l-2-Hydroxyglutarate remodeling of the epigenome and epitranscriptome creates a metabolic vulnerability in kidney cancer models.

Tumor cells are known to undergo considerable metabolic reprogramming to meet their unique demands and drive tumor growth. At the same time, this reprogramming may come at a cost with resultant metabolic vulnerabilities. The small molecule l-2-hydroxyglutarate (l-2HG) is elevated in the most common histology of renal cancer.

Teleological role of L-2-hydroxyglutarate dehydrogenase in the kidney.

L-2-hydroxyglutarate (L-2HG) is an oncometabolite found elevated in renal tumors. However, this molecule might have physiological roles that extend beyond its association with cancer, as L-2HG levels are elevated in response to hypoxia and during larval development. L-2HG is known to be metabolized by L-2HG dehydrogenase (L2HGDH), and loss of L2HGDH leads to elevated L-2HG levels.

PRDM16 suppresses HIF-targeted gene expression in kidney cancer.

Analysis of transcriptomic data demonstrates extensive epigenetic gene silencing of the transcription factor PRDM16 in renal cancer. We show that restoration of PRDM16 in RCC cells suppresses in vivo tumor growth. RNaseq analysis reveals that PRDM16 imparts a predominantly repressive effect on the RCC transcriptome including suppression of the gene encoding semaphorin 5B (SEMA5B).

PGC1α suppresses kidney cancer progression by inhibiting collagen-induced SNAIL expression.

The transcriptional events that promote invasive and metastatic phenotypes in renal cell carcinoma (RCC) remain poorly understood. Here we report that the decreased expression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1α) and the increased expression of several genes encoding collagen family members are associated with RCC tumor progression. PGC1α restoration attenuates invasive phenotypes and suppresses tumor progression in vivo.

14-3-3 proteins protect AMPK-phosphorylated ten-eleven translocation-2 (TET2) from PP2A-mediated dephosphorylation.

Ten-eleven translocation-2 (TET2) is a member of the methylcytosine dioxygenase family of enzymes and has been implicated in cancer and aging because of its role as a global epigenetic modifier. TET2 has a large N-terminal domain and a catalytic C-terminal region. Previous reports have demonstrated that the TET2 catalytic domain remains active independently of the N-terminal domain.

Biochemical and Epigenetic Insights into L-2-Hydroxyglutarate, a Potential Therapeutic Target in Renal Cancer.

Purpose: Elevation of L-2-hydroxylgutarate (L-2-HG) in renal cell carcinoma (RCC) is due in part to reduced expression of L-2-HG dehydrogenase (L2HGDH). However, the contribution of L-2-HG to renal carcinogenesis and insight into the biochemistry and targets of this small molecule remains to be elucidated.

Experimental Design: Genetic and pharmacologic approaches to modulate L-2-HG levels were assessed for effects on and phenotypes.

The role of public communication in decision making for waste management infrastructure.

Modern waste management provision seeks to meet challenging objectives and strategies while reflecting community aspirations and ensuring cost-effective compliance with statutory obligations. Its social acceptability, which affects both what systems (infrastructure) can be put in place and to what extent their implementation will be successful, is a multi-dimensional phenomenon, often not well understood. In light of the growing evidence that decisions to build new infrastructure are often contested by the public, there is a clear need to understand the role of scientific evidence in public perception, particularly as environmental infrastructure delivery is often objected to by the public on environmental grounds.

Navigating Bioethical Waters: Two Pilot Projects in Problem-Based Learning for Future Bioscience and Biotechnology Professionals.

We believe that the professional responsibility of bioscience and biotechnology professionals includes a social responsibility to contribute to the resolution of ethically fraught policy problems generated by their work. It follows that educators have a professional responsibility to prepare future professionals to discharge this responsibility. This essay discusses two pilot projects in ethics pedagogy focused on particularly challenging policy problems, which we call "fractious problems".

Point mutations of the mTOR-RHEB pathway in renal cell carcinoma.

Aberrations in the mTOR (mechanistic target of rapamycin) axis are frequently reported in cancer. Using publicly available tumor genome sequencing data, we identified several point mutations in MTOR and its upstream regulator RHEB (Ras homolog enriched in brain) in patients with clear cell renal cell carcinoma (ccRCC), the most common histology of kidney cancer. Interestingly, we found a prominent cluster of hyperactivating mutations in the FAT (FRAP-ATM-TTRAP) domain of mTOR in renal cell carcinoma that led to an increase in both mTORC1 and mTORC2 activities and led to an increased proliferation of cells.

L-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer.

Unlabelled: Through unbiased metabolomics, we identified elevations of the metabolite 2-hydroxyglutarate (2HG) in renal cell carcinoma (RCC). 2HG can inhibit 2-oxoglutaratre (2-OG)-dependent dioxygenases that mediate epigenetic events, including DNA and histone demethylation. 2HG accumulation, specifically the d enantiomer, can result from gain-of-function mutations of isocitrate dehydrogenase (IDH1, IDH2) found in several different tumors.

Retinoic acid hypersensitivity promotes peripheral tolerance in recent thymic emigrants.

Whereas thymic education eliminates most self-reactive T cells, additional mechanisms to promote tolerance in the periphery are critical to prevent excessive immune responses against benign environmental Ags and some self-Ags. In this study we show that murine CD4(+) recent thymic emigrants (RTEs) are programmed to facilitate tolerance in the periphery. Both in vitro and in vivo, naive RTEs more readily upregulate Foxp3 than do mature naive cells after stimulation under tolerogenic conditions.

Developmental regulation of Th17-cell capacity in human neonates.

Human neonates are at significantly greater risk of serious infection than immunocompetent adults. In particular, very low birth weight infants in the neonatal intensive care nursery are at high risk of developing life-threatening bacterial and fungal infections. Recent studies have identified Th17 cells as critical mediators of immunity to bacterial and fungal infections at epithelial barriers.

The Engineering and Science Issues Test (ESIT): a discipline-specific approach to assessing moral judgment.

To assess ethics pedagogy in science and engineering, we developed a new tool called the Engineering and Science Issues Test (ESIT). ESIT measures moral judgment in a manner similar to the Defining Issues Test, second edition, but is built around technical dilemmas in science and engineering. We used a quasi-experimental approach with pre- and post-tests, and we compared the results to those of a control group with no overt ethics instruction.

Extraordinary starvation resistance in Temnothorax rugatulus (Hymenoptera, Formicidae) colonies: Demography and adaptive behavior.

Ant colony mortality has not been sufficiently studied, even though it is crucial for understanding social insect population biology and can serve as an important model for general aging and mortality processes. Particularly, studies on proximate mechanisms on mortality and stress resistance of ant colonies are lacking. This study explores the long-term colony starvation resistance of the small myrmecine ant Temnothorax rugatulus.

tRNA isoacceptor preference prior to retrovirus Gag-Pol junction links primer selection and viral translation.

An essential step in the replication of all retroviruses is the capture of a cellular tRNA that is used as the primer for reverse transcription. The 3'-terminal 18 nucleotides of the tRNA are complementary to the primer binding site (PBS). Moloney murine leukemia virus (MuLV) preferentially captures tRNA(Pro).

A study to assess the prevalence of chronic testicular pain in post-vasectomy men compared to non-vasectomised men.

Objective: To assess the prevalence of chronic post-vasectomy testicular pain (CPTP) compared to the prevalence of chronic testicular pain in a control population of non-vasectomised men.

Methods: A retrospective postal study of 198 men who had a vasectomy more than 3 years previously at the Palatine Centre to determine the incidence of CPTP, of whom 101 (51%) replied (mean age 40.4 years, range 29-54 years, mean time since vasectomy 46.

Preferences for the selection of unique tRNA primers revealed from analysis of HIV-1 replication in peripheral blood mononuclear cells.

Background: All human immunodeficiency virus (HIV-1) uses a host tRNALys,3 as the primer for reverse transcription. The tRNALys,3 is bound to a region on the HIV-1 genome, the primer-binding site (PBS), that is complementary to the 18 terminal nucleotides of tRNALys,3. How HIV-1 selects the tRNA from the intracellular milieu is unresolved.

Inhibition of human immunodeficiency virus type 1 replication by siRNA targeted to the highly conserved primer binding site.

The initiation of HIV-1 reverse transcription occurs at an 18-nucleotide sequence in the viral genome designated as the primer binding site (PBS), which is complementary to the 3' terminal nucleotides of tRNA(Lys,3). Since the PBS is highly conserved among all infectious HIV-1, it represents an attractive target for the development of new therapeutics to inhibit viral replication. In this study, we have evaluated three approaches using small interfering RNA (siRNAs) targeted to the PBS for the capacity to inhibit HIV-1 replication.

HIV type 1 that select tRNA(His) or tRNA(Lys1,2) as primers for reverse transcription exhibit different infectivities in peripheral blood mononuclear cells.

The replication in human peripheral blood mononuclear cells (PBMC) of unique HIV-1 that select tRNA(His) or tRNA(Lys1,2) for reverse transcription was compared to the wild-type virus that uses tRNA(Lys,3). HIV-1 with only the primer-binding site (PBS) changed to be complementary to these alternative tRNAs initially replicated more slowly than the wild-type virus in PBMC, although all viruses eventually reached equivalent growth as measured by p24 antigen. Viruses with only a PBS complementary to the 3' terminal 18 nucleotides of tRNA(His) or tRNA(Lys1,2) reverted to use tRNA(Lys3).

Re-audit of referral compliance of chlamydia-positive women from a family planning clinic.

Background: Chlamydia infections represent a major public health problem, with a prevalence of 6-10% in family planning clinic (FPC) attendees. There has been recent concern expressed about the management of these patients in terms of treatment and follow-up.

Objective: An audit was carried out to monitor referral compliance and outcome with care pathways of women attending our FPC who were found to be positive for chlamydia.

Coil or intrauterine device? Patient preferences for contraceptive terminology.

Objective: To discover what terminology women prefer to use when referring to contraceptive methods and to investigate the understanding of and ideas associated with contraceptive names.

Design: A self-administered questionnaire was answered by 191 new patients at family planning clinics (FPCs). Women were asked if they understood the terms used by the fpa (Family Planning Association), if they knew of any alternatives and, if so, which they preferred.

Pharmacokinetics of daclizumab and mycophenolate mofetil with cyclosporine and steroids in renal transplantation.

Daclizumab and mycophenolate mofetil (MMF) decrease the incidence of acute allograft rejection. This double-blind, randomized, placebo-controlled trial was performed primarily to assess the pharmacokinetics of MMF in an immunosuppressive regimen incorporating daclizumab. At five centers, 75 renal transplant recipients were randomized 2:1 to receive either daclizumab 1 mg/kg or placebo pre-transplantation and every other week, for a total of five doses.

Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial.

Background: A single 10 mg dose of mifepristone, and two 0.75 mg doses of levonorgestrel 12 h apart, are effective for emergency contraception. Because no studies had compared the efficacies of both compounds, or investigated a single dose of 1.