Genetic variations in NER pathway gene polymorphisms and Wilms tumor risk: A six-center case-control study in East China.

The nucleotide excision repair (NER) system is one of the main ways to protect organisms from DNA damage caused by endogenous and exogenous carcinogens. NER deficiency increases genome mutations, chromosomal aberrations, and cancer viability. However, the genetic association between Wilms tumor and NER pathway gene polymorphisms needs to be further validated. We assessed the associations between 19 NER gene polymorphisms and Wilms tumor susceptibility in 416 cases and 936 controls from East China via the TaqMan method. We found that xeroderma pigmentosum group D (XPD) rs238406 and rs13181 significantly decreased the risk of Wilms tumor [adjusted odds ratio (OR) = 0.59, 95% confidence interval (CI) = 0.46-0.75, p <.0001; adjusted OR = 0.63, 95% CI = 0.44-0.89, p = .009, respectively]. Furthermore, the rs751402 and rs2296147 polymorphisms in the xeroderma pigmentosum group G (XPG) gene were significantly correlated with an increased risk for Wilms tumor (adjusted OR = 1.47, 95% CI = 1.03-2.09, p = .034; adjusted OR = 2.14, 95% CI = 1.29-3.56, p = .003, respectively). Expression quantitative trait loci (eQTL) analysis revealed that these four polymorphisms may affect the expression of genes that are adjacent to XPD and XPG. Our study provides evidence that XPD and XPG gene polymorphisms are associated with Wilms tumor risk. Nonetheless, these findings should be confirmed in a larger sample size.

LMO family gene polymorphisms and Wilms tumor susceptibility in Chinese children: a five-center case-control study.

BACKGROUND: Wilms tumor is the most prevalent embryonal kidney malignancy in children worldwide. Previous genome-wide association study (GWAS) identified that LIM domain only 1 (LMO1) gene polymorphisms affected the susceptibility to develop certain tumor types. Apart from LMO1, the LMO gene family members also include LMO2-4, each of which has oncogenic potential. METHODS: We conducted this five-center case‒control study to assess the correlations between single nucleotide polymorphisms in LMO family genes and Wilms tumor susceptibility. Odds ratios and 95% confidence intervals were calculated to evaluate the strength of the association. RESULTS: We found LMO1 rs2168101 G > T and rs11603024 C > T as well as LMO2 rs7933499 G > A were significantly associated with Wilms tumor risk. Stratified analysis demonstrated a protective role of rs2168101 GT/TT genotypes against Wilms tumor in the subgroups of age ≤ 18 months, males and clinical stages I/II compared to the rs2168101 GG genotype. Nevertheless, carriers with the rs11603024 TT genotype were more likely to have an increased risk of Wilms tumor than those with rs11603024 CC/CT genotypes in age > 18 months. And the rs11603024 was identified as a protective polymorphism for reducing the risk of Wilms tumor in the sex- and gender- subgroup. Likewise, carriers with the rs7933499 GA/AA genotypes were at significantly elevated risk of Wilms tumor in age ≤ 18 months and clinical stages I/II. CONCLUSION: Overall, our study identified the importance of LMO family gene polymorphisms on Wilms tumor susceptibility in Chinese children. Further investigations are needed to validate our conclusions.

Clozapine impaired glucose-stimulated insulin secretion partly by increasing plasma 5-HT levels due to the inhibition of OCT1-mediated hepatic 5-HT uptake in mice.

Patients taking atypical antipsychotics (AAPs), especially clozapine, are often associated with hyperglycaemia. Here, clozapine served as a representative agent for investigating how AAPs induce hyperglycaemia. In normal mice and mice fed a high fat diet (HFD), clozapine impaired glucose tolerance and glucose-stimulated insulin secretion (GSIS) following intraperitoneal glucose administration and increased plasma 5-HT levels. Intraperitoneal 5-HT administration also impaired glucose tolerance and GSIS in mice. In INS-1 cells, high 5-HT levels impaired GSIS, which was attenuated by the 5-HTR3 antagonist tropisetron or by silencing 5-HTR3a. The 5-HTR2a agonist TCB2 attenuated clozapine-induced GSIS impairment. Silencing 5-HTR2a or the 5-HTR2a antagonist ketanserin impaired GSIS. In mice, 5-HT administration impaired GSIS, which was attenuated by tropisetron but aggravated by clozapine. Clozapine increased plasma [2H]5-HT exposure following intravenous administration to mice. In HEK293-OCT1 cells, clozapine inhibited [2H]5-HT and MPP+ uptake. Clozapine or OCT1 silencing impaired 5-HT metabolism in mouse primary hepatocytes, demonstrating that clozapine increased plasma 5-HT levels via the inhibition of OCT1-mediated hepatic 5-HT uptake. Liver-specific silencing of OCT1 increased plasma [2H]5-HT exposure and 5-HT levels and impaired GSIS and glucose tolerance in mice. In conclusion, clozapine impaired GSIS and glucose tolerance by increasing plasma 5-HT levels via the inhibition of OCT1-mediated hepatic 5-HT uptake. Increased 5-HT impaired GSIS by activating islet 5-HTR3a. The antagonistic effect of clozapine on islet 5-HTR2a also contributed to GSIS impairment. The finding that clozapine-induced GSIS impairment was attributed to increased 5-HT levels via the inhibition of OCT1-mediated hepatic 5-HT uptake may partly explain hyperglycaemia caused by other AAPs.

LiLnGeS4 (Ln=La-Nd): Designing High Performance Infrared Nonlinear Optical Sulfides through "Band Reformation of AGS".

AgGaS2 (AGS) is the most commonly used commercial infrared nonlinear optical (IR NLO) material. However, AGS has a narrow band gap (Eg=2.58 eV) and a low laser-induced damage threshold (LIDT), primarily attributed to its mobile liquid-like Ag+ constituent and the unstable Ag-S chemical bond. Herein, we propose a "band reformation of AGS" strategy, which leads to the successful syntheses of four lanthanide sulfides, LiLnGeS4 (Ln=La-Nd), crystalizing in an asymmetric Ama2 structure. LiLaGeS4 demonstrates that eliminating the presence of Ag-4d band increases the Eg to 3.32 eV and enhances the LIDT (14-29×AGS, measured by both powder and single crystal); while increasing the nonbonding density of states of the S-3p band enhances the 2nd-nonlinear optical coefficient (1.06×AGS). Besides, the bond length discrepancy between [LiS4], [GeS4] and [LaS8] units leads to a moderate birefringence (Δn=0.052). Such a unique structure further results in extremely small thermal expansion with αL=0.41-1.74×10-5 K-1, along different crystallographic axes. Our theoretical studies indicate that the synergy of the structure building units contribute to the second harmonic generation performance. These results suggest that the "band reformation of AGS" strategy provides effective guidance to discover new NLO crystals with optimized performance.

Remarkable Second Harmonic Generation Response in (C5H6NO)+(CH3SO3)-: Unraveling the Role of Hydrogen Bond in Thermal Driven Nonlinear Optical Switch.

Heat-activated second harmonic generation (SHG) switching materials are gaining interest for their ability to switch between SHG on and off states, offering potential in optoelectronic applications. The novel nonlinear optical (NLO) switch, (C5H6NO)+(CH3SO3)- (4-hydroxypyridinium methylsulfonate, 4HPMS), is a near-room-temperature thermal driven material with a strong SHG response (3.3 × KDP), making it one of the most potent heat-stimulated NLO switches. It offers excellent contrast of 13 and a high laser-induced damage threshold (2.5 × KDP), with reversibility > 5 cycles. At 73 °C, 4HPMS transitions from the noncentrosymmetric Pna21 room temperature phase (RTP) to the centrosymmetric P21/c phase, caused by the rotation of the (C5H6NO)+ and (CH3SO3)- due to partially thermal breaking of intermolecular hydrogen bonds. The reverse phase change exhibits a large 50 °C thermal hysteresis. Density functional theory (DFT) calculations show that (C5H6NO)+ primarily dictates both the SHG coefficient (dij) and birefringence (▵n(Zeiss) = 0.216 vs ▵n(cal.) = 0.202 at 546 nm; Δn(Immersion) = 0.210 vs ▵n(cal.) = 0.198 at 589.3 nm), while the band gap (Eg) is influenced synergistically by (C5H6NO)+ and (CH3SO3)-. Additionally, 4HPMS-RTP also exhibits mechanochromism upon grinding as well as an aggregation-enhanced emission in a mixture of acetone and water.

Proteomic and metabolomic approaches elucidate the molecular mechanism of emodin against neuropathic pain through modulating the gamma-aminobutyric acid (GABA)-ergic pathway and PI3K/AKT/NF-κB pathway.

Neuropathic pain (NeP) is a major health concern. Due to the complex pathological mechanisms, management of NeP is challenging. Emodin, a natural anthraquinone derivative, exerts excellent analgesic effects. However, its mechanisms of action are still poorly understood. In this study, we investigated the mechanisms underlying pain-relief effects of emodin in the cerebral cortex using proteomic and metabolomic approaches. After 15 days of emodin administration, the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) values in the emodin groups were significantly higher than those in the chronic constriction injury (CCI) group (p < .05), suggesting emodin treatment could reverse CCI-induced hyperalgesia. Emodin treatment evoked the expression alteration of 402 proteins (153 up-regulated and 249 down-regulated) in the CCI models, which were primarily involved in PI3K/AKT signaling pathway, gamma-aminobutyric acid (GABA) receptor signaling, complement and coagulation cascades, cGMP/PKG signaling pathway, MAPK signaling pathway, and calcium signaling pathway. In parallel, emodin intervention regulated the abundance alteration of 27 brain metabolites (20 up-regulated and 7 down-regulated) in the CCI rats, which were primarily implicated in carbon metabolism, biosynthesis of amino acids, pentose phosphate pathway, and glucagon signaling pathway. After a comprehensive analysis and western blot validation, we demonstrated that emodin alleviated NeP mainly through regulating GABAergic pathway and PI3K/AKT/NF-κB pathway.

Enantioselective Deaminative Alkylation of Amino Acid Derivatives with Unactivated Olefins.

Herein, we report the first Ni-catalyzed enantioselective deaminative alkylation of amino acid and peptide derivatives with unactivated olefins. Key for success was the discovery of a new sterically encumbered bis(oxazoline) ligand backbone, thus offering a de novo technology for accessing enantioenriched sp3-sp3 linkages via sp3 C-N functionalization. Our protocol is distinguished by its broad scope and generality across a wide number of counterparts, even in the context of late-stage functionalization. In addition, an enantioselective deaminative remote hydroalkylation reaction of unactivated internal olefins is within reach, thus providing a useful entry point for forging enantioenriched sp3-sp3 centers at remote sp3 C-H sites.

Application of an L-shaped anterolateral thigh flap in reconstruction after hemiglossectomy.

OBJECTIVE: Tongue defect reconstruction is one of the key components of tongue cancer surgery. In this study, we used an L-shaped flap design adopted as a simple and efficient method to repair tongue defects after hemiglossectomy. Furthermore, we evaluated and contrasted the clinical effects of two methods, the L-shaped and traditional methods. STUDY DESIGN: Fifteen patients in the L-shaped group and 20 patients in the traditional group were evaluated and compared in terms of postoperative complications, dysphagia, language function and appearance satisfaction. RESULTS: The results (Table 1) showed that there were 2 cases of donor area invalid traumas, and 2 patients had scar hyperplasia in the traditional group. The degree of global and functional dysphagia of the L-shaped group (2.60 ± 0.29 and 11.47 ± 1.38) was lower than that of the traditional group (3.55 ± 0.29 and 15.75 ± 1.22) (P < 0.05). In the language evaluation, the traditional group (3.20 ± 0.26) had lower scores than the L-shaped group (4.13 ± 0.30) (P < 0.05). CONCLUSION: The L-shaped ALTP flap is a simple and efficient modification of ALTP, that can be used for half-tongue repair after radical operations for tongue cancer. It has better performance in the recovery of dysphagia and language function than the traditional ALTP flap.

[Mechanism of emodin in relieving neuropathic pain by regulating serum metabolism].

The present study investigated the effect of emodin on the serum metabolite profiles in the chronic constriction injury(CCI) model by non-target metabolomics and explored its analgesic mechanism. Twenty-four Sprague Dawley(SD) rats were randomly divided into a sham group(S), a CCI group(C), and an emodin group(E). The rats in the emodin group were taken emodin via gavage once a day for fifteen days(50 mg·kg~(-1)) on the first day after the CCI surgery. Mechanical withdrawal threshold(MWT) and thermal withdrawal threshold(TWL) in each group were performed before the CCI surgery and 3,7, 11, and 15 days after surgery. After 15 days, blood samples were collected from the abdominal aorta. The differential metabolites were screened out by non-target metabolomics and analyzed with Kyoto Encyclopedia of Genes and Genomes(KEGG) and ingenuity pathway analysis(IPA). From the third day after CCI surgery, the MWT and TWL values were reduced significantly in both CCI group and emodin group, compared with the sham group(P<0.01). At 15 days post-surgery, the MWT and TWL values in emodin group increased significantly compared with the CCI group(P<0.05). As revealed by non-target metabolomics, 72 differential serum metabolites were screened out from the C-S comparison, including 41 up-regulated and 31 down-regulated ones, while 26 differential serum metabolites from E-C comparison, including 10 up-regulated and 16 down-regulated ones. KEGG analysis showed that the differential metabolites in E-C comparison were enriched in the signaling pathways, such as sphingolipid metabolism, arginine biosynthesis, glycerophospholipid metabolism, and tryptophan metabolism. IPA showed that the differential metabolites were mainly involved in the lipid metabolism-molecular transport-small molecule biochemistry network. In conclusion, emodin can exert an analgesic role via regulating sphingolipid metabolism and arginine biosynthesis.

Role of FTO gene polymorphisms in Wilms tumor predisposition: A five-center case-control study.

BACKGROUND: Wilms tumor is the most frequently occurring renal malignancy in pediatrics. The FTO gene exhibits a featured genetic contribution to cancer development. Nonetheless, its single nucleotide polymorphism (SNP) contribution to Wilms tumor remains unknown. METHODS: In the present study, 402 Wilms tumor patients and 1198 healthy controls were successfully genotyped for FTO gene SNPs (rs1477196 G>A, rs9939609 T>A, rs7206790 C>G and rs8047395 A>G) using TaqMan SNP genotyping assays. Odds ratios (ORs) and 95% confidence intervals (CIs), generated from unconditional logistic regression, were applied to quantify the effects of FTO gene SNPs on Wilms tumor risk. RESULTS: We found that the rs8047395 A>G polymorphism was significantly correlated with an increased risk for Wilms tumor (GG versus AA/AG: adjusted OR = 1.38, 95% CI = 1.04-1.85, p = 0.027). Carriers with 1 and 1-2 risk genotypes are more susceptible of developing Wilms tumor than those without risk genotypes. Stratified analysis of rs8047395 and risk genotypes revealed more significant relationships with Wilms tumor risk in certain subgroups. Preliminary functional annotations revealed that the rs8047395 A allele increases expression levels of the FTO gene as determined by expression quantitative trait locus analysis. CONCLUSIONS: The present study provides evidence that rs8047395 may regulate FTO gene expression and thus confer susceptibility to Wilms tumor. The candidate FTO gene rs8047395 A>G polymorphism identified in this study warrants independent investigation.

METTL14 gene polymorphisms decrease Wilms tumor susceptibility in Chinese children.

BACKGROUND: Wilms tumor is a highly heritable malignancy. Aberrant METTL14, a critical component of N6-methyladenosine (m6A) methyltransferase, is involved in carcinogenesis. The association between genetic variants in the METTL14 gene and Wilms tumor susceptibility remains to be fully elucidated. We aimed to assess whether variants within this gene are implicated in Wilms tumor susceptibility. METHODS: A total of 403 patients and 1198 controls were analyzed. METTL14 genotypes were assessed by TaqMan genotyping assay. RESULT: Among the five SNPs analyzed, rs1064034 T > A and rs298982 G > A exhibited a significant association with decreased susceptibility to Wilms tumor. Moreover, the joint analysis revealed that the combination of five protective genotypes exerted significantly more protective effects against Wilms tumor than 0-4 protective genotypes with an OR of 0.69. The stratified analysis further identified the protective effect of rs1064034 T > A, rs298982 G > A, and combined five protective genotypes in specific subgroups. The above significant associations were further validated by haplotype analysis and false-positive report probability analysis. Preliminary mechanism exploration indicated that rs1064034 T > A and rs298982 G > A are correlated with the expression and splicing event of their surrounding genes. CONCLUSIONS: Collectively, our results suggest that METTL14 gene SNPs may be genetic modifiers for the development of Wilms tumor.

Impact of YTHDF1 gene polymorphisms on Wilms tumor susceptibility: A five-center case-control study.

BACKGROUND: Wilms tumor is the most frequent renal malignancy in children. YTHDF1 is associated with the development of several kinds of cancers, yet whether common variants of the YTHDF1 gene influence Wilms tumor risk is unknown. We present, here, a hospital-based case-control study specifically designed to investigate the role of YTHDF1 genetic variants on Wilms tumor. METHODS: We successfully genotyped samples of 408 Wilms tumor cases and 1198 controls which were collected from five hospitals across China. The unconditional logistic regression was adopted to analyze the contributions of YTHDF1 gene single nucleotide polymorphisms (SNPs) to the risk of Wilms tumor. The odds ratio (OR) and 95% confidence interval (CI) were generated to evaluate the conferring risk of YTHDF1 gene SNPs (rs6011668 C>T, rs6090311 A>G). RESULTS: Neither of the two SNPs could contribute to the risk of Wilms tumor. A negative association was also detected in the combined effects of protective genotypes on Wilms tumor risk. The stratification analysis revealed that compared with those with CC genotype, rs6011668 CT/TT genotype was associated with increased Wilms tumor risk in those ≤18 months (OR = 1.54, 95% CI = 1.02-2.30, p = 0.038), and with decreased Wilms tumor risk in those >18 months (OR = 0.70, 95% CI = 0.50-0.97, p = 0.034). CONCLUSION: Our present work sheds some light on the potential role of YTHDF1 gene polymorphisms on Wilms tumor risk.

Dasatinib protects against acute respiratory distress syndrome via Nrf2-regulated M2 macrophages polarization.

Dasatinib, a tyrosine kinase inhibitor, has a protective effect on experimental acute respiratory distress syndrome (ARDS). This study investigated the effect and mechanism of dasatinib in ARDS. C57BL/6 mice were administered with dasatinib (1 and 10 mg/kg) after lipopolysaccharide (LPS) treatment to evaluate the effect of dasatinib on white blood cells (WBC), neutrophils, lymphocytes and macrophages in bronchoalveolar lavage fluid (BALF). The levels and mRNA expressions of inflammation-related cytokines in lung tissues and RAW 264.7 cells were detected by enzyme-linked immunosorbent assay and quantitative real-time PCR, respectively. The protein expressions of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase 1 (HO1) were determined by Western blot. MTT assay was performed to detect the viability of RAW 264.7 cell. Rescue experiments were used to assess the effect of Nrf2 silencing on the LPS- and dasatinib-treated mice. Under LPS treatment, levels of the WBC, neutrophils, lymphocytes and macrophages in BALF and mRNA expressions of IL-6, TNF-α and IL-10 as well as expression of iNOS were increased, but the expression of arginase-1 was inhibited, while no obvious changes of the protein expressions of Nrf2 and HO1 were observed. Dasatinib partially reversed the effects of LPS above, and further promoted the mRNA expression of IL-10 and the protein expressions of Nrf2 and HO1, while Nrf2 silencing counteracted the effect of dasatinib. Dasatinib induced the polarization of M2 subtype of macrophages and alleviated LPS-induced ARDS through activating Nrf2 signaling pathway, which may provide a new strategy for the treatment of ARDS.

LIN28A gene polymorphisms modify neuroblastoma susceptibility: A four-centre case-control study.

Neuroblastoma ranks the most common seen solid tumour in childhood. Overexpression of LIN28A gene has been linked to the development of multiple human malignancies, but the relationship between LIN28A single nucleotide polymorphisms (SNPs) and neuroblastoma susceptibility is still under debate. Herein, we evaluated the correlation of four potentially functional LIN28A SNPs (rs3811464 G>A, rs3811463 T>C, rs34787247 G>A, and rs11247957 G>A) and neuroblastoma susceptibility in 505 neuroblastoma patients and 1070 controls from four independent hospitals in China. The correlation strengths were determined by using odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Among these SNPs, rs34787247 G>A exhibited a significant association with increased susceptibility in neuroblastoma (GA vs GG: adjusted OR = 1.30, 95% CI = 1.03-1.64; AA vs GG: adjusted OR = 2.51, 95% CI = 1.36-4.64, AA/GA vs GG: adjusted OR = 1.42, 95% CI = 1.12-1.80, AA vs GG/GA: adjusted OR = 2.39, 95% CI = 1.29-4.42). Furthermore, the combined analysis of risk genotypes revealed that subjects carrying three risk genotypes (adjusted OR = 1.64, 95% CI = 1.02-2.63) are more inclined to develop neuroblastoma than those without risk genotype, and so do carriers of 1-4 risk genotypes (adjusted OR = 1.26, 95% CI = 1.01-1.56). Stratification analysis further revealed risk effect of rs3811464 G>A, rs34787247 G>A and 1-4 risk genotypes in some subgroups. Haplotype analysis of these four SNPs yields two haplotypes significantly correlated with increased neuroblastoma susceptibility. Overall, our finding indicated that LIN28A SNPs, especially rs34787247 G>A, may increase neuroblastoma risk.

METTL3 polymorphisms and Wilms tumor susceptibility in Chinese children: A five-center case-control study.

BACKGROUND: Wilms tumor is a common pediatric tumor worldwide. Methyltransferase like 3 (METTL3) is a core gene of the N6 -methyladenosine (m6 A) modification that widely affects the transcription of tumor-related genes in eukaryotes. METTL3 has been extensively investigated in various tumors but not Wilms tumor. METHODS: We describe a five-center case-control study with 414 patients and 1199 controls aiming to explore the associations between METTL3 polymorphisms (rs1061026 T>G, rs1061027 C>A, rs1139130 A>G and rs1263801 G>C) and Wilms tumor susceptibility. A TaqMan real-time polymerase chain reaction was performed for genotyping. Odds ratios (ORs) and 95% confidence intervals (CIs) were reported as evaluation indicators to determine any associations. RESULTS: Referring to the preliminary analysis results, protective genotypes were identified as rs1061026 TG/GG, rs1061027 CA/AA, rs1139130 GG and rs1263801 GC/CC. The children with three protective genotypes were less likely to develop Wilms tumor than children without protective genotypes (adjusted OR = 0.68, 95% CI = 0.46-0.999, p = 0.0496). Similarly, stratified analysis of the subgroup aged > 18 months, carrying 3 or 4 protective genotypes, was a protective factor for Wilms tumor compared to carrying 0-2 protective genotypes (adjusted OR = 0.59 95% CI = 0.39-0.91, p = 0.016). However, we did not observe any other significant results. CONCLUSIONS: The combined effect of METTL3 polymorphisms reduce Wilms tumor susceptibility in Chinese children. This conclusion requires further verification.

ALKBH5 gene polymorphisms and Wilms tumor risk in Chinese children: A five-center case-control study.

BACKGROUND: Wilms tumor is a frequently diagnosed renal cancer among children with unclear genetic causes. N6-methyladenosine (m6 A) modification genes play critical roles in tumorigenesis. However, whether genetic variations of m6 A modification genes predispose to Wilms tumor remain unclear. ALKBH5 (AlkB homolog 5), a crucial member of m6 A modification genes, encodes a demethylase that functions to reverse m6 A RNA methylation. METHODS: Herein, we evaluated the association of single nucleotide polymorphisms (SNPs) in the m6 A modification gene ALKBH5 and Wilms tumor susceptibility in a large multi-center case-control study. A total of 414 Wilms tumor cases and 1199 healthy controls were genotyped for ALKBH5 rs1378602 and rs8400 polymorphisms by TaqMan. RESULTS: No significant association was detected between these two polymorphisms and Wilms tumor risk. Moreover, 1, 2, and 1-2 protective genotypes (rs1378602 AG/AA or rs8400 GG) did not significantly reduce Wilms tumor risk, compared with risk genotypes only. Stratification analysis revealed a significant relationship between rs1378602 AG/AA genotypes and decreased Wilms tumor risk in children in clinical stage I diseases [adjusted odds ratio (OR) = 0.56, 95% confidence interval (CI) = 0.32-0.98, P = .042]. The presence of 1-2 protective genotypes was correlated with decreased Wilms tumor risk in subgroups of age > 18 months, when compared to the absence of protective genotypes (adjusted OR = 0.74, 95% CI = 0.56-0.98, P = .035). CONCLUSION: Collectively, our results demonstrate that ALKBH5 SNPs may exert a weak influence on susceptibility to Wilms tumor. This finding increases the understanding of the role of the m6 A gene in tumorigenesis of Wilms tumor.

The Effect of Mechanical Ventilation on Peripheral Perfusion Index and Its Association With the Prognosis of Critically Ill Patients.

OBJECTIVES: This study aimed to explore the relationship between the variables of mechanical ventilation and circulatory perfusion and its association with ICU mortality during the first day of mechanical ventilation. DESIGN: Retrospective cohort study. SETTING: The Department of Critical Care Medicine, Peking Union Medical College Hospital. PATIENTS: Patients who have undergone mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: This study used the main clinical data obtained from the real-time bedside messaging systems of mechanically ventilated patients during their first day in the ICU from May 2013 to May 2016, including data on the variables of mechanical ventilation and circulatory perfusion. An analysis was then performed on the association of the above data with the patient's in-ICU mortality. There were 5,103 patients who received mechanical ventilation during this period, and of these, 309 patients died during their ICU treatment. Peak airway pressure, mean airway pressure, respiratory rate, heart rate, mean arterial pressure, FIO2, blood oxygen saturation, PO2, peripheral perfusion index, and lactate level were correlated with patient outcomes. A Cox logistic regression analysis suggested that mean airway pressure and perfusion index were the most independent risk and protective factors, respectively, for patient ICU mortality. The areas under the curve for a poor prognosis for mean airway pressure and perfusion index were 0.799 (95% CI, 0.77-0.829) and 0.759 (95% CI, 0.729-0.789), respectively. Further, mean airway pressure and perfusion index exhibited a causal interaction. The relative excess risk due to interaction was 2.061 (-0.691 to 4.814), the attributable proportion due to interaction was 0.210 (-0.027 to 0.447), and the synergy index was 1.306 (0.930-1.833). CONCLUSIONS: A higher mean airway pressure and lower perfusion index provided a worse prognosis in mechanically ventilated patients, and it appears that these two variables have a casual interaction.

Total Synthesis of Spirotryprostatins through Organomediated Intramolecular Umpolung Cyclization.

Cyclodipeptide 2,5-diketopiperazines (DKP) are privileged structural units present in drugs and natural alkaloids. This work reports a new method for the synthesis of biologically important DKP scaffolds based on an intramolecular nucleophilic α-addition of general amides towards an alkynamide system. The utility of this umpolung cyclization mediated by trimethyl phosphine and l-glutamic acid is highlighted by its application to the concise total syntheses of 6-methoxyspirotryprostatin B (the first total synthesis), spirotryprostatin A, and spirotryprostatin B.

[Role of p38 Mitogen-activated Protein Kinase Signaling Pathway in the Hippocampal Neurons Autophagy of Rats with Sepsis].

OBJECTIVE: To investigate the role of p38 mitogen-activated protein kinase (MAPK) signaling pathway in autophagy of neurons in hippocampus of sepsis rats. METHODS: A sepsis model was established by cecal ligation and puncture (CLP). SD rats were randomly divided into sham-operated group (sham group), model group (CLP group), vehicle-treated group (CLP+Veh group) and inhibitor-treated group (CLP+SB203580 group), and each group was divided into 3, 6, 12, 24 and 48 h subgroups. CLP+Veh group and CLP+SB203580 group were injected with 1% DMSO 5 µL and 0.1 mmol/L SB203580 5 µL respectively in the lateral ventricle, and CLP was established 30 min after injection. The sham group only turned over the cecum and closed the abdomen without other treatments. The vital signs of rats were monitored, including mean arterial pressure (MAP) and heart rate (HR). Neurobehavioral score was used to investigate the brain injury in rats. Histopathological changes in hippocampus of rats were observed by HE staining. The process of neuronal autophagy in hippocampal of rats was observed under transmission electron microscope (TEM). Western blot assay was performed to detect the expression of microtubule associated protein 1 light chain 3 (LC3)Ⅱ, LC3Ⅰ, selective autophagy adaptor protein p62/sequestosome-1 (p62/SQSTM1), MAPK-activated protein kinase 2 (MK-2) and phosphorylation MK-2 (p-MK-2) in the hippocampus. The expressions of LC3 and p62/SQSTM1 in hippocampal neurons of rats were observed by immunofluorescence. RESULTS: At different time points, MAP of CLP group was lower than sham group, while HR was higher than sham group, the change was most obvious at 12 h after molding; the neurobehavioral score of CLP group was the lowest; the histopathological changes in the hippocampus were obvious; and many autophagy vacuoles were observed under transmission electron microscope; compared with CLP group, the neurobehavioral score of CLP+SB203580 group increased; the pathological changes in the hippocampus improved; the inclusions in autophagy vacuoles were degraded under transmission electron microscopy; Western blot results showed:compared with sham group, expression of-LC3Ⅱ/LC3Ⅰ, p-MK-2/MK-2 increased, and p62/SQSTM1 decreased in hippocampal tissue of CLP group in rat, the former reaches its peak at 12 h, the latter bottomed out at 12 h. Compared with the other groups, at 12 h of modeling, the expression of LC3Ⅱ/LC3Ⅰ, p-MK-2/MK-2 was further increased, the expression of p62/SQSTM1 decreased further in hippocampal tissue of CLP+SB203580 group in rat (P < 0.05); immunofluorescence observation showed that localization and expression of LC3 and p62/SQSTM1 in NeuN were consistent with Western blot. CONCLUSION: Inhibition of p38 MAPK signaling pathway in sepsis rats can further activate autophagy and protect neurons in the hippocampus.

Complement C5a inhibition moderates lipid metabolism and reduces tubulointerstitial fibrosis in diabetic nephropathy.

Background: Complement C5 mediates pro-inflammatory responses in many immune-related renal diseases. Given that the C5a level is elevated in diabetes, we investigated whether activation of C5a/C5aR signalling plays a pathogenic role in diabetic nephropathy (DN) and the therapeutic potential of C5a inhibition for renal fibrosis. Methods: Human renal biopsies from patients with DN and control subjects were used for immunohistochemical staining of complement C5 components. Renal function and tubulointerstitial injury were compared between db/m mice, vehicle-treated mice and C5a inhibitor-treated db/db mice. A cell culture model of tubule epithelial cells (HK-2) was used to demonstrate the effect of C5a on the renal fibrotic pathway. Results: Increased levels of C5a, but not of its receptor C5aR, were detected in renal tubules from patients with DN. The intensity of C5a staining was positively correlated with the progression of the disease. In db/db mice, administration of a novel C5a inhibitor, NOX-D21, reduced the serum triglyceride level and attenuated the upregulation of diacylglycerolacyltransferase-1 and sterol-regulatory element binding protein-1 expression and lipid accumulation in diabetic kidney. NOX-D21-treated diabetic mice also had reduced serum blood urea nitrogen and creatinine levels with less glomerular and tubulointerstitial damage. Renal transforming growth factor beta 1 (TGF-ß1), fibronectin and collagen type I expressions were reduced by NOX-D21. In HK-2 cells, C5a stimulated TGF-ß production through the activation of the PI3K/Akt signalling pathway. Conclusions: Blockade of C5a signalling by NOX-D21 moderates altered lipid metabolism in diabetes and improved tubulointerstitial fibrosis by reduction of lipid accumulation and TGF-ß-driven fibrosis in diabetic kidney.