Whole-exome and targeted gene sequencing of large-cell lung carcinoma reveals recurrent mutations in the PI3K pathway.

BACKGROUND: Large cell lung carcinoma (LCLC) is an exceptionally aggressive disease with a poor prognosis. At present, little is known about the molecular pathology of LCLC. METHODS: Ultra-deep sequencing of cancer-related genes and exome sequencing were used to detect the LCLC mutational in 118 tumor-normal pairs. The cell function test was employed to confirm the potential carcinogenic mutation of PI3K pathway. RESULTS: The mutation pattern is determined by the predominance of A > C mutations. Genes with a significant non-silent mutation frequency (FDR) < 0.05) include TP53 (47.5%), EGFR (13.6%) and PTEN (12.1%). Moreover, PI3K signaling (including EGFR, FGRG4, ITGA1, ITGA5, and ITGA2B) is the most mutated pathway, influencing 61.9% (73/118) of the LCLC samples. The cell function test confirmed that the potential carcinogenic mutation of PI3K pathway had a more malignant cell function phenotype. Multivariate analysis further revealed that patients with the PI3K signaling pathway mutations have a poor prognosis (P = 0.007). CONCLUSIONS: These results initially identified frequent mutation of PI3K signaling pathways in LCLC and indicate potential targets for the treatment of this fatal type of LCLC.

Seeds Act as Vectors for Antibiotic Resistance Gene Dissemination in a Soil-Plant Continuum.

Though the evidence for antibiotic resistance spread via plant microbiome is mounting, studies regarding antibiotic resistome in the plant seed, a reproductive organ and important food resource, are still in their infancy. This study investigated the effects of long-term organic fertilization on seed bacterial endophytes, resistome, and their intergenerational transfer in the microcosm. A total of 99 antibiotic resistance genes (ARGs) and 26 mobile genetic elements (MGEs) were detected by high-throughput quantitative PCR. The amount of organic fertilizer applied was positively correlated to the number and relative abundance of seed-associated ARGs and MGEs. Moreover, the transmission of ARGs from the rhizosphere to the seed was mainly mediated by the shared bacteria and MGEs. Notably, the rhizosphere of progeny seedlings derived from seeds harboring abundant ARGs was found to have a higher relative abundance of ARGs. Using structural equation models, we further revealed that seed resistome and MGEs were key factors affecting the ARGs in the progeny rhizosphere, implying the seed was a potential resistome reservoir for rhizosphere soil. This study highlights the overlooked role of seed endophytes in the dissemination of resistome in the soil-plant continuum, and more attention should be paid to plant seeds as vectors of ARGs within the "One-Health" framework.

Liquid biopsy in lung cancer: significance in diagnostics, prediction, and treatment monitoring.

Primary lung cancer is one of the most common malignant tumors in China. Approximately 60% of lung cancer patients have distant metastasis at the initial diagnosis, so it is necessary to find new tumor markers for early diagnosis and individualized treatment. Tumor markers contribute to the early diagnosis of lung cancer and play important roles in early detection and treatment, as well as in precision medicine, efficacy monitoring, and prognosis prediction. The pathological diagnosis of lung cancer in small biopsy specimens determines whether there are tumor cells in the biopsy and tumor type. Because biopsy is traumatic and the compliance of patients with multiple biopsies is poor, liquid biopsy has become a hot research direction. Liquid biopsies are advantageous because they are nontraumatic, easy to obtain, reflect the overall state of the tumor, and allow for real-time monitoring. At present, liquid biopsies mainly include circulating tumor cells, circulating tumor DNA, exosomes, microRNA, circulating RNA, tumor platelets, and tumor endothelial cells. This review introduces the research progress and clinical application prospect of liquid biopsy technology for lung cancer.

Non-Ultrawide Bandgap Semiconductor GaSe Nanobelts for Sensitive Deep Ultraviolet Light Photodetector Application.

In this paper, the authors report the fabrication of a sensitive deep ultraviolet (DUV) photodetector by using an individual GaSe nanobelt with a thickness of 52.1 nm, which presents the highest photoresponse at 265 nm illumination with a responsivity and photoconductive gain of about 663 A W-1 and 3103 at a 3 V bias, respectively, comparable to or even better than other reported devices based on conventional wide bandgap semiconductors. According to the simulation, this photoelectric property is associated with the wavelength-dependent absorption coefficient of the GaSe crystal, for which incident light with shorter wavelengths will be absorbed near the surface, while light with longer wavelengths will have a larger penetration depth, leading to a blueshift of the absorption edge with decreasing thickness. Further finite element method (FEM) simulation reveals that the relatively thin GaSe nanobelt exhibits an enhanced transversal standing wave pattern compared to its thicker counterpart at a wavelength of 265 nm, leading to an enhanced light-matter interaction and thereby more efficient photocurrent generation. The device can also function as an effective image sensor with acceptable spatial resolution. This work will shed light on the facile fabrication of a high-performance DUV photodetector from non-ultrawide bandgap semiconductors.

Pd-Catalyzed Hydroxyl-Directed Cascade Hydroarylation/C-H Germylation of Nonterminal Alkenes and Aryl Iodides.

Pd-catalyzed cascade hydroarylation and C-H germylation of nonterminal alkenes and aryl iodides enabled by hydroxyl assistance have been developed. The key step in this C-H germylation cascade is the formation of a highly reactive oxo-palladacycle intermediate, which markedly restrained the ß-H elimination process. Mechanistically, control experiments indicated that the hydroxyl group played an important role in this process. This transformation shows excellent reactivity and selectivity for most substrates investigated.

The role of pirfenidone in the treatment of interstitial pneumonia with autoimmune features.

OBJECTIVES: No approved pharmacotherapies are available for patients with interstitial pneumonia with autoimmune features (IPAF). In the present work, we aimed to evaluate the efficacy and safety of pirfenidone for the treatment of IPAF. METHODS: A retrospective cohort study consisting of patients who met diagnostic criteria for IPAF was performed after a multidisciplinary review, and the patients receiving pirfenidone were compared with those in the non-pirfenidone group. The baseline data and diagnostic characteristics of patients were assessed. Pulmonary function and prednisone dose were analysed by a mix-effects model. RESULTS: A total of 184 patients, who met the diagnostic criteria of IPAF, were divided into two groups: pirfenidone group (n=81) and non-pirfenidone group (n=103). Patients in the pirfenidone group had a lower forced vital capacity (FVC%, p<0.001) and a lower diffusion capacity for carbon monoxide (DLCO%, p=0.003). The pirfenidone group exhibited a greater increase of FVC% at 6 (p=0.003), 12 (p=0.013), and 24 (p=0.003) months. After adjustment for sex, age, UIP pattern, baseline FVC% and DLCO%, patients in the pirfenidone group continued to show a greater improvement in FVC% (χ2(1)=4.59, p=0.032). Subgroup analysis identified superior therapeutic effects of pirfenidone in patients with dosage >600 mg/day (p=0.010) and medication course >12 months (p=0.007). Besides, the pirfenidone group had a lower prednisone dose than the non-pirfenidone group after 12 months of treatment (p=0.002). Moreover, 17 patients (19.32%) experienced side effects after taking pirfenidone, including one case of anaphylactic shock. CONCLUSIONS: Pirfenidone (600-1,800 mg/day) might help improve FVC, with an acceptable safety and tolerability profile in IPAF patients.

microRNA-320b suppresses HNF4G and IGF2BP2 expression to inhibit angiogenesis and tumor growth of lung cancer.

We examined the effect of microRNA-320b (miR-320b) on tumor growth and angiogenesis in lung cancer and also determined its downstream molecular mechanisms. Lung cancer tissues and adjacent non-cancerous tissues were collected from 66 patients with lung cancer. miR-320b expression was experimentally determined to be expressed at low level in cancer tissues. The results of gain-of-function experiments suggested that miR-320b overexpression suppressed cancer cell invasion, tube formation, tumor volume and angiogenesis in xenografted nude mice. Hepatocyte nuclear factor 4 gamma (HNF4G) was identified as a target of miR-320b based on in silico analysis. Dual-luciferase reporter gene assays further identified the binding relationship between HNF4G and miR-320b. Lung cancer tissues exhibited increased expression of HNF4G and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). Meanwhile, HNF4G knockdown suppressed IGF2BP2 expression, thereby repressing cancer cell invasion and tube formation. Furthermore, IGF2BP2 modified m6A to increase the expression of thymidine kinase 1 (TK1), thus promoting angiogenesis. In nude mice, restoration of TK1 reversed the suppressive effect of miR-320b overexpression on tumor growth rate and CD31 expression. In conclusion, miR-320b suppresses lung cancer growth and angiogenesis by inhibiting HNF4G, IGF2BP2 and TK1.

A mobile terminal application program was used for endotracheal tube cuff pressure measurement.

We studied the application of a mobile terminal application program in endotracheal tube (ETT) cuff pressure measurement to improve the implementation rate of scientific ETT cuff pressure measurement and to ensure that the pressure falls within the recommended range. A pre-post controlled study lasting for 18 months was undertaken in a 40-bed general intensive care unit (GICU). This included a 6-month baseline period (baseline group) and a 6-month intervention period (intervention group). The mobile terminal application program was applied to monitor the cuff pressure of endotracheal intubation as an intervention measure during the intervention period. ETT pressure was the main outcome measure, while gender, age, causes for ICU admission, sedation score, duration of prior intubation, size of ETT, and number of VAP patients were secondary outcomes. ETT cuff pressure was monitored 742 times in both the baseline group and the intervention group. A total of 56.9% of the cuff pressure measurements in the baseline group were within the recommended range, while 78.4% of measurements in the intervention group were within the recommended range, reflecting a statistically significant difference (P < 0.05). The application of the mobile terminal application program used for ETT cuff pressure measurement could improve the percentage of ETT cuff pressure measurements falling within the recommended range.

Graphene-Assisted Growth of Patterned Perovskite Films for Sensitive Light Detector and Optical Image Sensor Application.

Controlled growth of high-quality patterned perovskite films on a large scale is essentially required for the application of this class of materials in functional integrated devices and systems. Herein, graphene-assisted hydrophilic-hydrophobic surface-induced growth of Cs-doped FAPbI3 perovskite films with well-patterned shapes by a one-step spin-coating process is developed. Such a facile fabrication technique is compatible with a range of spin-coated perovskite materials, perovskite manufacturing processes, and substrates. By employing this growing method, controllable perovskite photodetector arrays are realized, which have not only prominent photoresponse properties with a responsivity and specific detectivity of 4.8 AW-1 and 4.2 × 1012 Jones, respectively, but also relatively small pixel-to-pixel variation. Moreover, the photodetectors array can function as an effective visible light image sensor with a decent spatial resolution. Holding the above merits, the proposed technique provides a convenient and effective pathway for large-scale preparation of patterned perovskite films for multifunctional application purposes.

miR-30 Family Reduction Maintains Self-Renewal and Promotes Tumorigenesis in NSCLC-Initiating Cells by Targeting Oncogene TM4SF1.

Increasing evidence indicates that tumor-initiating cells (TICs) are responsible for the occurrence, development, recurrence, and development of the drug resistance of cancer. MicroRNA (miRNA) plays a significant functional role by directly regulating targets of TIC-triggered non-small-cell lung cancer (NSCLC), but little is known about the function of the miR-30 family in TICs. In this study, we found the miR-30 family to be downregulated during the spheroid formation of NSCLC cells, and patients with lower miR-30a/c expression had shorter overall survival (OS) and progression-free survival (PFS). Moreover, transmembrane 4 super family member 1 (TM4SF1) was confirmed to be a direct target of miR-30a/c. Concomitant low expression of miR-30a/c and high expression of TM4SF1 correlated with a shorter median OS and PFS in NSCLC patients. miR-30a/c significantly inhibited stem-like characteristics in vitro and in vivo via suppression of its target gene TM4SF1, and then it inhibited the activity of the mTOR/AKT-signaling pathway. Thus, our data provide the first evidence that TM4SF1 is a direct target of miR-30a/c and miR-30a/c inhibits the stemness and proliferation of NSCLC cells by targeting TM4SF1, suggesting that miR-30a/c and TM4SF1 may be useful as tumor biomarkers for the diagnosis and treatment of NSCLC patients.

Thickness-Dependent Resistive Switching Behavior of KCu7S4/CuxO/Au Device.

We report the fabrication of KCu7S4/CuxO/Au devices with interfacial CuxO layers of different thicknesses through the spontaneous oxidation of Cu film during deposition. Deposition was conducted with an electron-beam evaporation system under the deposition rate and the chamber pressure of 0.1 Å s-1 and 9.8×10-3 Pa, respectively. X-ray diffraction and X-ray photoelectron spectroscopy characterizations reveal that the interfacial CuxO layers mostly comprise Cu2O and CuO. Electrical characterization reveals that the devices exhibit remarkably thickness-dependent resistive switching behavior. After undergoing an electroforming process under a high compliant current of 1000 µA, the KCu7S4/16 nm CuxO/Au device exhibits stable bipolar resistive switching behavior with the set voltage of 0.58 V and reset voltage of -0.21 V, whereas the KCu7S4/32 nm CuxO/Au device only shows a hysteresis loop in the forward voltage regime. These findings are ascribed to the existence of high-insulation CuO, which is difficult to be softly broken down. Therefore, the depositional condition of Cu film and the thickness of the interfacial layer should be appropriately controlled for the effective performance of devices with Cu electrodes. The results may also provide guidance for the improvement of the performance and stability of Cu-based nonvolatile memory devices.

Heterostructures Composed of N-Doped Carbon Nanotubes Encapsulating Cobalt and ß-Mo2 C Nanoparticles as Bifunctional Electrodes for Water Splitting.

Herein, we demonstrate the use of heterostructures comprised of Co/ß-Mo2 C@N-CNT hybrids for the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) in an alkaline electrolyte. The Co can not only create a well-defined heterointerface with ß-Mo2 C but also overcomes the poor OER activity of ß-Mo2 C, thus leading to enhanced electrocatalytic activity for HER and OER. DFT calculations further proved that cooperation between the N-CNTs, Co, and ß-Mo2 C results in lower energy barriers of intermediates and thus greatly enhances the HER and OER performance. This study not only provides a simple strategy for the construction of heterostructures with nonprecious metals, but also provides in-depth insight into the HER and OER mechanism in alkaline solution.

Embryonic transcriptome and proteome analyses on hepatic lipid metabolism in chickens divergently selected for abdominal fat content.

BACKGROUND: In avian species, liver is the main site of de novo lipogenesis, and hepatic lipid metabolism relates closely to adipose fat deposition. Using our fat and lean chicken lines of striking differences in abdominal fat content, post-hatch lipid metabolism in both liver and adipose tissues has been studied extensively. However, whether molecular discrepancy for hepatic lipid metabolism exists in chicken embryos remains obscure. RESULTS: We performed transcriptome and proteome profiling on chicken livers at five embryonic stages (E7, E12, E14, E17 and E21) between the fat and lean chicken lines. At each stage, 521, 141, 882, 979 and 169 differentially expressed genes were found by the digital gene expression, respectively, which were significantly enriched in the metabolic, PPAR signaling and fatty acid metabolism pathways. Quantitative proteomics analysis found 20 differentially expressed proteins related to lipid metabolism, PPAR signaling, fat digestion and absorption, and oxidative phosphorylation pathways. Combined analysis showed that genes and proteins related to lipid transport (intestinal fatty acid-binding protein, nucleoside diphosphate kinase, and apolipoprotein A-I), lipid clearance (heat shock protein beta-1) and energy metabolism (NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10 and succinate dehydrogenase flavoprotein subunit) were significantly differentially expressed between the two lines. CONCLUSIONS: For hepatic lipid metabolism at embryonic stages, molecular differences related to lipid transport, lipid clearance and energy metabolism exist between the fat and lean chicken lines, which might contribute to the striking differences of abdominal fat deposition at post-hatch stages.

Dual-plasmonic Au/graphene/Au-enhanced ultrafast, broadband, self-driven silicon Schottky photodetector.

High-performance photodetectors are desirable for various applications, including multi-wavelength image sensing, communication, and safety monitoring. In this study, we report the construction of a dual-surface plasmon-enhanced silicon Schottky photodetector using Au nanoparticles (NPs)/graphene/Au NPs hybrid structure as the electrode. It was found that the as-assembled device exhibited broad sensitivity, ranging from ultraviolet to near-infrared light (360-1330 nm) at room temperature, with a high response speed of 360 ns and a 3 dB bandwidth of 780 kHz at zero bias. Further theoretical simulation based on the finite-element method revealed that good device performance is associated with the contribution of the Au NPs/graphene/Au NPs electrode: intense dual-plasmonic resonance coupling is induced in a hybrid structure of two layers of metallic NPs separated by a uniform monolayer graphene. It not only can enhance light trapping and the localized electric field at the resonant and off-resonant wavelength regions, but is also beneficial for the tunneling of hot electrons. This work demonstrated the great potential of dual-plasmonic resonance coupling in optoelectronic devices and will lead to the development of advanced plasmonic devices.

Lowering serum lipids via PCSK9-targeting drugs: current advances and future perspectives.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), also known as neural apoptosis regulated convertase (NARC1), is a key modulator of cholesterol metabolism. PCSK9 increases the serum concentration of low-density lipoprotein cholesterol by escorting low-density lipoprotein receptors (LDLRs) from the membrane of hepatic cells into lysosomes, where the LDLRs are degraded. Owing to the importance of PCSK9 in lipid metabolism, considerable effort has been made over the past decade in developing drugs targeting PCSK9 to lower serum lipid levels. Nevertheless, some problems and challenges remain. In this review we first describes the structure and function of PCSK9 and its gene polymorphisms. We then discuss the various designs of pharmacological targets of PCSK9, including those that block the binding of PCSK9 to hepatic LDLRs (mimetic peptides, adnectins, and monoclonal antibodies), inhibit PCSK9 expression (the clustered regularly interspaced short palindromic repeats/Cas9 platform, small molecules, antisense oligonucleotides, and small interfering RNAs), and interfere with PCSK9 secretion. Finally, this review highlights future challenges in this field, including safety concerns associated with PCSK9 monoclonal antibodies, the limited utility of PCSK9 inhibitors in the central nervous system, and the cost-effectiveness of PCSK9 inhibitors.

Comparative proteome analysis of abdominal adipose tissues between fat and lean broilers.

BACKGROUND: The molecular mechanism underlying broiler fat deposition is still poorly understood. METHOD: Currently, we used two-dimensional gel electrophoresis (2DE) to identify differentially expressed proteins in abdominal adipose tissues of birds at 4 week of age derived from Northeast Agricultural University broiler lines divergently selected for abdominal fat content (NEAUHLF). RESULTS: Thirteen differentially expressed protein spots were screened out and identified by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The protein spots were matched to thirteen proteins by searching against the NCBInr database. These identified proteins were apolipoprotein A-I (Apo A-I), cytokeratin otokeratin, ATP synthase subunit alpha, peptidyl-prolyl cis-trans isomerase FKBP4 (PPIase FKBP4), aspartate aminotransferase, carbonic anhydrase II (CA-II), prostaglandin-H2 D-isomerase precursor, fibrinogen alpha chain, lamin-A (LMNA), superoxide dismutase [Mn] (MnSOD), heat shock protein beta-1 (HSPß1) and two predicted proteins. These differentially expressed proteins are involved mainly in lipid metabolism, amino acid metabolism, signal transduction, energy conversion, antioxidant, and cytoskeleton. Differential expression of Apo A-I, PPIase FKBP4, and cytokeratin otokeratin proteins were further confirmed by Western blot analysis. Quantitative real-time RT-PCR analyses showed that, of these 13 differentially expressed proteins, only PPIase FKBP4 and cytokeratin otokeratin were differentially expressed at mRNA level between the two lines. CONCLUSIONS: Our results have provided further information for understanding the basic genetics control of growth and development of broiler adipose tissue.

Plasmonic silver nanosphere enhanced ZnSe nanoribbon/Si heterojunction optoelectronic devices.

In this study, we report a localized surface plasmon resonance (LSPR) enhanced optoelectronic device based on a ZnSe:Sb nanoribbon (NR)/Si nano-heterojunction. We experimentally demonstrated that the LSPR peaks of plasmonic Ag nanoparticles (Ag NPs) can be readily tuned by changing their size distribution. Optical analysis reveals that the absorption of ZnSe:Sb NRs was increased after the decoration of the Ag NPs with strong LSPR. Further analysis of the optoelectronic device confirmed the device performance can be promoted: for example, the short-circuit photocurrent density of the ZnSe/Si heterojunction solar cell was improved by 57.6% from 11.75 to 18.52 mA cm(-2) compared to that without Ag NPs. Meanwhile, the responsivity and detectivity of the ZnSe:Sb NRs/Si heterojunction device increased from 117.2 to 184.8 mA W(-1), and from 5.86 × 10(11) to 9.20 × 10(11) cm Hz(1/2) W(-1), respectively.

The effect of plasmonic nanoparticles on the optoelectronic characteristics of CdTe nanowires.

In this work, a simple strategy is proposed to improve the device performance of photodetector by modifying plasmonic nanoparticles onto the surface of semiconductors nanostructure. Both experimental analysis and theoretical simulation show that the plasmonic metal nanoparticles (AuNPs) exhibits obvious localized surface plasmon resonance (LSPR) which can trap incident light efficiently, leading to enhanced photocurrents and improved performance of photoelectronic devices. It is also observed that the AuNPs modified CdTeNW photodetector exhibit apparent sensitivity to 510 nm light, to which pure CdTeNWs is virtually blind. What is more, after AuNPs decoration, the response speed of the photodetector is increased substantially from 6.12 to 1.92 s. It is believed that this result will open up new doors for manipulating light and further improving the efficiency of semiconductor nanostructures based optoelectronic devices.

Prognostic significance of cyclooxygenase-2 protein in pancreatic cancer: a meta-analysis.

We conducted a meta-analysis of relevant cohort studies to investigate the relationships between cyclooxygenase-2 (COX-2) protein and the prognosis of pancreatic cancer. The following electronic databases were searched without language restrictions: MEDLINE (1966∼2013), the Library Database (Issue 12, 2013), EMBASE (1980∼2013), CINAHL (1982∼2013), Web of Science (1945∼2013), and the Chinese Biomedical Database (CBM) (1982∼2013). Meta-analysis was performed using the STATA statistical software. Six cohort studies with a total of 712 pancreatic cancer patients were involved in this meta-analysis. Our findings showed that COX-2-positive patients were significantly associated with a shorter overall survival (OS) than COX-2-negative patients (hazard ratio (HR) = 1.48, 95 % confidence interval (95%CI) = 1.12∼1.85, P < 0.001). A subgroup analysis by ethnicity also revealed that pancreatic cancer patients with an abnormal COX-2 expression exhibited a worse OS than COX-2-negative patients among both Asians and Caucasians (Asians: HR = 1.40, 95%CI = -0.09∼2.89, P = 0.066; Caucasians: HR = 1.49, 95%CI = 1.11∼1.87, P < 0.001, respectively). Our findings provide empirical evidence that abnormal COX-2 expression may be strongly correlated with poor prognosis for patients with pancreatic cancer. Thus, COX-2 protein may be a useful biomarker for pancreatic cancer.

Expression and functional analyses of Krüppel-like factor 3 in chicken adipose tissue.

Studies in mammalian species showed that Krüppel-like factor 3 (KLF3) regulated adipose tissue development. However, it was not reported in chicken. In the current study, we found that during the growth and development of abdominal fat tissue, chicken KLF3 (Gallus gallus KLF3, gKLF3) was consecutively expressed, and its transcripts were higher at 7 weeks of age and lower at 10 weeks of age in lean broilers than in fat broilers. In addition, gKLF3 overexpression suppressed chicken CCAAT/enhancer binding protein alpha (C/EBPα), fatty acid binding protein 4 (FABP4), fatty acid synthase (FASN), and lipoprotein lipase (LPL) promoter activities, but increased chicken peroxisome proliferator-activated receptor gamma (PPARγ) promoter activity. Additionally, point mutagenesis analysis showed that the substitution of Asp by Gly within the Pro-Val-Asp-Leu-Thr (PVDLT) motif of gKLF3 significantly reduced the ability of gKLF3 to regulate the promoter activities of FABP4, FASN, LPL, C/EBPα, and PPARγ.