Curriculum policy reform in an era of technical accountability: 'fixing' curriculum, teachers and students in English schools

Drawing on a Levinasian ethical perspective, the argument driving this paper is that the technical accountability movement currently dominating the educational system in England is less than adequate because it overlooks educators’ responsibility for ethical relations in responding to difference in respect of the other. Curriculum policy makes a significant contribution to the technical accountability culture through complicity in performativity, high-stakes testing and datafication, at the same time as constituting student and teacher subjectivities. I present two different conceptualizations of subjectivity and education, before engaging these in the analysis of data arising from an empirical study which investigated teachers’ and stakeholders’ experiences of curriculum policy reform in ‘disadvantaged’ English schools. The study’s findings demonstrate how a prescribed programme of technical curriculum regulation attempts to ‘fix’ or mend educational problems by ‘fixing’ or prescribing educational solutions. This not only denies ethical professional relations between students, teachers and parents, but also deflects responsibility for educational success from government to teachers and hastens the move from public to private educational provision. Complying with prescribed curriculum policy requirements shifts attention from broad philosophical and ethical questions about educational purpose as well as conferring a violence by assuming control over student and teacher subjectivities

An approach for the identification of targets specific to bone metastasis using cancer genes interactome and gene ontology analysis

Metastasis is one of the most enigmatic aspects of cancer pathogenesis and is a major cause of cancer-associated mortality. Secondary bone cancer (SBC) is a complex disease caused by metastasis of tumor cells from their primary site and is characterized by intricate interplay of molecular interactions. Identification of targets for multifactorial diseases such as SBC, the most frequent complication of breast and prostate cancers, is a challenge. Towards achieving our aim of identification of targets specific to SBC, we constructed a 'Cancer Genes Network', a representative protein interactome of cancer genes. Using graph theoretical methods, we obtained a set of key genes that are relevant for generic mechanisms of cancers and have a role in biological essentiality. We also compiled a curated dataset of 391 SBC genes from published literature which serves as a basis of ontological correlates of secondary bone cancer. Building on these results, we implement a strategy based on generic cancer genes, SBC genes and gene ontology enrichment method, to obtain a set of targets that are specific to bone metastasis. Through this study, we present an approach for probing one of the major complications in cancers, namely, metastasis. The results on genes that play generic roles in cancer phenotype, obtained by network analysis of 'Cancer Genes Network', have broader implications in understanding the role of molecular regulators in mechanisms of cancers. Specifically, our study provides a set of potential targets that are of ontological and regulatory relevance to secondary bone cancer.Comment: 54 pages (19 pages main text; 11 Figures; 26 pages of supplementary information). Revised after critical reviews. Accepted for Publication in PLoS ON

Loss of heterozygosity at 18q21 is indicative of recurrence and therefore poor prognosis in a subset of colorectal cancers

Adjuvant therapies are increasingly used in colorectal cancers for the prevention of recurrence. These therapies have side-effects and should, thus, be used only if really beneficial. However, the development of recurrence cannot be predicted reliably at the moment of diagnosis, and targeting of adjuvant therapies is thus based only on the primary stage of the cancer. Loss of heterozygosity (LOH) in the long arm of chromosome 18 is suggested to be related to poor survival and possibly to the development of metastases. We studied the value of LOH at 18q21 as a marker of colorectal cancer prognosis, association with clinicopathological variables, tumour recurrence and survival of the patients. Of the 255 patients studied, 195 were informative as regards LOH status when analysed in primary colorectal cancer specimens using the polymerase chain reaction (PCR) and fragment analysis. LOH at 18q21 was significantly associated with the development of recurrence (P= 0.01) and indicated poor survival in patients of Dukes' classes B and C, in which most recurrences (82%) occurred. An increased rate of tumour recurrence is the reason for poor survival among patients with LOH at 18q21 in primary cancer. These patients are a possible target group for recurrence-preventing adjuvant therapies. © 1999 Cancer Research Campaig

miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells

SummaryTo investigate miRNA function in human acute myeloid leukemia (AML) stem cells (LSC), we generated a prognostic LSC-associated miRNA signature derived from functionally validated subpopulations of AML samples. For one signature miRNA, miR-126, high bioactivity aggregated all in vivo patient sample LSC activity into a single sorted population, tightly coupling miR-126 expression to LSC function. Through functional studies, miR-126 was found to restrain cell cycle progression, prevent differentiation, and increase self-renewal of primary LSC in vivo. Compared with prior results showing miR-126 regulation of normal hematopoietic stem cell (HSC) cycling, these functional stem effects are opposite between LSC and HSC. Combined transcriptome and proteome analysis demonstrates that miR-126 targets the PI3K/AKT/MTOR signaling pathway, preserving LSC quiescence and promoting chemotherapy resistance

ZIP8 Zinc Transporter: Indispensable Role for Both Multiple-Organ Organogenesis and Hematopoiesis In Utero

Previously this laboratory characterized Slc39a8-encoded ZIP8 as a Zn2+/(HCO3–)2 symporter; yet, the overall physiological importance of ZIP8 at the whole-organism level remains unclear. Herein we describe the phenotype of the hypomorphic Slc39a8(neo/neo) mouse which has retained the neomycin-resistance gene in intron 3, hence causing significantly decreased ZIP8 mRNA and protein levels in embryo, fetus, placenta, yolk sac, and several tissues of neonates. The Slc39a8(neo) allele is associated with diminished zinc and iron uptake in mouse fetal fibroblast and liver-derived cultures; consequently, Slc39a8(neo/neo) newborns exhibit diminished zinc and iron levels in several tissues. Slc39a8(neo/neo) homozygotes from gestational day(GD)-11.5 onward are pale, growth-stunted, and die between GD18.5 and 48 h postnatally. Defects include: severely hypoplastic spleen; hypoplasia of liver, kidney, lung, and lower limbs. Histologically, Slc39a8(neo/neo) neonates show decreased numbers of hematopoietic islands in yolk sac and liver. Low hemoglobin, hematocrit, red cell count, serum iron, and total iron-binding capacity confirmed severe anemia. Flow cytometry of fetal liver cells revealed the erythroid series strikingly affected in the hypomorph. Zinc-dependent 5-aminolevulinic acid dehydratase, required for heme synthesis, was not different between Slc39a8(+/+) and Slc39a8(neo/neo) offspring. To demonstrate further that the mouse phenotype is due to ZIP8 deficiency, we bred Slc39a8(+/neo) with BAC-transgenic BTZIP8-3 line (carrying three extra copies of the Slc39a8 allele); this cross generated viable Slc39a8(neo/neo)_BTZIP8-3(+/+) pups showing none of the above-mentioned congenital defects–proving Slc39a8(neo/neo) causes the described phenotype. Our study demonstrates that ZIP8-mediated zinc transport plays an unappreciated critical role during in utero and neonatal growth, organ morphogenesis, and hematopoiesis

SMAD4 is a predictive marker for 5-fluorouracil-based chemotherapy in patients with colorectal cancer

The gene for the transducer of transforming growth factor-beta/bone morphogenetic protein signalling SMAD4, a potential suppressor of colorectal carcinogenesis, is located at the chromosomal region 18q21. In order to evaluate the clinical relevance of SMAD4 deletion, gene copy alterations were determined by copy dosage using real-time quantitative PCR in 202 colorectal tumour biopsies from a previous randomised study of adjuvant chemotherapy. Patients with normal SMAD4 diploidy turned out to have a three-fold higher benefit of 5-fluorouracil-based adjuvant chemotherapy with a border line significance (overall survival: 3.23, P=0.056; disease-free survival: 2.89, P=0.045). These data are consistent with the previous observation that patients whose cancer had retention of the 18q21 region had a significantly higher benefit from 5-fluorouracil-based therapy. Moreover, these results may provide a refinement at the gene level of the clinical relevance of 18q21 deletion, thereby suggesting SMAD4 as a predictive marker in colorectal cancer. This data also indicate that integrity of this component of the transforming growth factor-beta/bone morphogenetic protein signalling pathway may be a critical factor for benefit of chemotherapy in patients with colorectal cancer

The transcriptional architecture of early human hematopoiesis identifies multilevel control of lymphoid commitment.

Understanding how differentiation programs originate from the gene-expression 'landscape' of hematopoietic stem cells (HSCs) is crucial for the development of new clinical therapies. We mapped the transcriptional dynamics underlying the first steps of commitment by tracking transcriptome changes in human HSCs and eight early progenitor populations. We found that transcriptional programs were extensively shared, extended across lineage-potential boundaries and were not strictly lineage affiliated. Elements of stem, lymphoid and myeloid programs were retained in multilymphoid progenitors (MLPs), which reflected a hybrid transcriptional state. By functional single cell analysis, we found that the transcription factors Bcl-11A, Sox4 and TEAD1 (TEF1) governed transcriptional networks in MLPs, which led to B cell specification. Overall, we found that integrated transcriptome approaches can be used to identify previously unknown regulators of multipotency and show additional complexity in lymphoid commitment

TGF-beta receptor 2 downregulation in tumour-associated stroma worsens prognosis and high-grade tumours show more tumour-associated macrophages and lower TGF-beta1 expression in colon carcinoma: a retrospective study

<p>Abstract</p> <p>Background</p> <p>Histological phenotype and clinical behaviour of malignant tumours are not only dependent on alterations in the epithelial cell compartment, but are affected by their interaction with inflammatory cells and tumour-associated stroma. Studies in animal models have shown influence of tumour-associated macrophages (TAM) on histological grade of differentiation in colon carcinoma. Disruption of transforming growth factor beta (TGF-beta) signalling in tumour cells is related to more aggressive clinical behaviour. Expression data of components of this pathway in tumour-associated stroma is limited.</p> <p>Methods</p> <p>Tissue micro arrays of 310 colon carcinomas from curatively resected patients in UICC stage II and III were established. In a first step we quantified amount of CD68 positive TAMs and expression of components of TGF-beta signalling (TGF-beta1, TGF-beta receptors type 1 and 2, Smad 3 and 4) in tumour and associated stroma. Further we analyzed correlation to histological and clinical parameters (histological grade of differentiation (low-grade (i.e. grade 1 and 2) vs. high-grade (i.e. grade 3 and 4)), lymph node metastasis, distant metastasis, 5 year cancer related survival) using Chi-square or Fisher's exact test, when appropriate, to compare frequencies, Kaplan-Meier method to calculate 5-year rates of distant metastases and cancer-related survival and log rank test to compare the rates of distant metastases and survival. To identify independent prognostic factors Cox regression analysis including lymph node status and grading was performed.</p> <p>Results</p> <p>High-grade tumours and those with lymph node metastases showed higher rates of TAMs and lower expression of TGF-beta1. Loss of nuclear Smad4 expression in tumor was associated with presence of lymph node metastasis, but no influence on prognosis could be demonstrated. Decrease of both TGF-beta receptors in tumour-associated stroma was associated with increased lymph node metastasis and shorter survival. Stromal TGF-beta receptor 2 expression was an independent prognostic factor for cancer related survival.</p> <p>Conclusion</p> <p>Histological phenotype and clinical behaviour of colon cancer is not only influenced by mutational incidents in tumour cells but also affected by interaction of tumour tissue with inflammatory cells like macrophages and associated stroma and TGF-beta signalling is one important part of this crosstalk. Further studies are needed to elucidate the exact mechanisms.</p

Interactions between Natural Populations of Human and Rodent Schistosomes in the Lake Victoria Region of Kenya: A Molecular Epidemiological Approach

One of the world's most prevalent neglected diseases is schistosomiasis, which infects approximately 200 million people worldwide. Schistosoma mansoni is transmitted to humans by skin penetration by free-living larvae that develop in freshwater snails. The origin of this species is East Africa, where it coexists with its sister species, S. rodhaini. Interactions between these species potentially influence their epidemiology, ecology, and evolutionary biology, because they infect the same species of hosts and can hybridize. Over two years, we examined their distribution in Kenya to determine their degree of overlap geographically, within snail hosts, and in the water column as infective stages. Both species were spatially and temporally patchy, although S. mansoni was eight times more common than S. rodhaini. Both species overlap in the time of day they were present in the water column, which increases the potential for the species to coinfect the same host and interbreed. Peak infective time for S. mansoni was midday and dawn and dusk for S. rodhaini. Three snails were coinfected, which was more common than expected by chance. These findings indicate a lack of obvious isolating mechanisms to prevent hybridization, raising the intriguing question of how the two species retain separate identities

Latent transforming growth factor binding protein 4 (LTBP4) is downregulated in mouse and human DCIS and mammary carcinomas

Transforming growth factor beta (TGF-) is able to inhibit the proliferation of epithelial cells and is involved in the carcinogenesis of mammary tumors. Three latent transforming growth factor- binding proteins (LTBPs) are known to modulate TGF- functions. The current study analyses the expression profiles of LTBP4, its isoforms LTBP1 and LTBP3, and TGF-1, TGF-2, TGF-3, and SMAD2, SMAD3 and SMAD4 in human and murine (WAP-TNP8) DCIS compared to invasive mammary tumors. Additionally mammary malignant (MCF7, Hs578T, MDA-MB361) and non malignant cell lines (Hs578BsT) were analysed. Microarray, q-PCR, immunoblot, immunohistochemistry and immunofluorescence were used. In comparison to non-malignant tissues (n = 5), LTBP4 was downregulated in all human and mouse DCIS (n = 9) and invasive mammary adenocarcinomas (n = 5) that were investigated. We also found decreased expression of bone morphogenic protein 4 (BMP4) and increased expression of its inhibitor gremlin (GREM1). Treatment of the mammary tumor cell line (Hs578T) with recombinant TGF-1 rescued BMP4 and GREM1 expression. We conclude that the lack of LTBP4-mediated targeting in malignant mammary tumor tissues may lead to a possible modification of TGF-1 and BMP bioavailability and function