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New Platform and Methods for Generating Safe Cell Therapeutics

While some cell therapies have experienced success, many current cell therapies fall short in that enough cells do not reach the target tissue and/or the cells are incapable of producing clinically relevant thresholds of desired products sufficient to impact the disease state. Consequently, there is a major fundamental need to genetically engineer therapeutic cells to be more effective and robust using integrating viruses and powerful gene editing technologies like CRISPR, which can target ten to hundreds of genes simultaneously. However, this is highly problematic because the process of genetic engineering introduces dangerous unwanted mutations into the genome that can lead to cancer and other life-threatening diseases, especially if such cells permanently engraft into the body or fuse with host cells, which is common with stem cells. Therefore, the FDA does not readily permit the introduction of new genetic material or the extensive alteration of endogenous genes in cell-based therapies with the exception of CAR-T cells. For this reason, there is a major underlying need in the cell therapy sector to genetically enhance therapeutic cells to express gene products encoding biologics and then render them safe prior to clinical use. 

Identification of Novel Biomarkers to Detect Chronic Myelogenous Leukemia (CML) Progression

Generally, our current knowledge about cancer is based upon the mutations in protein coding genes, such as tumor suppressors and oncogenes. Recently, with advancements in the deep sequencing arena, focus has turned to the importance of epigenetic and post-transcriptional events in cancer progression and resistance associated with therapeutic treatments. These findings have revealed the complexity of gene expression at the RNA level. To that end, two of the most common RNA modifications are the editing of N6-methyl adenosines (m6A) and adenosine-to-inosine (A-to-I). For A-I conversion, Adenosine Deaminases Act on RNA (ADARs) enzymes targeting non-coding sequences and alterations in ADAR expression or activity can lead to cancer, but the pathogenic mechanisms remain under investigation.  Furthermore, malignant RNA editing, driven by ADAR1 activation has been shown to be a major contributor to cancer relapse and progression.

Efficient Library Preparation for CRISPR Pooled Single-Guide RNAs Screens

There is great interest in both academic and commercial labs in performing pooled CRISPR screens for a variety of purposes, including identifying drug resistance and delivery mechanisms, genes essential for survival, death and disease phenotypes, differentiation, regulation of gene expression, and various other mechanisms.

A Novel Method and Protocol to Induce Pluripotent Stem Cells Toward Astrocyte Differentiation

Rett syndrome (RTT) is a devastating disease that affects 1 in every 10,000 children born in the United States, primarily females. RTT patients undergo apparently normal development until 6-18 months of age, followed by impaired motor function, stagnation and then regression of developmental skills, hypotonia, seizures and a spectrum of autistic behaviors. Rett syndrome is a rare disease that shares certain pathways with major developmental disorders such as autism and schizophrenia, increasing the potential impact. There is no cure for Rett syndrome and the animal model does not entirely recapitulate the human disease. Thus, having the possibility to screen drugs directly in human neurons is a major milestone.

Non-Mechanical Multi-Wavelength Integrated Photonic Beam Steering Device

Today, projecting optical energy is performed using high power laser sources coupled to free-space optical systems comprised of mechanical components, moving parts, and bulk optics. Unfortunately, the application range of these legacy systems is limited by their size, weight, reliability and cost. Consequently, a substantial research effort has been directed toward the miniaturization and simplification of these systems. Recent work has focused on beam steering using phased arrays. Although optical phased arrays are an elegant non-mechanical beam steering approach, the technical and environmental challenges compared to RF systems (10,000 times smaller wavelengths and tolerances) are daunting. Multi-octave operation across the UV to LWIR regions with acceptable losses poses additional technical challenge for any optical phased array beam steering approach. For these reasons, a need exists for a non-mechanical beam steering approach that lends itself to miniaturization as well as high power ultra-wideband operation.

Development of Novel Inhibitors of New Delhi Metallo-beta-lactamase-1 (NDM-1)

Antibiotic-resistance in pathogenic bacteria has become a critical public health threat. A major mechanism of antibiotic resistance is microbial degradation of drugs by enzymes such as β-lactamases which degrade the β-lactam ring of β-lactam antibiotics, namely penicillins, cephalosporins, carbapenems and monobactams, inactivating them. There are four different molecular classes of β-lactamases (A-D). Three classes of β-lactamases (A, C, and D) utilize an active-site serine in covalent mechanisms that can be targeted by β-lactamase inhibitors coformulated with β-lactam drugs. In contrast, class B consists of metallo-β- lactamases (MBLs) that utilize one or two active site Zn(II) ion(s) to catalyze the hydrolysis of the β-lactam ring. The emergence of carbapenemase producing bacteria, especially New Delhi metallo-β-lactamase (NDM-1) and its variants, worldwide, has raised a major public health concern. NDM-1 hydrolyzes a wide range of β-lactam antibiotics, imipenem, meropenem, ertapenem, gentamicin, amikacin, tobramycin, and ciprofloxacin including carbapenems, which are the last resort of antibiotics for the treatment of infections caused by multidrug-resistant bacteria such as carbanenem-resistant Enterobacteriacae and Klebsiella pneumoniae. Currently, there are Inhibitors of NDM-1, both of which have liabilities, either due to adverse effects in mammals or off-target inhibitory activity. Therefore, a new type of NDM-1 inhibitor is needed.

High Dynamic Range (HDR) Digital Imaging with Neural Networks

Standard digital cameras typically take images with under/overexposed regions because of their sensors’ limited dynamic range. The most common way to capture high dynamic range (HDR) images using these cameras is to take a series of low dynamic range (LDR) images at different exposures and then merge them into an HDR image. Producing a high dynamic range (HDR) image from a set of images with different exposures is a challenging process for dynamic scenes. A category of existing techniques first register the input images to a reference image and then merge the aligned images into an HDR image. However, the artifacts of the registration usually appear as ghosting and tearing in the final HDR images.

Development of an Optimized Detection Test for Human Papilloma Virus (HPV) Associated Head and Neck Squamous Cell Carcinomas

Head and neck squamous cell carcinoma (HNSCC) is a highly lethal cancer that annually affects over 60,000 people in the United States (US) and has been traditionally associated with tobacco and ethanol exposure. Recently, the incidence of HPV-induced oropharyngeal squamous cell carcinomas (OPSCC) has seen a rapid increase, especially in the US and other Western countries. Early oral HPV infections do not typically cause any clinical signs or symptoms. Currently, there is no standard screening test to reliably identify High Risk HP-related oral tumors, most of the current tests have been validated for cervical tumor samples and not for saliva or blood. Furthermore, the tests presently in use usually require some sort of confirmatory secondary test.