Claudia Salgado - Academia.edu (original) (raw)

Papers by Claudia Salgado

Purpose:Ewing sarcoma and osteosarcoma are primary bone sarcomas occurring most commonly in adole... more Purpose:Ewing sarcoma and osteosarcoma are primary bone sarcomas occurring most commonly in adolescents. Metastatic and relapsed disease are associated with dismal prognosis. Although effective for some soft tissue sarcomas, current immunotherapeutic approaches for the treatment of bone sarcomas have been largely ineffective, necessitating a deeper understanding of bone sarcoma immunobiology.Experimental Design:Multiplex immunofluorescence analysis of immune infiltration in relapsed versus primary disease was conducted. To better understand immune states and drivers of immune infiltration, especially during disease progression, we performed single-cell RNA sequencing (scRNAseq) of immune populations from paired blood and bone sarcoma tumor samples.Results:Our multiplex immunofluorescence analysis revealed increased immune infiltration in relapsed versus primary disease in both Ewing sarcoma and osteosarcoma. scRNAseq analyses revealed terminally exhausted CD8+ T cells expressing co-...

Supplementary Figure from Ewing Sarcoma and Osteosarcoma Have Distinct Immune Signatures and Inte... more Supplementary Figure from Ewing Sarcoma and Osteosarcoma Have Distinct Immune Signatures and Intercellular Communication Networks

Supplementary Table from Ewing Sarcoma and Osteosarcoma Have Distinct Immune Signatures and Inter... more Supplementary Table from Ewing Sarcoma and Osteosarcoma Have Distinct Immune Signatures and Intercellular Communication Networks

Clinical Cancer Research

Purpose: Ewing sarcoma and osteosarcoma are primary bone sarcomas occurring most commonly in adol... more Purpose: Ewing sarcoma and osteosarcoma are primary bone sarcomas occurring most commonly in adolescents. Metastatic and relapsed disease are associated with dismal prognosis. Although effective for some soft tissue sarcomas, current immunotherapeutic approaches for the treatment of bone sarcomas have been largely ineffective, necessitating a deeper understanding of bone sarcoma immunobiology. Experimental Design: Multiplex immunofluorescence analysis of immune infiltration in relapsed versus primary disease was conducted. To better understand immune states and drivers of immune infiltration, especially during disease progression, we performed single-cell RNA sequencing (scRNAseq) of immune populations from paired blood and bone sarcoma tumor samples. Results: Our multiplex immunofluorescence analysis revealed increased immune infiltration in relapsed versus primary disease in both Ewing sarcoma and osteosarcoma. scRNAseq analyses revealed terminally exhausted CD8+ T cells expressin...

Arthritis & Rheumatology, 2021

Juvenile localized scleroderma (LS) is an autoimmune disease of the skin whose pathogenesis is no... more Juvenile localized scleroderma (LS) is an autoimmune disease of the skin whose pathogenesis is not well understood due to the rarity of the disease. This study was undertaken to determine the skin transcriptome in skin biopsy tissue from children with juvenile LS compared to pediatric healthy controls, with identification of significant molecular targets using RNA sequencing (RNA‐Seq). In this study, differentially expressed genes (DEGs) were assessed for correlations with histopathologic and clinical features in children with juvenile LS, and were used to group the children into distinct genetic clusters based on immunophenotype.

Cancer genomics & proteomics

Omipalisib has been found to affect the viability of cancer cells. However, its effect on clonoge... more Omipalisib has been found to affect the viability of cancer cells. However, its effect on clonogenicity - a feature of cancer stem cells, is not clear. Cells isolated from neurocutaneous melanocytosis (NCM) patients' lesions grow clonogenically. The aim of this study was to investigate the effect of omipalisib treatment on clonogenic growth of NCM cells in vitro. Clonogenic growth efficiency was evaluated by colony formation assays with or without specific growth factors. Activation of MEK and Akt was determined by immunoblots. Colony formation and cell viability were assessed upon pharmacological inhibition of MEK, Akt and mToR. Clonogenicity appeared to depend on bFGF and IGF1signaling through ERK and Akt. Omipalisib treatment prevented colony formation and induced autophagic cell death. Signaling through Akt is important for survival of clonogenic cells in NCM, and omipalisib treatment as a monotherapy or in combination with MEK162 could be an effective therapeutic strategy t...

Pediatric transplantation, Jan 2, 2017

Fibrosis is commonly described in heart allografts lost late after transplantation. CMR-derived E... more Fibrosis is commonly described in heart allografts lost late after transplantation. CMR-derived ECV is a validated measure of DMF in native adult hearts that may predict heart failure and mortality. We explored associations of ECV with histologic myocardial fibrosis and clinical features after pediatric heart transplantation. Twenty-five recipients (7.0±6.3 years at transplant and 10.7±6.5 years post-transplant) were prospectively recruited for CMR and BNP measurement at the time of surveillance biopsy. All had normal ejection fractions and lacked heart failure symptoms. Fibrosis was quantified on biopsy after picrosirius red staining as CVF. ECV was quantified using contemporaneous hematocrit on basal and mid-short-axis slices. ECV was moderately correlated with CVF (r=.47; P=.019). We found no associations of ECV with hemodynamics, ischemic time, time since transplantation, or number of prior biopsies or acute rejections. Compared to healthy non-transplant controls, there was no s...

The American Journal of Dermatopathology, 2016

ing capillary channels with intervening collagen bundles. There have also been rare reports of ML... more ing capillary channels with intervening collagen bundles. There have also been rare reports of MLG-derived lesions with malignant behavior including extramammary Paget disease, invasive ductal carcinoma, lobular carcinoma, tubulolobular carcinoma, and mucinous carcinoma. As with benign MLG-derived lesions, they share a striking homology with their counterparts in the breast. In summary, MLGs are a normal tissue constituent of the anogenital region capable of giving rise to lesions of both benign and malignant character with homologous counterparts in breast tissue. Although rare, these lesions should be in the differential for any vulvar or perianal lesion because of their potential for malignant behavior. Our case illustrates, for the first time, that overlap features of fibroadenoma and phyllodes tumor can occur in MLG-derived tumors just as they can in the breast.

Pediatric and Developmental Pathology, 2016

In the absence of work on prenatal nevogenesis, it has long been necessary to define congenital m... more In the absence of work on prenatal nevogenesis, it has long been necessary to define congenital melanocytic nevi by clinical detection on neonatal skin examination. They are seen in approximately 1% of newborns, with multiplicity in approximately 3% of cases. Melan-A staining of grossly normal fetal skin recently demonstrated fetal nevi, whose features validated certain traditional histologic criteria for “congenital type” nevi that may not have been detectable at birth. This suggested that many clinically acquired nevi actually formed in utero, like congenital nevi. Prenatal nevi has been suggested as a preferred synonym for “congenital type” nevi. Prenatal nevi were detected in 6 of 25 fetuses (24%), a strikingly higher incidence than congenital nevi in newborns. In this series of 354 patients with prenatal (congenital type) nevi encountered in routine practice at a community hospital, over 30% of both adolescents and adults had multiple prenatal nevi; a strikingly higher rate of ...

Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society, Jan 18, 2015

Cystinosis is a rare autosomal recessive disorder and the most common cause of inherited renal Fa... more Cystinosis is a rare autosomal recessive disorder and the most common cause of inherited renal Fanconi syndrome in young children. Renal biopsy is usually not necessary to establish the diagnosis, but when the patient presents with atypical signs and symptoms, a renal biopsy may be extremely valuable. We describe here renal biopsy findings in a patient with cystinosis. A 20-month-old male presented with failure to thrive, polyuria, polydipsia and rickets. He initially showed evidence of a renal tubular acidosis, mild renal insufficiency and nephrogenic diabetes insipidus. His initial ophthalmologic exam did not demonstrate corneal crystals. His subsequent workup revealed phosphaturia, suggesting a partial proximal tubulopathy. Concomitantly, a renal biopsy revealed prominent podocytes with an immature glomerular appearance and electron microscopy analysis showed numerous intracellular crystals within tubular epithelial cells. Subsequent laboratory and genetic testing confirmed a dia...

Neuro-oncology, Jan 9, 2015

Neurocutaneous melanocytosis (NCM) is characterized by clonal nevomelanocytic proliferations in t... more Neurocutaneous melanocytosis (NCM) is characterized by clonal nevomelanocytic proliferations in the CNS and skin. Given the scarcity of effective therapeutic targets, testing new drugs requires a reliable and reproducible in vitro cellular model of the disease. We generated nevomelanocytic spheroids in vitro from lesions of the spinal cord, brain, and skin from 4 NCM patients. Nevomelanocytic cells were grown as monolayers or spheroids and their growth characteristics were evaluated. Cultured cell identity was confirmed by demonstration of the same NRAS mutation found in the original lesions and by immunophenotyping. Nevomelanocytic spheroids were treated with inhibitors of specific mediators of the NRAS signaling pathway (vemurafenib, MEK162, GDC0941, and GSK2126458). Drug sensitivity and cell viability were assessed. Cultured cells were growth-factor dependent, grew as spheroids on Geltrex matrix, and maintained their clonogenicity in vitro over passages. Skin-derived cells formed...

Melanoma Research, 2015

The mechanisms behind malignant progression in patients with giant nevi are largely unknown. Here... more The mechanisms behind malignant progression in patients with giant nevi are largely unknown. Here, we aim to describe novel genetic findings and explain possible mechanisms resulting in the most severe form of neurocutaneous melanocytosis. Detailed histological (biopsy and post-mortem) studies, tissue culture, and highresolution cytogenetic analysis, including chromosome and array comparative genomic hybridization, Ion AmpliSeq Cancer Panel, and Sanger sequencing, were performed on tissues from a white male who succumbed at 17 months of age to congenital melanoma associated with a bathingtrunk nevus. We also used quantitative PCR to quantitatively assess the expression of NRAS among normal cells, including fibroblast and melanocytes, as well as melanoma cells from our patient. Full autopsy documented tumors in the brain, spinal cord, lung, liver, testis, bone marrow, and, retrospectively, in the placenta. Next-generation sequencing and chromosome microarray in our patient revealed novel findings, including duplication of a mutated NRAS gene, leading to an aggressive clinical course and disseminated disease. Quantitative PCR showed a five-fold increase in NRAS expression in the melanoma cell line when compared with normal melanocytes. Finally, three amino acidchanging germline variants were detected: homozygous TP53 p.P72R, heterozygous KIT p.M541L, and homozygous KDR (VEGFR2) p.Q472H. These genes are involved in malignancy and other potentially relevant pathways, such as mast cell and melanocytic signaling, as well as angiogenesis. These findings provide novel insights into the biology of congenital melanocytic proliferations, showing that amplification of mutated NRAS seems to represent a new genetic mechanism leading to melanoma in the context of neurocutaneous melanocytosis. Melanoma Res 25:453-460

Pediatric and Developmental Pathology, 2015

NRAS and BRAF mutations occur in congenital melanocytic nevi (CMN), but results are contradictory... more NRAS and BRAF mutations occur in congenital melanocytic nevi (CMN), but results are contradictory. Sixty-six prospectively collected CMN patients were analyzed for NRAS Q61 mutations using Sanger sequencing. Negative cases were evaluated for BRAF V600E mutation. NRAS Q61 mutations affected 51 patients (77.3%), and BRAF V600E was found in 5 (7.6%). NRAS Q61 mutation affected 29 (80.6%) of 36 giant, 16 (80.0%) of 20 large, and 5 (62.5%) of 8 medium-size CMN; BRAF mutation affected 1 (5%) of 20 large and 4 (11.4%) of 36 giant CMN. Compared to NRAS, BRAF-mutated nevi show scattered/extensive dermal and subcutaneous nodules (100% BRAF+ vs 34.8% NRAS+) ( P = 0.002). Neurocutaneous melanocytosis (NCM) affected 16 (24.2%) of 66 patients, with NRAS Q61 mutation in 12 (75.0%), and BRAF V600E in 2 (12.5%), P = 0.009. Two patients were negative for both mutations (12.5%). In conclusion, although NRAS Q61 mutations predominate, BRAF V600E mutation also affects patients with large/giant CMN (L/GC...

Jornal de Pediatria, 2003

Resumo Objetivos: realizar uma revisão crítica da literatura atual, enfocando aspectos práticos e... more Resumo Objetivos: realizar uma revisão crítica da literatura atual, enfocando aspectos práticos e relevantes para o diagnóstico e tratamento ambulatorial da criança com hipertensão arterial. Fonte de dados: artigos clássicos e revisão sistemática da literatura atual através de busca eletrônica nos bancos de dados Medline e Lilacs, nos últimos 10 anos, utilizando-se as palavraschave hipertensão arterial, recém-nascido, lactente, pré-escolar, criança e adolescente, selecionando-se aqueles que trouxeram informações relevantes. Síntese dos dados: a hipertensão arterial e a obesidade são um problema de saúde pública em todo o mundo. A hipertensão arterial essencial do adulto inicia-se na infância, e, além disso, pode ser secundária a várias doenças. O pediatra tem por obrigação medir adequadamente a pressão arterial de seus pacientes. Quando descoberta, a hipertensão arterial deve ser investigada para ser adequadamente tratada. A investigação depende da idade e do grau de elevação da pressão arterial, devendo preocupar-se não somente com a causa da hipertensão, mas também com os seus efeitos em órgãos alvo. Conclusões: o reconhecimento precoce da pressão arterial anormal e a intervenção (investigação e tratamento) adequada são necessários para diminuir a morbidade/mortalidade cardiovascular e renal futura.

Pediatric and Developmental Pathology, 2014

Nevocytes (NC) and mastocytes (MC) have different progenitors but share stem cell factor as regul... more Nevocytes (NC) and mastocytes (MC) have different progenitors but share stem cell factor as regulator/activator of NC and for differentiation/proliferation of MC. Both cell types express stem cell factor receptor CD117. We hypothesize that large/giant congenital melanocytic nevi (L/GCMN) may associate with MC hyperplasia. Forty-nine L/GCMN were examined, 12 samples from uninvolved skin of L/GCMN patients and 6 control skin samples studied with Giemsa and immunohistochemistry for CD117 and MC-tryptase. Picrosirius red (PR) was used to assess fibrosis. Digital images were used to count MC/mm2 using ImageJ software. Western blot (WB) for MC-tryptase in 12 GCMN and 12 non-nevus samples was performed. Analysis of variance (Tukey) and Pearson statistical tests were applied. Increased MCs were observed in nevus tissue (75.1 ± 35.3 MCs/mm2) and in uninvolved skin (53.74 ± 27.7 MC/ mm2). P = 0.109 from patients with L/GCMN, compared with controls from individuals without L/GCMN (28.74 ± 8.4 ...

Arquivos Brasileiros de Cardiologia, 2009

Background: Arterial Hypertension (AH) is a mass disease, with consequences for the cardiocircula... more Background: Arterial Hypertension (AH) is a mass disease, with consequences for the cardiocirculatory system, since its complications raise the rates of morbidity and mortality. Controlling blood pressure (BP) reduces complications and may preserve the quality of life (QOL) of patients. Studies show positive effects of music therapy as an adjuvant in the treatment of several diseases. Objective: to evaluate the effect of music therapy on the QOL and BP control of hypertensive patients. Methods: This was a controlled clinical study that evaluated patients of both genders, aged over 50 years, with stage 1 hypertension, in use of medication and enrolled in multidisciplinary service for treatment of hypertension. They were divided into an experimental group (EG) and a control group (CG). The EG, in addition to the conventional treatment, participated in weekly music therapy sessions for twelve weeks. The CG received the standard treatment of the service. Before and after the intervention, the SF-36 questionnaire was applied in both groups, and the BP of each patient was measured. The voice, an important element of communication, reflecting the patient's physical, mental and emotional state, was the main resource used. Statistics: Student T-test and Wilcoxon test were considered significant at p <0.05. Results: The groups were initially similar in gender, age, education, and the assessed QOL. In the initial and final comparison of EG patients, we observed a significant improvement on the QOL (p <0.05) and BP control (p <0.05), with no change in adhesion. Conclusions: Music therapy has contributed to an improvement on the QOL and BP control of patients, suggesting that this activity may represent a therapeutic approach to help strengthen the programs of multidisciplinary care of hypertensive patients.

Ambulatory Pediatrics, 2007

In this issue of Ambulatory Pediatrics, Agha and colleagues demonstrate that lower socioeconomic ... more In this issue of Ambulatory Pediatrics, Agha and colleagues demonstrate that lower socioeconomic status, measured by neighborhood income, is associated with higher hospitalization rates for ambulatory care–sensitive conditions (ACSC) among children born in Toronto between 1993 and 2001. Their findings are consistent with prior research that has used census information, hospital discharge files, indices of clinician supply, and insurance claims to demonstrate a relationship between social disadvantage or limited access to health care and higher rates of ACSC hospitalization in children. Many researchers have assessed the association between social factors, delivery system characteristics, and ACSC hospitalizations over the last 10 years because the hypothesis that timely ambulatory care can prevent unnecessary hospitalizations has an intuitive appeal, and because rates of ACSC hospitalization can be easily measured from claims data. However, this research has proceeded without a critical assessment of 3 underlying assumptions about the meaning and use of ACSC: (1) that ACSC hospitalizations can in fact be prevented by timely ambulatory care; (2) that the forces associated with ACSC hospitalizations are distinct from those that affect hospitalizations for other reasons; and (3) that interventions at the level of the child, the clinic, or the delivery system as a whole can reduce the incidence of ACSC hospitalizations. Existing research does not conclusively support any of these assumptions. First, the term ambulatory care–sensitive conditions may be a misnomer. The commonly used list of ACSC in children includes acute illnesses such as pneumonia and gastrointestinal illnesses as well as chronic conditions such as asthma and seizure disorders. This list of ACSC was based on expert consensus about conditions for which early treatment might prevent hospitalizations, but little evidence supports this belief. Although some studies have found that children with ACSC hospitalizations have lower previous use of ambulatory care than children not hospitalized for these conditions, others have found similar or higher rates of ambulatory care for children later