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Programmable scanning diffuse speckle contrast imaging of cerebral blood flow

Neurophotonics 2025年第1期12卷 015006页

作者： Akbari, Faezeh Liu, Xuhui Hamedi, Fatemeh Mohtasebi, Mehrana Chen, Li Chen, Lei Yu, Guoqiang University of Kentucky Department of Biomedical Engineering LexingtonKY United States University of Kentucky Biostatistics and Bioinformatics Shared Resource Facility Markey Cancer Center LexingtonKY United States University of Kentucky Spinal Cord and Brain Injury Research Center Department of Physiology LexingtonKY United States

Significance: Cerebral blood flow (CBF) imaging is crucial for diagnosing cerebrovascular diseases. However, existing large neuroimaging techniques with high cost, low sampling rate, and poor mobility make them unsuitable for continuous and longitudinal CBF monitoring at the bedside. Aim: We aimed to develop a low-cost, portable, programmable scanning diffuse speckle contrast imaging (PS-DSCI) technology for fast, high-density, and depth-sensitive imaging of CBF in rodents. Approach: The PS-DSCI employed a programmable digital micromirror device (DMD) for remote line-shaped laser (785 nm) scanning on tissue surface and synchronized a 2D camera for capturing boundary diffuse laser speckle contrasts. New algorithms were developed to address deformations of line-shaped scanning, thus minimizing CBF reconstruction artifacts. The PS-DSCI was examined in head-simulating phantoms and adult mice. Results: The PS-DSCI enables resolving intralipid particle flow contrasts at different tissue depths. In vivo experiments in adult mice demonstrated the capability of PS-DSCI to image global/regional CBF variations induced by 8% CO2 inhalation and transient carotid artery ligations. Conclusions: Compared with conventional point scanning, line scanning in PS-DSCI significantly increases spatiotemporal resolution. The high sampling rate of PS-DSCI is crucial for capturing rapid CBF changes while high spatial resolution is important for visualizing brain vasculature. © The Authors. Published by SPIE under a Creative Commons Attribution 4.0 International License.

关键词： Neuroimaging

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Postmastectomy Radiation Therapy for Intermediate-Risk Breast Cancer Patients With 0-3 Positive Axillary Lymph Nodes: Emulating the SUPREMO Trial Using Real-World Data

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Clinical Breast Cancer 2025年

作者： Kulkarni, Sarah E. Patel, Sagar A. Jiang, Chen Schwieger, Lara Postlewait, Lauren M. Arciero, Cletus A. Gillespie, Theresa W. Liu, Yuan Department of Biostatistics and Bioinformatics Rollins School of Public Health Emory University Atlanta GA United States Department of Radiation Oncology Emory University School of Medicine Atlanta GA United States Department of Surgery Cedars-Sinai Medical Center Los Angeles CA United States Department of Surgery Emory University School of Medicine Atlanta GA United States Biostatistics and Bioinformatics Shared Resource Winship Cancer Institute Emory University Atlanta GA United States

Purpose: To emulate the Selective Use of Postoperative Radiotherapy After Mastectomy (SUPREMO) phase III clinical trial using real-world data to assess the impact of postmastectomy radiation therapy (PMRT) on overall survival (OS) among patients with intermediate-risk breast cancer. Patients and Methods: Using the National Cancer Database, women diagnosed between 2006 and 2013 with intermediate-risk breast cancer (defined as pT1-2N1;pT3N0;or pT2N0 and grade III or with lymphovascular invasion) and 0-3 positive axillary lymph nodes, who underwent total mastectomy, were identified as being in accordance with the SUPREMO trial protocol and included in this study. Multivariable logistic regression, Cox proportional hazards regression, and stabilized inverse probability of treatment weighting were used to explore the relationship between PMRT and OS. The effects of PMRT within subgroups were explored using multivariable interaction models. Results: In total, 49335 patients were included in the study, with 6882 (13.9%) receiving PMRT. Patients with stage T3N0 cancer, 1-3 positive axillary lymph nodes, or positive surgical margins were more likely to receive PMRT. Overall, PMRT was associated with no significant improvement in OS (HR: 0.98, 95% CI, 0.92-1.04). However, improved survival was observed among women with stage T3N0 cancer who received PMRT (HR: 0.72, 95% CI, 0.58-0.89). Conclusion: Although PMRT may not be associated with improved OS among all intermediate-risk breast cancer patients with 0-3 positive axillary lymph nodes, the subgroup of patients with stage T3N0 cancer seemed to benefit from PMRT. The study's retrospective nature introduces some uncertainty, but preliminary findings of the SUPREMO trial support these results. © 2025 Elsevier Inc.

关键词： Chest wall irradiation Clinical trial emulation Mastectomy Overall survival Postmastectomy radiation therapy

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Neurotensin promotes hepatic steatosis by regulating lipid uptake and mitochondrial adaptation in hepatocytes

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Cell Death and Disease 2025年第1期16卷 1-12页

作者： Banerjee, Moumita Song, Jun Yan, Baoxiang Wu, Haoming Norouzi, Shaghayegh Sengoku, Tomoko Sharma, Savita Fan, Teresa W. M. Lee, Eun He, Daheng Wang, Chi Liu, Jinpeng Schmitt, Timothy M. Gao, Tianyan Weiss, Heidi L. Li, Jing Evers, B. Mark Markey Cancer Center University of Kentucky Lexington KY United States Department of Surgery University of Kentucky Lexington KY United States Redox Metabolism Shared Resource Facility University of Kentucky Lexington KY United States Department of Toxicology and Cancer Biology University of Kentucky Lexington KY United States Department of Pathology and Laboratory Medicine University of Kentucky Lexington KY United States Bioinformatics Biostatistics and Bioinformatics Shared Resource Facility Markey Cancer Center University of Kentucky Lexington KY United States Division of Cancer Biostatistics Department of Internal Medicine University of Kentucky Lexington KY United States Department of Surgery University of Kansas Medical Center Kansas City KS United States Department of Molecular and Cellular Biochemistry University of Kentucky Lexington KY United States

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial disease characterized by hepatic steatosis. Mitochondrial dysfunction resulting in the incomplete digestion of surplus fat is one of the key factors that lead to hepatic steatosis but the reason for this remains unclear. We investigated the role of neurotensin (NTS), a gut hormone, in inducing maladaptive fat metabolism in steatotic liver. We identify CD36 and PGC1α, two critical drivers of MASLD, as direct NTS signaling targets in the liver. NTS upregulates CD36, a free fatty acid receptor, in hepatocytes and promotes long chain lipid uptake. Conversely, NTS inhibits PGC1α, which acts as a lipid sensor and translocates to the nucleus to activate lipid catabolism-related genes in an AMPK-dependent manner. Thus, a high fat diet decreases the fatty acid oxidation and oxidative phosphorylation capacity of the liver and hepatocytes from NTS or NTS receptor 1 (NTSR1) wild type mice;whereas NTS deficiency preserves the lipid metabolism capacity of the liver. NTS signaling is significantly upregulated in MASLD and in metabolic dysfunction-associated steatohepatitis (MASH) human liver samples when compared to normal livers, which correlates with the expression of CD36 and oxidative phosphorylation proteins. These findings provide critical mechanistic insights into the maladaptive fat metabolism noted with steatosis in mice and humans and suggest novel strategies for therapeutic intervention of MASLD, which affects nearly one-quarter of the global population. © The Author(s) 2025.

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Association between transcriptomic metrics of exogenous antigen presentation and adaptive immunity with locoregional recurrence in localized estrogen receptor negative breast cancer: retrospective review of multi-institutional datasets

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Breast cancer research : BCR 2025年第1期27卷 77页

作者： Timothy J Robinson Casey L Liveringhouse Christopher Wilson Sam Friedman Justyn Nakashima Matthew N Mills Jacob D Purcell Nicholas B Figura Du Dongliang Ram Thapa Eric Welsh Kamran A Ahmed G Daniel Grass Brooke L Fridley Roberto Diaz Department of Therapeutic Radiology Yale School of Medicine New Haven CT USA. Department of Radiation Oncology H. Lee Moffitt Cancer Center and Research Institute Tampa FL USA. Biostatistics and Bioinformatics Shared Resource H. Lee Moffitt Cancer Center and Research Institute Tampa FL USA. Michigan State University College of Human Medicine East Lansing MI USA. Department of Radiation Oncology H. Lee Moffitt Cancer Center and Research Institute Tampa FL USA. Roberto.Diaz@***.

BACKGROUND:Transcriptomic features of breast cancer locoregional recurrence (LRR) remain poorly understood. We therefore sought to investigate transcriptomic features associated with LRR in newly diagnosed invasive breast tumors from our institutional dataset. METHODS:Transcriptomic profiling was performed on 632 tumors from consecutive patients treated within our health system for newly diagnosed non-metastatic breast cancer. Univariable Cox models identified genes whose expression was associated with LRR (q-value < 0.05). Up-regulated (UR) genes were defined as hazard ratio (HR) > 1 and down-regulated (DR) genes were defined as HR < 1. Gene set enrichment analyses were performed for UR and DR gene sets and validated within two external cohorts of ER- tumors. RESULTS:With a median follow-up of 7.6 years, we observed 38 LRRs: 28/481 (5.8%) in ER + and 10/151 (6.6%) in ER-. There were 43 UR and 7 DR genes associated with LRR in ER + tumors, while 417 UR and 1150 DR genes were associated with LRR in ER- tumors. UR genes in ER + tumors were enriched for roles in cell proliferation (q < 0.05). In contrast, LRR in ER- tumors was most strongly associated with DR genes enriched for MHC-II-mediated antigen presentation and T cell activation (q < 0.05). In external cohorts of ER- tumors, 97 significant DR genes (p < 0.05) were enriched for 18 pathways, including 5 pathways involved in MHC-II signaling, antigen presentation and T-cell activation. CONCLUSIONS:Transcriptomic patterns associated with LRR appear distinct between ER + and ER- tumors. In ER + tumors, LRR appears predominantly associated with proliferation, whereas ER- LRR suggests a robust pattern of suppressed antigen presentation via MHC-II.

关键词： Breast cancer Estrogen receptor negative Immune response Locoregional control

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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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Barriers to Autologous Stem Cell Transplant Referral in Multiple Myeloma: Impact of Social Determinants on Referral, Evaluation, and Transplant Outcomes

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Transplantation and Cellular Therapy 2025年第2期31卷 S344-S345页

作者： Sainvil, Marie-Michele, MD Lowe, Melissa Underwood, Delaney Li, Yan Akinyemiju, Tomi Choi, Taewoong, MD Gasparetto, Cristina, MD Horwitz, Mitchell, MD Long, Gwynn D, MD Lopez, Richard D, MD Sarantopoulos, Stefanie, MD, PhD Alyea, Edwin P, MD Chao, Nelson J., MD, MBA LeBlanc, Thomas W., MD, MA, MHS, FAAHPM, FASCO Kang, Yubin, MD Kirby, Suzanne, MD, PhD Ramalingam, Sendhilnathan, MD Sung, Anthony D, MD Hong, Sanghee, MD Division of Hematologic Malignancies and Cellular Therapy Duke University School of Medicine Durham NC Duke Cancer Institute Duke University School of Medicine Durham NC Duke Cancer Institute Biostatistics Shared Resource Duke University Durham NC Department of Biostatistics and Bioinformatics Duke University Medical Center Durham NC Department of Population Health Sciences Duke University Durham NC Division of Hematologic Malignancies and Cellular Therapy Duke University Medical Center Durham NC Division of Hematologic Malignancies and Cellular Therapy University of Kansas Medical Center Kansas City KS

IntroductionAutologous stem cell transplant (ASCT) is a crucial therapy for eligible patients with multiple myeloma (MM). Despite proven benefits and recommendations by organizations like NCCN, ASCT utilization remains suboptimal. We investigated referral practices to assess barriers to ASCT referral in MM patients. MethodsThis retrospective study analyzed adults with MM residing within Duke's primary catchment area from the North Carolina Central Cancer Registry (NCCCR), and Duke referred data from July 2019-July 2023. We categorized the Duke referred cohort ( Duke Referred) into: Referred but Not Evaluated (RNE)—referred but not seen; Referred and Evaluated Only (REO)—evaluated but not transplanted; and Transplanted (TRN)—received HCT. This study extracted Social Vulnerability Index (SVI) data from the CDC database for each participant's county of residence at the time of referral. Themed percentile rankings assessed social vulnerability and compare the impact of social determinants on transplantation referral outcomes. We compared differences in characteristics using Chi-squared or Fisher's exact test for categorical variables, and ANOVA or Wilcoxon Rank Sum test for continuous variables. Results2,430 MM patients eligible for ASCT referral were identified from the NCCCR across 64 counties in Duke's primary catchment area, with 368 referred to Duke. Table 1 highlights sociodemographic differences between the two cohorts, with the NCCCR cohort showing a higher proportion of African American patients, lower income, and reduced private insurance coverage. Among referred patients, 288 (78%) were internally referred, 298 (81%) were evaluated, and 80 (22%) received ASCT during the study period, with median times from referral to evaluation and evaluation to transplant of 39 and 184 days, respectively. Non-White patients and those with unknown insurance had lower initial evaluation rates, but similar transplantation odds once evaluated. Increased vulnerability from the S

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Random Forest Variable Importance-based Selection Algorithm in Class Imbalance Problem

arXiv

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arXiv 2023年

作者： Nam, Yunbi Han, Sunwoo Department of Biostatistics University of Washington United States Biostatistics and Bioinformatics Shared Resource Sylvester Comprehensive Cancer Center University of Miami Miller School of Medicine United States

Random Forest is a machine learning method that offers many advantages, including the ability to easily measure variable importance. Class balancing technique is a well-known solution to deal with class imbalance problem. However, it has not been actively studied on RF variable importance. In this paper, we study the effect of class balancing on RF variable importance. Our simulation results show that over-sampling is effective in correctly measuring variable importance in class imbalanced situations with small sample size, while under-sampling fails to differentiate important and non-informative variables. We then propose a variable selection algorithm that utilizes RF variable importance and its confidence interval. Through an experimental study using many real and artificial datasets, we demonstrate that our proposed algorithm efficiently selects an optimal feature set, leading to improved prediction performance in class imbalance problem. Copyright © 2023, The Authors. All rights reserved.

关键词： Importance sampling

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Chronic rejection models for vascularized composite tissue allotransplantation

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Scientific Reports 2025年第1期15卷 1-16页

作者： Daniel T. Fisher Eugene Kononov Pawel Kalinski Elizabeth A. Repasky Minhyung Kim Emily Mackey Paul N. Bogner Umesh Sharma Han Yu Curtis L. Cetrulo Mukund Seshadri Joseph J. Skitzki Department of Immunology Roswell Park Comprehensive Cancer Center Buffalo NY USA Comparative Oncology Shared Resource Roswell Park Comprehensive Cancer Center Buffalo NY USA Department of Pathology Roswell Park Comprehensive Cancer Center Buffalo NY USA Department of Medicine Division of Cardiology University at Buffalo Buffalo NY USA Department of Biostatistics and Bioinformatics Roswell Park Comprehensive Cancer Center Buffalo NY USA Department of Surgery Division of Plastic Surgery Cedars-Sinai Medical Center Los Angeles CA USA Department of Oral Oncology Roswell Park Comprehensive Cancer Center Buffalo NY USA Department of General Surgery Cleveland Clinic Cleveland OH USA

Vascularized composite tissue allotransplantation (VCA) has transformed patients’ lives by enabling limb, face, abdominal wall, and penile transplants. Despite advancements in screening and immunosuppression, chronic rejection continues to limit the success of VCA. Lack of reliable preclinical models exacerbates this challenge. Here, we report on new mouse models of chronic rejection following heterotopic hind limb VCA. We employed different levels of MHC mismatch using CD8 knockout C57BL/6 mice as recipients along with BALB/c or B6 H2-Ab1bm12mice as donors. Transient CD4 T cell depletion was induced to allow graft maturation. Evaluation included gross findings, changes in immune status changes, production of donor-specific antibodies (DSA), C4d levels, and histopathological alterations. Two chronic rejection models displayed common features of clinical chronic graft rejection, such as skin stricture, hair loss, adnexal atrophy, extensive fibrosis and mast cell infiltration without widespread necrotic changes common in acute rejection. Similar to chronic rejection patients, large populations of activated B and plasma cells were detected in the recipient’s immune system as well as increased DSA and C4d production. Collectively, our models closely replicate the immunological and histopathological aspects of chronic graft rejection post-VCA, and could provide a new platform for evaluation of novel therapeutic interventions prior to clinical evaluation.

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Domestic Job Shortage or Job Maldistribution? A Geographic Analysis of the Current Radiation Oncology Job Market

Domestic Job Shortage or Job Maldistribution? A Geographic ...

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作者： Chowdhary, Mudit Chhabra, Arpit M. Switchenko, Jeffrey M. Jhaveri, Jaymin Sen, Neilayan Patel, Pretesh R. Curran, Walter J. Abrams, Ross A. Patel, Kirtesh R. Marwaha, Gaurav Department of Radiation Oncology Rush University Medical Center ChicagoIllinois United States Department of Radiation Oncology Winship Cancer Institute of Emory University AtlantaGeorgia United States Biostatistics and Bioinformatics Shared Resource Winship Cancer Institute of Emory University AtlantaGeorgia United States Department of Radiation Oncology University of Maryland School of Medicine BaltimoreMaryland United States

Purpose To examine whether permanent radiation oncologist (RO) employment opportunities vary based on geography. Methods and Materials A database of full-time RO jobs was created by use of American Society for Radiation Oncology (ASTRO) Career Center website posts between March 28, 2016, and March 31, 2017. Jobs were first classified by region based on US Census Bureau data. Jobs were further categorized as academic or nonacademic depending on the employer. The prevalence of job openings per 10 million population was calculated to account for regional population differences. The χ2 test was implemented to compare position type across regions. The number and locations of graduating RO during our study period was calculated using National Resident Matching Program data. The χ2 goodness-of-fit test was then used to compare a set of observed proportions of jobs with a corresponding set of hypothesized proportions of jobs based on the proportions of graduates per region. Results A total of 211 unique jobs were recorded. The highest and lowest percentages of jobs were seen in the South (31.8%) and Northeast (18.5%), respectively. Of the total jobs, 82 (38.9%) were academic;the South had the highest percentage of overall academic jobs (35.4%), while the West had the lowest (14.6%). Regionally, the Northeast had the highest percentage of academic jobs (56.4%), while the West had the lowest (26.7%). A statistically significant difference was noted between regional academic and nonacademic job availability (P=.021). After we accounted for unit population, the Midwest had the highest number of total jobs per 10 million (9.0) while the South had the lowest (5.9). A significant difference was also observed in the proportion of RO graduates versus actual jobs per region (P=.003), with a surplus of trainees seen in the Northeast. Conclusions This study presents a quantitative analysis of the RO job market. We found a disproportionately small number of opportunities compared with g

关键词： Commerce

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Causal effect estimation in sequencing studies: a Bayesian method to account for confounder adjustment uncertainty

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BMC proceedings 2016年第SUPPL 7期10卷 411-415页

作者： Chi Wang Jinpeng Liu David W Fardo Department of Biostatistics College of Public Health University of Kentucky 725 Rose St Lexington KY 40536 USA Biostatistics and Bioinformatics Shared Resource Facility Markey Cancer Center University of Kentucky 800 Rose St Lexington KY 40536 USA. Biostatistics and Bioinformatics Shared Resource Facility Markey Cancer Center University of Kentucky 800 Rose St Lexington KY 40536 USA. Department of Biostatistics College of Public Health University of Kentucky 725 Rose St Lexington KY 40536 USA.

Estimating the causal effect of a single nucleotide variant (SNV) on clinical phenotypes is of interest in many genetic studies. The effect estimation may be confounded by other SNVs as a result of linkage disequilibrium as well as demographic and clinical characteristics. Because a large number of these other variables, which we call potential confounders, are collected, it is challenging to select and adjust for the variables that truly confound the causal effect. The Bayesian adjustment for confounding (BAC) method has been proposed as a general method to estimate the average causal effect in the presence of a large number of potential confounders under the assumption of no unmeasured confounders. In this paper, we explore the application of BAC in genetic studies using Genetic Analysis Workshop 19 exome sequencing data. Our results show that BAC can efficiently estimate the causal effect of genetic variants with adjustment for confounding. Consequently, BAC may serve as a useful tool for genome-wide association studies data analysis to effectively assess the causal effect of genetic variants and the impact of potential interventions.

关键词： Causal Effect Single Nucleotide Variant Bayesian Model Average Exposure Model Alternative Allele

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