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J Surg Res ; 274: 185-195, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35180495


INTRODUCTION: Intraoperative deaths (IODs) are rare but catastrophic. We systematically analyzed IODs to identify clinical and patient safety patterns. METHODS: IODs in a large academic center between 2015 and 2019 were included. Perioperative details were systematically reviewed, focusing on (1) identifying phenotypes of IOD, (2) describing emerging themes immediately preceding cardiac arrest, and (3) suggesting interventions to mitigate IOD in each phenotype. RESULTS: Forty-one patients were included. Three IOD phenotypes were identified: trauma (T), nontrauma emergency (NT), and elective (EL) surgery patients, each with 2 sub-phenotypes (e.g., ELm and ELv for elective surgery with medical arrests or vascular injury and bleeding, respectively). In phenotype T, cardiopulmonary resuscitation was initiated before incision in 42%, resuscitative thoracotomy was performed in 33%, and transient return of spontaneous circulation was achieved in 30% of patients. In phenotype NT, ruptured aortic aneurysms accounted for half the cases, and median blood product utilization was 2,694 mL. In phenotype ELm, preoperative evaluation did not include electrocardiogram in 12%, cardiac consultation in 62%, stress test in 87%, and chest x-ray in 37% of patients. In phenotype ELv, 83% had a single peripheral intravenous line, and vascular injury was almost always followed by escalation in monitoring (e.g., central/arterial line), alert to the blood bank, and call for surgical backup. CONCLUSIONS: We have created a framework for IOD that can help with intraoperative safety and quality analysis. Focusing on interventions that address appropriateness versus futility in care in phenotypes T and NT, and on prevention and mitigation of intraoperative vessel injury (e.g., intraoperative rescue team) or preoperative optimization in phenotype EL may help prevent IODs.

Reanimação Cardiopulmonar , Parada Cardíaca , Lesões do Sistema Vascular , Parada Cardíaca/etiologia , Parada Cardíaca/prevenção & controle , Hemorragia , Humanos , Toracotomia
Mol Cancer Res ; 16(4): 720-727, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29453314


Molecular drivers underlying bone metastases in human cancer are not well understood, in part due to constraints in bone tissue sampling. Here, RNA sequencing was performed of circulating tumor cells (CTC) isolated from blood samples of women with metastatic estrogen receptor (ER)+ breast cancer, comparing cases with progression in bone versus visceral organs. Among the activated cellular pathways in CTCs from bone-predominant breast cancer is androgen receptor (AR) signaling. AR gene expression is evident, as is its constitutively active splice variant AR-v7. AR expression within CTCs is correlated with the duration of treatment with aromatase inhibitors, suggesting that it contributes to acquired resistance to endocrine therapy. In an established breast cancer xenograft model, a bone-tropic derivative displays increased AR expression, whose genetic or pharmacologic suppression reduces metastases to bone but not to lungs. Together, these observations identify AR signaling in CTCs from women with bone-predominant ER+ breast cancer, and provide a rationale for testing androgen inhibitors in this subset of patients.Implications: This study highlights a role for the AR in breast cancer bone metastasis, and suggests that therapeutic targeting of the AR may benefit patients with metastatic breast cancer. Mol Cancer Res; 16(4); 720-7. ©2018 AACR.

Neoplasias Ósseas/secundário , Neoplasias da Mama/genética , Células Neoplásicas Circulantes/química , Receptores Androgênicos/genética , Neoplasias Abdominais/secundário , Processamento Alternativo , Animais , Antineoplásicos Hormonais/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Camundongos , Análise de Sequência de RNA , Análise de Célula Única
JCI Insight ; 2(3): e91078, 2017 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-28194445


There is tremendous excitement for the potential of epigenetic therapies in cancer, but the ability to predict and monitor response to these drugs remains elusive. This is in part due to the inability to differentiate the direct cytotoxic and the immunomodulatory effects of these drugs. The DNA-hypomethylating agent 5-azacitidine (AZA) has shown these distinct effects in colon cancer and appears to be linked to the derepression of repeat RNAs. LINE and HERV are two of the largest classes of repeats in the genome, and despite many commonalities, we found that there is heterogeneity in behavior among repeat subtypes. Specifically, the LINE-1 and HERV-H subtypes detected by RNA sequencing and RNA in situ hybridization in colon cancers had distinct expression patterns, which suggested that these repeats are correlated to transcriptional programs marking different biological states. We found that low LINE-1 expression correlates with global DNA hypermethylation, wild-type TP53 status, and responsiveness to AZA. HERV-H repeats were not concordant with LINE-1 expression but were found to be linked with differences in FOXP3+ Treg tumor infiltrates. Together, distinct repeat RNA expression patterns define new molecular classifications of colon cancer and provide biomarkers that better distinguish cytotoxic from immunomodulatory effects by epigenetic drugs.

Azacitidina/farmacologia , Neoplasias do Colo/genética , Metilação de DNA , Sequências Repetitivas de Ácido Nucleico , Idoso , Linhagem Celular Tumoral , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Sequências Repetitivas de Ácido Nucleico/efeitos dos fármacos , Análise de Sequência de RNA/métodos
Mol Microbiol ; 104(3): 499-519, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28187496


The morphological transition of the opportunistic fungal pathogen Candida albicans from budding to hyphal growth has been implicated in its ability to cause disease in animal models. Absence of SR-like RNA-binding protein Slr1 slows hyphal formation and decreases virulence in a systemic candidiasis model, suggesting a role for post-transcriptional regulation in these processes. SR (serine-arginine)-rich proteins influence multiple steps in mRNA metabolism and their localization and function are frequently controlled by modification. We now demonstrate that Slr1 binds to polyadenylated RNA and that its intracellular localization is modulated by phosphorylation and methylation. Wildtype Slr1-GFP is predominantly nuclear, but also co-fractionates with translating ribosomes. The non-phosphorylatable slr1-6SA-GFP protein, in which six serines in SR/RS clusters are substituted with alanines, primarily localizes to the cytoplasm in budding cells. Intriguingly, hyphal cells display a slr1-6SA-GFP focus at the tip near the Spitzenkörper, a vesicular structure involved in molecular trafficking to the tip. The presence of slr1-6SA-GFP hyphal tip foci is reduced in the absence of the mRNA-transport protein She3, suggesting that unphosphorylated Slr1 associates with mRNA-protein complexes transported to the tip. The impact of SLR1 deletion on hyphal formation and function thus may be partially due to a role in hyphal mRNA transport.

Candida albicans/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas de Ligação a RNA/metabolismo , Candida albicans/genética , Candida albicans/crescimento & desenvolvimento , Citoplasma/metabolismo , Proteínas Fúngicas/metabolismo , Deleção de Genes , Hifas/genética , Hifas/crescimento & desenvolvimento , Hifas/metabolismo , Fosforilação , RNA Mensageiro/metabolismo
Proc Natl Acad Sci U S A ; 112(49): 15148-53, 2015 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-26575630


Aberrant transcription of the pericentromeric human satellite II (HSATII) repeat is present in a wide variety of epithelial cancers. In deriving experimental systems to study its deregulation, we observed that HSATII expression is induced in colon cancer cells cultured as xenografts or under nonadherent conditions in vitro, but it is rapidly lost in standard 2D cultures. Unexpectedly, physiological induction of endogenous HSATII RNA, as well as introduction of synthetic HSATII transcripts, generated cDNA intermediates in the form of DNA/RNA hybrids. Single molecule sequencing of tumor xenografts showed that HSATII RNA-derived DNA (rdDNA) molecules are stably incorporated within pericentromeric loci. Suppression of RT activity using small molecule inhibitors reduced HSATII copy gain. Analysis of whole-genome sequencing data revealed that HSATII copy number gain is a common feature in primary human colon tumors and is associated with a lower overall survival. Together, our observations suggest that cancer-associated derepression of specific repetitive sequences can promote their RNA-driven genomic expansion, with potential implications on pericentromeric architecture.

Centrômero/genética , DNA Satélite/genética , Neoplasias/genética , Sequências Repetitivas de Ácido Nucleico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , Hibridização de Ácido Nucleico , RNA/genética
Cell Rep ; 8(6): 1905-1918, 2014 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-25242334


Circulating tumor cells (CTCs) are shed from primary tumors into the bloodstream, mediating the hematogenous spread of cancer to distant organs. To define their composition, we compared genome-wide expression profiles of CTCs with matched primary tumors in a mouse model of pancreatic cancer, isolating individual CTCs using epitope-independent microfluidic capture, followed by single-cell RNA sequencing. CTCs clustered separately from primary tumors and tumor-derived cell lines, showing low-proliferative signatures, enrichment for the stem-cell-associated gene Aldh1a2, biphenotypic expression of epithelial and mesenchymal markers, and expression of Igfbp5, a gene transcript enriched at the epithelial-stromal interface. Mouse as well as human pancreatic CTCs exhibit a very high expression of stromal-derived extracellular matrix (ECM) proteins, including SPARC, whose knockdown in cancer cells suppresses cell migration and invasiveness. The aberrant expression by CTCs of stromal ECM genes points to their contribution of microenvironmental signals for the spread of cancer to distant organs.

Matriz Extracelular/genética , Regulação Neoplásica da Expressão Gênica , Células Neoplásicas Circulantes/metabolismo , Neoplasias Pancreáticas/patologia , Família Aldeído Desidrogenase 1 , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Movimento Celular , Matriz Extracelular/metabolismo , Humanos , Camundongos , Osteonectina/antagonistas & inibidores , Osteonectina/genética , Osteonectina/metabolismo , Neoplasias Pancreáticas/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Retinal Desidrogenase/genética , Retinal Desidrogenase/metabolismo , Análise de Sequência de RNA , Células Tumorais Cultivadas