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Author(s): B. Q. Lv [1, 2]; Z.-L. Feng [1, 2]; Q.-N. Xu [1, 2]; X. Gao [1, 2]; J.-Z. Ma [1, 2]; L.-Y. Kong [1, 2]; P. Richard [1, 2, [...]

Ferroptosis is a regulated cell death process initiated by iron-dependent phospholipid peroxidation and is mainly suppressed by GPX4-dependent and FSP1-dependent surveillance mechanisms. However, how the ferroptosis surveillance system is regulated during cancer development remains largely unknown. Here, we report that the YTHDC1-mediated m 6 A epigenetic regulation of FSP1 alleviates the FSP1-dependent ferroptosis suppression that partially contributes to the tumor suppressive role of YTHDC1 in lung cancer progression. YTHDC1 knockdown promoted the lung tumor progression and upregulated FSP1 protein level that resulted in ferroptosis resistance of lung cancer cells. Silencing FSP1 abrogated YTHDC1 knockdown-induced proliferation increase and ferroptosis resistance. Mechanistically, YTHDC1 binding to the m 6 A sites in the FSP1 3'-UTR recruited the alternative polyadenylation regulator CSTF3 to generate a less stable shorter 3'-UTR contained FSP1 mRNA, whereas YTHDC1 downregulation generated the longer 3'-UTR contained FSP1 mRNA that is stabilized by RNA binding protein HuR and thus led to the enhanced FSP1 protein level. Therefore, our findings identify YTHDC1 as a tumor progression suppressor in lung cancer and a ferroptosis regulator through modulating the FSP1 mRNA stability and thus suggest a ferroptosis-related therapeutic option for YTHDC1 high lung cancer., (© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Our study aimed to investigate the prognostic value of neutrophil count to albumin ratio (NAR) in predicting short-term mortality of patients with decompensated cirrhosis (DC). A total of 623 DC patients were recruited from a retrospective observational cohort study. They were admitted to our hospital from January 2014 to December 2015. NAR of each patient was calculated and analyzed for the association with 90-day liver transplantation-free (LT-free) outcome. The performance of NAR and the integrated model were tested by a receiver-operator curve (ROC) and C-index. The 90-day LT-free mortality of patients with DC was 10.6%. NAR was significantly higher in 90-day non-survivors than in survivors (The median: 1.73 vs 0.76, P < 0.001). A threshold of 1.40 of NAR differentiated patients with a high risk of death (27.45%) from those with a low risk (5.11%). By multivariate analysis, high NAR was independently associated with poor short-term prognosis (high group: 5.07 (2.78, 9.22)). NAR alone had an area under the ROC curve of 0.794 and C-index of 0.7789 (0.7287, 0.8291) in predicting 90-day mortality. The integrated MELD-NAR (iMELD) model had a higher area under the ROC (0.872) and C-index (0.8558 (0.8122, 0.8994)) than the original MELD in predicting 90-day mortality. NAR can be used as an independent predictor of poor outcomes for patients with DC during short-term follow-up., (© 2023. The Author(s).)

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults. This study aimed to determine the prognostic significance of endoplasmic reticulum (ER) stress-related genes in DLBCL. ER stress-related genes were obtained from the molecular signatures database. Gene expression data and clinical outcomes from the gene expression omnibus and TCGA datasets were collected, and differentially expressed genes (DEGs) were screened out. Gene ontology enrichment analysis, the kyoto encyclopaedia of genes and genomes pathway analysis, and geneset enrichment analysis were used to analyse the possible biological function of ER stress-related DEGs in DLBCL. Protein-protein interaction network construction using the STRING online and hub genes were identified by cytoHubba on Cytoscape software. The significant prognosis-related genes were screened, and the differential expression was validated. The immune microenvironment assessment of significant genes were evaluated. Next, the nomogram was built using univariate and multivariate Cox regression analysis. 26 ER stress-related DEGs were screened. Functional enrichment analysis showed them to be involved in the regulation of the endoplasmic reticulum mainly. NUPR1 and TRIB3 were identified as the most significant prognostic-related genes by comparison with the GSE10846, GSE11318, and TCGA datasets. NUPR1 was correlated with a good prognosis and immune infiltration in DLBCL; on the other hand, high expression of TRIB3 significantly correlated with a poor prognosis, which was an independent prognostic factor for DLBCL. In summary, we identified NUPR1 and TRIB3 as critical ER stress-related genes in DLBCL. NUPR1 might be involved in immune infiltration in DLBCL, and TRIB3 might serve as a potential therapeutic target and prognostic factor in DLBCL., (© 2023. Springer Nature Limited.)

Background: Kawasaki disease (KD) is an acute and systemic vasculitis whose etiology remains unclear. The most crucial complication is the formation of coronary artery aneurysm (CAA). Annexin A1 (ANXA1) is an endogenous anti-inflammatory agent and pro-resolving mediator involved in inflammation-related diseases. This study sought to investigate the serum ANXA1 levels in KD patients and further explore the relationship between ANXA1 and CAA, as well as additional clinical parameters., Methods: Serum samples were collected from 95 KD patients and 39 healthy controls (HCs). KD patients were further divided into two groups: KD with CAAs (KD-CAAs) and KD non-CAAs (KD-NCAAs). Serum levels of ANXA1 and interleukin-6 (IL-6) were determined using enzyme-linked immunosorbent assays., Results: Serum ANXA1 levels in the KD group were significantly lower than in the HC group. In particular, serum ANXA1 levels were substantially lower in the KD-CAA groups. Moreover, serum ANXA1 levels were positively correlated with N%, C-reactive protein (CRP), and IL-6 but negatively correlated with L% in the KD group. Positive correlations between serum ANXA1 levels and erythrocyte sedimentation rate (ESR), IL-6, and D-dimer (DD) were observed in the KD-CAA group., Conclusions: ANXA1 may be involved in the development of KD, and downregulation of ANXA1 may lead to the hypercoagulability seen in KD., Impact: For the first time, it was demonstrated that serum ANXA1 levels were significantly decreased in Kawasaki disease with coronary artery aneurysms. ANXA1 might be involved in the acute phase of Kawasaki disease. Low serum concentrations of ANXA1 might lead to the hypercoagulability stage in Kawasaki disease. ANXA1 might be a potential therapeutic target for patients with Kawasaki disease.

Retinoic acid and retinoid acid receptor (RA-RAR) signaling exhibits suppressive functions in the progression of hepatocellular carcinoma (HCC) through multiple mechanisms. However, whether RA-RAR signaling induces autophagy that contributes its anti-tumor activity in HCC remains elusive. In the current study, the effects of RA-RAR pathway on autophagy were investigated in two HCC cell lines: alpha-fetoprotein (AFP) positive PLC/PRF/5 and AFP negative HLE cells. Cell autophagy was analyzed with western blot for detection of LC3 conversion and p62/SQSTM1 degradation while autophagy flux was assayed using the mRFP-GFP-LC3 reporter. Cell apoptosis and viability were analyzed by caspase-3 activity, TdT-mediated dUTP nick end labeling (TUNEL) assay, and Cell Counting Kit (CCK)-8, respectively. Chromatin immunoprecipitation (ChIP) was employed to detect the binding of RAR onto the promoter of autophagy-relevant 7 (ATG7), and co-immunoprecipitation (CoIP) was used to analyze the interaction of AFP and RAR. The results showed that ATRA dosage and time-dependently induced high levels of cell autophagy in both the PLC/PRF/5 and HLE cells, which was accompanied with up-regulation of ATG7. ChIP assay showed that RAR was able to bind to its responsive elements on ATG7 promoter. Impairment of ATG7 induction or blockade of autophagy with chloroquine aggravated ATRA induced apoptosis of HCC cells. Furthermore, intracellular AFP was able to complex with RAR in PLC/PRF/5 cells. Knockdown of AFP in PLC/PRF/5 cells augmented the up-regulation of ATG7 by ATRA while overexpression of AFP in HLE cells attenuated ATRA induced ATG7 expression and autophagy. Thus, ATRA induced ATG7 and autophagy participated in its cytotoxicity on HCC cells and AFP interfere with the induction of ATG7 and autophagy through forming complex with RAR.

Hypertension and hyperhomocystinemia have a joint effect on the risk of stroke. We aimed to evaluate the relationship between plasma total homocysteine (tHcy) and blood pressure in two independent Chinese populations. Four thousand five hundred and fifty-five participants who underwent health examinations between March 2016 and September 2016 at Peking University First Hospital were enrolled as 'Population 1', and 2689 participants who were admitted to Peking University First Hospital between January 2014 and December 2015 were enrolled as 'Population 2'. None of the study participants were taking antihypertensive medication or vitamins, or had cardio-cerebrovascular disease or chronic kidney disease stages 4 or 5. In Population 1, a 5 μmol/L increase in tHcy was associated with a 0.47 mmHg (95% confidence interval [CI]: 0.23-0.70 mmHg, p < 0.01) increase in systolic blood pressure (SBP) and a 0.14 mmHg (95% CI: -0.02 to 0.30 mmHg, p = 0.08) increase in diastolic blood pressure (DBP). In Population 2, a 5 μmol/L increase in tHcy was associated with a 0.42 mmHg (95% CI: 0.13-0.72 mmHg, p < 0.01) increase in SBP and a 0.29 mmHg (95% CI: 0.09-0.49 mmHg, p < 0.01) increase in DBP. The prevalence of hypertension was significantly higher in Population 1 (by 47%; odds ratio [OR] 1.47, 95% CI: 1.09-1.98, p = 0.01) and in Population 2 (by 55%;OR 1.55, 95% CI: 1.15-2.08, p < 0.01) in participants with tHcy ≥ 15 μmol/l than in those with tHcy < 10 μmol/L. Stratified analysis showed that the association was stronger in women than in men.

We aimed to investigate the association of brachial-ankle pulse wave velocity (baPWV) with carotid plaque presence and carotid plaque number in a Chinese hypertensive population. A total of 13,554 hypertensive subjects from the China Stroke Primary Prevention Trial (CSPPT) were recruited. Arterial stiffness and carotid plaque were evaluated by baPWV and B-mode ultrasonography, respectively. Multivariate logistic regression analysis was used to determine the correlation of baPWV and carotid plaque presence. Multinomial logistic regression analysis was used to determine the correlation of baPWV and carotid plaque number. Further interactions between baPWV and carotid plaque presence were examined using subgroup analysis. Continuous baPWV was positively correlated with carotid plaque presence (OR = 1.05, 95% CI: 1.04-1.07) and carotid plaque number (one- to two-plaque group: OR = 1.04, 95% CI: 1.02-1.06; three-or-more-plaque group: OR = 1.09, 95% CI: 1.07-1.12). When baPWV was classified into quartiles, with the lowest quartile as reference, the ORs for having one, two, or three or more plaques increased in parallel with the quartiles of baPWV, indicating a dose-dependent effect. In a subgroup analysis, the association of baPWV and carotid plaque presence was more pronounced among younger participants (OR: 1.14 vs. 1.06 and 1.03 for the age groups <60 years, 60 ≤ 70 years, and ≥70 years, respectively, P for interaction <0.001). In a Chinese hypertensive population, baPWV was positively associated with carotid plaque presence and carotid plaque number. A more pronounced positive association between baPWV and carotid plaque presence was observed in younger participants.

Parkinson's disease (PD) is a common dyskinesia disease, the mitochondrial unfolded protein response (mtUPR) may be directly or indirectly involved in the occurrence and development of PD, although the exact mechanism is unclear. We established a dopaminergic neuronal-like cell model of PD, by overexpression of PGC-1α to detect evaluate the expression of proteases and molecular chaperones of involved in the mtUPR, as well as the expression of PGC-1α and LRPPRC, illustrated the distribution of LRPPRC. Remarkably, the mtUPR activation reached maximal at 24 h after MPP + treatment in SH-SY5Y cells, which the protein and transcription levels of the proteases and molecular chaperones reached maximal. The proteases and molecular chaperones were significantly increased when overexpressed PGC-1α, which indicated that PGC-1α overexpression activated the mtUPR, and PGC-1α had a protective effect on SH-SY5Y cells. The expression levels of PGC-1α and LRPPRC were significantly improved in the PGC-1α overexpression groups. LRPPRC was markedly reduced in the nucleus, suggesting that PGC-1α overexpression may play a protective role to the mitochondria through LRPPRC. Our finding indicates that overexpression of PGC-1α may activate mtUPR, reducing the oxidative stress injury induced by MPP + through LRPPRC signaling, thus maintain mitochondrial homeostasis.

Natural emissions of air pollutants from the surface play major roles in air quality and climate change. In particular, nitrogen oxides (NO x ) emitted from soils contribute ~15% of global NO x emissions, sea salt aerosols are a major player in the climate and chemistry of the marine atmosphere, and biogenic emissions are the dominant source of non-methane volatile organic compounds at the global scale. These natural emissions are often estimated using nonlinear parameterizations, which are sensitive to the horizontal resolutions of inputted meteorological and ancillary data. Here we use the HEMCO model to compute these emissions worldwide at horizontal resolutions of 0.5° lat. × 0.625° lon. for 1980-2017 and 0.25° lat. × 0.3125° lon. for 2014-2017. We further offer the respective emissions at lower resolutions, which can be used to evaluate the impacts of resolution on estimated global and regional emissions. Our long-term high-resolution emission datasets offer useful information to study natural pollution sources and their impacts on air quality, climate, and the carbon cycle.

Calcium (Ca 2+ ) signals are decoded by the Ca 2+ -sensor protein calmodulin (CaM) and are transduced to Ca 2+ /CaM-binding transcription factors to directly regulate gene expression necessary for acclimation responses in plants. The molecular mechanisms of Ca 2+ /CaM signal transduction processes and their functional significance remains enigmatic. Here we report a novel Ca 2+ /CaM signal transduction mechanism that allosterically regulates DNA-binding activity of GT2-LIKE 1 (GTL1), a transrepressor of STOMATAL DENSITY AND DISTRIBUTION 1 (SDD1), to repress stomatal development in response to water stress. We demonstrated that Ca 2+ /CaM interaction with the 2 nd helix of the GTL1 N-terminal trihelix DNA-binding domain (GTL1N) destabilizes a hydrophobic core of GTL1N and allosterically inhibits 3 rd helix docking to the SDD1 promoter, leading to osmotic stress-induced Ca 2+ /CaM-dependent activation (de-repression) of SDD1 expression. This resulted in GTL1-dependent repression of stomatal development in response to water-deficit stress. Together, our results demonstrate that a Ca 2+ /CaM-regulated transcriptional switch on a trihelix transrepressor directly transduces osmotic stress to repress stomatal development to improve plant water-use efficiency as an acclimation response.

Chirality-the geometric property of objects that do not coincide with their mirror image-is found in nature, for example, in molecules, crystals, galaxies and life forms. In quantum field theory, the chirality of a massless particle is defined by whether the directions of its spin and motion are parallel or antiparallel. Although massless chiral fermions-Weyl fermions-were predicted 90 years ago, their existence as fundamental particles has not been experimentally confirmed. However, their analogues have been observed as quasiparticles in condensed matter systems. In addition to Weyl fermions 1-4 , theorists have proposed a number of unconventional (that is, beyond the standard model) chiral fermions in condensed matter systems 5-8 , but direct experimental evidence of their existence is still lacking. Here, by using angle-resolved photoemission spectroscopy, we reveal two types of unconventional chiral fermion-spin-1 and charge-2 fermions-at the band-crossing points near the Fermi level in CoSi. The projections of these chiral fermions on the (001) surface are connected by giant Fermi arcs traversing the entire surface Brillouin zone. These chiral fermions are enforced at the centre or corner of the bulk Brillouin zone by the crystal symmetries, making CoSi a system with only one pair of chiral nodes with large separation in momentum space and extremely long surface Fermi arcs, in sharp contrast to Weyl semimetals, which have multiple pairs of Weyl nodes with small separation. Our results confirm the existence of unconventional chiral fermions and provide a platform for exploring the physical properties associated with chiral fermions.

DNA and histone modifications have notable effects on gene expression 1 . Being the most prevalent internal modification in mRNA, the N 6 -methyladenosine (m 6 A) mRNA modification is as an important post-transcriptional mechanism of gene regulation 2-4 and has crucial roles in various normal and pathological processes 5-12 . However, it is unclear how m 6 A is specifically and dynamically deposited in the transcriptome. Here we report that histone H3 trimethylation at Lys36 (H3K36me3), a marker for transcription elongation, guides m 6 A deposition globally. We show that m 6 A modifications are enriched in the vicinity of H3K36me3 peaks, and are reduced globally when cellular H3K36me3 is depleted. Mechanistically, H3K36me3 is recognized and bound directly by METTL14, a crucial component of the m 6 A methyltransferase complex (MTC), which in turn facilitates the binding of the m 6 A MTC to adjacent RNA polymerase II, thereby delivering the m 6 A MTC to actively transcribed nascent RNAs to deposit m 6 A co-transcriptionally. In mouse embryonic stem cells, phenocopying METTL14 knockdown, H3K36me3 depletion also markedly reduces m 6 A abundance transcriptome-wide and in pluripotency transcripts, resulting in increased cell stemness. Collectively, our studies reveal the important roles of H3K36me3 and METTL14 in determining specific and dynamic deposition of m 6 A in mRNA, and uncover another layer of gene expression regulation that involves crosstalk between histone modification and RNA methylation.

Topological electronic materials such as bismuth selenide, tantalum arsenide and sodium bismuthide show unconventional linear response in the bulk, as well as anomalous gapless states at their boundaries. They are of both fundamental and applied interest, with the potential for use in high-performance electronics and quantum computing. But their detection has so far been hindered by the difficulty of calculating topological invariant properties (or topological nodes), which requires both experience with materials and expertise with advanced theoretical tools. Here we introduce an effective, efficient and fully automated algorithm that diagnoses the nontrivial band topology in a large fraction of nonmagnetic materials. Our algorithm is based on recently developed exhaustive mappings between the symmetry representations of occupied bands and topological invariants. We sweep through a total of 39,519 materials available in a crystal database, and find that as many as 8,056 of them are topologically nontrivial. All results are available and searchable in a database with an interactive user interface.

As a global problem in coastal environments, harmful algal blooms (HABs) have seriously affected the health of coastal ecosystems and regional economies. Here we report an aerosol-trigger mechanism for the occurrence of HABs based on long-term field data and laboratory experiments. The occurrence times of HABs and aerosol events had a significant correlation from 2005 to 2013 in the East China Sea, indicating that aerosol transport was probably an alternative trigger of HABs. HABs mostly occur in the transition time between winter and summer, during which northwest monsoon transport substantial aerosol (rich in phosphate, iron and other trace metals) to coastal waters, as revealed by chemical measurements, transmission electron microscope and electron microprober results. Such nutrients can stimulate algal growth in our incubation experiments, suggesting that such aerosol transport can be important nutrient sources for the East China Sea where phytoplankton growth is relatively phosphate limited. Air-borne nutrients are available for algal growth by rapid downward air flow, which additional results a clear weather condition, and thus adequate light intensity for algal growth. At last, the transition from northwest monsoon to warm southwest monsoon establishes favorable seawater temperature for algal blooms. Such weather-related aerosol-trigger mechanism suggests possibly forecast of HABs.

Liver tumor-initiating cells (TICs), the drivers for liver tumorigenesis, accounts for liver tumor initiation, metastasis, drug resistance and relapse. Wnt/β-catenin signaling pathway emerges as a critical modulator in liver TIC self-renewal. However, the molecular mechanism of Wnt/β-catenin initiation in liver tumorigenesis and liver TICs is still elusive. Here, we examined the expression pattern of 10 Wnt receptors (FZD1-FZD10), and found only FZD6 is overexpressed along with liver tumorigenesis. What's more, a divergent lncRNA of FZD6, termed lncFZD6, is also highly expressed in liver cancer and liver TICs. LncFZD6 drives liver TIC self-renewal and tumor initiation capacity through FZD6-dependent manner. LncFZD6 interacts with BRG1-embedded SWI/SNF complex and recruits it to FZD6 promoter, and thus drives the transcriptional initiation of FZD6 by chromatin remodeling. WNT5A, a ligand of FZD6, is highly expressed in liver non-TICs and drives the self-renewal of liver TICs through lncFZD6-BRG1-FZD6-dependent manner. Through FZD6 transcriptional regulation in cis, lncFZD6 activates Wnt/β-catenin signaling in liver TICs. LncFZD6-BRG1-Wnt5A/β-catenin pathway can serve as a target for liver TIC elimination. Altogether, lncFZD6 promotes Wnt/β-catenin activation and liver TIC self-renewal through BRG1-dependent FZD6 expression.

N 6 -methyladenosine (m 6 A), the most abundant internal modification in eukaryotic messenger RNAs (mRNAs), has been shown to play critical roles in various normal bioprocesses such as tissue development, stem cell self-renewal and differentiation, heat shock or DNA damage response, and maternal-to-zygotic transition. The m 6 A modification is deposited by the m 6 A methyltransferase complex (MTC; i.e., writer) composed of METTL3, METTL14 and WTAP, and probably also VIRMA and RBM15, and can be removed by m 6 A demethylases (i.e., erasers) such as FTO and ALKBH5. The fates of m 6 A-modified mRNAs rely on the functions of distinct proteins that recognize them (i.e., readers), which may affect the stability, splicing, and/or translation of target mRNAs. Given the functional importance of the m 6 A modification machinery in normal bioprocesses, it is not surprising that evidence is emerging that dysregulation of m 6 A modification and the associated proteins also contributes to the initiation, progression, and drug response of cancers. In this review, we focus on recent advances in the study of biological functions and the underlying molecular mechanisms of dysregulated m 6 A modification and the associated machinery in the pathogenesis and drug response of various types of cancers. In addition, we also discuss possible therapeutic interventions against the dysregulated m 6 A machinery to treat cancers.

Kidney biopsy is considered the golden criterion for diagnosing the etiology of kidney disease but accompanied by non-negligible complications. We explored the possibility of using urinary microRNA (miRNA) as a non-invasive biomarker for hypertensive kidney injury. We assessed differential miRNA expressions in the kidneys and urine of hypertensive mice with kidney injury induced by deoxycorticosterone acetate (DOCA)-salt compared to the controls. DOCA-salt treatment significantly increased renal tubular lesions from day 2 and mRNA expression of fibrosis-related genes from day 4 compared to the controls, respectively. Urinary albumin and N-acetyl-beta-D-glucosaminidase was significantly increased on day 8 compared to the controls. Array results showed that 20 out of 585 miRNAs were highly expressed in the kidneys and significantly increased on day 8 compared to the controls, including miR-21, miR-146b, miR-155 and miR-132, which were confirmed by real-time polymerase chain reaction and were significantly higher from day 4. The miR-21/creatinine in the urine from day 4 was significantly higher than that of the controls and was detected earlier than urinary albumin. In conclusion, we have identified urinary miR-21 that correlates with histopathological lesions and functional markers of kidney damage to facilitate a potential noninvasive detection for hypertensive kidney injury.

Long noncoding RNAs (lncRNAs) play roles in the development and progression of many cancers; however, the contributions of lncRNAs to human gallbladder cancer (GBC) remain largely unknown. In this study, we identify a group of differentially expressed lncRNAs in human GBC tissues, including prognosis-associated gallbladder cancer lncRNA (lncRNA-PAGBC), which we find to be an independent prognostic marker in GBC Functional analysis indicates that lncRNA-PAGBC promotes tumour growth and metastasis of GBC cells. More importantly, as a competitive endogenous RNA (ceRNA), lncRNA-PAGBC competitively binds to the tumour suppressive microRNAs miR-133b and miR-511. This competitive role of lncRNA-PAGBC is required for its ability to promote tumour growth and metastasis and to activate the AKT/mTOR pathway. Moreover, lncRNA-PAGBC interacts with polyadenylate binding protein cytoplasmic 1 (PABPC1) and is stabilized by this interaction. This work provides novel insight on the molecular pathogenesis of GBC., (© 2017 The Authors.)

The present study aimed to systematically evaluate the effectiveness and safety of the intrafascial and interfascial nerve sparing (ITR-NS and ITE-NS) radical prostatectomy. PubMed, Embase, and Cochrane Library databases were searched for eligible studies. Meta-analysis with random-effects model was performed. Six comparative trials were selected and embraced in this research, including one randomized controlled trial, three prospective comparative trials, and two retrospective comparative trials. With regard to perioperative parameters, no significant association of operative time, blood loss, transfusion rates, duration of catheterization, and hospital stay existed between ITR-NS and ITE-NS. With respect to the functional results, ITR-NS had advantages in terms of both continence and potency recovery compared with ITE-NS. In reference to the oncologic results, the ITR-NS showed lower overall positive surgical margin (PSM) compared with ITE-NS but pT2 PSM and biochemical recurrence free rates were similar to the two surgical types. This study demonstrates that ITR-NS has better continence at 6 mo and 36 mo and better potency recovery at 6 mo and 12 mo postoperatively, regardless of the surgical technique. The cancer control of ITR-NS was also better than that of ITE-NS. This may be explained by the fact that patients in ITE-NS group present higher risk cancer than patients in ITR-NS group.

Topological materials with exotic quantum properties are promising candidates for quantum spin electronics. Different classes of topological materials, including Weyl semimetal, topological superconductor, topological insulator and Axion insulator, etc., can be connected to each other via quantum phase transition. For example, it is believed that a trivial band insulator can be twisted into topological phase by increasing spin-orbital coupling or changing the parameters of crystal lattice. With the results of LDA calculation and measurement by angle-resolved photoemission spectroscopy (ARPES), we demonstrate in this work that the electronic structure of SrSn 2 As 2 single crystal has the texture of band inversion near the critical point. The results indicate the possibility of realizing topological quantum phase transition in SrSn 2 As 2 single crystal and obtaining different exotic quantum states.

MLL-rearranged acute myeloid leukemia (AML) remains a fatal disease with a high rate of relapse and therapeutic failure due to chemotherapy resistance. In analysis of our Affymetrix microarray profiling and chromatin immunoprecipitation (ChIP) assays, we found that ALOX5 is especially down-regulated in MLL-rearranged AML, via transcription repression mediated by Polycomb repressive complex 2 (PRC2). Colony forming/replating and bone marrow transplantation (BMT) assays showed that Alox5 exhibited a moderate anti-tumor effect both in vitro and in vivo. Strikingly, leukemic cells with Alox5 overexpression showed a significantly higher sensitivity to the standard chemotherapeutic agents, i.e., doxorubicin (DOX) and cytarabine (Ara-C). The drug-sensitizing role of Alox5 was further confirmed in human and murine MLL-rearranged AML cell models in vitro, as well as in the in vivo MLL-rearranged AML BMT model coupled with treatment of "5 + 3" (i.e. DOX plus Ara-C) regimen. Stat and K-Ras signaling pathways were negatively correlated with Alox5 overexpression in MLL-AF9-leukemic blast cells; inhibition of the above signaling pathways mimicked the drug-sensitizing effect of ALOX5 in AML cells. Collectively, our work shows that ALOX5 plays a moderate anti-tumor role and functions as a drug sensitizer, with a therapeutic potential, in MLL-rearranged AML.

Inosine monophosphate dehydrogenase type II (IMPDH2) has been shown to play critical roles in the development and progression of several human cancers. However, little is known about IMPDH2 expression and its clinical significance in nasopharyngeal carcinoma (NPC). Western blotting, qRT-PCR and immunohistochemistry were employed to evaluate IMPDH2 expression in NPC cell lines and tissues. In our study, elevated expression of IMPDH2 was observed at both the protein and mRNA levels in NPC cell lines than in NPEC2 Bmi-1. IMPDH2 protein expression was markedly higher in NPC tissues than in adjacent non-tumorous tissues. Moreover, IMPDH2 expression in NPC correlated with several clinicopathological parameters, including T classification (P = 0.023), TNM stage (P = 0.020), distant metastasis (P = 0.001) and death (P = 0.002). Further Cox regression analysis suggested that IMPDH2 expression was an independent prognostic factor for overall survival (P = 0.001) and disease-free survival (P < 0.001). In addition, stratified survival analysis showed that high expression of IMPDH2 could be a prognostic factor for NPC patients with TNM stage I/II (OS: P = 0.012; DMFS: P = 0.007), TNM stage III/IV (OS: P = 0.028; DMFS: P = 0.020). Our study demonstrates IMPDH2 may be served as an independent prognostic biomarker for NPC patients, in which high IMPDH expression suggests poor prognosis of NPC patients.

Recently, theoretical studies show that layered HfTe 5 is at the boundary of weak &strong topological insulator (TI) and might crossover to a Dirac semimetal state by changing lattice parameters. The topological properties of 3D stacked HfTe 5 are expected hence to be sensitive to pressures tuning. Here, we report pressure induced phase evolution in both electronic &crystal structures for HfTe 5 with a culmination of pressure induced superconductivity. Our experiments indicated that the temperature for anomaly resistance peak (Tp) due to Lifshitz transition decreases first before climbs up to a maximum with pressure while the Tp minimum corresponds to the transition from a weak TI to strong TI. The HfTe 5 crystal becomes superconductive above ~5.5 GPa where the Tp reaches maximum. The highest superconducting transition temperature (Tc) around 5 K was achieved at 20 GPa. Crystal structure studies indicate that HfTe 5 transforms from a Cmcm phase across a monoclinic C2/m phase then to a P-1 phase with increasing pressure. Based on transport, structure studies a comprehensive phase diagram of HfTe 5 is constructed as function of pressure. The work provides valuable experimental insights into the evolution on how to proceed from a weak TI precursor across a strong TI to superconductors.

Gallbladder cancer (GBC) is a leading cause of cancer-related deaths worldwide, and its prognosis remains poor, with a 5-year survival rate of ~5%. Given the crucial role of microRNAs (miRNAs) in cancer metastasis, we aimed to analyze the expression and function of the metastasis-associated miRNA miR-29c-5p in GBC.We validated that expression of miR-29c-5p was significantly downregulated in GBC and was closely associated with lymph node metastasis, overall survival and disease-free survival in 40 GBC patients who were followed clinically. Ectopic overexpression of miR-29c-5p dramatically repressed proliferation, metastasis, and colony formation and induced apoptosis in vitro, and it suppressed tumorigenicity in vivo through the MAPK pathway. Cytoplasmic polyadenylation element binding protein 4 (CPEB4) was identified as a critical effector target of miR-29c-5p. Enforced expression of miR-29c-5p significantly inhibited the expression of CPEB4, and restoration of CPEB4 expression reversed the inhibitory effects of miR-29c-5p on GBC cell proliferation and metastasis. Transforming growth factor-β (TGF-β) upregulated CPEB4 by downregulating miR-29c-5p, leading to MAPK pathway activation. In conclusion, the TGF-β/miR-29c-5p/CPEB4 axis has a pivotal role in the pathogenesis and poor prognosis of GBC, suggesting that miR-29c-5p is a tumor-suppressive miRNA that may serve as potential prognostic biomarker or therapeutic target for GBC.

Inducing degradation of oncoproteins by small molecule compounds has the potential to avoid drug resistance and therefore deserves to be exploited for new therapies. Oridonin is a natural compound with promising antitumor efficacy that can trigger the degradation of oncoproteins; however, the direct cellular targets and underlying mechanisms remain unclear. Here we report that oridonin depletes BCR-ABL through chaperon-mediated proteasomal degradation in leukemia. Mechanistically, oridonin poses oxidative stress in cancer cells and directly binds to cysteines of HSF1, leading to the activation of this master regulator of the chaperone system. The resulting induction of HSP70 and ubiquitin proteins and the enhanced binding to CHIP E3 ligase hence target BCR-ABL for ubiquitin-proteasome degradation. Both wild-type and mutant forms of BCR-ABL can be efficiently degraded by oridonin, supporting its efficacy observed in cultured cells as well as mouse tumor xenograft assays with either imatinib-sensitive or -resistant cells. Collectively, our results identify a novel mechanism by which oridonin induces rapid degradation of BCR-ABL as well as a novel pharmaceutical activator of HSF1 that represents a promising treatment for leukemia., Competing Interests: The authors declare no competing financial interests.

Proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H 2 RAs) are used for gastro-esophageal reflux disease (GERD); however, the clinical evidence for treatment is poor. We evaluated the effectiveness and tolerability of different doses of PPIs, H 2 RAs and placebo in adults with GERD. Six online databases were searched through September 1, 2016. All related articles were included and combined with a Bayesian network meta-analysis from randomized controlled trials (RCTs). The GRADE systems were employed to assess the main outcome. Ninety-eight RCTs were identified, which included 45,964 participants. Our analysis indicated that the full/standard dose of esomeprazole at 40 mg per day was the most efficient in healing among nine different dosages of PPIs and H 2 RAs. The main efficacy outcome did not change after adjustments for the area, age, level of disease from endoscopy, year of publication, pharmaceutical industry sponsorship, Intention-to-treat (ITT)/per-protocol (PP), withdrawal rate, pre-set select design bias, single blinded and unblinded studies, study origination in China, study arms that included zero events, inconsistency node or discontinued drug were accounted for in the meta-regressions and sensitivity analyses. This research suggests that the full/standard doses (40 mg per day) of esomeprazole should be recommended as first-line treatments for GERD in adults for short-term therapy.

Although the association between CAG and GGN repeats in the androgen receptor gene and prostate cancer risk has been widely studied, it remains controversial from previous meta-analyses and narrative reviews. Therefore, we performed this meta-analysis to provide more precise estimates with sufficient power. A total of 51 publications with 61 studies for CAG repeats and 14 publications with 16 studies for GGN repeats were identified in the meta-analysis. The results showed that short CAG repeats (<22 repeats) carriers presented an elevated risk of prostate cancer than long CAG repeats (≥22) carriers (OR = 1.31, 95% CI 1.16 to 1.47). Prostate cancer cases presented an average fewer CAG repeats (MD = -0.85, 95% CI -1.28 to -0.42) than controls. Short GGN repeats (≤16) carriers presented an increased risk of prostate cancer than long GGN repeats (>16) carriers (OR = 1.38, 95% CI 1.05 to 1.82). In subgroup analyses, the abovementioned significant association was predominantly observed in Caucasian populations. The meta-analysis showed that short CAG and GGN repeats in androgen receptor gene were associated with increased risk of prostate cancer, especially in Caucasians.

Guanine nucleotide binding protein alpha 13 (GNA13) has been found to play critical roles in the development of several human cancers. However, little is known about GNA13 expression and its clinical significance in hepatocellular carcinoma (HCC). In our study, GNA13 was reported to be significantly up-regulated in HCC tissues, and this was correlated with several clinicopathological parameters, including tumor multiplicity (P = 0.004), TNM stage (P = 0.002), and BCLC stage (P = 0.010). Further Cox regression analysis suggested that GNA13 expression was an independent prognostic factor for overall survival (P = 0.014) and disease-free survival (P = 0.005). Moreover, we found that overexpression of GNA13 couldn't promote cell proliferation in vitro, but could significantly increase the invasion ability of HCC cells. Together, our study demonstrates GNA13 may be served as a prognostic biomarker for HCC patients after curative hepatectomy, in which high expression of GNA13 suggests poor prognosis of HCC patients.

We aimed to systematically investigate the potential association of matrix metalloproteinase (MMP)-9, -3, -2, and -8 gene polymorphisms with susceptibility to periodontitis using meta-analysis. A literature search in PubMed, Embase, and Web of Science was conducted to obtain relevant publications. Finally a total of 16 articles with 24 case-control studies (nine on MMP-9-1562 C/T, seven on MMP-3-1171 A5/A6, four on MMP-2-753C/T, and four on MMP-8-799 C/T) were considered in this meta-analysis. The results based on 2,724 periodontitis patients and 3,438 controls showed that MMP-9-1562C/T, MMP-3-1171 A5/A6, and MMP-8-799C/T polymorphisms were associated with periodontitis susceptibility. No significant association was found between MMP-2-753 C/T and periodontitis susceptibility. Subgroup analyses suggested that the MMP-9-1562 C/T polymorphism reduced chronic periodontitis susceptibility and MMP-3-1171 A5/A6 polymorphism increased chronic periodontitis susceptibility. In summary, current evidence demonstrated that MMP-9-753 C/T polymorphism reduced the risk of periodontitis, MMP-3-1171 5A/6A and MMP-8-799 C/T polymorphisms increased the risk of periodontitis, and MMP-2-753 C/T was not associated with risk of periodontitis.

The low energy electronic structure of Sr2IrO4 has been well studied and understood in terms of an effective Jeff = 1/2 Mott insulator model. However, little work has been done in studying its high energy electronic behaviors. Here we report a new observation of the anomalous high energy electronic structure in Sr2IrO4. By taking high-resolution angle-resolved photoemission measurements on Sr2IrO4 over a wide energy range, we have revealed for the first time that the high energy electronic structures show unusual nearly-vertical bands that extend over a large energy range. Such anomalous high energy behaviors resemble the high energy waterfall features observed in the cuprate superconductors. While strong electron correlation plays an important role in producing high energy waterfall features in the cuprate superconductors, the revelation of the high energy anomalies in Sr2IrO4, which exhibits strong spin-orbit coupling and a moderate electron correlation, points to an unknown and novel route in generating exotic electronic excitations.

The aim of this study was to compare plasmakinetic resection of the prostate (PKRP) with transurethral resection of the prostate (TURP) for benign prostatic hyperplasia (BPH) in terms of efficacy and safety. Published RCTs were searched from PubMed, Embase, Science Citation Index, and Cochrane Library up to April 10, 2014. After methodological quality assessment and data extraction, meta-analysis was performed using the STATA 12.0 software. 18 reports of 16 RCTs were included in this analysis. Meta-analyses showed that PKRP significantly improved Qmax at 12 months, but no significant difference was found for other efficacy outcomes. In terms of safety, treatment of PKRP was associated with reduced drop in serum sodium, lower TUR syndrome, reduced need of blood transfusion, clot retention, and shorter catheterization time and hospital stay; in contrast, there were no significant differences in the analysis of operative time, postoperative fever, and long-term postoperative complications. In summary, current evidence suggests that, although PKRP and TURP are both effective for BPH, PKRP is associated with additional potential benefits in efficacy and more favorable safety profile. It may be possible that PKRP may replace the TURP in the future and become a new standard surgical procedure.

Topological superconductivity is one of most fascinating properties of topological quantum matters that was theoretically proposed and can support Majorana Fermions at the edge state. Superconductivity was previously realized in a Cu-intercalated Bi2Se3 topological compound or a Bi2Te3 topological compound at high pressure. Here we report the discovery of superconductivity in the topological compound Sb2Te3 when pressure was applied. The crystal structure analysis results reveal that superconductivity at a low-pressure range occurs at the ambient phase. The Hall coefficient measurements indicate the change of p-type carriers at a low-pressure range within the ambient phase, into n-type at higher pressures, showing intimate relation to superconducting transition temperature. The first principle calculations based on experimental measurements of the crystal lattice show that Sb2Te3 retains its Dirac surface states within the low-pressure ambient phase where superconductivity was observed, which indicates a strong relationship between superconductivity and topology nature.

The P2X(7) receptor is a ligand-gated ion channel activated by extracellular ATP, and a common genetic variation in the P2X(7) gene significantly affects blood pressure. P2X(7) receptor expression is associated with renal injury and some inflammatory diseases. Brilliant blue G (BBG) is a selective rat P2X(7) receptor antagonist. In this study, to test whether BBG has protective effects on salt-sensitive hypertension and renal injury, Dahl salt-sensitive (DS) rats fed an 8% NaCl diet were i.p. injected with BBG (50 mg kg(-1) per day) for 4 weeks. We also tested another P2X(7) receptor antagonist, namely A-438079 (100 mg kg(-1) per day), for 7 days. We found that P2X(7) antagonism markedly attenuated salt-sensitive hypertension, urinary protein or albumin excretion, renal interstitial fibrosis and macrophage and T-cell infiltration in the DS rats, and significantly improved creatinine clearance. In an in vitro experiment using macrophages, we showed that lipopolysaccharide (LPS)-primed macrophages from the DS rats released more interleukin-1 beta in response to BzATP, a P2X(7) receptor agonist, than the macrophages from Lewis rats, possibly due to higher P2X(7) expression in the DS rats. In conclusion, in vivo blockade of P2X(7) receptors attenuated salt-sensitive hypertension and renal injury in the DS rats. Thus, P2X(7) appears to be responsible for a vicious cycle of salt-sensitive hypertension and renal injury in the DS rats, through higher expression in the immune cells. Furthermore, P2X(7) antagonists can prevent the development of salt-sensitive hypertension and renal injury, thus confirming that the P2X(7) receptor is an important therapeutic target.

Expression of survivin has been reported to be correlated with shorter survival in patients with non-small cell lung cancer (NSCLC), and overexpression of survivin may lead to radioresistance in various human cancers. In this study, we inhibited survivin expression by using an adenoviral vector (AdsiSurvivin)-mediated RNA interference to elucidate the combined effect of survivin-targeting gene therapy and radiotherapy on the NSCLC cells. Our data showed that AdsiSurvivin exerted survivin gene silencing, induced apoptosis, and significantly attenuated the growth potential in NSCLC cells within 72 h after infection. The combined treatment modalities with AdsiSurvivin infection and radiation were significantly more potent on cell-growth inhibition than monotherapy. In H1650, H460, A549, and H1975 human NSCLC cells, the survival ratios of AdsiSurvivin-treated groups at multiplicity of infection of 25 and 50 were significantly lower than those of control groups at varying radiation dose (0-8 Gy; three-way analysis of variance, P<0.05). The cytotoxicity of combined AdsiSurvivin infection and irradiation increased in a dose-dependent manner in both the virus and the irradiation treatment. Knockdown of the survivin gene expression seems to be a promising treatment strategy for NSCLC. Our data warrant the need for further effort to develop survivin-targeted radiosensitizer for lung cancer treatment.

Aim: To study the pharmacokinetics and toxicity of intravitreal erythropoietin (EPO) for potential clinical use., Methods: For toxicity study, 4 groups (60 rabbits) with intravitreal injection (IVit) of EPO were studied (10 U, 100 U, or 1,000 U) per eye for single injection and 0.6 U/eye (the designed therapeutic level in rabbits) for monthly injections (6X). Eye examination, flash electroretinogram (ERG), and fluorescein angiography (FA) were carried out before and after injection. The rabbits were killed for histological study at different intervals. For the pharmacokinetic study, after IVit of 5 U EPO into left eyes, 44 rabbits were killed at different intervals, and the EPO levels in vitreous, aqueous, retina and serum were analyzed by enzyme-linked immunosorbent assay., Results: At all of the time points examined, the eyes were within normal limits. No significant ERG or FA change was observed. The histology of retina remained unchanged. The pharmacokinetic profile of EPO in ocular compartments was summarized as follows. The half-life times of EPO in vitreous, aqueous and serum were 2.84, 3.24 and 2.12 d, respectively; and Cmax were 4615.75, 294.31 and 1.60 U/L, respectively. EPO concentrations in the retina of the injected eye peaked at 1.36 U/g protein at 6 h following injection, with the half-life observed to be 3.42 d., Conclusions: IVit of EPO in a wide range is well tolerated and safe for rabbit eyes. At doses up to 10-fold higher than therapeutic levels, EPO has a pharmacokinetic profile with faster clearance, which is favorable for episodic IVit.