The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key events in the development of glioma, acute myeloid leukemia (AML), chondrosarcoma, intrahepatic cholangiocarcinoma (ICC), and angioimmunoblastic T-cell lymphoma. They also cause D-2-hydroxyglutaric aciduria and Ollier and Maffucci syndromes. IDH1/2 mutations are associated with prolonged survival in glioma and in ICC, but not in AML. The reason for this is unknown. In their wild-type forms, IDH1 and IDH2 convert isocitrate and NADP⁺ to α-ketoglutarate (αKG) and NADPH. Missense mutations in the active sites of these enzymes induce a neo-enzymatic reaction wherein NADPH reduces αKG to D-2-hydroxyglutarate (D-2HG). The resulting D-2HG accumulation leads to hypoxia-inducible factor 1α degradation, and changes in epigenetics and extracellular matrix homeostasis. Such mutations also imply less NADPH production capacity. Each of these effects could play a role in cancer formation. Here, we provide an overview of the literature and discuss which downstream molecular effects are likely to be the drivers of the oncogenic and survival-prolonging properties of IDH1/2 mutations. We discuss interactions between mutant IDH1/2 inhibitors and conventional therapies. Understanding of the biochemical consequences of IDH1/2 mutations in oncogenesis and survival prolongation will yield valuable information for rational therapy design: it will tell us which oncogenic processes should be blocked and which “survivalogenic” effects should be retained.     

Reference database of the gait cycle for young healthy Tunisian adults

BackgroundQuantified gait analysis is a rising technology used increasingly to assess motor disorders. Normal reference data are required in order to evaluate patients, but there are no reference data available for the Tunisian healthy population.AimTo assess the features of normal Tunisian gait pattern, and examine the intrinsic reliability of spatio-temporal, kinematic and kinetic parameters within a new specific reference database.MethodsEighteen healthy active-young adults (age: 23.30 ± 2.54 years, height: 1.78 ± 0.04 m and, weight: 70.00 ± 4.80 kg) have participated to five trials of step gait where the dominant lower limb were recorded. Two over the five trials were randomly selected to be further analyzed. Twenty-three spatio-temporal, kinematic and kinetic parameters determined from 3-dimensional gait analysis. The intrinsic reliability was examined for each variable and our results were compared with those available in the literature.ResultsTwelve over 23 parameters have an excellent intrinsic reliability (P > 0.05, ICC > 0.9 and SEM < 5% of the grand mean). There are similarities with other studies (P < 0.05) but we noticed the existence of some specificity (the height of hip extension peak and the low cadence of gait) that could characterize the Tunisian population.ConclusionA specific reference database of the gait cycle has been established for healthy Tunisian active-young adults and excellent inter-trial reliability may be observed for different variables.     

High-definition spatiotemporal mapping of contractile activity in the isolated proximal colon of the rabbit

Four types of contractile activity were identified and characterised in the isolated triple haustrated proximal colon of the rabbit using high-definition spatiotemporal mapping techniques. Mass peristalses were hexamethonium-sensitive deep circular contractions with associated taenial longitudinal contractile activity that occurred irregularly and propagated rapidly aborad, preceded by a zone of local lumen distension. They were sufficiently sustained for each event to occupy the length of the isolated colonic segment and the contraction persisted longer orally than aborally, the difference being more pronounced when lumen contents were viscous. Haustra were bounded by deep even-spaced ring contractions that progressed slowly aborad (haustral progression). Haustral formation and progression were hexamethonium-sensitive and coordinated across intertaenial domains. Ripples were hexamethonium-resistant phasic circular contractions that propagated predominantly orad at varying rates. In the presence of haustra, they were uncoordinated across intertaenial domains but were more coordinated when haustra were absent. Fast phasic contractions were relatively shallow hexamethonium-resistant contractions that propagated rapidly in a predominantly aborad direction. Fast phasic circular contractions were accompanied by taenial longitudinal muscle contractions which increased in amplitude prior to a mass peristaltic event and following the administration of hexamethonium. On the basis of the concurrence and interaction of these contractile activities, we hypothesise that dual pacemakers are present with fast phasic contractions being modulated by the interstitial cells of Cajal in the Auerbach’s plexus (ICC-MY) while ripples are due to the submucosal ICC (ICC-SM). Further, that ICC-SM mediate the enteric motor neurons that generate haustral progression, while the intramuscular ICC (ICC-IM) mediate mass peristalsis. The orad movement of watery fluid was possibly due to ripples in the absence of haustra.     

人胎胰腺巢蛋白阳性细胞的分离培养及其生物学特性研究

胰腺巢蛋白(nestin)阳性细胞是近年发现的与胰腺发育密切相关的一种多能干细胞。我们对人胎胰腺中的nestin~+细胞进行了分离和体外培养,并对其生物学特性进行了研究结果表明:(1)胎胰nestin~+细胞表达高水平ABCG2/BCRP1,并在形态和生长方式上均不同于导管上皮细胞;(2)Nestin~+细胞在体外可自发形成类胰岛细胞团(ICC,islet-likc cell clusters);(3)ICC中的nestin~+细胞具有多向分化潜能,可表达多种细胞特异抗原,经体外诱导可产生少量胰岛素阳性的类β细胞。     

IL-9 enhances growth of ICC, maintains network structure and strengthens rhythmicity of contraction in culture

Interstitial cells of Cajal (ICC) play a critical role in the control of gastrointestinal motility as pacemaker cells and as regulators of enteric innervation. ICC are one of the first cell types that are injured during an inflammatory process and maintenance of ICC health or promotion of growth and development maybe crucial in recovery after injury. The aim of this study was to evaluate the role of IL-9 in the growth, development and maintenance of ICC in culture. IL-9 in concentrations from 0.02 to 1 microg/ml promoted individual ICC growth and maintenance of the ICC network structure inside tissue explants under culture conditions. The number of ICC grown out of the explants increased significantly at day 4 of culture in the presence of 0.02, 0.5 and 1 microg/ml IL-9. In the presence of 0.5 microg/ml IL-9, explants in culture maintained a higher frequency and stabilized the frequency of spontaneous contractile activity. The ultrastructure of the ICC after 4 days in culture was similar to that in situ. Our data indicate that IL-9 promotes ICC growth in culture and it can be hypothesized that IL-9 is a critical factor in the maintenance of ICC health and ICC repair after injury.     

Consistent individual differences in cooperative behaviour in meerkats (Suricata suricatta)

Although recent models for the evolution of personality, using game theory and life‐history theory, predict that individuals should differ consistently in their cooperative behaviour, consistent individual differences in cooperative behaviour have rarely been documented. In this study, we used a long‐term data set on wild meerkats to quantify the repeatability of two types of cooperative care (babysitting and provisioning) within individuals and examined how repeatability varied across age, sex and status categories. Contributions to babysitting and provisioning were significantly repeatable and positively correlated within individuals, with provisioning more repeatable than babysitting. While repeatability of provisioning was relatively invariant across categories of individuals, repeatability of babysitting increased with age and was higher for subordinates than dominants. These results provide support for theoretical predictions that life‐history trade‐offs favour the evolution of consistent individual differences in cooperative behaviour and raise questions about why some individuals consistently help more than others across a suite of cooperative behaviours.     

TELOCYTES – a case of serendipity: the winding way from Interstitial Cells of Cajal (ICC), via Interstitial Cajal-Like Cells (ICLC) to TELOCYTES

Ramon y Cajal discovered a particular cell type in the gut, which he named ‘interstitial neurons’ more that 100 years ago. In the early 1970s, electron microscopy/electron microscope (EM) studies showed that indeed a special interstitial cell type corresponding to the cells discovered by Cajal is localized in the gut muscle coat, but it became obvious that they were not neurons. Consequently, they were renamed ‘interstitial cells of Cajal’ (ICC) and considered to be pace-makers for gut motility. For the past 10 years many groups were interested in whether or not ICC are present outside the gastrointestinal tract, and indeed, peculiar interstitial cells were found in: upper and lower urinary tracts, blood vessels, pancreas, male and female reproductive tracts, mammary gland, placenta, and, recently, in the heart as well as in the gut. Such cells, now mostly known as interstitial Cajal-like cells (ICLC), were given different and confusing names. Moreover, ICLC are only apparently similar to canonical ICC. In fact, EM and cell cultures revealed very particular features of ICLC, which unequivocally distinguishes them from ICC and all other interstitial cells: the presence of 2–5 cell body prolongations that are very thin (less than 0.2 μm, under resolving power of light microscopy), extremely long (tens to hundreds of μm), with a moniliform aspect (many dilations along), as well as caveolae. Given the unique dimensions of these prolongations (very long and very thin) and to avoid further confusion with other interstitial cell types (e.g. fibroblast, fibrocyte, fibroblast-like cells, mesenchymal cells), we are proposing the term TELOCYTES for them, and TELOPODES for their prolongations, by using the Greek affix ‘telos’.     

Acquisition of chemoresistance in intrahepatic cholangiocarcinoma cells by activation of AKT and extracellular signal-regulated kinase (ERK)1/2

Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignant tumor and is refractory to conventional chemotherapy. The aim of this study is therefore to elucidate the mechanism of chemoresistance in ICC which is not fully understood. We generated cisplatin resistant ICC cells via long term exposure to cisplatin and found that these cells are also resistant to 5-fluorouracil (5-FU) and gemcitabine. The chemoresistant cells showed enhanced Bcl-2 expression and reduced Bax expression compared to parental ICC cells. In addition, the resistant cells showed enhanced activation of AKT and extracellular signal-regulated kinase (ERK) 1/2. Inhibition of AKT activation by phosphoinocitide 3-kinase (PI3K) inhibitor LY294002 resulted in reduced Bcl-2 expression and enhanced Bax expression and thus induced apoptosis in the resistant cells, whereas inhibition of ERK1/2 activation by mitogen-activated protein kinase (MEK) inhibitor U0126 did not induce apoptosis without affecting the expression of Bcl-2 and Bax but decreased cell growth. Moreover, the inhibition of AKT or ERK1/2 sensitized the resistant cells to cisplatin and therefore resulted in greatly enhanced cisplatin-induced apoptosis and growth inhibition in the cells. The results indicate that AKT and ERK1/2 signaling mediate chemoresistance in the cells and could be important therapeutic targets for overcoming chemoresistance in ICC.     

In vitro enhanced differentiation of neural networks in ES gut-like organ from mouse ES cells by a 5-HT4-receptor activation

Using an embryoid body (EB) culture system, we developed a functional organ-like cluster, a “gut”, from mouse embryonic stem (ES) cells (ES gut). Each ES gut exhibited various types of spontaneous movements. In these spontaneously contracting ES guts, dense distributions of interstitial cells of Cajal (ICC) (c-kit, a transmembrane receptor that has tyrosine kinase activity, positive cells; gut pacemaker cells) and smooth muscle cells were discernibly identified, but enteric neural networks were not identified. In the present study, we succeeded in forming dense enteric neural networks by a 5-HT₄-receptor (SR4) agonist, mosapride citrate (1–10 μM) added only during EB formation. Addition of an SR4-antagonist, GR113808 (10 μM) abolished the SR4-agonist-induced formation of enteric neural networks. The SR4-agonist (1 μM) up-regulated the expression of mRNA of SR4 and the SR4-antagonist abolished this upregulation. 5-HT per se exerted similar effects to those of SR4-agonist, though less potent. These results suggest SR4-agonist differentiated enteric neural networks, mediated via activation of SR4 in the ES gut.     

Performance on a manual tracking task differentiates individuals at risk of developing carpal tunnel syndrome from those not at risk

Introduction

The purpose of this study was to determine whether sensorimotor abnormalities are detectable in asymptomatic individuals deemed at risk of developing carpal tunnel syndrome (CTS)

Methods

Seventeen individuals deemed at risk of developing CTS and 16 asymptomatic individuals deemed to be at minimal risk of developing CTS participated. Nerve conduction velocity, two-point discrimination ability, pressure acuity, Purdue Pegboard Test performance and tracking error and tracking variance on a manual tracking task performed at two different speeds were measured in all participants and compared between the groups.

Results

None of the measures of nerve conduction, sensory perception, or Purdue Pegboard task performance were different between the groups. The error in the manual tracking tasks was significantly different between the groups, where the at-risk group demonstrated more error than the control group.

Conclusion

These results suggest that manual tracking tasks may be useful in the identification of those individuals at risk of developing CTS before they develop any measurable sensorimotor impairment.