Cancer Immunology: Impact of Radioembolization of Hepatocellular Carcinoma on Immune Response Modulation.

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and the fourth most common cause of cancer mortality. The tumor microenvironment is increasingly recognized as having a central role in HCC carcinogenesis; factors such as tumor and immune cell interactions, cytokines, and extracellular matrix have key roles. Transarterial radioembolization (TARE) is a locoregional therapy for HCC that not only has a direct tumoricidal effect but also induces an immune response against tumor cells with subsequent immunogenic cell death. This TARE-induced tumor immunogenicity occurs through enhancement of tumor-associated antigen expression and recruitment and diversification of tumor-infiltrating lymphocytes. In addition, immunologic biomarkers, including neutrophil-to-lymphocyte ratio, lymphocyte count, and cytokine levels, may be useful for predicting outcomes after TARE. Early data are promising regarding the potential synergistic benefit of treatment algorithms that combine TARE and immunotherapies, and interest is growing in the clinical application of such combinations. The purpose of this article is to provide an overview of cancer immunology, summarize the available data on the biologic effects of TARE on local and systemic immune responses, and explore the potential role of the combination of TARE and immunotherapy for HCC.

LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections.

The major diseases affecting the thoracic aorta are aneurysms and acute dissections, and pathogenic variants in 11 genes are confirmed to lead to heritable thoracic aortic disease. However, many families in which multiple members have thoracic aortic disease do not have alterations in the known aortopathy genes. Genes highly expressed in the aorta were assessed for rare variants in exome sequencing data from such families, and compound rare heterozygous variants (p.Pro45Argfs∗25 and p.Glu750∗) in LTBP3 were identified in affected members of one family. A homozygous variant (p.Asn678_Gly681delinsThrCys) that introduces an additional cysteine into an epidermal growth factor (EGF)-like domain in the corresponding protein, latent TGF-ß binding protein (LTBP-3), was identified in a second family. Individuals with compound heterozygous or homozygous variants in these families have aneurysms and dissections of the thoracic aorta, as well as aneurysms of the abdominal aorta and other arteries, along with dental abnormalities and short stature. Heterozygous carriers of the p.Asn678_Gly681delinsThrCys variant have later onset of thoracic aortic disease, as well as dental abnormalities. In these families, LTBP3 variants segregated with thoracic aortic disease with a combined LOD score of 3.9. Additionally, heterozygous rare LTBP3 variants were found in individuals with early onset of acute aortic dissections, and some of these variants disrupted LTBP-3 levels or EGF-like domains. When compared to wild-type mice, Ltbp3-/- mice have enlarged aortic roots and ascending aortas. In summary, homozygous LTBP3 pathogenic variants predispose individuals to thoracic aortic aneurysms and dissections, along with the previously described skeletal and dental abnormalities.

The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy.

PURPOSE: Moyamoya angiopathy (MMA) is a cerebrovascular disease characterized by occlusion of large arteries, which leads to strokes starting in childhood. Twelve altered genes predispose to MMA but the majority of cases of European descent do not have an identified genetic trigger. METHODS: Exome sequencing from 39 trios were analyzed. RESULTS: We identified four de novo variants in three genes not previously associated with MMA: CHD4, CNOT3, and SETD5. Identification of additional rare variants in these genes in 158 unrelated MMA probands provided further support that rare pathogenic variants in CHD4 and CNOT3 predispose to MMA. Previous studies identified de novo variants in these genes in children with developmental disorders (DD), intellectual disability, and congenital heart disease. CONCLUSION: These genes encode proteins involved in chromatin remodeling, and taken together with previously reported genes leading to MMA-like cerebrovascular occlusive disease (YY1AP1, SMARCAL1), implicate disrupted chromatin remodeling as a molecular pathway predisposing to early onset, large artery occlusive cerebrovascular disease. Furthermore, these data expand the spectrum of phenotypic pleiotropy due to alterations of CHD4, CNOT3, and SETD5 beyond DD to later onset disease in the cerebrovascular arteries and emphasize the need to assess clinical complications into adulthood for genes associated with DD.

SMAD3 pathogenic variants: risk for thoracic aortic disease and associated complications from the Montalcino Aortic Consortium.

BACKGROUND: Pathogenic variants in SMAD3 cause thoracic aortic aneurysms and dissections, along with aneurysms and rupture of other arteries. Here, we examined differences in clinical presentation of aortic events (dissection or surgical repair of an aneurysm) with respect to age and variant type in an international cohort of individuals with SMAD3 variants. METHODS: Aortic status and events, vital status and clinical features were abstracted through retrospective review of medical records of 212 individuals with 51 unique SMAD3 variants, including haploinsufficiency (HI) and missense substitutions in the MH2 domain, as well as novel in-frame deletions and missense variants in the MH1 domain. RESULTS: Aortic events were documented in 37% of cases, with dissections accounting for 70% of events. The median age at first aortic event was significantly lower in individuals with SMAD3 MH2 missense variants than those with HI variants (42years vs 49 years; p=0.003), but there was no difference in frequency of aortic events by variant type. The cumulative risk of an aortic event was 50% at 54 years of age. No aortic events in childhood were observed. CONCLUSIONS: SMAD3 pathogenic variants cause thoracic aortic aneurysms and dissections in the majority of individuals with variable age of onset and reduced penetrance. Of the covariates examined, the type of underlying SMAD3 variant was responsible for some of this variation. Later onset of aortic events and the absence of aortic events in children associated with SMAD3 variants support gene-specific management of this disorder.

Assessment of the Information Sources and Interest in Research Collaboration Among Individuals with Vascular Ehlers-Danlos Syndrome.

BACKGROUND: Patient-centered research requires active engagement of patients. The vascular Ehlers-Danlos Syndrome (vEDS) research collaborative was established to ascertain patient-centered vEDS research priorities and to engage affected individuals as research partners. Evaluation of access to information and interest in research among individuals with vEDS was the first step undertaken as part of this work. METHODS: A 28-question survey was created to evaluate 4 domains of interest: diagnostic and clinical care history, vEDS experience, information resources, and willingness to collaborate with researchers. The survey was created in REDCap™ and disseminated between January and April 2018 via the vEDS social media pages, blogs, and advocacy Web sites. Results were collated and described. A single open-ended question yielded additional narrative data, which were analyzed qualitatively. RESULTS: Of the 300 responses, 228 (76%) were completed on behalf of oneself. The vEDS diagnosis was confirmed by genetic testing for 85% of respondents. When asked "Did a physician explain vEDS to you and how to manage it?" 25% answered no. Most had a primary care provider (65%), cardiologist (56%), and vascular surgeon (52%). Only 32% had a local vascular surgeon. The most commonly reported frustration was no cure/treatment available and the emergency rooms do not know what VEDS is (64.5% and 61.8%, respectively). The Internet was the most useful information source (62.3%) followed by a geneticist (18.4%). Most (87.7%) are willing to share their medical records for research studies (87.7%) and wished to be contacted about future studies (83.8%); however, only 65.4% would be willing to upload medical records via a secure confidential Web application. The most common reason for interest in research partnership was to advance research for a treatment/cure (83.8%) and helping others learn from their experiences (82.9%). The qualitative analysis provided additional insights into the patient experience living with vEDS. CONCLUSIONS: Among individuals with vEDS, there is substantial frustration with the lack of treatment, lack of knowledge among health care providers, and a high degree of interest in research involvement. The survey highlights an opportunity to discuss the optimal modality for research participation and methodologies for building trust in the research teams. The methodology lessons learned can also be applied to other rare vascular diseases.

MYLK pathogenic variants aortic disease presentation, pregnancy risk, and characterization of pathogenic missense variants.

PURPOSE: Heritable thoracic aortic disease can result from null variants in MYLK, which encodes myosin light-chain kinase (MLCK). Data on which MYLK missense variants are pathogenic and information to guide aortic disease management are limited. METHODS: Clinical data from 60 cases with MYLK pathogenic variants were analyzed (five null and two missense variants), and the effect of missense variants on kinase activity was assessed. RESULTS: Twenty-three individuals (39%) experienced an aortic event (defined as aneurysm repair or dissection); the majority of these events (87%) were aortic dissections. Aortic diameters were minimally enlarged at the time of dissection in many cases. Time-to-aortic-event curves showed that missense pathogenic variant (PV) carriers have earlier-onset aortic events than null PV carriers. An MYLK missense variant segregated with aortic disease over five generations but decreases MYLK kinase acitivity marginally. Functional Assays fail to identify all pathogenic variants in MYLK. CONCLUSION: These data further define the aortic phenotype associated with MYLK pathogenic variants. Given minimal aortic enlargement before dissection, an alternative approach to guide the timing of aortic repair is proposed based on the probability of a dissection at a given age.

Recessive mutations in VPS13D cause childhood onset movement disorders.

VPS13 protein family members VPS13A through VPS13C have been associated with various recessive movement disorders. We describe the first disease association of rare recessive VPS13D variants including frameshift, missense, and partial duplication mutations with a novel complex, hyperkinetic neurological disorder. The clinical features include developmental delay, a childhood onset movement disorder (chorea, dystonia, or tremor), and progressive spastic ataxia or paraparesis. Characteristic brain magnetic resonance imaging shows basal ganglia or diffuse white matter T2 hyperintensities as seen in Leigh syndrome and choreoacanthocytosis. Muscle biopsy in 1 case showed mitochondrial aggregates and lipidosis, suggesting mitochondrial dysfunction. These findings underline the importance of the VPS13 complex in neurological diseases and a possible role in mitochondrial function. Ann Neurol 2018;83:1089-1095.

Parent Perspectives of Support Received from Physicians and/or Genetic Counselors Following a Decision to Continue a Pregnancy with a Prenatal Diagnosis of Trisomy 13/18.

Families that choose to continue a pregnancy with a prenatal diagnosis of Trisomy 13/18 are a minority that present unique challenges for those in charge of their care. This study investigated the extent to which these patients felt supported by their healthcare providers, and any differences in the perceived level of support experienced by those working with a physician versus those working with a genetic counselor. Two online support groups, SOFT and Hope for Trisomy, distributed an online survey to their members. Means, standard deviations and chi-square analysis were calculated to describe their responses. One-hundred fourteen surveys were included in the final analysis. Respondents were more likely to agree that genetic counselors provided unbiased information in a way that they understood, compared to physicians. Review of qualitative responses found that portrayal of Trisomy 13/18 by healthcare providers used directive language when describing the lethality, morbidity and burden of the condition. Language included terms such as "incompatible with life" and comments on burden to other family members. Healthcare providers can assist families that receive a prenatal diagnosis of Trisomy 13 or 18 by providing up-to-date written resources and connecting them with support groups for parents who have received a similar diagnosis. Our study found that involving genetic counselors in the prenatal care of these patients is likely beneficial.

Cumulative Effect of Racial Discrimination on the Mental Health of Ethnic Minorities in the United Kingdom.

OBJECTIVES: To examine the longitudinal association between cumulative exposure to racial discrimination and changes in the mental health of ethnic minority people. METHODS: We used data from 4 waves (2009-2013) of the UK Household Longitudinal Study, a longitudinal household panel survey of approximately 40 000 households, including an ethnic minority boost sample of approximately 4000 households. RESULTS: Ethnic minority people who reported exposure to racial discrimination at 1 time point had 12-Item Short Form Health Survey (SF-12) mental component scores 1.93 (95% confidence interval [CI] = -3.31, -0.56) points lower than did those who reported no exposure to racial discrimination, whereas those who had been exposed to 2 or more domains of racial discrimination, at 2 different time points, had SF-12 mental component scores 8.26 (95% CI = -13.33, -3.18) points lower than did those who reported no experiences of racial discrimination. Controlling for racial discrimination and other socioeconomic factors reduced ethnic inequalities in mental health. CONCLUSIONS: Cumulative exposure to racial discrimination has incremental negative long-term effects on the mental health of ethnic minority people in the United Kingdom. Studies that examine exposure to racial discrimination at 1 point in time may underestimate the contribution of racism to poor health.

Sexual and general offending trajectories of men referred for civil commitment.

Policies aimed at managing high-risk offenders, which include sex offenders, often assume they are a homogeneous population. These policies also tend to assume the pattern of offending is the same for all sex offenders, and is stable. This study challenges these assumptions by examining the life course offending trajectories of 780 convicted adult male sexual offenders. The men were referred to the Massachusetts Treatment Center for civil commitment between 1959 and 1984. The changing number of both sexual and any offenses were examined by age using Group-Based Trajectory Modeling. We identified a four-trajectory model for all offending and a four-trajectory model for sexual offending. The identified groups varied in several offending patterns including criminal onset, length of criminal careers, age of peak offending, and time of entry into the treatment center. Late adult onset of sex offending was found to be associated with child molestation, whereas early-onset trajectories were associated with rape. Implications for future research and policy are discussed.

Pre-existing Hepatic Encephalopathy: Really a Contraindication to Elective TIPS?

PURPOSE: To evaluate the impact of pre-transjugular intrahepatic portosystemic shunt (TIPS) hepatic encephalopathy (HE) on developing post-TIPS HE. MATERIALS AND METHODS: In this retrospective, single center observational study, all patients who underwent successful TIPS placement between January 2005 and May 2020 with data pertaining to HE in their chart were included. Patient demographics and procedural details were recorded. Clinical outcomes post-TIPS, were collected and compared across patients with and without pre-TIPS HE. RESULTS: Of 326 included patients, 159 (159/326, 48.8%) had a history of pre-TIPS HE. In total those without a history of HE were more likely to develop HE during follow up (136 (136/167, 81.4%) vs 107 (107/159, 67.3%), p = 0.001). When evaluating for predictors of developing HE within 3 months of TIPS placement, no significant variables were found on logistic regression, including prior history of HE (HR 1.16 (95% CI 0.73-1.84), p = 0.529). Univariate and multivariate regression analysis, however, showed that a history of HE was predictive of developing HE at any point in the follow-up period (p = 0.002 and p = 0.008, respectively). However, on Kaplan-Meier analysis no significant difference in the development of HE (p = 0.574) or hospital admission for HE (p = 0.554) post-TIPS was seen between patients with and without pre-TIPS HE. Additionally, there was no difference in 3-month survival (p = 0.412) or overall survival post-TIPS survival (p = 0.798). CONCLUSION: Pre-TIPS HE did not predict the development of HE within 3 months of TIPS. Outcomes such as hospital admission and survivability were not different between patients with and without prior HE.

Living review framework for better policy design and management of hazardous waste in Australia.

The significant increase in hazardous waste generation in Australia has led to the discussion over the incorporation of artificial intelligence into the hazardous waste management system. Recent studies explored the potential applications of artificial intelligence in various processes of managing waste. However, no study has examined the use of text mining in the hazardous waste management sector for the purpose of informing policymakers. This study developed a living review framework which applied supervised text classification and text mining techniques to extract knowledge using the domain literature data between 2022 and 2023. The framework employed statistical classification models trained using iterative training and the best model XGBoost achieved an F1 score of 0.87. Using a small set of 126 manually labelled global articles, XGBoost automatically predicted the labels of 678 Australian articles with high confidence. Then, keyword extraction and unsupervised topic modelling with Latent Dirichlet Allocation (LDA) were performed. Results indicated that there were 2 main research themes in Australian literature: (1) the key waste streams and (2) the resource recovery and recycling of waste. The implication of this framework would benefit the policymakers, researchers, and hazardous waste management organisations by serving as a real time guideline of the current key waste streams and research themes in the literature which allow robust knowledge to be applied to waste management and highlight where the gap in research remains.

Population growth of two limno-terrestrial Antarctic microinvertebrates in different aqueous soil media.

Terrestrial microinvertebrates provide important carbon and nutrient cycling roles in soil environments, particularly in Antarctica where larger macroinvertebrates are absent. The environmental preferences and ecology of rotifers and tardigrades in terrestrial environments, including in Antarctica, are not as well understood as their temperate aquatic counterparts. Developing laboratory cultures is critical to provide adequate numbers of individuals for controlled laboratory experimentation. In this study, we explore aspects of optimising laboratory culturing for two terrestrially sourced Antarctic microinvertebrates, a rotifer (Habrotrocha sp.) and a tardigrade (Acutuncus antarcticus). We tested a soil elutriate and a balanced salt solution (BSS) to determine their suitability as culturing media. Substantial population growth of rotifers and tardigrades was observed in both media, with mean rotifer population size increasing from 5 to 448 ± 95 (soil elutriate) and 274 ± 78 (BSS) individuals over 60 days and mean tardigrade population size increasing from 5 to 187 ± 65 (soil elutriate) and 138 ± 37 (BSS) over 160 days. We also tested for optimal dilution of soil elutriate in rotifer cultures, with 20-80% dilutions producing the largest population growth with the least variation in the 40% dilution after 36 days. Culturing methods developed in this study are recommended for use with Antarctica microinvertebrates and may be suitable for similar limno-terrestrial microinvertebrates from other regions.

Recurrent HERV-H-mediated 3q13.2-q13.31 deletions cause a syndrome of hypotonia and motor, language, and cognitive delays.

We describe the molecular and clinical characterization of nine individuals with recurrent, 3.4-Mb, de novo deletions of 3q13.2-q13.31 detected by chromosomal microarray analysis. All individuals have hypotonia and language and motor delays; they variably express mild to moderate cognitive delays (8/9), abnormal behavior (7/9), and autism spectrum disorders (3/9). Common facial features include downslanting palpebral fissures with epicanthal folds, a slightly bulbous nose, and relative macrocephaly. Twenty-eight genes map to the deleted region, including four strong candidate genes, DRD3, ZBTB20, GAP43, and BOC, with important roles in neural and/or muscular development. Analysis of the breakpoint regions based on array data revealed directly oriented human endogenous retrovirus (HERV-H) elements of ~5 kb in size and of >95% DNA sequence identity flanking the deletion. Subsequent DNA sequencing revealed different deletion breakpoints and suggested nonallelic homologous recombination (NAHR) between HERV-H elements as a mechanism of deletion formation, analogous to HERV-I-flanked and NAHR-mediated AZFa deletions. We propose that similar HERV elements may also mediate other recurrent deletion and duplication events on a genome-wide scale. Observation of rare recurrent chromosomal events such as these deletions helps to further the understanding of mechanisms behind naturally occurring variation in the human genome and its contribution to genetic disease.

Post-Embolization Hemoglobin Changes: When to Consider Re-intervention.

PURPOSE: Decline in hemoglobin (Hgb) levels is common post-embolization, but there is no consensus on the classification of patients based on risk for re-bleeding or re-intervention. The current study evaluated post-embolization Hgb level trends with the goal of understanding the factors predictive of re-bleeding and re-intervention. MATERIALS AND METHODS: All patients who underwent embolization for gastrointestinal (GI), genitourinary, peripheral, or thoracic arterial hemorrhage from 01/2017 to 01/2022 were reviewed. Data included demographics, periprocedural pRBC transfusion (TF) or pressor requirements, and outcome. Lab data consisted of Hgb values pre-embolization, immediately post-embolization, and daily values on days 1-10 after embolization. Hgb trends were compared between patients across TF and re-bleeding outcomes. Regression model was used to examine factors predictive of re-bleeding and magnitude of Hgb reduction post-embolization. RESULTS: A total of 199 patients were embolized for active arterial hemorrhage. Perioperative Hgb level trends were similar for all sites and between TF + and TF- patients, showing a decline reaching a nadir within 6 days post-embolization followed by an upward trend. Maximum Hgb drift was predicted by GI embolization (p = 0.018), TF before embolization (p = 0.001), and use of vasopressor (p = 0.000). Patients with Hgb drop > 15% within the first two days post-embolization had a higher chance of having a re-bleeding episode (p = 0.04). CONCLUSION: Perioperative Hgb trends showed a consistent downward drift followed by an upward shift, irrespective of TF requirement status or site of embolization. Using a cut-off value of 15% Hgb reduction within the first two days post-embolization may be helpful to assess re-bleeding risk.

Multiplexed Biosensing of Proteins and Virions with Disposable Plasmonic Assays.

Our growing ability to tailor healthcare to the needs of individuals has the potential to transform clinical treatment. However, the measurement of multiple biomarkers to inform clinical decisions requires rapid, effective, and affordable diagnostics. Chronic diseases and rapidly evolving pathogens in a larger population have also escalated the need for improved diagnostic capabilities. Current chemical diagnostics are often performed in centralized facilities and are still dependent on multiple steps, molecular labeling, and detailed analysis, causing the result turnaround time to be over hours and days. Rapid diagnostic kits based on lateral flow devices can return results quickly but are only capable of detecting a handful of pathogens or markers. Herein, we present the use of disposable plasmonics with chiroptical nanostructures as a platform for low-cost, label-free optical biosensing with multiplexing and without the need for flow systems often required in current optical biosensors. We showcase the detection of SARS-CoV-2 in complex media as well as an assay for the Norovirus and Zika virus as an early developmental milestone toward high-throughput, single-step diagnostic kits for differential diagnosis of multiple respiratory viruses and any other emerging diagnostic needs. Diagnostics based on this platform, which we term "disposable plasmonics assays," would be suitable for low-cost screening of multiple pathogens or biomarkers in a near-point-of-care setting.

Emerging Targets for the Treatment of Osteoarthritis: New Investigational Methods to Identify Neo-Vessels as Possible Targets for Embolization.

Osteoarthritis (OA) is the major cause of disability, affecting over 30 million US adults. Continued research into the role of neovascularization and inflammation related to osteoarthritis in large-animal models and human clinical trials is paramount. Recent literature on the pathogenetic model of OA has refocused on low-level inflammation, resulting in joint remodeling. As a result, this has redirected osteoarthritis research toward limiting or treating joint changes associated with persistent synovitis. The overall goal of this review is to better understand the cellular and tissue-specific mechanisms of inflammation in relation to a novel OA treatment modality, Genicular Artery Embolization (GAE). This article also assesses the utility and mechanism of periarticular neovascular embolization for the treatment of OA with a particular emphasis on the balance between pro-angiogenic and anti-angiogenic cytokines, inflammatory biomarkers, and imaging changes.

Preliminary investigation of effects of copper on a terrestrial population of the antarctic rotifer Philodina sp.

Terrestrial microinvertebrates in Antarctica are potentially exposed to contaminants due to the concentration of human activity on ice-free areas of the continent. As such, knowledge of the response of Antarctic microinvertebrates to contaminants is important to determine the extent of anthropogenic impacts. Antarctic Philodina sp. were extracted from soils and mosses at Casey station, East Antarctica and exposed to aqueous Cu for 96 h. The Philodina sp. was sensitive to excess Cu, with concentrations of 36 µg L-1 Cu (48 h) and 24 µg L-1 Cu (96 h) inhibiting activity by 50%. This is the first study to be published describing the ecotoxicologically derived sensitivity of a rotifer from a terrestrial population to metals, and an Antarctic rotifer to contaminants. It is also the first study to utilise bdelloid rotifer cryptobiosis (chemobiosis) as a sublethal ecotoxicological endpoint. This preliminary investigation highlights the need for further research into the responses of terrestrial Antarctic microinvertebrates to contaminants.

Biocompatible, Multi-Mode, Fluorescent, T2 MRI Contrast Magnetoelectric-Silica Nanoparticles (MagSiNs), for On-Demand Doxorubicin Delivery to Metastatic Cancer Cells.

There is a need to improve current cancer treatment regimens to reduce systemic toxicity, to positively impact the quality-of-life post-treatment. We hypothesized the negation of off-target toxicity of anthracyclines (e.g., Doxorubicin) by delivering Doxorubicin on magneto-electric silica nanoparticles (Dox-MagSiNs) to cancer cells. Dox-MagSiNs were completely biocompatible with all cell types and are therapeutically inert till the release of Doxorubicin from the MagSiNs at the cancer cells location. The MagSiNs themselves are comprised of biocompatible components with a magnetostrictive cobalt ferrite core (4−6 nm) surrounded by a piezoelectric fused silica shell of 1.5 nm to 2 nm thickness. The MagSiNs possess T2-MRI contrast properties on par with RESOVIST™ due to their cobalt ferrite core. Additionally, the silica shell surrounding the core was volume loaded with green or red fluorophores to fluorescently track the MagSiNs in vitro. This makes the MagSiNs a suitable candidate for trackable, drug nanocarriers. We used metastatic triple-negative breast cancer cells (MDAMB231), ovarian cancer cells (A2780), and prostate cancer cells (PC3) as our model cancer cell lines. Human umbilical vein endothelial cells (HUVEC) were used as control cell lines to represent blood-vessel cells that suffer from the systemic toxicity of Doxorubicin. In the presence of an external magnetic field that is 300× times lower than an MRI field, we successfully nanoporated the cancer cells, then triggered the release of 500 nM of doxorubicin from Dox-MagSiNs to successfully kill >50% PC3, >50% A2780 cells, and killed 125% more MDAMB231 cells than free Dox.HCl. In control HUVECs, the Dox-MagSiNs did not nanoporate into the HUVECS and did not exhibited any cytotoxicity at all when there was no triggered release of Dox.HCl. Currently, the major advantages of our approach are, (i) the MagSiNs are biocompatible in vitro and in vivo; (ii) the label-free nanoporation of Dox-MagSiNs into cancer cells and not the model blood vessel cell line; (iii) the complete cancellation of the cytotoxicity of Doxorubicin in the Dox-MagSiNs form; (iv) the clinical impact of such a nanocarrier will be that it will be possible to increase the current upper limit for cumulative-dosages of anthracyclines through multiple dosing, which in turn will improve the anti-cancer efficacy of anthracyclines.

Genetic aortic disease epidemiology, management principles, and disparities in care.

Patients with syndromic and nonsyndromic heritable aortopathies (also known as genetic aortic disease) are a heterogeneous group of patients who present at younger ages with more rapid growth of aortic aneurysms and/or increased frequency of dissections compared with patients with atherosclerotic aortopathies. In this review, we describe the etiology, epidemiology, and appropriate care delivery for these conditions at each stage of management. Within each section, we discuss sex, gender, and race differences and highlight disparities in care and knowledge. We then discuss the role of the vascular team throughout the cycle of care and the evolving inclusion of patient input in research. This understanding is essential to the creation of effective health care policies that support equitable, appropriate, and patient-centered clinical practices.