Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.Signal Transduction and Targeted Therapy (2020) 5:8; https://doi.

The glymphatic system is a brain-wide clearance pathway; its impairment contributes to the accumulation of amyloid-β. Influx of cerebrospinal fluid (CSF) depends upon the expression and perivascular localization of the astroglial water channel aquaporin-4 (AQP4). Prompted by a recent failure to find an effect of Aqp4 knock-out (KO) on CSF and interstitial fluid (ISF) tracer transport, five groups re-examined the importance of AQP4 in glymphatic transport. We concur that CSF influx is higher in wild-type mice than in four different Aqp4 KO lines and in one line that lacks perivascular AQP4 (Snta1 KO). Meta-analysis of all studies demonstrated a significant decrease in tracer transport in KO mice and rats compared to controls. Meta-regression indicated that anesthesia, age, and tracer delivery explain the opposing results. We also report that intrastriatal injections suppress glymphatic function. This validates the role of AQP4 and shows that glymphatic studies must avoid the use of invasive procedures.

Mitochondria are multifunctional organelles whose dysfunction leads to neuromuscular degeneration and ageing. The multi-functionality poses a great challenge for understanding the mechanisms by which mitochondrial dysfunction causes specific pathologies. Among the leading mitochondrial mediators of cell death are energy depletion, free radical production, defect in iron-sulfur cluster biosynthesis, the release of pro-apoptotic and non-cell-autonomous signaling molecules, and altered stress signaling 1–5. Here, we identified a novel pathway of mitochondria-mediated cell death. This pathway was named mitochondrial Precursor Over-accumulation Stress (mPOS), characterized by aberrant accumulation of mitochondrial precursors in the cytosol. mPOS can be triggered by clinically relevant mitochondrial damage which is not limited to the core machineries of protein import. We also identified a large network of genes that suppress mPOS, by modulating ribosomal biogenesis, mRNA decapping, transcript-specific translation, protein chaperoning and turnover. In response to mPOS, several ribosome-associated proteins were up-regulated including Gis2 and Nog2, which promote cap-independent translation and inhibit the nuclear export of the 60S ribosomal subunit respectively 6, 7. Gis2 and Nog2 up-regulation promotes cell survival, which may be part of a feedback loop that attenuates mPOS. Our data indicate that mitochondrial dysfunction contributes directly to cytosolic proteostatic stress, and provide an explanation for the enigmatic association between these two hallmarks of degenerative diseases and ageing. The results are relevant to understanding diseases (e.g., spinocerebellar ataxia, amyotrophic lateral sclerosis and myotonic dystrophy) that involve mutations within the anti-degenerative network.

Mitochondrial DNA (mtDNA) is essential for cells to maintain respiratory competency and is inherited as a protein-DNA complex called the nucleoid. We have identified 22 mtDNA-associated proteins in yeast, among which is mitochondrial aconitase (Aco1p). We show that this Krebs-cycle enzyme is essential for mtDNA maintenance independent of its catalytic activity. Regulation of ACO1 expression by the HAP and retrograde metabolic signaling pathways directly affects mtDNA maintenance. When constitutively expressed, Aco1p can replace the mtDNA packaging function of the high-mobility-group protein Abf2p. Thus, Aco1p may integrate metabolic signals and mtDNA maintenance.

A review of stabilizing systems for metal nanocatalysts, such as surfactants, complexants, polymers, SiO2, Fe3O4, graphene materials, and combined components thereof.

OBJECTIVE The authors previously described a graded approach to skull base repair following endonasal microscopic or endoscope-assisted tumor surgery. In this paper they review their experience with skull base reconstruction in the endoscopic era. METHODS A retrospective review of a single-institution endonasal endoscopic patient database (April 2010-April 2017) was undertaken. Intraoperative CSF leaks were graded based on size (grade 0 [no leak], 1, 2, or 3), and repair technique was documented across grades. The series was divided into 2 epochs based on implementation of a strict perioperative antibiotic protocol and more liberal use of permanent and/or temporary buttresses; repair failure rates and postoperative meningitis rates were assessed for the 2 epochs and compared. RESULTS In total, 551 operations were performed in 509 patients for parasellar pathology, including pituitary adenoma (66%), Rathke's cleft cyst (7%), meningioma (6%), craniopharyngioma (4%), and other (17%). Extended approaches were used in 41% of cases. There were 9 postoperative CSF leaks (1.6%) and 6 cases of meningitis (1.1%). Postoperative leak rates for all 551 operations by grade 0, 1, 2, and 3 were 0%, 1.9%, 3.1%, and 4.8%, respectively. Fat grafts were used in 33%, 84%, 97%, and 100% of grade 0, 1, 2, and 3 leaks, respectively. Pedicled mucosal flaps (78 total) were used in 2.6% of grade 0-2 leaks (combined) and 79.5% of grade 3 leaks (60 nasoseptal and 6 middle turbinate flaps). Nasoseptal flap usage was highest for craniopharyngioma operations (80%) and lowest for pituitary adenoma operations (2%). Two (3%) nasoseptal flaps failed. Contributing factors for the 9 repair failures were BMI ≥ 30 (7/9), lack of buttress (4/9), grade 3 leak (4/9), and postoperative vomiting (4/9). Comparison of the epochs showed that grade 1-3 repair failures decreased from 6/143 (4.1%) to 3/141 (2.1%) and grade 1-3 meningitis rates decreased from 5 (3.5%) to 1 (0.7%) (p = 0.08). Prophylactic lumbar CSF drainage was used in only 4 cases (< 1%), was associated with a higher meningitis rate in grades 1-3 (25% vs 2%), and was discontinued in 2012. Comparison of the 2 epochs showed increase buttress use in the second, with use of a permanent buttress in grade 1 and 3 leaks increasing from 13% to 55% and 32% to 76%, respectively (p < 0.001), and use of autologous septal/keel bone as a permanent buttress in grade 1, 2, and 3 leaks increasing from 15% to 51% (p < 0.001). CONCLUSIONS A graded approach to skull base repair after endonasal surgery remains valid in the endoscopic era. However, the technique has evolved significantly, with further reduction of postoperative CSF leak rates. These data suggest that buttresses are beneficial for repair of most grade 1 and 2 leaks and all grade 3 leaks. Similarly, pedicled flaps appear advantageous for grade 3 leaks, while CSF diversion may be unnecessary and a risk factor for meningitis. High BMI should prompt an aggressive multilayered repair strategy. Achieving repair failure and meningitis rates lower than 1% is a...

Vitiligo melanocytes possess higher susceptibility to oxidative insults. Consistent with this, impairment of the antioxidant defense system has been reported to be involved in the onset and progression of vitiligo. Our previous study showed that the nuclear factor E2-related factor 2-antioxidant response element (Nrf2-ARE) pathway and its downstream antioxidant enzyme heme oxygenase-1 (HO-1) are crucial for melanocytes to cope with H2O2-induced oxidative damage. Here, we sought to determine whether the diminished Nrf2-ARE activity that contributes to reduced downstream antioxidant enzymes and increased oxidative stress could be the reason why melanocytes are more vulnerable to vitiligo. We found that vitiligo melanocytes exhibited hypersensitivity to H2O2-induced oxidative injury because of reduced Nrf2 nuclear translocation and transcriptional activity, which led to decreased HO-1 expression and aberrant redox balance. Moreover, we also found that the level of serum HO-1 was significantly decreased and that of IL-2 was markedly increased in 113 vitiligo patients when compared with healthy controls. These data demonstrate that impaired activation of Nrf2 under oxidative stress could result in decreased expression of antioxidant enzymes and increased death of vitiligo melanocytes.

Epidemiological studies strongly suggest that chronic psychological stress promotes tumorigenesis. However, its direct link in vivo and the underlying mechanisms that cause this remain unclear. This study provides direct evidence that chronic stress promotes tumorigenesis in vivo; chronic restraint, a well-established mouse model to induce chronic stress, greatly promotes ionizing radiation (IR)-induced tumorigenesis in p53 +/− mice. The tumor suppressor protein p53 plays a central role in tumor prevention. Loss or attenuation of p53 function contriubutes greatly to tumorigenesis. We found that chronic restraint decreases the levels and function of p53 in mice, and furthermore, promotes the growth of human xenograft tumors in a largely p53-dependent manner. Our results show that glucocorticoids elevated during chronic restraint mediate the effect of chronic restraint on p53 through the induction of serum-and glucocorticoid-induced protein kinase (SGK1), which in turn increases MDM2 activity and decreases p53 function. Taken together, this study demonstrates that chronic stress promotes tumorigenesis in mice, and the attenuation of p53 function is an important part of the underlying mechanism, which can be mediated by glucocortcoids elevated during chronic restraint.