osl-dynamics, a toolbox for modeling fast dynamic brain activity.

Neural activity contains rich spatiotemporal structure that corresponds to cognition. This includes oscillatory bursting and dynamic activity that span across networks of brain regions, all of which can occur on timescales of tens of milliseconds. While these processes can be accessed through brain recordings and imaging, modeling them presents methodological challenges due to their fast and transient nature. Furthermore, the exact timing and duration of interesting cognitive events are often a priori unknown. Here, we present the OHBA Software Library Dynamics Toolbox (osl-dynamics), a Python-based package that can identify and describe recurrent dynamics in functional neuroimaging data on timescales as fast as tens of milliseconds. At its core are machine learning generative models that are able to adapt to the data and learn the timing, as well as the spatial and spectral characteristics, of brain activity with few assumptions. osl-dynamics incorporates state-of-the-art approaches that can be, and have been, used to elucidate brain dynamics in a wide range of data types, including magneto/electroencephalography, functional magnetic resonance imaging, invasive local field potential recordings, and electrocorticography. It also provides novel summary measures of brain dynamics that can be used to inform our understanding of cognition, behavior, and disease. We hope osl-dynamics will further our understanding of brain function, through its ability to enhance the modeling of fast dynamic processes.

Targeted Bioluminescent Imaging of Pancreatic Ductal Adenocarcinoma Using Nanocarrier-Complexed EGFR-Binding Affibody-Gaussia Luciferase Fusion Protein.

In vivo imaging has enabled impressive advances in biological research, both preclinical and clinical, and researchers have an arsenal of imaging methods available. Bioluminescence imaging is an advantageous method for in vivo studies that allows for the simple acquisition of images with low background signals. Researchers have increasingly been looking for ways to improve bioluminescent imaging for in vivo applications, which we sought to achieve by developing a bioluminescent probe that could specifically target cells of interest. We chose pancreatic ductal adenocarcinoma (PDAC) as the disease model because it is the most common type of pancreatic cancer and has an extremely low survival rate. We targeted the epidermal growth factor receptor (EGFR), which is frequently overexpressed in pancreatic cancer cells, using an EGFR-specific affibody to selectively identify PDAC cells and delivered a Gaussia luciferase (GLuc) bioluminescent protein for imaging by engineering a fusion protein with both the affibody and the bioluminescent protein. This fusion protein was then complexed with a G5-PAMAM dendrimer nanocarrier. The dendrimer was used to improve the protein stability in vivo and increase signal strength. Our targeted bioluminescent complex had an enhanced uptake into PDAC cells in vitro and localized to PDAC tumors in vivo in pancreatic cancer xenograft mice. The bioluminescent complexes could delineate the tumor shape, identify multiple masses, and locate metastases. Through this work, an EGFR-targeted bioluminescent-dendrimer complex enabled the straightforward identification and imaging of pancreatic cancer cells in vivo in preclinical models. This argues for the targeted nanocarrier-mediated delivery of bioluminescent proteins as a way to improve in vivo bioluminescent imaging.

Childhood Growth and Socioeconomic Outcomes in Early Adulthood Evidence from the Inter-War United States.

Childhood malnutrition and its later life effects were important concerns in European and North American social policy in the early twentieth century. However, there have been few studies of the long-term socioeconomic consequences of malnutrition in childhood. We use a unique longitudinal dataset to provide credible causal estimates of the effects of childhood nutrition on early-adult educational and employment outcomes. Our dataset includes 2,499 children in Saint Paul, Minnesota who were weighed and measured in a national children's health survey in 1918/1919 at 0-6 years of age. We observe those same people in the 1920, 1930 and 1940 U.S. censuses allowing us to measure childhood socioeconomic status (1920), adolescent school attendance (1930) and early-adult wages, and employment and educational attainment (1940). Examining variation between biological siblings, we are able to obtain credibly causal estimates of the relationship between childhood stature and weight and later life outcomes, largely canceling out the bias otherwise resulting from their joint correlation with genes and socioeconomic background. Because the initial survey located children within households, we identify the effect of differences in early childhood nutrition from differences between male siblings. Consistent with contemporary evidence from developing countries we find that being taller and heavier in early childhood is associated with better educational and labor market outcomes. Identifying all effects within families to control for socioeconomic background and family structure we find a standard deviation increase in BMI in early childhood was associated with a 3% increase in weekly earnings and that boys who were heavier for their age at the initial survey were 10% less likely to be unemployed in 1940. Taken together, these results confirm the importance of investments in early life health for later-life outcomes.

Gonadal tumors in a contemporary cohort of patients with differences in sex development undergoing surgery - A multi-site study from the Pediatric Urologic Oncology Working Group of the societies for pediatric urology.

BACKGROUND: Disturbances in gonadal development lead to increased risk of gonadal malignancy in some but not all patients with differences in sex development (DSD). However, the natural history of these tumors is poorly described, and the literature remains sparse. OBJECTIVE: The objective of this study was to describe the incidence of germ cell neoplasia in situ (GCNIS) and germ cell tumor (GCT) in a contemporary cohort of patients with DSD undergoing surgery and to provide long-term oncologic outcomes for these patients. STUDY DESIGN: Patients with DSD who have undergone gonadectomy or gonadal biopsy were identified at four institutions. Clinical characteristics, pathology, and treatment details were obtained retrospectively. Patients were stratified into risk categories based on DSD diagnosis. Oncologic treatment and outcomes were recorded. Descriptive statistics are reported using parametric methods. RESULTS: 83 patients were identified. Distribution of diagnoses is summarized in the summary table. 14 (16.9%) patients underwent gonadal biopsy, and 71 (85.5%) patients underwent gonadectomy (50/71 gonadectomies were bilateral). 8/83 (9.6%) patients had GCNIS or GCT (7 GCNIS, 1 GCT). Median age at surgery was 2.95 years (y) (interquartile range [IQR] 0.6-12.2) and 14y (IQR 0.85-16.9) in patients without and with GCNIS/GCT, respectively. All 8 patients with GCNIS/GCT had high or intermediate risk DSD diagnoses (4 mixed gonadal dysgenesis, 3 Turner with Y, 1 partial gonadal dysgenesis). Of the patients with high-risk diagnoses, 8/54 (15%) had GCNIS/GCT. No patient received adjuvant therapy, no patient had a recurrence, and all patients were living with mean follow up 6.4y. DISCUSSION: The risk of gonadal malignancy is heterogeneous in the DSD population and can vary based on DSD diagnosis as well as maturation, testicularization, and location of the gonads. The most recent consensus recommendations on gonadal management emphasize risk stratification and consideration of gonadal surveillance based on gender of rearing, but supporting literature remains sparse. In this contemporary cohort of DSD patients who underwent gonadal surgery, most patients did not have evidence of adverse pathology, all patients with malignant or premalignant pathology had a high/intermediate risk DSD diagnosis, and all patients with GCNIS/GCT were treated with surgery alone without recurrence. CONCLUSIONS: The distribution of patients with premalignant and malignant gonadal pathology and DSD in this cohort aligns with prior literature, and oncologic outcomes were excellent. These data add valuable information to the current literature and highlight the necessity to develop appropriate screening regimens for retained gonads.

Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia.

TET2 haploinsufficiency is a driving event in myeloid cancers and is associated with a worse prognosis in patients with acute myeloid leukemia (AML). Enhancing residual TET2 activity using vitamin C increases oxidized 5-methylcytosine (mC) formation and promotes active DNA demethylation via base excision repair (BER), which slows leukemia progression. We utilize genetic and compound library screening approaches to identify rational combination treatment strategies to improve use of vitamin C as an adjuvant therapy for AML. In addition to increasing the efficacy of several US Food and Drug Administration (FDA)-approved drugs, vitamin C treatment with poly-ADP-ribosyl polymerase inhibitors (PARPis) elicits a strong synergistic effect to block AML self-renewal in murine and human AML models. Vitamin-C-mediated TET activation combined with PARPis causes enrichment of chromatin-bound PARP1 at oxidized mCs and γH2AX accumulation during mid-S phase, leading to cell cycle stalling and differentiation. Given that most AML subtypes maintain residual TET2 expression, vitamin C could elicit broad efficacy as a PARPi therapeutic adjuvant.

Breathing new life into death certificates: Extracting handwritten cause of death in the LIFE-M project.

The demographic and epidemiological transitions of the past 200 years are well documented at an aggregate level. Understanding differences in individual and group risks for mortality during these transitions requires linkage between demographic data and detailed individual cause of death information. This paper describes the digitization of almost 185,000 causes of death for Ohio to supplement demographic information in the Longitudinal, Intergenerational Family Electronic Micro-database (LIFE-M). To extract causes of death, our methodology combines handwriting recognition, extensive data cleaning algorithms, and the semi-automated classification of causes of death into International Classification of Diseases (ICD) codes. Our procedures are adaptable to other collections of handwritten data, which require both handwriting recognition and semi-automated coding of the information extracted.

Weight gain is associated with shorter lifespan: a longitudinal study of New Zealand soldiers serving in both world wars.

Obesity is an increasing public health concern with important mortality consequences. Weight gain or maximum adult BMI, not BMI at one point in time, has been shown to be an important risk factor in cohorts studied recently during an era of rapid increase in population levels of overweight and obesity. However, there is limited evidence on individual weight trajectories from cohorts born before the mid-twentieth century. Archival world war military personnel files from New Zealand are freely available online, and identify service in both wars. A pilot study of 316 soldiers confirmed the files contain sufficient information to examine health trajectories and lifespan. Because this cohort are now entirely deceased, nearly the entire sample can be found in death records to estimate the impact of weight increases on lifespan. Weight change over 20-30 years and its relationship with lifespan is examined using ordinary least squares regression. The study demonstrates that military records are a feasible source for collecting data on adult weight and health trajectories in the first half of the twentieth century. Although this sample is likely to be composed of men fitter than average, there is a clear pattern of increasing weight from early to mid-adulthood. Weight gain from early adulthood to middle-age was found to be more strongly associated with mortality than weight in early adulthood. A one unit increase in BMI over the inter-war period was found to be associated with an 8 month decline in lifespan. These results confirm that weight gain in adulthood has an important impact on mortality in an earlier birth cohort than previously studied, and that data exist to measure any changes more precisely over time.

Urine-derived exosomes from individuals with IPF carry pro-fibrotic cargo.

Background: MicroRNAs (miRNA) and other components contained in extracellular vesicles may reflect the presence of a disease. Lung tissue, sputum, and sera of individuals with idiopathic pulmonary fibrosis (IPF) show alterations in miRNA expression. We designed this study to test whether urine and/or tissue derived exosomal miRNAs from individuals with IPF carry cargo that can promote fibrosis. Methods: Exosomes were isolated from urine (U-IPFexo), lung tissue myofibroblasts (MF-IPFexo), serum from individuals with IPF (n=16) and age/sex-matched controls without lung disease (n=10). We analyzed microRNA expression of isolated exosomes and their in vivo bio-distribution. We investigated the effect on ex vivo skin wound healing and in in vivo mouse lung models. Results: U-IPFexo or MF-IPFexo expressed miR-let-7d, miR-29a-5p, miR-181b-3p and miR-199a-3p consistent with previous reports of miRNA expression obtained from lung tissue/sera from patients with IPF. In vivo bio-distribution experiments detected bioluminescent exosomes in the lung of normal C57Bl6 mice within 5 min after intravenous infusion, followed by distribution to other organs irrespective of exosome source. Exosomes labeled with gold nanoparticles and imaged by transmission electron microscopy were visualized in alveolar epithelial type I and type II cells. Treatment of human and mouse lung punches obtained from control, non-fibrotic lungs with either U-IPFexo or MF-IPFexo produced a fibrotic phenotype. A fibrotic phenotype was also induced in a human ex vivo skin model and in in vivo lung models. Conclusions: Our results provide evidence of a systemic feature of IPF whereby exosomes contain pro-fibrotic miRNAs when obtained from a fibrotic source and interfere with response to tissue injury as measured in skin and lung models. Funding: This work was supported in part by Lester and Sue Smith Foundation and The Samrick Family Foundation and NIH grants R21 AG060338 (SE and MKG), U01 DK119085 (IP, RS, MTC).

Combination venetoclax and selinexor effective in relapsed refractory multiple myeloma with translocation t(11;14).

Patients with multiple myeloma-bearing translocation t(11;14) have recently been shown to benefit from the apoptosis-inducing drug venetoclax; however, the drug lacks FDA approval in multiple myeloma thus far due to a potential safety signal in the overall patient population. Selinexor is an inhibitor of nuclear export that is FDA-approved for patients with multiple myeloma refractory to multiple lines of therapy. Here, we report that in four patients with multiple myeloma with t(11;14), the concomitant administration of venetoclax and selinexor was safe and associated with disease response. Moreover, the combination was synergistic in t(11;14) multiple myeloma cell lines and caused decreased levels of Cyclin D1 (which is overexpressed due to the CCND1-IGH fusion) when given in combination as compared to single agents. These data suggest that the combination of venetoclax and selinexor is effective and t(11;14) may serve as a therapeutic marker for response and target for future clinical trials.

Mixtures of large-scale dynamic functional brain network modes.

Accurate temporal modelling of functional brain networks is essential in the quest for understanding how such networks facilitate cognition. Researchers are beginning to adopt time-varying analyses for electrophysiological data that capture highly dynamic processes on the order of milliseconds. Typically, these approaches, such as clustering of functional connectivity profiles and Hidden Markov Modelling (HMM), assume mutual exclusivity of networks over time. Whilst a powerful constraint, this assumption may be compromising the ability of these approaches to describe the data effectively. Here, we propose a new generative model for functional connectivity as a time-varying linear mixture of spatially distributed statistical "modes". The temporal evolution of this mixture is governed by a recurrent neural network, which enables the model to generate data with a rich temporal structure. We use a Bayesian framework known as amortised variational inference to learn model parameters from observed data. We call the approach DyNeMo (for Dynamic Network Modes), and show using simulations it outperforms the HMM when the assumption of mutual exclusivity is violated. In resting-state MEG, DyNeMo reveals a mixture of modes that activate on fast time scales of 100-150 ms, which is similar to state lifetimes found using an HMM. In task MEG data, DyNeMo finds modes with plausible, task-dependent evoked responses without any knowledge of the task timings. Overall, DyNeMo provides decompositions that are an approximate remapping of the HMM's while showing improvements in overall explanatory power. However, the magnitude of the improvements suggests that the HMM's assumption of mutual exclusivity can be reasonable in practice. Nonetheless, DyNeMo provides a flexible framework for implementing and assessing future modelling developments.

Long-Term Effects of Local-Area New Deal Work Relief in Childhood on Educational, Economic, and Health Outcomes Over the Life Course: Evidence From the Wisconsin Longitudinal Study.

The economic characteristics of one's childhood neighborhood have been found to determine long-term well-being. Policies enacted during childhood may change neighborhood trajectories and thus impact long-term outcomes for children. We use individual-level data from the Wisconsin Longitudinal Study to examine the enduring consequences of childhood exposure to local-area New Deal emergency employment work-relief activity. Our outcomes include adolescent cognition, educational attainment, midlife income, health behaviors, late-life cognition, and mortality. We find that children (ages 0-3) living in neighborhoods with moderate work-relief activity in 1940 had higher adolescent IQ scores, had higher class rank, and were more likely to obtain at least a bachelor's degree. We find enduring benefits for midlife income and late-life cognition for males who grew up in areas with a moderate amount of work relief. We find mixed results for males who grew up in the most disadvantaged areas with the highest levels of work-relief activity. These children had similar educational outcomes as those in the most advantaged districts with the lowest work-relief activity but had higher adult smoking rates. Our findings provide some of the first evidence of the long-term consequences of New Deal policies on children's long-term life course outcomes.

Aminopyridine analogs selectively target metastatic pancreatic cancer.

Metastatic outgrowth is supported by metabolic adaptations that may differ from the primary tumor of origin. However, it is unknown if such adaptations are therapeutically actionable. Here we report a novel aminopyridine compound that targets a unique Phosphogluconate Dehydrogenase (PGD)-dependent metabolic adaptation in distant metastases from pancreatic cancer patients. Compared to structurally similar analogs, 6-aminopicolamine (6AP) potently and selectively reversed PGD-dependent metastatic properties, including intrinsic tumorigenic capacity, excess glucose consumption, and global histone hyperacetylation. 6AP acted as a water-soluble prodrug that was converted into intracellular bioactive metabolites that inhibited PGD in vitro, and 6AP monotherapy demonstrated anti-metastatic efficacy with minimal toxicity in vivo. Collectively, these studies identify 6AP and possibly other 6-aminopyridines as well-tolerated prodrugs with selectivity for metastatic pancreatic cancers. If unique metabolic adaptations are a common feature of metastatic or otherwise aggressive human malignancies, then such dependencies could provide a largely untapped pool of druggable targets for patients with advanced cancers.

The mortality risk of being overweight in the twentieth century: Evidence from two cohorts of New Zealand men.

How have health and social mortality risks changed over time? Evidence from pre-1945 cohorts is sparse, mostly from the United States, and evidence is mixed on long-term changes in the risk of being overweight. We develop a dataset of men entering the NZ army in the two world wars, with objectively measured height and weight, and socioeconomic status in early adulthood. Our sample includes significant numbers of indigenous Maori, providing estimates of weight and mortality risk in an indigenous population. We follow men from war's end until death, with data on more than 12,000 men from each war. Overweight and obesity were important risk factors for mortality, and associated with shorter life expectancy. However, the reduction in life expectancy associated with being overweight declined from 5 to 3 years between the two cohorts, consistent with the hypothesis that being overweight became less risky during the twentieth century.

Life-Course Transitions in Rural Residence and Old-Age Mortality in Iowa, 1930-2014.

Early-life conditions are associated with mortality in men, but not studied to the same extent in women. We add new evidence by studying a cohort of women born between 1916 and 1931 and followed for mortality between 1986 and 2013. Our sample from Iowa includes a significant number of rural women, from both farms and small towns. The long-term effects of growing up in a rural area were mixed: farmers' daughters lived longer than women growing up off-farm in rural areas. Daughters of farm laborers and skilled or semi-skilled trades workers fared worst, when considering early-life socioeconomic status. We also find evidence that migrating to small-town Iowa was associated with lower life expectancy after age fifty-five. Considering social class and farm-nonfarm status is important for understanding the health of rural America.

Proteomics reveal cap-dependent translation inhibitors remodel the translation machinery and translatome.

Tactical disruption of protein synthesis is an attractive therapeutic strategy, with the first-in-class eIF4A-targeting compound zotatifin in clinical evaluation for cancer and COVID-19. The full cellular impact and mechanisms of these potent molecules are undefined at a proteomic level. Here, we report mass spectrometry analysis of translational reprogramming by rocaglates, cap-dependent initiation disruptors that include zotatifin. We find effects to be far more complex than simple "translational inhibition" as currently defined. Translatome analysis by TMT-pSILAC (tandem mass tag-pulse stable isotope labeling with amino acids in cell culture mass spectrometry) reveals myriad upregulated proteins that drive hitherto unrecognized cytotoxic mechanisms, including GEF-H1-mediated anti-survival RHOA/JNK activation. Surprisingly, these responses are not replicated by eIF4A silencing, indicating a broader translational adaptation than currently understood. Translation machinery analysis by MATRIX (mass spectrometry analysis of active translation factors using ribosome density fractionation and isotopic labeling experiments) identifies rocaglate-specific dependence on specific translation factors including eEF1ε1 that drive translatome remodeling. Our proteome-level interrogation reveals that the complete cellular response to these historical "translation inhibitors" is mediated by comprehensive translational landscape remodeling.

The Influence of Kin Proximity on the Reproductive Success of American Couples, 1900-1910.

Children require a large amount of time, effort, and resources to raise. Physical help, financial contributions, medical care, and other types of assistance from kin and social network members allow couples to space births closer together while maintaining or increasing child survival. We examine the impact of kin availability on couples' reproductive success in the early twentieth-century United States with a panel data set of over 3.1 million couples linked between the 1900 and 1910 U.S. censuses. Our results indicate that kin proximity outside the household was positively associated with fertility, child survival, and net reproduction, and suggest that declining kin availability was an important contributing factor to the fertility transition in the United States. We also find important differences between maternal and paternal kin inside the household-including higher fertility among women residing with their mother-in-law than among those residing with their mother-that support hypotheses related to the contrasting motivations and concerns of parents and parents-in-law.

A qualitative study examining prosthesis use in everyday life in individuals with lower limb amputations.

BACKGROUND: Lower limb amputation (LLA) is a life-changing event that affects functional mobility and participation in everyday life. Prostheses provide individuals with LLA the opportunity to improve mobility and quality of life; however, existing literature suggests that there is underuse of prostheses. OBJECTIVES: The purpose of this study is to describe how individuals with major LLA use their prosthesis in everyday life and describe barriers and facilitators that influence prosthesis use. STUDY DESIGN: A qualitative descriptive methodology was used. METHODS: Ten community dwelling adults (>18 years) with unilateral major LLAs (transtibial, transfemoral, and knee disarticulation) attending outpatient follow-up at a specialized rehabilitation center were recruited. Participants were purposively sampled for variation in prosthesis use and level of amputation. One-on-one semistructured in-depth interviews were conducted in person or by telephone. The interviews were audio recorded, transcribed verbatim, and analyzed inductively using thematic analysis. RESULTS: The experiences of individuals with major LLA were organized into three overarching themes: everyday experiences using a prosthesis, extrinsic factors influencing prosthesis use, and intrinsic factors influencing prosthesis use. These themes, and their associated subthemes, highlight how individuals use their prosthesis and the various factors perceived to act as barriers and facilitators to prosthesis use in everyday life. CONCLUSIONS: These findings provide valuable insight into the everyday experiences of individuals with LLA and can be used to implement strategies to optimize prosthesis use.

Dual Screen for Efficacy and Toxicity Identifies HDAC Inhibitor with Distinctive Activity Spectrum for BAP1-Mutant Uveal Melanoma.

Drug screens leading to successful targeted therapies in cancer have been mainly based on cell viability assays identifying inhibitors of dominantly acting oncogenes. In contrast, there has been little success in discovering targeted therapies that reverse the effects of inactivating mutations in tumor-suppressor genes. BAP1 is one such tumor suppressor that is frequently inactivated in a variety of cancers, including uveal melanoma, renal cell carcinoma, and mesothelioma. Because BAP1 is an epigenetic transcriptional regulator of developmental genes, we designed a two-phase drug screen involving a cell-based rescue screen of transcriptional repression caused by BAP1 loss, followed by an in vivo screen of lead compounds for rescue of a BAP1-deficient phenotype with minimal toxicity in Xenopus embryos. The first screen identified 9 compounds, 8 of which were HDAC inhibitors. The second screen eliminated all except one compound due to inefficacy or toxicity. The resulting lead compound, quisinostat, has a distinctive activity spectrum, including high potency against HDAC4, which was recently shown to be a key target of BAP1. Quisinostat was further validated in a mouse model and found to prevent the growth of BAP1-mutant uveal melanomas. This innovative strategy demonstrates the potential for identifying therapeutic compounds that target tumor-suppressor mutations in cancer. IMPLICATIONS: Few drugs have been identified that target mutations in tumor suppressors. Using a novel 2-step screening approach, strategy, we identified quisinostat as a candidate for therapy in BAP1-mutant uveal melanoma. HDAC4 is implicated as a key target in uveal melanoma and perhaps other BAP1-mutant cancers.

Optimized Doxorubicin Chemotherapy for Diffuse Large B-cell Lymphoma Exploits Nanocarrier Delivery to Transferrin Receptors.

New treatments are needed to address persistent unmet clinical needs for diffuse large B-cell lymphoma (DLBCL). Overexpression of transferrin receptor 1 (TFR1) is common across cancer and permits cell-surface targeting of specific therapies in preclinical and clinical studies of various solid tumors. Here, we developed novel nanocarrier delivery of chemotherapy via TFR1-mediated endocytosis, assessing this target for the first time in DLBCL. Analysis of published datasets showed novel association of increased TFR1 expression with high-risk DLBCL cases. Carbon-nitride dots (CND) are emerging nanoparticles with excellent in vivo stability and distribution and are adaptable to covalent conjugation with multiple substrates. In vitro, linking doxorubicin (Dox) and transferrin (TF) to CND (CND-Dox-TF, CDT) was 10-100 times more potent than Dox against DLBCL cell lines. Gain- and loss-of-function studies and fluorescent confocal microscopy confirmed dependence of these effects on TFR1-mediated endocytosis. In contrast with previous therapeutics directly linking Dox and TF, cytotoxicity of CDT resulted from nuclear entry by Dox, promoting double-stranded DNA breaks and apoptosis. CDT proved safe to administer in vivo, and when incorporated into standard frontline chemoimmunotherapy in place of Dox, it improved overall survival by controlling patient-derived xenograft tumors with greatly reduced host toxicities. Nanocarrier-mediated Dox delivery to cell-surface TFR1, therefore, warrants optimization as a potential new therapeutic option in DLBCL. SIGNIFICANCE: Targeted nanoparticle delivery of doxorubicin chemotherapy via the TRF1 receptor presents a new opportunity against high-risk DLBCL tumors using potency and precision.