IKZF1 alterations are not associated with outcome in 498 adults with B-precursor ALL enrolled in the UKALL14 trial

IKZF1 deletions (ΔIKZF1) are commonly detected in B-precursor acute lymphoblastic leukemia (ALL; B-ALL) and are widely assumed to have a significant impact on outcome. We compared the ability of multiplex ligand-dependent probe amplification (MLPA) and polymerase chain reaction (PCR) to detect ΔIKZF1 and to determine the impact on event-free survival of patients with precursor B-ALL aged 23 to 65 years recruited to the completed trial UKALL14 (ISRCTN 66541317). From 655 recruits with BCR-ABL1+ and BCR-ABL1− B-ALL, all available diagnostic DNA samples (76% of the recruited population) were screened by multiplex end point PCR covering 4 deletions: dominant-negative (DN) Δ4-7 or the loss of function Δ2-7, Δ4-8, and Δ2-8 (n = 498), MLPA (n = 436), or by both (n = 420). Although patients with BCR-ABL1− ΔIKZF1 were more likely to have minimal residual disease at the end of induction, we did not find any impact of ΔIKZF1 (including subgroup analysis for DN or loss-of-function lesions) or the IKZF1plus genotype on event-free, overall survival, or relapse risk by univariable or multivariable analyses. Consistent with the technical approach, MLPA not only detected a wider range of deletions than PCR but also failed to detect some PCR-detected lesions. The main difference between our study and others reporting an association between ΔIKZF1 and outcome is the older age of participants in our population. The impact of ΔIKZF1 in ALL may be less marked in an older population of patients. Our study underscores the need for analyses in large, harmonized data sets. This trial was registered at www.clinicaltrials.gov as #NCT01085617

Alcohol-related hypoglycemia in rural Uganda: socioeconomic and physiologic contrasts

Hypoglycemia is a rare but important complication seen in patients who present with alcohol intoxication. In a study by Marks and Teale, less than one percent of people with alcohol intoxication who presented to an American emergency department were hypoglycemic [1]. It is even more rare to see an intoxicated patient, who had been eating appropriately prior to or during the intoxication, present in a hypoglycemic coma. However, our analysis of the first 500 patients seen in a newly opened five-bed Emergency Department (ED) at Nyakibale Karoli Lwanga Hospital in rural southwestern Uganda, revealed multiple intoxicated patients who presented in hypoglycemic coma within hours of eating a full meal. Three of these cases are summarized and discussed below

Comparative evaluation of the treatment efficacy of suberoylanilide hydroxamic acid (SAHA) and paclitaxel in ovarian cancer cell lines and primary ovarian cancer cells from patients

BACKGROUND: In most patients with ovarian cancer, diagnosis occurs after the tumour has disseminated beyond the ovaries. In these cases, post-surgical taxane/platinum combination chemotherapy is the "gold standard". However, most of the patients experience disease relapse and eventually die due to the emergence of chemotherapy resistance. Histone deacetylase inhibitors are novel anticancer agents that hold promise to improve patient outcome. METHODS: We compared a prototypic histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), and paclitaxel for their treatment efficacy in ovarian cancer cell lines and in primary patient-derived ovarian cancer cells. The primary cancer cells were isolated from malignant ascites collected from five patients with stage III ovarian carcinomas. Cytotoxic activities were evaluated by Alamar Blue assay and by caspase-3 activation. The ability of SAHA to kill drug-resistant 2780AD cells was also assessed. RESULTS: By employing the cell lines OVCAR-3, SK-OV-3, and A2780, we established SAHA at concentrations of 1 to 20 μM to be as efficient in inducing cell death as paclitaxel at concentrations of 3 to 300 nM. Consequently, we treated the patient-derived cancer cells with these doses of the drugs. All five isolates were sensitive to SAHA, with cell killing ranging from 21% to 63% after a 72-h exposure to 20 μM SAHA, while four of them were resistant to paclitaxel (i.e., <10% cell death at 300 nM paclitaxel for 72 hours). Likewise, treatment with SAHA led to an increase in caspase-3 activity in all five isolates, whereas treatment with paclitaxel had no effect on caspase-3 activity in three of them. 2780AD cells were responsive to SAHA but resistant to paclitaxel. CONCLUSION: These ex vivo findings raise the possibility that SAHA may prove effective in the treatment of paclitaxel-resistant ovarian cancer in vivo

A False Start in the Race Against Doping in Sport: Concerns With Cycling’s Biological Passport

Professional cycling has suffered from a number of doping scandals. The sport’s governing bodies have responded by implementing an aggressive new antidoping program known as the biological passport. Cycling’s biological passport marks a departure from traditional antidoping efforts, which have focused on directly detecting prohibited substances in a cyclist’s system. Instead, the biological passport tracks biological variables in a cyclist’s blood and urine over time, monitoring for fluctuations that are thought to indirectly reveal the effects of doping. Although this method of indirect detection is promising, it also raises serious legal and scientific concerns. Since its introduction, the cycling community has debated the reliability of indirect biological-passport evidence and the clarity, consistency, and transparency of its use in proving doping violations. Such uncertainty undermines the legitimacy of finding cyclists guilty of doping based on this indirect evidence alone. Antidoping authorities should address these important concerns before continuing to pursue doping sanctions against cyclists solely on the basis of their biological passports

Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia.

The role of Hedgehog signaling in normal and malignant T-cell development is controversial. Recently, Hedgehog pathway mutations have been described in T-ALL, but whether mutational activation of Hedgehog signaling drives T-cell transformation is unknown, hindering the rationale for therapeutic intervention. Here, we show that Hedgehog pathway mutations predict chemotherapy resistance in human T-ALL, and drive oncogenic transformation in a zebrafish model of the disease. We found Hedgehog pathway mutations in 16% of 109 childhood T-ALL cases, most commonly affecting its negative regulator PTCH1. Hedgehog mutations were associated with resistance to induction chemotherapy (P = 0.009). Transduction of wild-type PTCH1 into PTCH1-mutant T-ALL cells induced apoptosis (P = 0.005), a phenotype that was reversed by downstream Hedgehog pathway activation (P = 0.007). Transduction of most mutant PTCH1, SUFU, and GLI alleles into mammalian cells induced aberrant regulation of Hedgehog signaling, indicating that these mutations are pathogenic. Using a CRISPR/Cas9 system for lineage-restricted gene disruption in transgenic zebrafish, we found that ptch1 mutations accelerated the onset of notch1-induced T-ALL (P = 0.0001), and pharmacologic Hedgehog pathway inhibition had therapeutic activity. Thus, Hedgehog-activating mutations are driver oncogenic alterations in high-risk T-ALL, providing a molecular rationale for targeted therapy in this disease

The stellar and sub-stellar IMF of simple and composite populations

The current knowledge on the stellar IMF is documented. It appears to become top-heavy when the star-formation rate density surpasses about 0.1Msun/(yr pc^3) on a pc scale and it may become increasingly bottom-heavy with increasing metallicity and in increasingly massive early-type galaxies. It declines quite steeply below about 0.07Msun with brown dwarfs (BDs) and very low mass stars having their own IMF. The most massive star of mass mmax formed in an embedded cluster with stellar mass Mecl correlates strongly with Mecl being a result of gravitation-driven but resource-limited growth and fragmentation induced starvation. There is no convincing evidence whatsoever that massive stars do form in isolation. Various methods of discretising a stellar population are introduced: optimal sampling leads to a mass distribution that perfectly represents the exact form of the desired IMF and the mmax-to-Mecl relation, while random sampling results in statistical variations of the shape of the IMF. The observed mmax-to-Mecl correlation and the small spread of IMF power-law indices together suggest that optimally sampling the IMF may be the more realistic description of star formation than random sampling from a universal IMF with a constant upper mass limit. Composite populations on galaxy scales, which are formed from many pc scale star formation events, need to be described by the integrated galactic IMF. This IGIMF varies systematically from top-light to top-heavy in dependence of galaxy type and star formation rate, with dramatic implications for theories of galaxy formation and evolution.Comment: 167 pages, 37 figures, 3 tables, published in Stellar Systems and Galactic Structure, Vol.5, Springer. This revised version is consistent with the published version and includes additional references and minor additions to the text as well as a recomputed Table 1. ISBN 978-90-481-8817-

A cross-national study on the antecedents of work–life balance from the fit and balance perspective

Drawing on the perceived work–family fit and balance perspective, this study investigates demands and resources as antecedents of work–life balance (WLB) across four countries (New Zealand, France, Italy and Spain), so as to provide empirical cross-national evidence. Using structural equation modelling analysis on a sample of 870 full time employees, we found that work demands, hours worked and family demands were negatively related to WLB, while job autonomy and supervisor support were positively related to WLB. We also found evidence that resources (job autonomy and supervisor support) moderated the relationships between demands and work–life balance, with high resources consistently buffering any detrimental influence of demands on WLB. Furthermore, our study identified additional predictors of WLB that were unique to some national contexts. For example, in France and Italy, overtime hours worked were negatively associated with WLB, while parental status was positively associated with WLB. Overall, the implications for theory and practice are discussed.Peer ReviewedPostprint (author's final draft

Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.

Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex