Macrophage migration inhibitory factor and its binding partner HTRA1 are expressed by olfactory ensheathing cells.

Macrophage migration inhibitory factor (MIF) is an important regulator of innate immunity with key roles in neural regeneration and responses to pathogens, amongst a multitude of other functions. The expression of MIF and its binding partners has been characterised throughout the nervous system, with one key exception: the primary olfactory nervous system. Here, we showed in young mice (postnatal day 10) that MIF is expressed in the olfactory nerve by olfactory ensheathing glial cells (OECs) and by olfactory nerve fibroblasts. We also examined the expression of potential binding partners for MIF, and found that the serine protease HTRA1, known to be inhibited by MIF, was also expressed at high levels by OECs and olfactory fibroblasts in vivo and in vitro. We also demonstrated that MIF mediated segregation between OECs and J774a.1 cells (a monocyte/macrophage cell line) in co-culture, which suggests that MIF contributes to the fact that macrophages are largely absent from olfactory nerve fascicles. Phagocytosis assays of axonal debris demonstrated that MIF strongly stimulates phagocytosis by OECs, which indicates that MIF may play a role in the response of OECs to the continual turnover of olfactory axons that occurs throughout life.

Making tiestalls more comfortable: I. Adjusting tie-rail height and forward position to improve dairy cows' ability to rise and lie down.

The overall goal of the study was to develop new recommendations for tie-rail placement combining both vertical and horizontal positions to improve dairy cow welfare. Four treatments were tested: 2 new tie-rail positions that followed the natural neckline of cows when feeding and rising [neckline 1 (NL1), neckline 2 (NL2)], current recommendation (CR), and the average tie-rail position currently found on Quebec farms (current average on farm; CF). All other stall dimensions followed CR based on average cow size. Forty-eight cows blocked by parity and stage of lactation were randomly allocated to a treatment for 10 wk. Live scoring was performed weekly to evaluate injury, cow and stall cleanliness, and bedding quantity. Daily lying time, lying bout frequency, and lying bout duration were continuously recorded using leg-mounted accelerometers. Cows were recorded 1 d/wk by overhead cameras to evaluate lying down and rising events. Tie-rail placement did not affect cow and stall cleanliness, bedding quantity, and lying time. All tie-rail placements tested resulted in neck injuries with the position of neck injuries shifting based on the change in tie-rail placement: CR increased in proximal neck injuries (mean ± standard deviation, difference in injury score from baseline: +0.89 ± 0.153) compared with NL2 (+0.06 ± 0.153), but decreased in medial neck injuries (-0.11 ± 0.166) compared with NL2 (+0.78 ± 0.166) and NL1 (+0.53 ± 0.166). All treatments showed a decrease over time in average lying intention time (mean, difference between overall short- and long-term: -5.8 s/event), lying-down time (-1.1 s/event), contact with stall during lying (-32.5%), slipping during lying (-9.1%), backward movement on knees during rising (-10.9%), contact with tie-rail during rising (-14.3%), and overall abnormal rising (-15.6%) over time. Although lying and rising ability improved over time, abnormal lying and rising behaviors were still highly prevalent in the long term. Overall, our results show that dairy cows are limited in their ability to move within their environment without coming in contact with the stall confines (tie-rail and divider bars), warranting further research to determine alternatives to metal tie-rail bars, such as a flexible bar or chain, or provide fewer obstacles through the elimination of some stall hardware.

Measurement of the Target-Normal Single-Spin Asymmetry in Quasielastic Scattering from the Reaction (3)He(↑)(e,e').

We report the first measurement of the target single-spin asymmetry, A(y), in quasielastic scattering from the inclusive reaction (3)He(↑)(e,e') on a (3)He gas target polarized normal to the lepton scattering plane. Assuming time-reversal invariance, this asymmetry is strictly zero for one-photon exchange. A nonzero A(y) can arise from the interference between the one- and two-photon exchange processes which is sensitive to the details of the substructure of the nucleon. An experiment recently completed at Jefferson Lab yielded asymmetries with high statistical precision at Q(2)=0.13, 0.46, and 0.97 GeV(2). These measurements demonstrate, for the first time, that the (3)He asymmetry is clearly nonzero and negative at the 4σ-9σ level. Using measured proton-to-(3)He cross-section ratios and the effective polarization approximation, neutron asymmetries of -(1-3)% were obtained. The neutron asymmetry at high Q(2) is related to moments of the generalized parton distributions (GPDs). Our measured neutron asymmetry at Q(2)=0.97 GeV(2) agrees well with a prediction based on two-photon exchange using a GPD model and thus provides a new, independent constraint on these distributions.

Damaging legacy: maternal cigarette smoking has long-term consequences for male offspring fertility.

STUDY QUESTION: What are the effects on fertility of cigarette smoke-induced toxicity on male offspring exposed during the gestational/weaning period? SUMMARY ANSWER: Maternal cigarette smoke exposure during the gestational/weaning period causes long-term defects in male offspring fertility. WHAT IS KNOWN ALREADY: Cigarette smoke is a well-known reproductive toxicant which is particularly harmful to both fetal and neonatal germ cells. However, recent studies suggest a significant portion of young mothers in the developed world still smoke during pregnancy. In the context of male reproductive health, our understanding of the effects of in utero exposure on offspring fertility is limited. STUDY DESIGN, SIZE, DURATION: In this study, 27 C57BL/6 5-week-old female mice were exposed via the nose-only to cigarette smoke (treatment) or 27 were exposed to room air (control) for 6 weeks before being housed with stud males to produce litters. In the treatment group, smoke exposure continued throughout mating, pregnancy and lactation until weaning of pups at 21 days post birth. Male offspring were examined at post-natal days 3, 6, 12, 21 and 98 (adult). PARTICIPANTS/MATERIALS, SETTING, METHODS: Approximately 108 maternal smoke-exposed C57BL/6 offspring and controls were examined. Spermatogenesis was examined using testicular histology and apoptosis/DNA damage was assessed using caspase immunohistochemistry and TUNEL. Sertoli cell morphology and fluctuations in the spermatogonial stem cell population were also examined using immunohistochemistry. Microarray and QPCR analysis were performed on adult testes to examine specific long-term transcriptomic alteration as a consequence of maternal smoke exposure. Sperm counts and motility, zona/oolemma binding assays, COMET analysis and mitochondrial genomic sequencing were also performed on spermatozoa obtained from adult treated and control mice. Fertility trials using exposed adult male offspring were also performed. MAIN RESULTS AND THE ROLE OF CHANCE: Maternal cigarette smoke exposure caused increased gonocyte and meiotic spermatocyte apoptosis (P < 0.01) as well as germ cell depletion in the seminiferous tubules of neonatal and juvenile offspring. Aberrant testicular development characterized by abnormal Sertoli and germ cell organization, a depleted spermatogonial stem cell population (P < 0.01), atrophic seminiferous tubules and increased germ cell DNA damage (P < 0.01) persisted in adult offspring 11 weeks after exposure. Microarray analysis of adult offspring testes associated these defects with meiotic germ cell development, sex hormone metabolism, oxidative stress and Sertoli cell signalling. Next generation sequencing also revealed a high mitochondrial DNA mutational load in the testes of adult offspring (P < 0.01). Adult maternal smoke-exposed offspring also had reduced sperm counts with spermatozoa exhibiting morphological abnormalities (P < 0.01), affecting motility and fertilization potential. Odf2, a spermatozoa flagellum component required for coordinated ciliary beating, was also significantly down-regulated (P < 0.01) in maternal smoke-exposed adult offspring, with aberrant localization along the spermatozoa flagellum. Adult maternal smoke-exposed offspring took significantly longer to impregnate control females and had a slight but significant (P < 0.01) reduction in litter size. LIMITATIONS, REASONS FOR CAUTION: This study examined only one species (mouse) using a smoking model which only simulates human cigarette smoke exposure. WIDER IMPLICATIONS OF THE FINDINGS: This study represents the first comprehensive animal model of maternal smoking on male offspring reproductive function, suggesting that exposure during the gestational/weaning period causes long-term defects in male offspring fertility. This is due to a compromised spermatogonial stem cell population resulting from gonocyte apoptosis and impaired spermatogenic development. This results in significant germ cell damage and Sertoli cell dysfunction, impacting germ cell number, tubule organization, DNA damage and spermatozoa in adult offspring. This study strengthens the current literature suggesting that maternal exposure impairs male offspring fertility, which is currently debated due to conflicting studies. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Australian Research Council, Hunter Medical Research Institute, National Health and Medical Research Council of Australia and the Newcastle Permanent Building Society Charitable Trust. The authors declare no conflict of interest.

Anterior skull base olfactory tumours, which is what? A case report and review.

Intracranial schwannomas not originating from cranial nerves are rare. In this paper, we report a case of a 50-year-old male who presented with worsening headaches, diplopia and nausea over two years. Radiological imaging revealed a large tumour arising from the olfactory groove region with a preoperative diagnosis of olfactory groove meningioma (OGM). Intraoperatively, the tumour originated from the region of the attachment of the falx to the crista galli. The patient recovered without complication and histopathology reported an unexpected diagnosis of WHO Grade 1 schwannoma. However, as olfactory groove schwannomas (OGSs) cannot be distinguished from olfactory ensheathing cell tumours (OECTs), it is possible that the tumour could have been either an OGS or an OECT. Distinguishing between OGSs, OECTs and OGMs preoperatively is difficult. OGMs exhibit distinct histopathological features from OGSs/OECTs, however, OGSs and OECTs currently cannot be distinguished from each other. Here, we review the literature to discuss the differentiating features and cellular origins of these three tumours.

The plant natural product 2-methoxy-1,4-naphthoquinone stimulates therapeutic neural repair properties of olfactory ensheathing cells.

Olfactory ensheathing cells (OECs) are crucial for promoting the regeneration of the primary olfactory nervous system that occurs throughout life. Transplantation of OECs has emerged as a promising therapy for nervous system injuries, in particular for spinal cord injury repair. Functional outcomes in both animals and humans are, however, highly variable, primarily because it is difficult to rapidly obtain enough OECs for transplantation. Compounds which can stimulate OEC proliferation without changing the phenotype of the cells are therefore highly sought after. Additionally, compounds which can stimulate favourable cell behaviours such as migration and phagocytic activity are desirable. We conducted a medium-throughput screen testing the Davis open access natural product-based library (472 compounds) and subsequently identified the known plant natural product 2-methoxy-1,4-naphthoquinone as a stimulant of OEC viability. We showed that 2-methoxy-1,4-naphthoquinone: (i) strongly stimulates proliferation over several weeks in culture whilst maintaining the OEC phenotype; (ii) stimulates the phagocytic activity of OECs, and (iii) modulates the cell cycle. We also identified the transcription factor Nrf2 as the compound's potential molecular target. From these extensive investigations we conclude that 2-methoxy-1,4-naphthoquinone may enhance the therapeutic potential of OECs by stimulating proliferation prior to transplantation.

Key differences between olfactory ensheathing cells and Schwann cells regarding phagocytosis of necrotic cells: implications for transplantation therapies.

Transplantation of peripheral nervous system glia is being explored for treating neural injuries, in particular central nervous system injuries. These glia, olfactory ensheathing cells (OECs) and Schwann cells (SCs), are thought to aid regeneration by clearing necrotic cells, (necrotic bodies, NBs), as well as myelin debris. The mechanism by which the glia phagocytose and traffic NBs are not understood. Here, we show that OECs and SCs recognize phosphatidylserine on NBs, followed by engulfment and trafficking to endosomes and lysosomes. We also showed that both glia can phagocytose and process myelin debris. We compared the time-course of glial phagocytosis (of both NBs and myelin) to that of macrophages. Internalization and trafficking were considerably slower in glia than in macrophages, and OECs were more efficient phagocytes than SCs. The two glial types also differed regarding their cytokine responses after NB challenge. SCs produced low amounts of the pro-inflammatory cytokine TNF-α while OECs did not produce detectable TNF-α. Thus, OECs have a higher capacity than SCs for phagocytosis and trafficking, whilst producing lower amounts of pro-inflammatory cytokines. These findings suggest that OEC transplantation into the injured nervous system may lead to better outcomes than SC transplantation.

Lovesick: immunological costs of mating to male sagebrush crickets.

A growing body of evidence suggests that resources invested in reproduction often come at the expense of the ability to mount an immune response. During mating, female sagebrush crickets, Cyphoderris strepitans, consume the ends of the male's hind wings and ingest his haemolymph. Previous research has shown that this behaviour impairs the ability of males to secure additional matings. One hypothesis to account for this effect is that wing wounding triggers an energetically costly immune response, such that nonvirgin males are unable to sustain the costly acoustical signalling needed to attract additional females. To test this hypothesis, we injected virgin males with lipopolysaccharides (LPS) to provoke an immune response, and monitored their mating success in the field. LPS-injected virgin males took significantly longer to mate than sham-injected virgin males, and spent significantly less time calling. We also compared virgin, nonvirgin and experimentally wing-wounded virgin males with respect to: (1) their ability to encapsulate a foreign invader via the accumulation of haemocytes and deposition of melanin and (2) baseline levels of phenoloxidase (PO), a key enzyme in the biochemical cascade leading to the production of melanin. Although encapsulation ability did not differ with reproductive experience, virgin males had significantly higher levels of PO than either nonvirgin or experimentally wing-wounded virgin males. These results suggest that wing-wounding alone is sufficient to impair male immunity, and that males trade-off investment in reproduction and immunity.

Enhancing the Therapeutic Potential of Olfactory Ensheathing Cells in Spinal Cord Repair Using Neurotrophins.

Autologous olfactory ensheathing cell (OEC) transplantation is a promising therapy for spinal cord injury; however, the efficacy varies between trials in both animals and humans. The main reason for this variability is that the purity and phenotype of the transplanted cells differs between studies. OECs are susceptible to modulation with neurotrophic factors, and thus, neurotrophins can be used to manipulate the transplanted cells into an optimal, consistent phenotype. OEC transplantation can be divided into 3 phases: (1) cell preparation, (2) cell administration, and (3) continuous support to the transplanted cells in situ. The ideal behaviour of OECs differs between these 3 phases; in the cell preparation phase, rapid cell expansion is desirable to decrease the time between damage and transplantation. In the cell administration phase, OEC survival and integration at the injury site, in particular migration into the glial scar, are the most critical factors, along with OEC-mediated phagocytosis of cellular debris. Finally, continuous support needs to be provided to the transplantation site to promote survival of both transplanted cells and endogenous cells within injury site and to promote long-term integration of the transplanted cells and angiogenesis. In this review, we define the 3 phases of OEC transplantation into the injured spinal cord and the optimal cell behaviors required for each phase. Optimising functional outcomes of OEC transplantation can be achieved by modulation of cell behaviours with neurotrophins. We identify the key growth factors that exhibit the strongest potential for optimizing the OEC phenotype required for each phase.

Olfactory Ensheathing Cells for Spinal Cord Injury: Sniffing Out the Issues.

Olfactory ensheathing cells (OECs) are glia reported to sustain the continuous axon extension and successful topographic targeting of the olfactory receptor neurons responsible for the sense of smell (olfaction). Due to this distinctive property, OECs have been trialed in human cell transplant therapies to assist in the repair of central nervous system injuries, particularly those of the spinal cord. Though many studies have reported neurological improvement, the therapy remains inconsistent and requires further improvement. Much of this variability stems from differing olfactory cell populations prior to transplantation into the injury site. While some studies have used purified cells, others have used unpurified transplants. Although both preparations have merits and faults, the latter increases the variability between transplants received by recipients. Without a robust purification procedure in OEC transplantation therapies, the full potential of OECs for spinal cord injury may not be realised.

Nitric oxide synthase (NOS) inhibition for one week improves renal sodium and water excretion in cirrhotic rats with ascites.

Normalization of the increased vascular nitric oxide (NO) generation with low doses of NG-nitro-L-arginine methyl ester (L-NAME) corrects the hemodynamic abnormalities of cirrhotic rats with ascites. We have undertaken this study to investigate the effect of the normalization of vascular NO production, as estimated by aortic cyclic guanosine monophosphate (cGMP) concentration and endothelial nitric oxide synthase (eNOS) protein expression in the aorta and mesenteric artery, on sodium and water excretion. Rats with carbon tetrachloride-induced cirrhosis and ascites were investigated using balance studies. The cirrhotic rats were separated into two groups, one receiving 0.5 mg/kg per day of L-NAME (CIR-NAME) during 7 d, whereas the other group (CIR) was administrated the same volume of vehicle. Two other groups of rats were used as controls, one group treated with L-NAME and another group receiving the same volume of vehicle. Sodium and water excretion was measured on days 0 and 7. On day 8, blood samples were collected for electrolyte and hormone measurements, and aorta and mesenteric arteries were harvested for cGMP determination and nitric oxide synthase (NOS) immunoblotting. Aortic cGMP and eNOS protein expression in the aorta and mesenteric artery were increased in CIR as compared with CIR-NAME. Both cirrhotic groups had a similar decrease in sodium excretion on day 0 (0.7 versus 0.6 mmol per day, NS) and a positive sodium balance (+0.9 versus +1.2 mmol per day, NS). On day 7, CIR-NAME rats had an increase in sodium excretion as compared with the CIR rats (sodium excretion: 2.4 versus 0.7 mmol per day, P < 0.001) and a negative sodium balance (-0.5 versus +0.8 mmol per day, P < 0.001). The excretion of a water load was also increased after L-NAME administration (from 28+/-5% to 65+/-7, P < 0.05). Plasma renin activity, aldosterone and arginine vasopressin were also significantly decreased in the CIR-NAME, as compared with the CIR rats. The results thus indicate that normalization of aortic cGMP and eNOS protein expression in vascular tissue is associated with increased sodium and water excretion in cirrhotic rats with ascites.

Upregulation of aquaporin-2 water channel expression in chronic heart failure rat.

Aquaporin-2 (AQP2) mediates vasopressin-regulated collecting duct water permeability. Chronic heart failure (CHF) is characterized by abnormal renal water retention. We hypothetized that upregulation of aquaporin-2 water channel could account for the water retention in CHF. Male rats underwent either a left coronary artery ligation, a model of CHF, or were sham operated. 31-33 d after surgery, mean arterial pressure (MAP) and cardiac output were measured in conscious animals, and the animals were killed 24 h later. Cardiac output (CO) and plasma osmolality were significantly decreased and plasma vasopressin increased in the CHF as compared to the sham-operated rats. Both mRNA and protein AQP2 were significantly increased in the kidneys of the CHF rats. The effect of oral administration of a nonpeptide V2 vasopressin receptor antagonist, OPC 31260, was therefore investigated. OPC 31260 induced a significant increase in diuresis, decrease in urinary osmolality, and rise in plasma osmolality in the OPC 31260-treated CHF rats as compared to untreated CHF rats. The mRNA and protein AQP2 were significantly diminished in both cortex and inner medulla of the treated CHF rats. In conclusion, an early upregulation of AQP2 is present in CHF rats and this upregulation is inhibited by the administration of a V2 receptor antagonist. The results indicate a major role for vasopressin in the upregulation of AQP2 water channels and water retention in experimental CHF in the rat.

Upregulation of aquaporin 2 water channel expression in pregnant rats.

Water retention is characteristic of pregnancy but the mechanism(s) of the altered water metabolism has yet to be elucidated. The collecting duct water channel, aquaporin 2 (AQP2), plays a pivotal role in the renal water regulation, and we hypothesized that AQP2 expression could be modified during pregnancy. Sprague-Dawley female rats were studied on days 7 (P7), 14 (P14), and 20 (P20) of pregnancy, and expression of AQP2 in papillae was examined. Nonpregnant (NP) littermates were used as controls. Plasma osmolalities were significantly lower in pregnant rats by day 7 of gestation (P7 283.8+/-1.82, P14 284.3+/-1.64, P < 0.001, P20 282. 4+/-1.32, P < 0.0001, vs. NP 291.8+/-1.06 mosmol/kgH2O). However, plasma vasopressin concentrations in pregnant rats were not significantly different than in nonpregnant rats (NP 1.03+/-0.14, P7 1.11+/-0.21, P14 1.15+/-0.21, P20 1.36+/-0.24 pg/ml, NS). The mRNA of AQP2 was increased early during pregnancy: AQP2/beta actin: P7 196+/-17.9, P14 200+/-6.8, and P20 208+/-15.5%, P < 0.005 vs. NP (100+/-11.1%). AQP2 protein was also increased during pregnancy: AQP2 protein: P7 269+/-10.0, P14 251+/-12.0, P < 0.0001, and P20 250+/-13.6%, P < 0.001 vs. NP (100+/-12.5%). The effect of V2 vasopressin receptor antagonist, OPC-31260, was then investigated. AQP2 mRNA was suppressed significantly by OPC-31260 administration to P14 rats (AQP2/beta actin: P14 with OPC-31260 39.6+/-1.7%, P < 0.001 vs. P14 with vehicle) and was decreased to the same level of expression as NP rats receiving OPC-31260. Similar findings were found with the analysis of AQP2 protein. The decreased plasma osmolality of P14 rats was not modified by OPC-31260. The results of the study indicate that upregulation of AQP2 contributes to the water retention in pregnancy through a V2 receptor-mediated effect. In addition to vasopressin, other factors may be involved in this upregulation.

Delayed type IV hypersensitivity reaction to porcine acellular dermal matrix masquerading as infection resulting in multiple debridements.

INTRODUCTION: Delayed type IV hypersensitivity reactions are well established in the surgical setting with respect to external exposure via topical antibiotics and internal exposure via synthetic materials. In contrast, biologic matrix is derived from decellularized human or animal tissues and is consequently believed to elicit a minimal host inflammatory response. OBJECTIVE: We report a case of delayed type IV hypersensitivity reaction secondary to a biologic comprised of porcine-derived acellular dermal matrix, [Strattice™]. CONCLUSIONS: While biologic matrix is often preferred over synthetic mesh due to its decreased risk for infection, this case emphasizes that potential for hypersensitivity to the material persists. Type IV hypersensitivity reactions should be included in the differential diagnosis for suspected post-operative infections.

Genetic basis of TNF-α antagonist associated psoriasis in inflammatory bowel diseases: a genotype-phenotype analysis.

BACKGROUND: Anti-tumour necrosis factor (anti-TNF) biologic associated psoriasis has been reported in inflammatory bowel disease (IBD) patients. However, little is known regarding its pathogenesis. AIM: To identify potential genetic predispositions to anti-TNF associated psoriasis in IBD patients. METHODS: This retrospective chart review included IBD patients enrolled in a prospective registry. Cases of anti-TNF associated psoriasis and idiopathic psoriasis unrelated to anti-TNF exposure were confirmed by an expert dermatologist. All patients were genotyped on the Illumina Immunochip. A weighted genetic risk score ascertaining genetic pre-disposition towards psoriasis was calculated and overall genetic pre-disposition as well as differential distribution of individual polymorphisms was compared across the three groups. RESULTS: Our study included 724 IBD patients who initiated anti-TNF therapy and did not develop psoriasis, 35 patients with anti-TNF associated psoriasis, and 38 patients with idiopathic psoriasis. Anti-TNF users who developed psoriasis had a modest but statistically significantly greater psoriasis genetic risk score than anti-TNF controls (mean 0.64 vs. 0.61, P = 0.04), and had a similar genetic risk score as those with idiopathic psoriasis (0.64 vs. 0.62, P = 0.22). Two loci associated with NOS2 and ETS1 genes achieved P < 0.05 when comparing anti-TNF associated psoriasis to anti-TNF controls. Three loci were significantly different between anti-TNF associated psoriasis and idiopathic psoriasis including a polymorphism near NOS2 encoding for inducible nitric oxide synthase that is produced by dendritic cells in skin lesions in psoriasis. CONCLUSION: Patients with anti-TNF associated psoriasis had a modestly greater genetic pre-disposition towards psoriasis but no single causative polymorphism was identified.

Stimulating the proliferation, migration and lamellipodia of Schwann cells using low-dose curcumin.

Transplantation of peripheral glia is being trialled for neural repair therapies, and identification of compounds that enhance the activity of glia is therefore of therapeutic interest. We have previously shown that curcumin potently stimulates the activity of olfactory glia. We have now examined the effect of curcumin on Schwann cell (SC) activities including proliferation, migration and the expression of protein markers. SCs were treated with control media and with different concentrations of curcumin (0.02-20 µM). Cell proliferation was determined by MTS assay and migration changes were determined by single live cell migration tracking. We found that small doses of curcumin (40 nM) dramatically increased the proliferation and migration in SCs within just one day. When compared with olfactory glia, curcumin stimulated SC proliferation more rapidly and at lower concentrations. Curcumin significantly increased the migration of SCs, and also increased the dynamic activity of lamellipodial waves which are essential for SC migration. Expression of the activated form of the MAP kinase p38 (p-p38) was significantly decreased in curcumin-treated SCs. These results show that curcumin's effects on SCs differ remarkably to its effects on olfactory glia, suggesting that subtypes of closely related glia can be differentially stimulated by curcumin. Overall these results demonstrate that the therapeutically beneficial activities of glia can be differentially enhanced by curcumin which could be used to improve outcomes of neural repair therapies.

Oncogenic activation of the PI3-kinase p110ß isoform via the tumor-derived PIK3Cß(D1067V) kinase domain mutation.

Activation of the phosphoinositide 3-kinase (PI3K) pathway occurs widely in human cancers. Although somatic mutations in the PI3K pathway genes PIK3CA and PTEN are known to drive PI3K pathway activation and cancer growth, the significance of somatic mutations in other PI3K pathway genes is less clear. Here, we establish the signaling and oncogenic properties of a recurrent somatic mutation in the PI3K p110ß isoform that resides within its kinase domain (PIK3Cß(D1067V)). We initially observed PIK3Cß(D1067V) by exome sequencing analysis of an EGFR-mutant non-small cell lung cancer (NSCLC) tumor biopsy from a patient with acquired erlotinib resistance. On the basis of this finding, we hypothesized that PIK3Cß(D1067V) might function as a novel tumor-promoting genetic alteration, and potentially an oncogene, in certain cancers. Consistent with this hypothesis, analysis of additional tumor exome data sets revealed the presence of PIK3Cß(D1067V) at low frequency in other patient tumor samples (including renal cell carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, melanoma, thyroid carcinoma and endometrial carcinoma). Functional studies revealed that PIK3Cß(D1067V) promoted PI3K pathway signaling, enhanced cell growth in vitro, and was sufficient for tumor formation in vivo. Pharmacologic inhibition of PIK3Cß with TGX-221 (isoform-selective p110ß inhibitor) specifically suppressed growth in patient-derived renal-cell carcinoma cells with endogenous PIK3Cß(D1067V) and in NIH-3T3 and human EGFR-mutant lung adenocarcinoma cells engineered to express this mutant PI3K. In the EGFR-mutant lung adenocarcinoma cells, expression of PIK3Cß(D1067V) also promoted erlotinib resistance. Our data establish a novel oncogenic form of PI3K, revealing the signaling and oncogenic properties of PIK3Cß(D1067V) and its potential therapeutic relevance in cancer. Our findings provide new insight into the genetic mechanisms underlying PI3K pathway activation in human tumors and indicate that PIK3Cß(D1067V) is a rational therapeutic target in certain cancers.

Mitochondrial DNA plasticity is an essential inducer of tumorigenesis.

Although mitochondrial DNA has been implicated in diseases such as cancer, its role remains to be defined. Using three models of tumorigenesis, namely glioblastoma multiforme, multiple myeloma and osteosarcoma, we show that mitochondrial DNA plays defining roles at early and late tumour progression. Specifically, tumour cells partially or completely depleted of mitochondrial DNA either restored their mitochondrial DNA content or actively recruited mitochondrial DNA, which affected the rate of tumorigenesis. Nevertheless, non-depleted tumour cells modulated mitochondrial DNA copy number at early and late progression in a mitochondrial DNA genotype-specific manner. In glioblastoma multiforme and osteosarcoma, this was coupled with loss and gain of mitochondrial DNA variants. Changes in mitochondrial DNA genotype affected tumour morphology and gene expression patterns at early and late progression. Importantly, this identified a subset of genes that are essential to early progression. Consequently, mitochondrial DNA and commonly expressed early tumour-specific genes provide novel targets against tumorigenesis.