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1.
J Atten Disord ; : 1087054719886359, 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31707913

RESUMO

Objective: ADHD is common in patients with epilepsy, but adult patients with possible epilepsy are not routinely screened for ADHD. We aimed to characterize the results of two validated screening tools in the setting of an Epilepsy Monitoring Unit (EMU). Method: This study utilized the validated Adult ADHD Self-Report Scale version 1.1 (ASRS) and Conners Continuous Performance Test, third edition (CPT-III) to screen patients who were admitted to the EMU at a Level 4 epilepsy center. Patients with epileptic seizures (ES) were compared with patients with psychogenic nonepileptic seizures (PNES). Results: In all, 40.6% of patients screened positive using the ASRS. A significantly greater proportion of patients with PNES (63.6%) screened positive compared with patients with ES (27.8%, Fisher's exact test, p = .005). Positive ASRS screens showed no significant association with positive CPT screens (chi-square test, p = .146). Conclusion: Adult patients admitted to the EMU are at a high risk of comorbid attention deficits.

2.
Int J Pediatr Otorhinolaryngol ; 129: 109757, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31704576

RESUMO

INTRODUCTION: Auditory Neuropathy Spectrum Disorder (ANSD) is characterized by hearing loss ranging from normal to profound. Additionally, results are confounded by commonly fluctuating hearing thresholds in ANSD. As such, we sought to evaluate results of audiometric testing on children with ANSD and the impact of age and time on testing results. METHODS: Retrospective chart review on children <18 years of age diagnosed with ANSD at two tertiary care academic institutions. Data analyzed included initial audiogram with speech detection thresholds (SDT) and pure tone averages (PTA) as well as most recent unaided audiogram SDT and PTA. RESULTS: 75 ANSD patients were analyzed, of which 32 (42.7%) were female. Bilateral and unilateral ANSD was seen in 55 (73.3%) and 20 (26.7%), respectively. A total of 130 ears with ANSD were assessed with 80 (61.5%) meeting inclusion criteria. Of these patients, the median age in years at first audiogram and most recent audiogram were 1.94 (0.45-13.68) and 4.22 (0.97-14.61), respectively. The median ages at which an SDT and PTA could first be acquired on the audiogram in ANSD patients were 1.94 (0.50-13.68) and 2.86 (0.45-13.68), respectively. The average SDT/PTA at the initial and most recent audiogram were 47.5/45.7 and 49.4/53.0 dB, respectively. SDT to PTA within the same audiogram exhibited strong correlation (r = 0.82, p < 0.001). Similarly, comparison of initial SDT to SDT at a later time interval showed strong correlation (r = 0.73, p < 0.001). SDT and PTA at initial audiogram and PTA at later time demonstrated lower correlation but was still statistically significant (r = 0.49, p < 0.009 and r = 0.51, p < 0.044, respectively). Individual PTA was associated with age (r = -0.56, p < 0.001). CONCLUSIONS: SDT and PTA within the same audiogram and initial SDT to SDT acquired at a later time correlate strongly in audiometric testing in children with ANSD. Although not as strong, initial SDT and PTA still correlate with PTA at a later time interval. These findings suggest that audiometric results yielding a reliable SDT and frequency specific information necessary to calculate the PTA is not typically obtained until 2-3 years old. However, once this information is obtained, the child's hearing is fairly stable but may fluctuate over time.

3.
Clin Cancer Res ; 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31582516

RESUMO

PURPOSE: Transforming growth factor-ßs (TGF-ßs) are overexpressed in many advanced cancers and promote cancer progression through mechanisms that include suppression of immunosurveillance. Multiple strategies to antagonize the TGF-ß pathway are in early phase oncology trials. However, TGF-ßs also have tumor suppressive activities early in tumorigenesis, and the extent to which these might be retained in advanced disease has not been fully explored. EXPERIMENTAL DESIGN: A panel of twelve immunocompetent mouse allograft models of metastatic breast cancer was tested for the effect of neutralizing anti-TGF-ß antibodies on lung metastatic burden. Extensive correlative biology analyses were performed to assess potential predictive biomarkers and probe underlying mechanisms. RESULTS: Heterogeneous responses to anti-TGF-ß treatment were observed, with 5/12 models (42%) showing suppression of metastasis, 4/12 (33%) showing no response and 3/12 (25%) showing an undesirable stimulation (up to 9-fold) of metastasis. Inhibition of metastasis was immune-dependent, while stimulation of metastasis was immune-independent and targeted the tumor cell compartment, potentially affecting the cancer stem cell. Thus the integrated outcome of TGF-ß antagonism depends on a complex balance between enhancing effective anti-tumor immunity and disrupting persistent tumor suppressive effects of TGF-ß on the tumor cell. Applying transcriptomic signatures derived from treatment-naive mouse primary tumors to human breast cancer datasets suggested that breast cancer patients with high-grade, estrogen receptor-negative disease are most likely to benefit from anti-TGF-ß therapy. CONCLUSIONS: Contrary to dogma, tumor suppressive responses to TGF-ß are retained in some advanced metastatic tumors. Safe deployment of TGF-ß antagonists in the clinic will require good predictive biomarkers.

4.
Cancer Prev Res (Phila) ; 12(11): 781-790, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31481539

RESUMO

Black women in the United States are disproportionately affected by early-onset, triple-negative breast cancer. DNA methylation has shown differences by race in healthy and tumor breast tissues. We examined associations between genome-wide DNA methylation levels in breast milk and breast cancer risk factors, including race, to explain how this reproductive stage influences a woman's risk for, and potentially contributes to racial disparities in, breast cancer. Breast milk samples and demographic, behavioral, and reproductive data, were obtained from cancer-free, uniparous, and lactating U.S. black (n = 57) and white (n = 82) women, ages 19-44. Genome-wide DNA methylation analysis was performed on extracted breast milk DNA using the Infinium HumanMethylation450 BeadChip. Statistically significant associations between breast cancer risk factors and DNA methylation beta values, adjusting for potential confounders, were determined using linear regression followed by Bonferroni Correction (P < 1.63 × 10-7). Epigenetic analysis in breast milk revealed statistically significant associations with race and lactation duration. Of the 284 CpG sites associated with race, 242 were hypermethylated in black women. All 227 CpG sites associated with lactation duration were hypomethylated in women who lactated longer. Ingenuity Pathway Analysis of differentially methylated promoter region CpGs by race and lactation duration revealed enrichment for networks implicated in carcinogenesis. Associations between DNA methylation and lactation duration may offer insight on its role in lowering breast cancer risk. Epigenetic associations with race may mediate social, behavioral, or other factors related to breast cancer and may provide insight into potential mechanisms underlying racial disparities in breast cancer incidence.

5.
Genes Chromosomes Cancer ; 58(11): 783-797, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31334584

RESUMO

Aberrant methylation of DNA is supposed to be a major and early driver of colonic adenoma development, which may result in colorectal cancer (CRC). Although gene methylation assays are used already for CRC screening, differential epigenetic alterations of recurring and nonrecurring colorectal adenomas have yet not been systematically investigated. Here, we collected a sample set of formalin-fixed paraffin-embedded colorectal low-grade adenomas (n = 72) consisting of primary adenomas without and with recurrence (n = 59), recurrent adenomas (n = 10), and normal mucosa specimens (n = 3). We aimed to unveil differentially methylated CpG positions (DMPs) across the methylome comparing not only primary adenomas without recurrence vs primary adenomas with recurrence but also primary adenomas vs recurrent adenomas using the Illumina Human Methylation 450K BeadChip array. Unsupervised hierarchical clustering exhibited a significant association of methylation patterns with histological adenoma subtypes. No significant DMPs were identified comparing primary adenomas with and without recurrence. Despite that, a total of 5094 DMPs (false discovery rate <0.05; fold change >10%) were identified in the comparisons of recurrent adenomas vs primary adenomas with recurrence (674; 98% hypermethylated), recurrent adenomas vs primary adenomas with and without recurrence (241; 99% hypermethylated) and colorectal adenomas vs normal mucosa (4179; 46% hypermethylated). DMPs in cytosine-phosphate-guanine (CpG) islands were frequently hypermethylated, whereas open sea- and shelf-regions exhibited hypomethylation. Gene ontology analysis revealed enrichment of genes associated with the immune system, inflammatory processes, and cancer pathways. In conclusion, our methylation data could assist in establishing a more robust and reproducible histological adenoma classification, which is a prerequisite for improving surveillance guidelines.

6.
J Neurosurg Spine ; : 1-8, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31349220

RESUMO

OBJECTIVE: Iatrogenic spine injury remains one of the most dreaded complications of pedicle subtraction osteotomies (PSOs) and spine deformity surgeries. Thus, intraoperative multimodal monitoring (IOM), which has the potential to provide real-time feedback on spinal cord signal transmission, has become the gold standard in such operations. However, while the benefits of IOM are well established in PSOs of the thoracic spine and scoliosis surgery, its utility in PSOs of the lumbar spine has not been robustly documented. The authors' aim was to determine the impact of IOM on outcomes in patients undergoing PSO of the lumbar spine. METHODS: All patients older than 18 years who underwent lumbar PSOs at the authors' institution from 2007 to 2017 were analyzed via retrospective chart review and categorized into one of two groups: those who had IOM guidance and those who did not. Perioperative complications were designated as the primary outcome measure and postoperative quality of life (QOL) scores, specifically the Parkinson's Disease Questionnaire-39 (PDQ-39) and Patient Health Questionnaire-9 (PHQ-9), were designated as secondary outcome measures. Data on patient demographics, surgical and monitoring parameters, and outcomes were gathered, and statistical analysis was performed to compare the development of perioperative complications and QOL scores between the two cohorts. In addition, the proportion of patients who reached minimal clinically important difference (MCID), defined as an increase of 4.72 points in the PDQ-39 score or a decrease of 5 points in the PHQ-9 score, in the two cohorts was also determined. RESULTS: A total of 95 patients were included in the final analysis. IOM was not found to significantly impact the development of new postoperative deficits (p = 0.107). However, the presence of preoperative neurological comorbidities was found to significantly correlate with postoperative neurological complications (p = 0.009). Univariate analysis showed that age was positively correlated with MCID achievement 3 months after surgery (p = 0.018), but this significance disappeared at the 12-month postoperative time point (p = 0.858). IOM was not found to significantly impact MCID achievement at either the 3- or 12-month postoperative period as measured by PDQ-39 (p = 0.398 and p = 0.156, respectively). Similarly, IOM was not found to significantly impact MCID achievement at either the 3- or 12-month postoperative period, as measured by PHQ-9 (p = 0.230 and p = 0.542, respectively). Multivariate analysis showed that female sex was significantly correlated with MCID achievement (p = 0.024), but this significance disappeared at the 12-month postoperative time point (p = 0.064). IOM was not found to independently correlate with MCID achievement in PDQ-39 scores at either the 3- or 12-month postoperative time points (p = 0.220 and p = 0.097, respectively). CONCLUSIONS: In this particular cohort, IOM did not lead to statistically significant improvement in outcomes in patients undergoing PSOs of the lumbar spine (p = 0.220). The existing clinical equipoise, however, indicates that future studies in this arena are necessary to achieve systematic guidelines on IOM usage in PSOs of the lumbar spine.

7.
Laryngoscope ; 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31361334

RESUMO

BACKGROUND: Predictive models to forecast the likelihood of specific outcomes after surgical intervention allow informed shared decision-making by surgeons and patients. Previous studies have suggested that existing general surgical risk calculators poorly forecast head and neck surgical outcomes. However, no large study has addressed this question while subdividing subjects by surgery performed. OBJECTIVES: To determine the accuracy of the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) Surgical Risk Calculator in estimating length of hospital stay and risk of postoperative complications after free tissue transfer surgery. STUDY DESIGN: A retrospective chart review of patients at one institution was performed using Current Procedural Terminology codes for anterolateral thigh (ALT) flap, fibula free flap (FFF), and radial forearm free flap (RFFF) reconstruction. Output data from the ACS NSQIP surgical risk calculator were compared with the observed rates in our patients. METHODS: Incidences of cardiac complications, pneumonia, venous thromboembolism, return to the operating room, and discharge to skilled nursing facility (SNF) were compared to predicted incidences. Length of stay was also compared to the predicted length of stay. RESULTS: Three hundred thirty-six free flap reconstructions with 197 ALT flaps, 85 RFFFs, and 54 FFFFs were included. Brier scores were calculated using ACS NSQIP forecast and actual incidences. No Brier score was <0.01 for the entire sample or any subgroup, which indicates that the NSQIP risk calculator does not accurately forecast outcomes after free tissue reconstruction. CONCLUSION: The ACS NSQIP failed to accurately forecast postoperative outcomes after head and neck free flap reconstruction for the entire sample or subgroup analyses. LEVEL OF EVIDENCE: 4 Laryngoscope, 2019.

8.
Neoplasia ; 21(7): 721-729, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174021

RESUMO

Chromosomal aneuploidy is a defining feature of epithelial cancers. The pattern of aneuploidies is cancer-type specific. For instance, the gain of chromosome 13 occurs almost exclusively in colorectal cancer. We used microcell-mediated chromosome transfer to generate gains of chromosome 13 in the diploid human colorectal cancer cell line DLD-1. Extra copies of chromosome 13 resulted in a significant and reproducible up-regulation of transcript levels of genes on chromosome 13 (P = .0004, FDR = 0.01) and a genome-wide transcriptional deregulation in all 8 independent clones generated. Genes contained in two clusters were particularly affected: the first cluster on cytoband 13q13 contained 7 highly up-regulated genes (NBEA, MAB21L1, DCLK1, SOHLH2, CCDC169, SPG20 and CCNA1, P = .0003) in all clones. A second cluster was located on 13q32.1 and contained five upregulated genes (ABCC4, CLDN10, DZIP1, DNAJC3 and UGGT2, P = .003). One gene, RASL11A, localized on chromosome band 13q12.2, escaped the copy number-induced overexpression and was reproducibly and significantly down-regulated on the mRNA and protein level (P = .0001, FDR = 0.002). RASL11A expression levels were also lower in primary colorectal tumors as compared to matched normal mucosa (P = .0001, FDR = 0.0001. Overexpression of RASL11A increases cell proliferation and anchorage independent growth while decreasing cell migration in +13 clones. In summary, we observed a strict correlation of genomic copy number and resident gene expression levels, and aneuploidy dependent consistent genome-wide transcriptional deregulation.

9.
Mol Cancer Res ; 17(8): 1759-1773, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31164412

RESUMO

Cancer development requires a favorable tissue microenvironment. By deleting Myd88 in keratinocytes or specific bone marrow subpopulations in oncogenic RAS-mediated skin carcinogenesis, we show that IL17 from infiltrating T cells and IκBζ signaling in keratinocytes are essential to produce a permissive microenvironment and tumor formation. Both normal and RAS-transformed keratinocytes respond to tumor promoters by activating canonical NF-κB and IκBζ signaling, releasing specific cytokines and chemokines that attract Th17 cells through MyD88-dependent signaling in T cells. The release of IL17 into the microenvironment elevates IκBζ in normal and RAS-transformed keratinocytes. Activation of IκBζ signaling is required for the expression of specific promoting factors induced by IL17 in normal keratinocytes and constitutively expressed in RAS-initiated keratinocytes. Deletion of Nfkbiz in keratinocytes impairs RAS-mediated benign tumor formation. Transcriptional profiling and gene set enrichment analysis of IκBζ-deficient RAS-initiated keratinocytes indicate that IκBζ signaling is common for RAS transformation of multiple epithelial cancers. Probing The Cancer Genome Atlas datasets using this transcriptional profile indicates that reduction of IκBζ signaling during cancer progression associates with poor prognosis in RAS-driven human cancers. IMPLICATIONS: The paradox that elevation of IκBζ and stimulation of IκBζ signaling through tumor extrinsic factors is required for RAS-mediated benign tumor formation while relative IκBζ expression is reduced in advanced cancers with poor prognosis implies that tumor cells switch from microenvironmental dependency early in carcinogenesis to cell-autonomous pathways during cancer progression.

10.
PLoS Genet ; 15(5): e1008020, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31125342

RESUMO

Breast cancer is the second leading cause of cancer-related deaths in the United States, with the majority of these deaths due to metastatic lesions rather than the primary tumor. Thus, a better understanding of the etiology of metastatic disease is crucial for improving survival. Using a haplotype mapping strategy in mouse and shRNA-mediated gene knockdown, we identified Rnaseh2c, a scaffolding protein of the heterotrimeric RNase H2 endoribonuclease complex, as a novel metastasis susceptibility factor. We found that the role of Rnaseh2c in metastatic disease is independent of RNase H2 enzymatic activity, and immunophenotyping and RNA-sequencing analysis revealed engagement of the T cell-mediated adaptive immune response. Furthermore, the cGAS-Sting pathway was not activated in the metastatic cancer cells used in this study, suggesting that the mechanism of immune response in breast cancer is different from the mechanism proposed for Aicardi-Goutières Syndrome, a rare interferonopathy caused by RNase H2 mutation. These results suggest an important novel, non-enzymatic role for RNASEH2C during breast cancer progression and add Rnaseh2c to a panel of genes we have identified that together could determine patients with high risk for metastasis. These results also highlight a potential new target for combination with immunotherapies and may contribute to a better understanding of the etiology of Aicardi-Goutières Syndrome autoimmunity.

11.
Nat Commun ; 10(1): 2071, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-31061501

RESUMO

Translation and transcription are frequently dysregulated in cancer. These two processes are generally regulated by distinct sets of factors. The CBFB gene, which encodes a transcription factor, has recently emerged as a highly mutated driver in a variety of human cancers including breast cancer. Here we report a noncanonical role of CBFB in translation regulation. RNA immunoprecipitation followed by deep sequencing (RIP-seq) reveals that cytoplasmic CBFB binds to hundreds of transcripts and regulates their translation. CBFB binds to mRNAs via hnRNPK and enhances translation through eIF4B, a general translation initiation factor. Interestingly, the RUNX1 mRNA, which encodes the transcriptional partner of CBFB, is bound and translationally regulated by CBFB. Furthermore, nuclear CBFB/RUNX1 complex transcriptionally represses the oncogenic NOTCH signaling pathway in breast cancer. Thus, our data reveal an unexpected function of CBFB in translation regulation and propose that breast cancer cells evade translation and transcription surveillance simultaneously through downregulating CBFB.


Assuntos
Neoplasias da Mama/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade beta de Fator de Ligação ao Core/metabolismo , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo , Animais , Mama/patologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Regulação para Baixo , Fatores de Iniciação em Eucariotos/metabolismo , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Nus , RNA Mensageiro/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais/genética , Análise Serial de Tecidos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Clin Spine Surg ; 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30407261

RESUMO

The use of intraoperative multimodal monitoring (IOM) in spinal deformity surgeries is well documented. In particular, pedicle subtraction osteotomy (PSO), a corrective procedure for sagittal deformity of the spine, often involves IOM usage. By providing immediate feedback to the operating surgeon, IOM has the potential to eliminate or at least minimize the risk of iatrogenic neurological injury. However, despite the widespread usage of IOM, there is currently no standardization of IOM usage in complex spine surgeries, including lumbar PSOs, and decisions concerning IOM utilization are often driven by surgeon experience and preference. This creates a state of clinical equipoise, which is further complicated by the varying degrees of benefit that IOM has on patient outcomes depending on the operation and spinal levels involved. For instance, while IOM use in thoracic PSOs has been shown to be effective, there is no established consensus on the net impact of IOM use in PSOs of the lumbar spine. Although IOM has the potential to mitigate neurological damage, it also increases operation time and cost; thus, it should only be used in operations where it will have a net positive impact on patient outcomes. The question thus becomes whether PSO of the lumbar spine is one such operation. To address this, we examine the most frequently used IOM modalities and evaluate their current usage and efficacy in lumbar PSOs. Furthermore, we will also examine the utility of IOM for other surgeries of the lumbar spine, including corrective procedures for idiopathic scoliosis and degenerative scoliosis, and routine lumbar procedures, such as discectomies and decompression surgeries for foraminal and canal stenosis.

13.
Oncotarget ; 9(14): 11677-11690, 2018 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-29545929

RESUMO

Breast cancer, a heterogeneous disease with variable pathophysiology and biology, is classified into four major subtypes. While hormonal- and antibody-targeted therapies are effective in the patients with luminal and HER-2 subtypes, the patients with triple-negative breast cancer (TNBC) subtype do not benefit from these therapies. The incidence rates of TNBC subtype are higher in African-American women, and the evidence indicates that these women have worse prognosis compared to women of European descent. The reasons for this disparity remain unclear but are often attributed to TNBC biology. In this study, we performed metabolic analysis of breast tissues to identify how TNBC differs from luminal A breast cancer (LABC) subtypes within the African-American and Caucasian breast cancer patients, respectively. We used High-Resolution Magic Angle Spinning (HR-MAS) 1H Nuclear magnetic resonance (NMR) to perform the metabolomic analysis of breast cancer and adjacent normal tissues (total n=82 samples). TNBC and LABC subtypes in African American women exhibited different metabolic profiles. Metabolic profiles of these subtypes were also distinct from those revealed in Caucasian women. TNBC in African-American women expressed higher levels of glutathione, choline, and glutamine as well as profound metabolic alterations characterized by decreased mitochondrial respiration and increased glycolysis concomitant with decreased levels of ATP. TNBC in Caucasian women was associated with increased pyrimidine synthesis. These metabolic alterations could potentially be exploited as novel treatment targets for TNBC.

14.
Mol Cancer Ther ; 16(9): 2008-2021, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28522584

RESUMO

Cancer treatments often require combinations of molecularly targeted agents to be effective. mTORi (rapamycin) and HDACi (MS-275/entinostat) inhibitors have been shown to be effective in limiting tumor growth, and here we define part of the cooperative action of this drug combination. More than 60 human cancer cell lines responded synergistically (CI<1) when treated with this drug combination compared with single agents. In addition, a breast cancer patient-derived xenograft, and a BCL-XL plasmacytoma mouse model both showed enhanced responses to the combination compared with single agents. Mice bearing plasma cell tumors lived an average of 70 days longer on combination treatment compared with single agents. A set of 37 genes cooperatively affected (34 downregulated; 3 upregulated) by the combination responded pharmacodynamically in human myeloma cell lines, xenografts, and a P493 model, and were both enriched in tumors, and correlated with prognostic markers in myeloma patient datasets. Genes downregulated by the combination were overexpressed in several untreated cancers (breast, lung, colon, sarcoma, head and neck, myeloma) compared with normal tissues. The MYC/E2F axis, identified by upstream regulator analyses and validated by immunoblots, was significantly inhibited by the drug combination in several myeloma cell lines. Furthermore, 88% of the 34 genes downregulated have MYC-binding sites in their promoters, and the drug combination cooperatively reduced MYC half-life by 55% and increased degradation. Cells with MYC mutations were refractory to the combination. Thus, integrative approaches to understand drug synergy identified a clinically actionable strategy to inhibit MYC/E2F activity and tumor cell growth in vivoMol Cancer Ther; 16(9); 2008-21. ©2017 AACR.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Reparo do DNA , Replicação do DNA/efeitos dos fármacos , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Perfilação da Expressão Gênica , Humanos , Camundongos , Farmacogenética , Variantes Farmacogenômicos , Estabilidade Proteica , Proteólise , Transcriptoma , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Oncotarget ; 8(19): 30621-30643, 2017 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-28430642

RESUMO

Effective drug development to combat metastatic disease in breast cancer would be aided by the availability of well-characterized preclinical animal models that (a) metastasize with high efficiency, (b) metastasize in a reasonable time-frame, (c) have an intact immune system, and (d) capture some of the heterogeneity of the human disease. To address these issues, we have assembled a panel of twelve mouse mammary cancer cell lines that can metastasize efficiently on implantation into syngeneic immunocompetent hosts. Genomic characterization shows that more than half of the 30 most commonly mutated genes in human breast cancer are represented within the panel. Transcriptomically, most of the models fall into the luminal A or B intrinsic molecular subtypes, despite the predominance of an aggressive, poorly-differentiated or spindled histopathology in all models. Patterns of immune cell infiltration, proliferation rates, apoptosis and angiogenesis differed significantly among models. Inherent within-model variability of the metastatic phenotype mandates large cohort sizes for intervention studies but may also capture some relevant non-genetic sources of variability. The varied molecular and phenotypic characteristics of this expanded panel of models should aid in model selection for development of antimetastatic therapies in vivo, and serve as a useful platform for predictive biomarker identification.


Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias Mamárias Experimentais , Aloenxertos , Animais , Biomarcadores Tumorais , Biópsia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Genômica/métodos , Xenoenxertos , Humanos , Imuno-Histoquímica , Camundongos , Terapia de Alvo Molecular , Metástase Neoplásica , Polimorfismo de Nucleotídeo Único
16.
Clin Epigenetics ; 8: 38, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27081402

RESUMO

BACKGROUND: Oncogene overexpression in primary cells often triggers the induction of a cellular safeguard response promoting senescence or apoptosis. Secondary cooperating genetic events are generally required for oncogene-induced tumorigenesis to overcome these biologic obstacles. We employed comparative genomic hybridization for eight genetically engineered mouse models of mammary cancer to identify loci that might harbor genes that enhance oncogene-induced tumorigenesis. RESULTS: Unlike many other mammary tumor models, the MMTV-Myc tumors displayed few copy number variants except for amplification of distal mouse chromosome 11 in 80 % of the tumors (syntenic to human 17q23-qter often amplified in human breast cancer). Analyses of candidate genes located in this region identified JMJD6 as an epigenetic regulatory gene that cooperates with Myc to enhance tumorigenesis. It suppresses Myc-induced apoptosis under varying stress conditions through inhibition of p19ARF messenger RNA (mRNA) and protein, leading to reduced levels of p53. JMJD6 binds to the p19ARF promoter and exerts its inhibitory function through demethylation of H4R3me2a. JMJD6 overexpression in MMTV-Myc cell lines increases tumor burden, induces EMT, and greatly enhances tumor metastasis. Importantly, we demonstrate that co-expression of high levels of JMJD6 and Myc is associated with poor prognosis for human ER+ breast cancer patients. CONCLUSIONS: A novel epigenetic mechanism has been identified for how JMJD6 cooperates with Myc during oncogenic transformation. Combined high expression of Myc and JMJD6 confers a more aggressive phenotype in mouse and human tumors. Given the pleiotropic pro-tumorigenic activities of JMJD6, it may be useful as a prognostic factor and a therapeutic target for Myc-driven mammary tumorigenesis.


Assuntos
Neoplasias da Mama/patologia , Transformação Celular Neoplásica/genética , Epigênese Genética , Histona Desmetilases com o Domínio Jumonji/genética , Neoplasias Mamárias Experimentais/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Animais , Apoptose , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/metabolismo , Hibridização Genômica Comparativa , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Metástase Neoplásica , Prognóstico , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais
17.
Breast Cancer Res Treat ; 157(1): 13-22, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27107568

RESUMO

This review summarizes methods related to the study of human breastmilk in etiologic and biomarkers research. Despite the importance of reproductive factors in breast carcinogenesis, factors that act early in life are difficult to study because young women rarely require breast imaging or biopsy, and analysis of critical circulating factors (e.g., hormones) is often complicated by the requirement to accurately account for menstrual cycle date. Accordingly, novel approaches are needed to understand how events such as pregnancy, breastfeeding, weaning, and post-weaning breast remodeling influence breast cancer risk. Analysis of breastmilk offers opportunities to understand mechanisms related to carcinogenesis in the breast, and to identify risk markers that may inform efforts to identify high-risk women early in the carcinogenic process. In addition, analysis of breastmilk could have value in early detection or diagnosis of breast cancer. In this article, we describe the potential for using breastmilk to characterize the microenvironment of the lactating breast with the goal of advancing research on risk assessment, prevention, and detection of breast cancer.


Assuntos
Neoplasias da Mama/diagnóstico , Detecção Precoce de Câncer/métodos , Leite Humano/química , Aleitamento Materno , Neoplasias da Mama/etiologia , Feminino , Humanos , Lactação , Gravidez , Fatores de Risco , Manejo de Espécimes , Desmame
18.
PLoS Genet ; 12(4): e1005989, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27074153

RESUMO

Metastasis remains the primary cause of patient morbidity and mortality in solid tumors and is due to the action of a large number of tumor-autonomous and non-autonomous factors. Here we report the results of a genome-wide integrated strategy to identify novel metastasis susceptibility candidate genes and molecular pathways in breast cancer metastasis. This analysis implicates a number of transcriptional regulators and suggests cell-mediated immunity is an important determinant. Moreover, the analysis identified novel or FDA-approved drugs as potentially useful for anti-metastatic therapy. Further explorations implementing this strategy may therefore provide a variety of information for clinical applications in the control and treatment of advanced neoplastic disease.


Assuntos
Predisposição Genética para Doença , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Animais/genética , Animais , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Estudo de Associação Genômica Ampla , Fatores de Transcrição Kruppel-Like/biossíntese , Fatores de Transcrição Kruppel-Like/genética , Neoplasias Mamárias Animais/diagnóstico , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos NZB , Camundongos Transgênicos , Nectinas , Proteína com Dedos de Zinco da Leucemia Promielocítica , Interferência de RNA , RNA Interferente Pequeno/genética , Rosiglitazona , Tiazolidinedionas/farmacologia
19.
Semin Oncol ; 43(1): 36-48, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26970123

RESUMO

Cancer is a complex category of diseases caused in large part by genetic or genomic, transcriptomic, and epigenetic or epigenomic alterations in affected cells and the surrounding microenvironment. Carcinogenesis reflects the clonal expansion of cells that progressively acquire these genetic and epigenetic alterations-changes that, in turn, lead to modifications at the RNA level. Gradually advancing technology and most recently, the advent of next-generation sequencing (NGS), combined with bioinformatics analytic tools, have revolutionized our ability to interrogate cancer cells. The ultimate goal is to apply these high-throughput technologies to the various aspects of clinical cancer care: cancer-risk assessment, diagnosis, as well as target identification for treatment and prevention. In this article, we emphasize how the knowledge gained through large-scale omics-oriented approaches, with a focus on variations at the level of nucleic acids, can inform the field of chemoprevention.


Assuntos
Variação Genética , Genômica/métodos , Neoplasias/genética , Neoplasias/prevenção & controle , Animais , Biomarcadores Tumorais/genética , Carcinogênese/genética , Epigênese Genética , Dosagem de Genes , Perfilação da Expressão Gênica/métodos , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Análise de Sequência de DNA , Análise de Sequência de RNA , Transcriptoma
20.
Cancer Res ; 76(7): 1714-23, 2016 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-26857264

RESUMO

Gastric cancer and esophageal cancer are the second and sixth leading causes of cancer-related death worldwide. Multiple genomic alterations underlying gastric cancer and esophageal squamous cell carcinoma (ESCC) have been identified, but the full spectrum of genomic structural variations and mutations have yet to be uncovered. Here, we report the results of whole-genome sequencing of 30 samples comprising tumor and blood from 15 patients, four of whom presented with ESCC, seven with gastric cardia adenocarcinoma (GCA), and four with gastric noncardia adenocarcinoma. Analyses revealed that an A>C mutation was common in GCA, and in addition to the preferential nucleotide sequence of A located 5 prime to the mutation as noted in previous studies, we found enrichment of T in the 5 prime base. The A>C mutations in GCA suggested that oxidation of guanine may be a potential mechanism underlying cancer mutagenesis. Furthermore, we identified genes with mutations in gastric cancer and ESCC, including well-known cancer genes, TP53, JAK3, BRCA2, FGF2, FBXW7, MSH3, PTCH, NF1, ERBB2, and CHEK2, and potentially novel cancer-associated genes, KISS1R, AMH, MNX1, WNK2, and PRKRIR Finally, we identified recurrent chromosome alterations in at least 30% of tumors in genes, including MACROD2, FHIT, and PARK2 that were often intragenic deletions. These structural alterations were validated using the The Cancer Genome Atlas dataset. Our studies provide new insights into understanding the genomic landscape, genome instability, and mutation profile underlying gastric cancer and ESCC development. Cancer Res; 76(7); 1714-23. ©2016 AACR.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Genômica/métodos , Neoplasias Gástricas/genética , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Neoplasias Gástricas/patologia
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