Cardiovascular disease remains the most common cause of mortality in patients with end-stage kidney disease treated by regular hemodialysis. To improve blood pressure control and reduce cardiovascular risk, the United Kingdom Renal Association standards committee introduced pre- and post-dialysis target blood pressures of less than 140/90 and 130/80 mm Hg, respectively. We audited blood pressure control and symptomatic intradialytic hypotension requiring fluid resuscitation in the Greater London area renal centers that serve 2630 patients. The study captured 7890 hemodialysis sessions during a 1-week period where only 36% of the patients achieved the pre-dialysis target and 42% the post-dialysis target, with a wide variation between centers. Different antihypertensive medication prescriptions did not affect achievement of these targets. Fifteen percent of the patients suffered symptomatic hypotension requiring fluid resuscitation associated with significantly greater interdialytic weight gains. Our study found that intradialytic hypotension was significantly greater in centers that achieved better post-dialysis blood pressure targeting.

dPosttranscriptional regulatory mechanisms are crucial for protein synthesis during spermatogenesis and are often organized by the chromatoid body. Here, we identify the RNA methyltransferase NSun2 as a novel component of the chromatoid body and, further, show that NSun2 is essential for germ cell differentiation in the mouse testis. In NSun2-depleted testes, genes encoding Ddx4, Miwi, and Tudor domain-containing (Tdr) proteins are repressed, indicating that RNA-processing and posttranscriptional pathways are impaired. Loss of NSun2 specifically blocked meiotic progression of germ cells into the pachytene stage, as spermatogonial and Sertoli cells were unaffected in knockout mice. We observed the same phenotype when we simultaneously deleted NSun2 and Dnmt2, the only other cytosine-5 RNA methyltransferase characterized to date, indicating that Dnmt2 was not functionally redundant with NSun2 in spermatogonial stem cells or Sertoli cells. Specific NSun2-and Dnmt2-methylated tRNAs decreased in abundance when both methyltransferases were deleted, suggesting that RNA methylation pathways play an essential role in male germ cell differentiation.

Most human breast cancers have diversified genomically and biologically by the time they become clinically evident. Early events involved in their genesis and the cellular context in which these events occur have thus been difficult to characterize. Here we present the first formal evidence of the shared and independent ability of basal cells and luminal progenitors, isolated from normal human mammary tissue and transduced with a single oncogene (KRAS(G12D)), to produce serially transplantable, polyclonal, invasive ductal carcinomas within 8 weeks of being introduced either subrenally or subcutaneously into immunodeficient mice. DNA barcoding of the initial cells revealed a dramatic change in the numbers and sizes of clones generated from them within 2 weeks, and the first appearance of many 'new' clones in tumours passaged into secondary recipients. Both primary and secondary tumours were phenotypically heterogeneous and primary tumours were categorized transcriptionally as 'normal-like'. This system challenges previous concepts that carcinogenesis in normal human epithelia is necessarily a slow process requiring the acquisition of multiple driver mutations. It also presents the first description of initial events that accompany the genesis and evolution of malignant human mammary cell populations, thereby contributing new understanding of the rapidity with which heterogeneity in their properties can develop.

Genomic and phenotypic analyses indicate extensive intra- as well as intertumoral heterogeneity in primary human malignant cell populations despite their clonal origin. Cellular DNA barcoding offers a powerful and unbiased alternative to track the number and size of multiple subclones within a single human tumour xenograft and their response to continued in vivo passaging. Using this approach we find clone-initiating cell frequencies that vary from ~1/10 to ~1/10,000 cells transplanted for two human breast cancer cell lines and breast cancer xenografts derived from three different patients. For the cell lines, these frequencies are negatively affected in transplants of more than 20,000 cells. Serial transplants reveal five clonal growth patterns (unchanging, expanding, diminishing, fluctuating or of delayed onset), whose predominance is highly variable both between and within original samples. This study thus demonstrates the high growth potential and diverse growth properties of xenografted human breast cancer cells.

How the proto-oncogene c-Myc balances the processes of stem cell self-renewal, proliferation and differentiation in adult tissues is largely unknown. We explored c-Myc’s transcriptional roles at the Epidermal Differentiation Complex (EDC) a locus essential for skin maturation. Binding of c-Myc can simultaneously recruit (Klf4, Ovo1-1) and displace (C/EBPα, Mxi1 and Sin3A) specific sets of differentiation-specific transcriptional regulators to EDC genes. We found that Sin3A causes de-acetylation of c-Myc protein to directly repress c-Myc activity. In the absence of Sin3A, genomic recruitment of c-Myc to the EDC is enhanced, and re-activation of c-Myc-target genes drives aberrant epidermal proliferation and differentiation. Simultaneous deletion of c-Myc and Sin3A reverts the skin phenotype to normal. Our results identify how the balance of two transcriptional key regulators can maintain tissue homeostasis via a negative feedback loop.

(Int J Artif Organs 2008; 31: 411-7)

Background:Cardiovascular disease remains the most common cause of mortality in end-stage kidney failure patients with diabetes. To improve blood pressure control, and reduce cardiovascular risk, in 2002 the UK Renal Association Standards’ Committee introduced pre- and post-dialysis target blood pressures of <140/90 and <130/80 mm Hg, respectively. Methods: We audited blood pressure control and symptomatic intradialytic hypotension during 1 week in the eleven renal centres in the Greater London Urban Area in 2,193 patients, capturing 6,579 haemodialysis sessions. Results: Although 73.9% of the 658 diabetic patients were prescribed antihypertensive medications, compared to 57.8% of the 1,535 non-diabetic patients (p < 0.001), both the mean pre- and post-dialysis blood pressures were greater in the diabetic patients: before dialysis 152 ± 23/77 ± 13 versus 144 ± 23/79 ± 13 mm Hg and after dialysis 138 ± 24/71 ± 12 versus 132 ± 26/73 ± 13 mm Hg, and fewer diabetic patients achieved the pre- and post-dialysis blood pressure targets: 28.6 versus 40.8% and 37.9 versus 46.3%, respectively (p < 0.01). In addition, more diabetic patients suffered symptomatic intradialytic hypotension, 20.3 versus 14.9% (p < 0.01), associated with greater interdialytic weight gains. Conclusion: Diabetic haemodialysis patients had higher blood pressures, both before and after dialysis, associated with greater interdialytic weight gains and more frequent symptomatic intradialytic hypotension.

Glyceraldehyde-3-phosphate dehydrogenase gene (GAPDH) and its paralogues were implicated in late-onset Alzheimer's disease (LOAD), although the strength and direction of association have not been consistent. We genotyped three previously reported SNPs (rs3741916-GAPDH 5'UTR, rs2029721-pGAPD and rs4806173-GAPDHS) in three case-control series (2112 cases and 3808 controls). Rs3741916 showed the strongest LOAD association (p=0.003). The minor allele of rs3741916 showed a protective effect in our combined series (OR=0.87, 95% confidence interval (CI)=0.79-0.96). This is consistent with results from the two published follow-up studies and in © 2010 Elsevier Inc. All rights reserved. # To whom correspondence should be address: taner.nilufer@mayo.edu or younkin.steven@mayo.edu, ). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Figure A and Supplemental Data Information: Supplementary Text, Search Terms