Kevin Grimes

All Publications

• SPARKing academic technologies across the valley of death. Nature biotechnology Kim, J. S., Kargotich, S., Lee, S. H., Yajima, R., Garcia, A. A., Ehrenkaufer, G., Romeo, M., Maria, P. S., Grimes, K. V., Mochly-Rosen, D. 2024; 42 (2): 339-342

  View details for DOI 10.1038/s41587-024-02130-5

  View details for PubMedID 38361072

  View details for PubMedCentralID 6226120

• Beta-2 adrenergic receptor agonism alters astrocyte phagocytic activity and has potential applications to psychiatric disease. Discover mental health Bowen, E. R., DiGiacomo, P., Fraser, H. P., Guttenplan, K., Smith, B. A., Heberling, M. L., Vidano, L., Shah, N., Shamloo, M., Wilson, J. L., Grimes, K. V. 2023; 3 (1): 27

  Abstract

  Schizophrenia is a debilitating condition necessitating more efficacious therapies. Previous studies suggested that schizophrenia development is associated with aberrant synaptic pruning by glial cells. We pursued an interdisciplinary approach to understand whether therapeutic reduction in glial cell-specifically astrocytic-phagocytosis might benefit neuropsychiatric patients. We discovered that beta-2 adrenergic receptor (ADRB2) agonists reduced phagocytosis using a high-throughput, phenotypic screen of over 3200 compounds in primary human fetal astrocytes. We used protein interaction pathways analysis to associate ADRB2, to schizophrenia and endocytosis. We demonstrated that patients with a pediatric exposure to salmeterol, an ADRB2 agonist, had reduced in-patient psychiatry visits using a novel observational study in the electronic health record. We used a mouse model of inflammatory neurodegenerative disease and measured changes in proteins associated with endocytosis and vesicle-mediated transport after ADRB2 agonism. These results provide substantial rationale for clinical consideration of ADRB2 agonists as possible therapies for patients with schizophrenia.

  View details for DOI 10.1007/s44192-023-00050-5

  View details for PubMedID 38036718

  View details for PubMedCentralID 3129332

• An electronic health record cohort of Veterans with amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis & frontotemporal degeneration Reimer, R. J., Goncalves, A., Soper, B., Cadena, J., Wilson, J. L., Gryshuk, A. L., Suarez, P., Osborne, T. F., Grimes, K. V., Ray, P. 2023: 1-7

  Abstract

  Objective: To assemble and characterize an electronic health record (EHR) dataset for a large cohort of US military Veterans diagnosed with ALS (Amyotrophic Lateral Sclerosis). Methods: An EHR dataset for 19,662 Veterans diagnosed with ALS between January 1, 2000 to December 31, 2020 was compiled from the Veterans Health Administration (VHA) EHR database by a query for ICD9 diagnosis (335.20) or ICD10 diagnosis (G12.21) for Amyotrophic Lateral Sclerosis. Results: The cohort is predominantly male (98.94%) and white (72.37%) with a median age at disease onset of 68 years and median survival from the date of diagnosis of 590 days. With the designation of ALS as a compensable illness in 2009, there was a subsequent increase in the number of Veterans diagnosed per year in the VHA, but no change in median survival. The cohort included a greater-than-expected proportion of individuals whose branch of service at the time of separation was the Army. Conclusions: The composition of the cohort reflects the VHA population who are at greatest risk for ALS. The greater than expected proportion of individuals whose branch of service at the time of separation was the Army suggests the possibility of a branch-specific risk factor for ALS.

  View details for DOI 10.1080/21678421.2023.2239300

  View details for PubMedID 37555559

• A Call for Discovery and Therapeutic Development for Cutaneous Neurofibromas. The Journal of investigative dermatology Blakeley, J. O., Le, L. Q., Lee, S. Y., Ly, I., Rhodes, S. D., Romo, C. G., Sarin, K. Y., Staedtke, V., Steensma, M. R., Wolkenstein, P. 2023

  View details for DOI 10.1016/j.jid.2022.11.027

  View details for PubMedID 37354152

• Existing and Developing Preclinical Models for Neurofibromatosis Type 1-Related Cutaneous Neurofibromas. The Journal of investigative dermatology Staedtke, V., Topilko, P., Le, L. Q., Grimes, K., Largaespada, D. A., Cagan, R. L., Steensma, M. R., Stemmer-Rachamimov, A., Blakeley, J. O., Rhodes, S. D., Ly, I., Romo, C. G., Lee, S. Y., Serra, E. 2023

  Abstract

  Neurofibromatosis 1 (NF1) is caused by a nonfunctional copy of the NF1 tumor suppressor gene that predisposes patients to the development of cutaneous neurofibromas (cNFs), the skin tumor that is the hallmark of this condition. Innumerable benign cNFs, each appearing by an independent somatic inactivation of the remaining functional NF1 allele, form in nearly all patients with NF1. One of the limitations in developing a treatment for cNFs is an incomplete understanding of the underlying pathophysiology and limitations in experimental modeling. Recent advances in preclinical invitro and invivo modeling have substantially enhanced our understanding of cNF biology and created unprecedented opportunities for therapeutic discovery. We discuss the current state of cNF preclinical invitro and invivo model systems, including two- and three-dimensional cell cultures, organoids, genetically engineered mice, patient-derived xenografts, and porcine models. We highlight the models' relationship to human cNFs and how they can be used to gain insight into cNF development and therapeutic discovery.

  View details for DOI 10.1016/j.jid.2023.01.042

  View details for PubMedID 37330719

• A network paradigm predicts drug synergistic effects using downstream protein-protein interactions. CPT: pharmacometrics & systems pharmacology Wilson, J. L., Steinberg, E., Racz, R., Altman, R. B., Shah, N., Grimes, K. 2022

  Abstract

  In some cases, drug combinations affect adverse outcome phenotypes by binding the same protein; however, drug-binding proteins are associated through protein-protein interaction (PPI) networks within the cell, suggesting that drug phenotypes may result from long-range network effects. We first used PPI network analysis to classify drugs based on proteins downstream of their targets and next predicted drug combination effects where drugs shared network proteins but had distinct binding proteins (e.g., targets, enzymes, or transporters). By classifying drugs using their downstream proteins, we had an 80.7% sensitivity for predicting rare drug combination effects documented in gold-standard datasets. We further measured the effect of predicted drug combinations on adverse outcome phenotypes using novel observational studies in the electronic health record. We tested predictions for 60 network-drug classes on seven adverse outcomes and measured changes in clinical outcomes for predicted combinations. These results demonstrate a novel paradigm for anticipating drug synergistic effects using proteins downstream of drug targets.

  View details for DOI 10.1002/psp4.12861

  View details for PubMedID 36204824

• A US clinical trial network is needed for the next pandemic. Nature medicine Yajima, R., More, A. F., Garvan, C., Harper, C., Grimes, K. V. 2022

  View details for DOI 10.1038/s41591-022-01831-1

  View details for PubMedID 35641823

• Azetidine-2-Carboxylic Acid-Induced Oligodendrogliopathy: Relevance to the Pathogenesis of Multiple Sclerosis. Journal of neuropathology and experimental neurology Sobel, R. A., Albertelli, M., Hinojoza, J. R., Eaton, M. J., Grimes, K. V., Rubenstein, E. 2022

  Abstract

  The naturally occurring imino acid azetidine-2-carboxylic acid (Aze) is consumed by humans and can be misincorporated in place of proline in myelin basic protein (MBP) in vitro. To determine Aze effects on the mammalian CNS in vivo, adult CD1 mice were given Aze orally or intraperitoneally. Clinical signs reminiscent of MBP-mutant mice occurred with 600mg/kg Aze exposure. Aze induced oligodendrocyte (OL) nucleomegaly and nucleoplasm clearing, dilated endoplasmic reticulum, cytoplasmic vacuolation, abnormal mitochondria, and Aze dose-dependent apoptosis. Immunohistochemistry demonstrated myelin blistering and nuclear translocation of unfolded protein response (UPR)/proinflammatory molecules (ATF3, ATF4, ATF6, eIF2alpha, GADD153, NFkappaB, PERK, XBP1), MHC I expression, and MBP cytoplasmic aggregation in OL. There were scattered microglial nodules in CNS white matter (WM); other CNS cells appeared unaffected. Mice given Aze in utero and postnatally showed more marked effects than their dams. These OL, myelin, and microglial alterations are found in normal-appearing WM (NAWM) in multiple sclerosis (MS) patients. Thus, Aze induces a distinct oligodendrogliopathy in mice that recapitulates MS NAWM pathology without leukocyte infiltration. Because myelin proteins are relatively stable throughout life, we hypothesize that Aze misincorporation in myelin proteins during myelinogenesis in humans results in a progressive UPR that may be a primary process in MS pathogenesis.

  View details for DOI 10.1093/jnen/nlac028

  View details for PubMedID 35521963

• Controlling astrocyte-mediated synaptic pruning signals for schizophrenia drug repurposing with deep graph networks. PLoS computational biology Gravina, A., Wilson, J. L., Bacciu, D., Grimes, K. J., Priami, C. 2022; 18 (5): e1009531

  Abstract

  Schizophrenia is a debilitating psychiatric disorder, leading to both physical and social morbidity. Worldwide 1% of the population is struggling with the disease, with 100,000 new cases annually only in the United States. Despite its importance, the goal of finding effective treatments for schizophrenia remains a challenging task, and previous work conducted expensive large-scale phenotypic screens. This work investigates the benefits of Machine Learning for graphs to optimize drug phenotypic screens and predict compounds that mitigate abnormal brain reduction induced by excessive glial phagocytic activity in schizophrenia subjects. Given a compound and its concentration as input, we propose a method that predicts a score associated with three possible compound effects, i.e., reduce, increase, or not influence phagocytosis. We leverage a high-throughput screening to prove experimentally that our method achieves good generalization capabilities. The screening involves 2218 compounds at five different concentrations. Then, we analyze the usability of our approach in a practical setting, i.e., prioritizing the selection of compounds in the SWEETLEAD library. We provide a list of 64 compounds from the library that have the most potential clinical utility for glial phagocytosis mitigation. Lastly, we propose a novel approach to computationally validate their utility as possible therapies for schizophrenia.

  View details for DOI 10.1371/journal.pcbi.1009531

  View details for PubMedID 35507580

• Preventive drugs for Huntington's disease: A choice-based conjoint survey of patient preferences. Journal of clinical and translational science Parrish, M. C., Hanson-Kahn, A., Srinivasan, V., Grimes, K. V. 2022; 6 (1): e35

  Abstract

  Introduction: This research examined the perspective of the Huntington's disease (HD) community regarding the use of predictive biomarkers as endpoints for regulatory approval of therapeutics to prevent or delay the onset of clinical HD in asymptomatic mutation carriers.Methods: An online, choice-based conjoint survey was shared with HD community members including untested at-risk individuals, presymptomatic mutation carriers, and symptomatic individuals. Across 15 scenarios, participants chose among two proposed therapies with differing degrees of biomarker improvement and side effects or a third option of no treatment.Results: Two hundred and thirty-eight responses were received. Attributes reflecting biomarker efficacy (e.g., prevention of brain atrophy on magnetic resonance imaging, reduced mutant huntingtin, or reduced inflammation biomarkers) had 3- to 7-fold greater importance than attributes representing side effects (e.g., increased risk of heart disease, cancer, and stroke over 20 years) and were more influential in directing choice of treatments. Reduction in mutant huntingtin protein was the most valued attribute overall. Multinomial logit model simulations based on survey responses demonstrated high interest among respondents (87-99% of the population) for drugs that might prevent or delay HD solely based upon biomarker evidence, even at the risk of serious side effects.Conclusion: These results indicate a strong desire among members of the HD community for preventive therapeutics and a willingness to accept significant side effects, even before the drug has been shown to definitively delay disease onset if the drug improves biomarker evidence of HD progression. Preferences of the HD community should inform regulatory policies for approving preventive therapies.

  View details for DOI 10.1017/cts.2022.372

  View details for PubMedID 35433035

• From random to predictive: a context-specific interaction framework improves selection of drug protein-protein interactions for unknown drug pathways. Integrative biology : quantitative biosciences from nano to macro Wilson, J. L., Gravina, A., Grimes, K. 2022

  Abstract

  With high drug attrition, protein-protein interaction (PPI) network models are attractive as efficient methods for predicting drug outcomes by analyzing proteins downstream of drug targets. Unfortunately, these methods tend to overpredict associations and they have low precision and prediction performance; performance is often no better than random (AUROC ~0.5). Typically, PPI models identify ranked phenotypes associated with downstream proteins, yet methods differ in prioritization of downstream proteins. Most methods apply global approaches for assessing all phenotypes. We hypothesized that a per-phenotype analysis could improve prediction performance. We compared two global approaches-statistical and distance-based-and our novel per-phenotype approach, 'context-specific interaction' (CSI) analysis, on severe side effect prediction. We used a novel dataset of adverse events (or designated medical events, DMEs) and discovered that CSI had a 50% improvement over global approaches (AUROC 0.77 compared to 0.51), and a 76-95% improvement in average precision (0.499 compared to 0.284, 0.256). Our results provide a quantitative rationale for considering downstream proteins on a per-phenotype basis when using PPI network methods to predict drug phenotypes.

  View details for DOI 10.1093/intbio/zyac002

  View details for PubMedID 35293584

• Treatment-refractory ulcerative colitis responsive to indigo naturalis. BMJ open gastroenterology Saiki, J. P., Andreasson, J. O., Grimes, K. V., Frumkin, L. R., Sanjines, E., Davidson, M. G., Park, K. T., Limketkai, B. 1800; 8 (1)

  Abstract

  BACKGROUND: Indigo naturalis (IN) is an herbal medicine that has been used for ulcerative colitis with an unclear mechanism of action. Indigo and indirubin, its main constituents, are ligands of the aryl hydrocarbon receptor (AhR). We assessed the safety, efficacy, and colon AhR activity of IN given orally to patients with treatment-refractory ulcerative colitis. The role of AhR in IN benefit was further evaluated with an AhR antagonist in a murine colitis model.METHODS: This open-label, dose-escalation study sequentially treated 11 patients with ulcerative colitis with either IN 500mg/day or 1.5g/day for 8 weeks, followed by a 4-week non-treatment period. The primary efficacy endpoint was clinical response at week 8, assessed by total Mayo score. Secondary endpoints included clinical remission, Ulcerative Colitis Endoscopic Index of Severity, quality of life, and colon AhR activity measured by cytochrome P450 1A1 (CYP1A1) RNA expression.RESULTS: Ten of 11 (91%) patients, including 8/9 (89%) with moderate-to-severe disease, achieved a clinical response. Among these 10 patients, all had failed treatment with 5-aminosalicylic acid, 8 patients with a tumour necrosis factor (TNF)-alpha inhibitor, and 6 patients with TNF-alpha inhibitor and vedolizumab. Five patients were corticosteroid dependent. Clinical response was observed in all five patients who had been recommended for colectomy. Three patients achieved clinical remission. All patients experienced improved endoscopic severity and quality of life. Four weeks after treatment completion, six patients had worsened partial Mayo scores. Four patients progressed to colectomy after study completion. Colon CYP1A1 RNA expression increased 12 557-fold at week 8 among six patients evaluated. No patient discontinued IN due to an adverse event. Concomitant administration of 3-methoxy-4-nitroflavone, an AhR antagonist, in a murine colitis model abrogated the benefit of IN.CONCLUSION: IN is a potentially effective therapy for patients with treatment-refractory ulcerative colitis. This benefit is likely through AhR activation.TRIAL REGISTRATION NUMBER: NCT02442960.

  View details for DOI 10.1136/bmjgast-2021-000813

  View details for PubMedID 34969665

• Mechanisms of Azetidine-2-carboxylic Acid (Aze)-Induced Oligodendrogliopathy In Vivo and In Vitro Sobel, R., Albertelli, M., Hinojoza, J., Eaton, M., Grimes, K., Rubenstein, E. OXFORD UNIV PRESS INC. 2020: 661

  View details for Web of Science ID 000538796100035

• p38 MAPK inhibition: A promising therapeutic approach for COVID-19. Journal of molecular and cellular cardiology Grimes, J. M., Grimes, K. V. 2020

  Abstract

  COVID-19, caused by the SARS-CoV-2 virus, is a major source of morbidity and mortality due to its inflammatory effects in the lungs and heart. The p38 MAPK pathway plays a crucial role in the release of pro-inflammatory cytokines such as IL-6 and has been implicated in acute lung injury and myocardial dysfunction. The overwhelming inflammatory response in COVID-19 infection may be caused by disproportionately upregulated p38 activity, explained by two mechanisms. First, angiotensin-converting enzyme 2 (ACE2) activity is lost during SARS-CoV-2 viral entry. ACE2 is highly expressed in the lungs and heart and converts Angiotensin II into Angiotensin 1-7. Angiotensin II signals proinflammatory, pro-vasoconstrictive, pro-thrombotic activity through p38 MAPK activation, which is countered by Angiotensin 1-7 downregulation of p38 activity. Loss of ACE2 upon viral entry may tip the balance towards destructive p38 signaling through Angiotensin II. Second, SARS-CoV was previously shown to directly upregulate p38 activity via a viral protein, similar to other RNA respiratory viruses that may hijack p38 activity to promote replication. Given the homology between SARS-CoV and SARS-CoV-2, the latter may employ a similar mechanism. Thus, SARS-CoV-2 may induce overwhelming inflammation by directly activating p38 and downregulating a key inhibitory pathway, while simultaneously taking advantage of p38 activity to replicate. Therapeutic inhibition of p38 could therefore attenuate COVID-19 infection. Interestingly, a prior preclinical study showed protective effects of p38 inhibition in a SARS-CoV mouse model. A number of p38 inhibitors are in the clinical stage and should be considered for clinical trials in serious COVID-19 infection.

  View details for DOI 10.1016/j.yjmcc.2020.05.007

  View details for PubMedID 32422320

• A Qualitative Study on the Differences Between Trial Populations and the Approved Therapeutic Indications of Antineoplastic Agents by 3 Regulatory Agencies From 2010 to 2018. Clinical therapeutics Sumi, E., Asada, R., Lu, Y., Ito-Ihara, T., Grimes, K. V. 2020

  Abstract

  PURPOSE: The present study aimed to examine the differences between enrolled subject populations and use of combination therapies as defined by the pivotal clinical trial protocols and the approved indications of anticancer drugs as determined by 3 major regulatory agencies.METHODS: Thirty-eight approvals were collected that received market authorization from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Pharmaceuticals and Medical Devices Agency (PMDA) between January 2010 and September 2018 for initial approval of an anticancer drug or for an expanded therapeutic indication for a previously approved anticancer drug, based on the same pivotal clinical trial(s). The subject eligibility criteria of the pivotal clinical trials and the approved indications as established by these agencies were compared, and the differences were categorized according to patient biomarkers status, prior treatment status, and the use of combination therapies.FINDINGS: In 20 (53%) approvals, there was a discrepancy between biomarker status of enrolled subjects in the pivotal trial and the therapeutic indication. In 7 of these cases, the biomarkers were used to diagnose the target cancer or to stratify the study subjects in the pivotal trial. In 9 cases, the biomarker discrepancies were related to minor histologic subtypes of the target cancer. Regarding prior treatment status, the FDA and the EMA generally approved indications for the same treatment line as the pivotal trials, whereas the PMDA did not restrict approval to untreated patients when the pivotal trial included only treatment-naive subjects. In 14 approvals, the FDA and the EMA designated the same co-administered drugs as part of the approved indications in line with the pivotal trials. However, the PMDA did not specify the co-administered drugs in 2 approvals and did not require combination therapy in 1 case.IMPLICATIONS: In principle, the approved therapeutic indications should be determined by the characteristics of the pivotal trial subjects and combination therapies. The use of biomarkers can be essential for identifying those patients who are most likely to benefit from a drug. Unfortunately, biomarker-defined subgroups are often insufficient in size to allow meaningful interpretation of results. Consequently, regulatory agencies may deviate from one another and from the pivotal trial protocol when interpreting study results and attempting to define the optimal treatment population. The PMDA-approved indications deviated more liberally from the pivotal trial protocols regarding specification of prior treatment status and the use of co-administered drugs.

  View details for DOI 10.1016/j.clinthera.2020.01.002

  View details for PubMedID 32008723

• Results from a Phase 1 Study of Sodium Selenite in Combination with Palliative Radiation Therapy in Patients with Metastatic Cancer. Translational oncology Knox, S. J., Jayachandran, P. n., Keeling, C. A., Stevens, K. J., Sandhu, N. n., Stamps-DeAnda, S. L., Savic, R. n., Shura, L. n., Buyyounouski, M. K., Grimes, K. n. 2019; 12 (11): 1525–31

  Abstract

  In preclinical studies, selenite had single agent activity and radiosensitized tumors in vivo. Here we report results from a Phase 1 trial in 15 patients with metastatic cancer treated with selenite (5.5 to 49.5 mg) orally as a single dose 2 hours before each radiation therapy (RT) treatment. Patients received RT regimens that were standard of care. The primary objective of the study was to assess the safety of this combination therapy. Secondary objectives included measurement of pharmacokinetics (PK) and evaluation of efficacy. Endpoints included assessment of PK, toxicity, tumor response, and pain before and after treatment. The half-life of selenite was 18.5 hours. There were no adverse events attributable to selenite until the 33 mg dose level, at which the primary toxicities were grade 1 GI side effects. One patient treated with 49.5 mg had grade 2 GI toxicity. Although this was not a DLT, it was felt that the highest acceptable dose in this patient population was 33 mg. Most patients had stabilization of disease within the RT fields, with some demonstrating objective evidence of tumor regression. Most patients had a marked improvement in pain and seven out of nine patients with prostate cancer had a decrease in PSA ranging from 11-78%. Doses up to 33 mg selenite were well tolerated in combination with RT. A randomized, well controlled study is needed at the 33 mg dose level to determine if selenite results in clinically meaningful improvements in the response to palliative RT.

  View details for DOI 10.1016/j.tranon.2019.08.006

  View details for PubMedID 31454725

• Surviving in the Valley of Death: Opportunities and Challenges in Translating Academic Drug Discoveries. Annual review of pharmacology and toxicology Parrish, M. C., Tan, Y. J., Grimes, K. V., Mochly-Rosen, D. 2018

  Abstract

  With pharmaceutical companies shrinking their research departments and exiting out of efforts related to unprofitable diseases, society has become increasingly dependent on academic institutions to perform drug discovery and early-stage translational research. Academic drug discovery and translational research programs assist in shepherding promising therapeutic opportunities through the so-called valley of death in the hope that a successful new drug will result in saved lives, improved health, economic growth, and financial return. We have interviewed directors of 16 such academic programs in the United States and found that these programs and the projects therein face numerous challenges in reaching the clinic, including limited funding, lack of know-how, and lack of a regional drug development ecosystem. If these issues can be addressed through novel industry partnerships, the revision of government policies, and expanded programs in translational education, more effective new therapies are more likely to reach patients in need. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 59 is January 6, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  View details for PubMedID 30208282

• Human Chitotriosidase Does Not Catabolize Hyaluronan. International journal of biological macromolecules Danielson, B. n., Chen, C. H., Kaber, G. n., Mochly-Rosen, D. n., Grimes, K. n., Stern, R. n., Bollyky, P. L. 2017

  Abstract

  Humans express an enzyme that degrades chitin, called chitotriosidase, despite the fact that we do not produce chitin. One possible explanation for this is that chitinase also degrades hyaluronan, a polysaccharide that is abundant in human tissues and shares structural attributes in common with chitinase. The objective of this study was to determine whether human chitotriosidase is capable of hydrolyzing hyaluronan. Hyaluronan of various sizes under a range of pH conditions displayed no degradation when incubated with various chitinases over a period of 5 days, while commercial hyaluronidase readily digested the hyaluronan. Under the same conditions, recombinant chitinase but not our negative control chitinase, was able to digest chitosan. We conclude that human chitinase does not digest hyaluronan. Because chitin is a prominent component of certain fungi and insects, it seems likely that human chitinase evolved for roles in host defense rather than serving to catabolize the endogenous polymer hyaluronan.

  View details for PubMedID 29247734

• Protein kinase C, an elusive therapeutic target? NATURE REVIEWS DRUG DISCOVERY Mochly-Rosen, D., Das, K., Grimes, K. V. 2012; 11 (12): 937-957

  Abstract

  Protein kinase C (PKC) has been a tantalizing target for drug discovery ever since it was first identified as the receptor for the tumour promoter phorbol ester in 1982. Although initial therapeutic efforts focused on cancer, additional indications--including diabetic complications, heart failure, myocardial infarction, pain and bipolar disorder--were targeted as researchers developed a better understanding of the roles of eight conventional and novel PKC isozymes in health and disease. Unfortunately, both academic and pharmaceutical efforts have yet to result in the approval of a single new drug that specifically targets PKC. Why does PKC remain an elusive drug target? This Review provides a short account of some of the efforts, challenges and opportunities in developing PKC modulators to address unmet clinical needs.

  View details for DOI 10.1038/nrd3871

  View details for PubMedID 23197040

• Myocardial salvage in acute myocardial infarction - Challenges in clinical translation JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY Mochly-Rosen, D., Grimes, K. V. 2011; 51 (4): 451-453

  View details for DOI 10.1016/j.yjmcc.2011.08.002

  View details for Web of Science ID 000295302900006

  View details for PubMedID 21851825

• Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction CIRCULATION Roe, M. T., Hartmann, F., LINS, J., Batchelor, W., Ruzyllo, W., Kochman, J., Armstrong, B., Buszman, P., Buszman, P., Leisch, F., Baran, K., Roubin, G., Zenni, M., Bilodeau, L., Caputo, R., Chu, A., Lombardi, W., Adamus, J., Hermiller, J., Darius, H., Krzeminska-Pakula, M., Saucedo, J., Simek, S., Zmudka, K., Farah, T., Hauptmann, K., Lee, D., Lemos, P., Rohrbeck, S., Moshage, W., Strasser, R., Albirini, A., Anderson, E., Bode, C., Caramori, P., Eaton, G., Hoffman, S., Huber, K., Khoury, S., Miller, J., Peterson, J., Porizka, V., Rivera, E., Roe, M., Schuster, P., Stasek, J., Zago, A. 2008; 117 (7): 886-896

  Abstract

  KAI-9803, a delta-protein kinase C inhibitor, has been shown to ameliorate injury associated with ischemia and reperfusion in animal models of acute myocardial infarction (MI).Direct Inhibition of delta-Protein Kinase C Enzyme to Limit Total Infarct Size in Acute Myocardial Infarction (DELTA MI) was a "first-in-human," dose-escalation study that evaluated the safety, tolerability, and activity of KAI-9803 for patients with acute anterior ST-segment elevation MI undergoing primary percutaneous coronary intervention. Patients who presented within 6 hours of symptom onset and had an occluded left anterior descending infarct artery on angiography were randomized in a 2:1 fashion to receive 1 of 4 doses of KAI-9803 (cohort 1, 0.05 mg; cohort 2, 0.5 mg; cohort 3, 1.25 mg; cohort 4, 5.0 mg) versus blinded concurrent placebo delivered in 2 divided doses via intracoronary injection before and after reestablishment of antegrade epicardial flow with percutaneous coronary intervention. Safety and biomarker end points were assessed. Overall, 154 patients were randomized and treated with study drug (37 in cohort 1, 38 in cohort 2, 38 in cohort 3, 41 in cohort 4). The incidence of serious adverse events was similar between patients treated with KAI-9803 versus placebo. Other safety end points, including changes in QT intervals and standard laboratory values after study drug administration, were similar between treatment groups. Although the study was not powered to demonstrate efficacy with the biomarker end points assessed, signs of drug activity with KAI-9803 were suggested by trends for consistent, nonsignificant reductions in creatine kinase-MB area under the curve and ST-recovery area under the curve values across all dosing cohorts with KAI-9803 compared with concurrent placebo, and similar trends were demonstrated for improvements in (99m)technetium sestamibi infarct size values with active study drug in cohorts 1, 2, and 3.KAI-9803 had an acceptable safety and tolerability profile when delivered via intracoronary injection during primary percutaneous coronary intervention for ST-segment elevation MI. Signs of potential drug activity were demonstrated with biomarker end points in this small exploratory study, indicating that further testing of KAI-9803 as an adjunctive therapy for ST-segment elevation MI is warranted.

  View details for DOI 10.1161/CIRCULATIONAHA.107.759167

  View details for Web of Science ID 000253428100005

  View details for PubMedID 18250271

• Recognition, diagnosis, and treatment of primary focal hyperhidrosis JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Hornberger, J., Grimes, K., NAUMANN, M., Glaser, D. A., Lowe, N. J., Naver, H., Ahn, S., Stolman, L. R. 2004; 51 (2): 274-286

  View details for DOI 10.1016/j.jaad.2003.12.029

  View details for PubMedID 15280848

• GRANULOCYTE COLONY-STIMULATING FACTOR MOBILIZED PERIPHERAL-BLOOD PROGENITOR CELLS ACCELERATE GRANULOCYTE AND PLATELET RECOVERY AFTER HIGH-DOSE CHEMOTHERAPY BLOOD Chao, N. J., Schriber, J. R., Grimes, K., Long, G. D., Negrin, R. S., RAIMONDI, C. M., Horning, S. J., Brown, S. L., Miller, L., Blume, K. G. 1993; 81 (8): 2031-2035

  Abstract

  Hematopoietic growth factors have been used to accelerate engraftment after bone marrow transplantation and to "mobilize" peripheral blood progenitor cells (PBPC). We report on the data in 85 consecutive patients with Hodgkin's disease who were treated in a single institution using different methods to obtain PB progenitor cells. Use of granulocyte colony-stimulating factor for mobilization resulted in a significantly accelerated time to recovery of granulocytes (10 days v 12 days, P < .01) when compared with "nonmobilized" PBPC recipients. Similarly, use of mobilized PBPC resulted in a significantly accelerated time to platelet engraftment (13 days v 30 days, P < .001) when compared with "nonmobilized" recipients. Moreover, there was a statistically significant difference in total costs in favor of the group receiving "mobilized" PBPC.

  View details for Web of Science ID A1993KY00500008

  View details for PubMedID 7682454