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The Transcription Factor ATF6 Promotes Mesodermal Differentiation in Human Stem Cells

The endoplasmic reticulum (ER) is the most abundant membrane-bound organelle in eukaryotic cells that has many functions, including lipid and protein synthesis, metabolism, intracellular signaling and storage of free calcium. It also plays a significant role in the folding and maturation of secretory and membrane proteins. During ER stress, brought about by a number of pathogenic and/or physical insults, misfolded/unfolded proteins accumulate within the ER, activating a cellular stress response, named the unfolded protein response (UPR). The UPR is activated in attempt to restore ER homeostasis. Activating transcription factor 6 (ATF6) is one of three protein ER transmembrane receptor proteins that is activated in response to ER stress resulting in the further activation of a number of genes involved in protein folding and degradation, to repair ER function. Loss of ATF6 function disrupts cellular homeostasis, leading to an increase in ER stress-induced damage and cell death.

Joint Tissue Examination and Damage Exam (JADE) Protocol for Quantification of Joint Ultrasound Findings in Hemophilia Arthropathy

Hemophilic arthropathy is a frequent and debilitating comorbidity. Point-of-care musculoskeletal ultrasound (MSKUS) with Power Doppler capacity has become critical during the past several years to evaluate progression of joint disease longitudinally, as well as to detect the presence or absence of joint bleeding associated with joint pains in a timely fashion. With the advent of emerging new treatment modalities the hemophilia population is aging, bringing hemophilic arthropathy rapidly into focus. Based on the increasing need to develop and validate a joint ultrasound imaging protocol that could easily be used in clinical practice as well as a research outcome tool UC San Diego Clinician-Investigators and Collaborators, specialized in Hemophilia, Ultrasound, Musculoskeletal Medicine and Radiology (Drs. Annette von Drygalski, Eric Chang and Randy Moore, as well as Lena Volland, DPT ) developed and validated a unique MSKUS protocol, specifically adept to assess the extent of hemophilic arthropathy in the acute and chronic setting.  This protocol is named JADE protocol (Joint Tissue Assessment and Damage Exam), as described below. The protocol is taught “hands on” during the CME accredited course “Musculoskeletal Ultrasound in Hemophilia”, and is also accessible through online modules. https://cme.ucsd.edu/muh/

Methods for Treating and Alleviating Neuropathic Pain Using ApoA-I Binding Protein (AIBP)

Neuropathic pain is a type of persistent pain usually occurring longer than 3 months, associated with peripheral nerve problems, but also can arise from chronic inflammatory diseases like arthritis, chemotherapeutic-induced peripheral neuropathy in the treatment of cancer or a neurodegenerative disease or condition. The chronic pain has an extraordinary negative impact on quality of life. While opiates, NSAIDs, and anticonvulsants can relieve pain for short intervals, they are less effective for chronic therapy, particularly when components of the pain state involve persistent inflammation and/or injury to the peripheral nerve. Aside from efficacy, many of the potent agents are beset with limiting side effects and issues related to dependence and addiction. This relative lack of long-term efficacy of even approved agents is evident from clinical trial results, which often indicate that most subjects complete even successful trials with pain that is sufficiently severe as to permit reentry into the same trial. What is needed is a new treatment modality.

Use of Cell-Penetrating Peptides and/or Antibody Drug Conjugates for Tumor Radiosensitization

Tumor resistance to radiotherapy can be an obstacle to patient therapy. On way to overcome radioresistance is via the use of drugs to sensitize cells to ionizing radiation (IR). Although many radiosensitizers have been developed, their clinical benefit is hampered by a failure to improve the therapeutic ratio due to a lack of tumor specific delivery over normal tissue. To overcome this obstacle, activatable cell penetrating peptides (ACPPs) target various cargoes to sites of protease activity in vivo. ACPPs consist of a polycationic cell penetrating peptide attached to a cargo and a polyanionic inhibitory domain with a protease cleavable linker. Probe activation and cargo uptake depends on localized proteolysis of the linker sequence that connects the polyanionic and polycationic domains, which converts the probe to an adherent form. This method provides detection of spatially localized enzymatic activity in living tissues via accumulation of cleaved probe. Recently, the use of anti-tumor drugs conjugated to antibodies has been introduced as a way to increase tumor kill and improve patient outcomes.

Generation of Novel Genomic Tools for Use in the Normalization of Endogeneous RNA Expression Between Different Samples

Genome searching tools are a growing field within the medical and biological research communities. There are now a large number of companies offering services relating to understanding genetic information, and typical laboratory functional genomic assays produce a range of data, including sequencing of transcription factors and regulatory regions. Researchers routinely search over 1,417 functional genomic datasets that are publically available, and users have a range of tools to search the data, including many online. Genetic information requires further processing to become biologically meaningful and a pressing challenge is to effectively search functional genomic data and new tools and processes are needed for searching genomic information.

A New Preventive And Therapeutic Strategy For Liver Cancer

While the overall cancer incidences and mortality are decreasing, primary liver cancer, in particular hepatocellular carcinoma (HCC), is increasing rapidly  and has become the second leading cause of cancer-related death worldwide attributing to the rise of metabolic disorders, including alcoholic and non-alcoholic fatty liver diseases, and viral hepatitis. The significance for development of an effective prevention strategy cannot be over-emphasized, given the extremely poor prognosis of liver cancer patients at the advanced stages and the rapidly expanding population with chronic liver diseases and at high risk for subsequent liver tumorigenesis. Unfortunately, this rapid increase of the malignant disease is unmet by more efficient therapeutics in the clinic.

A Method for Making a Human Alzheimer’s Disease Neuronal Model Using Purified ApoE-HDL

Alzheimer's disease (AD) is a common neurodegenerative disease and the most common cause of dementia. Alzheimer’s disease is defined post-mortem by the increased presence of amyloid plaques and neurofibrillary tangles (NFTs) in the brain. Amyloid plaques are extracellular deposits consisting primarily of amyloid-ß (Aß) peptides, and NFTs are intraneuronal aggregations of hyperphosphorylated tau, a microtubule-associated protein involved in microtubule stabilization. The discovery of new drugs for treating Alzheimer’s disease is currently limited by difficulties in obtaining live neurons from patients and the inability to accurately model Alzheimer’s disease. Animal models of Alzheimer’s disease have been developed, however, these animal models do not completely mimic true human disease, and none of these animal models are neuronal models of the disease. There is a need to develop a human neuronal model that more accurately mimics true human Alzheimer’s disease, and then use such a model for Alzheimer’s disease drug discovery and research.

Functional Manipulation of the Gut Microbiome Using a Personalized Approach

The use of traditional probiotic microorganisms to provide therapeutic function for the gut microbiome has a number of limitations. Probiotic bacteria do not colonize the gut because they can’t compete with the resident flora that have evolved for that environment. Current probiotics are a single strain which when used in multiple hosts have not had great success in broad populations and are therefore unpredictable. To alleviate the above problem, a new approach is necessary to colonize the human gastrointestinal tract with greater reliability and for therapeutic value to the patient.