High Dimensional Apollonian Networks

We propose a simple algorithm which produces high dimensional Apollonian networks with both small-world and scale-free characteristics. We derive analytical expressions for the degree distribution, the clustering coefficient and the diameter of the networks, which are determined by their dimension

Comprehensive histopathological comparison of epidermotropic/dermal metastatic melanoma and primary nodular melanoma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141829/1/his13384.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141829/2/his13384_am.pd

Overexpression of proto-oncogene FBI-1 activates membrane type 1-matrix metalloproteinase in association with adverse outcome in ovarian cancers

<p>Abstract</p> <p>Background</p> <p>FBI-1 (factor that binds to the inducer of short transcripts of human immunodeficiency virus-1) is a member of the POK (POZ and Kruppel) family of transcription factors and play important roles in cellular differentiation and oncogenesis. Recent evidence suggests that FBI-1 is expressed at high levels in a subset of human lymphomas and some epithelial solid tumors. However, the function of FBI-1 in human ovarian cancers remains elusive.</p> <p>Results</p> <p>In this study, we investigated the role of FBI-1 in human ovarian cancers, in particularly, its function in cancer cell invasion via modulating membrane type 1-matrix metalloproteinase (MT1-MMP). Significantly higher FBI-1 protein and mRNA expression levels were demonstrated in ovarian cancers samples and cell lines compared with borderline tumors and benign cystadenomas. Increased FBI-1 mRNA expression was correlated significantly with gene amplification (P = 0.037). Moreover, higher FBI-1 expression was found in metastatic foci (P = 0.036) and malignant ascites (P = 0.021), and was significantly associated with advanced stage (P = 0.012), shorter overall survival (P = 0.032) and disease-free survival (P = 0.016). <it>In vitro</it>, overexpressed FBI-1 significantly enhanced cell migration and invasion both in OVCA 420 and SKOV-3 ovarian carcinoma cells, irrespective of <it>p53 </it>status, accompanied with elevated expression of MT1-MMP, but not MMP-2 or TIMP-2. Moreover, knockdown of MT1-MMP abolished FBI-1-mediated cell migration and invasion. Conversely, stable knockdown of FBI-1 remarkably reduced the motility of these cells with decreased expression of MT1-MMP. Promoter assay and chromatin immunoprecipitation study indicated that FBI-1 could directly interact with the promoter spanning ~600bp of the 5'-flanking sequence of MT1-MMP and enhanced its expression in a dose-dependent manner. Furthermore, stable knockdown and ectopic expression of FBI-1 decreased and increased cell proliferation respectively in OVCA 420, but not in the p53 null SKOV-3 cells.</p> <p>Conclusions</p> <p>Our results suggested an important role of FBI-1 in ovarian cancer cell proliferation, cell mobility, and invasiveness, and that FBI-1 can be a potential target of chemotherapy.</p

Corrigendum:Epigenetic inactivation of the CpG demethylase TET1 as a DNA methylation feedback loop in human cancers

Scientific Reports 6: Article number: 26591; published online: 26 May 2016; updated: 06 October 2016. This Article contains errors in Figure 2D where the Hodgkin lymphoma ‘TET1-MSP’ methylated and unmethylated MSP bands are incorrect. The correct Figure 2D appears below as Figure 1.</jats:p

Mutated Ptpn11 alters leukemic stem cell frequency and reduces the sensitivity of acute myeloid leukemia cells to Mcl1 inhibition

PTPN11 encodes the Shp2 non-receptor protein-tyrosine phosphatase implicated in several signaling pathways. Activating mutations in Shp2 are commonly associated with juvenile myelomonocytic leukemia but are not as well defined in other neoplasms. Here we report that Shp2 mutations occur in human acute myeloid leukemia (AML) at a rate of 6.6% (6/91) in the ECOG E1900 data set. We examined the role of mutated Shp2 in leukemias harboring MLL translocations, which co-occur in human AML. The hyperactive Shp2E76K mutant, commonly observed in leukemia patients, significantly accelerated MLL-AF9-mediated leukemogenesis in vivo. Shp2E76K increased leukemic stem cell frequency and affords MLL-AF9 leukemic cells IL3 cytokine hypersensitivity. As Shp2 is reported to regulate anti-apoptotic genes, we investigated Bcl2, Bcl-xL and Mcl1 expression in MLL-AF9 leukemic cells with and without Shp2E76K. Although the Bcl2 family of genes was upregulated in Shp2E76K cells, Mcl1 showed the highest upregulation in MLL-AF9 cells in response to Shp2E76K. Indeed, expression of Mcl1 in MLL-AF9 cells phenocopies expression of Shp2E76K, suggesting Shp2 mutations cooperate through activation of anti-apoptotic genes. Finally, we show Shp2E76K mutations reduce sensitivity of AML cells to small-molecule-mediated Mcl1 inhibition, suggesting reduced efficacy of drugs targeting MCL1 in patients with hyperactive Shp2

The Epigenetic Modifier PRDM5 Functions as a Tumor Suppressor through Modulating WNT/β-Catenin Signaling and Is Frequently Silenced in Multiple Tumors

BACKGROUND: PRDM (PRDI-BF1 and RIZ domain containing) proteins are zinc finger proteins involved in multiple cellular regulations by acting as epigenetic modifiers. We studied a recently identified PRDM member PRDM5 for its epigenetic abnormality and tumor suppressive functions in multiple tumorigeneses. METHODOLOGY/PRINCIPAL FINDINGS: Semi-quantitative RT-PCR showed that PRDM5 was broadly expressed in human normal tissues, but frequently silenced or downregulated in multiple carcinoma cell lines due to promoter CpG methylation, including 80% (4/5) nasopharyngeal, 44% (8/18) esophageal, 76% (13/17) gastric, 50% (2/4) cervical, and 25% (3/12) hepatocellular carcinoma cell lines, but not in any immortalized normal epithelial cell lines. PRDM5 expression could be restored by 5-aza-2'-deoxycytidine demethylation treatment in silenced cell lines. PRDM5 methylation was frequently detected by methylation-specific PCR (MSP) in multiple primary tumors, including 93% (43/46) nasopharyngeal, 58% (25/43) esophageal, 88% (37/42) gastric and 63% (29/46) hepatocellular tumors. PRDM5 was further found a stress-responsive gene, but its response was impaired when the promoter was methylated. Ectopic PRDM5 expression significantly inhibited tumor cell clonogenicity, accompanied by the inhibition of TCF/β-catenin-dependent transcription and downregulation of CDK4, TWIST1 and MDM2 oncogenes, while knocking down of PRDM5 expression lead to increased cell proliferation. ChIP assay showed that PRDM5 bound to its target gene promoters and suppressed their transcription. An inverse correlation between the expression of PRDM5 and activated β-catenin was also observed in cell lines. CONCLUSIONS/SIGNIFICANCE: PRDM5 functions as a tumor suppressor at least partially through antagonizing aberrant WNT/β-catenin signaling and oncogene expression. Frequent epigenetic silencing of PRDM5 is involved in multiple tumorigeneses, which could serve as a tumor biomarker

Global and regional child deaths due to injuries::an assessment of the evidence

Background: Injuries result in substantial number of deaths among children globally. The burden across many settings is largely unknown. We estimated global and regional child deaths due to injuries from publicly available evidence. Methods: We searched for community-based studies and nationally representative data reporting on child injury deaths published after year 1990 from CINAHL, EMBASE, IndMed, LILACS, Global Health, MEDLINE, SCOPUS, and Web of Science. Specific and all-cause mortality due to injuries were extracted for three age groups (0-11 months, 1-4 years, and 0-4 years). We conducted random-effects meta-analysis on extracted crude estimates, and developed a meta-regression model to determine the number of deaths due to injuries among children aged 0-4 years globally and across the World Health Organization (WHO) regions. Results: Twenty-nine studies from 16 countries met the selection criteria. A total of 230 data-points on 15 causes of injury deaths were retrieved from all studies. Eighteen studies were rated as high quality, although heterogeneity was high (I2 = 99.7%, P < 0.001) reflecting variable data sources and study designs. For children aged 0-11 months, the pooled crude injury mortality rate was 29.6 (95% confidence interval (CI) = 21.1-38.1) per 100 000 child population, with asphyxiation being the leading cause of death (neonatal) at 189.1 (95% CI = 142.7-235.4) per 100 000 followed by suffocation (post-neonatal) at 18.7 (95% CI = 11.8-25.7) per 100 000. Among children aged 1-4 years, the pooled crude injury mortality rate was 32.7 (95% CI = 27.3-38.1) per 100 000, with traffic injuries and drowning the leading causes of deaths at 10.8 (95% CI = 8.9-12.8) and 8.8 (95% CI = 7.5-10.2) per 100 000, respectively. Among children under five years, the pooled injury mortality rate was 37.7 (95% CI = 32.7-42.7) per 100 000, with traffic injuries and drowning also the leading causes of deaths at 10.3 (95% CI = 8.8-11.8) and 8.9 (95% CI = 7.8-9.9) per 100 000 respectively. When crude mortality changes over age, WHO regions, and study period were accounted for in our model, we estimated that in 2015 there were 522 167 (95% CI = 395 823-648 630) deaths among children aged 0-4 years, with South East Asia (SEARO) recording the highest number of deaths at 195 084 (95% CI = 159476-230502), closely followed by the Africa region (AFRO) with 176523 (95% CI = 115 040-237 831) deaths. Globally, traffic injuries and drowning were the leading causes of under-five injury fatalities in 2015 with 142 661 (22.0/100 000) and 123 270 (19.0/100 000) child deaths, respectively. The exception being burns in AFRO with 57 784 deaths (38.6/100 000). Conclusions: Varying study designs, case definitions, and particularly limited country representation from Africa and South-East Asia (where we reported higher estimates), imply a need for more studies for better population representative estimates. This study may have however provided improved understanding on child injury death profiles needed to guide further research, policy reforms and relevant strategies globally

Rapid mass growth and enhanced light extinction of atmospheric aerosols during the heating season haze episodes in Beijing revealed by aerosol-chemistry-radiation-boundary layer interaction

Despite the numerous studies investigating haze formation mechanism in China, it is still puzzling that intensive haze episodes could form within hours directly following relatively clean periods. Haze has been suggested to be initiated by the variation of meteorological parameters and then to be substantially enhanced by aerosol-radiation-boundary layer feedback. However, knowledge on the detailed chemical processes and the driving factors for extensive aerosol mass accumulation during the feedback is still scarce. Here, the dependency of the aerosol number size distribution, mass concentration and chemical composition on the daytime mixing layer height (MLH) in urban Beijing is investigated. The size distribution and chemical composition-resolved dry aerosol light extinction is also explored. The results indicate that the aerosol mass concentration and fraction of nitrate increased dramatically when the MLH decreased from high to low conditions, corresponding to relatively clean and polluted conditions, respectively. Particles having their dry diameters in the size of similar to 400-700 nm, and especially particle-phase ammonium nitrate and liquid water, contributed greatly to visibility degradation during the winter haze periods. The dependency of aerosol composition on the MLH revealed that ammonium nitrate and aerosol water content increased the most during low MLH conditions, which may have further triggered enhanced formation of sulfate and organic aerosol via heterogeneous reactions. As a result, more sulfate, nitrate and water-soluble organics were formed, leading to an enhanced water uptake ability and increased light extinction by the aerosols. The results of this study contribute towards a more detailed understanding of the aerosol-chemistry-radiation-boundary layer feedback that is likely to be responsible for explosive aerosol mass growth events in urban Beijing.Peer reviewe

SHON expression predicts response and relapse risk of breast cancer patients after anthracycline-based combination chemotherapy or tamoxifen treatment

BACKGROUND: SHON nuclear expression (SHON-Nuc+) was previously reported to predict clinical outcomes to tamoxifen therapy in ERα+ breast cancer (BC). Herein we determined if SHON expression detected by specific monoclonal antibodies could provide a more accurate prediction and serve as a biomarker for anthracycline-based combination chemotherapy (ACT).METHODS: SHON expression was determined by immunohistochemistry in the Nottingham early-stage-BC cohort (n=1,650) who, if eligible, received adjuvant tamoxifen; the Nottingham ERα- early-stage-BC (n=697) patients who received adjuvant ACT; and the Nottingham locally advanced-BC cohort who received pre- operative ACT with/without taxanes (Neo-ACT, n=120) and if eligible, 5-year adjuvant tamoxifen treatment. Prognostic significance of SHON and its relationship with the clinical outcome of treatments were analysed.RESULTS: As previously reported, SHON-Nuc+ in high risk/ERα+ patients was significantly associated with a 48% death risk reduction after exclusive adjuvant tamoxifen treatment compared with SHON-Nuc- [HR(95%CI)=0.52(0.34-0.78), p=0.002]. Meanwhile, in ERα- patients treated with adjuvant ACT, SHON cytoplasmic expression (SHON-Cyto+) was significantly associated with a 50% death risk reduction compared with SHON-Cyto- [HR(95%CI)=0.50(0.34-0.73), p=0.0003]. Moreover, in patients received Neo-ACT, SHON-Nuc- or SHON-Cyto+ was associated with an increased pathological complete response (pCR) compared with SHON-Nuc+ [21% vs 4%; OR(95%CI)=5.88(1.28-27.03), p=0.012], or SHON-Cyto- [20.5% vs 4.5%; OR(95%CI)=5.43(1.18-25.03), p=0.017], respectively. After receiving Neo-ACT, patients with SHON-Nuc+ had a significantly lower distant relapse risk compared to those with SHON-Nuc- [HR(95%CI)=0.41(0.19-0.87), p=0.038], whereas SHON-Cyto+ patients had a significantly higher distant relapse risk compared to SHON-Cyto- patients [HR(95%CI)=4.63(1.05-20.39), p=0.043]. Furthermore, multivariate Cox regression analyses revealed that SHON-Cyto+ was independently associated with a higher risk of distant relapse after Neo-ACT and 5- year tamoxifen treatment [HR(95%CI)=5.08(1.13-44.52), p=0.037]. The interaction term between ERα status and SHON-Nuc+ (p=0.005), and between SHON-Nuc+ and tamoxifen therapy (p=0.007), were both statistically significant.CONCLUSION: SHON-Nuc+ in tumours predicts response to tamoxifen in ERα+ BC while SHON-Cyto+ predicts response to ACT