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Despite improvements in pre-clinical drug testing models, predictability of clinical outcomes continues to be inadequate and costly due to poor evidence of drug metabolism. Humanized miniature organs integrating decellularized rodent organs with tissue specific cells are translational models that can provide further physiological understanding and evidence. Here, we evaluated 4-Flow cannulated rat hearts as the fundamental humanized organ model for cardiovascular drug validation. Results show clearance of cellular components in all chambers in 4-Flow hearts with efficient perfusion into both coronary arteries and cardiac veins. Furthermore, material characterization depicts preserved organization and content of important matrix proteins such as collagens, laminin, and elastin. With access to the complete vascular network, different human cell types were delivered to show spatial distribution and integration into the matrix under perfusion for up to three weeks. The feature of 4-Flow cannulation is the preservation of whole heart conformity enabling ventricular pacing via the pulmonary vein as demonstrated by noninvasive monitoring with fluid pressure and ultrasound imaging. Consequently, 4-Flow hearts surmounting organ mimicry challenges with intact complexity in vasculature and mechanical compliance of the whole organ providing an ideal platform for improving pre-clinical drug validation in addition to understanding cardiovascular diseases.

Beta cell dysfunction accompanies and drives the progression of type 2 diabetes mellitus (T2D), but there are few clinical biomarkers available to assess islet cell stress in humans. Secretagogin, a protein enriched in pancreatic islets, demonstrates protective effects on beta cell function in animals. However, its potential as a circulating biomarker released from human beta cells and islets has not been studied. In this study primary human islets, beta cells and plasma samples were used to explore secretion and expression of secretagogin in relation to the T2D pathology. Secretagogin was abundantly and specifically expressed and secreted from human islets. Furthermore, T2D patients had an elevated plasma level of secretagogin compared with matched healthy controls, which was confirmed in plasma of diabetic mice transplanted with human islets. Additionally, the plasma secretagogin level of the human cohort had an inverse correlation to clinical assessments of beta cell function. To explore the mechanism of secretagogin release in vitro, human beta cells (EndoC-βH1) were exposed to elevated glucose or cellular stress-inducing agents. Secretagogin was not released in parallel with glucose stimulated insulin release, but was markedly elevated in response to endoplasmic reticulum stressors and cytokines. These findings indicate that secretagogin is a potential novel biomarker, reflecting stress and islet cell dysfunction in T2D patients.

Glycoproteins in cerebrospinal fluid (CSF) are altered in Alzheimer’s Disease (AD) patients compared to control individuals. We have utilized albumin depletion prior to 2D gel electrophoresis to enhance glycoprotein concentration for image analysis as well as structural glycoprotein determination without glycan release using mass spectrometry (MS). The benefits of a direct glycoprotein analysis approach include minimal sample manipulation and retention of structural details. A quantitative comparison of gel-separated glycoprotein isoforms from twelve AD patients and twelve control subjects was performed with glycoprotein-specific and total protein stains. We have also compared glycoforms in pooled CSF obtained from AD patients and control subjects with mass spectrometry. One isoform of α 1 -antitrypsin showed decreased glycosylation in AD patients while another glycosylated isoform of an unassigned protein was up-regulated. Protein expression levels of α 1 -antitrypsin were decreased, while the protein levels of apolipoprotein E and clusterin were increased in AD. No specific glycoform could be specifically assigned to AD.

Synaptic pathology has attained increasing attention as being central in the pathogenesis of Alzheimer's disease (AD). To address the question whether synaptic pathology in AD involves the whole synapse, or is limited to specific components thereof, we studied three different synaptic vesicle proteins (rab3a, synaptotagmin, synaptophysin) and also the presynaptic membrane protein GAP-43 and the postsynaptic protein neurogranin. The material included post-mortem brain tissue (frontal cortex, hippocampus, and cerebellum) from 8 patients with early-onset AD (EAD), 11 patients with late-onset AD (LAD), 6 patients with vascular dementia (VAD), and 9 control subjects. A reduction of all synaptic proteins was found in AD, more pronounced in EAD than in LAD, in both the frontal cortex (EAD 30% to 70% vs. LAD 82% to 88% of control value) and hippocampus (EAD 22% to 82% vs. LAD 76% to 89% of control value), whereas only minor changes were found in VAD. The finding that all synaptic proteins were reduced in AD suggests a degeneration and loss of whole synaptic elements that are more pronounced in EAD than in LAD.

Cerebrospinal fluid (CSF) levels of tau (total tau), growth-associated protein-43 (GAP-43), soluble amyloid precursor protein (sAPP; i.e. total sAPP), and β-amyloid 42 (Aβ 42 ) were studied in patients with frontotemporal dementia (FTD; n = 14), Alzheimer’s disease (AD; n = 47) and vascular dementia (VAD; n = 16), and in age-matched controls (n = 12). CSF-tau was increased in AD compared to controls and FTD (p < 0.001 for both). CSF-GAP-43 was increased in AD compared to controls (p < 0.05), and both CSF-GAP-43 and CSF-sAPP were increased in AD compared to FTD (p < 0.01). Positive and highly significant correlations were found between CSF-tau and CSF-GAP-43 in all groups and between CSF-tau, CSF-GAP-43 and CSF-sAPP in AD. The correlations found may reflect a common pathophysiologic process such as axonal degeneration.

Type 2 diabetes (T2D) is a complex and progressive disease requiring polypharmacy to manage hyperglycaemia and cardiovascular risk factors. However, most patients do not achieve combined treatment goals. To address this therapeutic gap, we have developed MEDI4166, a novel glucagon-like peptide-1 (GLP-1) receptor agonist peptide fused to a proprotein convertase subtilisin/kexin type 9 (PCSK9) neutralising antibody that allows for glycaemic control and low-density lipoprotein cholesterol (LDL-C) lowering in a single molecule. The fusion has been engineered to deliver sustained peptide activity in vivo in combination with reduced potency, to manage GLP-1 driven adverse effects at high dose, and a favourable manufacturability profile. MEDI4166 showed robust and sustained LDL-C lowering in cynomolgus monkeys and exhibited the anticipated GLP-1 effects in T2D mouse models. We believe MEDI4166 is a novel molecule combining long acting agonist peptide and neutralising antibody activities to deliver a unique pharmacology profile for the management of T2D.

Schizophrenia is a common and severe psychiatric disorder of unknown etiology. Numerous neuropathological studies have found subtle structural changes in limbic structures, especially medial temporal lobe structures and the gyrus cinguli. To test the hypothesis that synaptic disturbances are involved in the pathogenesis of schizophrenia, we studied the growth-associated protein 43 (GAP-43), a protein localized to presynaptic terminals, suggested to be involved in establishment and remodeling of synaptic connections, in postmortem brain tissue, using quantitative Western blotting immunohistochemistry. The material consisted of brain tissue from 17 schizophrenics (80 +/- 11 yr), diagnosed according to the DSM-III-R criteria, and 20 age-matched controls (75 +/- 13 yr). Quantitative analyses showed increased GAP-43 protein levels in schizophrenic compared to control brains, both in the hippocampus (2.43 +/- 0.78 vs 1.00 +/- 0.29; p < 0.0001) and in the gyrus cinguli (1.52 +/- 0.21 vs 1.00 +/- 0.35; p < 0.0001). Also by immunohistochemistry, increased GAP-43 staining was found in schizophrenic compared with control brains, throughout all layers of the gyrus cinguli and the hippocampus. Anomalous synaptic sprouting and reorganization, with resultant \"miswiring,\" as well as a defect in synaptic pruning have been hypothesized to be pathogenetic factors in schizophrenia. We suggest that a decreased synaptic density, whether caused by disturbed development or damage/degeneration, may elicit a reactive synaptogenesis (reflected by an increase in GAP-43), which may be functional or anomalous. Synaptic pathology in the limbic system may be of importance in the development of psychotic symptoms in schizophrenia.

BACKROUND Pathological tau protein concentrations in CSF are found in both Alzheimer's disease (AD) and frontotemporal dementia (FTD), but studies on brain tissue have suggested that the tau pathology in AD differs from that in FTD and that the difference may be related to the degree of phosphorylation. As CSF tau protein is increased after stroke, tau may also be implicated in the pathophysiology of vascular dementia, of which subcortical arteriosclerotic encephalopathy (SAE) is a putative subtype. OBJECTIVES To investigate the nature of tau protein in CSF and the involvement of total CSF tau and phosphorylated CSF tau (phosphotau) in various types of dementia. METHODS Using ELISAs for total tau and tau phosphorylated at Thr181 (phosphotau), the CSF concentrations of total tau and phosphotau were determined in patients with probable and possible AD (n=41 and 19, respectively), FTD (n=18), SAE (n=17), and Parkinson's disease (PD; n=15) and in age matched controls (n=17). All the antibodies stained the lower molecular weight bands, whereas only the antibodies that recognise phosphorylated tau stained the higher molecular bands. RESULTS Both CSF tau and CSF phosphotau were increased in probable AD compared with FTD (p<0.001), SAE (p<0.001), PD (p<0.001), and controls (p<0.001). CSF phosphotau was increased in possible AD compared with FTD (p<0.001) and SAE (p<0.001). CSF tau and CSF phosphotau were positively correlated in all the groups. Molecular weight forms of tau ranging from 25 kDa to 80 kDa were found in the CSF CONCLUSION Both phosphorylated and unphosphorylated tau isoforms were present in the CSF, and tau protein appeared in both truncated and full length forms. The results suggest that the CSF concentrations of tau and phosphotau are increased in about two thirds of patients with probable AD and in half of those with possible AD but are normal in FTD, SAE, and PD compared with normal aging. Values in the normal range do not exclude AD.

We investigated the clinical and biological effects of cholesterol-lowering treatment with a statin in 19 patients with Alzheimer’s disease. They received simvastatin 20 mg/day for 12 weeks in an open trial. Primary efficacy parameters were the changes after 12 weeks in the cerebrospinal fluid (CSF) levels of β-amyloid 42 (Aβ 42 ), α-secretase-cleaved amyloid precursor protein (α-sAPP), β-secretase-cleaved APP (β-sAPP), tau, phospho-tau and the plasma levels of Aβ 42 . A secondary efficacy parameter was the change in the Alzheimer’s Disease Assessment Scale-Cognition (ADAS-cog) score. After 12 weeks, CSF α-sAPP and CSF β-sAPP were significantly reduced (p < 0.001), but the CSF levels of tau, phospho-tau, Aβ 42 and the plasma levels of Aβ 42 were unchanged. The ADAS-cog score was slightly increased (p < 0.05). The results suggest that simvastatin acts directly on the processing of APP by inhibiting both the α- and the β-secretase pathways.

The main objective was to investigate the acetylcholinesterase E (AChE) activity in the cerebrospinal fluid (CSF) of patients with three common dementia disorders. We also wanted to investigate the influence of apolipoprotein E (ApoE) Ε4 allele possession and CSF-τ level on the CSF-AChE activity in these patients. The study included 17 consecutive patients with subcortical vascular dementia (SVD), 39 with Alzheimer’s disease (AD), 14 with frontotemporal dementia (FTD) and 12 controls. CSF was obtained by lumbar puncture and CSF-AChE activity was measured by an enzyme antigen immunoassay. CSF-AchE activity was significantly decreased compared to controls only in the SVD group (p = 0.010). The CSF-τ level was increased in the AD group compared to the control (p < 0.01) and FTD groups (p < 0.05). No influence of ApoE Ε4 allele possession on CSF-AChE activity was found. It is suggested that abnormal CSF-AChE activity in patients with SVD reflects a disturbance in the cholinergic system.