A novel polypeptide encoded by the circular RNA ZKSCAN1 suppresses HCC via degradation of mTOR.

BACKGROUND: hsa_circ_0001727 (circZKSCAN1) has been reported to be a tumor-associated circRNA by sponging microRNAs. Intriguingly, we found that circZKSCAN1 encoded a secretory peptide (circZKSaa) in the liver. The present study aims to elucidate the potential role and molecular mechanism of circZKSaa in the regulation of hepatocellular carcinoma (HCC) progression. METHODS: The circRNA profiling datasets (RNA-seq data GSE143233 and GSE140202) were reanalyzed and circZKSCAN1 was selected for further study. Mass spectrometry, polysome fractionation assay, dual-luciferase reporter, and a series of experiments showed that circZKSCAN1 encodes circZKSaa. Cell proliferation, apoptosis, and tumorigenesis in nude mice were examined to investigate the functions of circZKSaa. Mechanistically, the relationship between the circZKSaa and mTOR in HCC was verified by immunoprecipitation analyses, mass spectrometry, and immunofluorescence staining analyses. RESULTS: Receiver operating characteristic (ROC) analysis demonstrated that the secretory peptide circZKSaa encoded by circZKSCAN1 might be the potential biomarker for HCC tissues. Through a series of experiments, we found that circZKSaa inhibited HCC progression and sensitize HCC cells to sorafenib. Mechanistically, we found that the sponge function of circZKSCAN1 to microRNA is weak in HCC, while overexpression of circZKSaa promoted the interaction of FBXW7 with the mammalian target of rapamycin (mTOR) to promote the ubiquitination of mTOR, thereby inhibiting the PI3K/AKT/mTOR pathway. Furthermore, we found that the high expression of cicZKSCAN1 in sorafenib-treated HCC cells was regulated by QKI-5. CONCLUSIONS: These results reveal that a novel circZKSCAN1-encoded peptide acts as a tumor suppressor on PI3K/AKT/mTOR pathway, and sensitizes HCC cells to sorafenib via ubiquitination of mTOR. These findings demonstrated that circZKSaa has the potential to serve as a therapeutic target and biomarker for HCC treatment.

circMRPS35 promotes malignant progression and cisplatin resistance in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death worldwide. Circular RNAs (circRNAs), a novel class of non-coding RNA, have been reported to be involved in the etiology of various malignancies. However, the underlying cellular mechanisms of circRNAs implicated in the pathogenesis of HCC remain unknown. In this study, we identified a functional RNA, hsa_circ_0000384 (circMRPS35), from public tumor databases using a set of computational analyses, and we further identified that circMRPS35 was highly expressed in 35 pairs of HCC from patients. Moreover, knockdown of the expression of circMRPS35 in Huh-7 and HCC-LM3 cells suppressed their proliferation, migration, invasion, clone formation, and cell cycle in vitro, and it suppressed tumor growth in vivo as well. Mechanically, circMRPS35 sponged microRNA-148a-3p (miR-148a), regulating the expression of Syntaxin 3 (STX3), which modulated the ubiquitination and degradation of phosphatase and tensin homolog (PTEN). Unexpectedly, we detected a peptide encoded by circMRPS35 (circMRPS35-168aa), which was significantly induced by chemotherapeutic drugs and promoted cisplatin resistance in HCC. These results demonstrated that circMRPS35 might be a novel mediator in HCC progress, and they raise the potential of a new biomarker for HCC diagnosis and prognosis, as well as a novel therapeutic target for HCC patients.

Adtrp regulates thermogenic activity of adipose tissue via mediating the secretion of S100b.

Brown and beige adipose tissues dissipate chemical energy in the form of heat to maintain your body temperature in cold conditions. The impaired function of these tissues results in various metabolic diseases in humans and mice. By bioinformatical analyses, we identified a functional thermogenic regulator of adipose tissue, Androgen-dependent tissue factor pathway inhibitor [TFPI]-regulating protein (Adtrp), which was significantly overexpressed in and functionally activated the mature brown/beige adipocytes. Hereby, we knocked out Adtrp in mice which led to multiple abnormalities in thermogenesis, metabolism, and maturation of brown/beige adipocytes causing excess lipid accumulation in brown adipose tissue (BAT) and cold intolerance. The capability of thermogenesis in brown/beige adipose tissues could be recovered in Adtrp KO mice upon direct ß3-adrenergic receptor (ß3-AR) stimulation by CL316,243 treatment. Our mechanistic studies revealed that Adtrp by binding to S100 calcium-binding protein b (S100b) indirectly mediated the secretion of S100b, which in turn promoted the ß3-AR mediated thermogenesis via sympathetic innervation. These results may provide a novel insight into Adtrp in metabolism via regulating the differentiation and thermogenesis of adipose tissues in mice.

A Meta-Analysis of Randomized and Observational Studies: Aspirin Protects from Cardiac Surgery-Associated Acute Kidney Injury.

BACKGROUND: Antiplatelet therapy is critical in the management of coronary artery diseases. For patients undergoing cardiac surgeries, including coronary artery bypass graft (CABG) and valve replacement, controversy remains in preoperative antiplatelet therapy concerning risk of bleeding. For safety concern, aspirin is recommended to be withdrawn 5 to 10 days before a cardiac surgery. Recent studies, however, indicate that preoperative aspirin may have a protective effect on cardiac surgery-associated acute kidney injury (CSA-AKI). OBJECTIVE: To estimate the efficacy of preoperative aspirin in preventing CSA-AKI. METHODS AND RESULTS: Eligible studies included randomized controlled trials (RCTs) and observational studies (OSs) of patients, who had undergone CABG, valve replacement, or combined surgery. These studies compared preoperative aspirin with placebo/no aspirin and reported the least incidence of CSA-AKI. One RCT and five OSs met the inclusion criteria. Data retrieved suggested that aspirin prescribed within five days before cardiac surgery decreased post-operative renal failure [odds ratio (OR), 0.67; 95% confidence interval (CI), 0.50-0.89; P < 0.01] and 30-day mortality (OR, 0.64; 95% CI, 0.53-0.77; P < 0.01). One RCT and three OSs suggested aspirin protected from major adverse cardiocerebral events (MACE) (OR, 0.88; 95% CI, 0.76-1.01; P = 0.07). One RCT and two OSs suggested aspirin did not increase risk of re-exploration for bleeding (OR, 1.01; 95% CI, 0.76-1.34; P = 0.95). CONCLUSION: Preoperative low-dose aspirin decreases post-operative CSA-AKI, mortality, and MACE without increasing the risk of re-exploration. But most of the studies are observational. They lack a uniformed standard on prescription of aspirin and outcomes measurement. No stratification analysis is performed concerning different types of surgical procedures and comorbidities. More randomized controlled trials are necessary to confirm the efficacy and safety of preoperative aspirin prescription.

Type III Intraosseous Meningioma Invading Superior Sagittal Sinus and Skull Periosteum.

Type III intraosseous meningioma is a very rare type of meningioma with extracranial extension. Herein, the author reported a case of type IIIC intraosseous meningioma with invasion of the superior sagittal sinus and skull periosteum. A 67-year-old woman was admitted to our hospital due to a mass on the left frontoparietal region for 4 years. Magnetic resonance imaging showed a skull tumor with invasion of the superior sagittal sinus. After partial resection of the tumor, pathological and immunohistochemical staining revealed that the epithelial meningioma derived from skull involved the skull periosteum. There was no enlargement of residual parasagittal tumor after 1 year of follow-up. The intraosseous meningioma in the present case was a rare benign tumor with good prognosis after surgery.

Discrete π-Stacks from Self-Assembled Perylenediimide Analogues.

The formation of well-defined finite-sized aggregates represents an attractive goal in supramolecular chemistry. In particular, construction of discrete π-stacked dye assemblies remains a challenge. Reported here is the design and synthesis of a novel type of discrete π-stacked aggregate from two comparable perylenediimide (PDI) dyads (PEP and PBP). The criss-cross PEP-PBP dimers in solution and (PBP-PEP)-(PEP-PBP) tetramers in the solid state are well elucidated using single-crystal X-ray diffraction, dynamic light scattering, and diffusion-ordered NMR spectroscopy. Extensive π-π stacking between the PDI units of PEP and PBP as well as repulsive interactions of swallow-tailed alkyl substituents are responsible for the selective formation of discrete dimer and tetramer stacks. Our results reveal a new approach to preparing discrete π stacks that are appealing for making assemblies with well-defined optoelectronic properties.

The association between the ring finger protein 213 (RNF213) polymorphisms and moyamoya disease susceptibility: a meta-analysis based on case-control studies.

A number of studies assessed the association of ring finger protein 213 (RNF213) gene polymorphisms with moyamoya disease (MMD), but the results were not entirely consistent. This meta-analysis was performed to explore the relationship between RNF213 polymorphisms and moyamoya disease in Asian population. A systematic search from the PubMed, MEDLINE, EMBASE, ISI web of science, CNKI, China CBM and WANFANG DATA databases was conducted to retrieve published studies until March 2015. Statistical analyses were performed using the STATA12.0 software. Fixed or random effects model, subgroup analysis, sensitivity analysis, and publication bias were used to improve the comprehensive analysis. Eight papers including 904 MMD patients and 2258 controls were recruited in the meta-analysis. rs112735431 was closely associated with the risk of MMD among Asian population in all genetic models (dominant model: OR 103.39, 95 % CI 52.25-204.55, P = 1.69e-40; recessive model: OR 16.45, 95 % CI 6.00-45.10, P = 5.33e-08; additive model: OR 61.49, 95 % CI 22.07-171.33, P = 3.32e-15), especially in the Japanese population. Subgroup analysis revealed highly statistically significant higher risk in the patients with family histories. Although another polymorphism rs148731719 showed no significant association with the MMD, rs138130613 was found to be related to the higher risk in Chinese population (dominant model: OR 8.34, 95 % CI 1.72-40.47, P = 0.008). Our meta-analysis strengthens RNF213 rs112735431 is closely associated with the increased risk of MMD in Japanese, and the screening combined with rs112735431 and rs138130613may improve the detection rate for MMD in China.

Subcellular distribution, chemical forms of cadmium and rhizosphere microbial community in the process of cadmium hyperaccumulation in duckweed.

Duckweed is a newly reported Cd hyperaccumulator that grow rapidly; however, little is known about its tolerance and detoxification mechanisms. In this study, we investigated the tissue, subcellular, and chemical form distribution of the Cd in duckweed and studied the influences of Cd on duckweed growth, ultrastructure, and rhizosphere microbial community. The results showed that Cd could negatively affect the growth of duckweed and shorten the root length. More Cd accumulated in the roots than in the leaves, and Cd was transferred from the roots to the leaves with time. During 12-24 h, Cd mainly existed in the cell wall fraction (2.05 %-95.52 %) and the organelle fraction (5.03 %-97.80 %), followed the soluble fraction (0.14 %-16.98 %). Over time, the proportion of Cd in the organelles increased (46.64 %-92.83 %), exceeding that in the cell wall (6.79 %-66.23 %), which indicated that duckweed detoxification mechanism may be related to the retention of cell wall and vacuole. The main chemical form of Cd was the NaCl-extracted state (30.15 %-88.66 %), which was integrated with pectate and protein. With increasing stress concentration and time, the proportion of the HCl-extracted state and HAc-extracted state increased, and they were low-toxic Cd oxalate and Cd phosphate, respectively. Cd damaged the ultrastructure of cells such as chloroplasts and mitochondria and inhibited the diversity of microbial communities in the duckweed rhizosphere; however, the dominant populations that could tolerate heavy metals increased. It was speculated that duckweed distributed Cd in a less toxic chemical form in a less active location, mainly through retention in the root cell wall and sequestration in the leaf vacuoles, and is dynamically adjusted. The rhizosphere microbial communities tolerate heavy metals may also be one of the mechanisms by which duckweed can tolerate Cd. This study revealed the mechanism of duckweed tolerance and detoxification of Cd at the molecular level and provides a theoretical basis for further development of duckweed.

Nucleolar protein NOC4L inhibits tumorigenesis and progression by attenuating SIRT1-mediated p53 deacetylation.

SIRT1 is an NAD+-dependent deacetylase and plays an important role in the deacetylation of both histone and non-histone proteins. Many studies revealed that SIRT1 is upregulated in a variety of tumors and tightly associated with tumorigenesis and cancer progression, but the detailed underlying mechanism of the biological processes remains unclarified. In the present study, we found a nucleolar protein NOC4L, human ortholog of yeast Noc4p, which is essential for the nuclear export of the ribosomal 40S subunit and could bind to SIRT1 to inhibit SIRT1 mediated deacetylation of p53. NOC4L interacts with SIRT1 in variety of cells under nucleolar stress and directly interacts with SIRT1 in vitro. Furthermore, we determined the C-terminal of NOC4L and the catalytic domain of SIRT1 were required for their interaction. Overexpression of NOC4L did not change the protein levels of SIRT1 or p53, but increased the acetylation of p53 and promoted cell apoptosis. Additionally, NOC4L inhibited tumor cell proliferation in a p53-dependent manner and restrained tumor growth in a nude mice xenograft model. Clinically, colorectal cancer patients with the high expression of NOC4L had a better prognosis as TP53 was normally expressed, but no significant difference was observed in survival with mutant TP53. Taken together, our results identified a novel SIRT1 regulatory protein and broaden our understanding of the molecular mechanism of how nucleolar protein NOC4L regulates p53 under nucleolar stress. This research provides an insight into tumorigenesis and cell self-protection in the early stage of DNA damage.

Transcortical approach surgery versus external ventricular drainage in treating intraventricular hemorrhage.

ABSTRACT: Intraventricular hemorrhage is a serious intracerebral hemorrhagic disease with high mortality and poor prognosis. This retrospective study designed to investigate the therapeutic effect of transcortical approach surgery versus extraventricular drainage (EVD) on patients with intraventricular hemorrhage.Patients with intraventricular hemorrhage in Zhongshan City People's Hospital from January 01, 2014 to June 01, 2019 were retrospectively examined. They were divided into transcortical approach surgery groups and EVD groups to analyze the clinical characteristics and prognosis.A total of 96 patients were enrolled in the study (24 in the transcortical approach surgery group and 72 in the EVD group). The efficiency of postoperative operation was 15/19 in the transcortical approach surgery group and 24/48 in the EVD group (P = .012). The Glasgow Outcome Scale was 3.63 ±â€Š1.27 in the transcortical approach surgery group and 2.80 ±â€Š1.87 in the EVD group (P = .049). The postoperative residual blood volume was 9.62 ±â€Š3.64 mL in the transcortical approach surgery group and 33.60 ±â€Š3.53 mL in the EVD group (P < .001). The incidence of hydrocephalus after the operation was 1/23 in the transcortical approach surgery group and 19/53 in the EVD group. The 30-day postoperative mortality was 16/56 in the EVD group and 1/23 in the transcortical approach surgery group. The transcortical approach surgery group was significantly better compared with the EVD group.This study showed that the transcortical approach for ventricular hemorrhage compared with EVD improved the hematoma clearance rate, shortened catheterization time, reduced the incidence of postoperative hydrocephalus, decreased patient mortality, led to a better prognosis, and reduced complications of hydrocephalus.

Cannabidiol attenuates pulmonary arterial hypertension by improving vascular smooth muscle cells mitochondrial function.

Rationale: Pulmonary arterial hypertension (PAH) is a chronic disease associated with enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) and dysfunctional mitochondria, and the clinical therapeutic option for PAH is very limited. Recent studies showed that cannabidiol (CBD), a non-psychoactive constituent of cannabinoids, possessed antioxidant effect towards several cardiovascular diseases, whereas the mechanistic effect of CBD in PAH is unknown. Methods: In this study, the effects of CBD in PAH were determined by analyzing its preventive and therapeutic actions in PAH rodent models in vivo and PASMCs' proliferation test in vitro. Additionally, CBD's roles in mitochondrial function and oxidant stress were also assessed in PASMCs. Results: We found that CBD reversed the pathological changes observed in both Sugen-hypoxia and monocrotaline-induced PAH rodent models in a cannabinoid receptors-independent manner. Our results also demonstrated that CBD significantly inhibited the PASMCs' proliferation in PAH mice with less inflammation and reactive oxygen species levels. Moreover, CBD alleviated rodent PAH by recovering mitochondrial energy metabolism, normalizing the hypoxia-induced oxidant stress, reducing the lactate overaccumulation and abnormal glycolysis. Conclusions: Taken together, these findings confirm an important role for CBD in PAH pathobiology.

Macrophage deletion of Noc4l triggers endosomal TLR4/TRIF signal and leads to insulin resistance.

In obesity, macrophages drive a low-grade systemic inflammation (LSI) and insulin resistance (IR). The ribosome biosynthesis protein NOC4 (NOC4) mediates 40 S ribosomal subunits synthesis in yeast. Hereby, we reported an unexpected location and function of NOC4L, which was preferentially expressed in human and mouse macrophages. NOC4L was decreased in both obese human and mice. The macrophage-specific deletion of Noc4l in mice displayed IR and LSI. Conversely, Noc4l overexpression by lentivirus treatment and transgenic mouse model improved glucose metabolism in mice. Importantly, we found that Noc4l can interact with TLR4 to inhibit its endocytosis and block the TRIF pathway, thereafter ameliorated LSI and IR in mice.

Oncogenic Network and Hub Genes for Natural Killer/T-Cell Lymphoma Utilizing WGCNA.

Natural killer (NK)/T-cell lymphoma (NKTCL) is a subtype of non-Hodgkin lymphoma with aggressive progression and poor prognosis. The molecular mechanisms of NKTCL have not been well-studied. Herein, we revealed the lymphoma-associated dysregulated genes and signaling pathways or biological processes in NKTCL. We characterized that the extracellular matrix (ECM) receptor interaction pathway and T-cell receptor signaling pathway were the main dysregulated pathways in NKTCL by Gene Ontology (GO) analysis and pathway enrichment analysis. By using weighted gene co-expression network analysis (WGCNA), the gene co-expression network of NKTCL (SRP049695) was constructed, and hub genes (LMO3, GRB14) were identified. In addition, another Gene Expression Omnibus (GEO) dataset (GSE69406) was used to validate these hub genes. Furthermore, these hub genes were identified and validated by survival analysis (GSE90597). These results provided novel insights into the pathogenesis of NKTCL. Of particular interest, LMO3 and GRB14 might be potential oncoproteins and biomarkers for the diagnosis and treatment of NKTCL.

One-pot HTST synthesis of responsive fluorescent ZnO@apo-enzyme composite microgels for intracellular glucometry.

Responsive fluorescent microgels, that can selectively, reversibly, and rapidly convert the fluctuation in intracellular glucose level into fluorescence signal, have the potential use for intracellular glucometry to promote the understanding of physiology. Herein, we report one-pot synthesis of such a responsive fluorescent composite microgels, which is made of a representative apo-enzyme, apo-glucose oxidase (apo-GOx), interpenetrated in a composite gel network that is comprised of ZnO quantum dots covalently bonded onto crosslinked poly(ethylene glycol) dimethacrylate. The key of this one-pot synthesis is applying a high-temperature short-time heating (HTST) method, so that the naturally dynamic profile of apo-GOx can be maintained and harnessed on the composite microgels to allow the highly selective response to glucose over a glucose concentration range of 0-20 mM. While the composite microgels can undergo volume phase transitions and convert both an increase and a decrease in glucose concentration into fluorescence signal shortly (<1 s), the changes in average hydrodynamic diameter and fluorescence of the composite microgels can be fully reversible even after twenty cycles of adding/removing glucose, indicating a reversible and rapid time response to the glucose concentration variations. With the composite microgels as biosensors, the fluorescence of the composite microgels embedded in the model cancer cells B16F10 can be modulated in response to intracellular glucose level variations, which are derived from a change in glucose concentration in the culture medium by an external supply, or that can be triggered by biochemical reactions (with the ß-galactosidase catalysed hydrolysis of lactose as a model reaction for achieving increased glucose levels, and the GOx catalysed oxidation of glucose for achieving decreased glucose levels).

Glucocorticoid treatment of suspected organizing pneumonia after H7N9 infection: A case report.

RATIONALE: H7N9 infection causes acute respiratory distress syndrome with high mortality. The use of glucocorticoids in the acute phase lessened inflammatory responses. Some case reports suggested that secondary organizing pneumonia (SOP) could occur at the recovery stage of the influenza virus infection, and the treatment with glucocorticoid was effective. However, the reports of organizing pneumonia after H7N9 infection are lacking. This study reported a patient with H7N9 virus infection who presented a suspected SOP during the recovery stage. PATIENT CONCERN: A 68-year-old woman who was diagnosed with H7N9 viral pneumonia. After standard antiviral treatment, venous-venous extracorporeal membranous oxygenation (VV-ECMO) and other supportive treatment, the antigen in the alveolar lavage fluid turned negative, and the shadow in the lung was partially absorbed. However, the imaging manifestations were deteriorated at 3 weeks after disease onset, presented as exudation and consolidation shadow distributed under the pleura and along the bronchial vascular bundles. The oxygenation could not be improved. Repeated sputum, alveolar lavage fluid, and blood pathogen examinations showed negative results. Broad-spectrum anti-infective treatment was ineffective. However, the autoantibodies (ANA, anti-SSA/Ro60, anti-SSA/Ro52) were detected. DIAGNOSIS: SOP was considered. INTERVENTIONS: Glucocorticoid treatment begun at week 4 from the disease onset. The regimen was methylprednisolone at an initial dose of 40 mg twice a day for 1 week, tapering within 70 days until total withdrawal. OUTCOMES: The oxygenation was rapidly improved after initiation of methylprednisolone. The shadow in the lung gradually resolved, and the patient was discharged after improvement of the disease condition. The clinical disease course, imaging findings, and treatment effects in the previous cases of SOP after influenza virus infection were similar to those in this case, suggesting the occurrence of SOP after H7N9 virus infection. LESSONS: Organizing pneumonia might occur during the recovery stage of influenza virus infection. When the clinical symptoms do not improve and the shadow in the lung shows no obvious absorption after elimination of the H7N9 influenza virus, or the clinical symptoms are aggravated again after improvement, the probability of transforming into the organizing pneumonia should be taken into consideration.

Cyanidin-3-o-Glucoside Pharmacologically Inhibits Tumorigenesis via Estrogen Receptor ß in Melanoma Mice.

Expression patterns of estrogen receptors [ERα, ERß, and G-protein associated ER (GPER)] in melanoma and skin may suggest their differential roles in carcinogenesis. Phytoestrogenic compound cyanidin-3-o-glucoside (C3G) has been shown to inhibit the growth and metastatic potential of melanoma, although the underlying molecular mechanism remains unclear. The aim of this study was to clarify the mechanism of action of C3G in melanoma in vitro and in vivo, as well as to characterize the functional expressions of ERs in melanoma. In normal skin or melanoma (n = 20/each), no ERα protein was detectable, whereas expression of ERß was high in skin but weak focal or negative in melanoma; and finally high expression of GPER in all skin vs. 50% melanoma tissues (10/20) was found. These results correspond with our analysis of the melanoma survival rates (SRs) from Human Protein Atlas and The Cancer Genome Atlas GDC (362 patients), where low ERß expression in melanoma correlate with a poor relapse-free survival, and no correlations were observed between SRs and ERα or GPER expression in melanoma. Furthermore, we demonstrated that C3G treatment arrested the cell cycle at the G2/M phase by targeting cyclin B1 (CCNB1) and promoted apoptosis via ERß in both mouse and human melanoma cell lines, and inhibited melanoma cell growth in vivo. Our study suggested that C3G elicits an agonistic effect toward ERß signaling enhancement, which may serve as a potential novel therapeutic and preventive approach for melanoma.

Human U3 protein14a is a novel type ubiquitin ligase that binds RB and promotes RB degradation depending on a leucine-rich region.

The nucleolar protein hUTP14a promotes p53 degradation and possesses an oncogene potential. Here, we report that hUTP14a promotes degradation of tumor suppressor retinoblastoma (RB) protein. Sequences alignment showed that hUTP14a contains the RB-binding PENF motif in its C-terminus. We showed that hUTP14a interacted with RB in vivo and in vitro. Further, hUTP14a promoted polyubiquitination and proteasome-dependent turnover of RB. Importantly, purified Flag-hUTP14a facilitated RB ubiquitination in vitro, demonstrating that hUTP14a is an ubiquitin E3 ligase for RB. A BLAST alignment with hUTP14a does not reveal a RING or HECT domain. To define the conserved domain for E3 ligase activity in hUTP14a, the minimum domain for promoting RB degradation was mapped to residues 61-120 of hUTP14a, in which a leucine-rich region (LRR) LxLxxLL was suggested to be conserved. Flag-hUTP14a (ΔLRR), Flag-hUTP14a-MT1(LxLxxLL to LxLxxAA) and Flag-hUTP14a-MT2(LxLxxLL to AxAxxAA) lost the capability of ubiquitinating RB in vitro, demonstrating that LRR is required for the E3 ligase activity of hUTP14a. Consequently, expression of hUTP14a caused upregulation of E2F1 downstream genes, thus promoting cancer cell proliferation. Taken together, we demonstrate that hUTP14a promotes RB degradation through its E3 ligase activity and suggest that the LRR could be a potential conserved E3 ligase domain.

A novel mutation and a known mutation in the CLCN7 gene associated with relatively stable infantile malignant osteopetrosis in a Chinese patient.

Osteopetrosis is a group of heterogeneous disorders caused by the dysfunction of osteoclasts. The CLCN7 and TCIRG1 genes are the major obligate genes responsible for infantile malignant osteopetrosis (IMO). IMO patients usually die in infancy or before three years of age. In this study, we report a patient who was diagnosed with IMO at seven months of age. The patient presented with classical radiological features of IMO. She also exhibited erythropenia, thrombocytopenia, hepatosplenomegaly and neurodegeneration. The parents discontinued any medical treatment for the patient. Surprisingly, the patient's condition did not deteriorate when she was admitted a second time at the age of four years and nine months, despite not receiving any medical support during the untreated period. We sequenced the CLCN7 and TCIRG1 genes of the patient and her parents and identified a novel c.285+1G>A (IVS3+1G>A) mutation and the known c.896C>T (p.Ala299Val) mutation. The novel c.285+1G>A mutation occurred on the splice donor of the third intron of CLCN7. This mutation was predicted to interfere with normal splicing between exons 3 and 4, thereby truncating 711 amino acids from the C terminus and resulting in the loss of all of the functional domains of the encoded protein. The c.896C>T (p.Ala299Val) mutation was a previously known pathogenic mutation. We did not find any pathogenic mutations in the TCIRG1 gene. CLCN7-related osteopetrosis is known to have a high phenotype heterogeneity. Our study demonstrates a wide heterogeneity in the progression of the phenotypes and expanded the mutational spectrum for the CLCN7 gene.

Molecularly Targeted Drugs Plus Radiotherapy and Temozolomide Treatment for Newly Diagnosed Glioblastoma: A Meta-Analysis and Systematic Review.

Glioblastoma (GBM) is the most common primary malignant brain tumor that nearly always results in a bad prognosis. Temozolomide plus radiotherapy (TEM+RAD) is the most common treatment for newly diagnosed GBM. With the development of molecularly targeted drugs, several clinical trials were reported; however, the efficacy of the treatment remains controversial. So we attempted to measure the dose of the molecularly targeted drug that could improve the prognosis of those patients. The appropriate electronic databases (PubMed, MEDLINE, EMBASE, and the Cochrane Library) were searched for relevant studies. A meta-analysis was performed after determining which studies met the inclusion criteria. Six randomized, controlled trials (RCTs) were identified for this meta-analysis, comprising 2,637 GBM patients. The benefit of overall survival (OS) was hazard ratio (HZ), 0.936 [95% confidence interval (CI), 0.852-1.028]. The benefit with respect to progression-free survival (PFS) rate was HZ of 0.796 (95% CI, 0.701-0.903). OS benefit of cilengitide was HZ of 0.792 (95% CI, 0.642-0.977). The adverse effects higher than grade 3 were 57.7% in the experimental group and 44.1% in the placebo group (odds ratio, 1.679; 95% CI, 1.434-1.967). The addition of molecularly targeted drugs to TEM + RAD did not improve the OS of patients with GBM; however, it did improve PFS in patients treated by cilengitide who could not get improvement in OS. The rate of adverse effects was higher in the experimental group than in the placebo group.

Steroid Avoidance or Withdrawal Regimens in Paediatric Kidney Transplantation: A Meta-Analysis of Randomised Controlled Trials.

BACKGROUND: We combined the outcomes of all randomised controlled trials to investigate the safety and efficacy of steroid avoidance or withdrawal (SAW) regimens in paediatric kidney transplantation compared with steroid-based (SB) regimens. METHODS: A systematic literature search of PubMed, Embase, Cochrane Library, the trials registry and BIOSIS previews was performed. A change in the height standardised Z-score from baseline (ΔHSDS) and acute rejection were the primary endpoints. RESULTS: Eight reports from 5 randomised controlled trials were included, with a total of 528 patients. Sufficient evidence of a significant increase in the ΔHSDS was observed in the SAW group (mean difference (MD) = 0.38, 95% confidence interval (CI) 0.07-0.68, P = 0.01), particularly within the first year post-withdrawal (MD = 0.22, 95% CI 0.10-0.35, P = 0.0003) and in the prepubertal recipients (MD = 0.60, 95% CI 0.21-0.98, P = 0.002). There was no significant difference in the risk of acute rejection between the groups (relative risk = 1.04, 95% CI 0.80-1.36, P = 0.77). CONCLUSIONS: The SAW regimen is justified in select paediatric renal allograft recipients because it provides significant benefits in post-transplant growth within the first year post-withdrawal with minimal effects on the risk of acute rejection, graft function, and graft and patient survival within 3 years post-withdrawal. These select paediatric recipients should have the following characteristics: prepubertal; Caucasian; with primary disease not related to immunological factors; de novo kidney transplant recipient; with low panel reactive antibody.