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Animal and human observational studies suggest that iron deficiency impairs physical exercise performance, but findings from randomized trials on the effects of iron are equivocal. Iron deficiency and anemia are especially common in women of reproductive age (WRA). Clear evidence of benefit from iron supplementation would inform clinical and public health guidelines. Therefore, we performed a systematic review and meta-analysis to determine the effect of iron supplementation compared with control on exercise performance in WRA. We searched the Cochrane Central Register of Clinical Trials, MEDLINE, Scopus (comprising Embase and MEDLINE), WHO regional databases, and other sources in July 2013.Randomized controlled trials that measured exercise outcomes in WRA randomized to daily oral iron supplementation vs.control were eligible. Random-effects meta-analysis was used to calculate mean differences (MDs) and standardized MDs (SMDs). Risk of bias was assessed using the Cochrane risk-of-bias tool. Of 6757 titles screened, 24 eligible studies were identified, 22 of which contained extractable data. Only 3 studies were at overall low risk of bias. Iron supplementation improved both maximal exercise performance, demonstrated by an increase in maximal oxygen consumption (VO 2 max) [for relative VO 2 max, MD: 2.35 mL/(kg Á min); 95% CI: 0.82, 3.88; P = 0.003, 18 studies; for absolute VO 2 max, MD: 0.11 L/min; 95% CI: 0.03, 0.20; P = 0.01, 9 studies; for overall VO 2 max, SMD: 0.37; 95% CI: 0.11, 0.62; P = 0.005, 20 studies], and submaximal exercise performance, demonstrated by a lower heart rate (MD: 24.05 beats per minute; 95% CI: 27.25, 20.85; P = 0.01, 6 studies) and proportion of VO 2 max (MD: 22.68%; 95% CI: 24.94, 20.41; P = 0.02, 6 studies) required to achieve defined workloads. Daily iron supplementation significantly improves maximal and submaximal exercise performance in WRA, providing a rationale to prevent and treat iron deficiency in this group. This trial was registered with PROSPERO (http://www. crd.york.ac.uk/PROSPERO/prospero.asp) as CRD42013005166. J. Nutr. 144: 906-914, 2014.

ABSTRACT:Cytochrome P450 (P450) protein-protein interactions have been observed with various in vitro systems. It is interesting to note that these interactions seem to be isoform-dependent, with some combinations producing no effect and others producing increased or decreased catalytic activity. With some exceptions, most of the work to date has involved P450s from rabbit, rat, and other animal species, with few studies including human P450s. In the studies presented herein, the interactions of two key drug-metabolizing enzymes, CYP2C9 and CYP2D6, were analyzed in a purified, reconstituted enzyme system for changes in both substrate-binding affinity and rates of catalysis. In addition, an extensive study was conducted as to the "order of mixing" for the reconstituted enzyme system and the impact on the observations. CYP2D6 coincubation inhibited CYP2C9-mediated (S)-flurbiprofen metabolism in a protein concentration-dependent manner. V max values were reduced by up to 50%, but no appreciable effect on K m was observed. Spectral binding studies revealed a 20-fold increase in the K S of CYP2C9 toward (S)-flurbiprofen in the presence of CYP2D6. CYP2C9 coincubation had no effect on CYP2D6-mediated dextromethorphan O-demethylation. The order of combination of the proteins (CYP2C9, CYP2D6, and cytochrome P450 reductase) influenced the magnitude of catalysis inhibition as well as the ability of increased cytochrome P450 reductase to attenuate the change in activity. A simple model, congruent with current results and those of others, is proposed to explain oligomer formation. In summary, CYP2C9-CYP2D6 interactions can alter catalytic activity and, thus, influence in vitro-in vivo correlation predictions.Cytochrome P450s (P450s) are responsible for the metabolism of more than 75% of the drugs on the market (Guengerich, 2006). Multiple subfamilies of cytochrome P450s can activate and metabolize a wide spectrum of substrates by a two-electron transfer catalytic cycle, in which electrons are provided by either NADPH-cytochrome P450 reductase (CPR) or cytochrome b 5 (b5), depending on the stage of the cycle (Guengerich, 2001). A number of studies have investigated the role of CPR and b5 and the nature of P450, CPR, and b5 interactions. Although CPR is indispensable for metabolism, cytochrome b 5 either has no effect or significantly enhances metabolism (Shimada et al., 1994;Locuson et al., 2006). Yamazaki et al. (1997) demonstrated that b5 stimulated the metabolism of tolbutamide and (S)-warfarin by CYP2C10 but had no effect on bufuralol hydroxylation by CYP1A1 and CYP2D6. In addition, both apo-and holo-b5 enhanced metabolism by CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, and CYP3A5 in reconstituted systems (Shimada et al., 1994), suggesting that the effect of these protein-protein interactions of the redox partner with P450 may involve enzyme conformational changes or other mechanisms besides just provision of electrons.In addition to interactions with CPR and b5, P450s can also interact with each other, resulting in c...

Abstract Recent studies have demonstrated that the immunomodulatory drugs (IMiDs) lead to the degradation of the transcription factors Ikaros and Aiolos. However, why their loss subsequently leads to multiple myeloma (MM) cell death remains unclear. Using CRISPR-Cas9 genome editing, we have deleted IKZF1/Ikaros and IKZF3/Aiolos in human MM cell lines to gain further insight into their downstream gene regulatory networks. Inactivation of either factor alone recapitulates the cell intrinsic action of the IMiDs, resulting in cell cycle arrest and induction of apoptosis. Furthermore, evaluation of the transcriptional changes resulting from their loss demonstrates striking overlap with lenalidomide treatment. This was not dependent on reduction of the IRF4-MYC “axis,” as neither protein was consistently downregulated, despite cell death occurring, and overexpression of either factor failed to rescue for Ikaros loss. Importantly, Ikaros and Aiolos repress the expression of interferon-stimulated genes (ISGs), including CD38, and their loss led to the activation of an interferon-like response, contributing to MM cell death. Ikaros/Aiolos repressed CD38 expression through interaction with the nucleosome remodeling and deacetylase complex in MM. IMiD-induced loss of Ikaros or treatment with interferon resulted in an upregulation of CD38 surface expression on MM cells, priming for daratumumab-induced NK cell-mediated antibody-dependent cellular cytotoxicity. These results give further insight into the mechanism of action of the IMiDs and provide mechanistic rationale for combination with anti-CD38 monoclonal antibodies.

Conjunctival vascular tortuosity was the most common manifestation in this series. Conjunctival and retinal vessel tortuosity, and corneal verticillata are frequently observed in Fabry disease. The incidence of lenticular changes is not consistently reported, but in this series and many others, it is much less common than that of corneal, conjunctival and retinal changes.

Summary Central nervous system (CNS) multiple myeloma (MM) is exceedingly rare and portends a dismal prognosis. While immunomodulators have contributed to the improvement in survival in MM, they appear to have limited activity against CNS MM and, paradoxically, may contribute to the evolution of resistant MM clones capable of surviving within the CNS. We undertook a retrospective analysis to characterize the features of CNS MM and outcome in 17 patients from four institutions identified between 2000 and 2011. The median age was 58 years. Patients had received a median of three prior therapies and all had been exposed to at least one of the so‐called novel anti‐MM agents before the diagnosis of CNS MM. The median time to CNS disease from initial diagnosis was 36 months. Cerebrospinal fluid (CSF) light chain measurements produced discrepant results to serum light chain measurements in some patients. Treatments included systemic pharmacotherapy, intrathecal (IT) chemotherapy and/or radiotherapy (RT). The median overall survival (OS) from diagnosis of CNS MM was only 4 months. OS was significantly better in patients who received IT chemotherapy (20 months vs. 2 months, respectively; P < 0·02). We conclude that the systematic evaluation of IT therapy and diagnostic utility of CSF light chain measurements in CNS MM are warranted.

The transcription factor interferon regulatory factor 4 (IRF4) is critical for the development, maintenance, and function of plasma cells. The mechanism by which IRF4 exerts its action in mature plasma cells has been elusive due to the death of all such cells upon IRF4 loss. While we identify apoptosis as a critical pathway for the death of plasma cells caused by IRF4 loss, we also determine that IRF4 did not regulate the intrinsic apoptotic pathway directly. By using an inducible IRF4 deletion system in the presence of the overexpression of anti-apoptotic BCL2, we identify genes whose expression is coordinated by IRF4 and that in turn specify plasma cell identity and mitochondrial homeostasis.