Inflammatory cytokines and risk of allergic rhinitis: A Mendelian randomization study.

BACKGROUND: Epidemiological and experimental evidences have implicated chronic inflammation in the association with allergic rhinitis (AR). However, it remains unclear whether specific circulating cytokines are the cause of AR or the consequence of bias. To examine whether genetic-predicted changes in circulating cytokine concentrations are related to the occurrence of AR, we conducted a two-sample Mendelian randomization (MR) analysis. METHODS: We investigated the causal effects of 26 circulating inflammatory cytokines on AR through MR analysis. The primary method employed in this study was the inverse variance-weighted (IVW) method. Sensitivity analyses were conducted using simple median, weighted median, penalized weighted median, and MR-Egger regression. RESULTS: Our study revealed suggestive evidence that higher levels of circulating IL-18 (OR per one standard deviation [SD] increase: 1.006; 95 % CI, 1.002 to 1.011; P = 0.006, PFDR = 0.067, random-effects IVW method) and Macrophage inflammatory protein-1α (MIP-1α) (OR per one SD increase: 1.015; 95 % CI, 1.004 to 1.026; P = 0.009, PFDR = 0.048, random-effects IVW method) were associated with an increased risk of AR. Conversely, higher levels of circulating TRAIL were associated with a decreased risk of AR (OR per one SD increase: 0.993; 95 % CI, 0.989 to 0.997; P = 4.58E-4, PFDR = 0.004, random-effects IVW method). Only the results of TRAIL exist after Bonferroni-correction (the p-value < 0.0019). Sensitivity analysis yielded directionally consistent results. No significant associations were observed between other circulating inflammatory cytokines and AR. CONCLUSION: Genetically predicted levels of IL-18, and MIP-1α are likely to associated with an increased risk of AR occurrence. Genetically predicted levels of TRAIL are statistically significant in reducing the risk of AR occurrence. However, the current research evidence does not support an impact of other inflammatory cytokines on the risk of AR. Future studies are needed to provide additional evidence to support the current conclusions.

Structural connectome combining DTI features predicts postoperative language decline and its recovery in glioma patients.

OBJECTIVES: A decline in language function is a common complication after glioma surgery, affecting patients' quality of life and survival. This study predicts the postoperative decline in language function and whether it can be recovered based on the preoperative white matter structural network. MATERIALS AND METHODS: Eighty-one right-handed patients with glioma involving the left hemisphere were retrospectively included. Their language function was assessed using the Western Aphasia Battery before and 1 week and 3 months after surgery. Structural connectome combining DTI features was selected to predict postoperative language decline and recovery. Nested cross-validation was used to optimize the models, evaluate the prediction performance of the models, and identify the most predictive features. RESULTS: Five, seven, and seven features were finally selected as the predictive features in each model and used to establish predictive models for postoperative language decline (1 week after surgery), long-term language decline (3 months after surgery), and language recovery, respectively. The overall accuracy of the three models in nested cross-validation and overall area under the receiver operating characteristic curve were 0.840, 0.790, and 0.867, and 0.841, 0.778, and 0.901, respectively. CONCLUSION: We used machine learning algorithms to establish models to predict whether the language function of glioma patients will decline after surgery and whether postoperative language deficit can recover, which may help improve the development of treatment strategies. The difference in features in the non-language decline or the language recovery group may reflect the structural basis for the protection and compensation of language function in gliomas. CLINICAL RELEVANCE STATEMENT: Models can predict the postoperative language decline and whether it can recover in glioma patients, possibly improving the development of treatment strategies. The difference in selected features may reflect the structural basis for the protection and compensation of language function. KEY POINTS: • Structural connectome combining diffusion tensor imaging features predicted glioma patients' language decline after surgery. • Structural connectome combining diffusion tensor imaging features predicted language recovery of glioma patients with postoperative language disorder. • Diffusion tensor imaging and connectome features related to language function changes imply plastic brain regions and connections.

Study on the correlation of C-reactive protein/albumin ratio with sudden sensorineural hearing loss complicated by hypertension: a prospective study.

BACKGROUND: Understanding the pathophysiology of sudden sensorineural hearing loss (SSNHL) and identifying its clinical symptoms and associated risk factors are crucial for doctors in order to create effective prevention and therapeutic methods for this prevalent otolaryngologic emergency. METHODS: This study focuses on investigating the correlation between the C-reactive protein/albumin ratio (CAR) and SSNHL complicated by hypertension. In this study, 120 patients diagnosed with SSNHL were divided into groups with and without hypertension, and propensity score matching was used to compare and analyze the severity, type, prognosis, and CAR levels in SSNHL. RESULTS: The results showed that the SSNHL group with hypertension had significantly higher CAR levels, age, hearing curve abnormalities, and more severe hearing loss compared to the control group with isolated SSNHL. These differences were statistically significant (p < 0.001). Among different subtypes of SSNHL, CAR levels increased progressively with the advancement of the condition, and these differences were also statistically significant (p < 0.001). CONCLUSION: In summary, in patients with SSNHL, those with hypertension had higher CAR levels than those without a history of hypertension, and they experienced more severe hearing loss. Moreover, there was a clear correlation between CAR levels and the extent of SSNHL, indicating that greater CAR levels in patients with SSNHL are connected to more severe hearing loss in various hearing patterns and perhaps indicative of a poorer prognosis.

Distance-Triggered Distinct Aryl Migrations on Azidodiboranes.

Derived from structurally similar precursors, two different azidodiboranes went through distinct aryl migration reactions triggered by different boron-boron separation distances. Biphenylene based diborane with a shorter boron-boron distance underwent heterolateral aryl migration to form a seven-membered azadiborepin, while xanthrene based diborane with a longer boron-boron distance afforded a stable bis-azidoborane scaffold. The pyrolysis of such a bis-azidoborane led to eight-membered oxazadiborocine through homolateral aryl migration and subsequent [3+2] cycloaddition. Density functional theory (DFT) calculations unveiled that the boron-boron separation distances were the intrinsic factors for the distinct migrations.

Neutral Boryl Radicals in Mixed-Valent B(III) Br-B(II) Adducts.

The general strategies to stabilize a boryl radical involve single electron delocalization by π-system and the steric hinderance from bulky groups. Herein, a new class of boryl radicals is reported, with intramolecular mixed-valent B(III) Br-B(II) adducts ligated by a cyclic (alkyl)(amino)carbene (CAAC). The radicals feature a large spin density on the boron center, which is ascertained by EPR spectroscopy and DFT calculations. Structural and computational analyses revealed that the stability of radical species was assisted by the CAAC ligand and a weak but significant B(III)Br-B(II) interaction, suggesting a cooperative avenue for stabilization of boryl radicals. Two-electron reduction of these new boryl radicals provides C-H insertion products via a borylene intermediate.

Discovery of structural diverse reversible BTK inhibitors utilized to develop a novel in vivo CD69 and CD86 PK/PD mouse model.

For the past two decades, BTK a tyrosine kinase and member of the Tec family has been a drug target of significant interest due to its potential to selectively treat various B cell-mediated diseases such as CLL, MCL, RA, and MS. Owning to the challenges encountered in identifying drug candidates exhibiting the potency block B cell activation via BTK inhibition, the pharmaceutical industry has relied on the use of covalent/irreversible inhibitors to address this unmet medical need. Herein, we describe a medicinal chemistry campaign to identify structurally diverse reversible BTK inhibitors originating from HITS identified using a fragment base screen. The leads were optimized to improve the potency and in vivo ADME properties resulting in a structurally distinct chemical series used to develop and validate a novel in vivo CD69 and CD86 PD assay in rodents.

Hippo/YAP signaling pathway protects against neomycin-induced hair cell damage in the mouse cochlea.

The Hippo/Yes-associated protein (YAP) signaling pathway has been shown to be able to maintain organ size and homeostasis by regulating cell proliferation, differentiation, and apoptosis. The abuse of aminoglycosides is one of the main causes of sensorineural hearing loss (SSNHL). However, the role of the Hippo/YAP signaling pathway in cochlear hair cell (HC) damage protection in the auditory field is still unclear. In this study, we used the YAP agonist XMU-MP-1 (XMU) and the inhibitor Verteporfin (VP) to regulate the Hippo/YAP signaling pathway in vitro. We showed that YAP overexpression reduced neomycin-induced HC loss, while downregulated YAP expression increased HC vulnerability after neomycin exposure in vitro. We next found that activation of YAP expression inhibited C-Abl-mediated cell apoptosis, which led to reduced HC loss. Many previous studies have reported that the level of reactive oxygen species (ROS) is significantly increased in cochlear HCs after neomycin exposure. In our study, we also found that YAP overexpression significantly decreased ROS accumulation, while downregulation of YAP expression increased ROS accumulation. In summary, our results demonstrate that the Hippo/YAP signaling pathway plays an important role in reducing HC injury and maintaining auditory function after aminoglycoside exposure. YAP overexpression could protect against neomycin-induced HC loss by inhibiting C-Abl-mediated cell apoptosis and decreasing ROS accumulation, suggesting that YAP could be a novel therapeutic target for aminoglycosides-induced sensorineural hearing loss in the clinic.

PLEKHA4 is Associated with Tumour Microenvironment, Stemness, Proliferation and Poor Prognosis of Gliomas.

BACKGROUND: Glioma is the most common intracranial malignancy. Immune-infiltration and tumour stemness are associated with the prognosis of glioma. Although pleckstrin homology containing family A, number 4 (PLEKHA4) is widely expressed in various human cancers, its role in glioma remains unclear. METHODS: We examined the features and clinical significance of PLEKHA4 in gliomas by analysing relevant data from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases. Gene set enrichment analysis (GSEA) was performed to determine the possible functions and pathways involving PLEKHA4 in glioma. The relationship between PLEKHA4 expression and the degree of oncogenic dedifferentiation was analysed using stemness scores (ss) calculated from epigenetic and transcriptomic features. We also explored the relationship between PLEKHA4 expression and immune cell infiltration in gliomas using the CIBERSORT databases. Furthermore, drug sensitivity analysis was performed using datasets from the GDSC and GTRP databases. In addition, we performed relevant in vitro experimental studies. RESULTS: PLEKHA4 DNA hypomethylation status was associated with its high expression in glioma tissues as well as poor prognoses. Univariate and multivariate Cox analyses indicated that PLEKHA4 expression may be considered as an independent prognostic factor in patients with glioma. GSEA indicated that high PLEKHA4 expression was associated with Janus kinase (JAK)/signal transducer and activator of transcription (STAT), Wingless-Type MMTV Integration Site Family (Wnt), JUN N-terminal kinase (JNK) signalling pathways and involved in apoptotic, cytoskeletal, and cell adhesion biological processes (BPs). In addition, increased PLEKHA4 expression was associated with higher glioma stemness scores than lower PLEKHA4 expression levels. Furthermore, the expression of PLEKHA4 was shown to be associated with glioma infiltration by CD4+ T cells, B cells, neutrophils, macrophages, and dendritic cells. Drug sensitivity analysis also showed that PLEKHA4 expression was negatively correlated with the sensitivity of several small molecule kinase inhibitors. Furthermore, in vitro experiments confirmed that PLEKHA4 knockdown inhibited the proliferation of glioma cells. CONCLUSIONS: PLEKHA4 is highly expressed in glioma tissues and correlated with tumour stemness, immune cell infiltration and proliferation, suggesting its potential as a novel prognostic biomarker and therapeutic target in glioma.

The value of inflammatory biomarkers in the occurrence and prognosis of sudden sensorineural hearing loss: a meta-analysis.

OBJECTIVES: Sudden sensorineural hearing loss (SSNHL) is one of the common emergencies in otorhinolaryngology. Several studies have shown that chronic inflammation is associated with its onset and prognosis. However, the association between some inflammatory biomarkers and SSNHL is still unclear. Therefore, we conducted this meta-analysis to explore the value of inflammatory biomarkers in the occurrence and prognosis of SSNHL. METHODS: Pubmed, Embase, Cochrane and Web of Science databases were searched comprehensively, the eligible literatures were screened out by formulating the inclusion criteria and exclusion criteria. After extracting sample size, mean and standard deviation, we performed meta-analysis with standardized mean deviation (SMD) and 95% confidence interval (CI) as effect sizes. RESULTS: A total of 17 articles were included in this meta-analysis, including 2852 subjects, 1423 patients and 1429 healthy controls. The results of meta-analysis showed that the neutrophil-to-lymphocyte ratio (NLR) of the experimental group was significantly higher than the control group (SMD = 1.05, 95% CI 0.87-1.24, P < 0.001), the NLR of the recovery group was significantly lower than the unrecovered group (SMD = 0.68, 95% CI 0.27-1.08, P < 0.05); The platelet-to-lymphocyte ratio (PLR) of the experimental group was significantly higher than the control group (SMD = 0.55, 95% CI 0.34-0.76, P < 0.05), the PLR of the recovery group was significantly lower than the unrecovered group (SMD = 0.44, 95% CI 0.05-0.82, P < 0.05); The C-reactive protein-to-serum albumin ratio (CRP/Alb) of the experimental group was significantly higher than the control group (SMD = 0.39, 95% CI 0.04-0.74, P < 0.05). CONCLUSIONS: The results showed that high NLR, PLR, and CRP/Alb indicated the occurrence of SSNHL, NLR and PLR could predict prognosis of SSNHL.

Nitrogen fixation and transformation with main group elements.

Nitrogen fixation is essential for the maintenance of life and development of society, however, the large bond dissociation energy and nonpolarity of the triple bond constitute a considerable challenge. The transition metals, by virtue of their combination of empty and occupied d orbitals, are prevalent in the nitrogen fixation studies and are continuing to receive a significant focus. The main group metals have always been considered incapable in dinitrogen activation owing to the absence of energetically and symmetrically accessible orbitals. The past decades have witnessed significant breakthroughs in the dinitrogen activation with the main group elements and compounds via either matrix isolation, theoretical calculations or synthetic chemistry. The successful reactions of the low-valent species of the main group elements with inert dinitrogen have been reported via the π back-donation from either the d orbitals (Ca, Sr, Ba) or p orbitals (Be, B, C…). Herein, the significant achievements have been briefly summarized, along with predicting the future developments.

Cesium Amide-Catalyzed Selective Deuteration of Benzylic C-H Bonds with D2 and Application for Tritiation of Pharmaceuticals.

Hydrogen isotope exchange (HIE) represents one of the most attractive labeling methods to synthesize deuterium- and tritium-labeled compounds. Catalytic HIE methods that enable site-selective C-H bond activation and exchange labeling with gaseous isotopes D2 and T2 are of vital importance, in particular for high-specific-activity tritiation of pharmaceuticals. As part of our interest in exploring s-block metals for catalytic transformations, we found CsN(SiMe3 )2 to be an efficient catalyst for selective HIE of benzylic C-H bonds with D2 gas. The reaction proceeds through a kinetic deprotonative equilibrium that establishes an exchange pathway between C-H bonds and D2 gas. By virtue of multiple C-H bonds activation and high activity (isotope enrichment up to 99 %), the simple cesium amide catalyst provided a very powerful and practically convenient labeling protocol for synthesis of highly deuterated compounds and high-specific-activity tritiation of pharmaceuticals.

Reorganization of Hydrogen Bonding in Biobased Polyamide 5,13 under the Thermo-Mechanical Field: Hierarchical Microstructure Evolution and Achieving Excellent Mechanical Performance.

The hierarchical microstructure evolution of an emerging biobased odd-odd polyamide 5,13 (PA5,13) films under the thermo-mechanical field, stepping from hydrogen bond (H-bond) arrangement to the crystalline morphology, has been investigated systematically. It is found that the reorganization of H-bonds under the thermo-mechanical field plays a crucial role in the crystallization of PA5,13. Especially, it is revealed that the crystallization process under the thermo-mechanical field develops along the chain axis direction, while lamellar fragmentation occurs perpendicular to the chain axis. Consequently, a stable and well-organized H-bond arrangement and lengthened lamellae with significant orientation have been constructed. Laudably, an impressive tensile strength of about 500 MPa and modulus of about 4.7 GPa are thus achieved. The present study could provide important guidance for the industrial-scale manufacture of high-performance biobased odd-odd PAs with long polymethylene segment in the dicarboxylic unit combined with a large difference between the polymethylene segments in the dicarboxylic and diamine units.

Clinical efficacy and safety of MP-AzeFlu for the treatment of allergic rhinitis: a meta-analysis.

OBJECTIVE: MP-AzeFlu is a novel option for therapy of allergic rhinitis (AR). The purpose of our study was to assess the safety and efficacy of MP-AzeFlu for the treatment of allergic rhinitis, compared to placebo and azelastine monotherapy. METHODS: The PubMed, MEDLINE, EMBASE and Cochrane databases were comprehensively searched for all published randomized controlled trials (RCTs) of using MP-AzeFlu nasal spray on July 26, 2019. In these studies, we selected patients with clinical symptom scores. The heterogeneity of the included studies was assessed by I2. RESULTS: Among the 336 citations retrieved, 6 articles with over 6000 patients were finally included in the meta-analysis. The results of meta-analysis revealed that MP-AzeFlu was superior to placebo ( - 2.43 [95%CI,  - 2.73 to  - 2.14], P < 0.00001) and azelastine ( - 1.27 [95% CI,  - 1.57 to  - 0.97], P < 0.00001) in reflective total nasal symptom score. In the MP-AzeFlu group, the instantaneous total nasal symptom score ( - 2.56 [95% CI,  - 3.02 to  - 2.10], P < 0.00001) and the reflective total ocular symptom score ( - 1.22 [95% CI,  - 1.57 to  - 0.87], P < 0.00001) were significantly reduced compared to the placebo group. CONCLUSION: MP-AzeFlu is as safe and mild as placebo and azelastine, which also is associated with symptom relief and the improvement of quality of life in AR patients. MP-AzeFlu can provide better clinical benefits than two currently available first-line intranasal therapies. It is an ideal therapy for AR patients.

Theranostic Small-Molecule Prodrug Conjugates for Targeted Delivery and Controlled Release of Toll-like Receptor 7 Agonists.

We previously reported the design and synthesis of a small-molecule drug conjugate (SMDC) platform that demonstrated several advantages over antibody-drug conjugates (ADCs) in terms of in vivo pharmacokinetics, solid tumor penetration, definitive chemical structure, and adaptability for modular synthesis. Constructed on a tri-modal SMDC platform derived from 1,3,5-triazine (TZ) that consists of a targeting moiety (Lys-Urea-Glu) for prostate-specific membrane antigen (PSMA), here we report a novel class of chemically identical theranostic small-molecule prodrug conjugates (T-SMPDCs), [18/19F]F-TZ(PSMA)-LEGU-TLR7, for PSMA-targeted delivery and controlled release of toll-like receptor 7 (TLR7) agonists to elicit de novo immune response for cancer immunotherapy. In vitro competitive binding assay of [19F]F-TZ(PSMA)-LEGU-TLR7 showed that the chemical modification of Lys-Urea-Glu did not compromise its binding affinity to PSMA. Receptor-mediated cell internalization upon the PSMA binding of [18F]F-TZ(PSMA)-LEGU-TLR7 showed a time-dependent increase, indicative of targeted intracellular delivery of the theranostic prodrug conjugate. The designed controlled release of gardiquimod, a TLR7 agonist, was realized by a legumain cleavable linker. We further performed an in vivo PET/CT imaging study that showed significantly higher uptake of [18F]F-TZ(PSMA)-LEGU-TLR7 in PSMA+ PC3-PIP tumors (1.9 ± 0.4% ID/g) than in PSMA- PC3-Flu tumors (0.8 ± 0.3% ID/g) at 1 h post-injection. In addition, the conjugate showed a one-compartment kinetic profile and in vivo stability. Taken together, our proof-of-concept biological evaluation demonstrated the potential of our T-SMPDCs for cancer immunomodulatory therapies.

SPARC is a key mediator of TGF-ß-induced renal cancer metastasis.

Aberrant expression of transforming growth factor-ß1 (TGF-ß1) is associated with renal cell carcinoma (RCC) progression by inducing cancer metastasis. However, the downstream effector(s) in TGF-ß signaling pathway is not fully characterized. In the present study, the elevation of secreted protein acidic and rich in cysteine (SPARC) as a TGF-ß regulated gene in RCC was identified by applying differentially expressed gene analysis and microarray analysis, we further confirmed this result in several RCC cell lines. Clinically, the expression of these two genes is positively correlated in RCC patient specimens. Furthermore, elevated SPARC expression is found in all the subtypes of RCC and positively correlated with the RCC stage and grade. In contrast, SPARC expression is inversely correlated with overall and disease-free survival of patients with RCC, suggesting SPARC as a potent prognostic marker of RCC patient survival. Knocking down SPARC significantly inhibits RCC cell invasion and metastasis both in vitro and in vivo. Similarly, in vitro cell invasion can be diminished by using a specific monoclonal antibody. Mechanistically, SPARC activates protein kinase B (AKT) pathway leading to elevated expression of matrix metalloproteinase-2 that can facilitate RCC invasion. Altogether, our data support that SPARC is a critical role of TGF-ß signaling network underlying RCC progression and a potential therapeutic target as well as a prognostic marker.

Inhibition of the INa/K and the activation of peak INa contribute to the arrhythmogenic effects of aconitine and mesaconitine in guinea pigs.

Aconitine (ACO), a main active ingredient of Aconitum, is well-known for its cardiotoxicity. However, the mechanisms of toxic action of ACO remain unclear. In the current study, we investigated the cardiac effects of ACO and mesaconitine (MACO), a structurally related analog of ACO identified in Aconitum with undocumented cardiotoxicity in guinea pigs. We showed that intravenous administration of ACO or MACO (25 µg/kg) to guinea pigs caused various types of arrhythmias in electrocardiogram (ECG) recording, including ventricular premature beats (VPB), atrioventricular blockade (AVB), ventricular tachycardia (VT), and ventricular fibrillation (VF). MACO displayed more potent arrhythmogenic effect than ACO. We conducted whole-cell patch-clamp recording in isolated guinea pig ventricular myocytes, and observed that treatment with ACO (0.3, 3 µM) or MACO (0.1, 0.3 µM) depolarized the resting membrane potential (RMP) and reduced the action potential amplitude (APA) and durations (APDs) in a concentration-dependent manner. The ACO- and MACO-induced AP remodeling was largely abolished by an INa blocker tetrodotoxin (2 µM) and partly abolished by a specific Na+/K+ pump (NKP) blocker ouabain (0.1 µM). Furthermore, we observed that treatment with ACO or MACO attenuated NKP current (INa/K) and increased peak INa by accelerating the sodium channel activation with the EC50 of 8.36 ± 1.89 and 1.33 ± 0.16 µM, respectively. Incubation of ventricular myocytes with ACO or MACO concentration-dependently increased intracellular Na+ and Ca2+ concentrations. In conclusion, the current study demonstrates strong arrhythmogenic effects of ACO and MACO resulted from increasing the peak INa via accelerating sodium channel activation and inhibiting the INa/K. These results may help to improve our understanding of cardiotoxic mechanisms of ACO and MACO, and identify potential novel therapeutic targets for Aconitum poisoning.

Validation of SV2A-Targeted PET Imaging for Noninvasive Assessment of Neuroendocrine Differentiation in Prostate Cancer.

Neuroendocrine prostate cancer (NEPC) is an aggressive and lethal variant of prostate cancer (PCa), and it remains a diagnostic challenge. Herein we report our findings of using synaptic vesicle glycoprotein 2 isoform A (SV2A) as a promising marker for positron emission tomography (PET) imaging of neuroendocrine differentiation (NED). The bioinformatic analyses revealed an amplified SV2A gene expression in clinical samples of NEPC versus castration-resistant PCa with adenocarcinoma characteristics (CRPC-Adeno). Importantly, significantly upregulated SV2A protein levels were found in both NEPC cell lines and tumor tissues. PET imaging studies were carried out in NEPC xenograft models with 18F-SynVesT-1. Although 18F-SynVesT-1 is not a cancer imaging agent, it showed a significant uptake level in the SV2A+ tumor (NCI-H660: 0.70 ± 0.14 %ID/g at 50-60 min p.i.). The SV2A blockade resulted in a significant reduction of tumor uptake (0.25 ± 0.03 %ID/g, p = 0.025), indicating the desired SV2A imaging specificity. Moreover, the comparative PET imaging study showed that the DU145 tumors could be clearly visualized by 18F-SynVesT-1 but not 68Ga-PSMA-11 nor 68Ga-DOTATATE, further validating the role of SV2A-targeted imaging for noninvasive assessment of NED in PCa. In conclusion, we demonstrated that SV2A, highly expressed in NEPC, can serve as a promising target for noninvasive imaging evaluation of NED.

Alkyl lithium-catalyzed benzylic C-H bond addition of alkyl pyridines to α-alkenes.

Brønsted base catalyzed C-C bond formation reactions have been extensively utilized as reliable, efficient, and atom economical methods in organic synthesis. However, the electrophiles were mostly limited to polar ones such as imines, carbonyl compounds, α,ß-unsaturated compounds, styrenes and conjugated dienes. The use of α-alkenes as electrophiles in the C-C bond formation reactions always needs transition metal catalysts. Herein, we reported an alkyl lithium-catalyzed benzylic C-H bond addition of alkyl pyridines to α-alkenes. The alkyl lithium catalyst displayed quite different selectivity from those of transition metal catalysts.

Risk factors of pharyngocutaneous fistula after total laryngectomy: a systematic review and meta-analysis.

OBJECTIVE: The purpose of this study was to systematically evaluate the risk factors of pharyngocutaneous fistula (PCF) after total laryngectomy. METHODS: We systematically searched Pubmed, Web of Science, Cochrane Library, and Embase databases and included the literature according to the inclusion and exclusion criteria. RESULTS: A total of 52 studies with 8605 patients were included in the meta-analysis. The total incidence of PCF was 21% (1808/8605). Meta-analysis results indicated that age (OR = 1.29, 95% CI 1.06-1.58, P = 0.01), smoking (OR = 1.62, 95% CI 1.27-2.07, P < 0.01), COPD (chronic obstructive pulmonary disease) (OR = 1.62, 95% CI 1.19-2.22, P < 0.01), CAD (coronary atherosclerotic heart disease) (OR = 1.82, 95% CI 1.36-2.45, P < 0.01), T-stage (OR = 0.81, 95% CI 0.67-0.98, P = 0.03), previous radiotherapy (OR = 2.41, 95% CI 2.00-2.90, P < 0.01), preoperative albumin (OR = 2.95, 95% CI 1.47-5.91, P < 0.01), preoperative hemoglobin (OR = 1.97, 95% CI 1.28-3.03, P < 0.01), tumor site (OR = 0.28, 95% CI 0.22-0.36, P < 0.01), and treatment method (OR = 1.85, 95% CI 1.44-2.38, P < 0.01) were risk factors associated with PCF. CONCLUSIONS: In our study, age, smoking, COPD, CAD, T-stage, previous radiotherapy, preoperative albumin, preoperative hemoglobin, tumor site, and treatment method were risk factors of PCF.

KCNQ1OT1 facilitates progression of non-small-cell lung carcinoma via modulating miRNA-27b-3p/HSP90AA1 axis.

Long noncoding RNA KCNQ1OT1 participates in the regulation of imprinted genes within the kcnq1 domain. But its roles in carcinogenesis and metastasis remain largely elusive. Herein, we evaluated its potential in non-small-cell lung cancer (NSCLC) progression. We demonstrated that the KCNQ1OT1 level was upregulated in NSCLC tissues and cell lines. High KCNQ1OT1 level correlated with poor overall and progression-free survival in NSCLC patients. KCNQ1OT1 facilitated proliferation, migration, and invasion in H460 cells. Furthermore, knockdown of KCNQ1OT1 reduced the expression of HSP90AA1. KCNQ1OT1 presented a positive correlation with HSP90AA1 which predicted the tumor progression in NSCLC from The Cancer Genome Atlas database. Intriguingly, KCNQ1OT1 modulated HSP90AA1 expression by sponging miR-27b-3p. MiR-27b-3p counteracted the effect of KCNQ1OT1 on HSP90AA1 expression, H460 cell migration, and invasion. These data revealed a role for KCNQ1OT1 as an oncogene through miR-27b-3p/HSP90AA1 axis during NSCLC progression.