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Combination Therapy For Pancreatic Cancer

Pancreatic cancer is an aggressive disease with limited treatment options and a high mortality rate. Pancreatic cancer is the 3rd leading cause of cancer death in the United States; despite some recent advances in systemic therapy, survival remains dismal in large part due to its profound drug resistance and its propensity for early metastasis. Typically, diagnosis of pancreatic cancer occurs only with advanced stages of the disease since there are currently no early markers for detection. Individuals with pancreatic cancer have a poor prognosis due to the late diagnosis, the extent of metastasis, and ineffective treatments. Survival rates are dismal and pancreatic cancer is not typically responsive to radiation and chemotherapy. An alternative approach for the treatment of pancreatic cancer as well as the design of a new class of therapeutics that can be used to treat this devastating disease is an immediate unmet medical need.

Compositions And Methods For Allelic Gene Drive Systems And Lethal Mosaicism

Efficient super-Mendelian inheritance of transgenic insertional elements has been demonstrated in flies, mosquitoes, yeast, and mice. While numerous potentially impactful applications of such so-called gene-drive systems have been proposed they are currently limited to copying relatively large DNA cargo sequences (~1-10 Kb). Many desired genetic traits (e.g., drought tolerance in plants, crop yield, pest-resistance, or insecticide sensitivity), however, result from allelic variants altering only one or a few base pairs. An efficient system for super-Mendelian inheritance of such subtle genetic variants would accelerate a wide array of efforts to disseminate favorable traits throughout populations, or to assemble complex genotypes consisting of point-mutant alleles in combination with insertional transgenes for a multitude of research and applied purposes.

Development of a Thermal Endoscope for ENT Clinical Diagnostics

There is a clinical need for improved visual inspection for ENT diagnosis and surgeries. Endoscopy is required to access locations of ENT conditions. However, the assessment and identification of ENT abnormalities and pathologies remain challenging due to the difficult-to- reach ENT locations and the complex nature of the related pathologies. An imaging technique that could provide additional information, high contrast, and quantitative data about the patient condition will be useful, especially to assist ENT clinicians in diagnosis and surgeries and to avoid the need to resort to more expensive imaging techniques (e.g., CT scans, ultrasound imaging,MRI).

New Non-Invasive Markers To Assess Efficacy Of Anti-Integrin Therapies

Inflammatory bowel disease is a chronic disease, which affects the lower bowel parts or the entire GI tract, causing symptoms like abdominal pain, diarrhea, fever and weight loss. An estimated two million people in North America suffer from IBD seemingly caused by an overactive mucosal immune system. Crohn’s Disease and ulcerative colitis (UC) are the major groups of inflammatory conditions that make up IBD and are incurable, serious and chronic organic diseases of the intestinal tract.   Recently, anti-integrin monoclonal antibodies have been approved by the FDA as therapeutic agents for treatment of IBD and there are a number of phase three clinical trials ongoing using monoclonal antibody therapy. The immune system responds to the inflammation that is part of the immunopathology of IBD and acts by recruiting inflammatory cells to the intestinal lesions.  Intergrins, specifically alpha 4-β7, plays a key role in mediating leukocyte trafficking from the circulation to the vascular endothelial barrier in gut-associate lymphoid tissue with the ligand MAdCAM-1. The use of anti-integrin therapy targeting alpha 4-β7 reduces the number of immune cells to the gut endothelium. However, the precise identity of the cell subsets depleted from the intestinal lamina by these anti-integrin drugs have not been identified. Thus, there is an unmet need to further develop tools that allow for the identification of the critical effector cell subsets targeted by these drugs in the intestine.

Identification of a Novel Target for Inhibition of Leukemia

Rho-family small (~21kDa) GTPases are essential for regulation of numerous cellular functions. There are 20 members of the Rho family in mammals, of which four (Rac1, Rac2, Rac3, RhoG) belong to the Rac subfamily. Each Rac GTPase functions as a molecular switch by cycling between an active GTP-bound form and an inactive GDP-bound form. In addition to their normal cellular functions, Rac GTPases contribute to cancer development as downstream effectors of growth factor receptor signaling and oncogenic mutations in the Ras pathway. Rac GTPases represent attractive targets for therapy in hematologic cancer, however direct targeting of small GTPases has proved difficult and largely ineffective. A thorough understanding of the diverse mechanisms controlling Rac activation in cancer will therefore be essential towards identifying new therapeutic avenues and improving outcomes in patients One insight into the regulation/activation of the Rac GTPases involves examining Ras proteins and their signal transduction pathways since mutations that produce abnormally active Ras proteins are found in 30% of all human cancers. Moreover, after activation, RAS signaling is mediated through interaction with RAS-binding domains or through the domain RAS association (RA), transmitted to downstream effectors. Notably, many downstream effectors are oncogenes or tumor suppressor genes that are mutated or silenced in cancers independently of RAS. Ras proteins are involved in Ras association domain-containing protein 2 (RASSF2) and it has recently been shown that in Acute myeloid leukemia cells with low expression of RASSF2 are more resistant to pharmacological inhibition of Dedicator of cytokinesis protein 2 (DOCK2), a guanine nucleotide exchange factor (GEF). Acute myeloid leukemia cells with high expression of RASSF2 are sensitive to pharmacological inhibition of DOCK2.

Biosynthetic Production Of L-4-Chlorokynurenine

The non‐proteinogenic amino acid l‐4‐chlorokynurenine (l‐4‐Cl‐Kyn) is a next‐generation, fast‐acting oral prodrug for the treatment of major depressive disorder. Additional studies report that this drug candidate is effective in animal models for the treatment of neuropathic pain, epilepsy, and Huntington's disease.  After active transport across the blood–brain barrier, it is enzymatically converted into the active agent 7‐chlorokynurenic acid, which is a highly selective competitive antagonist of the N‐methyl‐d‐aspartic acid (NMDA) receptor.   Suicide is 2-7x higher in Veterans than non-veterans, and may be related to brain kynurenine pathway (KP) dysregulation and NMDA receptor (NMDAR) hyperactivation.  L-4-Chlorokynurenine (L-4-Cl-Kyn) is a neuropharmaceutical drug candidate that is in development for the treatment of major depressive disorder (Double-Blind, Placebo-Controlled, Phase 2 Trial to Test Efficacy and Safety of AV-101 (L-4-chlorokynurenine) as Adjunct to Current Antidepressant Therapy in Patients With Major Depressive Disorder (the ELEVATE Study)).

Development of a Detachable Endoscope

Endoscopes are used in many fields of medicine to investigate, diagnose, and treat patients. One common procedure that utilizes an endoscope (known as a bronchoscope), is the procedure of intubation that is conducted over 16 million times in the United States annually. To intubate a patient successfully, a physician needs to insert an endotracheal tube (ETT) into the patient’s mouth and secure it in the airway. A delay in securing the ETT into position of greater than 4 minutes can result in permanent brain injury or death of the patient. Malfunction of an indwelling ETT itself or changes in the airway anatomy may lead to emergent need for ETT exchange. The bronchoscope is the gold standard device for confirming the proper placement of an ETT in the trachea and the ultimate method for regaining control. A detachable endoscope design offers additional key advantages potentially allowing the insertion tube portion to be an economical, disposable, single patient use device, eliminating the concern over superbug cross contamination and reducing cost of processing and maintenance.

Development of Methods and Assay for Measurement of Total Oxidized Phospholipid (OxPL)

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States. It can be broadly sub-classified into nonalcoholic fatty liver (NAFL), which is thought to have minimal risk of progression to cirrhosis, and nonalcoholic steatohepatitis (NASH), which is thought to have an increased risk of progression to cirrhosis. The current diagnostic gold standard for differentiating whether a patient with NAFLD has NAFL versus NASH is liver biopsy. However, liver biopsy is an invasive procedure, which is limited by sampling variability, cost, and may be complicated by morbidity and even death, although rare. Accurate, non-invasive, biomarkers for the detection of liver disease and liver disease progression e.g., progression to NASH, are currently also not available.