Alzheimer's disease: synaptic dysfunction and Aβ

Synapse loss is an early and invariant feature of Alzheimer's disease (AD) and there is a strong correlation between the extent of synapse loss and the severity of dementia. Accordingly, it has been proposed that synapse loss underlies the memory impairment evident in the early phase of AD and that since plasticity is important for neuronal viability, persistent disruption of plasticity may account for the frank cell loss typical of later phases of the disease. Extensive multi-disciplinary research has implicated the amyloid β-protein (Aβ) in the aetiology of AD and here we review the evidence that non-fibrillar soluble forms of Aβ are mediators of synaptic compromise. We also discuss the possible mechanisms of Aβ synaptotoxicity and potential targets for therapeutic intervention

Functional outcomes following various reconstructive methods following various forms of maxillectomies- a tertiary centre experience

Background: The maxilla is the pivotal structure of the midface, separating the oral, antral, and orbital cavities, and providing support to the globes, lower eyelids, cheeks, lips, and nose. In addition, the maxilla play a critical role in speech, swallowing, and mastication. To evaluate the functional outcomes following various reconstructive methods following various forms of maxillectomiesMethods: Retrospective analysis of medical records of patients who underwent various forms of maxillectomies from January 2011 to December 2013. Postmaxillectomy defects were managed by either prosthesis or local flaps.Results: Forty patients had various forms of maxillectomies. Fifteen patients had Browns class 1 maxilectomy and all of these patients underwent reconstruction with Pectoralis major myocutaneous flap. Ten patients underwent class 2a maxillectomy and reconstruction with obturator and Split skin thickness grafting. Nine patients underwent class 3a-b resection and four patients class 4a-b resection and all had reconstruction with temporalis myofascial flap. Two patients underwent orbitomaxillary resection with palate preserved and reconstruction with temporalis myofascial and forehead flap. Mean follow up period was 8 months (Range 6- 24 months). Two patients developed moderate grade of trismus after completion of radiotherapy.  One patient developed recurrence in neck after 6 months of completion of adjuvant radiotherapy. All had moderate to fair speech and eating function which improved over time.Conclusions: There was no difference between flap reconstruction or obturator intervention of maxillary defects in speech and eating function. Small and lateral defects are better reconstructed with obturator and defects involving orbit and total maxilla are better reconstructed with regional flaps. Hence even in the era of microvascular flaps, obturator and regional flaps can still be considered for reconstruction of maxillectomy defects with fairly good outcome

Comparison of short-term outcomes following open and laparoscopic resections for colorectal malignancies

Background: The laparoscopic approach for colorectal cancers are still a matter of controversy. In the present study, we tried to compare the laparoscopy with open methods of colorectal resections.Methods: Retrospective study where patients diagnosed with colorectal cancer in our hospital from year 2014 January to December 2016 were taken. Total number of cases were 69 of which, the total number of right colon cases were 26. Out of twenty-six, 12 underwent open procedure and 14 underwent laparoscopic resections. Total number of left colon cancers were 09. Of these, 2 underwent open and 7 underwent laparoscopic procedure. Thirty-four (34) rectal cancers were included in the study. Of these, 12 underwent open rectal procedures and 22 underwent laparoscopic resections. Multiple parameters like duration of surgery, post-operative complications, postoperative stay, pathological T staging, lymph node yield, positive nodes, distal resection margins, circumferential radial margins were compared.Results: Operating time was significantly shorter in open procedure than laparoscopic surgery in both rectal resection and right hemicolectomies. The postoperative stay was significantly shorter in laparoscopic right hemicolectomy compared to open procedure. All other parameters like post-operative complications, T stage, lymph node yield, positive nodes, distal resection margins and CRMs were comparable in both groups. The lymph node yield was similar in upfront and post neoadjuvant carcinoma rectum cases.Conclusions: Laparoscopic colorectal resections have similar rates of complication, with shorter hospital stays with no compromise on oncological clearance with respect to lymph node yield, CRMs, distal resection margins compared to open procedures

Performance Exploration of Multiple Classifiers with Grid Search Hyperparameter Tuning for Detecting Epileptic Seizures from EEG Signals

This study evaluates the performance of two-level classifications using dimensionality reduction methods to determine the risk level of epilepsy from EEG dataset. To diminish the complexity of EEG data, dimensionality reduction techniques such as Singular Value Decomposition (SVD), Independent Component Analysis (ICA), and Principal Component Analysis (PCA) are utilized. The risk level of epilepsy classification from EEG dataset would then be carried out using three classifiers: Hidden Markov Model (HMM), Naïve Bayesian Classifier (NBC) and Gaussian Mixture Model (GMM). The Grid Search (GS) process is employed to tune the hyperparameters of GMM and NBC classifiers. This study analyzed twenty patients’ datasets. Performance evaluation of classifiers with and without GS hyperparameter tuning is examined, including performance index, sensitivity, specificity, and accuracy. The GMM classifier with the GS hyper-tuning approach for SVD dimensionality reduction technique achieved a higher accuracy of 98.18% than its counterpart classifiers

aCGHViewer: A Generic Visualization Tool For aCGH data

Array-Comparative Genomic Hybridization (aCGH) is a powerful high throughput technology for detecting chromosomal copy number aberrations (CNAs) in cancer, aiming at identifying related critical genes from the affected genomic regions. However, advancing from a dataset with thousands of tabular lines to a few candidate genes can be an onerous and time-consuming process. To expedite the aCGH data analysis process, we have developed a user-friendly aCGH data viewer (aCGHViewer) as a conduit between the aCGH data tables and a genome browser. The data from a given aCGH analysis are displayed in a genomic view comprised of individual chromosome panels which can be rapidly scanned for interesting features. A chromosome panel containing a feature of interest can be selected to launch a detail window for that single chromosome. Selecting a data point of interest in the detail window launches a query to the UCSC or NCBI genome browser to allow the user to explore the gene content in the chromosomal region. Additionally, aCGHViewer can display aCGH and expression array data concurrently to visually correlate the two. aCGHViewer is a stand alone Java visualization application that should be used in conjunction with separate statistical programs. It operates on all major computer platforms and is freely available at http://falcon.roswellpark.org/aCGHview/

Secreted Amyloid β-Proteins in a Cell Culture Model Include N-Terminally Extended Peptides That Impair Synaptic Plasticity

Evidence for a central role of amyloid β-protein (Aβ) in the genesis of Alzheimer’s disease (AD) has led to advanced human trials of Aβ-lowering agents. The “amyloid hypothesis” of AD postulates deleterious effects of small, soluble forms of Aβ on synaptic form and function. Because selectively targeting synaptotoxic forms of soluble Aβ could be therapeutically advantageous, it is important to understand the full range of soluble Aβ derivatives. We previously described a Chinese hamster ovary (CHO) cell line (7PA2 cells) that stably expresses mutant human amyloid precursor protein (APP). Here, we extend this work by purifying an sodium dodecyl sulfate (SDS)-stable, ∼8 kDa Aβ species from the 7PA2 medium. Mass spectrometry confirmed its identity as a noncovalently bonded Aβ40 homodimer that impaired hippocampal long-term potentiation (LTP) in vivo. We further report the detection of Aβ-containing fragments of APP in the 7PA2 medium that extend N-terminal from Asp1 of Aβ. These N-terminally extended Aβ-containing monomeric fragments are distinct from soluble Aβ oligomers formed from Aβ1-40/42 monomers and are bioactive synaptotoxins secreted by 7PA2 cells. Importantly, decreasing β-secretase processing of APP elevated these alternative synaptotoxic APP fragments. We conclude that certain synaptotoxic Aβ-containing species can arise from APP processing events N-terminal to the classical β-secretase cleavage site

Central nervous system immune interactome is a function of cancer lineage, tumor microenvironment, and STAT3 expression.

BACKGROUNDImmune cell profiling of primary and metastatic CNS tumors has been focused on the tumor, not the tumor microenvironment (TME), or has been analyzed via biopsies.METHODSEn bloc resections of gliomas (n = 10) and lung metastases (n = 10) were analyzed via tissue segmentation and high-dimension Opal 7-color multiplex imaging. Single-cell RNA analyses were used to infer immune cell functionality.RESULTSWithin gliomas, T cells were localized in the infiltrating edge and perivascular space of tumors, while residing mostly in the stroma of metastatic tumors. CD163+ macrophages were evident throughout the TME of metastatic tumors, whereas in gliomas, CD68+, CD11c+CD68+, and CD11c+CD68+CD163+ cell subtypes were commonly observed. In lung metastases, T cells interacted with CD163+ macrophages as dyads and clusters at the brain-tumor interface and within the tumor itself and as clusters within the necrotic core. In contrast, gliomas typically lacked dyad and cluster interactions, except for T cell CD68+ cell dyads within the tumor. Analysis of transcriptomic data in glioblastomas revealed that innate immune cells expressed both proinflammatory and immunosuppressive gene signatures.CONCLUSIONOur results show that immunosuppressive macrophages are abundant within the TME and that the immune cell interactome between cancer lineages is distinct. Further, these data provide information for evaluating the role of different immune cell populations in brain tumor growth and therapeutic responses.FUNDINGThis study was supported by the NIH (NS120547), a Developmental research project award (P50CA221747), ReMission Alliance, institutional funding from Northwestern University and the Lurie Comprehensive Cancer Center, and gifts from the Mosky family and Perry McKay. Performed in the Flow Cytometry & Cellular Imaging Core Facility at MD Anderson Cancer Center, this study received support in part from the NIH (CA016672) and the National Cancer Institute (NCI) Research Specialist award 1 (R50 CA243707). Additional support was provided by CCSG Bioinformatics Shared Resource 5 (P30 CA046592), a gift from Agilent Technologies, a Research Scholar Grant from the American Cancer Society (RSG-16-005-01), a Precision Health Investigator Award from University of Michigan (U-M) Precision Health, the NCI (R37-CA214955), startup institutional research funds from U-M, and a Biomedical Informatics & Data Science Training Grant (T32GM141746)