Effects of recombinant LH supplementation to recombinant FSH during induced ovarian stimulation in the GnRH-agonist protocol: a matched case-control study

<p>Abstract</p> <p>Background</p> <p>Some studies have suggested that the suppression of endogenous LH secretion does not seem to affect the majority of patients who are undergoing assisted reproduction and stimulation with recombinant FSH (r-FSH). Other studies have indicated that a group of normogonadotrophic women down-regulated and stimulated with pure FSH preparations may experience low LH concentrations that compromise the IVF parameters. The present study aimed to compare the efficacy of recombinant LH (r-LH) supplementation for controlled ovarian stimulation in r-FSH and GnRH-agonist (GnRH-a) protocol in ICSI cycles.</p> <p>Methods</p> <p>A total of 244 patients without ovulatory dysfunction, aged <40 years and at the first ICSI cycle were divided into two groups matched by age according to an ovarian stimulation scheme: Group I (n = 122): Down-regulation with GnRH-a + r-FSH and Group II (n = 122): Down-regulation with GnRH-a + r-FSH and r-LH (beginning simultaneously).</p> <p>Result(s)</p> <p>The number of oocytes collected, the number of oocytes in metaphase II and fertilization rate were significantly lower in the Group I than in Group II (<it>P </it>= 0.036, <it>P </it>= 0.0014 and <it>P </it>= 0.017, respectively). In addition, the mean number of embryos produced per cycle and the mean number of frozen embryos per cycle were statistically lower (<it>P </it>= 0.0092 and <it>P </it>= 0.0008, respectively) in Group I than in Group II. Finally the cumulative implantation rate (fresh+thaw ed embryos) was significantly lower (<it>P </it>= 0.04) in Group I than in Group II. The other clinical and laboratory results analyzed did not show difference between groups.</p> <p>Conclusion</p> <p>These data support r-LH supplementation in ovarian stimulation protocols with r-FSH and GnRH-a for assisted reproduction treatment.</p

Inhibition of translation initiation factor eIF4a inactivates heat shock factor 1 (HSF1) and exerts anti-leukemia activity in AML

Eukaryotic initiation factor 4A (eIF4A), the enzymatic core of the eIF4F complex essential for translation initiation, plays a key role in the oncogenic reprogramming of protein synthesis, and thus is a putative therapeutic target in cancer. As important component of its anticancer activity, inhibition of translation initiation can alleviate oncogenic activation of HSF1, a stress-inducible transcription factor that enables cancer cell growth and survival. Here, we show that primary acute myeloid leukemia (AML) cells exhibit the highest transcript levels of eIF4A1 compared to other cancer types. eIF4A inhibition by the potent and specific compound rohinitib (RHT) inactivated HSF1 in these cells, and exerted pronounced in vitro and in vivo anti-leukemia effects against progenitor and leukemia-initiating cells, especially those with FLT3-internal tandem duplication (ITD). In addition to its own anti-leukemic activity, genetic knockdown of HSF1 also sensitized FLT3-mutant AML cells to clinical FLT3 inhibitors, and this synergy was conserved in FLT3 double-mutant cells carrying both ITD and tyrosine kinase domain mutations. Consistently, the combination of RHT and FLT3 inhibitors was highly synergistic in primary FLT3-mutated AML cells. Our results provide a novel therapeutic rationale for co-targeting eIF4A and FLT3 to address the clinical challenge of treating FLT3-mutant AML.R01 CA175744 - NCI NIH HHS; R35 GM118173 - NIGMS NIH HHS; P30 CA016672 - NCI NIH HHSPublished versionSupporting documentationAccepted manuscrip

Constitutive modelling of skin ageing

The objective of this chapter is to review the main biomechanical and structural aspects associated with both intrinsic and extrinsic skin ageing, and to present potential research avenues to account for these effects in mathematical and computational models of the skin. This will be illustrated through recent work of the authors which provides a basis to those interested in developing mechanistic constitutive models capturing the mechanobiology of skin across the life course

Phosphorylation of GSK3α/β correlates with activation of AKT and is prognostic for poor overall survival in acute myeloid leukemia patients

Background: Acute myeloid leukemia (AML) patients with highly active AKT tend to do poorly. Cell cycle arrest and apoptosis are tightly regulated by AKT via phosphorylation of GSK3α and β isoforms which inactivates these kinases. In the current study we examine the prognostic role of AKT mediated GSK3 phosphorylation in AML. Methods: We analyzed GSK3α/β phosphorylation by reverse phase protein analysis (RPPA) in a cohort of 511 acute myeloid leukemia (AML) patients. Levels of phosphorylated GSK3 were correlated with patient characteristics including survival and with expression of other proteins important in AML cell survival. Results: High levels of p-GSK3α/β correlated with adverse overall survival and a lower incidence of complete remission duration in patients with intermediate cytogenetics, but not in those with unfavorable cytogenetics. Intermediate cytogenetic patients with FLT3 mutation also fared better respectively when p-GSK3α/β levels were lower. Phosphorylated GSK3α/β expression was compared and contrasted with that of 229 related cell cycle arrest and/or apoptosis proteins. Consistent with p-GSK3α/β as an indicator of AKT activation, RPPA revealed that p-GSK3α/β positively correlated with phosphorylation of AKT, BAD, and P70S6K, and negatively correlated with β-catenin and FOXO3A. PKCδ also positively correlated with p-GSK3α/β expression, suggesting crosstalk between the AKT and PKC signaling pathways in AML cells. Conclusions: These findings suggest that AKT-mediated phosphorylation of GSK3α/β may be beneficial to AML cell survival, and hence detrimental to the overall survival of AML patients. Intrinsically, p-GSK3α/β may serve as an important adverse prognostic factor for a subset of AML patients

The evolutionary history of the hominin hand since the last common ancestor of Pan and Homo

Molecular evidence indicates that the last common ancestor of the genus Pan and the hominin clade existed between 8 and 4 million years ago (Ma). The current fossil record indicates the Pan-Homo last common ancestor existed at least 5 Ma and most likely between 6 and 7 Ma. Together, the molecular and fossil evidence has important consequences for interpreting the evolutionary history of the hand within the tribe Hominini (hominins). Firstly, parsimony supports the hypothesis that the hand of the last common ancestor most likely resembled that of an extant great ape overall (Pan, Gorilla, and Pongo), and that of an African ape in particular. Second, it provides a context for interpreting the derived changes to the hand that have evolved in various hominins. For example, the Australopithecus afarensis hand is likely derived in comparison with that of the Pan–Homo last common ancestor in having shorter fingers relative to thumb length and more proximo-distally oriented joints between its capitate, second metacarpal, and trapezium. This evidence suggests that these derived features evolved prior to the intensification of stone tool-related hominin behaviors beginning around 2.5 Ma. However, a majority of primitive features most likely present in the Pan-Homo last common ancestor are retained in the hands of Australopithecus, Paranthropus/early Homo, and Homo floresiensis. This evidence suggests that further derived changes to the hands of other hominins such as modern humans and Neandertals did not evolve until after 2.5 Ma and possibly even later than 1.5 Ma, which is currently the earliest evidence of Acheulian technology. The derived hands of modern humans and Neandertals may indicate a morphological commitment to tool-related manipulative behaviors beyond that observed in other hominins, including those (e.g. H. floresiensis) which may be descended from earlier tool-making species