California Pacific Medical Center Research Institute

San Francisco, CA, United States

California Pacific Medical Center Research Institute

San Francisco, CA, United States
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News Article | May 9, 2017

Dr. Ben joins BioAtla with over 20 years of industry and academic experience in oncology. During his 13 years of increasing responsibility in biotechnology and pharmaceutical companies, he has led wide-spectrum clinical development efforts from phase 1 to phase 3 clinical trials, from strategy planning to study execution and BLA/NDA submissions. Prior to his career at AstraZeneca, Dr. Ben was Medical Director, Oncology Clinical Research at Millennium Pharmaceuticals where, in addition to leading the pivotal global phase 3 study for ixazomib in refractory/relapsed multiple myeloma, he was clinical lead in the orteronel and alisertib programs. Prior to that, Dr. Ben was Lead Clinician/Global Medical Monitor, Clinical Development for the Pfizer Oncology Business Unit and earlier was Project Manager, Asia Research & Development for Pfizer Global Research & Development. Dr. Ben began his career in industry with Shanghai Sunway Biotech Co., a leader in the field of oncolytic viruses. Dr. Ben started his career as a surgical oncologist at Peking Union Medical College Hospital and completed a postdoctoral fellowship at California Pacific Medical Center Research Institute.  Dr. Ben received his medical degree from Norman Bethune Medical University and his MBA from the University of California, San Diego. Conditionally Active Biologic proteins are generated using BioAtla's proprietary protein discovery, evolution and expression technologies. These proteins can be mAbs, enzymes and other proteins designed with functions dependent on changes in microphysiological conditions (e.g., pH level, oxidation, temperature, pressure, presence of certain ions, hydrophobicity and combinations thereof) both outside and inside cells. Studies have shown that cancerous tumors create highly specific conditions at their site that are not present in normal tissue. These cancerous microenvironments are primarily a result of the well understood unique glycolytic metabolism associated with cancer cells, referred to as the Warburg Effect. CAB proteins are designed to deliver their therapeutic payload and/or recruit the immune response in specific and selected locations and conditions within the body and to be active only in the presence of a particular cellular microenvironment. In addition, the activation is designed to be reversible to repeatedly switch 'on and off' should the CAB move from a diseased to a normal cellular microenvironment and vice versa. CABs can be developed in a variety of formats including antibodies, antibody drug conjugates (ADCs), bi-specifics, chimeric antigen receptor T-cells (CAR-Ts) and combination therapies. BioAtla is a global biotechnology company with operations in San Diego, California, and Beijing, China. BioAtla develops novel monoclonal antibody and other protein therapeutic product candidates designed to have more selective targeting, greater efficacy, and more cost-efficient and predictable manufacturing than traditional antibodies. To view the original version on PR Newswire, visit:

Toyoshima C.,University of Tokyo | Iwasawa S.,University of Tokyo | Ogawa H.,University of Tokyo | Hirata A.,University of Tokyo | And 2 more authors.
Nature | Year: 2013

P-type ATPases are ATP-powered ion pumps that establish ion concentration gradients across biological membranes, and are distinct from other ATPases in that the reaction cycle includes an autophosphorylation step. The best studied is Ca2+-ATPase from muscle sarcoplasmic reticulum (SERCA1a), a Ca2+ pump that relaxes muscle cells after contraction, and crystal structures have been determined for most of the reaction intermediates. An important outstanding structure is that of the E1 intermediate, which has empty high-affinity Ca2+-binding sites ready to accept new cytosolic Ca2+. In the absence of Ca2+ and at pH 7 or higher, the ATPase is predominantly in E1, not in E2 (low affinity for Ca2+), and if millimolar Mg2+ is present, one Mg2+ is expected to occupy one of the Ca2+-binding sites with a millimolar dissociation constant. This Mg2+ accelerates the reaction cycle, not permitting phosphorylation without Ca2+ binding. Here we describe the crystal structure of native SERCA1a (from rabbit) in this E1·Mg2+ state at 3.0 Å resolution in addition to crystal structures of SERCA1a in E2 free from exogenous inhibitors, and address the structural basis of the activation signal for phosphoryl transfer. Unexpectedly, sarcolipin, a small regulatory membrane protein of Ca2+-ATPase, is bound, stabilizing the E1·Mg2+ state. Sarcolipin is a close homologue of phospholamban, which is a critical mediator of β-adrenergic signal in Ca2+ regulation in heart (for reviews, see, for example, refs 8-10), and seems to play an important role in muscle-based thermogenesis. We also determined the crystal structure of recombinant SERCA1a devoid of sarcolipin, and describe the structural basis of inhibition by sarcolipin/phospholamban. Thus, the crystal structures reported here fill a gap in the structural elucidation of the reaction cycle and provide a solid basis for understanding the physiological regulation of the calcium pump. © 2013 Macmillan Publishers Limited. All rights reserved.

Schousboe J.T.,Park Nicollet Institute | Kerlikowske K.,Veterans Affairs Medical Center | Loh A.,California Pacific Medical Center Research Institute | Cummings S.R.,Coordinating Center
Annals of Internal Medicine | Year: 2011

Background: Current guidelines recommend mammography every 1 or 2 years starting at age 40 or 50 years, regardless of individual risk for breast cancer. Objective: To estimate the cost-effectiveness of mammography by age, breast density, history of breast biopsy, family history of breast cancer, and screening interval. Design: Markov microsimulation model. Data Sources: Surveillance, Epidemiology, and End Results program, Breast Cancer Surveillance Consortium, and the medical literature. Target Population: U.S. women aged 40 to 49, 50 to 59, 60 to 69, and 70 to 79 years with initial mammography at age 40 years and breast density of Breast Imaging Reporting and Data System (BI-RADS) categories 1 to 4. Time Horizon: Lifetime. Perspective: National health payer. Intervention: Mammography annually, biennially, or every 3 to 4 years or no mammography. Outcome Measures: Costs per quality-adjusted life-year (QALY) gained and number of women screened over 10 years to prevent 1 death from breast cancer. Results of Base-Case Analysis: Biennial mammography cost less than $100 000 per QALY gained for women aged 40 to 79 years with BI-RADS category 3 or 4 breast density or aged 50 to 69 years with category 2 density; women aged 60 to 79 years with category 1 density and either a family history of breast cancer or a previous breast biopsy; and all women aged 40 to 79 years with both a family history of breast cancer and a previous breast biopsy, regardless of breast density. Biennial mammography cost less than $50 000 per QALY gained for women aged 40 to 49 years with category 3 or 4 breast density and either a previous breast biopsy or a family history of breast cancer. Annual mammography was not cost-effective for any group, regardless of age or breast density. Results of Sensitivity Analysis: Mammography is expensive if the disutility of false-positive mammography results and the costs of detecting nonprogressive and nonlethal invasive cancer are considered. Limitation: Results are not applicable to carriers of BRCA1 or BRCA2 mutations. Conclusion: Mammography screening should be personalized on the basis of a woman's age, breast density, history of breast biopsy, family history of breast cancer, and beliefs about the potential benefit and harms of screening. Primary Funding Source: Eli Lilly, Da Costa Family Foundation for Research in Breast Cancer Prevention of the California Pacific Medical Center, and Breast Cancer Surveillance Consortium. © 2011 American College of Physicians.

Inesi G.,California Pacific Medical Center Research Institute | Tadini-Buoninsegni F.,University of Florence
Journal of Cell Communication and Signaling | Year: 2014

The Ca2+ transport ATPase (SERCA) of sarcoplasmic reticulum (SR) plays an important role in muscle cytosolic signaling, as it stores Ca 2+ in intracellular membrane bound compartments, thereby lowering cytosolic Ca2+ to induce relaxation. The stored Ca2+ is in turn released upon membrane excitation to trigger muscle contraction. SERCA is activated by high affinity binding of cytosolic Ca2+, whereupon ATP is utilized by formation of a phosphoenzyme intermediate, which undergoes protein conformational transitions yielding reduced affinity and vectorial translocation of bound Ca2+. We review here biochemical and biophysical evidence demonstrating that release of bound Ca2+ into the lumen of SR requires Ca2+/H+ exchange at the low affinity Ca2+ sites. Rise of lumenal Ca2+ above its dissociation constant from low affinity sites, or reduction of the H+ concentration by high pH, prevent Ca2+/H+ exchange. Under these conditions Ca2+ release into the lumen of SR is bypassed, and hydrolytic cleavage of phosphoenzyme may yield uncoupled ATPase cycles. We clarify how such Ca2+pump slippage does not occur within the time length of muscle twitches, but under special conditions and in special cells may contribute to thermogenesis. © 2013 The Author(s).

Leong S.P.L.,California Pacific Medical Center Research Institute | Tseng W.W.,University of Houston
CA Cancer Journal for Clinicians | Year: 2014

Cancer metastasis may be regarded as a progressive process from its inception in the primary tumor microenvironment to distant sites by way of the lymphovascular system. Although this type of tumor dissemination often occurs in an orderly fashion via the sentinel lymph node (SLN), acting as a possible gateway to the regional lymph nodes, bone marrow, and peripheral blood and ultimately to distant metastatic sites, this is not a general rule as tumor cells may enter the blood and spread to distant sites, bypassing the SLN. Methods of detecting micrometastatic cancer cells in the SLN, bone marrow, and peripheral blood of patients have been established. Patients with cancer cells in their SLN, bone marrow, or peripheral blood have worse clinical outcomes than patients with no evidence of spread to these compartments. The presence of these cells also has important biologic implications for disease progression and the clinician's understanding of the process of cancer metastasis. Further characterization of these micrometastatic cancer cells at each stage and site of metastasis is needed to design novel selective therapies for a more "personalized" treatment. CA Cancer J Clin 2014;64:195-206. © 2014 American Cancer Society, Inc.

Prasad A.M.,California Pacific Medical Center Research Institute
Molecular and cellular biochemistry | Year: 2012

Involvement of the calcineurin/NFAT pathway in transcription of cardiac sarcoplasmic reticulum Ca(2+) ATPase (SERCA2) was demonstrated (Prasad and Inesi, Am J Physiol Heart Circ Physiol 300(1):H173-H180, 2011) by upregulation of SERCA2 following calcineurin (CN) activation by cytosolic Ca(2+), and downregulation of SERCA2 following CN inhibition with cyclosporine (CsA) or CN subunits gene silencing. We show here that in cultured cardiac myocytes, competitive engagement of the CN/NFAT pathway is accompanied by downregulation of SERCA2 and Ca(2+) signaling alterations. In fact, SERCA2 downregulation occurs following infection of myocytes with adenovirus vectors carrying luciferase or SERCA1 cDNA under control of NFAT-dependent promoters, but not under control of CMV promoters that do not depend on NFAT. SERCA2 downregulation is demonstrated by comparison with endogenous transcription and protein expression standards such as GAPDH and actin, indicating prominent SERCA2 involvement by the CN/NFAT pathway. Transcription of genes involved in hypertrophy, triggered by adrenergic agonist or by direct protein kinase C (PKC) activation with phorbol 12-myristate 13-acetate (PMA), is also prominently dependent on CN/NFAT. This is demonstrated by CN inhibition with CsA, CN subunits gene silencing with siRNA, displacement of NFAT from CN with 9,10-Dihydro-9,10[1',2']-benzenoanthracene-1,4-dione (INCA-6), and myocyte infection with vectors carrying luciferase cDNA under control of NFAT-dependent promoter. We show here that competitive engagement of the CN/NFAT pathway by endogenous genes involved in hypertrophy produces downregulation of SERCA2, reduction of Ca(2+) transport and inadequate Ca(2+) signaling. It is most interesting that, in the presence of adrenergic agonist, specific protein kinase C (PKC) inhibition with 3-[1-[3-(dimethylamino)propyl]-5-methoxy-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione (Gö 6983) prevents development of hypertrophy and maintains adequate SERCA2 levels and Ca(2+) signaling.

Muschler J.,California Pacific Medical Center Research Institute
Cold Spring Harbor perspectives in biology | Year: 2010

The mammary gland is an organ that at once gives life to the young, but at the same time poses one of the greatest threats to the mother. Understanding how the tissue develops and functions is of pressing importance in determining how its control mechanisms break down in breast cancer. Here we argue that the interactions between mammary epithelial cells and their extracellular matrix (ECM) are crucial in the development and function of the tissue. Current strategies for treating breast cancer take advantage of our knowledge of the endocrine regulation of breast development, and the emerging role of stromal-epithelial interactions (Fig. 1). Focusing, in addition, on the microenvironmental influences that arise from cell-matrix interactions will open new opportunities for therapeutic intervention. We suggest that ultimately a three-pronged approach targeting endocrine, growth factor, and cell-matrix interactions will provide the best chance of curing the disease.

Cawthon P.M.,California Pacific Medical Center Research Institute
Clinical Orthopaedics and Related Research | Year: 2011

Background: Osteoporosis is generally thought of as a "woman's disease" because the prevalence of osteoporosis and the rate of fractures are much higher in postmenopausal women than in older men. However, the absolute number of men affected by osteoporosis and fractures is large, as at least 2.8 million men in the United States are thought to have osteoporosis. Questions/purposes: The purposes of this review are to (1) highlight gender differences in osteoporosis and fracture risk, (2) describe disparities in treatment and outcomes after fractures between men and women, and (3) propose solutions to reducing disparities in treatment and prevention. Methods: A literature survey was conducted using MEDLINE with a variety of search terms and using references from the author's personal collection of articles. A formal search strategy and exclusion criteria were not employed and the review is therefore selective. Where are we now? Postmenopausal women have a higher prevalence of osteoporosis and greater incidence of fracture than older men. Despite the higher fracture risk in postmenopausal women, older men tend to have worse outcomes after fracture and poorer treatment rates, although less is known about the disease course in men. Multifaceted interventions to improve the screening and treatment for osteoporosis were recently developed. Where do we need to go? Improvement in treatment rates of those at risk, regardless of gender, is an important goal in osteoporosis management. How do we get there? Further development and evaluation of cost-effective, multifaceted interventions for screening and treatment of osteoporosis and fractures are needed; such interventions will likely improve the primary prevention of fractures. © 2011 The Association of Bone and Joint Surgeons®.

Kashani-Sabet M.,California Pacific Medical Center Research Institute
British Journal of Dermatology | Year: 2014

The last few years have witnessed the dawn of the molecular era in melanoma treatment. With the advent of successful therapy targeting mutant BRAF, melanoma is leading the field of cancer research in the molecular approach to therapy of advanced disease. Attempting to keep pace with advances in therapy are advances in the molecular assessment of melanoma progression, facilitated by the availability of genome-wide approaches to interrogate the malignant phenotype. At the DNA level, this has included approaches such as comparative genomic hybridization. At the RNA level, this has consisted of gene expression profiling using various assay methodologies. In certain instances, markers identified using these platforms have been further examined and developed using fluorescence in situ hybridization and immunohistochemical analysis. In this article, we will review recent progress in the development of novel molecular markers for melanoma that are nearing clinical application. We will review developments in the molecular classification of melanoma, in the molecular diagnosis of melanoma, and in the molecular assessment of melanoma prognosis. © 2013 British Association of Dermatologists.

California Pacific Medical Center Research Institute and The Regents Of The University Of California | Date: 2011-10-03

A method for treatment of breast cancer and other types of cancer. The method comprises targeting and modulating Id-1 gene expression, if any, for the Id-1 gene, or gene products in breast or other epithelial cancers in a patient by delivering products that modulate Id-1 gene expression. When expressed, Id-1 gene is a prognostic indicator that cancer cells are invasive and metastatic.

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