Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis.

Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.

A PML/Slit Axis Controls Physiological Cell Migration and Cancer Invasion in the CNS.

Cell migration through the brain parenchyma underpins neurogenesis and glioblastoma (GBM) development. Since GBM cells and neuroblasts use the same migratory routes, mechanisms underlying migration during neurogenesis and brain cancer pathogenesis may be similar. Here, we identify a common pathway controlling cell migration in normal and neoplastic cells in the CNS. The nuclear scaffold protein promyelocytic leukemia (PML), a regulator of forebrain development, promotes neural progenitor/stem cell (NPC) and neuroblast migration in the adult mouse brain. The PML pro-migratory role is active also in transformed mouse NPCs and in human primary GBM cells. In both normal and neoplastic settings, PML controls cell migration via Polycomb repressive complex 2 (PRC2)-mediated repression of Slits, key regulators of axon guidance. Finally, a PML/SLIT1 axis regulates sensitivity to the PML-targeting drug arsenic trioxide in primary GBM cells. Taken together, these findings uncover a drug-targetable molecular axis controlling cell migration in both normal and neoplastic cells.

Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells.

Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations. Furthermore, the p53 tumor suppressor, which has emerged as a key regulator of mitochondrial respiration at the expense of glycolysis, is genetically inactivated in a large proportion of HGG cases. Therefore, it is becoming evident that genetic modifications can affect cell metabolism in HGG; however, it is currently unclear whether mitochondrial metabolism alterations could vice versa promote genomic instability as a mechanism for neoplastic transformation. Here, we show that, in neural progenitor/stem cells (NPCs), which can act as HGG cell of origin, inhibition of mitochondrial metabolism leads to p53 genetic inactivation. Impairment of respiration via inhibition of complex I or decreased mitochondrial DNA copy number leads to p53 genetic loss and a glycolytic switch. p53 genetic inactivation in ETC-impaired neural stem cells is caused by increased reactive oxygen species and associated oxidative DNA damage. ETC-impaired cells display a marked growth advantage in the presence or absence of oncogenic RAS, and form undifferentiated tumors when transplanted into the mouse brain. Finally, p53 mutations correlated with alterations in ETC subunit composition and activity in primary glioma-initiating neural stem cells. Together, these findings provide previously unidentified insights into the relationship between mitochondria, genomic stability, and tumor suppressive control, with implications for our understanding of brain cancer pathogenesis.

[A meta-analysis for the efficacy and safety of tourniquet in total knee arthroplasty].

OBJECTIVE: To evaluate the efficacy and safety of tourniquet in total knee arthroplasty. METHOD: Studies on comparison between with and without tourniquet in total knee arthroplasty were identified from Medline, PubMed, EMASE, Cochrane Library, CBM, Highwire, CNKI, VIP, Articles Digital Periodicals.All the randomized controlled trials were included for meta-analysis with RevMan 4.2.2 software. RESULTS: Nineteen studies involving 15 in foreign languages, 4 in Chinese were identified. There were 1159 cases of knee replacement patients. The results of meta-analysis indicated that there were statistical difference between two groups on intraoperative blood loss (P = 0.000), the number of deep venous thrombosis (P = 0.020), thigh pain (P = 0.000), knee hematoma (P = 0.030), wound infection (P = 0.040), skin ecchymosis area (P = 0.000), and the increasing rate of knee circumference of 3 days after the operation (P = 0.000), while there were no statistical differences with respect to the total blood loss (P = 0.100), the number of blood transfusions (P = 0.150), operation time (P = 0.120), length of hospital stay (P = 0.350), the number of pulmonary embolism (P = 0.310), and skin blisters (P = 0.170). CONCLUSIONS: The tourniquet for total knee arthroplasty can reduce intraoperative blood loss, but can not reduce total blood loss and the number of blood transfusions transfusion, can not improve operative efficiency, can not shorten the hospitalization time and promote the knee joint functional recovery. Furthermore the tourniquet increases the probability of occurrence on deep vein thrombosis, wound infection, hematoma and ecchymosis knee, it also causes knee swelling and thigh pain. It suggests minimize to use tourniquet in total knee arthroplasty.

[Early clinical outcomes of fixed-bearing versus mobile-bearing total knee arthroplasty].

OBJECTIVE: To compare the early clinical outcomes of primary total knee arthroplasty by a fixed-bearing versus mobile-bearing prosthesis. METHODS: A total of 80 patients with osteoarthritis at our hospital from January 2008 to October 2008 were sequentially and randomly assigned into Group A (fixed-bearing prosthesis) (40 knees) and Group B (mobile-bearing prosthesis) (40 knees). And the data of the range of motion (ROM), Knee Society Score (KSS) and Western Ontario MacMaster (WOMAC) were collected at pre-operation and 6, 12 and 24 months post-operation respectively. RESULTS: The P values were as follows: KSS: 0.754, 0.802, 0.561, 0.764; HSS (Hospital for Special Surgery): 0.737, 0.361, 0.254, 0.330; WOMAC (Western Ontario and McMaster Universities) osteoarthritis index: 0.976, 0.557, 0.946, 0.818; ROM follow-up: 0.519, 0.646, 0.175, 0.276. No significant differences were found in clinical outcomes between two groups. CONCLUSION: The fixed-bearing and mobile-bearing prostheses show no difference in clinical outcomes.

Regulation of cellular senescence by the essential caveolar component PTRF/Cavin-1.

Polymerase I and transcript release factor (PTRF, also known as Cavin-1) is an essential component in the biogenesis and function of caveolae. Here, we show that PTRF expression is increased in senescent human fibroblasts. Importantly, overexpression of PTRF induced features characteristic of cellular senescence, whereas reduced PTRF expression extended the cellular replicative lifespan. Interestingly, we found that PTRF localized primarily to the nuclei of young and quiescent WI-38 human fibroblasts, but translocated to the cytosol and plasma membrane during cellular senescence. Furthermore, electron microscopic analysis demonstrated an increased number of caveolar structures in senescent and PTRF-transfected WI-38 cells. Our data suggest that the role of PTRF in cellular senescence is dependent on its targeting to caveolae and its interaction with caveolin-1, which appeared to be regulated by the phosphorylation of PTRF. Taken together, our findings identify PTRF as a novel regulator of cellular senescence that acts through the p53/p21 and caveolar pathways.