Citations

AbstractIntroductionFour less well‐studied but promising “emerging” cerebrospinal fluid (CSF) biomarkers are elevated in late‐onset Alzheimer disease (AD): neurogranin, synaptosomal‐associated protein‐25 (SNAP‐25), visinin‐like protein 1 (VILIP‐1), and chitinase‐3‐like protein 1 (YKL‐40).MethodsCSF neurogranin, SNAP‐25, VILIP‐1, and YKL‐40 were measured in families carrying autosomal‐dominant AD mutations.ResultsThe four emerging CSF biomarkers were significantly elevated in the mutation carriers (n = 235) versus noncarriers (n = 145). CSF SNAP‐25, VILIP‐1, and YKL‐40 were altered very early in the AD time course, approximately 15–19 years before estimated symptom onset. All CSF biomarkers predicted important AD‐related outcomes including performance on a cognitive composite, brain amyloid burden as measured by amyloid positron emission tomography, and the estimated years from symptom onset.DiscussionEarly abnormalities in CSF tTau, pTau, SNAP‐25, VILIP‐1, and YKL‐40 suggest that synaptic damage, neuronal injury, and neuroinflammation begin shortly after the commencement of brain amyloid accumulation.

Aβ deposition in the basal ganglia is common in autosomal dominant Alzheimer’s disease. Vöglein et al. report an increased severity of motor symptoms in autosomal dominant versus sporadic disease in advanced disease stages. Motor symptoms are more severe in post-codon 200 presenilin 1 mutation carriers and correlate with basal ganglia Aβ.

AbstractIntroductionLittle is known about effects of physical activity (PA) in genetically driven early‐onset autosomal dominant Alzheimer's disease (AD).MethodsA total of 372 individuals participating at the Dominantly Inherited Alzheimer Network study were examined to evaluate the cross‐sectional relationship of PA with cognitive performance, functional status, cognitive decline, and AD biomarkers in cerebrospinal fluid. Mutation carriers were categorized as high or low exercisers according to WHO recommendations.ResultsMutation carriers with high PA showed significantly better cognitive and functional performance and significantly less AD‐like pathology in cerebrospinal fluid than individuals with low PA. Mutation carriers with high PA scored 3.4 points better on Mini Mental State Examination at expected symptom onset and fulfilled the diagnosis of very mild dementia 15.1 years later compared with low exercisers.DiscussionThese results support a beneficial effect of PA on cognition and AD pathology even in individuals with genetically driven autosomal dominant AD.

TPS7571 Background: Patients ineligible for stem cell transplantation (SCT) or who relapse after SCT, and those who fail to respond to second-line or salvage chemotherapy, represent an unmet medical need for which new therapeutic strategies are required. MOR208 is a novel Fc-enhanced, humanized, monoclonal antibody directed against CD19. Significant single-agent activity of MOR208 in patients with R-R DLBCL (Jurczak et al., J Clin Oncol 34, 2016 [suppl; abstr 7545]) and enhancement of MOR208-mediated cytotoxicity by BEN in preclinical studies, provide a strong rationale to study MOR208 + BEN in patients with R-R DLBCL. Methods: B-MIND is a randomized (1:1), two-arm, multicenter, open-label, adaptive design, phase II/III study of MOR208 + BEN vs RTX + BEN in adult patients with histologically confirmed DLBCL who have relapsed after or are refractory to 1 to 3 prior lines of therapy and who are not candidates for high-dose chemotherapy and autologous SCT. At least 1 prior therapy line must have included a CD20-targeted therapy. Other key inclusion criteria: age ≥18 years; measurable disease; availability of tumor tissue for central pathology review; ECOG 0–2, and adequate major organ systems function. Key exclusion criteria: primary refractory DLBCL; central nervous system involvement, and known double/triple hit DLBCL genetics. The safety of the combination will be assessed in an initial phase II evaluation. Treatment will comprise 6 cycles of MOR208 (12 mg/kg IV) + BEN (90 mg/m2 IV) or RTX 375 mg/m2 IV + BEN. Patients achieving a response after cycle 6 will continue to receive antibody treatment for up to 18 additional cycles. Primary endpoint: progression-free survival (PFS); secondary endpoints include: best overall response, overall survival, safety, quality of life, immunogenicity and pharmacokinetics. Enrollment of 330 patients is anticipated in Europe, US and Asia-Pacific countries. Fourteen patients have been randomized to date. Clinical trial information: NCT02763319.

Abstract Background Chronic diarrhea can be categorized as fatty, watery, or inflammatory. Watery diarrhea is further divided into secretory or osmotic types and can be differentiated by measuring fecal electrolytes and osmotic gap. However, with widespread use of endoscopy, it is unclear if these measurements are being used clinically. Furthermore, because stool is not a validated specimen type for Food and Drug Administration–approved electrolyte assays, utilization is a practical concern for laboratories before analytical validation. Here, we determined the clinical utility and validated the performance characteristics of stool electrolytes on the Beckman Coulter AU680. Methods Historical results and literature review were used to determine the clinically relevant ranges for stool electrolytes (Na+, Cl−, K+, phosphate, and Mg2+). Additionally, medical chart review was performed (n = 44 patients) on results to evaluate their clinical utility in chronic diarrhea work-up. Linearity, precision, and stability studies were performed on the AU680. Accuracy was evaluated by comparing results to the Roche Cobas 6000 c501. Results For all cases, stool electrolytes and osmotic gap proved valuable in chronic diarrhea work-up. The imprecision of the assays ranged from 0% to 5.9%. All assays were found to be linear within the instrument's analytical measurement range with appropriate slopes and intercepts. The bias between the AU680 and the Roche c501 ranged from −0.48 to 2.39 (mmol/L or mg/dL). Na+, Cl−, and K+ were stable refrigerated for 5 days and up to 1 freeze-thaw cycle. Phosphate and Mg2+ were stable refrigerated for 48 h, but unstable to freeze-thaw cycles. Conclusions Stool osmotic gap is valuable for evaluating chronic diarrhea and can be calculated using electrolyte concentrations measured on the AU680.

Background and Purpose— White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods— In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results— At 17q25, we confirmed the association of multiple common variants in TRIM65 , FBF1 , and ACOX1 ( P <6×10 −7 ). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; P EA =4.5×10 −8 ) partially independent of known common signal ( P EA(conditional) =1.4×10 −3 ). We further identified a locus at 2q33 containing common variants in NBEAL1 , CARF , and WDR12 (lead, rs2351524; P all =1.9×10 −10 ). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( P rs34136221 =2.8×10 −8 ). Conclusions— Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

Abstract The protein kinase D (PKD) family of kinases belongs to the CAMK group and consists of three highly homologous enzymes. They play a versatile role in cancer cell signaling, primarily downstream of PKC isoforms. Classically PKDs are activated upon co-localization with PKC at DAG containing membranes, where PKC phosphorylates the PKD activation loop, generating active PKD. Besides this, PKDs are also activated in oxidative stress conditions, where PKD1 protects against cellular damage via signaling to NF-kB. While the three isoforms are highly homologous, they are not redundant in their biological function and oncogenic potential. A picture has emerged which associates PKD1 expression and activity with decreased migration and inhibition of epithelial mesenchymal transition (EMT). PKD2 and PKD3 on the other hand are upregulated in various cancers, and show oncogenic potential e.g. via enhanced ECM breakdown and potentiation of angiogenesis. While non-redundant biological roles continue to surface, the biochemical mechanisms behind these discrepant functions remain mostly elusive. Here, we identify an isoform specific regulation of PKD2 in oxidative stress conditions via the phosphorylation of a key Tyrosine residue in the substrate binding loop of the activation segment which is highly conserved in most Ser/Thr kinases. Phosphorylation of this residue selectively occurs in PKD2 (and not in PKD1). While wild-type PKD1 signals to NF-kB in oxidative stress, we could show that wild-type PKD2 signaling to NF-kB is impeded in these conditions. Substitution of the activation segment Tyr-717 in PKD2 with a non-phosphorylatable Phe restores signaling to NF-kB, indicating that Tyr-717 phosphorylation is a key determinant for the signaling outcome of PKDs in oxidative stress. Note: This abstract was not presented at the conference. Citation Format: Mathias Cobbaut, Rita Derua, Etienne Waelkens, Peter Störz, Veerle Janssens, Johan Van Lint. Differential regulation of Protein Kinase D isoforms in oxidative stress conditions via tyrosine phosphorylation in the activation segment [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B08.

ObjectiveTo confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder.MethodData were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth‐cohort, family history, polarity of first episode and country physician density.ResultsThere was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth‐cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth‐cohort (all estimated coefficientsP< 0.001).ConclusionA large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LEDlighting, mobile devices backlit withLEDs) may influence adaptability to a springtime circadian challenge.