University of California

Shu Chien

Yingxiao Wang

Shaoying Lu

Liangfang Zhang

Che-Ming Jack Hu

Ronnie H Fang

Brian T Luk

Marshall J Levesque

Kirk K Shung

Jie Sun

Phillip D Pham

Kuei-Chun Wang

Lei Lei

Matt Mui

Yijia Pan

Yiqian Wu

Jason H Haga

John Y-j Shyy

Provided are Shp2- and Spleen tyrosine kinase (Syk)-integrated sensing and actuating protein (iSNAP) (Shp2- and Syk-iSNAP) chimeric proteins comprising: a bi-phosphorylatable peptide, optionally a bisphosphoryl tyrosine-based activation (BTAM) motif; a Fluorescent Protein (FP) F&#xf6;rster Resonance Energy Transfer (FRET) (or FP FRET) pair or pair of motifs; a truncated Shp2 domain comprising an N-Src Homology 2(N-SH2) domain and a C-Src Homology 2(C-SH2) domain; and, a phosphatase (PTP) domain or a kinase domain. Provided are engineered cells and methods for cancer cell or tumor eradication, or for the treatment or amelioration of a cancer, tumor or dysfunctional cell, or for promoting an anti-cancer, anti-tumor or anti-dysfunctional cell inflammatory response, including enhancing macrophage-, monocyte-, microglia-, osteoclast-, Kupffer cell- or dendritic cell-mediated antibody- or monoclonal antibody (mAb)-guided cancer or dysfunctional cell or tumor eradication, amelioration, or treatment.

Compositions and methods for enhancing macrophage-mediated antibody guided cancer cell or tumor eradication

In alternative embodiments, provided are compositions, including products of manufacture and kits, and methods, for remotely-controlled and non-invasive manipulation of intracellular nucleic acid expression, genetic processes, function and activity in live cells, e.g., adding functions or changing or adding specificities for immune cells, for monitoring physiologic processes, for the correction of pathological processes and for control of therapeutic outcomes. In alternative embodiments, provided are ultrasound-based thermal or mechanical stimulations, and thermo- or mechano-sensitive protein, either synthetically engineered or natively (endogenously) occurring, integrated to control the production of intracellular nucleic acid and gene expression, e.g., for the expression of biological-active proteins, which can be used, in alternative embodiments, for diagnostic or therapeutic purposes. In alternative embodiments, exemplary thermo- and mechanogenetic systems provided herein allow a deep penetration of stimulation and manipulation in vivo at centimeter-level depth with high spatiotemporal precision.

Acoustic and ultrasound-based mechanogenetics and thermogenetics for immunotherapy

The present invention relates to prevention and/or treatment of diseases or disorders associated with a damaged or leaky vasculature in a subject. The present invention provides for methods, combinations and pharmaceutical compositions for preventing and/or treating a disease or disorder associated with a damaged or leaky vasculature in a subject, using, inter alia, an effective amount of a nanoparticle comprising an inner core comprising a non-cellular material, an outer surface comprising a cellular membrane derived from a platelet; and optionally an agent for preventing, treating, diagnosing, or prognosing the disease or disorder and/or monitoring prevention or treatment of the disease or disorder. Exemplary diseases or disorders include hemorrhage (bleeding), cardiovascular diseases or disorders, diseases or disorders associated with narrowing of a blood vessel, tumors or cancers.

Treating vasculature related diseases or disorders using nanoparticles

In alternative embodiments, the invention provides compositions that inhibit the polypeptide SSH-2, or SlingSHot-2, a phosphatase enzyme that regulates actin filaments, and methods for making and using them, including methods comprising administering compositions of the invention to regulate or modify actin filament polymerization by inhibiting SSH-2, where in one embodiment compositions of the invention slow or inhibit F-actin depolymerization and severing. In alternative embodiments, compositions and methods of the invention are used to slow or inhibit cell motility and/or internal remodeling. In alternative embodiments, compositions and methods of the invention are used to slow or inhibit, or reverse, or ameliorate the progression of a cancer or a metastasis or other uncontrolled or unregulated cell growth, and/or Alzheimer's disease.

SSH-2 (slingshot-2) inhibitors and methods for making and using them

Methods and compositions for identifying neoplastic cells in a biological sample are provided.

Methods and compositions for detecting neoplastic cells

Hemodynamic forces play a key role in inducing 2, theroscler-osis-implicated gene in Vascular endothelial cells. To ellcitate the signal transduction pathway leading to such gene expression, the effects of fluid shearing on the activities of upstream signaling molecules is reported here. Fluid shearing (shear stress&equals;12 dynes/cm ) induced a transient and rapid activation of p21 and preferentially activated c-jun NH terminal kinases (JNK 1, 2) over extracellular signal-regulated kinases (ERK-1, -2). Co-transfection of RasNI7, a dominant negative mutant of Ha-Ras, attenuated the shear-activated JNK and luciferase reporters driven by TPA-responsive elements. JNIK(K-R) and MEKK(K-M), the respective catalytically inactive mutants of JNKI and MEKK, also partially inhibited the shear-induced luciferase reporters. In contrast, Raf301, ERK(K71R), and ERK(K52R), the dominant negative mutants of Raf-1, ERK-1, and ERK-2, respectively, had little effects on the activities of these reporters. The activation of JNK was also correlated with an increased c-Jun transcriptional activity, which was attenuated by a negative mutant of Son of sevenless (Sos). Thus, mechanical stimulation exerted by fluid shearing activates, primarily the Ras-MEKK-JNK pathway in inducing endothelial gene expression.

Gene therapy in coronary angioplasty and bypass

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La Jolla, CA, United States of America

Shu Chien