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1.
Artículo en Inglés | MEDLINE | ID: mdl-38701341

RESUMEN

BACKGROUND: Single-tier newborn screening (NBS) for CAH using 17-hydroxyprogesterone (17OHP) measured by fluoroimmunoassay (FIA) in samples collected at 24-48 hours produces a high false-positive rate (FPR). 2nd tier steroid testing can reduce the FPR and has been widely implemented. We investigated the accuracy of an alternative multi-tier CAH NBS protocol that incorporates molecular testing of the CYP21A2 gene and reduces the 1st tier 17OHP cutoff to minimize missed cases. METHODS: Created a Minnesota-specific CYP21A2 pathogenic variants panel; develop a rapid, high-throughput multiplex, allele-specific-primer-extension assay; perform 1-year retrospective analysis of Minnesota NBS results comparing metrics between a conventional steroid-based two-tier protocol and a molecular-based multi-tier NBS protocol, applied post-hoc. RESULTS: CYP21A2 gene sequencing of 103 Minnesota families resulted in a Minnesota-specific panel of 21 pathogenic variants. Centers for Disease Control and Prevention (CDC) created a molecular assay with 100% accuracy and reproducibility. Two-tier steroid-based screening of 68,659 live births during 2015 resulted in 2 false negatives (FNs), 91 FPs, and 1 true positive (TP). A three-tier protocol with a lower 1st-tier steroid cutoff, 2nd-tier 21-variant CYP21A2 panel and 3rd-tier CYP21A2 sequencing would have resulted in 0 FNs, 52 FPs and 3 TPs. CONCLUSIONS: Incorporation of molecular testing could improve the accuracy of CAH NBS, although some distinct challenges of molecular testing may need to be considered before implementation by NBS programs.

2.
J Expo Sci Environ Epidemiol ; 34(1): 136-147, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37193773

RESUMEN

BACKGROUND: The number of chemicals present in the environment exceeds the capacity of government bodies to characterize risk. Therefore, data-informed and reproducible processes are needed for identifying chemicals for further assessment. The Minnesota Department of Health (MDH), under its Contaminants of Emerging Concern (CEC) initiative, uses a standardized process to screen potential drinking water contaminants based on toxicity and exposure potential. OBJECTIVE: Recently, MDH partnered with the U.S. Environmental Protection Agency (EPA) Office of Research and Development (ORD) to accelerate the screening process via development of an automated workflow accessing relevant exposure data, including exposure new approach methodologies (NAMs) from ORD's ExpoCast project. METHODS: The workflow incorporated information from 27 data sources related to persistence and fate, release potential, water occurrence, and exposure potential, making use of ORD tools for harmonization of chemical names and identifiers. The workflow also incorporated data and criteria specific to Minnesota and MDH's regulatory authority. The collected data were used to score chemicals using quantitative algorithms developed by MDH. The workflow was applied to 1867 case study chemicals, including 82 chemicals that were previously manually evaluated by MDH. RESULTS: Evaluation of the automated and manual results for these 82 chemicals indicated reasonable agreement between the scores although agreement depended on data availability; automated scores were lower than manual scores for chemicals with fewer available data. Case study chemicals with high exposure scores included disinfection by-products, pharmaceuticals, consumer product chemicals, per- and polyfluoroalkyl substances, pesticides, and metals. Scores were integrated with in vitro bioactivity data to assess the feasibility of using NAMs for further risk prioritization. SIGNIFICANCE: This workflow will allow MDH to accelerate exposure screening and expand the number of chemicals examined, freeing resources for in-depth assessments. The workflow will be useful in screening large libraries of chemicals for candidates for the CEC program.


Asunto(s)
Agua Potable , Humanos , Estados Unidos , Flujo de Trabajo , Algoritmos , Recolección de Datos , Minnesota
3.
Clin Pract Cases Emerg Med ; 7(4): 242-245, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38353193

RESUMEN

Introduction: Mycotic pseudoaneurysms are rare but severe sequelae of an arterial wall infection. If undiagnosed and untreated they can lead to significant morbidity and mortality through complications such as arterial rupture or dissection. Case report: This report details the case of a 64-year-old-male who developed a left common iliac artery mycotic pseudoaneurysm from Proteus mirabilis, which was associated with a prevertebral abscess. The patient presented with isolated, left lower extremity edema and intermittent fevers. The case is unique in both the pathogen (P mirabilis) and in its association with presumed direct arterial wall infection from an adjacent prevertebral abscess. Conclusion: The obscure presentation highlights the need for a high clinical suspicion of such a diagnosis when a patient presents with a certain constellation of symptoms and the right predisposing risk factors in their history.

4.
Front Oncol ; 12: 923043, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35992801

RESUMEN

Iron is a potent catalyst of oxidative stress and cellular proliferation implicated in renal cell carcinoma (RCC) tumorigenesis, yet it also drives ferroptosis that suppresses cancer progression and represents a novel therapeutic target for advanced RCC. The von Hippel Lindau (VHL)/hypoxia-inducible factor-α (HIF-α) axis is a major regulator of cellular iron, and its inactivation underlying most clear cell (cc) RCC tumors introduces both iron dependency and ferroptosis susceptibility. Despite the central role for iron in VHL/HIF-α signaling and ferroptosis, RCC iron levels and their dynamics during RCC initiation/progression are poorly defined. Here, we conducted a large-scale investigation into the incidence and prognostic significance of total tissue iron in ccRCC and non-ccRCC patient primary tumor cancer cells, tumor microenvironment (TME), metastases and non-neoplastic kidneys. Prussian Blue staining was performed to detect non-heme iron accumulation in over 1600 needle-core sections across multiple tissue microarrays. We found that RCC had significantly higher iron staining scores compared with other solid cancers and, on average, >40 times higher than adjacent renal epithelium. RCC cell iron levels correlated positively with TME iron levels and inversely with RCC levels of the main iron uptake protein, transferrin receptor 1 (TfR1/TFRC/CD71). Intriguingly, RCC iron levels, including in the TME, decreased significantly with pathologic (size/stage/grade) progression, sarcomatoid dedifferentiation, and metastasis, particularly among patients with ccRCC, despite increasing TfR1 levels, consistent with an increasingly iron-deficient tumor state. Opposite to tumor iron changes, adjacent renal epithelial iron increased significantly with RCC/ccRCC progression, sarcomatoid dedifferentiation, and metastasis. Lower tumor iron and higher renal epithelial iron each predicted significantly shorter ccRCC patient metastasis-free survival. In conclusion, iron accumulation typifies RCC tumors but declines toward a relative iron-deficient tumor state during progression to metastasis, despite precisely opposite dynamics in adjacent renal epithelium. These findings raise questions regarding the historically presumed selective advantage for high iron during all phases of cancer evolution, suggesting instead distinct tissue-specific roles during RCC carcinogenesis and early tumorigenesis versus later progression. Future study is warranted to determine how the relative iron deficiency of advanced RCC contributes to ferroptosis resistance and/or introduces a heightened susceptibility to iron deprivation that might be therapeutically exploitable.

5.
Acad Emerg Med ; 29(7): 851-861, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35531649

RESUMEN

BACKGROUND: During the COVID-19 pandemic, health care provider well-being was affected by various challenges in the work environment. The purpose of this study was to evaluate the relationship between the perceived work environment and mental well-being of a sample of emergency physicians (EPs), emergency medicine (EM) nurses, and emergency medical services (EMS) providers during the pandemic. METHODS: We surveyed attending EPs, resident EPs, EM nurses, and EMS providers from 10 academic sites across the United States. We used latent class analysis (LCA) to estimate the effect of the perceived work environment on screening positive for depression/anxiety and burnout controlling for respondent characteristics. We tested possible predictors in the multivariate regression models and included the predictors that were significant in the final model. RESULTS: Our final sample included 701 emergency health care workers. Almost 23% of respondents screened positive for depression/anxiety and 39.7% for burnout. Nurses were significantly more likely to screen positive for depression/anxiety (adjusted odds ratio [aOR] 2.04, 95% confidence interval [CI] 1.11-3.86) and burnout (aOR 2.05, 95% CI 1.22-3.49) compared to attendings. The LCA analysis identified four subgroups of our respondents that differed in their responses to the work environment questions. These groups were identified as Work Environment Risk Group 1, an overall good work environment; Risk Group 2, inadequate resources; Risk Group 3, lack of perceived organizational support; and Risk Group 4, an overall poor work environment. Participants in the two groups who perceived their work conditions as most adverse were significantly more likely to screen positive for depression/anxiety (aOR 1.89, 95% CI 1.05-3.42; and aOR 2.04, 95% CI 1.14-3.66) compared to participants working in environments perceived as less adverse. CONCLUSIONS: We found a strong association between a perceived adverse working environment and poor mental health, particularly when organizational support was deemed inadequate. Targeted strategies to promote better perceptions of the workplace are needed.


Asunto(s)
Agotamiento Profesional , COVID-19 , Agotamiento Profesional/epidemiología , Agotamiento Profesional/psicología , COVID-19/epidemiología , Depresión/diagnóstico , Depresión/epidemiología , Personal de Salud , Humanos , Pandemias , Encuestas y Cuestionarios , Estados Unidos/epidemiología , Lugar de Trabajo
6.
Acad Emerg Med ; 29(8): 974-986, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35332615

RESUMEN

BACKGROUND: During the COVID-19 pandemic, a substantial number of emergency health care workers (HCWs) have screened positive for anxiety, depression, risk of posttraumatic stress disorder, and burnout. The purpose of this qualitative study was to describe the impact of COVID-19 on emergency care providers' health and well-being using personal perspectives. We conducted in-depth interviews with emergency physicians, emergency medicine nurses, and emergency medical services providers at 10 collaborating sites across the United States between September 21, 2020, and October 26, 2020. METHODS: We developed a conceptual framework that described the relationship between the work environment and employee health. We used qualitative content analysis to evaluate our interview transcripts classified the domains, themes, and subthemes that emerged from the transcribed interviews. RESULTS: We interviewed 32 emergency HCWs. They described difficult working conditions, such as constrained physical space, inadequate personnel protective equipment, and care protocols that kept changing. Organizational leadership was largely viewed as unprepared, distant, and unsupportive of employees. Providers expressed high moral distress caused by ethically challenging situations, such as the perception of not being able to provide the normal standard of care and emotional support to patients and their families at all times, being responsible for too many sick patients, relying on inexperienced staff to treat infected patients, and caring for patients that put their own health and the health of their families at risk. Moral distress was commonly experienced by emergency HCWs, exacerbated by an unsupportive organizational environment. CONCLUSIONS: Future preparedness efforts should include mechanisms to support frontline HCWs when faced with ethical challenges in addition to an adverse working environment caused by a pandemic such as COVID-19.


Asunto(s)
Agotamiento Profesional , COVID-19 , Agotamiento Profesional/epidemiología , Agotamiento Profesional/prevención & control , Agotamiento Profesional/psicología , Personal de Salud , Humanos , Pandemias , Estados Unidos/epidemiología , Lugar de Trabajo
7.
Clin Transl Immunology ; 10(2): e1246, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33552509

RESUMEN

OBJECTIVES: With a rapidly growing list of candidate immune-based cancer therapeutics, there is a critical need to generate highly reliable animal models to preclinically evaluate the efficacy of emerging immune-based therapies, facilitating successful clinical translation. Our aim was to design and validate a novel in vivo model (called Xenomimetic or 'X' mouse) that allows monitoring of the ability of human tumor-specific T cells to suppress tumor growth following their entry into the tumor. METHODS: Tumor xenografts are established rapidly in the greater omentum of globally immunodeficient NOD-scid IL2Rγnull (NSG) mice following an intraperitoneal injection of melanoma target cells expressing tumor neoantigen peptides, as well as green fluorescent protein and/or luciferase. Changes in tumor burden, as well as in the number and phenotype of adoptively transferred patient-derived tumor neoantigen-specific T cells in response to immunotherapy, are measured by imaging to detect fluorescence/luminescence and flow cytometry, respectively. RESULTS: The tumors progress rapidly and disseminate in the mice unless patient-derived tumor-specific T cells are introduced. An initial T cell-mediated tumor arrest is later followed by a tumor escape, which correlates with the upregulation of the checkpoint molecules programmed cell death-1 (PD-1) and lymphocyte-activation gene 3 (LAG3) on T cells. Treatment with immune-based therapies that target these checkpoints, such as anti-PD-1 antibody (nivolumab) or interleukin-12 (IL-12), prevented or delayed the tumor escape. Furthermore, IL-12 treatment suppressed PD-1 and LAG3 upregulation on T cells. CONCLUSION: Together, these results validate the X-mouse model and establish its potential to preclinically evaluate the therapeutic efficacy of immune-based therapies.

8.
Acad Emerg Med ; 28(6): 666-674, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33368833

RESUMEN

BACKGROUND: Social determinants of health (SDoH) have significant implications for health outcomes in the United States. Emergency departments (EDs) function as the safety nets of the American health care system, caring for many vulnerable populations. ED-based interventions to assess social risk and mitigate social needs have been reported in the literature. However, the breadth and scope of these interventions have not been evaluated. As the field of social emergency medicine (SEM) expands, a mapping and categorization of previous interventions may help shape future research. We sought to identify, summarize, and characterize ED-based interventions aimed at mitigating negative SDoH. METHODS: We conducted a scoping review to identify and characterize peer-reviewed research articles that report ED-based interventions to address or impact SDoH in the United States. We designed and conducted a search in Medline, CINAHL, and Cochrane CENTRAL databases. Abstracts and, subsequently, full articles were reviewed independently by two reviewers to identify potentially relevant articles. Included articles were categorized by type of intervention and primary SDoH domain. Reported outcomes were also categorized by type and efficacy. RESULTS: A total of 10,856 abstracts were identified and reviewed, and 596 potentially relevant studies were identified. Full article review identified 135 articles for inclusion. These articles were further subdivided into three intervention types: a) provider educational intervention (18%), b) disease modification with SDoH focus (26%), and c) direct SDoH intervention (60%), with 4% including two "types." Articles were subsequently further grouped into seven SDoH domains: 1) access to care (33%), 2) discrimination/group disparities (7%), 3) exposure to violence/crime (34%), 4) food insecurity (2%), 5) housing issues/homelessness (3%), 6) language/literacy/health literacy (12%), 7) socioeconomic disparities/poverty (10%). The majority of articles reported that the intervention studied was effective for the primary outcome identified (78%). CONCLUSION: Emergency department-based interventions that address seven different SDoH domains have been reported in the peer-reviewed literature over the past 30 years, utilizing a variety of approaches including provider education and direct and indirect focus on social risk and need. Characterization and understanding of previous interventions may help identify opportunities for future interventions as well as guide a SEM research agenda.


Asunto(s)
Pobreza , Determinantes Sociales de la Salud , Escolaridad , Servicio de Urgencia en Hospital , Humanos , Estados Unidos , Poblaciones Vulnerables
9.
Ultrasound J ; 12(1): 53, 2020 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-33284368

RESUMEN

BACKGROUND: Many point-of-care ultrasound devices are now "pocket-sized" or handheld, allowing easy transport during travel and facilitating use in crowded spaces or in austere low-resource settings. Concerns remain about their durability, image quality, and clinical utility in those environments. METHOD: Five emergency physicians with training in point-of-care ultrasound employed the Butterfly iQ, a novel handheld ultrasound device, in routine clinical care in a busy, high-acuity African emergency department over a period of 10 weeks. We retrospectively evaluated the performance of the Butterfly iQ from the perspectives of both the clinicians using the device and expert ultrasound faculty reviewing the images. RESULTS: We found advantages of the Butterfly iQ in a high-acuity African emergency department include its use of a single probe for multiple functions, small size, ease of transport, relatively low cost, and good image quality in most functions. Disadvantages include large probe footprint, lower, though still adequate, cardiac imaging quality, frequent overheating, and reliance on internet-based cloud storage, but these were surmountable. We also report a wide variety of patient presentations, pathology, and procedures to which the device was used. CONCLUSION: We conclude the Butterfly iQ is an effective, though imperfect, point-of-care ultrasound device in a low-resource emergency setting. We will continue to employ the device in clinical emergency care and teaching in this setting.

10.
J Am Coll Emerg Physicians Open ; 1(3): 231-237, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32838367

RESUMEN

The COVID-19 outbreak has disrupted global health care networks and caused thousands of deaths and an international economic downturn. Multiple drugs are being used on patients with COVID-19 based on theoretical and in vitro therapeutic targets. Several of these therapies have been studied, but many have limited evidence behind their use, and clinical trials to evaluate their efficacy are either ongoing or have not yet begun. This review summarizes the existing evidence for medications currently under investigation for treatment of COVID-19, including remdesivir, chloroquine/hydroxychlorquine, convalescent plasma, lopinavir/ritonavir, IL-6 inhibitors, corticosteroids, and angiotensin-converting enzyme inhibitors.

11.
J Am Coll Emerg Physicians Open ; 1(6): 1374-1379, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32838392

RESUMEN

The novel coronavirus disease 2019 (COVID-19) pandemic, with its public health implications, high case fatality rate, and strain on hospital resources, will continue to challenge clinicians and researchers alike for months to come. Accurate triage of patients during the pandemic will assign patients to the appropriate level of care, provide the best care for the maximum number of patients, rationally limit personal protective equipment (PPE) usage, and mitigate nosocomial exposures. The authors describe an adapted COVID-19 pandemic triage algorithm for emergency departments (EDs) guided by the best available evidence and responses to prior pandemics, with recommendations for clinician PPE use for each level of encounter in the setting of an ongoing PPE shortage. Our algorithm adheres to Centers for Disease Control and Prevention guidelines and supports discharge of patients with mild symptoms coupled with explicit and strict return precautions and infection control education.

12.
J Am Coll Emerg Physicians Open ; 1(2): 70-77, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32427157

RESUMEN

On December 31, 2019, the Chinese government announced an outbreak of a novel coronavirus, recently named COVID-19. During the following weeks the international medical community has witnessed with unprecedented coverage the public health response both domestically by the Chinese government, and on an international scale as cases have spread to dozens of countries. While much regarding the virus and the Chinese public health response is still unknown, national and public health institutions globally are preparing for a pandemic. As cases and spread of the virus grow, emergency and other front-line providers may become more anxious about the possibility of encountering a potential case. This review describes the tenets of a public health response to an infectious outbreak by using recent historical examples and also by characterizing what is known about the ongoing response to the COVID-19 outbreak. The intent of the review is to empower the practitioner to monitor and evaluate the local, national and global public health response to an emerging infectious disease.

13.
Ultrasound J ; 12(1): 14, 2020 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-32193724

RESUMEN

BACKGROUND: The role of point-of-care ultrasonography (POCUS) is rapidly expanding in both resource-rich and resource-limited settings (RLS). One limitation to this rapid expansion has been the lack of educators adequately trained to teach this user-dependent skill. This is particularly true in RLS, where disease presentations, infrastructure limitations, and approach to medical education present unique challenges to the direct application of resource-rich emergency department POCUS curricula. OBJECTIVES: We describe the point-of-care ultrasound in resource-limited settings (PURLS) fellowship, a novel curriculum designed to provide advanced training and expertise in clinical care and POCUS application and education in RLS. CONCLUSION: Our curriculum design is one approach to create context-specific POCUS education for use in RLS, thereby improving patient care.

14.
J Expo Sci Environ Epidemiol ; 30(2): 395, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31767926

RESUMEN

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

15.
Emerg Med Pract ; 21(9): 1-16, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31461612

RESUMEN

When medical emergencies arise in flight, commercial airline flight crews may ask for help from onboard medical professionals. Qualified, active, licensed, and sober providers should volunteer to assist in the event of a medical emergency rather than decline out of fear of medicolegal reprisal. An understanding of the typically available resources, the hierarchy of authority, and medicolegal precedents can help providers feel confident in responding to these situations. This review addresses the pathophysiology related to air travel and common causes of in-flight medical emergencies and discusses the medications and equipment commonly stocked by commercial airlines. In addition, the complexity of flight diversion and the medicolegal concerns surrounding volunteering to provide medical care are addressed.


Asunto(s)
Medicina Aeroespacial/métodos , Viaje en Avión , Servicios Médicos de Urgencia/métodos , Medicina Aeroespacial/tendencias , Servicios Médicos de Urgencia/estadística & datos numéricos , Humanos
16.
J Expo Sci Environ Epidemiol ; 29(6): 863, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31186498

RESUMEN

A correction to this paper has been published and can be accessed via a link at the top of the paper.

17.
J Expo Sci Environ Epidemiol ; 29(2): 183-195, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30631142

RESUMEN

Minnesota has been grappling with extensive per- and polyfluoroalkyl substances (PFASs) groundwater contamination since 2002, in a major metropolitan setting. As toxicological information has accumulated for these substances, the public health community has become increasingly aware of critically sensitive populations. The accumulation of some PFAS in women of childbearing age, and the placental and breastmilk transfer to their offspring, require new risk assessment methods to protect public health. The traditional water guidance paradigm is inadequate to address maternal-to-infant transfer of accumulated levels of perfluorooctanoate (PFOA), in particular. Even short exposures during infancy have dramatic impacts on serum levels for many years. In addition, developmental effects are the critical effects anchoring recent risk assessments. In response, the Minnesota Department of Health created an Excel-based model that incorporates chemical-specific properties and exposure parameters for early life stages. Serum levels were assessed in both formula-fed and breastfed infants, with placental transfer in both scenarios. Peak breastfed infant serum levels were 4.4-fold higher than in formula-fed infants, with both of these scenarios producing serum levels in excess of the adult steady-state level. The development and application of this model to PFOA are described.


Asunto(s)
Caprilatos/análisis , Agua Potable/química , Exposición a Riesgos Ambientales/análisis , Fluorocarburos/análisis , Contaminantes Químicos del Agua/análisis , Adulto , Femenino , Agua Subterránea , Humanos , Lactante , Minnesota , Embarazo , Toxicocinética , Adulto Joven
18.
Free Radic Biol Med ; 133: 295-309, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30553971

RESUMEN

Increasing data implicate iron accumulation in tumorigenesis of the kidney, particularly the clear cell renal cell carcinoma (ccRCC) subtype. The von Hippel Lindau (VHL)/hypoxia inducible factor-α (HIF-α) axis is uniquely dysregulated in ccRCC and is a major regulator and regulatory target of iron metabolism, yet the role of iron in ccRCC tumorigenesis and its potential interplay with VHL inactivation remains unclear. We investigated whether ccRCC iron accumulation occurs due to increased cell dependency on iron for growth and survival as a result of VHL inactivation. Free iron levels were compared between four VHL-mutant ccRCC cell lines (786-0, A704, 769-P, RCC4) and two benign renal tubule epithelial cell lines (RPTEC, HRCEp) using the Phen Green SK fluorescent iron stain. Intracellular iron deprivation was achieved using two clinical iron chelator drugs, deferasirox (DFX) and deferoxamine (DFO), and chelator effects were measured on cell line growth, cell cycle phase, apoptosis, HIF-1α and HIF-2α protein levels and HIF-α transcriptional activity based on expression of target genes CA9, OCT4/POU5F1 and PDGFß/PDGFB. Similar assays were performed in VHL-mutant ccRCC cells with and without ectopic wild-type VHL expression. Baseline free iron levels were significantly higher in ccRCC cell lines than benign renal cell lines. DFX depleted cellular free iron more rapidly than DFO and led to greater growth suppression of ccRCC cell lines (>90% at ~30-150 µM) than benign renal cell lines (~10-50% at up to 250 µM). Similar growth responses were observed using DFO, with the exception that a prolonged treatment duration was necessary to deplete cellular iron adequately for differential growth suppression of the less susceptible A704 ccRCC cell line relative to benign renal cell lines. Apoptosis and G1-phase cell cycle arrest were identified as potential mechanisms of chelator growth suppression based on their induction in ccRCC cell lines but not benign renal cell lines. Iron chelation in ccRCC cells but not benign renal cells suppressed HIF-1α and HIF-2α protein levels and transcriptional activity, and the degree and timing of HIF-2α suppression correlated with the onset of apoptosis. Restoration of wild-type VHL function in ccRCC cells was sufficient to prevent chelator-induced apoptosis and G1 cell cycle arrest, indicating that ccRCC susceptibility to iron deprivation is VHL inactivation-dependent. In conclusion, ccRCC cells are characterized by high free iron levels and a cancer-specific dependency on iron for HIF-α overexpression, cell cycle progression and apoptotic escape. This iron dependency is introduced by VHL inactivation, revealing a novel interplay between VHL/HIF-α dysregulation and ccRCC iron metabolism. Future study is warranted to determine if iron deprivation using chelator drugs provides an effective therapeutic strategy for targeting HIF-2α and suppressing tumor progression in ccRCC patients.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Carcinoma de Células Renales/tratamiento farmacológico , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Hierro/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Apoptosis/efectos de los fármacos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Quelantes del Hierro/farmacología
19.
Int J Mol Sci ; 20(1)2018 Dec 26.
Artículo en Inglés | MEDLINE | ID: mdl-30587795

RESUMEN

Triple negative breast cancer (TNBC) remains a serious health problem with poor prognosis and limited therapeutic options. To discover novel approaches to treat TNBC, we screened cholera toxin (CT) and the members of the bacterial type II heat-labile enterotoxin family (LT-IIa, LT-IIb, and LT-IIc) for cytotoxicity in TNBC cells. Only LT-IIc significantly reduced viability of the TNBC cell lines BT549 and MDA-MB-231 (IC50 = 82.32 nM). LT-IIc had no significant cytotoxic effect on MCF10A (IC50 = 2600 nM), a non-tumorigenic breast epithelial cell line, and minimal effects on MCF7 and T47D, ER⁺ cells, or SKBR-3 cells, HER2⁺ cells. LT-IIc stimulated autophagy through inhibition of the mTOR pathway, while simultaneously inhibiting autophagic progression, as seen by accumulation of LC3B-II and p62. Morphologically, LT-IIc induced the formation of enlarged LAMP2+ autolysosomes, which was blocked by co-treatment with bafilomycin A1. LT-IIc induced apoptosis as demonstrated by the increase in caspase 3/7 activity and Annexin V staining. Co-treatment with necrostatin-1, however, demonstrated that the lethal response of LT-IIc is elicited, in part, by concomitant induction of necroptosis. Knockdown of ATG-5 failed to rescue LT-IIc-induced cytotoxicity, suggesting LT-IIc can exert its cytotoxic effects downstream or independently of autophagophore initiation. Collectively, these experiments demonstrate that LT-IIc acts bifunctionally, inducing autophagy, while simultaneously blocking autolysosomal progression in TNBC cells, inducing a specific cytotoxicity in this breast cancer subtype.


Asunto(s)
Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Enterotoxinas/toxicidad , Proteína 5 Relacionada con la Autofagia/antagonistas & inhibidores , Proteína 5 Relacionada con la Autofagia/genética , Proteína 5 Relacionada con la Autofagia/metabolismo , Caspasa 3/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Calor , Humanos , Imidazoles/metabolismo , Indoles/metabolismo , Lisosomas/metabolismo , Necrosis , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Proteínas de Unión al ARN/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología
20.
J Environ Manage ; 208: 24-35, 2018 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-29247882

RESUMEN

Urban tree canopy provides a suite of ecological, social, and economic benefits to the residents of urban areas. With an expanding recognition of these benefits among city residents, there is growing concern that access to these benefits is not distributed equally and may represent the presence of an environmental injustice. This study examines the spatial relationship between median household income and tree canopy variables, specifically realized tree canopy cover and potential tree canopy cover, for Toronto, Canada. Toronto provides a strong empirical focus as it is a densely populated urban setting reported to be exhibiting an increase in the geographic polarization of residents based upon household income. Spatial relationships between median household income and tree canopy variables are evaluated using the bivariate Moran's I statistic, a specialized local indicator of spatial autocorrelation (LISA). This method explicitly identified where statistically significant spatial clusters of high and low household income coincide with significant clusters of high and low urban tree canopy, providing the basis for an examination of the policies and management decisions that led to this temporal snapshot. The importance of these spatial clusters is examined from the perspective of understanding the impact of urban change (both socio-demographic and built form), and from the standpoint of improving equality of access to city trees and their benefits resulting from future tree planting decisions.


Asunto(s)
Ciudades , Ecología , Árboles , Canadá , Demografía
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