining CVD risk in diabetic patients is still a subject of debate. We aimed to ...compare performance of different lipid measures as predictors of CVD using discrimination and fitting characteristics in individuals with and without diabetes mellitus from a Middle East Caucasian population.
The study population consisted of 1021 diabetic (men = 413, women = 608) and 5310 non-diabetic (men = 2317, women = 2993) subjects, aged > or = 30 years, free of CVD at baseline. The adjusted hazard ratios (HRs) for CVD were calculated for a 1 standard deviation (SD) change in total cholesterol (TC), log-transformed triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), non-HDL-C, TC/HDL-C and log-transformed TG/HDL-C using Cox proportional regression analysis. Incident CVD was ascertained over a median of 8.6 years of follow-up.
A total of 189 (men = 91, women = 98) and 263(men = 169, women = 94) CVD events occurred, in diabetic and non-diabetic population, respectively. The risk factor adjusted HRs to predict CVD, except for HDL-C, TG and TG/HDL-C, were significant for all lipid measures in diabetic males and were 1.39, 1.45, 1.36 and 1.16 for TC, LDL-C, non- HDL-C and TC/HDL-C respectively. In diabetic women, using multivariate analysis, only TC/HDL-C had significant risk adjusted HR1.31(1.10-1.57).Among non-diabetic men, all lipid measures, except for TG, were independent predictors for CVD however; a 1 SD increase in HDL-C significantly decreased the risk of CVD adjusted HR 0.83(0.70-0.97).In non-diabetic women, TC, LDL-C, non-HDL-C and TG were independent predictors.There was no difference in the discriminatory power of different lipid measures to predict incident CVD in the risk factor adjusted models, in either sex of diabetic and non-diabetic population.
Our data according to important test performance characteristics provided evidence based support for WHO recommendation that along with other CVD risk factors serum TC vs. LDL-C, non-HDL-C and TC/HDL-C is a reasonable lipid measure to predict incident CVD among diabetic men. Importantly, HDL-C did not have a protective effect for incident CVD among diabetic population; given that the HDL-C had a protective effect only among non- diabetic men.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To compare the predictive ability of adolescent lipoprotein classification using the National Examination Survey (NHANES) cut points and those of the National Cholesterol Education Program (NCEP) for ...predicting abnormal levels in adulthood.
From 1032 adolescents, aged 14-19 years, participants of the Tehran Lipid and Glucose Study, all lipid measures were determined at baseline and again after 6 years. Multivariable Odds Ratios (ORs) were calculated for borderline and high categories of lipids to predict dyslipidemia in adulthood, considering the normal level as a reference. Area under the receiving characteristics curve (AUC) was used to assess the predictive ability of each adolescent lipid classification.
Applying the NCEP classification, the prevalences of high total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides and low high density lipoprotein cholesterol (HDL-C) in males were 12.1%, 12.9%, 26.1% and 34.2% respectively; in females the corresponding prevalences were 15.4%, 17.9%, 21.4% and 25.0%, respectively. Using NHANES cut points, the prevalence of high TC, LDL-C and triglycerides were lower, than those defined by NCEP; the ORs of high categories of lipids (defined by NHANES) were higher than ORs based on the NECP classification, except for HDL-C. For all lipid measures, both classifications had similar predictive abilities, except for TC/HDL-C, which had higher predictive power applying the NHANES classification rather than the NCEP one (AUC 71% vs. 68%, respectively).
No differences were found between NCEP and NHANES classifications for prediction of adult dyslipidemia, except for TC/HDL-C. Because of their simple application, NCEP cut points can be used in clinical settings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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Patients < 60 years with acute ischemic stroke (AIS) are commonly tested for thrombophilia. Underlying this practice is the perception that the stroke may be the result of a hypercoagulable state, ...especially when an alternative cause is not evident. Although certain conditions, such as antiphospholipid antibody syndrome (APS), can be associated with AIS and require anticoagulation, inherited thrombophilia, largely, is not a risk factor for AIS even in young adults with cryptogenic stroke, as supported by case-control and prospective observational studies. Moreover, testing in the acute phase of AIS may give erroneous results (i.e., increase of Factor 8 as an acute phase reactant), and increase health care costs.
To assess our institutional performance on this matter, we conducted a retrospective chart review of 104 patients, age 18-60 years, who were admitted for AIS to Memorial Hermann Hospitals at the Texas Medical Center between 11/2016 and 7/2018, and whose stroke was considered cryptogenic or of undetermined origin (i.e., more than one possible causes) after initial diagnostic evaluation.
Mean age at the time of event was 43 (range 20-58) years. There were 61 (59%) males. Fifty nine (57%) patients were White, 42 (40%) Black, 18 (17%) Hispanic, 2 (2%) Asian, and one (1%) of unknown race. Risk factors for AIS were: hypertension in 64 (61%) patients, diabetes in 26 (25%), smoking in 27 (26%), dyslipidemia in 32 (31%), prior AIS in 17 (16%), coronary artery disease in 4 (4%), and obesity in 10 (10%). None had known atrial fibrillation or other cardiac arrhythmia.
Thrombophilia testing (at least one test) was performed in 82 (79%) of the patients. In the vast majority (70 patients, 85%) of cases, such testing was done within 1-3 days of admission as part of the initial stroke evaluation.
A total of 752 tests were performed on the 82 patients, 56 (7%) of which were positive. Increased Factor 8 (F8) activity (i.e., ≥200%) was the commonest abnormality observed (31/58 patients tested, or 53%), followed by low protein S (PS) activity (13/77, 17%), Factor V Leiden (FVL) mutation (3/71, 4%), low antithrombin (AT) activity (3/73, 4%), elevated homocysteine (2/79, 3%), low protein C (PC) activity (1/76, 1%), and positive APL (1/251, 1%), while no prothrombin gene mutation was seen. All but one of F8, PS, and AT tests were performed in the acute phase of the stroke. The estimated annual cost for testing was $65000.
Forty-two (51%) of the 82 patients tested had at least one abnormal test. In 2/42 (5%) of these patients, repeat testing (i.e., PS activity, F8) was done at least a month later, which, however, did not confirm the abnormality. Forty-seven (45%) patients were seen in the Outpatient Neurology Clinic after their stroke, for a median follow up of 5 (0.2 - 24) months. In 54 (52%) patients the cause of stroke remained undetermined even after thorough evaluation. Sixteen (15%) patients had a patent foramen ovale (PFO).
Of all patients tested, thrombophilia was confirmed in three, i.e., two patients with heterozygous FVL mutation and one with known homozygous FVL mutation and a significant personal history of venous thromboses.
Only in one patient (1/82, 1%) management was changed taking into account the thrombophilia testing results: a 57 year old male with low PS activity (tested 3 months after the stroke) and a PFO not amenable to closure, for whom anticoagulation was started despite the lack of venous thromboembolism.
Based on these results, and due to concerns of indiscriminate testing, we created a practice guideline supported by current literature, as a reference for clinicians (see Figure). Briefly, we eliminated inherited thrombophilia testing in the acute phase, and rendered it optional in the chronic phase at the discretion of the treating physician, when anticoagulation is considered (i.e., some cases of PFO or recurrent stroke). Accordingly, we removed these tests from the admission order panel in the Electronic Medical Record. After internal audit and feedback from health care providers across disciplines, we submitted the new guideline for multidisciplinary review and system-wide adoption (i.e., multiple hospitals).
We conclude that routine thrombophilia testing is not an effective tool for secondary stroke prevention even in young patients with cryptogenic AIS. Institutional practice guidelines are helpful in tailoring such testing, hence avoiding misdiagnosis of a thrombophilic state and unnecessary costs.
Display omitted
No relevant conflicts of interest to declare.
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