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1.
Pediatr Res ; 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39122822

RESUMO

BACKGROUND: Acute kidney injury (AKI) occurs in up to half of infants admitted to the neonatal intensive care unit (NICU) and is associated with increased risks of death and more days of mechanical ventilation, hospitalization, and vasopressor drug support. Our objective was to build a granular relational database to study the impact that AKI has on infants admitted to Level-IV NICUs. METHODS: A relational database was created by linking data from the Children's Hospitals Neonatal Database with AKI-focused data from electronic health records from 9 centers. RESULTS: The current cohort consists of 24,870 infants with a median (IQR) gestational age of birth of 37 weeks (32 weeks, 39 weeks), and a median birth weight of 2.720 kg (1.750 kg, 3.310 kg). There was a male predominance with 14,214 (57%) males. In all, 2434 (9.8%) of the mothers were of Hispanic ethnicity. The maternal race breakdown of the cohort was as follows: 741 (3.0%) Asian, 5911 (24%) Black, and 14,945 (60%) White. Overall mortality was 5.8%. CONCLUSION: The ADVANCE relational database is an innovative research tool to rigorously study the epidemiology of AKI in a large national cohort of infants admitted to Level-IV NICUs involved in the Children's Hospital Neonatal Consortium. IMPACT: We used a biomedical informatics approach to build a relational database to study acute kidney injury in infants. We highlight our methodology linking Children's Hospital Neonatal Consortium and electronic health record data from nine neonatal intensive care units. The ADVANCE relational database is a granular and innovative research tool to study risk factors and in-hospital outcomes of acute kidney injury and mortality in a vulnerable patient population.

2.
Int J Gynecol Pathol ; 43(3): 275-283, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38436360

RESUMO

Mucinous ovarian carcinoma is an uncommon malignancy characterized by resistance to chemotherapy and poor survival in the metastatic setting. HER2 amplification is a frequent late event in carcinogenesis, yet the incidence of HER2-low in mucinous ovarian carcinoma is unknown. Further, the optimal method for determining overexpression in these tumors is not established. We sought to assess the ASCO/CAP and ToGA trial scoring methods for HER2 IHC with correlation to FISH, p53, and mismatch repair protein status and to determine the incidence of HER2-low in mucinous ovarian carcinoma. A total of 29 tumors from 23 patients were included. Immunohistochemistry for HER2, p53, MLH1, PMS2, MSH2, and MSH6 was performed. Scoring was performed according to the ASCO/CAP and ToGA trial criteria. HER2 FISH was performed and scored according to the ASCO/CAP criteria. The proportion of HER2-low, defined as 1+ or 2+ staining with negative FISH, was determined. Using ASCO/CAP, 26% demonstrated 3+ while 35% demonstrated 2+ staining. Using ToGA, 30% demonstrated 3+ while 57% demonstrated 2+ staining. By FISH, 26% were positive for HER2 amplification. Both systems captured all FISH-positive cases; the use of ASCO/CAP resulted in fewer equivocal and false-positive cases. Among HER2-negative cases, 88% were HER2-low. Aberrant p53 expression was detected in 55% of cases; mismatch repair deficiency was not identified in any cases. ASCO/CAP guidelines are accurate and resource-effective in determining HER2 overexpression in mucinous ovarian carcinoma. HER2-low is common in these tumors; further studies to determine the role of HER2-targeted therapy including antibody-drug conjugates are indicated.


Assuntos
Neoplasias Ovarianas , Receptor ErbB-2 , Humanos , Feminino , Receptor ErbB-2/metabolismo , Hibridização in Situ Fluorescente/métodos , Proteína Supressora de Tumor p53 , Carcinoma Epitelial do Ovário , Biomarcadores Tumorais/análise
3.
Genes Chromosomes Cancer ; 61(11): 645-652, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35521817

RESUMO

Spindle cell rhabdomyosarcoma represents a rare neoplasm characterized by monomorphic spindle cells with a fascicular architecture and variable skeletal muscle differentiation. Following incidental identification of a ZFP64::NCOA3 gene fusion in an unclassified spindle cell sarcoma resembling adult-type fibrosarcoma, we performed a retrospective archival review and identified four additional cases with a similar histology and identical gene fusion. All tumors arose in adult males (28-71 years). The neoplasms were found in the deep soft tissues, two were gluteal, and one each arose in the thigh, abdominal wall, and chest wall. Morphologically, the tumors were characterized by spindle cells with a distinctive herringbone pattern and variable collagenous to myxoid stroma. The nuclei were relatively monomorphic with variable mitotic activity. Three tumors had immunoreactivity for MyoD1, and four contained variable expression of desmin and smooth muscle actin. All cases tested for myogenin, CD34, S100, pankeratin, and epithelial membrane antigen were negative. Targeted RNA sequencing revealed a ZFP64::NCOA3 fusion product in all five tumors. Three patients developed distant metastases, and two ultimately succumbed to their disease within 2 years of initial diagnosis. This study suggests ZFP64::NCOA3 fusions define a novel subtype of rhabdomyosarcoma with a spindle cell morphology and aggressive clinical behavior. The potential for morphologic and immunohistochemical overlap with several other sarcoma types underscores the value of molecular testing as a diagnostic adjunct to ensure accurate classification and management of these neoplasms.


Assuntos
Fibrossarcoma , Rabdomiossarcoma , Sarcoma , Neoplasias de Tecidos Moles , Adulto , Biomarcadores Tumorais/genética , Criança , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fusão Gênica , Humanos , Masculino , Coativador 3 de Receptor Nuclear/genética , Coativador 3 de Receptor Nuclear/metabolismo , Estudos Retrospectivos , Rabdomiossarcoma/química , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Sarcoma/genética , Neoplasias de Tecidos Moles/patologia , Fatores de Transcrição/genética
4.
Curr Psychiatry Rep ; 22(12): 66, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33030637

RESUMO

PURPOSE OF REVIEW: The ability to effectively prepare for and respond to the psychological fallout from large-scale disasters is a core competency of military mental health providers, as well as civilian emergency response teams. Disaster planning should be situation specific and data driven; vague, broad-spectrum planning can contribute to unprepared mental health teams and underserved patient populations. Herein, we review data on mental health sequelae from the twenty-first century pandemics, including SARS-CoV2 (COVID-19), and offer explanations for observed trends, insights regarding anticipated needs, and recommendations for preliminary planning on how to best allocate limited mental health resources. RECENT FINDINGS: Anxiety and distress, often attributed to isolation, were the most prominent mental health complaints during previous pandemics and with COVID-19. Additionally, post-traumatic stress was surprisingly common and possibly more enduring than depression, insomnia, and alcohol misuse. Predictions regarding COVID-19's economic impact suggest that depression and suicide rates may increase over time. Available data suggest that the mental health sequelae of COVID-19 will mirror those of previous pandemics. Clinicians and mental health leaders should focus planning efforts on the negative effects of isolation, particularly anxiety and distress, as well as post-traumatic stress symptoms.


Assuntos
Infecções por Coronavirus/psicologia , Necessidades e Demandas de Serviços de Saúde , Saúde Mental , Pneumonia Viral/psicologia , Ansiedade , Betacoronavirus , COVID-19 , Infecções por Coronavirus/epidemiologia , Humanos , Pandemias , Pneumonia Viral/epidemiologia , Angústia Psicológica , SARS-CoV-2 , Transtornos de Estresse Pós-Traumáticos
5.
Vet Pathol ; 55(2): 286-293, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29157190

RESUMO

Mucopolysaccharidoses are inherited metabolic disorders that result from a deficiency of lysosomal enzymes required for the catabolism of glycosaminoglycans. Lysosomal glycosaminoglycan accumulation results in cell and organ dysfunction. This study characterized the phenotype and genotype of mucopolysaccharidosis VI in a Great Dane puppy with clinical signs of stunted growth, facial dysmorphia, skeletal deformities, corneal opacities, and increased respiratory sounds. Clinical and pathologic evaluations, urine glycosaminoglycan analyses, lysosomal enzyme assays, and ARSB sequencing were performed. The urine mucopolysaccharide spot test was strongly positive predominantly due to the accumulation of dermatan sulfate. Enzyme assays in leukocytes and tissues indicated a deficiency of arylsulfatase B (ARSB) activity. Histologic examination revealed cytoplasmic vacuoles in many tissues. Analysis of the exonic ARSB DNA sequences from the affected puppy compared to the published canine genome sequence revealed a homozygous nonsense mutation (c.295C>T) in exon 1, replacing glutamine with a premature stop codon (p.Gln99*), predicting no enzyme synthesis. A polymerase chain reaction-based restriction fragment length polymorphism test was established to assist with the clinical diagnosis and breeding of Great Danes. This genotyping test revealed that the clinically healthy parents and some other relatives of the puppy were heterozygous for the mutant allele, but all 200 clinically healthy dogs screened including 15 Great Danes were homozygous for the normal allele. This ARSB mutation is the fourth identified genetic variant causing canine mucopolysaccharidosis VI. Mucopolysaccharidosis VI is the first lysosomal storage disorder described in Great Danes but does not appear to be widespread in this breed.


Assuntos
Códon sem Sentido/genética , Doenças do Cão/genética , Mucopolissacaridose VI/veterinária , N-Acetilgalactosamina-4-Sulfatase/genética , Animais , Doenças do Cão/patologia , Cães , Masculino , Mucopolissacaridose VI/genética , Mucopolissacaridose VI/patologia , Análise de Sequência de DNA/veterinária
6.
J Perinat Med ; 46(4): 441-449, 2018 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-28822225

RESUMO

BACKGROUND: The adaptive immune system of neonates is relatively underdeveloped. The thymus is an essential organ for adaptive T cell development and might be affected during the natural course of oxygen induced lung injury. The effect of prolonged hyperoxia on the thymus, thymocyte and T cell development, and its proliferation has not been studied extensively. METHODS: Neonatal mice were exposed to 85% oxygen (hyperoxia) or room air (normoxia) up to 28 days. Flow cytometry using surface markers were used to assay for thymocyte development and proliferation. RESULTS: Mice exposed to prolonged hyperoxia had evidence of lung injury associated alveolar simplification, a significantly lower mean weight, smaller thymic size, lower mean thymocyte count and higher percentage of apoptotic thymocytes. T cells subpopulation in the thymus showed a significant reduction in the count and proliferation of double positive and double negative T cells. There was a significant reduction in the count and proliferation of single positive CD4+ and CD8+ T cells. CONCLUSIONS: Prolonged hyperoxia in neonatal mice adversely affected thymic size, thymocyte count and altered the distribution of T cells sub-populations. These results are consistent with the hypothesis that prolonged hyperoxia causes defective development of T cells in the thymus.


Assuntos
Displasia Broncopulmonar/imunologia , Hiperóxia/imunologia , Timócitos/fisiologia , Timo/patologia , Animais , Displasia Broncopulmonar/patologia , Feminino , Hiperóxia/patologia , Hiperóxia/fisiopatologia , Pulmão/patologia , Camundongos Endogâmicos C57BL , Gravidez , Timo/fisiopatologia
7.
Int J Surg Pathol ; 32(2): 239-251, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37306115

RESUMO

Introduction. Triple negative breast carcinomas are characterized by a lack of hormone receptor and HER2 expression and inconsistent expression of breast-specific immunohistochemical markers. The expression of many site-specific markers in these tumors is largely unknown. The objective of the study was to examine the expression of widely used immunohistochemical markers on a large cohort of triple negative breast cancer. Methods. Sections from tissue microarrays were stained with 47 markers using routine protocols. Most markers were scored using a modified Allred method. ATRX, BAP1, SMAD4, e-cadherin, and beta-catenin were scored as retained or lost. Mammaglobin was considered positive if there was at least moderate intensity staining in any tumor cells. P16 was scored as overexpressed or not overexpressed; p53 was scored as wildtype, overexpressed, null, or cytoplasmic. Results. The cohort consisted of 639 tumors including 601 primary and 32 metastases. Overall, 96% expressed GATA3, mammaglobin, and/or SOX10 while 97% of no special type tumors expressed this panel. Carcinoma of apocrine differentiation demonstrated an AR positive, SOX10 negative, K5 negative/focal immunophenotype. PAX8 (SP348), WT1, Napsin A, and TTF1 (8G7G3/1) were never or rarely expressed while CA9, CDX2, NKX3.1, SATB2 (SATBA410), synaptophysin, and vimentin were variably expressed. Conclusions. Almost all TNBC express at least 1 of the 3 IHC markers: GATA3, mammaglobin, and/or SOX10. Carcinoma of apocrine differentiation is characterized by an AR positive, SOX10 negative, K5 negative or focal immunophenotype. Cautious interpretation of so-called site-specific markers, with knowledge of antibody clones, is required in excluding the diagnosis of triple negative breast cancer.


Assuntos
Carcinoma , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/diagnóstico , Mama , Anticorpos , Citoplasma
8.
Arch Pathol Lab Med ; 147(3): 368-375, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35802936

RESUMO

CONTEXT.­: Resident physicians face a higher rate of burnout and depression than the general population. Few studies have examined burnout and depression in Canadian laboratory medicine residents, and none during the COVID-19 pandemic. OBJECTIVE.­: To identify the prevalence of burnout and depression, contributing factors, and the impact of COVID-19 in this population. DESIGN.­: An electronic survey was distributed to Canadian laboratory medicine residents. Burnout was assessed using the Oldenburg Burnout Inventory. Depression was assessed using the Patient Health Questionnaire 9. RESULTS.­: Seventy-nine responses were collected. The prevalence of burnout was 63% (50 of 79). The prevalence of depression was 47% (37 of 79). Modifiable factors significantly associated with burnout included career dissatisfaction, below average academic performance, lack of time off for illness, stress related to finances, lack of a peer or staff physician mentor, and a high level of fatigue. Modifiable factors significantly associated with depression further included a lack of access to wellness resources, lack of time off for leisure, and fewer hours of sleep. Fifty-five percent (41 of 74) of participants reported direct impacts to their personal circumstances by the COVID-19 pandemic. CONCLUSIONS.­: Burnout and depression are significant issues affecting Canadian laboratory medicine residents. As the COVID-19 pandemic continues, we recommend the institution of flexible work arrangements, protected time off for illness and leisure, ongoing evaluation of career satisfaction, formal and informal wellness programming with trainee input, formal mentorship programming, and a financial literacy curriculum as measures to improve trainee wellness.


Assuntos
Esgotamento Profissional , COVID-19 , Internato e Residência , Humanos , COVID-19/epidemiologia , Depressão/epidemiologia , Pandemias , Canadá/epidemiologia , Esgotamento Profissional/epidemiologia , Inquéritos e Questionários
9.
J Perinatol ; 43(1): 86-90, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35978106

RESUMO

OBJECTIVE: To evaluate serum creatinine (SCr) patterns and the development of acute kidney injury (AKI), as potential biomarkers of necrotizing enterocolitis (NEC). STUDY DESIGN: Retrospective chart review of preterm infants with and without NEC born 23-32 weeks gestation admitted to Nationwide Children's Hospital NICU. Medical versus surgical NEC was determined by radiographic and clinical findings. Available inpatient SCr levels obtained on days 8 through 365 were included. RESULT: In this cohort, 77 NEC and a randomly selected group of 82 non-NEC infants met inclusion criteria. Fifteen of the 70 (21.4%) with NEC met criteria for AKI versus 0 of 43 (0.0%) without NEC. One of the 13 with AKI had AKI within 7 days prior to NEC diagnosis (7.7%). CONCLUSION: AKI is more prevalent in infants with NEC. The temporal association between AKI and NEC could not be evaluated due to inconsistent SCr surveillance and should be evaluated in future studies.


Assuntos
Injúria Renal Aguda , Enterocolite Necrosante , Doenças do Recém-Nascido , Criança , Recém-Nascido , Humanos , Lactente , Recém-Nascido Prematuro , Enterocolite Necrosante/epidemiologia , Estudos Retrospectivos , Creatinina , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/epidemiologia
10.
Blood ; 116(18): 3431-4, 2010 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-20656929

RESUMO

Influenza causes excess morbidity in sickle cell disease (SCD). H1N1 pandemic influenza has been severe in children. To compare H1N1 with seasonal influenza in SCD (patients younger than 22), we reviewed medical records (1993-2009). We identified 123 cases of laboratory-confirmed influenza (94 seasonal, 29 H1N1). Those with seasonal influenza were younger (median 4.4 vs 8.7 years old, P = .006) and had less asthma (24% vs 56%, P = .002). Those with H1N1 influenza more often had acute chest syndrome (ACS; 34% vs 13%, P = .01) and required intensive care (17% vs 3%, P = .02), including mechanical ventilation (10% vs 0%, P = .02). In multivariate analysis, older age (odds ratio [OR] 1.1 per year, P = .04) and H1N1 influenza (OR 3.0, P = .04) were associated with ACS, and older age (OR 1.1 per year, P = .02) and prior ACS (OR 3.3 per episode in last year, P < .006) with intensive care. Influenza, especially H1N1, causes critical illness in SCD and should be prevented.


Assuntos
Anemia Falciforme/complicações , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Influenza Humana/complicações , Influenza Humana/epidemiologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Influenza Humana/diagnóstico , Influenza Humana/terapia , Masculino , Pandemias , Resultado do Tratamento , Adulto Jovem
11.
Arch Pathol Lab Med ; 146(1): 123-131, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34133708

RESUMO

CONTEXT.­: Competency-based medical education relies on frequent formative in-service assessments to ascertain trainee progression. Currently at our institution, trainees receive a summative end-of-rotation In-Training Evaluation Report based on feedback collected from staff pathologists. There is no method of simulating report sign-out. OBJECTIVE.­: To develop a formative in-service assessment tool that is able to simulate report sign-out and provide case-by-case feedback to trainees. Further, to compare time- versus competency-based assessment models. DESIGN.­: Twenty-one pathology trainees were assessed for 20 months. Hot Seat Diagnosis by trainees and trainee assessment by pathologists were recorded in the laboratory information system. In the first iteration, trainees were assessed by using a time-based assessment scale on their ability to diagnose, report, use ancillary tests, comment on clinical implications, and provide intraoperative consultation and/or gross cases. The second iteration used a competency-based assessment scale. Trainees and pathologists completed surveys on the effectiveness of the In-Training Evaluation Report versus the Hot Seat Diagnosis tool. RESULTS.­: Scores from both iterations correlated significantly with other assessment tools including the Resident In-Service Examination (r = 0.93, P = .04 and r = 0.87, P = .03). The competency-based model was better able to demonstrate improvement over time and stratify junior versus senior trainees than the time-based model. Trainees and pathologists rated Hot Seat Diagnosis as significantly more objective, detailed, and timely than the In-Training Evaluation Report, and effective at simulating report sign-out. CONCLUSIONS.­: Hot Seat Diagnosis is an effective tool for the formative in-service assessment of pathology trainees and simulation of report sign-out, with the competency-based model outperforming the time-based model.


Assuntos
Competência Clínica , Educação de Pós-Graduação em Medicina , Retroalimentação , Humanos , Inquéritos e Questionários
12.
J Pediatr Surg ; 56(11): 1966-1975, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33785202

RESUMO

BACKGROUND: Early-stage symptomology of necrotizing enterocolitis (NEC) is similar in presentation to non-NEC sepsis, though the treatment plans differ based on antibiotic administration and withholding of feeds. Improved diagnostics for NEC differentiation would allow clinicians to more rapidly set individual patients on a targeted treatment path. Extracellular vesicle-derived miRNAs, have previously demonstrated efficacy as disease biomarkers. To determine if these miRNAs are differentially-expressed in NEC infants, we performed transcriptomic analysis of urine-derived extracellular vesicle-derived miRNAs. METHODS: Urine was non-invasively obtained from infants in one of four groups (n ≥ 8) (Medical NEC, Surgical NEC, non-NEC sepsis, and healthy age-matched controls). EV-derived miRNAs were isolated and transcriptomic analysis was performed. RESULTS: Multiple miRNAs, including miR-376a, miR-518a-3p and miR-604, were significantly altered when comparing NEC to non-NEC sepsis and healthy controls, and could potentially be used as specific NEC biomarkers. Additionally, Ingenuity Pathway Analysis demonstrated that miRs differentially-expressed in NEC were associated with inflammatory disease and intestinal disease. Signal transduction molecules associated with NEC including TP53 and RPS15, which were also reduced transcriptionally in a rat model of NEC. CONCLUSION: These data indicate that there is a pool of potential urine EV-derived miRNAs that may be validated as NEC biomarkers in the differentiation of NEC from non-NEC sepsis and from age-matched controls. Additionally, signal transduction molecules associated with miRNAs differentially-expressed in human NEC are altered in a murine model of NEC, suggesting potential crossover between murine models of the disease and actual human presentation. LEVEL OF EVIDENCE: Level III Study of Diagnostic Test.


Assuntos
Enterocolite Necrosante , Vesículas Extracelulares , MicroRNAs , Animais , Biomarcadores , Enterocolite Necrosante/genética , Humanos , Recém-Nascido , Camundongos , MicroRNAs/genética , Estudo de Prova de Conceito , Ratos
13.
Artigo em Inglês | MEDLINE | ID: mdl-36381649

RESUMO

Elemental ratios in biogenic marine calcium carbonates are widely used in geobiology, environmental science, and paleoenvironmental reconstructions. It is generally accepted that the elemental abundance of biogenic marine carbonates reflects a combination of the abundance of that ion in seawater, the physical properties of seawater, the mineralogy of the biomineral, and the pathways and mechanisms of biomineralization. Here we report measurements of a suite of nine elemental ratios (Li/Ca, B/Ca, Na/Ca, Mg/Ca, Zn/Ca, Sr/Ca, Cd/Ca, Ba/Ca, and U/Ca) in 18 species of benthic marine invertebrates spanning a range of biogenic carbonate polymorph mineralogies (low-Mg calcite, high-Mg calcite, aragonite, mixed mineralogy) and of phyla (including Mollusca, Echinodermata, Arthropoda, Annelida, Cnidaria, Chlorophyta, and Rhodophyta) cultured at a single temperature (25°C) and a range of pCO2 treatments (ca. 409, 606, 903, and 2856 ppm). This dataset was used to explore various controls over elemental partitioning in biogenic marine carbonates, including species-level and biomineralization-pathway-level controls, the influence of internal pH regulation compared to external pH changes, and biocalcification responses to changes in seawater carbonate chemistry. The dataset also enables exploration of broad scale phylogenetic patterns of elemental partitioning across calcifying species, exhibiting high phylogenetic signals estimated from both uni- and multivariate analyses of the elemental ratio data (univariate: λ = 0-0.889; multivariate: λ = 0.895-0.99). Comparing partial R 2 values returned from non-phylogenetic and phylogenetic regression analyses echo the importance of and show that phylogeny explains the elemental ratio data 1.4-59 times better than mineralogy in five out of nine of the elements analyzed. Therefore, the strong associations between biomineral elemental chemistry and species relatedness suggests mechanistic controls over element incorporation rooted in the evolution of biomineralization mechanisms.

14.
Arch Pathol Lab Med ; 144(10): 1262-1270, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32142368

RESUMO

CONTEXT.­: The use of neoadjuvant therapy in the management of early-stage invasive breast cancer is increasing. Residual Cancer Burden and other similar tools use pathologic characteristics of post-neoadjuvant therapy breast tumors to determine long-term outcome. However, there are no standardized guidelines for the pathologic evaluation of these specimens in the routine clinical setting. OBJECTIVE.­: To assess current practices among Canadian pathologists and pathology assistants with regard to the processing and reporting of post-neoadjuvant therapy breast specimens. DESIGN.­: An electronic survey was distributed to pathologists and pathology assistants across Canada. RESULTS.­: Sixty-three responses were obtained. A total of 48% (15 of 31) of surveyed pathologists reported familiarity with the Residual Cancer Burden tool. A total of 40% (25 of 63) of respondents reported a lack of routine use of specimen photography, and 35% (22 of 63) reported a lack of routine use of grossing diagrams. There was significant variation with respect to tumor bed sampling; the most common method was to submit 1 block per centimeter of tumor (20 of 63; 32%). There was also significant variation in the method of measuring residual tumor; the most common method was to measure the largest cross-section of residual tumor (16 of 32; 50%). CONCLUSIONS.­: There is a need for standardization of the evaluation of post-neoadjuvant therapy breast specimens in the routine clinical setting in Canada. We recommend the routine use of specimen mapping, submitting the largest cross section of tumor bed in toto, reporting tumor size as per American Joint Committee on Cancer and Residual Cancer Burden guidelines, and routinely including measurements of residual tumor cellularity and in situ disease in the final pathology report as per Residual Cancer Burden guidelines.


Assuntos
Neoplasias da Mama/patologia , Mama/patologia , Patologia Cirúrgica/normas , Manejo de Espécimes/normas , Neoplasias da Mama/tratamento farmacológico , Canadá , Quimioterapia Adjuvante , Feminino , Humanos , Terapia Neoadjuvante/métodos
15.
Redox Biol ; 20: 98-106, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30296702

RESUMO

Severe and recurrent cisplatin-induced acute kidney injury (AKI) as part of standard cancer therapy is a known risk factor for development of chronic kidney disease (CKD). The specific role of superoxide (O2•-)-mediated disruption of mitochondrial oxidative metabolism in CKD after cisplatin treatment is unexplored. Cisplatin is typically administered in weekly or tri-weekly cycles as part of standard cancer therapy. To investigate the role of O2•- in predisposing patients to future renal injury and in CKD, mice were treated with cisplatin and a mitochondrial-specific, superoxide dismutase (SOD) mimetic, GC4419. Renal function, biomarkers of oxidative stress, mitochondrial oxidative metabolism, and kidney injury markers, as well as renal histology, were assessed to evaluate the cellular changes that occur one week and one month (CKD phase) after the cisplatin insult. Cisplatin treatment resulted in persistent upregulation of kidney injury markers, increased steady-state levels of O2•-, increased O2•--mediated renal tubules damage, and upregulation of mitochondrial electron transport chain (ETC) complex I activity both one week and one month following cisplatin treatment. Treatment with a novel, clinically relevant, small-molecule superoxide dismutase (SOD) mimetic, GC4419, restored mitochondrial ETC complex I activity to control levels without affecting complexes II-IV activity, as well as ameliorated cisplatin-induced kidney injury. These data support the hypothesis that increased mitochondrial O2•- following cisplatin administration, as a result of disruptions of mitochondrial metabolism, may be an important contributor to both AKI and CKD progression.


Assuntos
Cisplatino/efeitos adversos , Mitocôndrias/metabolismo , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Superóxidos/metabolismo , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Mimetismo Biológico , Biópsia , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Modelos Biológicos , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Renal Crônica/patologia , Superóxido Dismutase/metabolismo
16.
Sci Rep ; 6: 28112, 2016 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-27346849

RESUMO

The high proliferation rate of embryonic stem cells (ESCs) is thought to arise partly from very low expression of p21. However, how p21 is suppressed in ESCs has been unclear. We found that p53 binds to the p21 promoter in human ESCs (hESCs) as efficiently as in differentiated human mesenchymal stem cells, however it does not promote p21 transcription in hESCs. We observed an enrichment for both the repressive histone H3K27me3 and activating histone H3K4me3 chromatin marks at the p21 locus in hESCs, suggesting it is a suppressed, bivalent domain which overrides activation by p53. Reducing H3K27me3 methylation in hESCs rescued p21 expression, and ectopic expression of p21 in hESCs triggered their differentiation. Further, we uncovered a subset of bivalent promoters bound by p53 in hESCs that are similarly induced upon differentiation in a p53-dependent manner, whereas p53 promotes the transcription of other target genes which do not show an enrichment of H3K27me3 in ESCs. Our studies reveal a unique epigenetic strategy used by ESCs to poise undesired p53 target genes, thus balancing the maintenance of pluripotency in the undifferentiated state with a robust response to differentiation signals, while utilizing p53 activity to maintain genomic stability and homeostasis in ESCs.


Assuntos
Inibidor de Quinase Dependente de Ciclina p21/genética , Histonas/metabolismo , Células-Tronco Embrionárias Humanas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Sequência de Bases , Diferenciação Celular , Linhagem Celular , Epigênese Genética , Técnica Indireta de Fluorescência para Anticorpo , Células-Tronco Embrionárias Humanas/citologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Metilação , Regiões Promotoras Genéticas/genética , Ligação Proteica , Estabilidade Proteica , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ativação Transcricional , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética
18.
Elife ; 5: e07101, 2016 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-26956429

RESUMO

Genetic alterations which impair the function of the TP53 signaling pathway in TP53 wild-type human tumors remain elusive. To identify new components of this pathway, we performed a screen for genes whose loss-of-function debilitated TP53 signaling and enabled oncogenic transformation of human mammary epithelial cells. We identified transglutaminase 2 (TGM2) as a putative tumor suppressor in the TP53 pathway. TGM2 suppressed colony formation in soft agar and tumor formation in a xenograft mouse model. The depletion of growth supplements induced both TGM2 expression and autophagy in a TP53-dependent manner, and TGM2 promoted autophagic flux by enhancing autophagic protein degradation and autolysosome clearance. Reduced expression of both CDKN1A, which regulates the cell cycle downstream of TP53, and TGM2 synergized to promote oncogenic transformation. Our findings suggest that TGM2-mediated autophagy and CDKN1A-mediated cell cycle arrest are two important barriers in the TP53 pathway that prevent oncogenic transformation.


Assuntos
Autofagia , Transformação Celular Neoplásica , Células Epiteliais/enzimologia , Células Epiteliais/fisiologia , Proteínas de Ligação ao GTP/metabolismo , Transglutaminases/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Proteínas de Ligação ao GTP/genética , Testes Genéticos , Xenoenxertos , Humanos , Neoplasias Mamárias Experimentais/patologia , Camundongos , Proteína 2 Glutamina gama-Glutamiltransferase , Transglutaminases/genética
19.
J Clin Invest ; 124(2): 656-69, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24401274

RESUMO

Interaction of the chemokine CXCL12 with its receptor CXCR4 promotes neuronal function and survival during embryonic development and throughout adulthood. Previous studies indicated that µ-opioid agonists specifically elevate neuronal levels of the protein ferritin heavy chain (FHC), which negatively regulates CXCR4 signaling and affects the neuroprotective function of the CXCL12/CXCR4 axis. Here, we determined that CXCL12/CXCR4 activity increased dendritic spine density, and also examined FHC expression and CXCR4 status in opiate abusers and patients with HIV-associated neurocognitive disorders (HAND), which is typically exacerbated by illicit drug use. Drug abusers and HIV patients with HAND had increased levels of FHC, which correlated with reduced CXCR4 activation, within cortical neurons. We confirmed these findings in a nonhuman primate model of SIV infection with morphine administration. Transfection of a CXCR4-expressing human cell line with an iron-deficient FHC mutant confirmed that increased FHC expression deregulated CXCR4 signaling and that this function of FHC was independent of iron binding. Furthermore, examination of morphine-treated rodents and isolated neurons expressing FHC shRNA revealed that FHC contributed to morphine-induced dendritic spine loss. Together, these data implicate FHC-dependent deregulation of CXCL12/CXCR4 as a contributing factor to cognitive dysfunction in neuroAIDS.


Assuntos
Complexo AIDS Demência/complicações , Apoferritinas/química , Neurônios/efeitos dos fármacos , Transtornos Relacionados ao Uso de Substâncias/complicações , Complexo AIDS Demência/fisiopatologia , Adulto , Idoso , Animais , Encéfalo/efeitos dos fármacos , Linhagem Celular , Quimiocina CXCL12/metabolismo , Espinhas Dendríticas/efeitos dos fármacos , Feminino , Humanos , Ferro/química , Macaca , Masculino , Pessoa de Meia-Idade , Morfina/química , Neurônios/metabolismo , Técnicas de Patch-Clamp , Fosforilação , RNA Interferente Pequeno/metabolismo , Ratos , Receptores CXCR4/metabolismo , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia
20.
Semin Cell Dev Biol ; 18(6): 846-58, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18024097

RESUMO

Mesenchymal stromal cells (MSC) are multipotent cells that can be derived from many different organs and tissues. They have been demonstrated to play a role in tissue repair and regeneration in both preclinical and clinical studies. They also have remarkable immunosuppressive properties. We describe their application in settings that include the cardiovascular, central nervous, gastrointestinal, renal, orthopaedic and haematopoietic systems. Manufacturing of MSC for clinical trials is also discussed. Since tissue matching between MSC donor and recipient does not appear to be required, MSC may be the first cell type able to be used as an "off-the-shelf" therapeutic product.


Assuntos
Transplante de Células-Tronco Mesenquimais/métodos , Células Estromais/citologia , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/fisiologia , Células-Tronco Multipotentes/citologia , Células-Tronco Multipotentes/fisiologia , Regeneração , Células Estromais/fisiologia , Células Estromais/transplante
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