Automatic MRI Quantification of Structural Brain Abnormalities

This invention enables the automatic detection of brain areas that are abnormally small or large. The diagnosis of many neurological diseases rely on the visual detection of areas in the brain that are abnormally small. With this technique, one may be able to map the locations in the brain where there is a difference in brain tissue compared to the normal population. The quantification through the use of Z-scores enables the observer to gauge how abnormal this area is compared to a standard. While this technique does not specifically diagnoses a disease, it may help the clinical judgement of MRI images.

Plasma Protein Biomarkers for Exposure to ROS/RNS & Drugs That Cause ROS/RNS

Disclosed is the identification of four separate plasma protein biomarkers found to be S-glutathionylated upon exposure to a formulation containing oxidized glutathione (NOV-002), along with a method for detection of the modified proteins.  S-glutathionylation is a reversible reaction in which glutathione is bound to a cysteine residue on a target protein and occurs in response to oxidative stress.  Oxidative stress can be toxic and can be induced by the administration of certain drugs, particularly anticancer agents such as Cisplatin, Busulfan and others.  Therefore, these biomarkers will be useful in monitoring the oxidative stress produced by anticancer agents as well as the pharmacological activity of S-glutathionylation-inducing agents such as NOV-002.

Investigators at the Medical University of South Carolina performed both in vivo and ex vivo studies with mice using NOV-002.  Mice were administered NOV-002 intravenously and plasma samples were recovered.  Upon analysis of the samples four proteins were found to be S-glutathionylated, and their identities were characterized.  In further studies plasma was removed from the animals and treated ex vivo with NOV-002.  It was confirmed that the same proteins were modified in this set of experiments as well.

A Peptide that Disrupts Hsp90:HIF Protein-Protein Interactions as a Therapeutic Treatment for Renal and Other Types of Cancer

Hypoxia inducible factor (HIF) is a heterodimeric transcription factor that regulates the expression of proteins involved in angiogenesis, glucose metabolism, and cell survival.  It is composed of two subunits, one of which is dynamically expressed (a) and one of which is constitutively expressed (ß) (see figure).  HIFa is stabilized in low oxygen conditions, is over-expressed in many solid tumors as a result of the hypoxic environment, and is associated with a poor prognosis.  HIFa is also a client protein for the molecular chaperone heat shock protein (HSP90).  Inventors at the Medical University of South Carolina have previously shown that pharmacologic inhibitors of Hsp90 deplete Hsp90 levels, interfere with HIF-1-mediated transcription, and antagonize angiogenesis.  It has been previously reported that HSP90 binds to the PAS-domain of HIFa.  This domain is found in several proteins and is involved in sensing and responding to changes in the cellular environment.  Conformational changes in PAS domains alter protein-protein interactions, leading to distinct signaling cascades. 

 

Disclosed here, includes the finding that Hsp90 binding in this region of HIF serves a role as a critical mediator of HIF binding partners and subsequent activity.  These inventors have developed a peptidic-based experimental approach to allow identification of the specific HSP90 binding region within this domain.  This strategy will allow our researchers to determine the dependence of HIF-1 and HIF-2 function upon Hsp90 and to understand the dynamics between HSP90 and regulatory proteins binding within the PAS domain.  Finally, this approach may lead to the development of a HIF inhibitor, which may have therapeutic potential.

New Biomarker for Diabetic Vascular Disease

Despite considerable advances in the treatment of type I diabetes, cardiovascular complications remain the primary cause of death and accounts for the greatest component of health care expenditures in people with diabetes. However, the risk factors for developing cardiovascular disease in diabetics remain undefined, until now. Researchers at the Medical University of South Carolina recently discovered a blood plasma biomarker in type I diabetes patients, that, when elevated, indicates an elevated risk of diabetic vascular disease.

A recent study was conducted based on cross-sectional data generated from the Diabetes Control and Complications Trial (DCCT) / Epidemiology of Diabetes Interventions and Complications (EDIC)-cohort of type 1 diabetic patients. An independent association was found between the biomarker levels in blood plasma of diabetics and microalbuminuria (an early indicator of renal dysfunction), hypertension, and elevated lipids. Furthermore, multivariable regression analysis provided the first evidence of an independent and positive association between the biomarker levels and surrogate markers of atherosclerosis in diabetics.

In addition, a novel single nucleotide polymorphism (SNP) in the coding region of the biomarker gene was identified. Survival analyses demonstrated that the onset of microalbuminuria occurs at a more rapid rate in diabetic subjects with the SNP than without the SNP.

Finally, the researchers discovered a novel mechanism by which the biomarker is thought to contribute to vascular inflammation/ endothelial dysfunction: The biomarker stimulates MAPK phosphorylation, independent of bradykinin signaling, and induces apoptosis of vascular smooth muscle cells. As a result, atherosclerotic plaques become instable, enhancing the risk of plaque rupture with subsequent myocardial infarction, organ failure, or stroke.

New Biomarker for Diabetic Kidney Disease

Diabetic nephropathy is the leading cause of end stage renal disease in the Western world and develops in about one-third of diabetic patients.  Although, several established risk factors such as duration of diabetes, hyperglycemia and hypertension have been shown to increase the risk to develop nephropathy, they do not solely account for the incidence and progression of diabetic nephropathy. Rather, there is growing evidence that the risk to develop diabetic nephropathy is in large part genetically determined. Although the evidence for genetic susceptibility in the pathogenesis of diabetic nephropathy is well-recognized, the causative genes remained to be identified.

Connective tissue growth factor (CTGF) is known to be an important risk factor in diabetic nephropathy.  CTGF is increased in diabetic nephropathy and correlates with the degree of albuminuria (leaking of albumin into urine, an early indicator of renal dysfunction). Researchers at the Medical University of South Carolina recently discovered a novel single nucleotide polymorphism (SNP) in the promoter region of the CTGF gene that predisposes diabetic subjects to develop albuminuria (an early indicator of kidney dysfunction). The researchers conducted a study based on cross-sectional data generated from the Diabetes Control and Complications Trial (DCCT) / Epidemiology of Diabetes Interventions and Complications (EDIC)-cohort of type 1 diabetic patients.

The novel CTGF SNP is associated with a 3-fold increased risk to develop albuminuria compared to diabetic patients without the SNP. Survival analyses demonstrated that the onset of albuminuria occurs at a more rapid rate in diabetic subjects with the polymorphism than without the polymorphism. Functional studies show that the basal activity of the mutant was significantly higher than wildtype. The novel SNP is located in one of the Smad 1 binding sites and functional analyses indicate that this region is critical for Smad1-dependent transcriptional regulation of the CTGF gene.

CaSm-A Gene Controlling Transformation in Cancer Cells

This invention combines the advantages of attenuated total reflection (ATR) for examining protein-lipid interactions, protein structure and protein orientation with captive bubble surfactometry (CBS) which measures surface active properties of proteins, lipids, and protein/lipid mixtures. This invention will permit simultaneous measurement of protein structure and function at an air/water interface. The ATR-CBS will be able to determine critical surfactant components necessary for pulmonary surfactant replacement therapy of respiratory distress syndrome in premature infants and for therapy of acute respiratory distress syndrome in children and adults.

High Through-Put Assay for Screening Phospholipase D Inhibitors

The invention is an assay system for rapid screening of potential inhibitors of phospholipase D (PLD). This is a new process with many significant improvements over current assays.

 

A Multimarker Gene Panel For Detection of Metastatic Disease In Epithelial-Derived Cancers

Methods are provided for detecting and prognosing Epithelial-derived cancers, including metastatic breast, lung and/or pancreatic cancer. The inventors combined microarray analysis with a novel data mining technique to identify a set of genes that are indicative of micrometastatic disease.

The method involves determining whether certain genes are overexpressed in the cell sample from a patient suspected of breast cancer compared to control tissue cells. The method also predicts the likelihood that a cancer patient will respond to hormonal therapy. Samples can be taken either from lymph node or cervix biopsy. Gene expression can be assessed at the protein or nucleic acid level.

Also provided are methods of predicting decreased probability of survival in a patient diagnosed with early-stage non-small cell lung cancer, by measurement of expression of another panel of genes that are tightly assosiated with metastatic disease.

Another method provides for methods of detecting pancreatic cancer based on the overexpression of a set of certain genes.

Also provided are methods of treating metastatic disease with an inhibitor of the Esx or AGR2 protein.

Dual Specific Phosphatases in Glaucoma

Glaucoma affects an estimated 2 million Americans, with 120,000 blind due to the condition. Even if people with glaucoma do not become blind, vision can be severely impaired. The primary risk factor for the development of glaucoma is elevated intraocular pressure. As a result, normal visual acuity is dependent on the maintenance of intraocular pressure within a relatively narrow range. The Medical University of South Carolina has identified the critical molecular change that leads to the development of elevated intraocular pressure and eventual retinal degeneration in glaucoma. This discovery can be used pharmacologically to treat patients that are currently suffering from glaucoma. In addition to treating, this discovery can be used in simple tests for the early detection of individuals at risk for developing glaucoma.

Plasma CTGF as a Marker/Risk factor for macrovascular disease in diabetes (types 1 and 2)

Currently there are no diagnostic markers available commercially for predicting the development of macrovascular disease in diabetics. An assay has been developed at the Medical University of South Carolina that utilizes an endogenous substance as a marker for hypertension, nephrophathy, and carotid wall thickness in diabetics (Type 1 and Type 2). These risk factors all play a role in vascular complications and the ability to access for these risk factors will allow for early preventative treatment and a decrease in common comorbid diseases found in diabetics.

Intellectual protection of the invention has been initiated to include the uses of this assay in a variety of therapeutic areas. The applications of this assay extend beyond treatment of diabetes.

Further information on this technology is available. Please call the MUSC Foundation for Research Development if you would like to consider receiving confidential information.

Tissue kallikrein is a biomarker for cerebral Ischemia

This invention identifies a sensitive biomarker that is upregulated by cerebral ischemia and participates in the formation of new collateral circulation aimed at restoring the perfusion of ischemic tissues. The excess of this biomarker, human tissue kallikein-specific immunoglobulin), produced in ischemic tissue is released into the circulatory system. Measuring serum levels of this biomarker is a uniquely simple, affordable, and accurate method for aiding in the diagnosis of, and monitoring the progression of cerebral ischemia such as stroke.

Serum levels elevated above the mean amount in normal population is an indication of ischemia in a symptomatic or an asymptomatic patient. The course of ischemic disease can also be monitored by measuring the biomarker level over time. Increasing serum levels over time are indicative of a deteriorating condition, whereas decreasing levels over time indicate an improving condition.

A Method of Identifying and Treating Invasive Carcinomas

Three inventions provide for several methods for determining human prostate and breast carcinoamas non-invasiveness by measuring prostasin levels in carcinoma tissue.

Prostasin is a trypsin-like serine peptidase originally purified as an active, soluble enzyme from human seminal fluid and is highly expressed in prostate, bronchus, lung, and kidney in mouse and human. At the amino acid level, prostasin is similar to plasma kallikrein. Recent studies have identified the physiological function of prostasin, namely it acts as a channel-activating protease (CAP)-1 and is the first of several membrane serine peptidases found to activate the epithelial sodium channel. Prostasin is downregulated in high-grade (Gleason 4/5) prostate tumors.

Researchers at the University of Florida and the Medical University of South Carolina have identified prostasin serine protease as a tumor invasion suppressor for prostate and breast cancers. Protein prostasin, as well as its mRNA levels and its gene promoter DNA methylation levels can be developed as a diagnostic to determine invasiveness levels of human carcinoma's.

Recombinant fusion proteins consisting of complement inhibitors and fragments of soluble P and E-selectin glycoprotein ligand-1 that taret to cell adhesion molecules

Disclosed are methods to produce novel fusion proteins, which rely on different targeting mechanisms, to bind to E-selectin and P-selectin with higher affinity and specificity then any prior construct. Historically the proteins were difficult to express recombinantly, however inventors at MUSC found that coexpression of enzymes allows them to produce the functional protein in reasonable quantities.

Complement Receptor 2 (CR2) Mediated Targeting of Complement Inhibitors

Complement is the collective term for a series of blood proteins and is a major effector mechanism of the immune system. Complement plays an important role in the pathology of many autoimmune and inflammatory diseases, and is also responsible for many disease states associated with bioincompatibility, e.g. post-cardiopulmonary inflammation and transplant rejection. Inappropriate complement activation and its deposition on host cells can lead to direct complement-mediated cell lysis of target structures, or can lead indirectly to tissue destruction due to the generation of powerful mediators of inflammation.

A safe and effective pharmaceutical inhibitor of complement is not available. Research has largely focused on developing soluble inhibitors based on host membrane-bound complement-regulatory proteins.

The efficacy and safety of complement inhibitors could be improved by targeting them to local sites of complement activation and disease. Local targeting of complement inhibitors is predicted to allow a much lower effective serum concentration and significantly reduce the level of systemic complement inhibition. Targeting may also address the problem of a short half life of soluble recombinant complement inhibitors in the circulation.

We have constructed fusion proteins combining targeting and inhibitor elements. The expressed fusion proteins show complement inhibitory activity. These proteins may be useful as anti-inflammatory or anti-rejection therapeutics.

A Process for Identifying and Classifying Functional Areas of the Brain From Functional Magnetic Resonance Imaging (fMRI) Images

Images from functional magnetic resonance imaging (fMRI) have been used to study the response of the brain from various stimuli, including audio, visual, sensorial, mechanical, and chemical. Instead of using a subjective method (i.e. visual inspection) to determine the effects (or the lack thereof) of the stimulus of interest, the invention is a computerized algorithmic process incorporating the location and intensity information of the two dimensional and/or three dimensional pixels (voxels) of the fMRI images to identify the part(s) of the brain that respond to the stimulus and to classify the responses of a subject to the stimulus into normal or various disease categories.

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