Torrey Pines Institute for Molecular Studies

About: Torrey Pines Institute for Molecular Studies is a nonprofit organization based out in San Diego, California, United States. It is known for research contribution in the topics: T cell & Antigen. The organization has 2323 authors who have published 2217 publications receiving 112618 citations.

Instant immunity through chemically programmable vaccination and covalent self-assembly

Abstract: The ability to instantly create a state of immunity as achieved in the passive transfer of hyperimmune globulin has had a tremendous impact on public health. Unlike passive immunization, active immunization, which is the foundation of vaccinology, is an anticipatory strategy with inherent limitations. Here we show that elements of active and passive immunization can be combined to create an effective chemistry-driven approach to vaccinology. Reactive immunization was used to create a reservoir of covalent polyclonal antibodies in 3 mouse strains that were subsequently engrafted with syngeneic CT26 colon or B16F10 melanoma tumors. Upon administration of designed integrin αvβ3 and αvβ5 adapter ligands, the induced covalent polyclonal antibodies self-assembled with the adapter ligands and the animals mounted an instant, chemically programmed, polyclonal response against the implanted tumors. Significant therapeutic responses were observed without recourse to adjuvant therapy. The chemically programmed immune responses were driven by antibody-dependent cellular cytotoxicity and complement-directed cytotoxicity. We suggest that this type of chemistry-driven approach to vaccinology is underexplored and may provide routes to vaccines to protect against diseases that have proven intractable to biology-driven vaccine approaches.

Digital medicine, on its way to being just plain medicine

Abstract: There are already nearly 30,000 peer-reviewed English-language scientific journals, producing an estimated 2.5 million articles a year. So why another, and why one focused specifically on digital medicine? To answer that question, we need to begin by defining what “digital medicine” means: using digital tools to upgrade the practice of medicine to one that is high-definition and far more individualized. It encompasses our ability to digitize human beings using biosensors that track our complex physiologic systems, but also the means to process the vast data generated via algorithms, cloud computing, and artificial intelligence. It has the potential to democratize medicine, with smartphones as the hub, enabling each individual to generate their own real world data and being far more engaged with their health. Add to this new imaging tools, mobile device laboratory capabilities, end-to-end digital clinical trials, telemedicine, and one can see there is a remarkable array of transformative technology which lays the groundwork for a new form of healthcare. As is obvious by its definition, the far-reaching scope of digital medicine straddles many and widely varied expertise. Computer scientists, healthcare providers, engineers, behavioral scientists, ethicists, clinical researchers, and epidemiologists are just some of the backgrounds necessary to move the field forward. But to truly accelerate the development of digital medicine solutions in health requires the collaborative and thoughtful interaction between individuals from several, if not most of these specialties. That is the primary goal of npj Digital Medicine: to serve as a cross-cutting resource for everyone interested in this area, fostering collaborations and accelerating its advancement. Current systems of healthcare face multiple insurmountable challenges. Patients are not receiving the kind of care they want and need, caregivers are dissatisfied with their role, and in most countries, especially the United States, the cost of care is unsustainable. We are confident that the development of new systems of care that take full advantage of the many capabilities that digital innovations bring can address all of these major issues. Researchers too, can take advantage of these leading-edge technologies as they enable clinical research to break free of the confines of the academic medical center and be brought into the real world of participants’ lives. The continuous capture of multiple interconnected streams of data will allow for a much deeper refinement of our understanding and definition of most phenotypes, with the discovery of novel signals in these enormous data sets made possible only through the use of machine learning. Our enthusiasm for the future of digital medicine is tempered by the recognition that presently too much of the publicized work in this field is characterized by irrational exuberance and excessive hype. Many technologies have yet to be formally studied in a clinical setting, and for those that have, too many began and ended with an under-powered pilot program. In addition, there are more than a few examples of digital “snake oil” with substantial uptake prior to their eventual discrediting. Both of these practices are barriers to advancing the field of digital medicine. Our vision for npj Digital Medicine is to provide a reliable, evidence-based forum for all clinicians, researchers, and even patients, curious about how digital technologies can transform every aspect of health management and care. Being open source, as all medical research should be, allows for the broadest possible dissemination, which we will strongly encourage, including through advocating for the publication of preprints And finally, quite paradoxically, we hope that npj Digital Medicine is so successful that in the coming years there will no longer be a need for this journal, or any journal specifically focused on digital medicine. Because if we are able to meet our primary goal of accelerating the advancement of digital medicine, then soon, we will just be calling it medicine. And there are already several excellent journals for that.

The Multi-Leu Peptide Inhibitor Discriminates Between PACE4 and Furin And Exhibits Antiproliferative Effects On Prostate Cancer Cells

Abstract: The proprotein convertases (PCs) play an important role in protein precursor activation through processing at paired basic residues. However, significant substrate cleavage redundancy has been reported between PCs. The question remains whether specific PC inhibitors can be designed. This study describes the identification of the sequence LLLLRVKR, named Multi-Leu (ML)-peptide, that displayed a 20-fold selectivity on PACE4 over furin, two enzymes with similar structural characteristics. We have previously demonstrated that PACE4 plays an important role in prostate cancer and could be a druggable target. The present study demonstrates that the ML-peptide significantly reduced the proliferation of DU145 and LNCaP prostate cancer-derived cell lines and induced G0/G1 cell cycle arrest. However, the ML-peptide must enter the cell to inhibit proliferation. It is concluded that peptide-based inhibitors can yield specific PC inhibitors and that the ML-peptide is an important lead compound that could potentially have applications in prostate cancer.

Amino acid conjugates of lithocholic acid as antagonists of the EphA2 receptor.

Abstract: The Eph receptor-ephrin system is an emerging target for the development of novel antiangiogenetic agents. We recently identified lithocholic acid (LCA) as a small molecule able to block EphA2-dependent signals in cancer cells, suggesting that its (5β)-cholan-24-oic acid scaffold can be used as a template to design a new generation of improved EphA2 antagonists. Here, we report the design and synthesis of an extended set of LCA derivatives obtained by conjugation of its carboxyl group with different α-amino acids. Structure-activity relationships indicate that the presence of a lipophilic amino acid side chain is fundamental to achieve good potencies. The l-Trp derivative (20, PCM126) was the most potent antagonist of the series disrupting EphA2-ephrinA1 interaction and blocking EphA2 phosphorylation in prostate cancer cells at low μM concentrations, thus being significantly more potent than LCA. Compound 20 is among the most potent small-molecule antagonists of the EphA2 receptor.