A quality improvement initiative standardizing the antibiotic treatment and feeding practices in patients with medical necrotizing enterocolitis.

OBJECTIVE: Evaluate the impact of a multidisciplinary guideline standardizing antibiotic duration and enteral feeding practices following medical necrotizing enterocolitis (mNEC). STUDY DESIGN: For preterm infants with Bell Stage 2 A mNEC and negative blood culture, antibiotic treatment was standardized to 7 days. Trophic feeds of unfortified human milk began 72 h after resolution of pneumatosis. Feeds were advanced by 20 cc/kg/day starting on the last day of antibiotics. Primary outcomes were antibiotic days and days to full feeds, defined as 120 cc/kg/day of enteral nutrition. Secondary outcomes included central line days and length of stay (LOS). RESULTS: Antibiotic duration decreased 23%. Time to start trophic feeds and time to full feeds decreased 33 and 16% respectively. Central line use dropped (98 to 72% of infants) and central line days were reduced by 59%. CONCLUSION: Implementation of a mNEC QI package reduced antibiotic duration, time to full feeds, central line use and CL days.

Assimilation and economic development: the case of federal Indian policy.

Throughout the nineteenth century, federal Indian policy oscillated between two extreme positions: assimilation versus isolation. While scholars have often been interested in the impact of past federal policy on current levels of economic development among American Indian tribes, none have explicitly examined the influence of federal assimilation policy on long-run economic development. In this paper, I take advantage of tribal-level variation in the application of federal policies to estimate the effect of assimilation on long-run economic performance. To quantify the impact of such policies, I introduce a novel measure of cultural assimilation: the prevalence of traditional indigenous names relative to common American first names. To calculate the distribution of name types, I have gathered the names and locations for all American Indians enumerated in the 1900 United States census. After classifying each name, I calculated the reservation-specific share of non-indigenous names. I estimate the relationship between cultural assimilation in 1900 and per capita income from 1970 through 2020. I find that historical levels of assimilation are consistently associated with higher levels of per capita income in all census years. The results are robust to the inclusion of a variety of cultural and institutional controls and regional fixed effects.

Effect of methadone on QTc in infants.

OBJECTIVE: Methadone has been associated with prolongation of the QTc interval (QTc) on electrocardiogram (ECG). In infants, the effects of methadone on the QTc are not well described. Our study's objective is to evaluate the QTc in infants being treated with methadone. METHODS: We conducted a retrospective study in infants receiving methadone. We collected demographic data, methadone dose, and QTc. A blinded-to-disease-state pediatric electrophysiologist determined the QTc. Baseline ECG was defined as an ECG obtained while not on methadone therapy, and QTc on baseline ECG was compared with treatment QTc. A significant change was defined as any absolute QTc greater than 500 or a QTc greater than 460 with an increase from baseline of greater than 40 ms. RESULTS: A total of 44 infants comprised the study population. The mean gestational age was 32.3 ± 5.51 weeks. The median age of initiation was 66 days. The median dose was 0.52 mg/kg/day in oral methadone equivalents. Nine patients were on high dose methadone (>1 mg/kg/day in oral methadone equivalents). The mean baseline QTc was 421 ± 27 and the mean change on methadone was -2 ms. No patient had a QTc greater than 500 on methadone. One patient had a QTc of 467 and 46 ms change from baseline, with no clinically significant impact. CONCLUSION: In our study population, methadone did not significantly prolong the QTc. Further prospective study is warranted to determine the utility and frequency of ECGs in infants receiving methadone.

Destroyed by Slavery? Slavery and African American Family Formation Following Emancipation.

This study introduces a new sample that links people and families across 1860, 1880, and 1900 census data to explore the intergenerational impact of slavery on black families in the United States. Slaveholding-the number of slaves owned by a single farmer or planter-is used as a proxy for experiences during slavery. Slave family structures varied systematically with slaveholding sizes. Enslaved children on smaller holdings were more likely to be members of single-parent or divided families. On larger holdings, however, children tended to reside in nuclear families. In 1880, a child whose mother had been on a farm with five slaves was 49 % more likely to live in a single-parent household than a child whose mother had been on a farm with 15 slaves. By 1900, slaveholding no longer had an impact. However, children whose parents lived in single-parent households were themselves more likely to live in single-parent households and to have been born outside marriage.

Klebsiella oxytoca tricuspid valve endocarditis in an elderly patient without known predisposing factors.

A 73-year-old man with history of nephrolithiasis was admitted after a witnessed cardiac arrest. In the emergency department, the patient had several runs of ventricular fibrillation treated with defibrillation and amiodarone infusion. Echocardiography revealed reduced ejection fraction with multiple mobile structures attached to the tricuspid valve leaflets. Due to concern for possible endocarditis, the patient was started on broad-spectrum antibiotics. On the following day, a renal ultrasound was performed for acute kidney injury followed by a non-contrast CT scan that revealed an obstructing 21 mm left-sided ureteral stone with pyohydronephrosis. He underwent emergent nephrostomy tube placement. Blood and urine cultures subsequently demonstrated the growth of Klebsiella oxytoca A follow-up transoesophageal echocardiogram confirmed multiple mobile, hyperechoic masses consistent with vegetations. The suspected source for the endocarditis was from the pyelonephritis. The patient's clinical condition improved after a course of intravenous antibiotics and was discharged on oral antibiotics.

Is it possible to recover from traumatic brain injury and a Glasgow coma scale score of 3 at emergency department presentation?

INTRODUCTION: A Glasgow Coma Scale (GCS) score of 3 on presentation in patients with traumatic brain injury (TBI) portends a poor prognosis. Consequently, there is often a tendency to treat these patients less aggressively because of low expectations for a good outcome. METHODS AND RESULTS: We performed a retrospective review of patients with TBI and a GCS score of 3. Patients were divided into 2 groups based on Glasgow Outcome Scale (GOS): Group 1 (GOS=1-3) and Group 2 (GOS=4-5). A total of 62 patients were included. The overall mortality rate was 80.6%. At 6-month, 9 patients (14.5%) achieved a GOS 4-5. Compared to Group 2 (n=9), Group 1 (n=53) had higher average APACHE IV score (104±19 vs 89±27, p=0.04), more patients with bilateral fixed pupils (59% vs 22%, p=0.04), and higher ICP burden (50±34 vs 0±0, p=0.0001). Using the CRASH calculator, the estimated mortality at 14days was 66% compared to actual mortality of 81%; difference of 15%, (p=0.05), and the estimated GOS 1-3 was 85.5% compared to actual of 85.5%, (p=1.0). CONCLUSIONS: 14.5% of patients with TBI and a GCS of 3 at presentation achieved a good outcome at 6months, and 6.9% of patients with GCS of 3 and bilateral fixed pupils on presentation to the ED achieved a good outcome at 6months.

Vivione Bioscience RAPID-B(®) E. coli O157 test kit and non-O157 STEC test kit evaluation.

RAPID-B(®) is a high performance, integrated microbiology/infectious disease diagnostic system. The system uses hardware and software that are specifically designed for optimal detection using custom, immuno-based reagents designed to react to cell surface antigens of the target bacteria. The Vivione Bioscience RAPID-B Escherichia coli O157 and non-O157 Shiga toxin-producing E. coli (STEC) kits were validated alongside the U.S. Department of Agriculture, Food Safety and Inspection Service (FSIS), Microbiology Laboratory Guidebook (MLG) 5.07 (for E. coli O157) and FSIS MLG 5B.04 (for non-O157 STEC) reference methods for the detection of E. coli O157 and STEC. The matrixes, ground beef and beef trim, were inoculated with appropriate CFU/test portion of E. coli O157 and STEC so as to generate fractional positives results, 5 to 15 positives out of 20 inoculated samples. Samples were enriched in prewarmed Brain Heart Infusion broth at 42 ± 1°C for 6.5-7.5 h or 8.5-9.5 h depending on the sample size. All samples were confirmed using the MLG reference method, regardless of initial screen result. The RAPID-B test methods were statistically equivalent to the reference method for the detection of E. coli O157 and STEC in all tested samples. Inclusivity and exclusivity testing of the RAPID-B methods showed 100% specificity for both kits. Finally, the RAPID-B test methods were shown to be robust when variations were applied to enrichment time, broth temperature, and vortexing time.

Basal anxiety-like behavior predicts differences in dendritic morphology in the medial prefrontal cortex in two strains of rats.

Basal differences in the brain may account for why some individuals are more vulnerable to stress than others. Although trait anxiety behavior varies greatly in human populations, most animal models of anxiety disorders tend to focus on the development of anxiety after a stressful experience. In this study, adult male Sprague-Dawley and Lewis rats were grouped according to baseline anxiety-like behavior in the open field, measured by time spent and distance traveled in the center. Individuals that fell one standard deviation above and below the mean, approximately the top and bottom 15%, were selected for the Low and High Anxiety groups. Pyramidal neurons from layer II/III of the prelimbic region of the medial prefrontal cortex were iontophoretically loaded with Lucifer yellow dye and reconstructed. In both strains, animals in the High Anxiety group had smaller apical dendrites than those in the Low Anxiety group. No difference was found in basal dendrites. Sholl analysis revealed a strain difference in the distribution of dendritic material between anxiety groups. These results illustrate significant variability in dendritic morphology in the prefrontal cortex of healthy adult male rats prior to experimental manipulation that correlates with baseline levels of anxiety-like behavior.

Interleukin-1 accounts for intrarenal Th17 cell activation during ureteral obstruction.

Interleukin 17A-secreting T-helper 17 (Th17) cells are pathogenic in inflammatory kidney diseases, but their intrarenal regulation is poorly understood. In order to better define Th17 cell dynamics during interstitial inflammation, we utilized the mouse unilateral ureteral obstruction model to analyze inflammatory cell subtypes by multicolor flow cytometry and cell sorting and by effects on in vitro-generated Th17 cells. Interleukin 17A expression localized to CCR6(+)CCR4(+/-)CD4(+) T-cells and progressively increased in obstructed kidneys. The number of CCR6(+)CD4(+) T-cells increased over 10-fold by 72 h, were enriched for interleukin 17A production, and were highly proliferative based on in vivo bromodeoxyuridine incorporation. Secreted products of leukocytes isolated from obstructed kidneys enhanced the interleukin 17A production of in vitro-generated Th17 cells. This Th17-enhancing activity was identified as interleukin-1 produced by renal dendritic cells and monocytes. The in vivo validity of these findings was confirmed in mice lacking the interleulin-1 receptor and in mice treated with a recombinant interleukin-1 receptor antagonist, each of which exhibited reduced intrarenal Th17 activity compared with control mice. Thus, the inflamed kidney accumulates CCR6(+) Th17 cells that undergo activation and proliferation. Production of interleukin 1 family cytokines by resident dendritic cells and infiltrating monocytes enhances intrarenal Th17 activation in acute kidney injury.

Accumulation of resident and peripheral dendritic cells in the aging CNS.

Dendritic cells (DC) are specialized antigen-presenting cells, responsible for peripheral immune responses. Recently, resident brain dendritic cells (bDC) were identified and functionally characterized in the young adult Itgax (CD11c) EYFP+ transgenic mouse brain. In the present study, we describe changes in number, phenotype, and source of bDC in the aging mouse brain. Immunohistochemistry and fluorescent activated cell sorting (FACS) analysis revealed an age-related increase in bDC with a concomitant rise in the expression of immune activation markers MHCII, CD80, and CD86. Quantification of immunolabeled bDC in the cortex, corpus callosum, and cerebellum of the aged brain revealed a 2- to 5-fold increase. In contrast, either no change or a decrease in bDC was noted in regions of adult neurogenesis. Chimeras (wild type host/EYFP+ bone marrow) suggest that the increase of EYFP+ cells in the aging brain is in part due to an accumulation of peripherally derived cells. Collectively, the numerical and phenotypic changes in bDC indicate these cells may serve as an important immune component in the functional and anatomic alterations associated with aging.

Stress and anxiety: structural plasticity and epigenetic regulation as a consequence of stress.

The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as the behavioral and physiological responses to the stressor. The adult, as well as developing brain, possess a remarkable ability to show reversible structural and functional plasticity in response to stressful and other experiences, including neuronal replacement, dendritic remodeling, and synapse turnover. This is particularly evident in the hippocampus, where all three types of structural plasticity have been recognized and investigated, using a combination of morphological, molecular, pharmacological, electrophysiological and behavioral approaches. The amygdala and the prefrontal cortex, brain regions involved in anxiety and fear, mood, cognitive function and behavioral control, also show structural plasticity. Acute and chronic stress cause an imbalance of neural circuitry subserving cognition, decision making, anxiety and mood that can increase or decrease expression of those behaviors and behavioral states. In the short term, such as for increased fearful vigilance and anxiety in a threatening environment, these changes may be adaptive; but, if the danger passes and the behavioral state persists along with the changes in neural circuitry, such maladaptation may need intervention with a combination of pharmacological and behavioral therapies, as is the case for chronic or mood anxiety disorders. We shall review cellular and molecular mechanisms, as well as recent work on individual differences in anxiety-like behavior and also developmental influences that bias how the brain responds to stressors. Finally, we suggest that such an approach needs to be extended to other brain areas that are also involved in anxiety and mood. This article is part of a Special Issue entitled 'Anxiety and Depression'.

Cage change influences serum corticosterone and anxiety-like behaviors in the mouse.

Environmental variables and husbandry practices can influence physiology and alter behavior in mice. Our study evaluated the effects of cage change on serum corticosterone levels and anxiety-like behaviors in C57BL/6 male mice. We examined the effects of 3 different methods of performing cage transfer and of transferring mice to a clean or a dirty familiar cage microenvironment. The 3 different handling methods were forceps transfer, gentle transfer with gloved hands, and a passive transfer technique that did not involve active handling. Active handling methods and transfer to both clean and dirty cage microenvironments significantly increased serum corticosterone 15 min after cage change; however, at 60 min after cage change, levels were comparable to those of unmanipulated mice. Although the effects were transient, cage change altered anxiety-like behaviors in the open field when behavioral testing was performed on the same day. These results demonstrate that the timing of cage change can influence behavioral results, an effect that is an important consideration for rodent behavioral studies.

PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer.

Several phosphoinositide 3-kinase (PI3K) catalytic subunit inhibitors are currently in clinical trial. We therefore sought to examine relationships between pharmacologic inhibition and somatic mutations in PI3K catalytic subunits in estrogen receptor (ER)-positive breast cancer, in which these mutations are particularly common. RNA interference (RNAi) was used to determine the effect of selective inhibition of PI3K catalytic subunits, p110alpha and p110beta, in ER(+) breast cancer cells harboring either mutation (PIK3CA) or gene amplification (PIK3CB). p110alpha RNAi inhibited growth and promoted apoptosis in all tested ER(+) breast cancer cells under estrogen deprived-conditions, whereas p110beta RNAi only affected cells harboring PIK3CB amplification. Moreover, dual p110alpha/p110beta inhibition potentiated these effects. In addition, treatment with the clinical-grade PI3K catalytic subunit inhibitor BEZ235 also promoted apoptosis in ER(+) breast cancer cells. Importantly, estradiol suppressed apoptosis induced by both gene knockdowns and BEZ235 treatment. Our results suggest that PI3K inhibitors should target both p110alpha and p110beta catalytic subunits, whether wild-type or mutant, and be combined with endocrine therapy for maximal efficacy when treating ER(+) breast cancer.

Dendritic cells facilitate accumulation of IL-17 T cells in the kidney following acute renal obstruction.

Acute urinary obstruction causes interstitial inflammation with leukocyte accumulation and the secretion of soluble mediators. Here we show that unilateral ureteral ligation caused a progressive increase in renal F4/80(+) and F4/80(-) dendritic cells, monocytes, neutrophils and T-cells 24-72 h following obstruction. Depletion of dendritic cells by clodronate pretreatment showed these cells to be the most potent source of tumor necrosis factor and other pro-inflammatory mediators in the obstructed kidney. F4/80(+) dendritic cells and T-cells co-localized in the cortico-medullary junction and cortex of the obstructed kidney. Cytokine secretion patterns and surface phenotypes of T-cells from obstructed kidneys were found to include interferon-gamma-secreting CD4(+) and CD8(+) memory T-cells as well as interleukin 17 (IL-17)-secreting CD4(+) memory T-cells. Depletion of the intra-renal dendritic cells prior to ligation did not numerically reduce T-cells in obstructed kidneys but attenuated interferon-gamma and IL-17-competent T-cells. Our study shows that intra-renal dendritic cells are a previously unidentified early source of proinflammatory mediators after acute urinary obstruction and play a specific role in recruitment and activation of effector-memory T-cells including IL-17-secreting CD4(+) T-cells.

Association of TMPRSS2-ERG gene fusion with clinical characteristics and outcomes: results from a population-based study of prostate cancer.

BACKGROUND: The presence of the TMPRSS2-ERG fusion gene in prostate tumors has recently been associated with an aggressive phenotype, as well as recurrence and death from prostate cancer. These associations suggest the hypothesis that the gene fusion may be used as a prognostic indicator for prostate cancer. METHODS: In this study, fluorescent in situ hybridization (FISH) assays were used to assess TMPRSS2-ERG fusion status in a group of 214 prostate cancer cases from two population-based studies. The FISH assays were designed to detect both fusion type (deletion vs. translocation) and the number of fusion copies (single vs. multiple). Genotyping of four ERG and one TMPRSS2 SNPs using germline DNA was also performed in a sample of the cases (n = 127). RESULTS: Of the 214 tumors scored for the TMPRSS2-ERG fusion, 64.5% were negative and 35.5% were positive for the fusion. Cases with the TMPRSS2-ERG fusion did not exhibit reduced prostate cancer survival (HR = 0.92, 95% CI = 0.22-3.93), nor was there a significant difference in cause-specific survival when stratifying by translocation or deletion (HR = 0.84, 95% CI = 0.23-3.12) or by the number of retained fusion copies (HR = 1.22, 95% CI = 0.45-3.34). However, evidence for reduced prostate cancer-specific survival was apparent in those cases whose tumor had multiple copies of the fusion. The variant T allele of the TMPRSS2 SNP, rs12329760, was positively associated with TMPRSS2-ERG fusion by translocation (p = 0.05) and with multiple copies of the gene fusion (p = 0.03). CONCLUSION: If replicated, the results presented here may provide insight into the mechanism by which the TMPRSS2-ERG gene fusion arises and also contribute to diagnostic evaluations for determining the subset of men who will go on to develop metastatic prostate cancer.

Xenografts of primary human gynecological tumors grown under the renal capsule of NOD/SCID mice show genetic stability during serial transplantation and respond to cytotoxic chemotherapy.

OBJECTIVES: Human cancer tissue xenograft models may provide a more accurate reflection of tumor biology than cell lines. This study evaluates the genetic and phenotypic stability of primary human gynecological tumors grown as serially transplanted xenografts. The response to conventional chemotherapy and novel molecular targeted chemotherapy is assessed in one of the transplantable xenograft lines. METHODS: Fresh tumor was transplanted beneath the renal capsule of NOD/SCID mice. Transplantable tumor lines were derived from 5 tumors (4 ovarian carcinomas and 1 uterine sarcoma), and serially transplanted for 2-6 generations. Comparisons were made between primary tumor and corresponding transplantable xenografts by CGH array, immunohistochemistry, and BRCA mutation analysis. Transplantable xenografts created from known BRCA1 germline mutation carriers were analyzed for histopathologic response (tumor volume, apoptotic and mitotic indices) to combination carboplatin/paclitaxel and to PARP inhibitor (PJ34). RESULTS: Unsupervised hierarchical cluster analysis applied to a 287 feature CGH array demonstrated a low degree of intratumoral genetic variation in 4/5 cases, with greater degree of variation in the fifth case (clear cell ovarian carcinoma derived from an omental sample). Assessment of proliferation using MIB-1 staining was concordant between primary tumor and transplantable xenograft in all ovarian cancer cases. BRCA mutation analysis identified germline BRCA1 mutation for further testing and this xenograft showed a significant response to carboplatin/paclitaxel chemotherapy, including a decrease in tumor volume and proliferation but did not demonstrate a response to the poly (ADP-ribose) polymerase-1 inhibitor PJ34. CONCLUSIONS: Xenografts derived from gynecologic tumors can be serially transplanted and grown under renal capsule of NOD/SCID mice with minimal genetic change. This model may be used to study progression of tumors, identify therapeutic targets, and test treatment modalities in tumors with well-characterized abnormalities in genes of fundamental importance in ovarian carcinogenesis, such as loss of BRCA1.

CD11c/EYFP transgene illuminates a discrete network of dendritic cells within the embryonic, neonatal, adult, and injured mouse brain.

The CD11c enhanced yellow fluorescent protein (EYFP) transgenic mouse was constructed to identify dendritic cells in the periphery (Lindquist et al. [2004] Nat. Immunol. 5:1243-1250). In this study, we used this mouse to characterize dendritic cells within the CNS. Our anatomic results showed discrete populations of EYFP(+) brain dendritic cells (EYFP(+) bDC) that colocalized with a small fraction of microglia immunoreactive for Mac-1, Iba-1, CD45, and F4/80 but not for NeuN, Dcx, NG2 proteoglycan, or GFAP. EYFP(+) bDC, isolated by fluorescent activated cell sorting (FACS), expressed mRNA for the Itgax (CD11c) gene, whereas FACS anlaysis of EYFP(+) bDC cultures revealed the presence of CD11c protein. Light microscopy studies revealed that EYFP(+) bDC were present in the embryonic CNS when the blood-brain barrier is formed and postnatally when brain cells are amenable to culturing. In adult male mice, EYFP(+) bDC distribution was prominent within regions of the CNS that 1) are subject to structural plasticity and neurogenesis, 2) receive sensory and humoral input from the external environment, and 3) lack a blood-brain barrier. Ultrastructural analysis of EYFP(+) bDC in adult neurogenic niches showed their proximity to developing neurons and a morphology characteristic of immune/microglia cells. Kainic acid-induced seizures revealed that EYFP(+) bDC responded to damage of the hippocampus and displayed morphologies similar to those described for seizure-activated EGFP(+) microglia in the hippocampus of cfms (CSF-1R) EGFP mice. Collectively, these findings suggest a new member of the dendritic cell family residing among the heterogeneous microglia population.

Amplification of 11q13 in ovarian carcinoma.

Amplification at the 11q13 locus is commonly observed in breast, ovarian, head and neck, oral, and esophageal cancer. Studies of this region led to the identification of multiple amplicons containing several potential oncogenes including EMSY, PAK1, RSF1, and GAB2. Here, we investigate the amplification of the above four genes and their prognostic significance in histologically and clinically defined subsets of ovarian cancer. Amplification of all four genes was assessed by fluorescent in situ hybridization in tissue microarrays containing 538 clinically annotated ovarian carcinomas with 12 years of follow-up data. Overall, for the entire cohort, EMSY was amplified in 44 (16%) of 269 cases, PAK1 was amplified in 38 (15%) of 255 cases, RSF1 was amplified in 37 (12%) of 310 cases, and GAB2 was amplified in 41 (16%) of 255 cases. Amplification of EMSY, PAK1, RSF1, and GAB2 were all highly correlated with each other and with a serous histology. Univariate survival analysis showed that tumors with EMSY and RSF1 amplification were associated with a significantly worse outcome. A molecular inversion probe array was then used to study the 11q13 amplicon in 33 high grade serous carcinomas. The core of the amplicon mapped to a 6-Mb region encompassing EMSY, PAK1, RSF1, and GAB2. However, a second more telomeric amplicon was also observed for which no candidate genes have been identified. In summary, amplification of these four putative oncogenes from 11q13 in early ovarian cancer is associated with a serous histology and in the case of EMSY and RSF1 a poor outcome. These findings support the hypothesis that the11q13 amplicon in ovarian cancer is likely driven by a cassette of genes rather than by a single oncogene. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

Amplification of PVT1 contributes to the pathophysiology of ovarian and breast cancer.

PURPOSE: This study was designed to elucidate the role of amplification at 8q24 in the pathophysiology of ovarian and breast cancer because increased copy number at this locus is one of the most frequent genomic abnormalities in these cancers. EXPERIMENTAL DESIGN: To accomplish this, we assessed the association of amplification at 8q24 with outcome in ovarian cancers using fluorescence in situ hybridization to tissue microarrays and measured responses of ovarian and breast cancer cell lines to specific small interfering RNAs against the oncogene MYC and a putative noncoding RNA, PVT1, both of which map to 8q24. RESULTS: Amplification of 8q24 was associated with significantly reduced survival duration. In addition, small interfering RNA-mediated reduction in either PVT1 or MYC expression inhibited proliferation in breast and ovarian cancer cell lines in which they were both amplified and overexpressed but not in lines in which they were not amplified/overexpressed. Inhibition of PVT1 expression also induced a strong apoptotic response in cell lines in which it was overexpressed but not in lines in which it was not amplified/overexpressed. Inhibition of MYC, on the other hand, did not induce an apoptotic response in cell lines in which MYC was amplified and overexpressed. CONCLUSIONS: These results suggest that MYC and PVT1 contribute independently to ovarian and breast pathogenesis when overexpressed because of genomic abnormalities. They also suggest that PVT1-mediated inhibition of apoptosis may explain why amplification of 8q24 is associated with reduced survival duration in patients treated with agents that act through apoptotic mechanisms.