California Institute Research Articles

A stem cell journey in ophthalmology: From the bench to the clinic.

Debilitating diseases of the eye represent a large unmet medical need potentially addressable with stem cell‐based approaches. Over the past decade, the California Institute for Regenerative Medicine (CIRM) has funded and supported the translation, from early research concepts to human trials, of therapeutic stem cell approaches for dry age‐related macular degeneration, retinitis pigmentosa, and limbal stem cell deficiency. This article chronicles CIRM's journey in the ophthalmology field and discusses some key challenges and questions that were addressed along the way as well as questions that remain.

Financial Incentives for Medical Assistants: A Mixed-Methods Exploration of Bonus Structures, Motivation, and Population Health Quality Measures.

Medical assistants (MAs) have seen their roles expand as a result of team-based primary care models. Unlike their physician counterparts, MAs rarely receive financial incentives as a part of their compensation. This exploratory study aims to understand MA acceptability of financial incentives and perceived MA control over common population health measures. We conducted semistructured focus groups between August and December of 2019 across 10 clinics affiliated with 3 institutions in California and Utah. MAs' perceptions of experienced and hypothetical financial incentives, their potential influence on workflow processes, and perceived levels of control over population health measures were discussed, recorded, and qualitatively analyzed for emerging themes. Perceived levels of control were further quantified using a Likert survey; measures were grouped into factors representing vaccinations, and workflow completed in the same day or multiple days (multiday). Mean scores for each factor were compared using repeated 1-way ANOVA with Tukey-Kramer adjustment. MAs reported little direct experience with financial incentives. They indicated that a hypothetical bonus representing 2% to 3% of their average annual base pay would be acceptable and influential in improving consistent performance during patient rooming workflow. MAs reported having greater perceived control over vaccinations (P <.001) and same-day measures (P <.001) as compared with multiday measures. MAs perceived that relatively small financial incentives would increase their motivation and quality of care. Our findings suggests target measures should focus on MA work processes that are completed in the same day as the patient encounter, particularly vaccinations. Future investigation is needed to understand the effectiveness of MA financial incentives in practice.

The Impact of Misinformation and Health Literacy on HIV Prevention and Service Usage.

Renee Garett, MSW, LCSW, is the Founding Director, ElevateU, Irvine, California, USA. Sean D. Young, PhD, MS, is an Associate Professor, Department of Emergency Medicine, and Executive Director, University of California Institute for Prediction Technology, Department of Informatics, University of California, Irvine, California, USA. *Corresponding author: Sean D. Young, e-mail: [email protected] Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

An interview with Nobel Laureate David Baltimore, PhD.

In an online interview, Nobel Laureate David Baltimore, Ph.D., reflected on his contributions to biomedical science that have had a major influence on the fields of molecular biology, virology, cancer, and immunology. Dr. Baltimore is President Emeritus and Distinguished Professor of Biology at the California Institute of Technology. Among other notable works, he discovered the critical nuclear transcription factor NF Kappa B and the Rag1 and Rag2 proteins that rearrange adaptive immune cell receptors.&#x0D; His career path, he says, evolved naturally, as math and science came easily to him. As a high school student, he participated in a summer program at the Jackson Lab in Bar Harbor, Maine, where he says he came away feeling that experimental biology was exciting and rewarding.&#x0D; “That's where I discovered that the frontiers of science, were not so distant; that I could actually make a discovery that nobody else in the world knew about,” he says. &#x0D; And that he did. Independently, he and Howard Temin discovered the viral enzyme reverse transcriptase revising the canon of cellular information transfer. They published back-to-back papers in Nature demonstrating that this enzyme in virus particles could transcribe RNA to DNA. Both received a Nobel Prize for this work.&#x0D; In reflecting on his early experience evaluating how to work with recombinant DNA and how we should scientifically and safely approach gain of function research, he says, “We have to be very honest with ourselves about what might hold danger, and we have to control our instinct … to do anything we can to generate progress and understanding of life. …At the same time, we don’t want to hold back progress, and so there is a balancing.”&#x0D; Dr. Baltimore also discussed his optimism about vectored immunoprophylaxis as a strategy for prevention of HIV and his doubt that scalable strategies will be able to cure HIV. He also reflected on his philosophy for the training of young scientists and the successful training program that he developed at the Whitehead Institute.

Better in Pictures

Better in Pictures

Faster drug prospecting

Over 60% of drugs are derived from natural products—chemicals made by living organisms like bacteria, fungi, and plants. But identifying and characterizing biologically active molecules in the complex chemical brew these organisms make can be a painstaking, yearslong process. By combining genome mining with microcrystal electron diffraction (microED), scientists have found what might be a faster way to identify drugs from natural products. Researchers led by University of California, Los Angeles, chemical biologist Yi Tang and California Institute of Technology organic chemist Hosea M. Nelson developed the prospecting process ( Nat. Chem. Biol. 2021, DOI: 10.1038/s41589-021-00834-2 ). The researchers comb through the DNA sequence of an interesting organism, looking for genes that are known to make enzymes responsible for constructing biomolecules. They then insert those genes into a host that they can grow in the lab. This host churns out those enzymes and the natural product of interest. “It’s a

Alumino-oxy-rossmanite from pegmatites in Variscan metamorphic rocks from Eibenstein an der Thaya, Lower Austria, Austria: A new tourmaline that represents the most Al-rich end-member composition

Abstract Alumino-oxy-rossmanite, ideally ☐Al3Al6(Si5AlO18)(BO3)3(OH)3O, is here described as a new member of the tourmaline supergroup. It is an early magmatic Al-rich oxy-tourmaline from a small pegmatitic body embedded in amphibolite and biotite-rich paragneiss. This new pink tourmaline was found in a Moldanubian pegmatite (of the Drosendorf Unit) that occurs in a large quarry near the village of Eibenstein an der Thaya, Waidhofen an der Thaya district, Lower Austria, Austria. The empirical formula of the holotype was determined on the basis of electron microprobe analysis (EMPA), secondary ion mass spectrometry (SIMS), spectroscopical methods (optical absorption and infrared spectroscopy), and crystal-structure refinement (SREF) as X(☐0.53Na0.46Ca0.01) Y(Al2.37Mn0.213+Li0.16☐0.14Mn0.072+Fe0.033+Fe0.012+Ti0.014+) ZAl6(Si5.37Al0.41B0.22O18)(BO3)3V[(OH)2.77O0.23] W[O0.80(OH)0.15F0.05]. Chemical composition (wt%) is: SiO2 33.96, TiO2 0.10, Al2O3 47.08, B2O3 11.77, FeO 0.08, Fe2O3 0.23, MnO 0.52, Mn2O3 1.70, CaO 0.04, Li2O 0.25, ZnO 0.03, Na2O 1.51, H2O 2.79, F 0.09, total 100.11. The presence of relatively high amounts of trivalent Mn in alumino-oxy-rossmanite is in agreement with the observation that the OH groups are present at a lower concentration than commonly found in other Al-rich and Li-bearing tourmalines. The crystal structure of alumino-oxy-rossmanite [space group R3m; a = 15.803(1), c = 7.088(1) Å; V = 1532.9(3) Å3] was refined to an R1(F) value of 1.68%. The eight strongest X-ray diffraction lines in the (calculated) powder pattern [d in Å (I) hkl] are: 2.5534 (100) 051, 3.9508 (85) 220, 2.9236 (78) 122, 4.1783 (61) 211, 2.4307 (55) 012, 2.0198 (39) 152, 1.8995 (30) 342, 6.294 (28) 101. The most common associated minerals are quartz, albite, microcline, and apatite. Beryl and, in places, schorl are also found as primary pegmatitic phases. Because of the low mode of associated mica (muscovite), we assume that the silica melt, which formed this pegmatite, crystallized under relatively dry conditions, in agreement with the observation that alumino-oxy-rossmanite contains a lower amount of OH than most other tourmalines. This new member of the tourmaline supergroup exhibits the most Al-rich end-member composition of the tourmaline supergroup (theoretical content: ~54 wt% Al2O3). The significant content of tetrahedrally coordinated Al could reflect the relatively high-temperature conditions (~700 °C) inferred for crystallization of the pegmatite. Alumino-oxy-rossmanite was named for its chemical relationship to rossmanite, ☐(LiAl2)Al6(Si6O18) (BO3)3(OH)3(OH), which in turn was named after George R. Rossman, Professor of Mineralogy at the California Institute of Technology (Pasadena, California, U.S.A.).

Hypervelocity Spherically-Blunted Cone Flows in Mars Entry Ground Testing

Bow-shock standoff distances over sphere and spherically-blunted cone geometries were examined through experiments in two facilities capable of high-stagnation enthalpy hypersonic flows simulating Mars planetary entry conditions. High-speed and high-resolution schlieren images were obtained in the California Institute of Technology T5 reflected shock tunnel and the Hypervelocity Expansion Tube to examine facility independence of the measurements. Accompanying reacting Navier–Stokes simulations were carried out. A recently developed unified model for sphere and sphere–cone behavior was first verified for high-stagnation enthalpy flows through simulations with thermal and chemical nonequilibrium. Shock standoff distance measurements in both facilities were found to be in good agreement with model predictions. The need to account for the divergence of the streamlines in conical nozzles was highlighted and an existing model extended to account for changes in shock curvature between parallel and conical flows. The contributions of vibrational and chemical nonequilibrium to the stagnation-line density profile were quantified using the simulation results comparing three chemical kinetic models.

Artificial intelligence and sexual health in the USA

Artificial intelligence and sexual health in the USA

Deinstitutionalization in California: Mortality of Persons with Developmental Disabilities after Transfer into Community Care, 1997-1999

More than 2,000 persons with developmental disability trans ferred from California institutions into community care during 1993 to early 1996. Using data on 1,878 children and adults moved between April 1, 1993 and March 5, 1996, Strauss, Shavelle, Baumeister and Anderson (1998) found a corresponding increase in mortality rates by comparison with those who stayed behind. Shavelle and Strauss (1999) updated the study through 1996 and found similar results. The present study is a further update through 1999. There were 81 deaths, a 47% increase in risk-adjusted mor tality over that expected in institutions (p &lt; 0.01). As in the two previous studies, we found that persons transferred later were at higher risk than those moving earlier, even after adjustment for differences in risk profiles. The difference cannot be explained by the short-term effects of the transfer, and therefore appear to reflect an increased mortality rate associated with the less intensive medical care and supervision available in the community.

Cu catalysts do chiral amide synthesis

A pair of copper catalysts can create chiral amides in a new, light-driven process, offering a useful alternative to the standard method for making these staples of medicinal chemistry ( Nature 2021, DOI: 10.1038/s41586-021-03730-w ). “Amides are ubiquitous functional groups in bioactive molecules, such as peptides,” says Gregory C. Fu , a chemist at the California Institute of Technology who co-led the work. The conventional route to chiral amides involves producing a single enantiomer of an amine and then reacting it with a carboxylic acid derivative. In contrast, the Caltech team’s method needs only a single step and controls the stereochemistry of the amide as it forms. The reaction relies on two different Cu catalysts and combines an amide with an alkyl bromide to form a chiral secondary amide—where the nitrogen atom is bonded to a hydrogen and two carbons, one of which is chiral. The first catalyst is a

In Memoriam of Jean‐Michel Savéant (1933–2020)

In Memoriam of Jean‐Michel Savéant (1933–2020)

Racial microaffirmations as a response to racial microaggressions: Exploring risk and protective factors

The urgency of the Black Lives Matter movement, and societal inequities emerging amid the COVID-19 pandemic call researchers to better understand the implications of racism in the lives of People of Color. In this paper, we utilize Critical Race Theory (CRT) to extend theorizing on the concept of racial microaffirmations as a response to everyday systemic racism—racial microaggressions. We reframe the psychological concept of risk and protective factors to illustrate the relationship between racial microaggressions and microaffirmations. Our findings identify types of racial microaffirmations experienced by Students of Color at a public four-year institution in California. We explore how these microaffirmations are experienced and the effects they have on the students well-being.

Andrea Dyrness and Enrique Sepúlveda III, Border Thinking: LatinX Youth: Decolonizing Citizenship

Reviewed by: Border Thinking: LatinX Youth: Decolonizing Citizenship by Andrea Dyrness and Enrique Sepúlveda III Gabriela Buitrón Vera (bio) Andrea Dyrness and Enrique Sepúlveda III, Border Thinking: LatinX Youth: Decolonizing Citizenship. University of Minnesota Press, 2020. Pp. 278. In Border Thinking, Andrea Dyrness and Enrique Sepúlveda III examine the ways Latinx diasporic youth dismantle rigid notions of citizenship. The book exposes how colonial discourses of the West cast Latino youth as either threats to the nation or unable to assimilate into discourses of the nation-state. Dyrness and Sepúlveda challenge such binary narratives by drawing from decolonial, Chicano, feminist theory, and participatory action research, as they contend that “diasporic youths’ connection to homeland and host countries offers them a critical perspective on national citizenship” (10). Border Thinking proposes that Latinx diasporic youth are well-equipped to redefine citizenship, particularly through the nurturing of their democratic yearnings and critical perspectives within pedagogic spheres and collective action. The book’s makeup reflects various Latino diasporic youth experiences with migration (in Latin America, the US, the Caribbean, and Spain),1 and studies how experiences with migration give diasporic youth new perspectives in decolonizing citizenship. Dyrness and Sepúlveda examine these perspectives by drawing on an array of active participatory research practices. These methods of engagement include “testimonio, poetry, participatory research, role play, interviews group [End Page 277] dialogues, identity mapping, and more” (28). These methods help diasporic youth reflect on their personal experiences and connect that knowledge to the political and the communal. Border Thinking’s five well-connected chapters present acompañamiento (borderlands allyship) in the form of pedagogic or activist solidarity that generate la facultad, “the capacity to see in surface phenomena, the meaning of deeper realities.”2 Chapter 1, “Acompañamiento in the Borderlands,” for instance, examines the role of humanizing pedagogy. Drawing from thinkers like Freire, Valenzuela, Valencia, and Spring, this chapter challenges rigid notions of nation-state narratives of Otherness. The chapter addresses Mexican migrant youth experiences navigating high school in a Northern California institution. Later, it highlights how educators who are not trained to be borderland allies can reproduce a system of marginalization that casts their students as uncultured and problematic, instead of agents of change. Dyrness and Sepúlveda assert that it is through acts of acompañamiento that educators and borderland brokers honor the stories and complexities of the Latino diasporic youth. One way of honoring these rich cultural complexities, the chapter claims, is by decentering educational achievements as the only measure of success. Chapter 2, “In the Shadow of the U.S. Empire,” explores the impact of the US interventions in the lives of youth from El Salvador. Using an ethnographic lens, this chapter examines how two schools in San Salvador introduce or omit notions of citizenship in the classroom. Significantly, what Dyrness and Sepúlveda observed is that in both schools (an elite and a low-income institution) students were socialized to imagine themselves as either neoliberal entrepreneurs or future undocumented or TPS holders in the US. These forced classifications damaged students’ sense of self because they were led to imagine a future of dispossession. Yet, through participatory research practices, Dyrness and Sepúlveda challenged these binaries, and students voiced their democratic yearnings and articulated desires for their future through communal dialogue. The disciplining narratives of Spanish nationalism on immigrant youth identities (156) are explored in chapter 3, “Negotiating Race and the Politics of Integration.” This chapter specifically examines how diasporic youth negotiate race and politics of integration in Madrid. To analyze this, Dyrness and Sepúlveda conducted citizenship workshops for diasporic youth. The participatory methods they used helped migrant youth articulate the frictions they faced with educators and national discourses that explicitly denied racialized conflicts. This chapter sheds light on how immigrant youths’ experiences with racism were silenced and misunderstood by national and official discourses, rendering them as problematic or unable to assimilate. Chapter 4, “Transnational Belonging,” likewise, analyzes how Latinx youth migration narratives challenged nation-state binary discourses. The diasporic youths’ comprehension of their fluid identities becomes crucial to [End Page 278] challenging rigid notion of citizenship. The final chapter, “Feminists in Transition,” inspects how transnational...

The Magic of Asking ‘What if?’: Radical Architectural Pedagogy

AbstractSince it was founded in 1972, the Southern California Institute of Architecture (SCI‐Arc) in Los Angeles has been one of a small cohort of peers at the forefront of progressive schools of architecture. This is an environment where everything is questioned and nothing taken for granted – a fecund, inventive and highly productive breeding ground for new architectures. Graduate Programs Chair Elena Manferdini proffers some of its recent graduate schemes and outlines its pedagogic philosophy.

Effect of Autologous Hematopoietic Stem Cell Transplant (aHSCT) on the Development of Second Primary Malignancies (SPM) in Multiple Myeloma Patients

Abstract Background: Since the 1960s, an increased risk of SPMs in multiple myeloma (MM) patients has been noted but less consequential due to relatively short survival. Given considerably improved survival as well as the potential association with modern anti-myeloma therapy, reassessment of this risk is prudent. Prior studies of aHSCT recipients have calculated standardized incidence ratios compared to the general population, but have not compared the cumulative incidence of SPMs among myeloma patients undergoing aHSCT to those who do not. Thus, a direct comparison of the effect of aHSCT on development of SPMs in MM patients is necessary to better advise patients and physicians on the potential risks of this treatment in the modern era. Methods: Patients diagnosed with MM between 1991 and 2013 were identified in the California Cancer Registry linked to the California hospital Patient Discharge Database. Inclusion criteria included a first primary diagnosis of MM and a minimum 1 year of follow up. SPMs were defined as distinct malignancies arising ≥1 year after MM diagnosis. The cumulative incidence (CI) of developing any SPM, solid tumors, and hematologic malignancies, and associated 95% confidence intervals were computed, accounting for the competing risk of death. To compare the cumulative incidence of SPMs between aHSCT recipients and those without aHSCT, patients were matched 1:2 on age, year of diagnosis, race/ethnicity, socioeconomic status and comorbidities. Multivariable cox proportional hazards regression models, using the methods of Fine and Gray to account for competing risk of death, and stratified for variables that did not meet the proportional hazards assumption, estimated the effect of aHSCT on the risk of SPM development accounting for baseline demographics. Results: Among 16,331 patients, 933 (5.7%) developed a SPM ≥1 year after diagnosis. Of these, 119 (12.8%) were hematologic malignancies, primarily leukemia (81, 9%). The most common solid tumors were malignancies of the digestive (184, 19.7%), respiratory (119, 12.8%), and male genital (115, 12.3%) systems. An additional 310 SPMs were diagnosed The 5- and 10-year CI of developing any SPM, accounting for the competing risk of death, was 4% (3.7% - 4.3%) and 6.6% (6.2% - 7.1%) respectively. There is no plateau in the incidence of SPM development (Figure). The 5- and 10-year cumulative incidence of developing solid SPM was 3.5% (3.3% - 3.9%) and 5.7% (5.3% - 6.2%). The 5- and 10-year cumulative incidence of developing hematologic SPM was 0.5% (0.4% - 0.6%) and 0.9% (0.7% - 1.1%). In the matched analysis, the 5- and 10-year CI of developing a SPM was similar among aHSCT recipients [5-year: 4.8% (3.6% - 5.9%); 10-year: 9.1% (7.7% - 10.7%)] and among non-aHSCT recipients [5-year: 4.7% (4.0% - 5.5%); 10-year: 7.5% (6.5% - 8.6%)] (Figure Part A) (P=0.26). However, the CI of hematologic SPMs differed among the aHSCT and non-aHSCT groups reaching 2.1% (1.4% - 2.9%) among aHSCT recipients vs 0.8% (0.5% - 1.2%) at 10 years (P = 0.005). There was no difference in the CI of solid SPMs between the two groups (Figure C) (P=0.98). Multivariable models adjusted for baseline characteristics and the competing of risk of death identified no increased risk of developing SPMs overall among aHSCT recipients (adjusted hazard ratio (aHR) 1.13, 95% CI 0.94 - 1.37). The risk of developing hematologic SPMs was increased in the aHSCT recipients (aHR 1.65, 1.03 - 2.63), while the risk of developing solid SPMs was not (aHR 1.06, 0.86 - 1.31). Era of diagnosis (1991-97, 1998-2002, 2003-07, 2008-13) was not associated with an increased risk of SPMs. Conclusions: MM patients are at risk for SPMs and we observed that the cumulative incidence increases over time. The use of aHSCT as part of treatment and the era of diagnosis were not associated with a change in risk of overall SPM development. Though no difference in SPM development over time was noted, follow up time during eras when continuous therapy was more common are still short. A small but significant increase in hematologic SPMs was noted among aHSCT recipients. As MM patients continue to live longer, efforts to effectively screen and prevent SPMs are warranted. Download : Download high-res image (103KB) Download : Download full-size image Figure . Disclosures Rosenberg: Amgen: Speakers Bureau. Tuscano: Novartis: Research Funding; Spectrum: Research Funding; Celgene: Research Funding, Speakers Bureau; Takeda: Research Funding; Amgen: Speakers Bureau. Jonas: AbbVie, Celgene, Daiichi Sankyo, Pharmacyclics, Genentech/Roche, Glycomimetics, Esanex, Kalobios: Research Funding; Rigel: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees. Abedi: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; California Institute of Regenerative Medicine: Research Funding; Seattle Genetics: Speakers Bureau; Amgen: Research Funding; BMS: Speakers Bureau; Takeda: Speakers Bureau; Gilead: Speakers Bureau. Wun: Pfizer: Other: Steering Committee: RESET study, Research Funding; Janssen: Other: Steering Committee for Cassini Study and Callisto Program, Research Funding.

Telomerase Inhibition Impairs Self-Renewal of ß-Catenin Activated Myeloproliferative Neoplasm Progenitors

IntroductionChronic phase myeloproliferative neoplasms (MPNs), including chronic myeloid leukemia (CML) and myelofibrosis (MF), arise from hematopoietic stem cells. However, they harbor varying propensities to undergo blast crisis (acute leukemic) transformation based on their capacity to give rise to tyrosine kinase inhibitor (TKI) resistant myeloid progenitors that activate self-renewal pathways, such as Wnt/b-catenin signaling. Because b-catenin has been reported to transcriptionally regulate human telomerase reverse transcriptase (hTERT), we investigated the capacity of a telomerase complex inhibitor, imetelstat, to prevent malignant progenitor self-renewal. The telomerase complex consists of hTERT, an RNA template subunit (TERC), and a protective shelterin scaffold. Imetelstat is a novel, first in class covalently lipidated 13-mer oligonucleotide telomerase inhibitor with clinical activity in myeloid malignancies. Recent clinical trials showed early signs of efficacy in myeloproliferative neoplasms such as MF. However, the role of imetelstat in selectively eradicating self-renewing MPN progenitors has not been elucidated. Thus, we performed progenitor RNA sequencing (RNA-seq), stromal co-cultures and humanized MPN progenitor primagraft studies to investigate the ability of imetelstat to selectively inhibit malignant progenitor self-renewal at doses that spare normal progenitors as well as to determine the mechanism of action.Methods and ResultsWhen FACS-purified progenitors from human blast crisis (BC; n=9) were compared with chronic phase (CP; n=8) CML and primary normal (n=6) samples, RNA-seq revealed upregulation of key genes in the TERT interactome suggesting a role for TERT activation in MPN progenitor blast crisis transformation. Human MPN progenitor supportive SL/M2 stromal co-culture experiments revealed that combined treatment with a potent BCR-ABL TKI, dasatinib at 1 nM, and imetelstat at 1 or 5 µM significantly inhibited (p <0.001, ANOVA) in vitro replating of BC CML (n=5) compared with age-matched normal bone marrow progenitors. Also, imetelstat (5 µM) significantly reduced replating of MF (n=9) compared with normal progenitor (n=4) samples. Treatment of humanized mouse models, established with four different BC CML samples, with 30 mg/kg of imetelstat three times a week for four weeks resulted in a significant reduction in both bone marrow and spleen malignant progenitor burden compared with mismatch controls (p=0.003, and p=0.009, t test), and a significant reduction in human CD45+ cells in the splenic niche compared with mismatch controls (p=0.03, t test). In a MF model established in NSG-S mice, imetelstat also reduced human CD45+ cell engraftment (p=0.03, t test). Notably, imetelstat treatment spares normal human cells in humanized normal stem cell mouse models. Furthermore, qRT-PCR showed decreased β-catenin transcript levels in imetelstat treated MF cells (p=0.18) and CML cells (p=0.4) compared with mismatch control. Finally, FACS analysis revealed a significant reduction in activated b-catenin protein levels in engrafted human progenitors after imetelstat treatment (p=0.02) compared with vehicle control.ConclusionsNiche responsive interactions between the telomerase complex and the Wnt/b-catenin self-renewal pathway sensitize b-catenin activated MPN progenitors to imetelstat in both in vitro and in vivo humanized pre-clinical MPN mouse models thereby providing a strong rationale for studies assessing eradication of malignant progenitors using imetelstat.Disclosures: This work was funded by the Moores Family Foundation, the Koman Family Foundation, the California Institute for Regenerative Medicine (DR1-01430), Janssen Research & Development, LLC, and by NIH NCI R21CA189705. DisclosuresHuang:Janssen Research & Development, LLC: Employment.

A Phase 1 Study of Everolimus and Bendamustine in Patients with Relapsed or Refractory Lymphoid Malignancies and Myeloma

Introduction:Bendamustine, an alkylating agent, and everolimus, an oral mTOR inhibitor, have independently shown single-agent activity in relapsed/refractory lymphoid malignancies and myeloma. Preclinical data supports a synergistic effect between the two agents via pro-apoptotic mechanisms.Methods:Patients (pts) aged ≥18 with relapsed/refractory (R/R) lymphoid cancers and myeloma were enrolled in a phase 1, dose-escalation, single-center study to determine the safety and efficacy of bendamustine and everolimus combination therapy. We present initial data on the safety profile and efficacy as of July 27th, 2017. Everolimus was administered daily with bendamustine 90mg/m2 IV on days 1 and 2 of each 28-day cycle. Successive everolimus dose escalation cohorts were 5mg, 7.5mg, and 10mg using a standard 3+3 design. Rituximab 375mg/m2 on day 1 of each cycle was also allowed for CD20-positive NHL. The primary outcome measure of the study was to maximum tolerated dose (MTD) and the secondary outcome measure was to assess the response rate. Four 28-day cycles were planned, with disease status/response assessments with CT imaging or bone marrow biopsy at baseline and after cycles 2 and 4. Adverse events (AEs) were graded according to NCI-CTCAE version 4.0. Lymphoma response was assessed using 2007 Cheson IWG response criteria. Multiple myeloma response was assessed per 2016 IMWG criteria. Dose-limited toxicity (DLT) were defined as grade 4 neutropenia lasting > 5 days, grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding or any requirement for platelet transfusion, febrile neutropenia of any duration and/or any grade 3 or 4 non-hematological toxicity. Patients were evaluable on the study if they received a minimum of 14 of the planned 28 doses of everolimus during cycle 1.Results:A total of 19 pts have been enrolled as of July 27, 2017, of which 2 needed to be replaced as they did not receive ≥75% of planned everolimus in the first cycle, resulting in 17 evaluable patients for safety analysis. Diagnoses were: Hodgkin's lymphoma (HL, n=4), diffuse large B-cell lymphoma (DLBCL, n=4), mantle cell lymphoma (MCL, n=1), follicular lymphoma (FL, n=2), and multiple myeloma (MM, n=6). Median age was 62 (range: 22-74). In total, 6/17 pts (35%) completed planned 4 cycles of everolimus and bendamustine combination therapy. Premature discontinuation was due to: progressive disease (n=5), physician discretion (n=3), adverse event (n=2), and patient choice (n=1).Treatment-related AEs of any grade in ≥20% of all 19 pts were: lymphopenia, thrombocytopenia, leukopenia, nausea, anemia, neutropenia, anorexia, sinus tachycardia, and elevated liver enzymes. Non-hematologic grade 3/4 AEs were: fatigue (n=3), hypokalemia (n=1), and hypophosphatemia (n=1). Hematologic grade 3/4 AEs were: lymphopenia (n=11), thrombocytopenia (n=4), leukopenia (n=3), neutropenia (n=2), and anemia (n=1). There were no treatment-related deaths. One pt in the 1st cohort and 2/6 pts in 3rd cohort experienced DLTs (fatigue and thrombocytopenia) therefore MTD was deemed to be 7.5mg everolimus daily.One pt with myeloma chose to withdraw prior to 1st assessment, thus 16 pts were evaluable for response. ORR for the 16 pts evaluable was 56% (4 with CR, 5 with PR or VGPR). Among the 5 evaluable pts with MM, the ORR was 80% (1 pt had VGPR, 3 had a PR, 1 had PD). The median number of prior therapies in this group was 6 (range 5-10), including at least 1 autologous stem cell transplant in all patients. Among the 4 pts with HL, 1 had CR, 1 had PR, and 2 had PD, for an ORR of 50%. Among the 7 pts with NHL, 3 pts had CR (2 with FL, 1 with MCL), and 3 had PD (all with DLBCL, 2 of which were transformed FL). 1 additional pt with DLBCL had a DLT prior to first response assessment and was not evaluable. Thus, the ORR for the NHL cohort was 50%.Conclusions:The combination of everolimus and bendamustine demonstrated a very tolerable safety profile in a wide spectrum of patients with R/R hematologic malignancies. Several pts in responded to therapy. The overall response rate in MM and indolent NHL were particularly high (80-100%). Data on the final cohort after completion of accrual will be presented at the meeting. Further investigation using MTD of 7.5mg daily everolimus with bendamustine is warranted in a phase 2 study, particularly in follicular lymphoma and multiple myeloma. DisclosuresJonas:Rigel: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie, Celgene, Daiichi Sankyo, Pharmacyclics, Genentech/Roche, Glycomimetics, Esanex, Kalobios: Research Funding. Tuscano:Celgene: Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Research Funding; Novartis: Research Funding; Spectrum: Research Funding. Rosenberg:Amgen: Speakers Bureau. Abedi:Amgen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; California Institute of Regenerative Medicine: Research Funding; BMS: Speakers Bureau; Gilead: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Speakers Bureau.

A Phase 1 Trial of the Combination of Ibrutinib and Azacitidine for the Treatment of Higher Risk Myelodysplastic Syndromes: University of California Hematologic Malignancies Consortium (UCHMC) Study 1503

Introduction: Higher risk myelodysplastic syndromes (HR-MDS) have poor outcomes, particularly after hypomethylating agent (HMA) failure. The HMA azacitidine (AZA) is a standard of care for HR-MDS and works through several mechanisms, including inhibition of NF-kB signaling. Ibrutinib (IBR) inhibits Bruton9s Tyrosine Kinase (BTK) and has an antiproliferative effect on myeloblasts in preclinical models through BTK binding and inhibition of NF-kB signaling. IBR also has immunomodulatory activity mediated through binding interleukin-2-inducible kinase (ITK) and promoting Th1-polarized immunity, which is decreased in HR-MDS. These features suggest that the combination of IBR and AZA may improve outcomes in HR-MDS. Methods: This is an ongoing multicenter prospective Phase 1 dose-escalation trial of IBR in combination with AZA in patients with HR-MDS (NCT02553941). Results of the dose escalation phase are reported. Eligibility included World Health Organization or French-American-British classification-defined MDS and Revised International Prognostic Scoring System (IPPS-R) intermediate or higher risk. Any prior therapy was allowed or patients could be untreated if unfit for, or had refused, high intensity chemotherapy. Transfusion-dependent patients were eligible. Patients received AZA 75 mg/m2 IV/SC daily for 7 days and IBR orally daily for 28 days. Cycles repeated every 28 days. Dose-escalation used a 3+3 design with IBR dose levels of 420 mg (Cohort 1) and 560 mg (Cohort 2). The primary objective was to determine the safety and tolerability of IBR in combination with AZA. Adverse events (AEs) were monitored throughout treatment, and dose-limiting toxicities (DLT) were assessed during cycle 1. The secondary objective was to assess preliminary efficacy using modified International Working Group Response Criteria. Exploratory objectives evaluated pharmacodynamic and biological effects of the combination, including BTK occupancy in CD34+ bone marrow mononuclear cells (BMMC). Results: As of June 1, 2017, 9 patients [89% male, median age 80 years (range 64-81)] were enrolled into Cohort 1 (n=3) and Cohort 2 (n=6). MDS subtypes included single lineage dysplasia (n=1), multilineage dysplasia (n=1), excess blasts (EB)-1 (n=2), EB-2 (n=3), refractory anemia with EB in transformation (n=1) and unclassifiable (n=1). IPSS-R scores were intermediate (n=2), high (n=2) and very high (n=5). Three patients were HMA-naive and six had prior HMA therapy [AZA (n=3), decitabine (n=2), both (n=1)]. All patients completed cycle 1. No DLTs were observed. All patients experienced at least one treatment-emergent adverse event (TEAE). Seven patients experienced a grade 3-4 TEAE with neutropenia (n=6), thrombocytopenia (n=3) and febrile neutropenia (n=3) most common. Four patients (three in Cohort 1 and one in Cohort 2) experienced a serious adverse event including febrile neutropenia (n=3) and gastric hemorrhage (n=1). No patients experienced atrial fibrillation. Median time on study was 160 days (range 42-283) with a median of five cycles (range 1-10) received. Six patients remain on IBR plus AZA, and three patients have discontinued study therapy (two disease progression and one withdrawal of consent and subsequent death on hospice). Four patients have reduced AZA to 5 days per cycle per investigator discretion, and four patients have had interruptions of IBR dosing due to febrile neutropenia (n=3) and concurrent azole use (n=1). Three patients (33%) achieved complete remission (CR), one (11%) had a partial remission (PR), and five (55%) had stable disease (SD). All three CRs occurred in patients without prior HMA exposure and included one complete and two partial cytogenetic responses. CR was achieved after 1, 4 and 6 cycles in these patients. One patient (11%) with SD had a hematologic improvement-erythroid response (HI-E). The overall hematologic normalization rate (CR+PR+HI) was 55%. BTK occupancy in CD34+ BMMC after cycle 1 was 42.0% and 51.7% in two patients at IBR 420 mg and 41.5% in one patient at IBR 560 mg. Conclusions: The combination of IBR and AZA demonstrates a tolerable safety profile in patients with HR-MDS. No DLTs were observed at either IBR dose level. The combination shows promising preliminary efficacy, including responses in patients with prior HMA exposure. CD34+ BMMC BTK occupancy was seen. An expansion cohort at the IBR 560 mg dose level in AZA-naive patients is ongoing. Disclosures Jonas: AbbVie, Celgene, Daiichi Sankyo, Pharmacyclics, Genentech/Roche, Glycomimetics, Esanex, Kalobios: Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees; Rigel: Consultancy. Logan: Novartis: Consultancy, Research Funding; Incyte: Consultancy; Astellas: Research Funding; Shire: Consultancy; Kite: Research Funding; Amgen: Consultancy; Pharmacyclics: Research Funding; Jazz: Consultancy. Abedi: Takeda: Speakers Bureau; Seattle Genetics: Speakers Bureau; Gilead: Speakers Bureau; BMS: Speakers Bureau; Amgen: Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; California Institute of Regenerative Medicine: Research Funding. Bejar: Celgene: Consultancy, Honoraria, Other: DSMB, Steering Committee, Research Funding; Genoptix: Consultancy, Honoraria, Patents & Royalties; AbbVie/Genetech: Honoraria, Other: Ad-hoc advisory board; Foundation Medicine: Honoraria, Other: Ad-hoc advisory board; Otsuka/Astex: Honoraria, Other: Ad-hoc advisory board; Modus Outcomes: Consultancy, Honoraria. Wieduwilt: Reata Pharmaceuticals: Equity Ownership; Sigma-Tau: Research Funding. Curtin: Amgen, Celgene, Onconova, Pharmacyclics: Research Funding.

The Pransky interview: Dr Gary Guthart, chief executive officer, Intuitive

Purpose The following paper is a “Q&amp;A interview” conducted by Joanne Pransky of Industrial Robot Journal as a method to impart the combined technological, business and personal experience of a prominent, robotic industry turned successful business leader, regarding the commercialization and challenges of bringing technological inventions to market while overseeing a company. This paper aims to discuss these issues. Design/methodology/approach The interviewee is Dr Gary Guthart, Chief Executive Officer (CEO) at Intuitive Surgical, Inc., and a member of the Board of Directors, both roles he has held since 2010. Guthart discusses his journey to becoming the CEO and also shares some of his lessons learned and challenges faced. Findings Guthart received a bachelor’s degree in engineering physics from California, Berkeley. He earned an MS and a PhD in engineering from the California Institute of Technology. Guthart’s first scientific experience came early in his career in a Human Factors Lab at NASA, supporting a team studying human performance assessment of pilots. Guthart was then part of the core team developing foundational technology for computer-enhanced surgery at SRI International. While at SRI, he also developed algorithms for vibration and acoustic control of large-scale systems. Guthart joined Intuitive Surgical as part of the first engineering team in 1996 as a Control Systems Analyst. He was promoted to Vice President of Engineering in 2002 and was appointed President and Chief Operating Officer in 2008. Originality/value Under Dr Gary Guthart’s leadership and his more than 25 years of medical technology, engineering, scientific and management experience, Intuitive Surgical, Inc., the world’s most successful medical robotics company, has grown to: more than 8,000 employees; nearly 6,000 da Vinci systems sold; more than 8.5 million procedures performed and an increase in stock (NASDAQ: ISRG) of more than 600%. Guthart is also on the Board of Directors for Illumina, Inc., and a member of the Board of Directors for the Silicon Leadership Group.