Several crosslinking strategies exist to generate injectable materials. However, the vast majority of materials have very rapid gelation kinetics, which do not allow for complex injection routes via catheter where the material must remain at body temperature inside the catheter for a period of time. An example of such a delivery route is cardiac catheter delivery, where the material must remain liquid in the catheter to facilitate multiple injections to the damaged region of the heart. The delivery of injectable materials into the heart has been studied to encourage endogenous cell infiltration and repair as well as for the delivery of cells or other therapeutics. These studies have, however, largely been performed in small animals since the gelation kinetics of most injectable materials prevent cardiac catheter delivery. (more...)

Current methods of transdermal drug delivery have found success using pulsed lasers.  However, pulsed lasers have been very expensive in the marketplace and have resulted in some treatment options to be cost prohibitive.  Therefore, the healthcare industry has been looking for a low-cost alternative to pulsed lasers to expand the list of treatable pathologies.                                (more...)

Bronchial asthma is a chronic and heterogeneous inflammatory disorder of the conducting airways with immune and non-immune etiologies. Although the underlying molecular basis of asthma is not completely understood, inflammation is a key pathological feature of bronchial asthma. The increasing prevalence in Western countries (approximately 15% of children and 8% of adults) supports the vast resources deployed to find treatments and drugs that act upon pathways not targeted in current therapies are of particular interest. (more...)

A method of reducing, delaying, preventing, and/or inhibiting the progression of a Cryptococcus infection into the central nervous system and a method for delivery of therapeutic agents to the central nervous system. (more...)

Acne affects 85 percent of adolescents, more than 10 percent of adults, and impacts people of all racial and ethnic groups. This translates to over 50 million people in the US, and over 150 million in the seven major markets. It is among the top five most economically burdensome skin diseases in the US, with total costs exceeding $3 billion per year. In spite of the large number of products in the market, acne remains the most prevalent skin disease in the world, demonstrating a high level of unmet clinical need. Innovative products in the drug development pipeline are scarce. An overwhelming number (90%) in the preclinical pipeline consist of reformulated versions of retinols and/or antibiotics. Of the 36 clinical trials actively recruiting acne patients, over 40% are using antibiotics or retinoids as the intervention. With limited market growth potential due to simple formulations, lack of patent protections and decreasing use of oral isotretinoin, novel acne therapeutics represent a key development opportunity that has the potential to quickly capture a percentage of the market share. While the top 5 performing topical anti-acne preparations are forecasted to have sales exceeding $950 million by 2013, all have expired patents, no innovative targets, and limited market growth. Since 4 major factors are involved in acne pathogenesis (overgrowth of the bacterium P. acnes, excess sebum production, follicular plugging with keratinocyte debris, and inflammationi), combination therapy to target multiple pathogenic mechanisms has become standard. However, efficacy of combination topical acne therapy has been limited since, to date, they can only address up to two of the above factors, and patients often experience untoward side-effects such as irritation, dryness, and redness. Regardless, anti-acne medications have sold impressively, with the U.S. market alone forecast to generate $3.25 billion in 2013. Hence, a significant opportunity exists for treatments that are novel, well-tolerated, and that target more than two pathogenic factors.        (more...)

Histones are proteins found in large numbers in most animal cells, where their primary job is to help DNA strands fold into compact and robust structures inside the nucleus. When purified, histones are very effective at killing bacteria, and there is some evidence that histones secreted from cells provide protection against bacteria living outside cells. In principle histones could also protect cells against such bacteria from the inside, but for many years this was thought to be unlikely because most histones are bound to DNA strands in the cell nucleus, whereas the bacteria replicate in the cytosol. Moreover, free histones can be extremely damaging to cells, so most species have developed mechanisms to detect and degrade free histones in the cytosol. (more...)

Nuclear Magnetic Resonance (NMR) spectroscopy is a widely-utilized method for analyzing small molecule compositions. It is among the most sensitive techniques available and has great potential for studying metabolic profiles in living organisms. Since variations in the metabolite concentrations are indicative of many disease states, NMR can be a powerful diagnostic tool. In practice, however, this requires sensitivity still beyond the capabilities of current instruments. As a result, using NMR for diagnostic purposes has been limited to academic research. A key component responsible for the sensitivity is the NMR probe, which holds the sample as it is inserted into the magnetic field. Advancing the probe design is critical to enabling practical medical applications of NMR. (more...)

Researchers at University of California, Davis have discovered that light emitting diode (LED) generated red light and infrared light can modulate skin cell functions associated with skin fibrosis. (more...)

Aging is a complex process that manifests different in different people. Chronological age does not accurately reflect the process of aging on a molecular level. Though fundamental processes underlying human aging are still not known, epigenetic changes such as nucleosome positioning, histone modifications, and genome wide DNA methylation patterns have been linked to the aging process. One of the challenges in studying these epigenetic effects is identifying biomarkers and precisely quantifying the actual rate of aging in an individual. There are reports available linking the methylation markers to the human aging, but no quantitative models have been established which can measure the actual rate of aging. (more...)

Advances in nanotechnology over the last two decades have allowed for use of nanoparticles in therapeutic applications. A number of nanoparticles such as quantum dots, polymer-based nanoparticles, and gold nanoshells have successfully been used in pre-clinical studies, clinical trials or become commercial products. Despite advances in nanoparticle therapeutics, there is a need for developing novel synthetic approaches in order to produce new-generation nanoparticles, which exhibits significantly improved characteristics, including controllable sizes/morphologies, low toxicity, and in-vivo degradability.        (more...)

Trauma to the central nervous system, for example spinal cord injury, can result in a reduction in the quality of life. Methods for improving nerve regeneration after injury or nerve transplantation are needed for improved patient outcome. Also, life expectancy is increasing world-wide leading to a growing ageing population and age-related disorders such as neurodegenerative diseases. Neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer’s Disease and Parkinson’s Disease negatively impact quality of life. There is a need for therapeutics for treating neurodegenerative diseases. The global neurodegenerative therapeutics market is growing with a total neurodegenerative disease market predicted to be greater than $23 billion by 2017. (more...)

Exposed collagen in injured blood vessels provides a substrate for platelets to adhere and aggregate, initiating the first step in thrombosis, the formation of blood clots inside a blood vessel.  Although platelets play an essential role in vascular injury, excessive platelet aggregation may also result in thrombotic disease such as stroke and heart attack. (more...)

Decellularized liver matrices have been successfully reconstituted with fetal or primary hepatocytes. Compositions of DLMs and methods for creating and use of DLMs are described. (more...)

ANCCA as a marker and therapeutic target in breast cancer (more...)

The chemokine domain fractalkine binds to integrins and this interaction is required for fractalkine signaling. The integrin binding is defective mutant acts as a dominant-negative mutant and is a therapeutic target for treating inflammatory diseases. (more...)

Available for licensing are patent rights to a method or composition which provides increased tensile strength and matrix content in native and engineered soft connective tissues. (more...)

Prion diseases are a class of neurodegenerative disorders associated with the accumulation of an infectious isoform of a normally innocuous soluble host prion protein (PrPC). In prion disease, the endogenous alpha-helix rich PrPC protein is converted by an unknown mechanism into a protease-resistant and β-sheet–rich PrPSc form. This conversion can occur spontaneously, result from inherited mutations in the PrPC gene, or be triggered by infection with exogenous PrPSc. Animal prion diseases include Bovine Spongiform Encephalopathy (BSE), Chronic Wasting Disease (CWD), and Scrapie, while human prion diseases include Creutzfeldt-Jakob disease (CJD), kuru, and Gerstmann-Sträussler-Scheinker syndrome. Prion diseases are invariably fatal, and no viable treatments are currently available for these devastating disorders. (more...)

Heparin and Low Molecular Weight Heparin (LMWH) are widely used anticoagulants, drugs which prevent blood clotting. However, they have the risk of potentially serious bleeding side effects. Protamine is currently the only approved drug used to reverse the action of heparin, and there is no approved reversing agent for LMWH. However, there are serious potential side effects associated with protamine. UCR researchers have demonstrated significant binding affinity in two synthetic peptide analogues of the HIP heparin-binding domain. Both peptide analogues have been found to be equally effective in neutralizing heparin activity using the Coatest heparin in vitro assay. Fig. Ball and stick model of s9-mer docked to heparin, shown in molecular surface format. For heparin, the sulfur atoms are shown in yellow, the oxygens are shown in red and the carbons are shown in white.   (more...)

Rapid, efficient, and low cost detection and identification of microorganisms including pathogenic bacteria, viruses, and fungi is a challenge facing plant and animal health. Current technologies such as Q-PCR rely on multiple assays and amplification methods to identify bacteria and viruses. Traditional optical detection methods also require fluorescent markers. These multiple independent steps and tests increase the processing time and cost for detection and identification. Researchers at the University of California, Davis, have developed a technique that uses nanotechnology to electrically detect and identify bacterial and viral RNA sequences without the necessity of using enzymatic amplification methods or fluorescent markers. In cases where microbe densities are particularly low, the technique provides additional sensitivity that allows for the target molecules to be detected in small quantities. Furthermore, the technique may be scaled into large multiplexed arrays for high-throughput and rapid screening. The implementation is further able to differentiate closely related variants of a given bacterial or viral species or strain. This technique addresses the need for a quick, efficient, and inexpensive bacterial and viral detection and identification system. (more...)

As much as 15% of the adult population exhibits symptoms of irritable bowel syndrome (IBS), a disorder characterized by abdominal pain, diarrhea and/or constipation, bloating, and discomfort. Although IBS does not cause permanent harm, it can render sufferers unable to work, attend social events, or even travel short distances. IBS is also associated with significant health care costs and economic burden. Lacking well-defined and specific diagnostic criteria, physicians currently diagnose IBS on the basis of a complete medical history, physical examination, and other assays. These may include invasive procedures such as sigmoidoscopy or colonoscopy. As such, there is a need for a simple and reliable method to diagnose this condition, as well as a therapeutic target for drug development. (more...)

The Hippo pathway is known to play a crucial role in controlling organ size and contributing to tumorigenesis but the signals regulating this pathway are only beginning to become clear. (more...)

Acyl-COA: cholesterol acyl transferases or ACAT is an enzyme that catalyzes the esterification of cholesterol to form cholesteryl ester. Minimally, ACAT-mediated formation of cholesteryl ester from cholesterol prevents the toxic accumulation of excess cholesterol in a cell and maintains a free diffusion gradient across the cell membrane, particularly in the small intestine. In addition, the assembly and secretion of Apolipoprotein-B containing lipoproteins in the liver and intestines is thought to be dependent on the ACAT-mediated formation of cholesteryl esters from cholesterol. In steroidogenic tissue such as the adrenal glands, ACAT activity produces cytosolic droplets loaded with cholesteryl esters from which they can be mobilized as cholesterol substrates for the generations of steroids. Furthermore, macrophages that accumulate cholesteryl ester in cytosolic lipid droplets as a result of ACAT activity appear foamy and are a characteristic early indicator of atherosclerotic lesions. Animal models that completely lack ACAT protein are viable, albeit with tissue-specific reductions in cholesteryl ester, suggesting that another ACAT enzyme is present in these animals. (more...)

Unlike infection by bacteria, persistent viral infections, such as hepatitis C virus (HCV) and human immune deficiency virus (HIV), can remain present through the course of a patient's life. Persistent viruses coexist within the host cell and suppress the immune system, thus perpetuating long term viral presence. Current therapies for HIV provide management of the viral load but are not curative, with patients resigned to a life-long regimen of multiple drugs such as nucleoside reverse transcriptase inhibitors and protease inhibitors, which have numerous side-effects. Patients with HCV undergo lengthy courses of anti-viral treatments that also have significant side effects and are frequently ineffective. A clear need remains for therapeutic alternatives that achieve complete clearance of these and other persistent viruses. (more...)

The delivery of biomolecules, including therapeutic drugs, genes and proteins, provides a promising vehicle for the treatment of many incurable diseases. Efficient delivery of biomolecules remains a technical challenge due to poor targeting and delivery efficiency. The use of viral-, liposome-, and nanotube-mediated techniques for the delivery of biomolecules has been hindered by their cytotoxicity, low efficiency and poor biocompatibility properties. Delivery mechanisms that utilize cell culture substrates, such as nanowire-grafted surfaces, have recently gained traction as a promising method for drug delivery. However, the use of nanowire-based delivery substrates require the cells to be pre-coated with biomolecules, preventing repeated doses or sequential combination of therapies. The invention disclosed here utilizes a novel nanowire-based delivery approach capable of achieving efficiency rates greater than 90%. (more...)

The method is a novel and convenient method to chemically modify the exterior surface of enveloped viruses so that such viruses can be easily purified. This chemical modification on the envelope of the virus is reversible. (more...)

Researchers at University of California, Davis, have developed a novel method for increasing the rate of muscle growth after exercise by inhibiting known proteins. (more...)

Among all solid organ or tissue transplantations, corneal transplantation is the most successful, with a 2-year survival rate of 90% in patients with inflamed and avascular (low-risk) graft beds.  Unfortunately, the rejection rate reaches as high as 50-90% when the grafting is performed on inflamed and highly vascularized (high-risk) corneas. Many patients who are blind as a result of corneal diseases fall in this category after traumatic, inflammatory, infectious, or chemical damage. Such patients are not considered as good candidates for transplantation surgery and have to give up their hope for vision restoration. To address these challenges, investigators at University of California at Berkeley have developed a technical strategy using a combined blockade of VEGFR-3 and VLA-1 that markedly improves high-risk corneal transplant transparency and survival. This strategy suppresses lymphatic vessels in grafted corneas. It provides a new and powerful strategy to combat high-risk corneal transplant rejection. The strategy may also be used to treat low-risk transplant rejection and other immune-or lymphatic-related diseases. It can be locally or systemically administered. (more...)

New use for Sorafenib as a p21 inhibitor for cancer treatment (more...)

Stem cells hold the promise of producing functional tissues that can replace those lost due to disease or injury. Stem cells exhibit "pluripotency," meaning that they have the potential to become any cell type in the body. New organ tissues, such as those found in the heart, liver, or nervous system, can be created from stem cells through the process of "differentiation." However, one major challenge in developing tissue replacement therapy is the heterogeneity and low yield associated with stem cell differentiation. It is well established that mechanical factors of the cellular microenvironment, including cell shape and density, influence stem cell differentiation and cell behaviors in general. Stem cells form isolated colonies in culture, and the geometry of these colonies can have a profound impact on their capacity for differentiation. There is currently a commercialized technology for controlling the size and shape of embryoid body formation and it has been shown that the size of embyroid bodies is important for differentiation. But many differentiation techniques do not involve the formation of embryoid bodies, and instead induce differentiation from 2D monolayer cultures of stem cells. Current 2D stem cell culturing protocols lack control over colony geometry because they allow for random attachment to tissue culturing surfaces. This leads to unpredictable stem cell growth which ultimately hurts our ability to successfully control the cell fate and differentiate into specific cell types. By patterning an extracellular matrix (ECM), such as Matrigel, colony formation, growth, and geometries can be highly regulated. By using silicone stencils a standard tissue culture plate can be converted into a cell patterning substrate while still using the normal ECM plating procedures. (more...)

UC Davis researchers from the NSF Center for Biophotonics and UC Davis Health System have developed a method of identifying and sorting cardiomyocytes derived from human pluripotent stem cells.  This method, based on second harmonic generation (SHG) - a nonlinear optical technique, does not require genetic modification of the cell or any exogenous labels to be used, which makes this an attractive technique for obtaining pure populations of cardiomyocytes under xeno- and vector- free conditions most appropriate for clinical and therapeutic use, as well for tissue engineering and drug discovery applications.There are currently no established methods for sorting pur populations of stem cell derived cardiomyocytes.  Methods that use fluorescent reporters require the introduction of a reporter vector and result in genetically modified cells, reducing their utility for clinical applications.  Other fluorescent-based staining methods have shown to be only applicable for selecting very mature cardiomyocytes.  Surface marker based methods require exposing human cells to products of animal origin, which may increase the risk of non-human pathogen transmission and render the cells unsuitable for clinical use.Second harmonic generation (SHG) is a laser-based technique that identifies stem cell derived cardiomyocytes based on the direct detection of myosin bundles, which generates a unique second harmonic signal when excited by intense laser pulses.  This signal is specific to the cardiomyocyte phenotype and is absent from undifferentiated stem cells and other non-cardiomyocyte cells that are found in the population following the directed differentiation of stem cells to the cardiac lineage.  SHG is able to discriminate cardionmyocytes at different stages of maturation/development, and can detect very immature cells.  When integrated into a flow cytometric configuration, non-invasive sorting for pure populations of stem cell derived cardiomyocytes is feasible. (more...)

 The agouti-related protein (AgRP) is produced in the brain and is a potent appetite stimulant. The normal 50 amino acid polypeptide is produced in the hypothalamus and binds with high affinity to the melanocortin 3 and 4 receptors (MC3R and MC4R). Along with alpha-melanocyte stimulating hormone (apha-MSH) and neuropeptide Y, AgRP plays a central role in the regulation of mammalian feeding and metabolism. From intracerebroventricular (ICV) injection studies, AgRP is well documented to enhance feeding for one to two days following a single injection, and is probably longer acting than any other known hormone or drug.  (more...)

Lymphatic dysfunction has been found in many disorders from transplant rejection to cancer metastasis, but there is little effective treatment for lymphatic diseases. The cornea is an ideal site for lymphatic research due to its accessible location, transparent nature, and lymphatic-free but –inducible features. Because there are no pre-existing vessels to consider at this site, it is exceptionally straightforward and accurate to evaluate new lymphatic events in the cornea. Since lymphatic vessels are not easily visible, previous studies using the cornea have relied on traditional immunohistochemistry assays with dead tissues. Currently, there is no means of direct and harmless visualization of lymphatic vessels within live cornea.   Investigators at University of California at Berkeley have addressed this challenge by developing the first live imaging of corneal lymphatic vessels. Lymphatic specific dye is injected into the subconjunctival space to visualize lymphatic vessels at various stages in the cornea under a fluorescence stereo-, confocal, or two-photon microscope. Lymphatic vessels can be labeled in different colors to produce two-, three-, and four-dimensional images or live videos at a molecular level. The investigators have demonstrated a proof of principle in live mouse cornea. The technique allows time course tracking of dynamic lymphatic processes within the same tissue or subject over a short or long period of time. Live imaging of corneal lymphatic vessels allows visualization of lymphatic vessels in their natural morphology, state, and interactions with the local environment. Live imaging of corneal lymphatic vessels is readily applicable to patient examination as the lymphatic dye of dextran is bio-degradable and harmless to human health. (more...)

The β-lactam ring is essential for antibiotic function within the broad class of    -lactam antibiotics, which is divided into subclasses based on additional structural elements. One subclass in particular, the carbapenems, is produced by chemical synthesis rather than by fermentation. Since the carbapenems have shown themselves to be an important basic structure for active antibiotics, a great deal of synthetic organic chemistry effort has been put toward the production of the key structural elements involved in the active pharmaceutical agents. (more...)

The 3-dimensional deposition pattern of drugs or particles in a subject’s airways strongly influences the impact of such drugs or particles on the subject.Scintigraphy is widely used to determine such deposition patterns.However, scintigraphy suffers from low spatial resolution and it requires exposing the subject to ionizing radiation. Researchers at University of California, Davis have developed a novel method for imaging the 3D distribution of particles in human airways that overcomes the above disadvantages of scintigraphy.The method has a significantly higher resolution than scintigraphy and does not expose the subject to ionizing radiation.The method also promises significant cost saving when compared to methods reliant on MRI. (more...)

Researchers at the University of California, Davis, have developed a novel and high throughput production process of making nano/submicro-sized fibers.  By extruding in-situ micro or submicrofibrillar blend of cellulose acetate butyrate (CAB) and  polymers (polyolefin, polyesters, and proteins) into regular size fibers, CAB serves as a sacrificial matrix and other polymers as micro/nano-fibrills in the matrix in coarse fiber form. After removal of CAB with acetone extraction, micro, as well as, submicro fibers can be produced. (more...)

Ovarian cancer is the 4th leading cause of cancer death in women. Each year in the United States, about 23,000 women are diagnosed with ovarian cancer, and more than 13,000 women die from this disease. Current therapies typically involve surgery to remove tumors followed by chemotherapy to eradicate any remaining cancer cells. Early detection is important, however, more than 85% of ovarian cancers are found at late stages when tumor growth has spread beyond the ovaries. Women with advanced ovarian cancer generally have a high recurrence rate (about 70%) and poor long-term survival. A safer and more effective therapy for late-stage and recurrent ovarian cancers is much needed. (more...)

Diacylglycerol acyltransferase-1 (DGAT-1) is an enzyme involved in triglyceride synthesis.  Inhibitors of DGAT-1 are currently in clinical trials as treatments for diabetes and obesity. (more...)

Currently, no malaria vaccines are available for clinical use. The need for a vaccine is also compounded by the emergence of multiple drug-resistant Plasmodium strains. In 2008, there were nearly 250 million cases of malaria and one million deaths worldwide according to the World Health Organization. Moreover, in addition to chloroquine resistance, resistance to newer anti-malarials is growing. Thus, innovative vaccines and anti-malarials are needed to reduce the morbidity and mortality caused by malaria infections in humans. (more...)

Researchers at the University of California, Irvine have developed a novel method to continuously pattern nanofibers on 2D and 3D substrates. A unique polymer ink formulation provides the right balance of viscosity and elasticity necessary to enable controlled, seamless near-field electrospinning of nanofibers at very low voltages. (more...)

Surface patterning for single-cell culture is of great importance in studies dealing with cell shape and microenvironment effects on the motility, migration, proliferation, and differentiation of cells.  These patterning techniques are key to effective cell printing needed for future medical advancements, such as 3D printing of artificial organs, tissue regeneration, and tissue engineering.  Despite advances in surface patterning methods, important material surfaces such as glass cannot be easily patterned with established printing methods without prior surface modification. Investigators at University of California at Berkeley have addressed this need by developing a single-cell patterning technique.  This innovation is accomplished by coating the substrate surface with a hydrophobic film and then patterning the film surface.  This surface patterning innovation for single-cell culture was achieved by combining plasma-assisted surface chemical modification, soft lithography, and protein-induced surface activation on glass.  In a proof of concept study, the investigators have accomplished surfaces seeding with mesenchymal stem cells in serum medium, resulting in single-cell patterning.   In additional research, using a dry lithography method, hydrophilic surface patterns on polystyrene were directly applied to cell culture dishes without the requirement of clean-room facilities or chemicals that could be harmful to sensitive cells. The long-term stability of single-cell patterns on PS dish surfaces produced by the present method was accomplished in cell culture experiments with neuron stem cells (NSCs) and bovine aorta endothelial cells. (more...)

In addition to their vast therapeutic potential in various neurological disorders, stem cells are also being developed for in vitro disease modeling and drug screening purposes. In vitro recapitulation of developmental differentiation processes permits the generation of specific neural cell types from pluripotent stem cell sources. For example, iPS cells from patients would allow the generation of patient-specific neural cell subtypes for disease modeling, target identification, drug screening and toxicity testing. Such approaches are anticipated to streamline drug development due to the use of more relevant human models instead of animal models.   While some cell types and sources have been identified as being potentially useful for these applications, their efficacy has not been proven and questions about their efficacy and safety still remain unanswered. Currently there is a need for advanced tools that would enable selection and generation of useful cell types for transplantation, and generation of cellular model systems for human diseases.   DESCRIPTION: UCSF investigators have discovered a highly efficient method of differentiating medial ganglionic eminence (MGE) cells from human iPS cells and embryonic stem cell sources. MGE cells are the precursors to forebrain inhibitory neurons that, when impaired, play a role in several diseases including epilepsy, Parkinson’s, Alzheimer’s, autism, schizophrenia, neuropathic pain and spasticity. The investigators’ prior work has shown that MGE cells possess several advantageous properties that would make them useful for treating neurological diseases, namely Parkinson’s disease and epilepsy, see references 1-8, below.   Recently, they have devised a robust method for generating MGE cells from iPS cell sources or embryonic stem cell sources, which consists of simple steps that do not require genetic engineering. The yield is close to 100% efficiency, which is a ten-fold improvement over currently available methods.   Ongoing work is focused on testing therapeutic efficacy of iPS-derived MGE cells in several animal disease models.  (more...)

A system using nanotechnology to synthetically replicate the body's immune function for uses in body fluid filtration, stimulation of immune system, therapeutics and diagnostics. (more...)

Researchers at the University of California, Irvine have developed a new controllable method to fabricate functionalized carbon nanowires that can then be covalently bound to antibodies, proteins, mRNA, DNA or other reagents. These antibodies and reagents may then bind with analytes of interest in solution causing a measurable change in the electrical current. Additionally, interdigitated electrode arrays may also be fabricated by using nanowires made from this method. (more...)

UCSF researchers have identified a set of biomarkers that can be used to diagnose sarcoidosis in whole blood samples. Currently, there are no routinely used non-invasive tests for diagnosing sarcoidosis, therefore these biomarkers are promising for the development of rapid and standardized diagnostic tests that can be widely implemented in the clinics. (more...)

Mode-locked lasers are widely used to produce ultrashort light pulses (in the femtosecond range), for use in science and industry. Poor dispersion compensation, also called chirp, is a limiting factor in reducing the pulse length in many of these systems. While linear chirp can be eliminated with simple and mature technology—grating pairs, chirped mirrors, dispersion-compensating fibers, etc.—higher-order chirp is more difficult to eliminate. One approach to eliminating higher-order chirp is to use a programmable spatial light modulator—for example, a liquid-crystal or acousto-optic modulator—in the Fourier plane of a grating pair. These modulators, however, are very expensive, easily damaged, and absorb some of the light. Deformable mirrors can perform a similar role, but are also very expensive. Other approaches to tunably compensate higher-order chirp require extra optical components that make them difficult to align and adjust. Still other approaches are not tunable, or else tunable over only one degree of freedom. The present invention is an optical component that compensates higher-order chirp. It is very inexpensive and simple to manufacture, has low light loss, and has enormous damage threshold. Most importantly, it has three independent degrees of freedom, which adjust linear chirp, quadratic chirp, and cubic chirp. Each of these adjustments requires no realignment: Only the component itself needs to be adjusted. Therefore the invention could have widespread use, both as an OEM component of commercial lasers, and also as an easily-implemented upgrade to legacy systems. (more...)

Although silk is commonly known as a fiber, dissolved silk protein has recently received significant attention for its use in creating biocompatible, biodegradable, and mechanically tough materials. These materials have been applied to tissue engineering, biosensors, and microfluidics. Reconstituted silk solutions present a promising alternative to polydimethylsiloxane (PDMS), currently the most commonly used material in micropatterning and soft lithography. However, it is not clear if this alternative can rectify the main problems associated with PDMS: the difficulty in replicating nano-scale features, and the inability of PDMS to support high aspect ratio structures (such as needles) without collapsing.Researchers at UC Berkeley have used reconstituted silk fibroin (RSF) to make microneedles, proving that RSF is an excellent material for molding of nano- and micro-scale patterned features. They demonstrated feature replication down to 25 nm, and the ability to support high aspect ratio structures up to 3.75 (height to diameter). Theoretical calculations suggest that silk films could support aspect ratios of up to 10. Furthermore, the researchers showed that the RSF films are in an alpha-helical/random coil water-soluble state, but can also be crystallized into a beta-sheet and water-insoluble conformation. Most importantly, they demonstrated the fabrication of silk microneedles that could be used in drug delivery and wound healing. (more...)

For producing RNA viruses, applications such as drug screening or basic research require immortalized tissue cultures that enable efficient production of fully infectious viruses of a genotype of clinical interest and are easy to use. In the case of hepatitis C virus (HCV), however, existing tissue culture systems yield incompletely replicated viruses (which do not infect cells in vitro), work only transiently, or are not robust enough and otherwise yield viruses with less prevalent HCV genotypes such as genotype 2. Thus, there is a need for a continuous or semi-continuous HCV production system that overcomes these limitations with the generation of a fully infectious HCV of genotype 1. (more...)

Cardiac dysfunction is the leading cause of death (> 50%) in diabetic and pre-diabetic population. However, the specific molecular mechanisms underlying diabetic heart failure remain largely unknown. To date, there is no heart failure diagnostic method or treatment specific to diabetes, even though diabetic heart failure has a poor prognosis. Researchers at University of California, Davis have indentified the islet amyloid polypeptide (IAPP) oligomer, a toxic entity causally implicated in dysfunction of pancreatic β-cells and development of type-2 diabetes mellitus (T2DM), as the primary molecular pathogen linking T2DM to heart failure. UC Davis researchers have discovered that secretory dysfunction of pancreatic β-cells leading to the formation of IAPP toxic oligomers results in a feed forward process, whereby the secretion of these toxic entities in the blood causes additional damage in organs other than pancreas, including heart and kidneys. Thus, these toxic oligomers represent pathogens of diabetic cardiac dysfunction. Researchers have shown that accumulation of IAPP toxic oligomers in the heart triggers a cascade of structural and physiological changes within myocytes culminating in heart failure. The discovery that the IAPP toxic oligomer is a biomarker of heart failure in T2DM has immediate relevance in the diagnosis and prognosis of cardiac dysfunction in T2DM and pre-diabetic patients. The UC Davis researchers’ findings reveal that the toxicity associated with accumulation IAPP oligomers in the heart manifests starting from early pre-diabetes. Thus, these oligomers may represent an effective target for diagnostic purposes and therapeutic strategies. (more...)

Integrin plays a key role in the angiogenesis and metastasis of human tumors. αvβ3 integrin binding ligands have value in cancer diagnostic imaging and targeted therapy. The RGD motif binds to several integins, including αvβ3, αIIbβ3, αvβ5, and α5β1. It is known that amino acids lateral to RGD affect RGD binding specificity to different integrins. Researchers at the University of California Davis have discovered a novel RGD-containing peptide useful in cancer imaging and as a targeted-therapy ligand. (more...)

UCSF researchers have developed a high-performance miniaturized bioreactor that fits inside a standard 5mm tube NMR spectrometer.  This bioreactor is ideal for growth of small, valuable cell samples, including stem cells and biopsies and for metabolomics in living cell samples.  Applications would include rapid metabolic testing of valuable new chemical entities and personalized medicine.    (more...)

Determining oxygen levels in tumors is critical for advancing cancer diagnosis and therapy. A detailed knowledge of real-time changes in oxygen gradients within a tumor can assist in the profiling of tumor growth and improve the effectiveness of current treatment strategies, which function optimally at different oxygen concentrations. Small molecule luminescence has been suggested as a low cost, non-invasive alternative to traditional methods for sensing oxygen levels that are invasive, expensive, and/or lack sufficient spatio-temporal resolution to monitor real-time changes. In addition to sensing oxygen in tumors, luminescent small molecules, such as porphyrins, have been used for photodynamic therapy (PDT) to treat certain cancers by sensitizing oxygen for the production of cytotoxic reactive oxygen species (ROS). However, the utility of porphyrins has been hampered by low biocompatibility, lack of targetable delivery, and limited photophysical properties. The current invention describes a method for incorporating emissive porphyrins into proteins that offers a novel platform to enhance both oxygen sensing capabilities and targeted delivery to tumors. The bioluminescent proteins described not only have promising photophysical properties for biological use, but also are readily modifiable, biocompatible, and biostable. (more...)

Normal.dotm 0 0 1 182 1041 UC Berkeley 8 2 1278 12.256 0 false 18 pt 18 pt 0 0 false false false /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} Normal.dotm 0 0 1 182 1041 UC Berkeley 8 2 1278 12.0 0 false 18 pt 18 pt 0 0 false false false /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin;} Luminescent (including fluorescent and phosphorescent) markers find a wide variety of applications in science, medicine and engineering. In many situations, these markers provide competitive replacements for radiolabels, chromogens, radiation-dense dyes, etc. Moreover, improvements in fluorimetric instrumentation have increased attainable sensitivities and permitted quantitative analysis. We present the synthesis, properties, and biological applications of Ratio Coppersensor-1 (RCS1), a new water-soluble fluorescent sensor for ratiometric imaging of copper in living cells. RCS1 combines an asymmetric BODIPY reporter and thioetherbased ligand receptor to provide high selectivity and sensitivity for Cu+ over other biologically relevant metal ions, including Cu2+ and Zn2+, a ca. 20-fold fluorescence ratio change upon Cu+ binding, and visible excitation and emission profiles compatible with standard fluorescence microscopy filter sets. Live-cell confocal microscopy experiments show that RCS1 is membrane-permeable and can sense changes in the levels of labile Cu+ pools within living cells by ratiometric imaging, including expansion of endogenous stores of exchangeable intracellular Cu+ triggered by ascorbate stimulation in kidney and brain cells. (more...)

Erythropoietin (EPO) is a cytokine that binds to its receptor (EPOR) and plays critical roles in hematopoiesis. Both Epo and EpoR are expressed in the nervous system during development and their expression levels are upregulated upon hypoxic injury. Exogenous EPO is neuroprotective and neurotrophic in CNS injury models. However, the endogenous role of EPO and the role of EPOR in neuroprotection and neurogenesis after stoke have not been identified.Stroke is the leading cause of adult disability due to the brains limited ability to repair after injury. Research tools to study the recovery of the brain after a stroke will aid in the development of future treatment options for stoke patients. (more...)

Systemic lupus erythematosus (SLE or lupus) is a disease characterized by the production of autoantibodies that react with native cells and tissues, causing inflammation, pain, and damage throughout the body. Increased production of IgG in SLE causes the precipitation of immune complexes in the kidney, resulting in irreversible renal damage and failure. There is no known definitive cure for SLE, and treatment is relegated to symptomatic relief of inflammation flare-ups and to non-antigen specific immunosuppression. Non-steroidal anti-inflammatory drugs and anti-malarials are used to treat milder forms of SLE, though corticosteroids and immunosuppressants are used in more severe cases. However, the efficacy of immunomodulating drugs is limited by the increased risk of infection in lupus patients, while corticosteroid therapy is also limited by its side effects, such as obesity, diabetes, and osteoporosis. There is an estimated 1.5 to 2 million Americans with lupus who will benefit from therapeutics that intervene at the gene product level and interrupt the pathogenic process. (more...)

PTEN has been shown to be central in the regulation of cellular growth and survival. In many forms of cancer, mutations or loss of function in PTEN results in tumor formation - and as such PTEN is now appreciated as a central player in tumor suppression. Furthermore, PTEN has been shown to have a modulating role on cellular functions other than growth and survival, implicating this protein in diseases such as diabetes. Therefore, examination of PTEN in other models of disease may provide insight towards the understanding of mechanism and treatment of these diseases. (more...)

The use of stem cells to treat a variety of degenerative diseases has been a promising area of research and treatment. However, the therapeutic use of stem cells depends on the availability of pluripotent cells that are not limited by technical, ethical, or immunological considerations. There have been research groups, including one at UCLA, that generated mouse iPS cells from fibroblast and demonstrated that these cells are functionally and molecularly virtually identical to embryonic stem cells. However, there is a need to generate human embryonic stem cells with human fibroblasts. (more...)

UCLA Researchers have identified a capsule-like organelle that has been conserved across different eukaryotic species. Its cellular function needs further elucidation although its structure has been thoroughly studied. (more...)

Transferrin (Tf) is a critical iron transport protein found in the blood. Tf loaded with iron binds to the cell surface Tf receptor (TfR) and is taken into the cell. Once inside the cell, Tf releases its iron load and both Tf and TfR are then recycled back to the cell surface and Tf is released into the extracellular space. Due to the observation that TfR is overexpressed in a broad range of cancers, Tf is currently being investigated in clinical trials as a potential drug carrier to allow specific targeting to cancer cells. It has been shown previously that the duration of Tf cellular trafficking is correlated with effectiveness of drug delivery. Therefore, increasing the cellular association of Tf should result in more efficient drug delivery. (more...)

The use of antibodies to target tumor cell-associated antigens for diagnostic and therapeutic purposes has been a critical step forward in cancer research. As protein engineering capabilities grow, researchers modify antibodies to alter inherent characteristics, such as affinity and immunogenicity, for enhanced imaging and tumor response. One example of this is in the conjugation of various radionuclides to small recombinant antibody fragments (i.e. diabodies and minibodies) for in vivo tumor cell targeting applications. However, it is not always advantageous to use radioactivity, and thus alternative detection systems are necessary. To that end, the search for high-sensitivity and high-specificity probes that circumvent the limitations of organic dyes and fluorescent proteins has led to the discovery and utilization of quantum dots, nanometer-sized semiconductor particles. Quantum dots are brighter than traditional chromophores, have greater stability, and can be used in multiplex imaging due to size-tunable emission wavelengths. To date, bioconjugates with quantum dots are coupled to intact antibodies whose large size makes it difficult to penetrate tissues and tumors. Therefore, it would be advantageous to monitor tumors with a robust, but small, bioconjugate for tandem in vivo monitoring and treatment. (more...)

RASopathies comprise a group of developmental syndromes arising from germline mutations in genes resulting in dysregulation of the Ras-MAPK signaling pathway. Among the RASopathies, Noonan syndrome and neurofibromatosis type 1 (NF1) alone account for an estimated 9 million cases worldwide. In addition to the physical symptoms associated with these diseases, physicians also observe cognitive defects, with patients exhibiting a decreased capacity to learn and form memories. Families with NF1 patients cite these as the most pernicious part of this disorder, and there are currently no treatments available to alleviate this cognitive dysfunction. (more...)

The only currently available TB vaccine, an attenuated Mycobacterium bovis strain Bacille Calmette-Guerin (BCG), is of variable efficacy. A large carefully conducted meta-analysis has estimated the potency of BCG to be approximately 50%. UCLA researchers developed and reported in the last several years a recombinant BCG expressing the Mycobacterium tuberculosis 30 kDa major secretory protein (r30). This vaccine, named rBCG30, induces greater protection than BCG against aerosol challenge with a highly virulent strain of M. tuberculosis.Immunocompromised individuals, such as HIV infected persons, are more susceptible to TB, and HIV infection significantly increases TB mortality. BCG has been used to vaccinate immunocompromised persons; however the live BCG vaccine can disseminate in an immunocompromised host and cause serious illness and even death. Therefore a safer TB vaccine is desired for immunocompromised individuals. (more...)

Amyloid formation plays a role in over 20 human diseases including Alzheimers disease, type II diabetes and the systemic amyloidoses. Dialysis-related amyloidosis (DRA) occurs in dialysis patients when -2 microglobulin builds up in the blood and deposits in the joints as amyloid. DRA eventually affects all long-term kidney dialysis patients and is only effectively treated by kidney transplant; if left untreated, the systemic amyloidosis can be deadly. Over 300,000 people in the United States and over 1 million worldwide are on kidney or peritoneal dialysis. Finding a treatment to dissolve the -2 microglobulin fibrils would provide the only alternative to a kidney transplant for these patients. (more...)

Polymeric vesicles are a new class of nanoscale self-assembled materials that show great promise in drug delivery applications. Compared to liposomes, polypeptide vesicles have increased stability and can respond to external stimuli. (more...)

UCSF cardiologists have developed a novel topical anesthetic composition that facilitates radial artery cannulation. This composition can be delivered either as a topical cream or through a transdermal patch and can be co-marketed with radial catheterization sheaths and cannulaes to increase product appeal to clinical users. In clinical trials, this novel composition causes local increase of the arterial diamter (by 25% or more for at least 30 minutes) and provides local anesthesia in the patient, without inducing undesirable systemic effects, thus enabling clinicians to insert radial arterial catheters with greater ease, reduce the risk of spasm, and reduce pain experienced by patients undergoing this procedure.  (more...)

Background: Prostate cancer, alopecia, hepatocellular carcinoma, and acne vulgaris are a few examples of the myriad of diseases linked to androgen receptor signaling. These diseases have a significant impact on human health; for example, The American Cancer Society estimates that in 2009, prostate cancer will cause 27,360 deaths and 192,280 new cases will be diagnosed. In fact, one man in six will get prostate cancer in his lifetime and one in thirty-five will die from this disease. Androgen receptor inhibitors are the primary treatment option for androgen-related diseases. Current inhibitors prevent ligand binding to the androgen receptor, but these treatments can result in acquired resistance and serious side effects. Due to the limitations of current treatment options, alternative antiandrogen therapies are urgently needed. Inventions: Prominent UCSF scientists have discovered a suite of novel small molecule inhibitors of the androgen receptor. Using an innovative approach to avoid the pitfalls associated with current antiandrogen therapies, Dr Diamond’s team identified multiple compounds that inhibit the androgen receptor post-ligand binding. The team validated this work by demonstrating the ability of these compounds to inhibit endogenous androgen receptor activity in prostate cancer-derived cell lines. Further validation in animal models of prostate cancer is underway for many of the novel compounds. Significantly, the team demonstrated that one such compound, pyrvinium pamoate, inhibits androgen receptor signaling in vivo and induces prostate atrophy. Furthermore, pyrvinium synergizes with known inhibitors that prevent ligand binding (Jones et al. 2009). In addition to the novel compounds, an assay to detect selective gene regulation by ligand dependent transcription factors has been developed. This assay could be used to uncover additional candidates for androgen receptor inhibition. The assay has been successfully tested on the glucocorticoid receptor and led to the discovery of selective modulators of this receptor for treatment of inflammation, allergic, and immune-mediated diseases.  Three patents have been filed on these technologies to provide a strong IP position for a licensee. (more...)

  Normal 0 0 1 137 783 UC Berkeley 6 1 961 11.1282 0 0 0 Imprinting regulates a number of genes essential for normal development in mammals and angiosperms. In mammals such imprinted genes contribute to the control of fetal growth and development. Human diseases may also be linked to mutations in imprinted genes or aberrant regulation of their expression.. Differential DNA methylation can be established during oogenesis or spermatogenesis by de novo methyltransferases and maintained somatically by methyltransferases. The conversion of cytosine to 5'-methylcytosine in promoter associated CpG islands has been linked to changes in chromatin structure and often results in transcriptional silencing of the associated gene. Transcriptional silencing by DNA methylation has been linked to mammalian development, imprinting and X-Chromosome inactivation, suppression of parasitic DNA and numerous cancer types. This invention provides for demethylase polypeptides that excise methylated cytosines in DNA. (more...)

BACKGROUND:  Patients with certain types of tumors, in particular brain tumors, will frequently rely on radiologic imaging, such as magnetic resonance imaging (MRI), for diagnosis and treatment monitoring. Unfortunately, MRI and similar modalities are often subject to interpretation and can be highly subjective in nature, making it difficult to differentiate between actual tumor recurrence and treatment effect. Subsequent or alternate methodology involving biopsy or other surgical procedures, can be highly invasive, dangerous, and lead to an extensive recovery time in patients undergoing such procedures. A less invasive method to reliably identify tumor recurrence would be valuable to clinicians and their patients during evaluations following treatment and/or surgical resection of a tumor.   TECHNOLOGY:   UCSF inventors have discovered a novel cancer biomarker that is expressed on the surfaces of myeloid cells, so that tumors can be evaluated for recurrence by screening small amounts of peripheral blood in patients. So far, these findings have been done in glioblastoma and prostate cancer patients, but further studies are underway for other types of solid tumors. (more...)

To meet the constant energy requirement in the face of highly variable food supply, mammals employ intricate and precise mechanisms for energy storage. When total energy intake is in excess of energy expenditure such as after a meal, excess carbohydrates are converted to fatty acids (de novo lipogenesis). Excess fatty acids are then converted to triacylglycerol to be stored in adipose tissue and released as oxidative fuels for other tissues during times of energy need such as fasting and exercise. The present invention describes for the first time that DNA-dependent protein kinase, DNA-PK, is connected to the signaling pathway involved in the formation of fat from carbohydrate in the liver. The enzymes that are involved in fatty acid and fat synthesis are tightly regulated during fasting/feeding. In the fed condition, especially after a high carbohydrate meal, activities of these enzymes drastically increase as blood glucose and insulin levels rise. The present invention demonstrates that DNA-PK regulates the transcription of fatty acid synthase (FAS), a central lipogenic enzyme that plays a crucial role in de novo lipogenesis by catalyzing all of the seven reactions involved in fatty acid synthesis. Therefore, DNA-PK is a pharmacological target for regulation of obesity and diabetes due to a diet high in carbohydrates. (more...)

Accurate interpretation of radiographic imaging studies requires knowledge of the patients angle of inclination at the time of image exposure. Conventional X-ray studies are presented in a two-dimensional format, effectively flattening the imaged body part or organ. The methods currently used for measuring the angle of inclination are crude and inconsistent, detecting only if a patient is lying flat or angled, but not the degree to which a patient may be angled. Such information is essentially ineffectual for the diagnostic radiologist and can result in interpretations that are misleading. A device which accurately reports the angle of the patient at the time of imaging would allow the relative effect of the gravitational force on the soft tissue structures, liquids and gaseous particles to be integrated into a more meaningful and informative interpretation of the radiographic image.  A prominent UCSF researcher and clinician has designed new inclinometers tailored for use in radiographic imaging. The designs range from an inexpensive, portable version, which could be carried around by a radiology technician performing routine x-ray examinations, to versions with additional features which could be either portable or incorporated directly into the imaging cassette. (more...)

Membrane type serine protease 1 (MT-SP1), or matriptase, is a serine protease that is over-expressed on the surface of epithelial cells involved in a variety of cancers, including breast, colon and prostate. UCSF inventors have developed a novel antibody inhibitor of MT-SP1 (A11) which gains potency and specificity through interactions with the protease surface loops and binds in the active site in a catalytically non-competent manner.  The A11 antibody has applications as a therapeutic, diagnostic, and research tool. (more...)

Gene therapy via viral vector technology has been associated with dangerous complications and risks. UCSF investigators have discovered a process that permits defective genetic sequences to be replaced with greater efficiency and potentially fewer side effects. The process, small fragment homologous replacement (SFHR), allows genes to be repaired in a site specific fashion and does not require the insertion of new genetic material into the genome. Thus, the SFHR approach should be applicable to a wide variety of gene therapy applications requiring the repair of specific mutations in DNA sequence. Furthermore, assay methods have been developed to monitor and quantify gene targeting frequency and to differentiate between cells carrying modified and unmodified DNA. (more...)

Researchers at the University of California have developed a fiber-based spectroscopic technique that can be used to quantify optical properties in superficial layers of tissue. (more...)

Phytochrome-Derived Fluorescent Markers (more...)

Altering chimeric pigs' DNA for the purpose of creating transgenic and knockout pigs (more...)

System for bioengineering functional phytochrome assemblies in living cells which produces functional phtochromes in nonphotosynthetic organism E.coli (more...)

Technology for engineering antibodies to bind irreversibly to their receptor has been developed by UC Davis researchers. This technology, enabling the formation of permanent antibody-antigen complexes has a number of potential applications in chemistry and biology, including: targeted medical imaging targeted medical therapies (e.g., cancer therapeutics) synthetic tag to replace avidin-biotin no competition from endogenous ligands no dissociation after capture humanized format Furthermore, UC Davis researchers have constructed a bispecific fusion protein that has tumor targeting properties and irreversibly captures a metal chelate. This combines irreversible metal chelate binding with tumor targeting activity for the first time in a highly homogenous genetic construction that can be expressed at high yields. In addition, this allows the substitution of other targeting sequences allowing for a wide range of cellular targets. The irreversible nature of the chelate binding has not been previously achieved in a single expressed protein fused to a tumor targeting functional segment. (more...)

Platform for Testing the Effects of Human PTP1B Inhibition on Insulin Signaling, Adipose Differentiation and Glucose Uptake (more...)

Researchers at the University of California, Davis have developed transgenic mouse models that constitutively express B cell Activating Factor (BAFF) in the Tumor Necrosis Factor (TNF) family, and Green Fluorescent Protein (GFP) under the control of Glial Fibrillary Acidic Protein (GFAP) promoter in astrocytes. (more...)

Method of using Dantrolene, a FDA-approved drug, currently used for treatment of muscular skeletal dysfunction, to treat T-lymphocyte mediated disorders (autoimmune diseases and chronic graft versus host disease) in humans and animals. (more...)

University of California researchers have developed a family of antibody fusion proteins with a potential for various therapeutic applications. These inventions represent both novel technologies and products with novel applications. These UC fusion proteins combine an antibody with various cytokines. While these cytokines have been used previously as direct antitumor agents, these antibody-cytokine fusion proteins can be employed in a novel therapeutic strategy. In this role, the fusion proteins enhance the immune response to a particular tumor marker. Studies in an animal model have demonstrated that these fusion proteins lead to significant anti-proliferative activity against a murine tumor expressing a breast cancer antigen; the results suggest that both humoral and cell-mediate responses contribute to the observed anti-tumoral activity. It is expected that these fusion proteins will lend themselves to both prophylactic and therapeutic vaccinations; they may be used separately or in combination to achieve an additive or synergistic anti-proliferative effect. (more...)

Beta-1 integrin is a critical member of the large family of integrin proteins necessary for cell-extracellular matrix adhesion and bi-directional signaling across the cell membrane. Conventional deletion of beta-1 integrin from the mouse genome results in embryonic death soon after implantation of the blastocyst. Thus, analysis of beta-1 integrin function beyond post-implantation embryogenesis is not possible in a classic deletion model. (more...)

Fusobatcerium nucleatum is an anaerobic Gram-negative microorganism that is commonly found in the mouth. For example, Fusobacterium nucleatum is the most frequently isolated pathogen from periodontal disease sites and is believed to be an initiator of periodontal diseases. Moreover, this bacterium is commonly found in abscesses and other infections in the abdomen, blood, chest, lung, sinuses, and female genital tract. Several F. nucleatum proteins that are believed to be associated with F. nucleatum pathogenesis have been identified, but their evaluation has been hampered by a lack of systems for genetic manipulation of this microbe. Therefore, there is a need for reliable gene transfer and expression systems for F. nucleatum. (more...)

Hospital-borne bacterial infections present a major challenge in patient care due to the rising number of strains resistant to multiple antibiotics in recent years. Gram-positive bacteria, such as Staphylococci, Streptococci and Pneumococci, are the most common cause of these often fatal infections and are particularly more difficult to treat in immunocompromised patients. Therefore, there is an urgent need for identifying novel targets sites in these pathogens for the development of antibiotics. A unique characteristic of these pathogens, including Staphylococci, is the presence of surface proteins anchored to the cell wall, many of which are essential for pathogenesis. The anchoring process involves secretion of the protein through the cellular membrane, followed by its cleavage at a C-terminal sorting signal and anchoring of the cleaved protein to the cell wall peptidoglycan. This two-step transpeptidation reaction is catalyzed by the enzyme sortase. Since these final processes catalyzed by sortase are crucial in the presentation of biologically active surface proteins and the enzyme is conserved in gram positive bacteria but absent in humans, sortase is an attractive novel target for the development of effective and safe antibiotics directed towards many gram positive pathogenic bacteria. (more...)

The hormone prolactin (PRL) exerts various effects in a wide range of physiological processes. Research suggests that PRL may promote cellular proliferation in both breast cancer and prostate cancer cells. University of California researchers have developed a modified PRL analog (S179D) that acts as a strong antagonist to PRL in cell proliferation assays. S179D consists of a wild-type PRL with a single amino acid substitution. This substitution alters the activity of the molecule such that it antagonizes the growth-promoting effects of unmodified PRL in experimental breast cancer and prostate cancer cell lines. Research results indicate that the modified S179D retains some functions of normal PRL. In other words, S179D may be a selective inhibitor of cell proliferation in certain systems, which suggests that it could potentially be used as a cancer therapeutic that did not wholly disrupt PRL metabolism throughout the body. The University of California holds a soon-to-issue United States Patent claiming S179D and related PRL mutants. The University is searching for commercial partners that are interested in investigating the potential of S179D as a therapeutic. Examples Figure 1.  Effects of S179D on the proliferation of MCF-7 breast cancer cells Normal MCF-7 cells produce PRL, making it difficult to study the effects of exogenous PRL. In this study, MCF-7 breast cancer cells were developed that are deficient in PRL production so that the effects of exogenously applied hormone could be elucidated. Cells were cultured in media containing wild-type human PRL at 100 ng/ml. Cell numbers were measured at 48 hours, and the percent increase over the number of cells in the vehicle only control was calculated. In the absence of S179D, wild type PRL induced a near doubling in the number of MCF-7 cells. When treated with either of two forms of S179D (A or B), the growth-promoting effects of PRL were significantly reduced in a dose-dependent manner. Figure 2.  In one experiment, the administration of S179D prior to cancer cell injection was effective in decreasing both the incidence and size of tumors in mice injected with prostate cancer cells (A and B). In a second experiment, mice previously injected with prostate cancer cells were treated with S179D, which was effective in reducing tumor size (C). 2A.  At day 1, nude mice were implanted with minipumps administering control vehicle, wild type PRL, or S179D. On day 4, mice were injected with DU145 human prostate cancer cells. On day 22, mice were assayed for tumor incidence and size. S179D significantly reduced the incidence of tumors. 2B.  PRL slightly increased tumor size while S179D significantly reduced tumor size. 2C.  In a separate experiment, mice were injected on day 1 with DU145 human prostate cancer cells. At day 18, mice were implanted with minipumps administering control vehicle, wild type PRL, or S179D. On day 42, tumor size was measured. PRL promoted increased tumor size while S179D significantly reduced the size of well-established tumors. References X. Xu, E. Kreye, C.B. Kuo, and A.M. Walker. A molecular mimic of phosphorylated prolactin markedly reduced tumor incidence and size when DU145 human prostate cancer cells were gown in nude mice. Cancer Research 61:6098 (2001) M.D. Schroeder, J.L. Brockman, A.M. Walker, and L.A. Schuler. Inhibition of Prolactin (PRL)-Induced Proliferative Signals in Breast Cancer Cells by a Molecular Mimic of Phosphorylated PRL, S179D-PRL. Endocrinology 144: 5300 ' 5307 (2003) T.J. Chen, C.B. Kuo, F.F. Tsai, J.W. Liu, D.Y. Chen, and A.M. Walker. Development of Recombinant Human Prolactin Receptor Antagonists by Molecular Mimicry of the Phosphorylated Hormone. Endocrinology 139: 609-616 (1998).   (more...)

Monoclonal antibodies (mAbs) are an essential tool in numerous research, therapeutic, and diagnostic applications, as mAbs can be customized to bind a desired antigen. While this is highly advantageous in generating very high binding specificity, the actual process of producing mAb-producing hybridomas is difficult and time-consuming, and involves mAb protein chains (immunoglobins) derived from animal sources that are not always suitable for use in humans. Researchers at the University of California have developed a set of vectors for use in an alternative method for producing purified, humanized antibodies, based on the expression of recombinant human immunoglobulins in cell culture. These vectors, which are being made available for bailment as tangible research property, can be used to express PCR-generated variable regions or variable regions cloned directly from a cell line in conjunction with the constant regions. Thus, expression of the UC vectors can provide complete heavy or light chains or libraries of heavy or light chains expressing variable regions of interest. This expression system eliminates the need for hybridomas, and makes possible the facile production of human mAb proteins that are suitable for in vivo or in vitro use. They include gene sequences for the kappa light chain and for the IgG-1, IgG-2, IgG-3, IgG-4, and IgA heavy chains, along with various selectable markers (his, neo, and gpt). In the case of the kappa and gamma-1 chains, more than one vector is available. This range of vectors permits the design of antibody-specific therapeutic and diagnostic agents based on human immunoglobulins. Such recombinant antibodies avoid allergic reactions typical of mAbs, and may also be useful in various specialized research applications where conventional techniques for generating antigen-specific beta lymphocyte cell strains, etc., are not practical. (more...)