The prognostic effect of DDX3 upregulation in distant breast cancer metastases

Metastatic breast cancer remains one of the leading causes of death in women and identification of novel treatment targets is therefore warranted. Functional studies showed that the RNA helicase DDX3 promotes metastasis, but DDX3 expression was never studied in patient samples of metastatic cancer. In order to validate previous functional studies and to evaluate DDX3 as a potential therapeutic target, we investigated DDX3 expression in paired samples of primary and metastatic breast cancer. Samples from 79 breast cancer patients with distant metastases at various anatomical sites were immunohistochemically stained for DDX3. Both cytoplasmic and nuclear DDX3 expression were compared between primary and metastatic tumors. In addition, the correlation between DDX3 expression and overall survival was assessed. Upregulation of cytoplasmic (28%; OR 3.7; p?=?0.002) was common in breast cancer metastases, especially in triple negative (TN) and high grade cases. High cytoplasmic DDX3 levels were most frequent in brain lesions (65%) and significantly correlated with high mitotic activity and triple negative subtype. In addition, worse overall survival was observed for patients with high DDX3 expression in the metastasis (HR 1.79, p?=?0.039). Overall, we conclude that DDX3 expression is upregulated in distant breast cancer metastases, especially in the brain and in TN cases. In addition, high metastatic DDX3 expression correlates with worse survival, implying that DDX3 is a potential therapeutic target in metastatic breast cancer, in particular in the clinically important group of TN patients.     

How disabling are pediatric burns? Functional independence in Dutch pediatric patients with burns

Although the attention for functional outcomes after burn injury has grown over the past decades, little is known about functional independence in performing activities of daily living in children after burn injury. Therefore, in this prospective cohort study functional independence was measured by burn care professionals with the WeeFIM^® instrument in 119 pediatric patients with burns (age: 6 months–16 years; 58.8% boys) in the Netherlands. In order to identify whether functional independence was affected, participants’ total scores on the WeeFIM^® instrument were compared to American norm values. Of the participants assessed at 2 weeks post burn (n = 117), 3 months post burn (n = 68) and/or 6 months post burn (n = 38), 22, 9 and 9 participants showed affected performance, respectively. Improvements in WeeFIM^® total scores for the total study population between 2 weeks and 6 months post burn were significant (Wilcoxon T = 2.5; p < .001, effect size = ?0.59). Individual improvements were found to be significant for 30.3% of the assessed participants between 2 weeks and 3 months post burn, and for 12.1% between 3 and 6 months post burn. This study is unique in providing data on functional independence for this large and special population. However, a proportion of participants were lost to follow-up and the use of the WeeFIM^® instrument in this specific population and setting has its limitations. To conclude, burn injury impacts functional independence in children, yet the vast majority of Dutch pediatric patients with burns returns to functional independence typical for age within 6 months post burn.     

Cerebral cortical microinfarcts in patients with internal carotid artery occlusion

Cerebral cortical microinfarcts (CMI) are small ischemic lesions that are associated with cognitive impairment and probably have multiple etiologies. Cerebral hypoperfusion has been proposed as a causal factor. We studied CMI in patients with internal carotid artery (ICA) occlusion, as a model for cerebral hemodynamic compromise. We included 95 patients with a complete ICA occlusion (age 66.2 ± 8.3, 22% female) and 125 reference participants (age 65.5 ± 7.4, 47% female). Participants underwent clinical, neuropsychological, and 3 T brain MRI assessment. CMI were more common in patients with an ICA occlusion (54%, median 2, range 1–33) than in the reference group (6%, median 0; range 1–7; OR 14.3; 95% CI 6.2–33.1; p<.001). CMI were more common ipsilateral to the occlusion than in the contralateral hemisphere (median 2 and 0 respectively; p<.001). In patients with CMI compared to patients without CMI, the number of additional occluded or stenosed cervical arteries was higher (p=.038), and cerebral blood flow was lower (B −6.2 ml/min/100 ml; 95% CI −12.0:–0.41; p=.036). In conclusion, CMI are common in patients with an ICA occlusion, particularly in the hemisphere of the occluded ICA. CMI burden was related to the severity of cervical arterial compromise, supporting a role of hemodynamics in CMI etiology.     

Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.     

Peptidoglycan increases firm adhesion of monocytes under flow conditions and primes monocyte chemotaxis

The Toll-like receptor (TLR) 2/nucleotide-binding oligomerization domain ligand peptidoglycan (PG) has been shown to be present in macrophage-rich regions within atherosclerotic lesions, and stimulation of TLR2 promotes atherosclerotic plaque and intima formation in in vivo mouse models. We determined the effect of a PG preparation and Pam(3)Cys-SK(4), a synthetic TLR2 activator, on (1) adhesion molecule expression by flow cytometry; (2) monocyte adhesion under flow conditions, and (3) monocyte migration. The total adhesion (rolling and firm adhesion) of the PG-preparation-stimulated monocytes to L cells, constitutively expressing ICAM-1 (intercellular adhesion molecule-1) and E-selectin, was decreased. This was most likely due to the L-selectin shedding, since monocyte incubation with a blocking L-selectin antibody resulted in a comparable number of adherent monocytes as PG-stimulated cells. The PG preparation induced an increased percentage of firmly adherent, polarized cells and a beta(2)-integrin-dependent binding to ICAM-1-coated beads. Interestingly, the PG preparation induced a priming of the monocytes for increased migration towards the chemoattractant C5a which was TLR2 and beta(2)-integrin dependent. Pam(3)Cys-SK(4) gave comparable results to the PG preparation in all assays tested. This study demonstrates that PG activation of monocytes results in an increase in adhesive and migratory capacities of these cells. This might be a mechanism by which PG promotes atherosclerotic disease in vivo.     

Staphylococcal superantigen-like 5 binds PSGL-1 and inhibits P-selectin-mediated neutrophil rolling

Staphylococcus aureus secretes several virulence factors interfering with host-cell functions. Staphylococcal superantigen-like (SSL) proteins are a family of 11 exotoxins with structural homology to superantigens but with generally unknown functions. Recently, we described that chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS(31-121)), a potent inhibitor of C5a-induced responses, is structurally homologous to the C-terminal domain of SSL5. Here, we identify P-selectin glycoprotein ligand-1 (PSGL-1), involved in the initial rolling of neutrophils along the endothelium, as a target for SSL5. SSL5 specifically bound to Chinese hamster ovary cells stably expressing PSGL-1 (CHO-PSGL-1), which was dependent of sulfation and sialylation. Furthermore, SSL5 bound to PSGL-1/Ig fusion protein immobilized on a biosensor chip. SSL5 affected binding of soluble P-selectin/Fc chimera, the principle ligand of PSGL-1, to CHO-PSGL-1 cells and inhibited adhesion of neutrophils to immobilized P-selectin under static conditions. Under flow conditions SSL5 strongly decreased neutrophil rolling on immobilized P-selectin/Fc and activated human endothelial cells. In conclusion, SSL5 interferes with the interaction between PSGL-1 and P-selectin, suggesting that S aureus uses SSL5 to prevent neutrophil extravasation toward the site of infection. This makes SSL5 a potential lead for the development of new anti-inflammatory compounds for disorders characterized by excessive recruitment of leukocytes.     

Cardiovascular disease risk factors and the relationships with physical activity, aerobic fitness, and body fat in adolescents and young adults with myelomeningocele

Buffart LM, van den Berg-Emons RJ, Burdorf A, Janssen WG, Stam HJ, Roebroeck ME. Cardiovascular disease risk factors and the relationships with physical activity, aerobic fitness, and body fat in adolescents and young adults with myelomeningocele.

Objectives

To describe cardiovascular disease (CVD) risk factors in adolescents and young adults with myelomeningocele (MMC) and to explore relationships with physical activity, aerobic fitness, and body fat.

Design

Cross-sectional study.

Setting

Outpatient clinic.

Participants

Adolescents and young adults (N=31) with MMC (58% men) age 16 through 30 years; 13 were ambulatory and 18 were nonambulatory.

Interventions

Not applicable.

Main Outcome Measures

We studied biologic and lifestyle-related CVD risk factors, including lipid and lipoprotein profiles, blood pressure, aerobic fitness (Vo₂peak), body fat, daily physical activity, and smoking behavior. We considered subjects at increased CVD risk when 2 or more of the following risk factors clustered: systolic blood pressure, total serum cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and cigarette smoking. Relationships were studied using regression analyses.

Results

Levels of TC, low-density lipoprotein cholesterol, and triglycerides were elevated in 29%, 38%, and 3% of the participants, respectively. HDL-C was reduced in 19%. Hypertension was found in 20%, and 19% were current cigarette smokers. Based on the clustering of risk factors, 42% of the participants were at increased CVD risk: 15% of ambulatory participants and 61% of nonambulatory participants (P=.03). Adjusted for sex and ambulatory status, participants with higher aerobic fitness tended to be more likely to have no CVD risk (odds ratio=13.0; P=.07). CVD risk was not associated to physical activity and body fat.

Conclusions

A large proportion of the study sample was at CVD risk, indicated by clustering of risk factors. Improving aerobic fitness in young adults with MMC may contribute in reducing CVD risk; this needs to be confirmed in future studies.