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1.
J Intellect Disabil Res ; 64(5): 345-356, 2020 05.
Article in English | MEDLINE | ID: mdl-32166785

ABSTRACT

INTRODUCTION: The experiences of Pakistanis with intellectual disabilities (IDs) and their family members have been underexplored empirically. METHOD: The present study sought to address this gap by understanding the lives of five Special Olympics Pakistan athletes and their guardians through PhotoVoice. FINDINGS: Through thematic analysis, we present the primary theme concerning Pakistan's cultural context that provides an empirical exploration of cultural beliefs about intellectual disability, cultural expectations and support received by people with intellectual disabilities and their guardians. DISCUSSION: We discuss implications for research and practice.


Subject(s)
Athletes/psychology , Health Knowledge, Attitudes, Practice/ethnology , Intellectual Disability/ethnology , Parents/psychology , Persons with Mental Disabilities/psychology , Sports , Adult , Female , Humans , Legal Guardians/psychology , Male , Middle Aged , Pakistan/ethnology , Qualitative Research
2.
Oncogene ; 36(5): 593-605, 2017 02 02.
Article in English | MEDLINE | ID: mdl-27375028

ABSTRACT

Cancer cell vascular invasion is a crucial step in the malignant progression toward metastasis. Here we used a genome-wide RNA interference screen with E0771 mammary cancer cells to uncover drivers of endothelial monolayer invasion. We identified keratin-associated protein 5-5 (Krtap5-5) as a candidate. Krtap5-5 belongs to a large protein family that is implicated in crosslinking keratin intermediate filaments during hair formation, yet these Krtaps have no reported role in cancer. Depletion of Krtap5-5 from cancer cells led to cell blebbing and a loss of keratins 14 and 18, in addition to the upregulation of vimentin intermediate filaments. This intermediate filament subtype switching induced dysregulation of the actin cytoskeleton and reduced the expression of hemidesmosomal α6/ß4-integrins. We further demonstrate that knockdown of keratin 18 phenocopies the loss of Krtap5-5, suggesting that Krtap5-5 crosstalks with keratin 18 in E0771 cells. Disruption of the keratin cytoskeleton by perturbing Krtap5-5 function broadly altered the expression of cytoskeleton regulators and the localization of cell surface markers. Krtap5-5 depletion did not impact cell viability but reduced cell motility and extracellular matrix invasion, as well as extravasation of cancer cells into tissues in zebrafish and mice. We conclude that Krtap5-5 is a previously unknown regulator of cytoskeletal function in cancer cells that modulates motility and vascular invasion. Thus, in addition to its physiologic function, a Krtap can serve as a switch toward malignant progression.


Subject(s)
Cytoskeletal Proteins/metabolism , Cytoskeleton/metabolism , Mammary Neoplasms, Experimental/blood supply , Animals , Female , Human Umbilical Vein Endothelial Cells , Humans , Keratins/metabolism , Male , Mammary Neoplasms, Experimental/metabolism , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Inbred C57BL , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Zebrafish
3.
Oncogene ; 34(48): 5879-89, 2015 Nov 26.
Article in English | MEDLINE | ID: mdl-25772246

ABSTRACT

Metastasis of cancer cells involves multiple steps, including their dissociation from the primary tumor and invasion through the endothelial cell barrier to enter the circulation and finding their way to distant organ sites where they extravasate and establish metastatic lesions. Deficient contact inhibition is a hallmark of invasive cancer cells, yet surprisingly the vascular invasiveness of commonly studied cancer cell lines is regulated by the density at which cells are propagated in culture. Cells grown at high density were less effective at invading an endothelial monolayer than cells grown at low density. This phenotypic difference was also observed in a zebrafish model of vascular invasion of cancer cells after injection into the yolk sac and extravasation of cancer cells into tissues from the vasculature. The vascular invasive phenotypes were reversible. A kinome-wide RNA interference screen was used to identify drivers of vascular invasion by panning small hairpin RNA (shRNA) library-transduced noninvasive cancer cell populations on endothelial monolayers. The selection of invasive subpopulations showed enrichment of shRNAs targeting the large tumor suppressor 1 (LATS1) kinase that inhibits the activity of the transcriptional coactivator yes-associated protein (YAP) in the Hippo pathway. Depletion of LATS1 from noninvasive cancer cells restored the invasive phenotype. Complementary to this, inhibition or depletion of YAP inhibited invasion in vitro and in vivo. The vascular invasive phenotype was associated with a YAP-dependent upregulation of the cytokines IL6, IL8 and C-X-C motif ligand 1, 2 and 3. Antibody blockade of cytokine receptors inhibited invasion and confirmed that they are rate-limiting drivers that promote cancer cell vascular invasiveness and could provide therapeutic targets.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Movement , Endothelium, Vascular/pathology , Gene Expression Regulation, Neoplastic , Phosphoproteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Receptors, Interleukin-8B/metabolism , Adaptor Proteins, Signal Transducing/genetics , Animals , Apoptosis , Blotting, Western , Breast Neoplasms/genetics , Cell Cycle , Cell Proliferation , Cytokines/genetics , Cytokines/metabolism , Endothelium, Vascular/metabolism , Female , Human Umbilical Vein Endothelial Cells , Humans , Mice , Mice, Nude , Neoplasm Invasiveness , Phosphoproteins/genetics , Phosphorylation , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/genetics , RNA Interference , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Receptors, Interleukin-8B/genetics , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factors , Tumor Cells, Cultured , Xenograft Model Antitumor Assays , YAP-Signaling Proteins , Zebrafish
4.
Oncogene ; 33(23): 3033-42, 2014 Jun 05.
Article in English | MEDLINE | ID: mdl-23851504

ABSTRACT

The key molecular events required for the formation of ductal carcinoma in situ (DCIS) and its progression to invasive breast carcinoma have not been defined. Here, we show that the nuclear receptor coactivator amplified in breast cancer 1 (AIB1) is expressed at low levels in normal breast but is highly expressed in DCIS lesions. This is of significance since reduction of AIB1 in human MCFDCIS cells restored a more normal three-dimensional mammary acinar structure. Reduction of AIB1 in MCFDCIS cells, both before DCIS development or in existing MCFDCIS lesions in vivo, inhibited tumor growth and led to smaller, necrotic lesions. AIB1 reduction in MCFDCIS cells was correlated with significant reduction in the CD24-/CD44+ breast cancer-initiating cell (BCIC) population, and a decrease in myoepithelial progenitor cells in the DCIS lesions in vitro and in vivo. The loss of AIB1 in MCFDCIS cells was also accompanied by a loss of expression of NOTCH 2, 3 and 4, JAG2, HES1, GATA3, human epidermal growth factor receptor 2 (HER2) and HER3 in vivo. These signaling molecules have been associated with differentiation of breast epithelial progenitor cells. These data indicate that AIB1 has a central role in the initiation and maintenance of DCIS and that reduction of AIB1 causes loss of BCIC, loss of components of the NOTCH, HER2 and HER3 signaling pathways and fewer DCIS myoepithelial progenitor cells in vivo. We propose that increased expression of AIB1, through the maintenance of BCIC, facilitates formation of DCIS, a necessary step before development of invasive disease.


Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Carcinoma, Intraductal, Noninfiltrating/metabolism , Carcinoma, Intraductal, Noninfiltrating/pathology , Neoplastic Stem Cells/physiology , Nuclear Receptor Coactivator 3/metabolism , Animals , Cell Differentiation/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Mammary Neoplasms, Experimental , Mice , Mice, Nude , Neoplastic Stem Cells/pathology , Nuclear Receptor Coactivator 3/antagonists & inhibitors , Nuclear Receptor Coactivator 3/genetics , RNA, Small Interfering/pharmacology , Signal Transduction/genetics , Xenograft Model Antitumor Assays
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