The E3 ubiquitin ligase adaptor speckle-type POZ protein (SPOP) is frequently dysregulated in prostate adenocarcinoma (PC), via either somatic mutations or mRNA downregulation, suggesting an ...important tumour suppressor function. To examine its physiologic role in the prostate epithelium in vivo, we generated mice with prostate-specific biallelic ablation of Spop. These mice exhibited increased prostate mass, prostate epithelial cell proliferation, and expression of c-MYC protein compared to littermate controls, and eventually developed prostatic intraepithelial neoplasia (PIN). We found that SPOP
can physically interact with c-MYC protein and, upon exogenous expression in vitro, can promote c-MYC ubiquitination and degradation. This effect was attenuated in PC cells by introducing PC-associated SPOP mutants or upon knockdown of SPOP via short-hairpin-RNA, suggesting that SPOP inactivation directly increases c-MYC protein levels. Gene Set Enrichment Analysis revealed enrichment of Myc-induced genes in transcriptomic signatures associated with SPOP
. Likewise, we observed strong inverse correlation between c-MYC activity and SPOP mRNA levels in two independent PC patient cohorts. The core SPOP
;MYC
transcriptomic response, defined by the overlap between the SPOP
and c-MYC transcriptomic programmes, was also associated with inferior clinical outcome in human PCs. Finally, the organoid-forming capacity of Spop-null murine prostate cells was more sensitive to c-MYC inhibition than that of Spop-WT cells, suggesting that c-MYC upregulation functionally contributes to the proliferative phenotype of Spop knock-out prostates. Taken together, our data highlight SPOP as an important regulator of luminal epithelial cell proliferation and c-MYC expression in prostate physiology, identify c-MYC as a novel bona fide SPOP substrate, and help explain the frequent inactivation of SPOP in human PC. We propose SPOP
-induced stabilization of c-MYC protein as a novel mechanism that can increase total c-MYC levels in PC cells, in addition to amplification of c-MYC locus.
Osteoarthritis (OA) as a debilitating affliction of joints currently affects millions of people and remains an unsolved problem. The disease involves multiple cellular and molecular pathways that ...converge on the progressive destruction of cartilage. Activation of cartilage regenerative potential and specific targeting pathogenic mediators have been the major focus of research efforts aimed at slowing the progression of cartilage degeneration and preserve joint function. This review will summarize recent key discoveries toward better understanding of the complex mechanisms behind OA development and highlight the latest advances in basic and clinical research in the approach for cartilage regeneration. Prospectively, more potent therapeutic strategies against progressive cartilage deterioration may use a combination of cytotherapy, pharmacotherapy, and bioscaffoldings for improved chondrogenic differentiation and stem/progenitor cell homing as well as the concomitant reduced enzymatic matrix degradation and inflammation. Further, treatments need to be provided with increased preciseness of targeted therapy. One might expect that the regenerative therapies could potentially control or even possibly cure OA if performed at early stages of the disease.
The management of intracranial pseudoaneurysms is controversial. The purpose of this study was to provide a preliminary evaluation of the clinical efficacy of a Willis covered stent specially ...designed for the intracranial vasculature in the management of a pseudoaneurysm of the cranial internal carotid artery (CICA).
Eight patients with pseudoaneurysms of the CICA were treated with use of the Willis covered stent. The flexibility of the entire stent system was gauged from the resistance met when reaching the target lesion and was categorized as no resistance, no apparent resistance, or resistance that could be overcome. The apposition of the Willis stent after deployment was scored as excellent with no endoleak, good with a small endoleak, or bad with an apparent endoleak. Follow-up angiography was performed 3 to 12 months after placement of the stent, and angiographic assessments were categorized as endoleak, stenosis of the covered segment of vessel, or occlusion of parent arteries. Follow-up clinical evaluations were also performed, and outcomes were graded as full recovery, improvement, unchanged, and aggravation.
Endovascular treatment was technically successful in all aneurysms without procedural-related complications, and all of the stents were easily navigated to the targeted lesions in the CICA. Complete resolution of the pseudoaneurysm was observed in 6 patients immediately after the procedure, and a minimal endoleak into the aneurysm persisted in 2 patients. No morbidity or mortality and no technical adverse event occurred. A follow-up angiogram confirmed complete reconstruction of the internal carotid artery, with no recurrent aneurysmal filling and no occurrence of stenosis in the area of the stent. By the final follow-up visit, 4 patients had fully recovered, 3 had improved, and 1 patient's condition was unchanged.
On the basis of our preliminary experience, the Willis covered stent specially designed for the intracranial vasculature can manage a CICA pseudoaneurysm safely and effectively, but longer follow-up and expanded clinical trials are needed.
With the development of critical care medicine, the case fatality rate in intensive care units (ICU) patients has decreased significantly, but most patients still suffer from the long-term problems ...of related complications after discharge, which seriously affects the quality of life and social integration after discharge. Complications such as ICU acquired weakness (ICU-AW) and Post-ICU Syndrome (PICS) are not uncommon throughout the treatment of severe patients. The treatment of critically ill patients should not only focus on the treatment of the disease, but also gradually extend to the whole-process physiological-psychological-social medical intervention mode in the ICU, during the stay in the general ward and after discharge. On the basis of ensuring patient safety, patients' physical and psychological status assessment in the early stage of ICU admission, and disease prevention as soon as possible, which can reduce the long-term impact on the quality of life and social work after discharge.
•Flower-like Ni-Mn LDH and Co-Mn LDH were synthesized by co-precipitation method.•Ni-Mn LDH and Co-Mn LDH are in-situ grown on the surface of reduced graphene oxide.•A high specific capacitance of ...1635Fg−1 at 1Ag−1 is achieved for Ni-Mn LDH/rGO.
Pure Ni-Mn layered double hydroxide (LDH), Co-Mn LDH with a flower-like morphology and sandwich-like Ni-Mn LDH/reduced graphene oxide (rGO), Co-Mn LDH/rGO hybrids are fabricated via a simple co-precipitation method. In the hybrids, Ni-Mn and Co-Mn hydroxide nanoflakes are tightly anchored on the both surfaces of rGO, leading to the composites with high specific surface areas. Electrochemical measurements prove that rGO can improve the capacitance and cyclic stability of the hybrid materials and that Ni-Mn LDH delivers a much higher specific capacitance but a worse cycling performance than Co-Mn LDH. A high specific capacitance of 1635Fg−1 at 1Ag−1 and a high rate retention of 71% at 10Ag−1 are achieved for Ni-Mn LDH/rGO. A hybrid capacitor with Ni-Mn LDH/rGO as positive electrode and activated carbon as negative electrode is assembled. It possesses a specific capacitance of 84.26Fg−1 at 1Ag−1 and an energy density of 33.8Whkg−1 within a potential window of 1.7V.
Interferon (IFN) signaling induces the expression of a wide array of genes, collectively referred to as IFN-stimulated genes (ISGs) that generally function to inhibit viral replication. RNA viruses ...are frequently targeted by ISGs through recognition of viral replicative intermediates and molecular features associated with viral genomes, or the lack of molecular features associated with host mRNAs. The ISGs reviewed here primarily inhibit viral replication in an RNA-centric manner, working to sense, degrade, or repress expression of viral RNA. This review focuses on dissecting how these ISGs exhibit multiple antiviral mechanisms, often through use of varied co-factors, highlighting the complexity of the type I IFN response. Specifically, these ISGs can mediate antiviral effects through viral RNA degradation, viral translation inhibition, or both. While the OAS/RNase L pathway globally degrades RNA and arrests translation, ISG20 and ZAP employ targeted RNA degradation and translation inhibition to block viral replication. Meanwhile, SHFL targets translation by inhibiting -1 ribosomal frameshifting, which is required by many RNA viruses. Finally, a number of E3 ligases inhibit viral transcription, an attractive antiviral target during the lifecycle of negative-sense RNA viruses which must transcribe their genome prior to translation. Through this review, we aim to provide an updated perspective on how these ISGs work together to form a complex network of antiviral arsenals targeting viral RNA processes.
Reliable characterization of particles freshly emitted from the ocean surface requires a sampling method that is able to isolate those particles and prevent them from interacting with ambient gases ...and particles. Here we report measurements of particles directly emitted from the ocean using a newly developed in situ particle generator (Sea Sweep). The Sea Sweep was deployed alongside R/V Atlantis off the coast of California during May of 2010. Bubbles were generated 0.75 m below the ocean surface with stainless steel frits and swept into a hood/vacuum hose to feed a suite of aerosol instrumentation on board the ship. The number size distribution of the directly emitted, nascent particles had a dominant mode at 55–60 nm (dry diameter) and secondary modes at 30–40 nm and 200–300 nm. The nascent aerosol was not volatile at 230°C and was not enriched in SO4=, Ca++, K+, or Mg++above that found in surface seawater. The organic component of the nascent aerosol (7% of the dry submicrometer mass) volatilized at a temperature between 230 and 600°C. The submicrometer organic aerosol characterized by mass spectrometry was dominated by non‐oxygenated hydrocarbons. The nascent aerosol at 50, 100, and 145 nm dry diameter behaved hygroscopically like an internal mixture of sea salt with a small organic component. The CCN/CN activation ratio for 60 nm Sea Sweep particles was near 1 for all supersaturations of 0.3 and higher indicating that all of the particles took up water and grew to cloud drop size. The nascent organic aerosol mass fraction did not increase in regions of higher surface seawater chlorophyll but did show a positive correlation with seawater dimethylsulfide (DMS).
Key Points
The ocean is a source of sub 100nm particles to the atmosphere
Hygroscopically the particles behave like an internal mixture of sea salt/organic
Organic mass fraction did not correlate with chlorophyll
In this study, chemical replacement combined with surface-enhanced laser-induced breakdown spectroscopy (CR-SENLIBS) was for the first time applied to improve the detection sensitivities of trace ...heavy metal elements in aqueous solutions. Utilizing chemical replacement effect, heavy metal ions in aqueous solution were enriched on the magnesium alloy surface as a solid replacement layer through reacting with the high chemical activity metallic magnesium (Mg) within 1 minute. Unitary and mixed solutions with Cu, Pb, Cd, and Cr elements were prepared to construct calibration curves, respectively. The CR-SENLIBS showed a much better detection sensitivity and accuracy for both unitary and mixed solutions. The coefficients of determination R
of the calibration curves were above 0.96, and the LoDs were of the same order of magnitude, i.e., in the range of 0.016-0.386 μg/mL for the unitary solution, and in the range of 0.025-0.420 μg/mL for the mixed solution. These results show that CR-SENLIBS is a feasible method for improving the detection sensitivity of trace element in liquid sample, which definitely provides a way for wider application of LIBS in water quality monitoring.
The accumulation of myeloid-derived suppressor cells (MDSCs) has been observed in solid tumors and is correlated with tumor progression; however, the underlying mechanism is still poorly understood. ...In this study, we identified a mechanism by which tumor cells induce MDSC accumulation and expansion in the bladder cancer (BC) microenvironment via CXCL2/MIF-CXCR2 signaling. Elevated expression of CXCL2 and MIF and an increased number of CD33
MDSCs were detected in BC tissues, and these increases were significantly associated with advanced disease stage and poor patient prognosis (P<0.01). A positive association was observed between CXCL2 or MIF expression and the number of tumor-infiltrating CD33
MDSCs (P<0.01). Subsequently, we demonstrated that CD45
CD33
CD11b
HLA-DR
MDSCs from fresh BC tissues displayed high levels of suppressive molecules, including Arg1, iNOS, ROS, PDL-1 and P-STAT3, and stronger suppression of T-cell proliferation. Interestingly, these CD45
CD33
CD11b
HLA-DR
MDSCs exhibited increased CXCR2 expression compared with that in peripheral blood from BC patients or healthy controls (P<0.05). Chemotaxis assay revealed that bladder cancer cell line J82 induced MDSC migration via CXCL2/MIF-CXCR2 signaling in vitro. Mechanistic studies demonstrated that J82-induced MDSC trafficking and CXCR2 expression were associated with increased phosphorylation of p38, ERK and p65. Conversely, inhibition of the phosphorylation of p38, ERK or p65 decreased J82-induced MDSC trafficking and CXCR2 expression. CXCL2/MIF-stimulated activation of the mitogen-activated protein kinase and nuclear factor kappa B pathways in MDSCs was MyD88 dependent. Overall, our results identify the CXCL2/MIF-CXCR2 axis as an important mediator in MDSC recruitment and as predictors and potential therapeutic targets in BC patients.
Background Peroral endoscopic myotomy (POEM) has been developed to provide a less-invasive myotomy for achalasia in adults but seldom has been used in pediatric patients. Objective To evaluate the ...feasibility, safety, and efficacy of POEM for pediatric patients with achalasia. Design Single-center, prospective study. Setting Academic medical center. Patients A total of 27 pediatric patients (mean age 13.8 years, range 6-17 years) with achalasia. Interventions POEM. Main Outcome Measurements The primary outcome was symptom relief during follow-up, defined as an Eckardt score of ≤3. Secondary outcomes were procedure-related adverse events, clinical reflux adverse events, and lower esophageal sphincter (LES) pressure on manometry before and after POEM. Results A total of 26 cases (96.3%) underwent successful POEM. A submucosal tunnelling attempt failed in 1 case because of serious inflammation and adhesion. No serious adverse events related to POEM were encountered. During a mean follow-up period of 24.6 months (range 15-38 months), treatment success was achieved in all patients (mean score before vs after treatment 8.3 vs 0.7; P < .001). Mean LES pressure also decreased from a mean of 31.6 mm Hg to 12.9 mm Hg after POEM ( P < .001). Five patients developed clinical reflux adverse events (19.2%). Limitations Single center and lack of some objective evaluations. Conclusion This relatively long-term follow-up study adds to the evidence that POEM seems to be a promising new treatment for pediatric patients with achalasia, resulting in long-term symptom relief in all cases and without serious adverse events.
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