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1.
J Med Imaging Radiat Oncol ; 68(2): 141-149, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38146085

RESUMO

INTRODUCTION: To compare diagnostic accuracy of contrast-enhanced mammography (CEM) with standard 2D digital mammography (equivalent to low-energy image; LEM) for detection of multifocal and multicentric breast cancer and evaluation of tumour size and disease extent for preoperative planning. METHODS: Biopsy proven breast cancer patients who underwent CEM preoperatively between January 2021 and January 2023 were included in this study. CEM and LEM images were independently reviewed by at least two blinded readers. Lesion location, number, size (maximal diameter) and extension across the midline and/or nipple invasion were recorded. Tumour number and size estimated on imaging were compared with final operative histology, which served as the gold standard. RESULTS: Forty-nine patients (48 females and 1 male) and 50 cases (one patient had bilateral breast lesions) were included in the analysis. Median patient age was 60 (IQR 51, 69). CEM had significantly higher lesion detection rate compared with LEM, with sensitivities of 78% for LEM and 92% for CEM for the index tumour and 15% for LEM and 100% for CEM for multicentric and multifocal cancer. We found no statistically significant difference in median tumour size measurements on CEM and final surgical specimen (P value = 0.97); however, a significant difference was identified in the tumour size measured on LEM and surgical specimen (P value < 0.001). CONCLUSION: CEM is superior to standard 2D digital mammography for detection of multifocal and multicentric breast cancer and is a reliable and more accurate method for estimating tumour size.


Assuntos
Neoplasias da Mama , Feminino , Humanos , Masculino , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/cirurgia , Mamografia/métodos , Mama/patologia , Meios de Contraste , Imageamento por Ressonância Magnética
2.
Front Cell Infect Microbiol ; 13: 1292768, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38053529

RESUMO

Human infection caused by bacteria of the Edwardsiella genus is rare and most often presents with gastroenteritis that rarely requires antibiotics. Our case report describes a medically complex patient with chronic steroid use contributing to an immunocompromised state, who presented with fever and abdominal pain. The patient was later found to have Edwardsiella tarda (E. tarda) bacteremia and underwent paracentesis confirming E. tarda bacterial peritonitis requiring a prolonged antibiotic course. This case report aims to illustrate the presentation, diagnosis, and management of an uncommon infection that can have severe complications especially among immunocompromised patients.


Assuntos
Bacteriemia , Infecções por Enterobacteriaceae , Humanos , Edwardsiella tarda , Infecções por Enterobacteriaceae/diagnóstico , Infecções por Enterobacteriaceae/tratamento farmacológico , Antibacterianos/uso terapêutico , Bacteriemia/diagnóstico , Bacteriemia/tratamento farmacológico , Hospedeiro Imunocomprometido
3.
J Surg Case Rep ; 2023(2): rjad060, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36846838

RESUMO

Metastatic colorectal cancer has poor prognosis for many patients at time of diagnosis with <20% 5-year survival rate. Recent advancements in palliative chemotherapy have improved patient outcomes as median survival has increased almost 2-fold. We report a 44-year-old gentleman who initially underwent palliative chemoradiotherapy and subsequently a Hartmann's procedure for ypT3N1M1 upper rectal adenocarcinoma with multiple liver metastases. Fortuitously, he made a remarkable recovery with complete radiological resolution of liver metastasis post-operatively. The patient has remained in remission for the past 10 years.

4.
Acad Pediatr ; 23(4): 755-761, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36516957

RESUMO

OBJECTIVE: Examine social media experiences of the suicidal adolescent presenting to the emergency department with an acute mental health crisis. METHODS: We used qualitative interviews to obtain in-depth understanding of both negative and positive impacts of social media use on acute adolescent suicidal behavior. A bilingual transcriptionist transcribed audio recordings. Three investigators independently reviewed transcripts to identify themes and develop initial coding scheme through "open coding." Using grounded theory, data collection proceeded along with cultivation of themes until thematic saturation was achieved. Thematic saturation was determined when no new themes were generated from the data. Data were coded in Dedoose software to facilitate reporting of themes and quotes. Techniques to ensure trustworthiness included iterative data collection, use of a coding framework, and multiple coders. RESULTS: Seventeen interviews were conducted from May to October 2020. Median participant age was 15 years. Twenty-four percent were of Hispanic ethnicity and 82% identified as cisgender. Major themes include distraction from negative emotions; facilitated communication resulting in improved social connectedness; metric of connectedness; comparison of self to others; and desensitization and normalization to suicidal acts. Minor theme of increased time on social media is also discussed. These themes echoed components of current suicide theory. CONCLUSIONS: Acutely suicidal adolescents report social media experiences that reflect themes of social alienation and learned capacity for suicidal acts. Themes echo components of current suicide theory. Our participants also reported positive uses of social media. These protective experiences should be leveraged to inform strategies to interrupt behaviors leading to acute suicidality.


Assuntos
Comportamento do Adolescente , Mídias Sociais , Suicídio , Humanos , Adolescente , Ideação Suicida , Suicídio/psicologia , Comportamento do Adolescente/psicologia
5.
Acad Pediatr ; 23(2): 448-456, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-35940570

RESUMO

OBJECTIVE: To identify locations with higher need for acute pediatric mental health (MH) interventions or services and describe these communities' socio-demographic characteristics. METHODS: This single-center retrospective study included patients 5 to 18 years old with an emergency department (ED) or hospital admission between 2017 and 2019 for a primary known MH diagnosis or symptoms. We extracted visit data from the electronic medical record, mapped patients to their home census tract, calculated normalized visit rates by census tract, and performed spatial analysis to identify nonrandom geographic clusters and outliers of high utilization. Census tract utilization rates were stratified into quartiles, and socioeconomic and demographic characteristics obtained from the US Census Bureau were compared using analysis of variance, chi-square tests, and multivariable analysis. RESULTS: There were 10,866 qualifying visits across 617 census tracts. ED and hospital admission rates ranged from 2.7 to 428.6 per 1000 children. High utilization clusters localized to neighborhoods with lower socioeconomic status (p < .05). Southern regions with high utilizers were more likely to have fewer children per neighborhood, higher rates of teen births, and lower socioeconomic status. Multivariate analysis showed regions with high utilizers had fewer children per neighborhood, lower median household income, and more families that lacked computer access. CONCLUSION: ED and hospital utilization for pediatric MH concerns varied significantly by neighborhood and demographics. Divergent social factors map onto these locations and are related to MH utilization. Leveraging geography can be a powerful tool in the development of targeted, culturally tailored interventions to decrease acute pediatric MH utilization and advance child MH equity.


Assuntos
Hospitalização , Saúde Mental , Adolescente , Criança , Humanos , Pré-Escolar , Estudos Retrospectivos , Serviço Hospitalar de Emergência , Renda
6.
Geohealth ; 6(9): e2022GH000637, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36545248

RESUMO

Lower respiratory tract infections disproportionately affect children and are one of the main causes of hospital referral and admission. COVID-19 stay-at-home orders in early 2020 led to substantial reductions in hospital admissions, but the specific contribution of changes in air quality through this natural experiment has not been examined. Capitalizing on the timing of the stay-at-home order, we quantified the specific contribution of fine-scale changes in PM2.5 concentrations to reduced respiratory emergency department (ED) visits in the pediatric population of San Diego County, California. We analyzed data on pediatric ED visits (n = 72,333) at the ZIP-code level for respiratory complaints obtained from the ED at Rady Children's Hospital in San Diego County (2015-2020) and ZIP-code level PM2.5 from an ensemble model integrating multiple machine learning algorithms. We examined the decrease in respiratory visits in the pediatric population attributable to the stay-at-home order and quantified the contribution of changes in PM2.5 exposure using mediation analysis (inverse of odds ratio weighting). Pediatric respiratory ED visits dropped during the stay-at-home order (starting on 19 March 2020). Immediately after this period, PM2.5 concentrations, relative to the counterfactual values based in the 4-year baseline period, also decreased with important spatial variability across ZIP codes in San Diego County. Overall, we found that decreases in PM2.5 attributed to the stay-at-home order contributed to explain 4% of the decrease in pediatric respiratory ED visits. We identified important spatial inequalities in the decreased incidence of pediatric respiratory illness and found that brief decline in air pollution levels contributed to a decrease in respiratory ED visits.

7.
BMC Pediatr ; 22(1): 655, 2022 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-36357876

RESUMO

BACKGROUND: The Centers for Disease Control and Prevention and the American Academy of Pediatrics recommend that symptomatic children remain home and get tested to identify potential coronavirus disease 2019 (COVID-19) cases. As the pandemic moves into a new phase, approaches to differentiate symptoms of COVID-19 versus other childhood infections can inform exclusion policies and potentially prevent future unnecessary missed school days. METHODS: Retrospective analysis of standardized symptom and exposure screens in symptomatic children 0-18 years tested for SARS-CoV-2 at three outpatient sites April to November 2020. Likelihood ratios (LR), number needed to screen to identify one COVID-19 case, and estimated missed school days were calculated. RESULTS: Of children studied (N = 2,167), 88.9% tested negative. Self-reported exposure to COVID-19 was the only factor that statistically significantly increased the likelihood of a positive test for all ages (Positive LR, 5-18 year olds: 5.26, 95% confidence interval (CI): 4.37-6.33; 0-4 year olds: 5.87, 95% CI: 4.67-7.38). Across ages 0-18, nasal congestion/rhinorrhea, sore throat, abdominal pain, and nausea/vomiting/diarrhea were commonly reported, and were either not associated or had decreased association with testing positive for COVID-19. The number of school days missed to identify one case of COVID-19 ranged from 19 to 48 across those common symptoms. CONCLUSIONS: We present an approach for identifying symptoms that are non-specific to COVID-19, for which exclusion would likely lead to limited impact on school safety but contribute to school-days missed. As variants and symptoms evolve, students and schools could benefit from reconsideration of exclusion and testing policies for non-specific symptoms, while maintaining testing for those who were exposed.


Assuntos
COVID-19 , Criança , Humanos , Estados Unidos/epidemiologia , Pré-Escolar , Recém-Nascido , Lactente , Adolescente , COVID-19/diagnóstico , SARS-CoV-2 , Estudos Retrospectivos , Pandemias/prevenção & controle , Teste para COVID-19
8.
Pediatr Emerg Care ; 38(10): 526-531, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-35507378

RESUMO

OBJECTIVE: This study aimed to identify motivating factors in why parents administer imported medications to their children. METHODS: In this qualitative study, we enrolled caregivers of patients younger than 18 years who presented for care at a pediatric emergency department. The study team conducted face-to-face interviews with caregivers in the emergency department and used a semistructured question guide to probe for themes regarding the use of imported medications in children. Interviews were recorded, transcribed, translated if necessary, and coded. We applied grounded theory methodology to assess for themes and adapted the Andersen model of health care utilization to provide a framework for the identified themes. RESULTS: We completed 30 interviews, 9 of which were conducted in Spanish. Themes surrounding imported medication usage were categorized into predisposing, enabling, and need factors. Predisposing factors included perception that an ill child needs medication to get better, perception of medication quality, and past experiences with medications. Enabling factors included proximity to foreign countries, cost, limited access to primary care, and convenience of obtaining medications. Need factors included utilization of foreign medications for a "simple illness" and utilization of foreign care for a "second opinion." CONCLUSIONS: Our study used qualitative methodology to gain important insights into the caregiver experience of a diverse patient population. We identify themes not previously published in the medication importation literature. These concepts can provide insights in educational strategies aimed at mitigating the potential dangers of imported medication use in pediatrics.


Assuntos
Cuidadores , Serviço Hospitalar de Emergência , Criança , Atenção à Saúde , Humanos , Pais , Pesquisa Qualitativa
9.
Pediatr Emerg Care ; 38(1): e23-e26, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32925704

RESUMO

OBJECTIVE: The infant lumbar puncture (LP) can be a technically challenging procedure. Understanding the anatomical lumbar dimensions may optimize LP conditions. Data from preterm neonates, older children, and adults indicate measurements of the lumbar spine in the seated LP position may be superior when compared with the lateral position. We use point-of-care ultrasound (US) to determine if the seated position, when compared with the lateral decubitus position, significantly affected the lumbar dimensions of infants 12 months or younger presenting to the pediatric emergency department. METHODS: We conducted a prospective observational study of a convenience sample of patients 12 months or younger. We used US to obtain 3 still images oriented longitudinally in the midline over the L3 to L4 interspace in the lateral decubitus and seated positions. A US fellowship-trained emergency physician, blinded to patient position, measured interspinous space, subarachnoid space width, and spinal canal depth. We then compared the means of all 3 dimensions in the lateral and seated positions. RESULTS: From 50 subjects, 49 subjects provided 46 evaluable sets of images for each measure. Interspinous space, spinal canal depth, and subarachnoid space width did not differ significantly between positions. Mean differences did not exceed 0.02 cm for any of the measured dimensions. We report no significant differences in the 3 lumbar dimensions at the seated position when compared with the lateral decubitus position. CONCLUSIONS: For infants younger than 12 months, sonographic measurements of lumbar dimensions did not differ between the positions commonly used for LP.


Assuntos
Região Lombossacral , Postura Sentada , Adolescente , Adulto , Criança , Humanos , Lactente , Recém-Nascido , Vértebras Lombares/diagnóstico por imagem , Região Lombossacral/diagnóstico por imagem , Punção Espinal , Ultrassonografia
10.
Cancer Immunol Res ; 9(12): 1451-1464, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34635485

RESUMO

Immune-checkpoint blockade has revolutionized cancer treatment. However, most patients do not respond to single-agent therapy. Combining checkpoint inhibitors with other immune-stimulating agents increases both efficacy and toxicity due to systemic T-cell activation. Protease-activatable antibody prodrugs, known as Probody therapeutics (Pb-Tx), localize antibody activity by attenuating capacity to bind antigen until protease activation in the tumor microenvironment. Herein, we show that systemic administration of anti-programmed cell death ligand 1 (anti-PD-L1) and anti-programmed cell death protein 1 (anti-PD-1) Pb-Tx to tumor-bearing mice elicited antitumor activity similar to that of traditional PD-1/PD-L1-targeted antibodies. Pb-Tx exhibited reduced systemic activity and an improved nonclinical safety profile, with markedly reduced target occupancy on peripheral T cells and reduced incidence of early-onset autoimmune diabetes in nonobese diabetic mice. Our results confirm that localized PD-1/PD-L1 inhibition by Pb-Tx can elicit robust antitumor immunity and minimize systemic immune-mediated toxicity. These data provide further preclinical rationale to support the ongoing development of the anti-PD-L1 Pb-Tx CX-072, which is currently in clinical trials.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/uso terapêutico , Imunoterapia/métodos , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/farmacologia , Antígeno B7-H1/farmacologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Camundongos , Microambiente Tumoral
11.
Clin Cancer Res ; 27(19): 5325-5333, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34253583

RESUMO

PURPOSE: CX-072, a PD-L1-targeting Probody therapeutic, is engineered to be activated by tumor proteases that remove a masking peptide. To study effects on biodistribution and pharmacokinetics, we performed 89Zr-CX-072 positron emission tomography (PET) imaging. EXPERIMENTAL DESIGN: Patients received ∼1 mg, 37 MBq 89Zr-CX-072 plus 0, 4, or 9 mg unlabeled CX-072 and PET scans at days 2, 4, and 7. After that, treatment comprised 10 mg/kg CX-072 q2 weeks (n = 7) + 3 mg/kg ipilimumab q3w 4× (n = 1). Normal organ tracer uptake was expressed as standardized uptake value (SUV)mean and tumor uptake as SUVmax. PD-L1 expression was measured immunohistochemically in archival tumor tissue. RESULTS: Three of the eight patients included received 10-mg protein dose resulting in a blood pool mean SUVmean ± SD of 4.27 ± 0.45 on day 4, indicating sufficient available tracer. Tumor uptake was highest at day 7, with a geometric mean SUVmax 5.89 (n = 113) and present in all patients. The median follow-up was 12 weeks (4-76+). One patient experienced stable disease and two patients a partial response. PD-L1 tumor expression was 90% in one patient and ≤1% in the other patients. Mean SUVmean ± SD day 4 at 10 mg in the spleen was 8.56 ± 1.04, bone marrow 2.21 ± 0.46, and liver 4.97 ± 0.97. Four patients out of seven showed uptake in normal lymph nodes and Waldeyer's ring. The tracer was intact in the serum or plasma. CONCLUSIONS: 89Zr-CX-072 showed tumor uptake, even in lesions with ≤1% PD-L1 expression, and modest uptake in normal lymphoid organs, with no unexpected uptake in other healthy tissues.


Assuntos
Neoplasias , Radioisótopos , Antígeno B7-H1/metabolismo , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Tomografia por Emissão de Pósitrons/métodos , Radioisótopos/uso terapêutico , Distribuição Tecidual , Zircônio
12.
J Pediatr Surg ; 56(6): 1208-1213, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33752913

RESUMO

BACKGROUND: Perforated appendicitis is a well-documented child health disparity. Geographic patterns in perforated appendicitis exist in several United States regions, but such patterns have not been described in California. We aimed to analyze spatial-temporal patterns of pediatric perforated appendicitis and identify population characteristics contributing to these cluster patterns. METHODS: We geocoded risk-adjusted perforated appendicitis rates per 1000 appendicitis cases in patients 1-17 years from 2005-2015 in California. We performed a space-time cube analysis to identify hot spot trends. We performed logistic regression to estimate rural classification associated with spatial-temporal hot spots and multivariate analysis to assess effects of socioeconomic factors. RESULTS: In 2005-2015, 43,888 cases of pediatric perforated appendicitis occurred in California. Median risk-adjusted perforated appendicitis rate was 312 per 1000 appendicitis cases. We identified 11 spatial-temporal hot spots of perforated appendicitis. Rural micropolitan counties had 14 times higher odds of being classified as a hot spot (p<0.05, 95% CI 1-185). Poverty was a significant predictor of high perforated appendicitis median risk-adjusted rate (p<0.004). CONCLUSIONS: We identified 11 California hot spots of perforated appendicitis that persisted across a ten-year time span. Incorporating geography alongside our understanding of socioeconomic factors is a critical step in addressing this important child health disparity.


Assuntos
Apendicite , Apendicectomia , Apendicite/epidemiologia , Apendicite/cirurgia , California/epidemiologia , Criança , Humanos , Modelos Logísticos , Estudos Retrospectivos , Estados Unidos
14.
Glob Pediatr Health ; 7: 2333794X20968459, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33195745

RESUMO

We describe trends in cell phone-related injuries in patients 21 years of age and under presenting to United States Emergency Departments. We calculated age-adjusted rates of cell phone-related injury per 100 000 individuals using data from the National Electronic Injury Surveillance System (NEISS) database and United States Census Bureau. From 2002 to 2015, an estimated 38 063 patients 21 years old and younger sustained a cell phone-related injury. The overall rate of injuries for all ages increased from 17.1 injuries per 100 000 in 2002 to 138 injuries per 100 000 in 2015, an increase of over 700%. The incidence of cell phone-related injuries increased across all age groups, with children 2 years of age and under experiencing the highest single incidence rate of 159 injuries per 100 000 in 2014. These findings highlight an important and relatively under-reported pediatric safety issue. Anticipatory guidance and injury prevention plans should be updated accordingly.

15.
J Prim Care Community Health ; 11: 2150132720940513, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32646267

RESUMO

Introduction: Compared with adults, children have higher emergency department (ED) utilization for asthma exacerbation. While community coalitions have been shown to prevent ED visits for asthma, there is little guidance on where to best implement these efforts. Geographical information systems (GIS) technology can help in the selection and coordination of potential coalition partners. This report proposes a model to be used by clinicians and child health equity advocates to strategize high-impact community health interventions. The aims were to identify the clusters of ED utilization for pediatric asthma, evaluate sociodemographic features of the population within the clusters, and identify potential primary care and school community partners. Methods: This model uses ED visit data from 450 nonmilitary California hospitals in 2012. We obtained ZIP code-level counts and rates for patients younger than 18 years discharged with a diagnosis code of 493 for asthma conditions from the California Office of Statewide Health Planning and Development's Open Portal. We applied GIS spatial analysis techniques to identify statistically significant cluster for pediatric asthma ED utilization. We then locate the candidate community partners within these clusters. Results: There were 181 720 ED visits for asthma for all age groups in 2012 with 70 127 visits for children younger than 18 years. The top 3 geographic clusters for ED utilization rates were located in Fresno, Inglewood, and Richmond City, respectively. Spatial analysis maps illustrate the schools located within 0.5- and 1-mile radii of primary care clinics and provide a visual and statistical description of the population within the clusters. Conclusion: This study demonstrates a model to help clinicians understand how GIS can aid in the selection and creation of coalition building. This is a potentially powerful tool in the addressing child health disparities.


Assuntos
Asma , Sistemas de Informação Geográfica , Adolescente , Adulto , Asma/epidemiologia , Criança , Serviço Hospitalar de Emergência , Humanos , Alta do Paciente , Atenção Primária à Saúde
16.
Theranostics ; 10(13): 5815-5828, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32483421

RESUMO

Probody® therapeutics are recombinant masked monoclonal antibody (mAb) prodrugs that become activated by proteases present in the tumor microenvironment. This makes them attractive for use as Probody drug conjugates (PDCs). CX-2009 is a novel PDC with the toxic drug DM4 coupled to an anti-CD166 Probody therapeutic. CD166 is overexpressed in multiple tumor types and to a lesser extent by healthy tissue. Methods: The tumor targeting potential of CX-2009 was assessed by performing 89Zr-immuno-PET/biodistribution/therapy studies in a CD166-positive H292 lung cancer mouse model. Head-to-head comparisons of CX-2009 with the Probody therapeutic without DM4 (CX-191), the unmasked antibody drug conjugate (ADC) CX-1031, and the parental mAb CX-090 were performed. All constructs were 89Zr labeled in a GMP compliant way, administered at 10, 110, or 510 µg, and ex vivo biodistribution was assessed at 24, 72, and 168 hours post-injection. Results: Comparable biodistribution was observed for all constructs, confirmed with PET/CT. Tumors showed the highest uptake: 21.8 ± 2.3 ([89Zr]Zr-CX-2009), 21.8 ± 5.0 ([89Zr]Zr­CX-191), 18.7 ± 2.5 ([89Zr]Zr-CX-1031) and 20.8 ± 0.9 %ID/g ([89Zr]Zr-CX-090) at 110 µg injected. Increasing the dose to 510 µg resulted in lower tumor uptake and higher blood levels for all constructs, suggesting receptor saturation. In addition, CX-2009 and CX-1031 showed similar therapeutic potential. Conclusions: CX-2009 is optimally capable of targeting CD166-expressing tumors when compared with its derivatives, implying that enzymatic activation inside the tumor, required to allow CD166 binding, does not limit tumor targeting. Because CX-2009 does not bind to mouse CD166, however, reduced targeting of healthy organs should be confirmed in ongoing clinical 89Zr-immuno-PET studies.


Assuntos
Molécula de Adesão de Leucócito Ativado/imunologia , Maitansina/farmacologia , Pró-Fármacos/farmacologia , Animais , Anticorpos Monoclonais/farmacologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Imunoconjugados/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Nus , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons/métodos , Radioisótopos/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Distribuição Tecidual/efeitos dos fármacos , Zircônio/química , Zircônio/farmacologia
17.
Sci Rep ; 10(1): 5894, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32246002

RESUMO

Proteases have been implicated in the development of many pathological conditions, including cancer. Detection of protease activity in diseased tissues could therefore be useful for diagnosis, prognosis, and the development of novel therapeutic approaches. Due to tight post-translational regulation, determination of the expression level of proteases alone may not be indicative of protease activities, and new methods for measuring protease activity in biological samples such as tumor biopsies are needed. Here we report a novel zymography-based technique, called the IHZTM assay, for the detection of specific protease activities in situ. The IHZ assay involves imaging the binding of a protease-activated monoclonal antibody prodrug, called a Probody® therapeutic, to tissue. Probody therapeutics are fully recombinant, masked antibodies that can only bind target antigen after removal of the mask by a selected protease. A fluorescently labeled Probody molecule is incubated with a biological tissue, thereby enabling its activation by tissue endogenous proteases. Protease activity is measured by imaging the activated Probody molecule binding to antigen present in the sample. The method was evaluated in xenograft tumor samples using protease specific substrates and inhibitors, and the measurements correlated with efficacy of the respective Probody therapeutics. Using this technique, a diverse profile of MMP and serine protease activities was characterized in breast cancer patient tumor samples. The IHZ assay represents a new type of in situ zymography technique that can be used for the screening of disease-associated proteases in patient samples from multiple pathological conditions.


Assuntos
Imagem Molecular/métodos , Sondas Moleculares/metabolismo , Neoplasias/diagnóstico , Peptídeo Hidrolases/análise , Pró-Fármacos/metabolismo , Animais , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Microscopia de Fluorescência , Sondas Moleculares/genética , Sondas Moleculares/farmacologia , Neoplasias/patologia , Peptídeo Hidrolases/metabolismo , Pró-Fármacos/farmacologia , Processamento de Proteína Pós-Traducional , Proteólise , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Clin Cancer Res ; 26(15): 3999-4009, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31953313

RESUMO

PURPOSE: Probody therapeutic CX-072 is a protease-activatable antibody that is cross-reactive with murine and human programmed death-ligand 1 (PD-L1). CX-072 can be activated in vivo by proteases present in the tumor microenvironment, thereby potentially reducing peripheral, anti-PD-L1-mediated toxicities. To study its targeting of PD-L1-expressing tissues, we radiolabeled CX-072 with the PET isotope zirconium-89 (89Zr). EXPERIMENTAL DESIGN: 89Zr-labeled CX-072, nonspecific Probody control molecule (PbCtrl) and CX-072 parental antibody (CX-075) were injected in BALB/c nude mice bearing human MDA-MB-231 tumors or C57BL/6J mice bearing syngeneic MC38 tumors. Mice underwent serial PET imaging 1, 3, and 6 days after intravenous injection (pi), followed by ex vivo biodistribution. Intratumoral 89Zr-CX-072 distribution was studied by autoradiography on tumor tissue sections, which were subsequently stained for PD-L1 by IHC. Activated CX-072 species in tissue lysates were detected by Western capillary electrophoresis. RESULTS: PET imaging revealed 89Zr-CX-072 accumulation in MDA-MB-231 tumors with 2.1-fold higher tumor-to-blood ratios at 6 days pi compared with 89Zr-PbCtrl. Tumor tissue autoradiography showed high 89Zr-CX-072 uptake in high PD-L1-expressing regions. Activated CX-072 species were detected in these tumors, with 5.3-fold lower levels found in the spleen. Furthermore, 89Zr-CX-072 uptake by lymphoid tissues of immune-competent mice bearing MC38 tumors was low compared with 89Zr-CX-075, which lacks the Probody design. CONCLUSIONS: 89Zr-CX-072 accumulates specifically in PD-L1-expressing tumors with limited uptake in murine peripheral lymphoid tissues. Our data may enable clinical evaluation of 89Zr-CX-072 whole-body distribution as a tool to support CX-072 drug development (NCT03013491).


Assuntos
Anticorpos Monoclonais/farmacocinética , Antígeno B7-H1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/farmacocinética , Neoplasias/tratamento farmacológico , Compostos Radiofarmacêuticos/farmacocinética , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/química , Autorradiografia , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/química , Masculino , Camundongos , Neoplasias/diagnóstico por imagem , Neoplasias/imunologia , Neoplasias/patologia , Tomografia por Emissão de Pósitrons , Radioisótopos/administração & dosagem , Radioisótopos/química , Radioisótopos/farmacocinética , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/química , Distribuição Tecidual , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto , Zircônio/administração & dosagem , Zircônio/química , Zircônio/farmacocinética
19.
Ann Am Thorac Soc ; 17(3): 313-320, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31860802

RESUMO

Rationale: There is significant evidence of increased healthcare utilization from cardiopulmonary causes in adults from exposure to wildfire smoke, but evidence in pediatric age groups is limited.Objectives: To quantify and examine the healthcare utilization effects of the December 2017 Lilac Fire in San Diego County among pediatric patients at the Rady Children's Hospital (RCH) emergency department and urgent care (UC) clinics.Methods: Using data from 2011 to 2017, including data on daily particulate matter <2.5 µm (PM2.5) in an inverse-distance interpolation model and RCH electronic medical records, we retrospectively analyzed pediatric respiratory visits at the RCH emergency department and UC clinics during the Santa Ana wind (SAW)-driven Lilac Fire from December 7 to 16, 2017. An interrupted time series study design was applied as our primary analysis to compare the observed pediatric respiratory visits from December 7 to 16, 2017 to what would have occurred in a counterfactual situation, namely, if the Lilac Fire had not occurred. A complementary descriptive spatial analysis was also used to evaluate the geographic distribution of respiratory visits in relationship to satellite imaging of the Lilac Fire and the associated wind pattern.Results: The Lilac Fire was associated with 16.0 (95% confidence interval [CI], 11.2-20.9) excess respiratory visits per day at the RCH emergency department across all pediatric age groups. Children aged 0 to 5 years had the highest absolute excess respiratory visits per day with 7.3 (95% CI, 3.0-11.7), whereas those aged 6 to 12 years had the highest relative increase in visits, with 3.4 (95% CI, 2.3-4.6). RCH UC clinics had similar results. The top five ZIP codes in San Diego County with the highest standard deviations of age-adjusted respiratory visits were all located generally downwind of the fire perimeter, as expected for the SAW pattern.Conclusions: We have demonstrated an increase in pediatric respiratory visits during the SAW-driven Lilac Fire in San Diego County in a patterned geographic distribution that is attributable to an increase in PM2.5 exposure. Younger children were particularly affected. Climate change is expected to result in more frequent and extensive wildfires in the region and will require greater preparedness and adaptation efforts to protect vulnerable populations, such as young children.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Exposição Ambiental , Material Particulado/efeitos adversos , Transtornos Respiratórios/epidemiologia , Fumaça/efeitos adversos , Incêndios Florestais , Adolescente , Assistência Ambulatorial/estatística & dados numéricos , California/epidemiologia , Criança , Pré-Escolar , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Transtornos Respiratórios/induzido quimicamente , Estudos Retrospectivos , Vento , Adulto Jovem
20.
Neoreviews ; 20(9): e500-e512, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31477598

RESUMO

Oxygen is commonly used in the delivery room during neonatal resuscitation. The transition from intrauterine to extrauterine life is a challenge to newborns, and exposure to too much oxygen can cause an increase in oxidative stress. The goal of resuscitation is to achieve normal oxygen levels as quickly as possible while avoiding excessive oxygen exposure and preventing inadequate oxygen supplementation. Although it has been shown that room air resuscitation is as effective as using 100% oxygen, often preterm infants need some degree of oxygen supplementation. The ideal concentration of oxygen with which to initiate resuscitation is yet to be determined. Current delivery room resuscitation guidelines recommend the use of room air for term newborns and preterm newborns of greater than or equal to 35 weeks' gestation and the use of a fraction of inspired oxygen of 0.21 to 0.3 for preterm infants of less than 35 weeks' gestation. Further recommendations include titrating oxygen supplementation as needed to obtain goal saturations. However, there is no current consensus on an intermediate oxygen concentration to start resuscitation or goal range saturations for preterm and asphyxiated term infants.


Assuntos
Salas de Parto , Recém-Nascido Prematuro , Oxigenoterapia/normas , Ressuscitação/normas , Humanos , Recém-Nascido
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