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Genomic Biomarkers for Personalized Medicine in Breast Cancer

International Journal of Clinical Pharmacology & Toxicology (IJCPT) 2012年第2期1卷 35-37页

作者： Min-Jun Chen Hui-Xiao Hong Weida Tong Division of Bioinformatics and Biostatistics National Center for Toxicological Research US Food and Drug Administration

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Restoration of LAT activity improves CAR T cell sensitivity and persistence in response to antigen-low acute lymphoblastic leukemia

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Cancer Cell 2025年第3期43卷 482-502.e9页

作者： Pham-Danis, Catherine Novak, Amanda J. Danis, Etienne McClellan, Samantha M. Leach, Lillie Yarnell, Michael C. Ebmeier, Christopher C. Tasian, Sarah K. Kohler, M. Eric Department of Pediatrics University of Colorado Anschutz Medical Campus Aurora 80045 CO United States Department of Biomedical Informatics University of Colorado Anschutz Medical Campus Aurora 80045 CO United States Biostatistics & Bioinformatics Shared Resource University of Colorado Cancer Center Aurora 80045 CO United States Division of Oncology and Center for Childhood Cancer Research Children's Hospital of Philadelphia Philadelphia 19104 PA United States Proteomics and Mass Spectrometry Core Department of Biochemistry University of Colorado Boulder 80309 CO United States Department of Pediatrics & Abramson Cancer Center University of Pennsylvania Perelman School of Medicine Philadelphia 19104 PA United States Division of Blood and Marrow Transplantation & Cellular Therapy Center for Cancer and Blood Disorders Children's Hospital Colorado Aurora 80045 CO United States

Chimeric antigen receptor (CAR) T cells induce responses in patients with relapsed/refractory leukemia;however, long-term efficacy is frequently limited by relapse. The inability to target antigen-low cells is an intrinsic vulnerability of second-generation CAR T cells and underlies most relapses following CD22BBz CAR T cell therapy. Here, we interrogate CD22BBz CAR signaling in response to low antigen and find inefficient phosphorylation of the linker for activation of T cells (LAT) limiting downstream signaling. To overcome this, we designed the adjunctive LAT-activating CAR T cell (ALA-CART) platform, pairing a second-generation CAR with a LAT-CAR incorporating the intracellular domain of LAT. ALA-CART cells demonstrate reduced differentiation during manufacturing and increased LAT phosphorylation, MAPK signaling, and AP-1 activity. ALA-CART cells show improved cytotoxicity, proliferation, persistence, and efficacy against antigen-low leukemias that were refractory to clinically active CD22BBz CAR T cells. Restoration of LAT signaling through the ALA-CART platform represents a promising strategy for overcoming multiple mechanisms of CAR T cell failure. © 2025 The Authors

关键词： ALL CAR T cells immunotherapy LAT T cell signaling

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TCRα/ß Depleted Mobilized Pbscs without Calcineurin Inhibitors in Patients with Fanconi Anemia

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Transplantation and Cellular Therapy 2025年第2期31卷 S64-S65页

作者： Margaret L MacMillan Qing Cao Martin Felices Megan Larson David H. McKenna Meera Srikanthan John E. Wagner Pediatrics Blood and Marrow Transplantation & Cellular Therapy Program University of Minnesota Minneapolis MN Biostatistics and Bioinformatics Masonic Cancer Center University of Minnesota Minneapolis MN Division of Hematology Oncology and Transplantation Department of Medicine University of Minnesota Minneapolis MN University of Minnesota Minneapolis MN Department of Laboratory Medicine and Pathology University of Minnesota Minneapolis MN

Background We performed a single center phase II prospective clinical trial (NCT03579875) to test the hypothesis that TCRα/ß depletion would sufficiently deplete GVHD causing α/ß T cells to eliminate the need for prolonged immunosuppression after PBSC transplantation in patients with FA. Methods Patients received conditioning regimen (MacMillan, Blood 2015) with fludarabine, cyclophosphamide and methylprednisolone alone if the patient had marrow failure only and an HLA matched sibling donor (n=2), or with total body irradiation with thymic shielding (n=12) or busulfan (n=17) if there was clonal disease, or if a haploidentical related or HLA matched or mismatched unrelated donor. All but the first patient received one dose of rituximab on day-1 for B cell depletion. Mycophenolate mofetil was given after transplant if the TCRα/ß dose ≥2 × 10 5 TCR α/β T cells/kg recipient (n=4). Mass cytometry (CyTOF) studies included targeting markers for delineating naïve, effector and effector memory CD4 cells and naïve, stem memory, central memory and effector memory CD8 cells, as well as T regulatory, B and γδ T cell subpopulations. Results 31 patients with FA, median 9.5 years (range 1.7-43.8) were enrolled. Patients had marrow failure (n=18), MDS (n=4), relapsed MDS (n=1), APML (n=1), ALL (n=1), immune deficiency (n=1), BRCA2 with clonal abnormality (n=2) or pre-emptively for BRCA2 (n=3), with 2 patients having had a prior transplant. Neutrophil engraftment occurred in all patients, median 9 days (Figure A). Platelet recovery occurred in 30 patients, median 15 days. To date, 3 patients developed grade II-IV acute GVHD. No patient has developed chronic GVHD requiring systemic therapy (Figure B). Probability of survival at 2 years is 90%, including 5/6 BRCA2 patients and all 7 adult patients (Figure C). By 1 year, only 6 patients developed viral infections requiring systemic therapy. Immune recovery in 15 patients was compared to 10 historical FA patients similarly transplanted e

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Efficient estimation of pathwise differentiable target parameters with the undersmoothed highly adaptive lasso

arXiv

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arXiv 2019年

作者： van der Laan, Mark J. Benkeser, David Cai, Weixin Division of Biostatistics University of California Berkeley United States Department of Biostatistics and Bioinformatics Emory University

We consider estimation of a functional parameter of a realistically modeled data distribution based on observing independent and identically distributed observations. We define an m-th order Spline Highly Adaptive Lasso Minimum Loss Estimator (Spline HAL-MLE) of a functional parameter that is defined by minimizing the empirical risk function over an m-th order smoothness class of functions. We show that this m-th order smoothness class consists of all functions that can be represented as an infinitesimal linear combination of tensor products of ≤ m-th order spline-basis functions, and involves assuming m-derivatives in each coordinate. By selecting m with cross-validation we obtain a Spline-HAL-MLE that is able to adapt to the underlying unknown smoothness of the true function, while guaranteeing a rate of convergence faster than n-1/4, as long as the true function is cadlag (right-continuous with left-hand limits) and has finite sectional variation norm. The m = 0-smoothness class consists of all cadlag functions with finite sectional variation norm and corresponds with the original HAL-MLE defined in van der Laan (2015). In this article we establish that this Spline-HAL-MLE yields an asymptotically efficient estimator of any smooth feature of the functional parameter under an easily verifiable global undersmoothing condition. A sufficient condition for the latter condition is that the minimum of the empirical mean of the selected basis functions is smaller than a constant times n-1/2, which is not parameter specific. Therefore, the undersmoothing condition enforces the selection of the L1-norm in the lasso to be large enough so that the fit includes sparsely supported basis functions. We demonstrate our general result for the m = 0-HAL-MLE of the average treatment effect and of the integral of the square of the data density. We also present simulations for these two examples confirming the theory. Copyright © 2019, The Authors. All rights reserved.

关键词： Functions

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Spatial transcriptomic analysis identifies epithelium-macrophage crosstalk in endometriotic lesions

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iScience 2025年第2期28卷 111790页

作者： Burns, Gregory W. Fu, Zhen Vegter, Erin L. Madaj, Zachary B. Greaves, Erin Flores, Idhaliz Fazleabas, Asgerally T. Department of Obstetrics Gynecology and Reproductive Biology Michigan State University Grand Rapids 49503 MI United States Bioinformatics and Biostatistics Van Andel Institute Grand Rapids 49503 MI United States Division of Biomedical Sciences Warwick Medical School University of Warwick Coventry CV4 7AL United Kingdom Centre for Early Life University of Warwick Coventry CV4 7AL United Kingdom Department of Basic Sciences Ponce Health Sciences University Ponce 00716 PR United States Department of Obstetrics & Gynecology Ponce Health Sciences University Ponce 00716 PR United States

The mechanisms underlying the pathophysiology of endometriosis, characterized by the presence of endometrium-like tissue outside the uterus, remain poorly understood. This study aimed to identify cell type-specific gene expression changes in superficial peritoneal endometriotic lesions and elucidate the crosstalk among the stroma, epithelium, and macrophages compared to patient-matched eutopic endometrium. Surprisingly, comparison between lesions and eutopic endometrium revealed transcriptional similarities, indicating minimal alterations in the sub-epithelial stroma and epithelium of lesions. Spatial transcriptomics highlighted increased signaling between the lesion epithelium and macrophages, emphasizing the role of the epithelium in driving lesion inflammation. We propose that the superficial endometriotic lesion epithelium orchestrates inflammatory signaling and promotes a pro-repair phenotype in macrophages, providing a new role for complement 3 in lesion pathobiology. This study underscores the significance of considering spatial context and cellular interactions in uncovering mechanisms governing disease in endometriotic lesions. © 2025 The Author(s)

关键词： integrative aspects of cell biology organizational aspects of cell biology reproductive medicine transcriptomics

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Drug-Induced Liver Toxicity 1

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丛书名： Methods in Pharmacology and Toxicology

2018年

作者： Minjun Chen Yvonne Will

ISBN: (数字)9781493976775

ISBN: (纸本)9781493976768;9781493992560

This book provides a comprehensive view of the methodologies used for the study of liver toxicity encountered throughout the whole life cycle of a drug, from drug discovery, to clinical trial, post-marketing, and even clinical practice. Organized into six sections, the first section introduces the mechanisms contributing to drug-induced liver toxicity. The second and third section explore in silico and in vitro approaches used to help mitigate hepatotoxicity liability at the early stages of drug development. The fourth section describes methodologies applied in regulatory processes, including preclinical studies, clinical trials, and post-marketing surveillance. The fifth section discusses clinical hepatotoxicity. Emerging technologies are examined in the final section. As a volume in the Methods in Pharmacology and Toxicology series, chapters include the kind of expert advice that will lead to optimal results.;Authoritative and practical,;serves all those who aim to improve assessment and understanding of hepatotoxic potentials of new medications and marketed drugs.;Chapter 30 is open access under a CC BY 4.0 license via ***.

关键词： Pharmacology/Toxicology

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Metabolite variation in hybrid corn grain from a large-scale multisite study

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The Crop Journal 2016年第3期4卷 177-187页

作者： Mingjie Chen R.Shyama Prasad Rao Yiming Zhang Cathy Zhong Jay J.Thelen Haixia Institute of Science and Technology Horticulture Biology and Metabolomics CenterFujian Agriculture and Forestry University Department of Biochemistry Christopher S.Bond Life Science CenterUniversity of Missouri Biostatistics and Bioinformatics Division Yenepoya Research CenterYenepoya University Regulatory Group Du Pont Experimental Station

Metabolite composition is strongly affected by genotype,environment,and interactions between genotype and environment,although the extent of variation caused by these factors may depend upon the type of *** characterize the complexity of genotype,environment,and their interaction in hybrid seeds,50 genetically diverse non-genetically modified(GM) maize hybrids were grown in six geographically diverse locations in North *** metabolites from 553 harvested corn grain samples were isolated and analyzed by gas chromatography–mass spectrometry and 45 metabolites detected in all samples were used to generate a data matrix for statistical *** was moderate variation among biological replicates and across genotypes and test *** genotype effects were detected by univariate and Hierarchical clustering analyses(HCA) when environmental effects were ***,environment exerted larger effects than genotype,and polar metabolite accumulation showed a geographic *** conclude that it is possible to increase seed polar metabolite content in hybrid corn by selection of appropriate inbred lines and growing regions.

关键词： Corn grain Genotype Environment GC–MS Metabolomics

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Perioperative Outcomes of Thymectomy in Myasthenia Gravis: A Thoracic Surgery Database Analysis

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ANNALS OF THORACIC SURGERY 2022年第3期113卷 904-910页

作者： Raja, Shruti M. Guptill, Jeffrey T. McConnell, Alec Al-Khalidi, Hussein R. Hartwig, Matthew G. Klapper, Jacob A. [a]Division of Neuromuscular Medicine Department of Neurology Duke University Medical Center Durham North Carolina [b]Department of Biostatistics and Bioinformatics Duke University School of Medicine Durham North Carolina [c]Division of Cardiothoracic Surgery Department of Surgery Duke University Medical Center Durham North Carolina

BACKGROUND There is clinical equipoise regarding the perioperative and long-term outcomes of autoimmune myasthenia gravis (MG) patients undergoing open vs minimally invasive thymectomy, particularly for nonthymomatous MG. This analysis utilizes multicenter, real-world clinical evidence to assess perioperative complications of open and minimally invasive thymectomy techniques in MG *** Thymectomy cases from 2009 to 2019 in MG patients were identified in The Society of Thoracic Surgeons General Thoracic Surgery Database. Thymectomies were grouped by surgical technique: transthoracic (TT), trans cervical (TC), video-assisted thoracoscopic surgery (VATS), or robotic VATS (RVATS). Multivariable logistic regression models assessed the association between surgical technique and perioperative *** Analysis of nonthymomatous cases (n = 1725) revealed VATS (odds ratio [OR], 0.44;95% confidence interval [CI], 0.23-0.83), RVATS (OR, 0.73;95% CI, 0.48-1.26), and TC (OR, 0.19;95% CI, 0.06-0.62) thymectomies had lower odds of perioperative complications than TT thymectomies. VATS (OR, 2.29;95% CI, 0.63-8.30) and RVATS (OR, 4.08;95% CI,1.21-3.78) thymectomies had higher odds of perioperative complications than TC thymectomies. Analysis of thymomatous cases (n = 311) found no significant difference in the odds of perioperative complications in TT vs minimally invasive (VATS/RVATS) procedures. The proportion of RVATS procedures increased from 6.43% to 44.27%, while TT (56.43% to 34.35%) and TC (19.29% to 6.87%) thymectomies *** Minimally invasive and TC thymectomies have fewer perioperative complications than TT thymectomies when performed for nonthymomatous MG. Minimally invasive procedures are increasingly performed for both nonthymomatous and thymomatous disease. There is a nationwide shift toward minimally invasive procedures, even for thymoma resections. Long-term neurological outcome data are needed to determine whether a reduced

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Statistical validation of traditional Chinese diagnostic procedures

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Drug Information Journal 2009年第1期43卷 83-95页

作者： Hsiao, Chin-Fu Tsou, Hsiao-Hui Pong, Annpey Liu, Jen-Pei Lin, Chien-Hsiung Chang, Yeu-Jhy Chow, Shein-Chung Division of Biostatistics and Bioinformatics Institute of Population Health Science National Health Research Institutes Zhunan Taiwan Division of Biostatistics and Bioinformatics National Health Research Institutes Zhunan Taiwan Schering Plough Kenilworth NJ United States Division of Biometry Department of Agronomy National Taiwan University Taipei Taiwan Department of Acupuncture and Moxibustion Center for Traditional Chinese Medicine Chang Gung Memorial Hospital Taoyuan Hsien Taiwan Stroke Center and Department of Neurology Chang Gung Memorial Hospital Chang Gung University Taoyuan Taiwan Department of Biostatistics and Bioinformatics Duke University School of Medicine Durham NC 27705 2400 Pratt St. United States Statistics Department National Cheng-Kung University Tainan Taiwan

In recent years, the modernization of traditional Chinese medicine (TCM) for treatment of patients with critical and life-threatening diseases has attracted much attention in the pharmaceutical industry. The modernization of TCM is based on a scientific evaluation of the safety and effectiveness of the TCM in terms of some well-established quantitative instruments. As a result, statistical validation of such an instrument is essential to have an accurate and reliable clinical assessment of the performance of the TCM. Similar to the validation of a typical quality of life instrument, some validation performance characteristics such as validity, reliability, and ruggedness are considered. In this article, a design for validation of a standard quantitative instrument that is commonly employed for diagnosis of a patient's functions and activities, performance, signs and symptoms of disease, and disease status and severity based on Chinese diagnostic practice is proposed. Methods for statistical validation of the standard instrument are derived. A numerical example is given to illustrate the proposed methods for validation of Chinese diagnostic procedures. Copyright © 2009 Drug Information Association, Inc.

关键词： Calibration Reliability Validation Validity

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Medical Resource Utilizations and Economic Burden in Chinese Cancer Patients with Chemotherapy-induced Anemia:A Populational Database Study

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Chinese Journal of Cancer Research 2008年第4期20卷 307-315页

作者：刘介宇刘沧梧刘季鑫萧金福陈立宗 Department of Nursing Taipei College of Nursing Division of Biostatistics and Bioinformatics Taiwan Health Research Institutes Institute of Cancer Research Taiwan Health Research Institutes

Objective： Most of published studies emphasized the medical cost of treating chemotherapy-induced anemia （CIA） by using specific agents, for example, epoetin α, epoetin β, darbepoetin α or combined with red blood cell transfusions, however, the investigation of the overall medical resources utilizations and economic burden of CIA is still limited. Besides, such studies which emphasized Chinese population still lack. The aim of this study is to investigate the medical resource utilization and the economic burden of Chinese cancer patients with CIA by using a populational representative claim database. Methods： The data for this study are from the 2000-2003 Population Health Insurance Research Database （PHIRD） in Taiwan. On the basis of issuing catastrophic illness cards in the enrollment data files, a total of 26,053 beneficiaries were identified from the PHIRD, who were newly diagnosed with these four cancers in 2001 and 2002 （2001： n=12,954; 2002： n=13099）. A generalized linear model （GLM） was employed for analyzing the differences of medical resource utilization and economic burden between the anemic and non-anemic groups. Results： Analyses showed that the anemic patients were significantly more likely to have longer length of hospital stay than non-anemic patients （P〈0.05） across all these four cancers and in two study periods （except women breast cancer in 2002/03）. As regards the health care expenditures, the average one-year total medical cost was USD$8,982 （2001/02） and USD$8,990 （2002/03） for anemic patients among these four cancers, and USD$7,769 （2001/02） and USD$7713 （2002/03） for non-anemic patients （P〈0.0001）. As for ambulatory costs, anemic patients＇ was significantly higher than non-anemic patients＇ for lung cancer （in 2001/02）, women breast cancer （in 2001/02 and 2002103） and the summarized data （in 2001/02）. As for inpatient costs, anemic patients＇ was significantly higher than non-anemic patients＇ for gastric cancer （in 2002/03）, colon and rectal c

关键词： Economic burden Medical cost Cancer Chemotherapy Anemia

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