A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers

We analyzed molecular data on 2,579 tumors from The Cancer Genome Atlas (TCGA) of four gynecological types plus breast. Our aims were to identify shared and unique molecular features, clinically significant subtypes, and potential therapeutic targets. We found 61 somatic copy-number alterations (SCNAs) and 46 significantly mutated genes (SMGs). Eleven SCNAs and 11 SMGs had not been identified in previous TCGA studies of the individual tumor types. We found functionally significant estrogen receptor-regulated long non-coding RNAs (lncRNAs) and gene/lncRNA interaction networks. Pathway analysis identified subtypes with high leukocyte infiltration, raising potential implications for immunotherapy. Using 16 key molecular features, we identified five prognostic subtypes and developed a decision tree that classified patients into the subtypes based on just six features that are assessable in clinical laboratories. By performing molecular analyses of 2,579 TCGA gynecological (OV, UCEC, CESC, and UCS) and breast tumors, Berger et al. identify five prognostic subtypes using 16 key molecular features and propose a decision tree based on six clinically assessable features that classifies patients into the subtypes

Analysis of N-WASP function in keratinocytes in vivo

N-WASP is a ubiquitously expressed cytoplasmic molecule mediating Arp2/3 nucleated actin polymerization. We found that mice with a keratinocyte-specific deletion of N-WASP showed normal interfollicular epidermis but delayed hair follicle morphogenesis and abnormal hair follicle cycling associated with cyclic alopecia and prolonged catagen and telogen phases. The delayed anagen onset correlated with an increased expression of the cell cycle inhibitor p21CIP and increased activity of the TGFβ pathway, a known inducer of p21CIP expression. We also found increased apoptosis during the catagen stage, which likely contributes to the hair loss. Differentiation of the hair follicle layers was not altered in absence of N-WASP. Primary N-WASP null keratinocytes showed reduced growth compared to control cells and enhanced expression of the cell cycle inhibitor p15INK4B, a TGFβ target gene. Inhibition of TGFβ signaling blocked overexpression of p15INK4B and restored proliferation of N-WASP-deficient keratinocytes in vitro. However, induction of N-WASP gene deletion in vitro did not result in obvious changes in TGFβ signaling or growth of keratinocytes, indicating that the in vivo environment is required for the phenotype development. These data identify the actin nucleation regulator N-WASP as a novel element in hair follicle morphogenesis and hair cycle control, which modulates the antiproliferative and pro-apoptotic TGFβ pathway in keratinocytes in vivo and in vitro

Controlling coaching and psychological athlete harassment and abuse : towards a cross-fertilization between both fields of research

A controlling coaching style is evident in the conditional use of rewards, and the presence of intimidation, excessive personal control, and negative conditional regard. The detrimental effects of a controlling style on athletes’ anxiety, perfectionism and self-esteem have already been widely demonstrated. Similarly, literature on psychological athlete harassment and abuse from coaches is growing rapidly and shows detrimental results. Psychological athlete harassment and abuse refers to a pattern of deliberate, prolonged, and repeated non-contact deteriorated interactions within a power-differentiated relationship. Even though, the constructs of controlling coaching and psychological athlete harassment and abuse show great conceptual overlap (e.g., coaches trying to control athletes’ spare time), both fields of research exist separately from each other. This study looked at the relation between controlling coaching and psychological athlete harassment and abuse, and how controlling coaching and psychological athlete harassment and abuse relate to athletes’ outcomes (anxiety, perfectionism, and self-esteem). In total, 565 Belgian (former) gymnasts (91.2% female; 33.7% active; age = 21.70 ± 4.26) reported perceived coach's controlling style, coach's psychological athlete harassment and abuse, feelings of anxiety, perfectionism, and self-esteem. Controlling coaching positively correlated with psychological athlete harassment and abuse, and the highest correlations were found with intimidation. Results also showed that more controlling coaching and psychological athlete harassment and abuse related to more anxiety and perfectionism in athletes. No relations with self-esteem were found. As psychological harassment and abuse may from a gateway to other forms of abuse (i.e., physical; sexual), adopting a controlling coaching style may do the same. Equipping coaches through evidence-based safeguarding education with suitable alternative coaching styles may help protect athletes from psychological harassment and abuse

Cdc42 controls progenitor cell differentiation and β-catenin turnover in skin

Differentiation of skin stem cells into hair follicles (HFs) requires the inhibition of β-catenin degradation, which is controlled by a complex containing axin and the protein kinase GSK3β. Using conditional gene targeting in mice, we show now that the small GTPase Cdc42 is crucial for differentiation of skin progenitor cells into HF lineage and that it regulates the turnover of β-catenin. In the absence of Cdc42, degradation of β-catenin was increased corresponding to a decreased phosphorylation of GSK3β at Ser 9 and an increased phosphorylation of axin, which is known to be required for binding of β-catenin to the degradation machinery. Cdc42-mediated regulation of β-catenin turnover was completely dependent on PKCζ, which associated with Cdc42, Par6, and Par3. These data suggest that Cdc42 regulation of β-catenin turnover is important for terminal differentiation of HF progenitor cells in vivo

Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek-Erk hyperactivation and hyperproliferation in vivo

Rac1 has a role in proliferation and survival of tumor cells in vitro. The exact effects of Rac1 on growth, apoptosis and corresponding signaling pathways during tumorigenesis in vivo, however, have not been explored yet. Using mice with a keratinocyte-restricted deletion of the Rac1 gene, we found that Rac1 is essential for DMBA/TPA-induced skin tumor formation. This corresponded to a decreased keratinocyte hyperproliferation, although apoptosis was not detectably altered. Activated Rac1 promoted Erk-dependent hyperproliferation by Pak1-mediated Mek activation independent of Mek1 phosporylation at serine 298. Rac1 was furthermore required for Pak2-dependent hyperactivation of Akt, which under in vivo condition was restricted to the suprabasal cell layers corresponding to a suprabasal-specific expression of Pak2. It is surprising that none of these signaling pathways was altered in untreated Rac1-deficient skin, indicating a hyperproliferation- specific function of Rac1 in vivo. These data suggest that blocking of Rac1 function might allow tumor-specific growth repression, as Rac1 is not required for normal growth and growth signaling controlling pathways in skin in vivo. Oncogene (2010) 29, 3362-3373; doi:10.1038/onc.2010.95; published online 12 April 201

N-WASP is a novel regulator of hair-follicle cycling that controls antiproliferative TGF beta pathways

N-WASP is a cytoplasmic molecule mediating Arp2/3 nucleated actin polymerization. Mice with a keratinocyte-specific deletion of the gene encoding N-WASP showed normal interfollicular epidermis, but delayed hair-follicle morphogenesis and abnormal hair-follicle cycling, associated with cyclic alopecia and prolonged catagen and telogen phases. The delayed anagen onset correlated with an increased expression of the cell-cycle inhibitor p21CIP, and increased activity of the TGF beta pathway, a known inducer of p21CIP expression. Primary N-WASP-null keratinocytes showed reduced growth compared with control cells and enhanced expression of the gene encoding the cell-cycle inhibitor p15INK4B, a TGF beta target gene. Inhibition of TGF beta signaling blocked overexpression of p15INK4B and restored proliferation of N-WASP-deficient keratinocytes in vitro. However, induction of N-WASP gene deletion in vitro did not result in obvious changes in TGF beta signaling or growth of keratinocytes, indicating that the in vivo environment is required for the phenotype development. These data identify the actin nucleation regulator N-WASP as a novel element of hair-cycle control that modulates the antiproliferative and pro-apoptotic TGF. pathway in keratinocytes in vivo and in vitro

N-WASP is a novel regulator of hair-follicle cycling that controls antiproliferative TGFβ pathways

N-WASP is a cytoplasmic molecule mediating Arp2/3 nucleated actin polymerization. Mice with a keratinocyte-specific deletion of the gene encoding N-WASP showed normal interfollicular epidermis, but delayed hair-follicle morphogenesis and abnormal hair-follicle cycling, associated with cyclic alopecia and prolonged catagen and telogen phases. The delayed anagen onset correlated with an increased expression of the cell-cycle inhibitor p21CIP, and increased activity of the TGF beta pathway, a known inducer of p21CIP expression. Primary N-WASP-null keratinocytes showed reduced growth compared with control cells and enhanced expression of the gene encoding the cell-cycle inhibitor p15INK4B, a TGF beta target gene. Inhibition of TGF beta signaling blocked overexpression of p15INK4B and restored proliferation of N-WASP-deficient keratinocytes in vitro. However, induction of N-WASP gene deletion in vitro did not result in obvious changes in TGF beta signaling or growth of keratinocytes, indicating that the in vivo environment is required for the phenotype development. These data identify the actin nucleation regulator N-WASP as a novel element of hair-cycle control that modulates the antiproliferative and pro-apoptotic TGF. pathway in keratinocytes in vivo and in vitro

RhoA is dispensable for skin development, but crucial for contraction and directed migration of keratinocytes

RhoA is a small GTPase shown to be crucial for cytokinesis, stress fiber formation, and epithelial cell–cell contacts. Analyzing mice with a keratinocyte-restricted deletion of the RhoA gene, we find that RhoA is not required for skin development and maintenance but has specific functions in vitro

The RNA Atlas, a single nucleotide resolution map of the human transcriptome

The human transcriptome consists of various RNA biotypes including multiple types of non-coding RNAs (ncRNAs). Current ncRNA compendia remain incomplete partially because they are almost exclusively derived from the interrogation of small- and polyadenylated RNAs. Here, we present a more comprehensive atlas of the human transcriptome that is derived from matching polyA-, total-, and small-RNA profiles of a heterogeneous collection of nearly 300 human tissues and cell lines. We report on thousands of novel RNA species across all major RNA biotypes, including a hitherto poorly-cataloged class of non-polyadenylated single-exon long non-coding RNAs. In addition, we exploit intron abundance estimates from total RNA-sequencing to test and verify functional regulation by novel non-coding RNAs. Our study represents a substantial expansion of the current catalogue of human ncRNAs and their regulatory interactions. All data, analyses, and results are available in the R2 web portal and serve as a basis to further explore RNA biology and function

The RNA Atlas expands the catalog of human non-coding RNAs

Existing compendia of non-coding RNA (ncRNA) are incomplete, in part because they are derived almost exclusively from small and polyadenylated RNAs. Here we present a more comprehensive atlas of the human transcriptome, which includes small and polyA RNA as well as total RNA from 300 human tissues and cell lines. We report thousands of previously uncharacterized RNAs, increasing the number of documented ncRNAs by approximately 8%. To infer functional regulation by known and newly characterized ncRNAs, we exploited pre-mRNA abundance estimates from total RNA sequencing, revealing 316 microRNAs and 3,310 long non-coding RNAs with multiple lines of evidence for roles in regulating protein-coding genes and pathways. Our study both refines and expands the current catalog of human ncRNAs and their regulatory interactions. All data, analyses and results are available for download and interrogation in the R2 web portal, serving as a basis for future exploration of RNA biology and function