Search

Objective: This article is a Meta-analysis aiming to systematically evaluate the difference in efficacy of immune checkpoint inhibitor in patients with non-small cell lung cancer (NSCLC) by age., Methods: We performed a Meta-analysis of published randomized controlled trials concerning for patients with NSCLC by age. We compared overall survival among three groups (age <65 years, age 65-75 years, age ≥75 years). Hazard ratios (HRs) and 95% confidence intervals (CIs) were collected and pooled., Results: A total of 10,291 patients from 17 RCTs were included. In the group under age 65 years, immune checkpoint inhibitor can significantly prolong the overall survival of patients with NSCLC (HR = 0.73, 95% CI: 0.66∼0.81, P < 0.00001). In the age 65-75 years group, immune checkpoint inhibitors prolonged overall survival in patients with NSCLC (HR = 0.78, 95% CI:0.71∼0.84, P < 0.00001). However, it has no significant effect on the overall survival of NSCLC patients (HR = 0.88, 95% CI:0.72∼1.08, P > 0.05) in the group older than 75 years., Conclusions: Immune checkpoint inhibitors prolonged the overall survival of NSCLC patients in the age <65 years group and the age 65-75 years group, but in the age ≥75 years group, there was no significant effect on overall survival. This may be related to innate immune and adaptive immune dysregulation due to "immunosenescence" in older patients., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Asian Surgical Association and Taiwan Society of Coloproctology. Published by Elsevier B.V. All rights reserved.)

Both artificially synthesized and naturally occurring cyclic chalcones have been widely studied for their excellent biological activities. However, research on its photophysical properties is still limited. In the present study, we designed and synthesized a small molecule fluorescent dye based on the ICT effect, using dimethylamino as the electron-donating group and carbonyl as the electron withdrawing group, and investigated its photophysical properties in depth. Although YB is a simple small molecule, it exhibits significant piezochromic properties. The fluorescence of YB can change from green to yellow through grinding. After solvent fumigation, the fluorescence reverts to green. Furthermore, YB was used successfully in the lysosomal targeting. This study expands the research on the photophysical properties of cyclic chalcone and give richness to application of cyclic chalcone compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

To evaluate the outcomes of robot-assisted partial nephrectomy (RAPN) for solid and cystic renal tumors. We systematically searched the Cochrane Library, PubMed, EMBASE, and Scopus databases up to March 2023. Review Manager 5.4 performed a pooled analysis of the data for random effects. Besides, sensitivity and subgroup analyses to explore heterogeneity, Newcastle-Ottawa scale, and GRADE to evaluate study quality and level of evidence. Five observational studies comprising 1353 patients (Cystic tumor: 183; Solid tumor: 1083) were included in this study. Compared to solid masses, cystic masses were associated with fewer major complications (odds ratio [OR] = 2.2; 95% confidence intervals [CI] = 1.17 to 4.13; p = 0.01). Additionally, no significant differences were observed between the two groups in terms of operative time, warm ischemia time, blood loss, hospital stay, intraoperative complications, postoperative complications, transfusion rate, postoperative estimated glomerular filtration rate (eGFR), eGFR preservation, positive surgical margin (PSM), recurrence, overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS) and trifecta achievement. RAPN can be performed in cystic renal tumors with perioperative, functional, and oncologic outcomes like those achievable in solid tumors. However, our findings need further validation in a large-sample prospective randomized study., Competing Interests: Declaration of competing interest The authors declares that they have no conflict of interest. All participating authors have no declaration of interest., (Copyright © 2023 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

The level of HClO/ClO - in mitochondria is essential to keep the normal function of mitochondria. Therefore, it is meaningful to accurately and quickly monitor ClO - in mitochondria. In this work, a new triphenylamine-based fluorescence probe PDTPA was designed and synthesized, in which pyridinium salt and dicyano-vinyl group were introduced as mitochondria targeting site and reaction site for ClO - . The probe showed high sensitivity and fast fluorescence response (<10 s) in the detection of ClO - . Moreover, the probe PDTPA had good linearity in a wide concentration range of ClO - and its detection limit was calculated as 10.5 μM. Confocal fluorescence images demonstrated that the probe could target mitochondria and track the fluctuations of endogenous/exogenous ClO - levels in the mitochondria of living cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Peroxynitrite is widely present in organisms and closely related to many pathophysiological functions. Therefore, it is of great physiological significance to develop capable probes for detecting ONOO - . In this work, a novel fluorescent probe B-Ch was designed based on the intramolecular charge transfer (ICT) effect. By means of molecular engineering, the replacement from diethylamine group to hydroxyl group has improved the detection sensitivity of the probe. After the addition of ONOO - , the solution color and fluorescence showed noticeable changes, which were visible to the naked eye. The probe showed excellent advantages: visualization, good selectivity, low sensitivity (22.4 nM), good stability and biocompatibility, exogenous and endogenous imaging of ONOO - in HeLa cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

There is an urgent need to develop highly sensitive and selective fluorescence probes for ONOO - in mitochondria. Herein, we reported a ratiometric fluorescent probe COUS with coumarin-cyanine hybrid as fluorophore and C = C bonds as reaction sites of ONOO - . The probe COUS was sensitive and selective to ONOO - , and had a large fluorescence emission shift (239 nm) as well as a low detection limit (41.88 nM). Moreover, COUS showed the mitochondrial targeting ability, and the targeting moiety could dissociate from the probe when reacting with ONOO - , which enabled COUS to accurately detect ONOO - in mitochondria., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Biothiols mainly include cysteine (Cys), homocysteine (Hcy) and glutathione (GSH), which play an important role in life activities and abnormal changes in their concentrations are closely related to certain diseases. Therefore, the quantitative tracking and analysis of biothiols in living organisms has become a hot research topic in recent years. In this work, a coumarin-based fluorescent probe COUN was designed and synthesized for the comparable color recognition of Cys/Hcy and GSH by introducing the phenylethynyl group as the recognition site of biothiols, which showed significant fluorescence enhancement and green fluorescence under the UV light at 365 nm. The probe specifically recognized Hcy, showing 40-fold fluorescence enhancement and strong green fluorescence at 492 nm. Moreover, there was a good linear relationship between the fluorescence intensity of the probe and certain concentrations of Cys/Hcy and GSH, with detection limits of 36.6 nM, 86.4 nM, and 174 nM, respectively. The recognition mechanism of COUN to distinguish Cys/Hcy and GSH was studied by TDDFT calculations. More importantly, COUN was successfully used for imaging biothiols in living cells. The results showed that this probe could provide an effective contribution to the understanding of the role of biothiols, especially Hcy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Fluorescent probes for H 2 S are often interfered by other thiols. In this work, a coumarin-pyrazole dye with 2,4-dinitrosulfonyl group was designed for the detection of H 2 S. The probe exhibits weak fluorescence in water due to the photo induced electron transfer (PET) by 2,4-dinitrosulfonyl. After the sulfonyl group is cleaved off by H 2 S, strong fluorescence appears. The probe can specifically detect H 2 S without being interfered by other biological thiols, and shows a wide applicable pH range, low detection and wide detection range. The excellent detection properties of the probe can also be used to detect endogenous and exogenous H 2 S in cells. In addition, the probes can be made into portable test paper for the detection of H 2 S in solutions and can detect H 2 S in different water samples., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Monitoring intracellular pH using ratiometric fluorescent probes can provide further insights into various biological processes including many diseases. Although ratiometric fluorescent probes with dual emission can efficiently exclude interferences (probe concentration, instrumental efficiency, and environmental conditions) compared with traditional off-on fluorescent probes, development of pH-responsive fluorescent probes with dual emission remains relatively unexplored and challenging. Herein we reported a new hemicyanine-based ratiometric fluorescent probe 1 with a hydroxyl group. The probe 1 exhibits dual emission and shows a real-time and selective fluorescence response to micro-environmental pH conditions in a range of 6.0 ∼ 8.0. Further studies revealed that 1 could exclusively enter and accumulate into mitochondria and monitor the pH micro-environmental conditions through fluorescence imaging in HepG2 cells. We suggest that this probe might be used as a probe to elucidate the role of pH in many physiological processes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Migraine is characterized by a well-defined premonitory phase occurring hours or even days before the headache. Also, many migraineurs report typical triggers for their headaches. Triggers, however, are not consistent in their ability to precipitate migraine headaches. When looking at the clinical characteristics of both premonitory symptoms and triggers, a shared pathophysiological basis seems evident. Both seem to have their origin in basic homeostatic networks such as the feeding/fasting, the sleeping/waking, and the stress response network, all of which strongly rely on the hypothalamus as a hub of integration and are densely interconnected. They also influence the trigeminal pain processing system. Additionally, thalamic and hormonal mechanisms are involved. Activity within all those networks is influenced by various endogenous and external factors and might even cyclically change dependent on physiological internal rhythms. This might affect the threshold for the generation of migraine headaches. Premonitory symptoms thus appear as the result of an already ongoing alteration within those networks, whereas triggers might in this special situation only be able to further stress the system over the threshold for attack generation as catalysts of a process already in motion., (Copyright © 2023 Elsevier B.V. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

A novel near-infrared fluorescent probe CyOE based on hemicyanine dye containing acetyl as a recognition site is reported. The probe CyOE shows high selectivity and sensitivity (LOD = 82 nM, 2.58 ppb), as well as good water solubility and quantitative detectability of hydrazine in the concentration range of 0-75 μM (R 2  = 0.993). Moreover, CyOE has a significant increase in fluorescence at 735 nm with the addition of N 2 H 4 , which provides a rapid, colorimetric and gas-phase detection method for N 2 H 4 in both aqueous solution and real water samples. In addition, CyOE is successfully utilized to visualize hydrazine in cells with low cytotoxicity and high cell permeability., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: We aimed to determine the association between newborn bacterial colonization and infant respiratory morbidity in the first 6 months of life., Methods: This prospective study included healthy newborn infants. Nasopharyngeal swabs performed within 72 hours of delivery were analyzed using polymerase chain reaction. We assessed cumulative respiratory morbidity of infants at 6 months., Results: A total of 426 mother-infant pairs were recruited. In 53.3% (n = 225) of newborns, Streptococcus pneumoniae (46%) and Staphylococcus aureus (7.3%) were isolated. None had Haemophilus influenzae nor Moraxella catarrhalis. At the age of 6 months, 50.7% of infants had experienced respiratory symptoms, 25% had unscheduled doctor visits, and 10% were treated with nebulizers. Colonization with S. pneumoniae was associated with reduced risk of any respiratory symptom (adjusted odds ratio [aOR] 0.39, 95% confidence interval [CI] 0.16, 0.50), unscheduled doctor visits (aOR 0.35; 95% CI 0.18, 0.67), and nebulizer treatment (aOR 0.23, 95% CI 0.07, 0.72) at 6 months. Pregnancy-induced hypertension was also associated with increased need for nebulizer treatment (aOR 9.11, 95% CI 1.43, 58.1)., Conclusion: Colonization of the newborn respiratory tract occurred in 53% of infants. S. pneumoniae was the most common organism, and this was associated with a reduced risk for respiratory morbidity at 6 months of life., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Complements and neutrophils are two key players of the innate immune system that are widely implicated as drivers of severe COVID-19 pathogenesis, as evident by the direct correlation of respiratory failure and mortality with elevated levels of terminal complement complex C5b-9 and neutrophils. In this study, we identified a feed-forward loop between complements and neutrophils that could amplify and perpetuate the cytokine storm seen in severe SARS-CoV-2-infected patients. We observed for the first time that the terminal complement activation complex C5b-9 directly triggered neutrophil extracellular trap (NET) release and interleukin (IL)-17 production by neutrophils. This is also the first report that the production of NETs and IL-17 induced by C5b-9 assembly on neutrophils could be abrogated by mesenchymal stem cell (MSC) exosomes. Neutralizing anti-CD59 antibodies abolished this abrogation. Based on our findings, we hypothesize that MSC exosomes could alleviate the immune dysregulation in acute respiratory failure, such as that observed in severe COVID-19 patients, by inhibiting complement activation through exosomal CD59, thereby disrupting the feed-forward loop between complements and neutrophils to inhibit the amplification and perpetuation of inflammation during SARS-CoV-2 infection., Competing Interests: Declaration of Competing Interests SKL holds founding shares in Paracrine Therapeutics., (Copyright © 2022 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Organic fluorescent molecules with π-conjugated system have shown great importance in numerous applications including bioimaging and optoelectronics. Planar aggregation-induced emissive (AIE) organic compounds with efficient solid-state luminescence are rarely developed and urgently needed in various applications. In this work, highly planar 4-styrylbenzonitrile derivatives have been synthesized. Most of these compounds show strong AIE properties with hundred-fold fluorescent enhancement. Moreover, these molecules are deep blue emissive in solid state, exhibiting good to excellent fluorescence quantum efficiency. The single crystal analysis shows that adjacent molecules could form special J-type aggregation. The intramolecular rotations are efficiently restricted by various noncovalent interactions. These molecular arrangements could be essential for the observed strong emission in aggregated and solid state. This work has paved a new path to efficient AIE-active organic emitters with highly planar conformations from 4-styrylbenzonitrile structure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Flavonoids, alkaloids, glucosides and tannins with good corrosion inhibition are the main natural components in plants. In this work, procyanidin B2 (PCB2), a natural flavonoid, was firstly isolated from Uncaria laevigata. Corrosion inhibition, chemical reactivity and adsorption of PCB2 on Q235 carbon steel were described by experimental and theoretical studies. The inhibition performance of PCB2 as a green corrosion inhibitor was evaluated by electrochemical and gravimetric tests. The binding active sites and activities thereof on the steel surface were illustrated by quantum chemistry, and the equilibrium configuration was predicted by molecular dynamics simulation. PCB2 exhibits good corrosion inhibition on Q235 steel over a wide temperature range. The electrochemical results show that PCB2 is a mixed inhibitor, and its inhibition efficiency increases with the addition of PCB2 concentration. Moreover, the protective film is formed on the steel and the active corrosion sites are blocked significantly by surface analysis. Additionally, the theoretical calculation proves a strong interaction between PCB2 molecule and carbon steel. Besides, the antimicrobial activity was also preliminarily studied. This suggests that PCB2 exhibits better antimicrobial activity against many Gram-positive and Gram-negative bacteria. As a novel green corrosion inhibitor and antimicrobial agent, PCB2 is worthy of further exploitation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Studies have shown that changes in the redox state of cells might be closely related to pathological and physiological processes. Sulfur dioxide and hydrogen peroxide, as a significant redox couple in living cells, are endogenously produced by cells. Here, we report a long-wavelength fluorescent probe to reversibly monitor sulfur dioxide and hydrogen peroxide. This probe (NBD) displayed high selectivity and sensitivity, which could be accumulated in mitochondria for real-time imaging of SO 2 /H 2 O 2 . These results indicated that NBD would be an ideal tool for monitoring the redox cycle state in living cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Amines are widely used in many fields including agriculture, dyes, medicine and food processing. However, volatile amine vapors could initiate acute and serious damage to human bodies. Thus, highly efficient detection of volatile amine vapors has great importance for academic research as well as practical application. In this work, a turn-on type fluorescent sensor BZCO has been developed, which could be used to detect volatile amine vapors. The portable BZCO sensor can be easily prepared through immersing filter paper into its CH 2 Cl 2 solution and then evaporating it to dryness. This paper-based amine vapor sensor exhibits high sensitivity with a relatively low detection limit at 3.82 ppm. It also has good selectivity for discriminating amine vapors from volatile organic solvents. The detection mechanism has been confirmed by UV-vis spectral analysis. The practical applications of this paper-based BZCO sensor, such as detection of food spoilage and fluorescent security ink, have been investigated. This work has developed a new fluorescent sensor BZCO, which has broad applications in various fields, including amine gas detection, security and anti-counterfeiting materials., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Rituximab is an important second line therapy in difficult nephrotic syndrome (NS), especially given toxicity of long-term glucocorticoid or calcineurin inhibitor (CNI) use. However, clinical response to rituximab is heterogenous. We hypothesized that this was underpinned by immunological differences amongst patients with NS. We recruited a cohort of 18 subjects with glucocorticoid-dependent or glucocorticoid-resistant childhood-onset minimal change NS who received rituximab either due to CNI nephrotoxicity, or due to persistent glucocorticoid toxicity with inadequate response to cyclophosphamide or CNIs. Immunological subsets, T-cell activation assays and plasma cytokines were measured at baseline and 6-months post-rituximab. Time to relapse was bifurcated: 56% relapsed within one year ("early relapse"), while the other 44% entered remission mainly lasting ≥3 years ("sustained remission"). At baseline, early relapse compared to sustained remission group had lower regulatory T-cells (Tregs) [2.94 (2.25, 3.33)% vs 6.48 (5.08, 7.24)%, P<0.001], PMA-stimulated IL-2 [0.03 (0, 1.85)% vs 4.78 (0.90, 9.18)%, P=0.014] and IFNγ [2.22 (0.18, 6.89)% vs 9.47 (2.72, 17.0)%, P=0.035] levels. Lower baseline Treg strongly predicted early relapse (ROC-AUC 0.99, 95% CI 0.97-1.00, P<0.001). There were no differences in baseline plasma cytokine levels. Following rituximab, there was significant downregulation of Th2 cytokines in sustained remission group (P=0.038). In particular, IL-13 showed a significant decrease in sustained remission group [-0.56 (-0.64, -0.35)pg/ml, P=0.007)], but not in the early relapse group. In conclusion, early relapse following rituximab is associated with baseline reductions in Treg and T-cell hyporesponsiveness, which suggest chronic T-cell activation and may be useful predictive biomarkers. Sustained remission, on the other hand, is associated with downregulation of Th2 cytokines following rituximab., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Herein, a new "turn on" fluorescent probe C-1 is developed to specifically detect hydrazine using coumarin nucleus as the fluorophore and β-diketone as the recognition group. The probe shows high selectivity towards hydrazine over other common ions and amine-containing species, as well as good water solubility and quantitative detectability of hydrazine in concentration range of 1-200 μM. The detection limit is as low as 1.89 ppb, which is lower than the threshold set by EPA (10 ppb). Probe-coated filter papers are confirmed to detect gaseous hydrazine successfully through obvious fluorescence color changes. In addition, the probe has been verified to detect hydrazine in actual water environment and living cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The spatiotemporal trend of renal involvement in coronavirus disease 2019 (COVID-19) patients is still unclear. Therefore, the aim of this study was to reveal the dynamics of renal involvement superimposed COVID-19 according to time and space., Methods: COVID-19 patients reporting renal involvement were included in this study. The following information was collected from relevant articles: first author, patient demographics, patient enrollment period, location, definition of acute kidney injury (AKI), prevalence of AKI, and use of renal replacement therapy (RRT)., Results: A total of 17 134 patients were finally included. The overall prevalence of AKI in COVID-19 patients was 19%, with 7% of them undergoing RRT. The overall risk of AKI in patients enrolled before March 1, 2020 (9%) was significantly lower than that after March 1, 2020 (36%) (P < 0.00001). Moreover, the overall risk of AKI outside Asia (35%) was significantly higher than that in Asia (10%) (P < 0.00001). Additionally, similar to patients requiring RRT, AKI patients were more likely to become seriously ill or even to die (P < 0.00001)., Conclusions: This study found that renal involvement superimposed COVID-19, a comorbidity portending a poor prognosis, has become an increasingly serious problem over time and is more common outside Asia. Thus, more attention should be paid to the management of this specific group of patients., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In insects, the cytochrome P450 CYP6B family plays key roles in the detoxification of toxic plant substances. However, the function of CYP6 family genes in degrading plant toxicants in Tribolium castaneum, an extremely destructive global storage pest, have yet to be elucidated. In this study, a T. castaneum CYP gene, TcCYP6BQ7, was characterized. TcCYP6BQ7 expression was significantly induced after exposure to essential oil of the plant Artemisia vulgaris (EOAV). Spatiotemporal expression profiling revealed that TcCYP6BQ7 expression was higher in larval and adult stages of T. castaneum than in other developmental stages, and that TcCYP6BQ7 was predominantly expressed in the brain and hemolymph from the late larval stage. TcCYP6BQ7 silencing by RNA interference increased larvae mortality in response to EOAV from 49.67% to 71.67%, suggesting that this gene is associated with plant toxicant detoxification. Combined results from this study indicate that the CYP6 family gene TcCYP6BQ7 likely plays a pivotal role in influencing the susceptibility of T. castaneum to plant toxicants. These findings may have implications for the development of novel therapeutics to control this agriculturally important pest., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Soils in large areas of China are enriched in fluorine (F). The present study analyzed F concentrations in cultivated soil, water, chemical fertilizer, and human hair, and metal concentrations in soils from an endemic fluorosis area in Southwest, China. In order to reveal the effects of industry on F concentration in the environment, 3 towns mainly with agriculture production and another 3 towns with developed phosphorus chemical industry in a same city were selected for sample collection. The total F concentrations of the 277 surface agricultural soil samples were 378.79-1576.13 μg g -1 , and F concentrations of nearly 95% of the soil samples were higher than the Chinese average topsoil F concentration (480 μg g -1 ). Only a small fraction (0.75%) of total F was water soluble. The average total F, water soluble F, Ca, Cr, Fe, K, Mn, Rb, and Sr concentrations in soil samples from towns with intensive industry were higher than those from towns mainly with agriculture. Significant correlations were found between soil pH with total F (p < 0.01) and with water soluble F concentration (p < 0.1). Low F concentrations (<0.5 mg L -1 ) were found in irrigation water, well water and tap water in a town where the industry is dense. The phosphorus fertilizer and compound fertilizer had hundreds of times of contribution to soil F increment than the nitrogen fertilizer and potassium fertilizer. Nearly half percent of F in the human hair samples was of exogenic origin. Based on soil ingestion pathway, the health risk for adults exposure to F in soils was acceptable, however, F may pose possible health risks to children in high F concentration areas., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Biological thiols including homocysteine (Hcy), cysteine (Cys), hydrogen sulfide (H 2 S) and glutathione (GSH) play crucial roles in various pathological and physiological processes. The development of optical probes for biothiols has been an active research area in recent years. Herein, a new turn-on fluorescence probe (HD-NBD) was designed and synthesized by fusing tetrahydro[5]helicene and 7-nitro-2,1,3-benzoxadiazole (NBD) for simultaneous discrimination of Hcy/Cys, H 2 S and GSH in aqueous solution. This probe is able to show unique absorbance enhancement at 548 nm for H 2 S and additional fluorescence enhancement at 536 nm only for Cys/Hcy, which can be used to discriminate H 2 S, Cys/Hcy and GSH simultaneously. In addition, HD-NBD also shows low background without any self-fluorescence, as well as high selectivity toward common biothiols. The low detection limits of this probe are about 0.15 μM for Hcy with a wide linear range (1-80 μM), 0.36 μM for Cys (linear range: 1-45 μM), 0.79 μM for H 2 S (linear range: 1-80 μM) and 4.44 μM for GSH (linear range: 1-60 μM). Moreover, HD-NBD can identify Hcy/Cys, H 2 S from GSH and other amino acids with high sensitivity and selectivity, therefore it could be used for detecting endogenous and exogenous Hcy/Cys under biological condition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Hydrogen sulfide shows great importance in various physiological and biochemical processes. The development of fluorescence probes for facile and efficient detection of H 2 S has attracted increasing attention of researchers. Herein, we synthesized two fluorescence probes based on simple naphthalene structure for detection of H 2 S. Upon reaction with H 2 S, the probe DN-DM exhibited a red fluorescence emission with large Stokes shift. The probe showed high sensitivity, pH insensitivity and good selectivity for H 2 S over other analytes including common biothiols. The detection mechanism was based on the thiolysis of the dinitrophenyl ether moiety, which was confirmed by 1 H NMR spectral analysis. The DFT calculation was also performed for a deeper understanding of the photophysical properties. In addition, these probes showed good cell-membrane permeability and could be utilized for detection of H 2 S in living cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019. Published by Elsevier B.V.)

Distal nerve transfer is used to treat lower brachial plexus palsy, but outcome series on these transfer procedures following lower plexus injuries are sparse. The objective of this study is to compare treatment outcomes after nerve transfer using the brachialis motor branch (BMB) versus that using the pronator teres motor branch (PTMB). One hundred twenty adult rats with C8T1 nerve root avulsion were randomly divided into three groups (40 each): A: BMB transfer to the anterior interosseous nerve (AIN), B: PTMB transfer to the AIN, and C: no repair. Electrophysiological examination result, muscle tension test result, muscle weight and muscle fiber cross-sectional area of the flexor digitorum profundus and flexor pollicis longus, and number of myelinated nerve fibers in the AIN were compared among the groups to evaluate the treatment outcome. Nerve regeneration and muscle recovery in group B was better than those in group A at 4 and 8 weeks postoperatively (P < 0.05). There was no significant difference in the myelinated nerve fibers in groups A and B at 12 and 16 weeks postoperatively. The rats in group B showed greater and more significant improvement in other measured values than those in group A (P < 0.05). In conclusion, the PTMB seems a better donor nerve than the BMB for distal nerve transfer to treat lower brachial plexus injury according to the electrophysiological and histological examination in this rat study., Competing Interests: Declaration of Competing Interest The authors have no personal financial or institutional interest in the materials or methods described in this paper., (Copyright © 2019. Published by Elsevier Ltd.)

Background: This study compared the genomes of influenza viruses that caused mild infections among outpatients and severe infections among hospitalized patients in Singapore, and characterized their molecular evolution and receptor-binding specificity., Methods: The complete genomes of influenza A/H1N1, A/H3N2 and B viruses that caused mild infections among outpatients and severe infections among inpatients in Singapore during 2012-2015 were sequenced and characterized. Using various bioinformatics approaches, we elucidated their evolutionary, mutational and structural patterns against the background of global and vaccine strains., Results: The phylogenetic trees of the 8 gene segments revealed that the outpatient and inpatient strains overlapped with representative global and vaccine strains. We observed a cluster of inpatients with A/H3N2 strains that were closely related to vaccine strain A/Texas/50/2012(H3N2). Several protein sites could accurately discriminate between outpatient versus inpatient strains, with site 221 in neuraminidase (NA) achieving the highest accuracy for A/H3N2. Interestingly, amino acid residues of inpatient but not outpatient isolates at those sites generally matched the corresponding residues in vaccine strains, except at site 145 of hemagglutinin (HA). This would be especially relevant for future surveillance of A/H3N2 strains in relation to their antigenicity and virulence. Furthermore, we observed a trend in which the HA proteins of influenza A/H3N2 and A/H1N1 exhibited enhanced ability to bind both avian and human host cell receptors. In contrast, the binding ability to each receptor was relatively stable for the HA of influenza B., Conclusions: Overall, our findings extend our understanding of the molecular and structural evolution of influenza virus strains in Singapore within the global context of these dynamic viruses., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The current review provides a recapitulation of recent advances in pharmacological neuroimaging in headache, a promising tool to understanding of how a drug works in the brain and how it may lead to new insights of disease mechanisms of headache., Results: Pharmacological positron emission tomography with radioligand-labeled medication may provide evidence whether and where a medication binds in the brain but is still mostly restricted to animal work. Pharmacological functional MRI using task-specific approaches identified central modulation patterns as a consequence of attack and preventative headache medication, which may be distinct to a specific drug mechanism. Pharmacological neuroimaging and specifically in combination with functional imaging is a promising tool to better understand not only certain medications but also certain disease mechanisms., Summary: Pharmacological imaging techniques have advanced over the last few years and showed great potential of providing new insights into drug pharmacodynamics and disease mechanism. There are still limitations and challenges to be overcome., (© 2020 Elsevier B.V. All rights reserved.)

Background: Emerging data suggest the crucial regulatory roles of circular RNAs (circRNAs) in hepatocellular carcinoma (HCC). However, the pathophysiology role of circZFR in HCC remains largely unknown., Aims: This study aims to disclose the functions of circZFR in HCC progression and its potential molecular mechanism., Methods: circZFR and miR-511 were identified by qRT-PCR. Colony formation assay, wound-healing assay, transwell assay, and flow cytometry assay were performed to determine the cell proliferation, migration, invasion and apoptosis. Western blotting and immunohistochemistry (IHC) were utilized to evaluate the expression level of AKT1, GSK3β, β-catenin and cascades of proliferation-related proteins both in vitro and in vivo. Dual luciferase reporter assay was conducted to evaluate the interactions among circZFR, miR-511 and AKT1., Results: The expression of circZFR was enhanced and the expression of miR-511 was down-regulated in HCC tissues and cells. Functionally, circZFR silencing or miR-511 overexpression suppressed cell proliferation, migration and invasion, and induced apoptosis of HCC cells. Mechanistically, circZFR acted as a miR-511 sponge to up-regulate its target gene AKT1, which activated cascades of proliferation-related proteins (c-Myc, cyclin D1, Survivin and Bcl-2). Furthermore, depletion of circZFR inhibited tumorigenesis and decreased the expression level of AKT1 in xenograft models., Conclusion: circZFR promotes HCC progression by directly down-regulating miR-511 to activate AKT1 signaling, suggesting that circZFR is a potential target in HCC treatment. Targeting circZFR may provide therapeutic benefits for HCC., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Hydrogen sulfide (H 2 S) is a kind of gaseous signal molecule in many physiological processes. In order to detect H 2 S, a novel "turn on" fluorescent probe 6,12-dihydroxyperylene-1,7-dione (DPD) was designed and synthesized. The probe DPD is fluorescence silence, while the addition of H 2 S induces an obvious green fluorescence with an obvious color change from dark blue to yellow-green. The probe shows excellent selectivity, fast response (2.5min) and linear curve (0-90μM) in wide effective pH range (4-10). Competition experiments are also revealed in corresponding studies and the detection limit is 3.6μM. The response mechanism is proved to be the reduction of the probe by H 2 S, which is confirmed by 1 H NMR. Furthermore, through the fluorescence turn-on signal toward H 2 S in Hela cells, probe DPD was successfully applied to monitor H 2 S in living Hela cells., (Copyright © 2019. Published by Elsevier B.V.)

Acute heat stress is common in aquaculture and can affect diverse physiological processes in fish; however, different species of fish have various mechanisms for heat stress adaptation. In this study, we profiled the transcriptome responses of the Atlantic salmon (Salmo salar) to heat stress at 23 °C for 6 or 24 h, compared with that of fish at a normal temperature of 13 °C. The liver was selected as the target tissue for this analysis. A total of 243 and 88 genes were differentially expressed after 6 and 24 h of heat stress, respectively. Of these, only 22 were common to both time points, and most of these common genes were molecular chaperones such as heat shock cognate 71 kDa protein and heat shock protein 90-alpha. Genes such as activating transcription factor 6, calreticulin, protein disulfide isomerase A3, and protein kinase R-like endoplasmic reticulum kinase-eukaryotic initiation factor 2-alpha were only up-regulated after 6 h of heat stress; most of these genes are involved in the endoplasmic reticulum stress pathway. Indeed, endoplasmic reticulum stress was identified at 6 h but not at 24 h, suggesting that stress response plays an important role in the adaptation of Atlantic salmon to acute heat stress. Other up-regulated genes at 6 h were related to the insulin and nucleotide oligomerization domain-like receptor signaling pathways, which directly eliminate misfolded proteins and sustain sugar and lipid homeostasis. At 24 h, heat stress influenced the expression of steroid and terpenoid backbone biosynthesis, which may influence the sexual development and differentiation of Atlantic salmon. Overall, our results elucidate the transcriptome mechanisms that contribute to short-term heat tolerance in the liver of Atlantic salmon., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In this work, we have designed and synthesized a dinitrobenzene-sulfonate tetrahydro[5]helicene (H-DNP) as an effective fluorescent probe for detection of hydrogen sulfide (H 2 S). Upon the addition of H 2 S, a significant fluorescence enhancement (75-fold) at 495 nm can be observed with a distinct color change from colorless to yellow. Additionally, H-DNP shows low background spectroscopic signal, large Stokes Shift up to ~140 nm, good sensitivity, rapid response time less than 2 min, low detection limit (48 nM) and high selectivity toward common bio-thiols (Cysteine, Homocysteine and Glutathione). Compared with the previous dinitrophenoxy tetrahydro[5]helicene, this probe has shorter response time and lower detection limit. Most importantly, this probe H-DNP has low toxicity to cells and excellent cell permeability, which can be applied to visualize H 2 S in living cells., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In this study, a new coumarin-based fluorescent and chromogenic dual channel probe (DC) was used for the selective detection of homocysteine (Hcy) over other amino acids, especially for cysteine (Cys) and glutathione (GSH). When Hcy is present in the solution, the remarkable fluorescence enhancement and obvious blue shift in UV-vis spectra can be observed. In addition, the color change from purple to yellow can be observed clearly by unaided eyes. This probe DC has fast response time, excellent sensitivity and selectivity to Hcy. A linear relationship exists between the ratio of emissions at 486 and 625 nm, and Hcy can be detected in a wide concentration range (0-200 μM). The signal-to-background ratio of fluorescence at 486 nm can reach 8.4, and the detection limit is calculated to be 3.5 µM. The response mechanism is proved to be the Michael addition reaction by Hcy. Preliminary results on cell imaging enable the practical application of Hcy tracing in living cells., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Carotenoid cleavage products (apocarotenoids; APOs) exert important biological functions in light perception and as vitamin A source, signaling molecules, hormone precursors, pigments and volatiles. However, an analytical method that allows simultaneous profiling of these diverse compounds is still missing. We developed an efficient method to analyze APOs present in plant tissues, which is based on ultra-high performance liquid chromatographic separation and high-resolution hybrid quadrupole-Orbitrap (Q-Orbitrap) mass spectrometry (MS). Our approach allowed unambiguous identification and quantification of volatile and non-volatile APOs in a single run. Modified sample preparation and optimized ultra-high performance liquid chromatography (UHPLC)-MS parameters permitted the measurement of APOs in Oryza sativa seedlings and Spinacia oleracea leaves, unraveling 20 endogenous APOs with chain lengths ranging from C 10 to C 30 , confirmed by high-resolution MS, MS/MS data and using synthetic standards. Our experimentation demonstrates that the usage of methanol with 0.1% butylated hydroxytoluene facilitates the extraction of both short-chain and long-chain APOs from plant materials. In addition, our validated analytical method allows the quantitative analysis of APOs with a wide content range from 2.5 pg/mg to 10 ng/mg dried weight. The adoption of the analytical protocol, as described in this study, realizes the measurement of volatile APOs by using a LC-MS method, hence, allowing informative and reliable profiling of APOs, which is important for determining the content of these compounds in food and crucial for understanding their function and metabolism in plants., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Endogenous hydrogen sulfide plays an important role in various physiological and pathological processes and the convenient and selective recognition of hydrogen sulfide has become a research hotspot. We designed and synthesized a tetrahydro[5]helicene and 2,4-dinitrobenzene conjugate (HD-DNP) as an effective fluorescent probe for selective detection of H 2 S. The selective deprotection of 2,4-dinitrophenyl ether group of HD-DNP by H 2 S led to a dramatic fluorescent enhancement (101-fold) at 500 nm and colorimetric change in DMSO-PBS solution. HD-DNP displays many advantages including low background without any self-fluorescence, as well as high selectivity towards common bio-thiols such as Cysteine, Homocysteine and Glutathione. The detection limit of this probe for H 2 S was found to be about 2.4 μM with a wide linear range (10-70 μM). The response mechanism of the probe with HS - is confirmed to be thiolysis of the dinitrophenyl ether induced by HS - through 1 H NMR comparison investigations., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: This study aimed to investigate the relationship between soluble RAGE and estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease (CKD) after controlling for the potential confounding factors such as medication usage and enzymatic antioxidants., Methods: A total of 222 CKD patients whose eGFR is less than 60ml/min/1.73m(2) and 111 non-CKD individuals were recruited. The study subjects were classified based on their diabetes status. The plasma glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities as well as plasma soluble RAGE level were measured., Results: The plasma GPx and SOD activities were significantly lower and the plasma soluble RAGE level was significantly higher in the CKD patients than in the non-CKD individuals, regardless of the diabetes status. Soluble RAGE was significantly correlated with eGFR in both diabetic CKD (D-CKD) and non-diabetic CKD (ND-CKD) patients. The association between soluble RAGE and eGFR remained largely unaffected by the confounding factors in D-CKD patients. However, the confounding effect of enzymatic antioxidants in the relationship between eGFR and soluble RAGE was observed in ND-CKD patients., Conclusion: The increased plasma level of soluble RAGE is a better indicator of renal function decline in diabetic CKD patients instead of non-diabetic CKD patients., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Genotypes of hepatitis C virus (HCV) are distributed differently across the world. There is a paucity of such data in a multi-ethnic Asian population like Malaysia. The objectives of this study were to determine the distribution of HCV genotypes between major ethnic groups and to ascertain their association with basic demographic variables like age and gender., Methods: This was a cross-sectional prospective study conducted from September 2007 to September 2013. Consecutive patients who were detected to have anti-HCV antibodies in the University of Malaya Medical Centre were included and tested for the presence of HCV RNA using Roche Cobas Amplicor Analyzer and HCV genotype using Roche single Linear Array HCV Genotyping strip., Results: Five hundred and ninety-six subjects were found to have positive anti-HCV antibodies during this period of time. However, only 396 (66.4%) were HCV RNA positive and included in the final analysis. Our results showed that HCV genotype 3 was the predominant genotype with overall frequency of 61.9% followed by genotypes 1 (35.9%), 2 (1.8%) and 6 (0.5%). There was a slightly higher prevalence of HCV genotype 3 among the Malays when compared to the Chinese (P=0.043). No other statistical significant differences were observed in the distribution of HCV genotypes among the major ethnic groups. There was also no association between the predominant genotypes and basic demographic variables., Conclusions: In a multi-ethnic Asian society in Malaysia, genotype 3 is the predominant genotype among all the major ethnic groups with genotype 1 as the second commonest genotype. Both genotypes 2 and 6 are uncommon. Neither genotype 4 nor 5 was detected. There is no identification of HCV genotype according to ethnic origin, age and gender.

Anthocyanins are critical for plants. It is shown that the expression of genes encoding the key enzymes such as dihydroflavonol 4-reductase (DFR), UDP-Glc: flavonoid 3-O-glucosyltransferase (UF3GT), and leucoanthocyanidin dioxygenase (LDOX) in anthocyanin biosynthesis pathway is regulated by MYB75, a R2R3 MYB transcription factor. The production of anthocyanin is known to be promoted by jasmonic acid (JA) in light but not in darkness. The photoreceptors cryptochrome 1 (CRY1), phytochrome B (phyB), and phytochrome A (phyA) are also shown to mediate light promotion of anthocyanin accumulation, respectively, whereas their downstream factor COP1, a master negative regulator of photomorphogensis, represses anthocyanin accumulation. However, whether JA coordinates with photoreceptors in the regulation of anthocyanin accumulation is unknown. Here, we show that under far-red light, JA promotes anthocyanin accumulation in a phyA signaling pathway-dependent manner. The phyA mutant is hyposensitive to jasmonic acid analog methyl jasmonic acid (MeJA) under far-red light. The dominant mutant of MYB75, pap1-D, accumulates significantly higher levels of anthocyanin than wild type under far-red light, whereas knockdown of MYBs (MYB75, MYB90, MYB113, and MYB114) through RNAi significantly reduces MeJA promotion of anthocyanin accumulation. The phyA pap1-D double mutant shows reduced responsiveness to MeJA, similar to phyA mutant under far-red light. In darkness, a mutant allele of cop1, cop1-4, shows enhanced responsiveness to MeJA, but pap1-D mutant is barely responsive to MeJA. Upon MeJA application, the cop1-4 pap1-D double mutant accumulates considerably higher levels of anthocyanin than cop1-4 in darkness. Protein studies indicate that MYB75 protein is stabilized by white light and far-red light. Further gene expression studies suggest that MeJA promotes the expression of DFR, UF3GT, and LDOX genes in a phyA- and MYB75-dependent manner under far-red light. Our findings suggest that JA promotion of anthocyanin accumulation under far-red light is dependent on phyA signaling pathway, consisting of phyA, COP1, and MYB75., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The distributions of dissolved methane in the central Bohai Sea were investigated in November 2011, May 2012, July 2012, and August 2012. Methane concentration in surface seawater, determined using an underway measurement system combined with wavelength-scanned cavity ring-down spectroscopy, showed marked spatiotemporal variations with saturation ratio from 107% to 1193%. The central Bohai Sea was thus a source of atmospheric methane during the survey periods. Several episodic oil and gas spill events increased surface methane concentration by up to 4.7 times and raised the local methane outgassing rate by up to 14.6 times. This study demonstrated a method to detect seafloor CH4 leakages at the sea surface, which may have applicability in many shallow sea areas with oil and gas exploration activities around the world., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

We describe the first case, to our knowledge, of Mycobacterium brisbanense species nova with the type strain W6743T (=ATCC 49938T=DSM 44680T) isolated from the lungs of a man with a 6-month history of productive cough and intermittent fever presenting with acute hypoglycemia. A CT scan of the thorax revealed multiple small nodules and consolidation over both lungs with cavitation. Sputum culture repeatedly grew M brisbanense species nova, a novel species never before isolated in Malaysia. The case met the American Thoracic Society criteria for the diagnosis of nontuberculous mycobacterial infection. There was dramatic clinical and radiologic response to treatment with an empirical combination of rifampicin, ethambutol, and levofloxacin and subsequently clarithromycin and levofloxacin once sensitivity was known. This report is the first, to our knowledge, of the pathogen isolated in a patient with chronic cavitary lung infection since it was first identified from an antral sinus in Brisbane, Queensland, Australia, and the first time it is isolated from a human subject in Malaysia.

Autophagy is a conserved mechanism for controlling the degradation of misfolded proteins and damaged organelles in eukaryotes and can be induced by nutrient withdrawal, including serum starvation. Although differential acetylation of autophagy-related proteins has been reported to be involved in autophagic flux, the regulation of acetylated microtubule-associated protein 1 light chain 3 (LC3) is incompletely understood. In this study, we found that the acetylation levels of phosphotidylethanolamine (PE)-conjugated LC3B (LC3B-II), which is a critical component of double-membrane autophagosome, were profoundly decreased in HeLa cells upon autophagy induction by serum starvation. Pretreatment with lysosomal inhibitor chloroquine did not attenuate such deacetylation. Under normal culture medium, we observed increased levels of acetylated LC3B-II in cells treated with tubacin, a specific inhibitor of histone deacetylase 6 (HDAC6). However, tubacin only partially suppressed serum-starvation-induced LC3B-II deacetylation, suggesting that HDAC6 is not the only deacetylase acting on LC3B-II during serum-starvation-induced autophagy. Interestingly, tubacin-induced increase in LC3B-II acetylation was associated with p62/SQSTM1 accumulation upon serum starvation. HDAC6 knockdown did not influence autophagosome formation but resulted in impaired degradation of p62/SQSTM1 during serum starvation. Collectively, our data indicated that LC3B-II deacetylation, which was partly mediated by HDAC6, is involved in autophagic degradation during serum starvation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Changes in cellular phenotypes and identities are fundamentally regulated by epigenetic mechanisms including DNA methylation, post-translational histone modifications and chromatin remodeling. Recent genome-wide profiles of the mammalian DNA 'methylome' suggest that hotspots of dynamic DNA methylation changes during cell fate transitions occur at distal regulatory regions with low or intermediate CpG densities. These changes are most prevalent early during the course of cellular differentiation and can be locally influenced by binding of cell-type specific transcription factors. With the advent of next-generation quantitative base-resolution maps of 5-methylcytosine and its oxidized derivatives and better coverage of the genome, we expect to learn more about the true significance of these DNA modifications in the regulation of cell fate choices., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: In major liver resection, bacterial translocation appears to be an important mechanism in the pathogenesis of spontaneous infection. This study was designed to investigate the effects of splenic artery ligation on bacterial translocation after major liver resection., Materials and Methods: Rats were divided into three groups: the sham operation group (SO group), the two-thirds partial hepatectomy group (PHx group) and the two-thirds partial hepatectomy plus splenic artery ligation group (PHx+Sp group). Bacterial translocation, endotoxemia, d-lactic acid and intestinal histology were analyzed among three groups., Results: The rate of bacterial translocation was higher in the PHx rats than in the SO rats (65.0% vs. 6.67%; P=0.001), so that in the PHx+Sp rats (25.0%; P=0.011). Endotoxemia was not evident in the SO rats (0pg/ml) and blood endotoxin levels decreased in the PHx+Sp rats (1.47pg/ml) compared with the PHx rats (4.05pg/ml, P<0.001). d-lactic acid was also higher in both the PHx and PHx+Sp rats compared with the SO rats (39.09mg/ml, 23.36mg/ml, and 1.68mg/ml; P<0.01)., Conclusion: Splenic artery ligation enhanced intestinal barrier function and diminished blood endotoxin levels and bacterial translocation in rats with major liver resection., (Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Introduction: The presence of a variety of MDM2 splice variants has been reported in a range of different tumor types and is associated with poor patient prognosis. Furthermore, several MDM2 variants have been shown to have oncogenic properties. Despite this, MDM2 splice variants have not been comprehensively characterized in oral squamous cell carcinoma (OSCC)., Materials and Methods: MDM2 splice variants were identified by polymerase chain reaction (PCR), using cDNA from 55 OSCC and 20 normal oral mucosa (NOM) tissues. MDM2 amplicons from the polymerase chain reactions were cloned and sequenced. The associations between the presence of MDM2 splice variants as well as the types of MDM2 splice variants with OSCC and patient clinico-pathological data was examined using Fisher Exact and Chi-square tests., Results: Thirty-eight MDM2 splice variants were identified from both OSCC and NOM tissues, where the majority (30/38) were exclusively detected in OSCC. Some of these variants were similar to those reported in other cancers whilst 14 novel MDM2 splice variants predicted to code for proteins were also identified. The majority of these variants retained their RING binding domain but had lost the p53 binding site. The presence of MDM2 splice variants was significantly associated with OSCC and increased the risk of OSCC development (OR=9.98; 95% CI=2.94-33.90)., Conclusion: MDM2 splice variants were identified in OSCC at a high frequency and were significantly associated with OSCC development. This suggests that MDM2 splice variants may play an important role in oral carcinogenesis and the functional role of these variants in OSCC should be examined further., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The deoxycytidine analog decitabine (DAC) can deplete DNA methyl-transferase 1 (DNMT1) and thereby modify cellular epigenetics, gene expression, and differentiation. However, a barrier to efficacious and accessible DNMT1-targeted therapy is cytidine deaminase, an enzyme highly expressed in the intestine and liver that rapidly metabolizes DAC into inactive uridine counterparts, severely limiting exposure time and oral bioavailability. In the present study, the effects of tetrahydrouridine (THU), a competitive inhibitor of cytidine deaminase, on the pharmacokinetics and pharmacodynamics of oral DAC were evaluated in mice and nonhuman primates. Oral administration of THU before oral DAC extended DAC absorption time and widened the concentration-time profile, increasing the exposure time for S-phase-specific depletion of DNMT1 without the high peak DAC levels that can cause DNA damage and cytotoxicity. THU also decreased interindividual variability in pharmacokinetics seen with DAC alone. One potential clinical application of DNMT1-targeted therapy is to increase fetal hemoglobin and treat hemoglobinopathy. Oral THU-DAC at a dose that would produce peak DAC concentrations of less than 0.2μM administered 2×/wk for 8 weeks to nonhuman primates was not myelotoxic, hypomethylated DNA in the γ-globin gene promoter, and produced large cumulative increases in fetal hemoglobin. Combining oral THU with oral DAC changes DAC pharmacology in a manner that may facilitate accessible noncytotoxic DNMT1-targeted therapy.

MicroRNAs (miRNAs) are short noncoding RNAs that regulate gene expression and are important for pre-B and follicular B lymphopoiesis as demonstrated, respectively, by mb-1-Cre- and cd19-Cre-mediated deletion of Dicer, the RNase III enzyme critical for generating mature miRNAs. To explore the role of miRNAs in B-cell terminal differentiation, we use Aicda-Cre to specifically delete Dicer in activated B cells where activation-induced cytidine deaminase is highly expressed. We demonstrate that mutant mice fail to produce high-affinity class-switched antibodies and generate memory B and long-lived plasma cells on immunization with a T cell-dependent antigen. More importantly, germinal center (GC) B-cell formation is drastically compromised in the absence of Dicer, as a result of defects in cell proliferation and survival. Dicer-deficient GC B cells express higher levels of cell cycle inhibitor genes and proapoptotic protein Bim. Ablation of Bim could partially rescue the defect in GC B-cell formation in Dicer-deficient mice. Taken together, our data suggest that Dicer and probably miRNAs are critical for GC B-cell formation during B-cell terminal differentiation.

The MDM2 SNP309 has been associated with increased expression of the protein which could suppress p53 function, and has been shown to modulate risk to cancer. We have previously shown that overexpression of MDM2 is a common event in oral cancers. In the present study, we determined the association between the MDM2 SNP309 polymorphism and oral cancer in 207 oral cancer patients and 116 normal subjects. We genotyped the MDM2 SNP309 by PCR-RFLP. Logistic regression was adapted to calculate odds ratios for MDM2 SNP309 polymorphism from univariate and multivariable adjusted models. Our results suggest that MDM2 SNP309 does not confer increased risk to oral cancer (OR=1.55, 95% CI=0.77-3.11). However, the GG/TG genotype was associated with later disease onset in women above 55 years of age. Collectively, our data suggests that MDM2 SNP309 may modulate the risk to oral cancer and is a modifier of the age at oral cancer onset in women above the age of 55 years.

The CD28/B7 and ICOS/B7-H2 pathways are both critical for costimulating T cell immune responses. Deficiency in either pathway results in defective T cell activation, cytokine production and germinal center formation. However, the relative importance and contribution of each pathway towards T cell-mediated immunity is still not clear. To address this issue, we compared T cell responses of WT, CD28 knockout (KO), B7-H2 KO, and CD28-B7-H2 double KO (DKO) mice in a model of delayed-type hypersensitivity (DTH). While CD28 KO mice have partially compromised DTH response, DKO mice exhibited greatly diminished response, suggesting that the ICOS/B7-H2 pathway could partially compensate for the costimulation of DTH. Surprisingly, B7-H2 KO mice had comparable DTH response as WT mice, indicating that the ICOS/B7-H2 pathway is secondary to the CD28/B7 pathway in costimulating DTH. Interestingly, prolonging the period of sensitization could overcome the compromised DTH response in CD28 KO but not DKO mice, revealing a novel form of functional redundancy of ICOS/B7-H2 costimulation that is dependent on time to take effect. Taken together, our data reveal a functional hierarchy of the CD28/B7 and ICOS/B7-H2 pathways and delineated their relative contributions to the elicitation of a DTH response.

p62(dok) and Dok-3 are members of the Dok family of adaptors found in B cells, with the former cloned as a substrate of the p210(bcr/abl) oncoprotein in Ph + chronic myelogenous leukemia. A role for p62(dok) in FcgammaRIIB-mediated negative regulation of B-cell proliferation had been established previously. Here, we generated Dok-3(-/-) mice to assess the function of Dok-3 in B cells. Mice lacking Dok-3 have normal B-cell development but possess higher level of IgM antibodies in their sera. In comparison to wild-type mice, Dok-3(-/-) mice mounted significantly enhanced humoral immune responses to T cell-independent type I and II antigens. Dok-3-deficient B cells hyperproliferated, exhibited elevated level of calcium signaling as well as enhanced activation of NF-kappaB, JNK, and p38MAPK in response to B-cell receptor (BCR) engagement. In the absence of Dok-3, the localization of the inhibitory phosphatase SHIP-1 to the plasma membrane is intact while its phosphorylation is compromised, suggesting that Dok-3 could function to facilitate or sustain the activation of SHIP-1. The phenotype and responses of Dok-3(-/-) mice and B cells could be differentiated from those of the Dok-1(-/-) counterparts. Hence, we propose that Dok-3 plays a distinct and nonredundant role in the negative regulation of BCR signaling.