Real-world effectiveness and safety of recombinant human endostatin plus PD-1 inhibitors and chemotherapy as first-line treatment for EGFR/ALK-negative, advanced or metastatic non-small cell lung cancer.

BACKGROUND: This study aimed to evaluate the effectiveness and safety of recombinant human endostatin (Rh-endostatin) plus programmed cell death 1 (PD-1) inhibitors and chemotherapy as first-line treatment for advanced or metastatic non-small cell lung cancer (NSCLC) in a real-world setting. METHODS: This was a retrospective study on patients with EGFR/ALK-negative, advanced or metastatic NSCLC. Patients received Rh-endostatin plus PD-1 inhibitors and chemotherapy every three weeks for 4 to 6 cycles. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. RESULTS: A total of 68 patients were included in this retrospective analysis. As of data cutoff (December 13, 2022), the median follow-up of 21.4 months (interquartile range [IQR], 8.3-44.4 months). The median PFS and OS was 22.0 (95% confidence interval [CI]: 16.6-27.4) and 31.0 months (95% CI: 23.4-not evaluable [NE]), respectively. The ORR was 72.06% (95% CI: 59.85-82.27%), and DCR was 95.59% (95% CI: 87.64-99.08%). Patients with stage IIIB/IIIC NSCLC had significantly longer median PFS (23.4 vs. 13.2 months), longer median OS (not reached vs. 18.0 months), and higher ORR (89.2% vs. 51.6%) than those with stage IV NSCLC (all p ≤ 0.001). The ORR was higher in patients with high PD-L1 expression (tumor proportion score [TPS] ≥ 50%) than in those with low PD-L1 expression or positive PD-L1 expression (75% vs. 50%, p = 0.025). All patients experienced treatment-related adverse events (TRAEs), and ≥ grade 3 TRAEs occurred in 16 (23.53%) patients. CONCLUSIONS: Rh-endostatin combined with PD-1 inhibitors plus chemotherapy as first-line treatment yielded favorable effectiveness with a manageable profile in patients with advanced or metastatic NSCLC, representing a promising treatment modality.

Dietary Selenium Insufficiency Induces Cardiac Inflammatory Injury in Chicks.

BACKGROUND: Laying hens undergo intensive metabolism and are vulnerable to cardiac insults. Previous research demonstrated overt heart disorders of broiler chickens induced by dietary Se deficiency. OBJECTIVES: This study aimed to reveal effects and mechanism of dietary Se insufficiency on cardiac injuries of egg-type chicks in their early life. METHODS: White Leghorn chicks (0-d-old, female) were fed a corn-soy, Se-insufficient basal diet (BD, 0.05 mg Se/kg; n = 11) or the BD supplemented with 0.3 mg Se/kg (as sodium selenite; n = 8) for 35 d. Cardiac tissues were collected at the end of study for histology and to determine its relationship with heart Se contents, selenoprotein expression profiles, antioxidant and inflammatory status, and the Toll-like receptor 4/extracellular signal-regulated kinases/p38 map kinase/c-Jun N-terminal kinase (TLR4/ERK/P38/JNK) pathway. RESULTS: Compared with those fed 0.35 mg Se/kg, chicks fed BD had significantly lower body weights and average daily gain, and 28% lower heart Se, and developed cardiac mononuclear inflammatory cell infiltration, along with elevated (P < 0.05) serum concentrations of creatine kinase, aldolase, and interleukin-1 (IL-1). The BD decreased (P < 0.05) body weight and heart glutathione contents and expression of selenoproteins but increased (P < 0.05) heart concentrations of malondialdehyde and reactive oxygen species. These changes were associated with increased (P < 0.05) mRNA and/or protein concentrations of cyclooxygenases, lipoxygenase-12, cytokines (IL-1ß), nuclear factor (NF) κB subunit, chemokines, and receptors (CCL20, CXCR1, and CXCLI2) and increased (P < 0.1) TLR4/ERK /P38/JNK in the heart of Se-insufficient chicks. CONCLUSIONS: Dietary Se insufficiency induces infiltration of mononuclear inflammatory cells in the heart of egg-type chicks. This cardiac injury was mediated by decreased functional expressions of selenoproteins, which resulted in apparent elevated oxidative stress and subsequent activations of the TLR4 pathway and NF κB.

Cpd-A1 alleviates acute kidney injury by inhibiting ferroptosis.

Acute kidney injury (AKI) is defined as sudden loss of renal function characterized by increased serum creatinine levels and reduced urinary output with a duration of 7 days. Ferroptosis, an iron-dependent regulated necrotic pathway, has been implicated in the progression of AKI, while ferrostatin-1 (Fer-1), a selective inhibitor of ferroptosis, inhibited renal damage, oxidative stress and tubular cell death in AKI mouse models. However, the clinical translation of Fer-1 is limited due to its lack of efficacy and metabolic instability. In this study we designed and synthesized four Fer-1 analogs (Cpd-A1, Cpd-B1, Cpd-B2, Cpd-B3) with superior plasma stability, and evaluated their therapeutic potential in the treatment of AKI. Compared with Fer-1, all the four analogs displayed a higher distribution in mouse renal tissue in a pharmacokinetic assay and a more effective ferroptosis inhibition in erastin-treated mouse tubular epithelial cells (mTECs) with Cpd-A1 (N-methyl-substituted-tetrazole-Fer-1 analog) being the most efficacious one. In hypoxia/reoxygenation (H/R)- or LPS-treated mTECs, treatment with Cpd-A1 (0.25 µM) effectively attenuated cell damage, reduced inflammatory responses, and inhibited ferroptosis. In ischemia/reperfusion (I/R)- or cecal ligation and puncture (CLP)-induced AKI mouse models, pre-injection of Cpd-A1 (1.25, 2.5, 5 mg·kg-1·d-1, i.p.) dose-dependently improved kidney function, mitigated renal tubular injury, and abrogated inflammation. We conclude that Cpd-A1 may serve as a promising therapeutic agent for the treatment of AKI.

Research Progress on Active Ingredients and Product Development of Lycium ruthenicum Murray.

Lycium ruthenicum Murray possesses significant applications in both food and medicine, including antioxidative, anti-tumor, anti-fatigue, anti-inflammatory, and various other effects. Consequently, there has been a surge in research endeavors dedicated to exploring its potential benefits, necessitating the organization and synthesis of these findings. This article systematically reviews the extraction and content determination methods of active substances such as polysaccharides, anthocyanins, flavonoids, and polyphenols in LRM in the past five years, as well as some active ingredient composition determination methods, biological activities, and product development. This review is divided into three main parts: extraction and determination methods, their bioactivity, and product development. Building upon prior research, we also delve into the economic and medicinal value of Lycium ruthenicum Murray, thereby contributing significantly to its further exploration and development. It is anticipated that this comprehensive review will serve as a valuable resource for advancing research on Lycium ruthenicum Murray.

Population pharmacokinetics and dosing regimen optimization of levetiracetam in epilepsy during pregnancy.

AIMS: The pharmacokinetics of levetiracetam (LEV) significantly changed during pregnancy. It is a great challenge to predict the adjusted doses of LEV to reach the preconception target concentrations. This study aimed to establish a population pharmacokinetic model of LEV in women with epilepsy (WWE) during pregnancy to analyse the factors of pharmacokinetic variability and to develop a model-based individualized dosing regimen. METHODS: A total of 166 concentration-time points from 37 WWE during pregnancy treated with LEV were collected to analyse LEV pharmacokinetics with nonlinear mixed-effects modelling. The dosing regimen was optimized by Monte Carlo simulations based on the final model. RESULTS: The LEV pharmacokinetics in pregnant WWE were best described by a 1-compartment model of first-order absorption and elimination. The population typical value of apparent clearance (CL/F) in the final model was estimated to be 3.82 L/h (95% confidence interval 3.283-4.357 L/h) with a relative standard error of 7.2%. Both total body weight (TBW) and trimester of pregnancy were significantly associated with LEV-CL/F during pregnancy; LEV-CL/F increased by 42.72% when TBW increased from 55 to 65 kg from the first trimester to the second trimester. Monte Carlo simulations showed that dosing regimens for LEV should be individualized based on the patient's TBW and trimester of pregnancy to maximize the likelihood of achieving the therapeutic range. CONCLUSION: This first population pharmacokinetic study of LEV in WWE during pregnancy supports the use of a weight-based and pregnancy-based dosing regimen and can lay a foundation for further optimizing the individualized dosing regimens.

C-Type Lectin Maintains the Homeostasis of Intestinal Microbiota and Mediates Biofilm Formation by Intestinal Bacteria in Shrimp.

Intestinal microbiota are closely related to host physiology. Over the long course of evolution and interaction, both commensal bacteria and their host have evolved multiple strategies to adapt to each other. However, in invertebrates, the regulatory mechanism of intestinal microbiota homeostasis is largely unknown. In the current study, a digestive tract-specific C-type lectin, designated as CTL33, was identified because of its abundance and response to bacteria in the intestine of kuruma shrimp (Marsupenaeus japonicus). Silencing of CTL33 expression led directly to intestinal dysbiosis, tissue damage, and shrimp death. CTL33 could facilitate biofilm formation by the intestinal bacteria. This function originated from its unique architecture, with a lectin domain responsible for bacteria recognition and a coiled coil region that mediated CTL33 dimerization and cross-linked the bacteria into a biofilm-like complex. By mediating the formation of a biofilm, CTL33 promoted the establishment of intestinal bacteria in intestine and maintained the homeostasis of the microbiota. Thus, to our knowledge, we demonstrated a new mechanism of C-type lectin-mediated biofilm formation by intestinal bacteria, providing new insights into intestinal homeostasis regulation in invertebrates.

Switchable, Reagent-Controlled C(sp3)-H Selective Iodination and Acetoxylation of 8-Methylquinolines.

An efficient Pd-catalyzed C(sp3)-H selective iodination of 8-methylquinolines is reported herein for the first time. Because of the versatility of organic iodides, the method offers a facile access to various C8-substituted quinolines. By slightly switching the reaction conditions, an efficient C(sp3)-H acetoxylation of 8-methylquinolines has also been enabled. Both approaches feature mild reaction conditions, good tolerance of functional groups, and a broad substrate scope.

Ghrelin infusion into the basolateral amygdala suppresses CTA memory formation in rats via the PI3K/Akt/mTOR and PLC/PKC signaling pathways.

Ghrelin is a circulating orexigenic hormone that promotes feeding behavior and regulates metabolism in humans and rodents. We previously reported that local infusion of ghrelin into the basolateral amygdala (BLA) blocked memory acquisition for conditioned taste aversion (CTA) by activating growth hormone secretagogue receptor 1a. In this study, we further explored the underlying mechanism and signaling pathways mediating ghrelin modulation of CTA memory in rats. Pharmacological agents targeting distinct signaling pathways were infused into the BLA during conditioning. We showed that preadministration of the PI3K inhibitor LY294002 abolished the repressive effect of ghrelin on CTA memory. Moreover, LY294002 pretreatment prevented ghrelin from inhibiting Arc and zif268 mRNA expression in the BLA triggered by CTA memory retrieval. Preadministration of rapamycin eliminated the repressive effect of ghrelin, while Gsk3 inhibitors failed to mimic ghrelin's effect. In addition, PLC and PKC inhibitors microinfused in the BLA blocked ghrelin's repression of CTA acquisition. These results demonstrate that ghrelin signaling in the BLA shapes CTA memory via the PI3K/Akt/mTOR and PLC/PKC pathways. We conducted in vivo multichannel recordings from mouse BLA neurons and found that microinjection of ghrelin (20 µM) suppressed intrinsic excitability. By means of whole-cell recordings from rat brain slices, we showed that bath application of ghrelin (200 nM) had no effect on basal synaptic transmission or synaptic plasticity of BLA pyramidal neurons. Together, this study reveals the mechanism underlying ghrelin-induced interference with CTA memory acquisition in rats, i.e., suppression of intrinsic excitability of BLA principal neurons via the PI3K/Akt/mTOR and PLC/PKC pathways.

Estrogen profile- and pharmacogenetics-based lamotrigine dosing regimen optimization: Recommendations for pregnant women with epilepsy.

During pregnancy, various physiological changes occur that can alter the pharmacokinetics of antiepileptic drugs, such as lamotrigine (LTG). Anticipating the change in LTG dose required to achieve a pre-pregnancy target concentration is challenging. This study aimed to develop a refined population pharmacokinetic (PopPK) model of LTG in pregnant women with epilepsy (WWE) to identify factors explaining the variability in pharmacokinetics and to establish a model-informed individualized dosing regimen. On that basis, a coarsened model containing only clinical variables was also developed to examine its predictive performance compared to the refined model. In total, 322 concentration-time points from 51 pregnant WWE treated with LTG were employed to establish a refined PopPK model that included endogenous estrogen profiles, variants of candidate genes encoding LTG-metabolizing enzymes and -transporter proteins, and other clinical variables and a coarsened model that included only clinical variables, respectively. Data from an additional 11 patients were used for external validation of these two models. A nonlinear mixed-effect modeling approach was used for PopPK analysis of LTG. The standard goodness-of-fit method, bootstrap, normalized prediction distribution errors and external evaluation were adopted to estimate the stability and predictive performance of the candidate models. Akaike information criterion (AIC) was used to compare the goodness of fit between these two models. A lower AIC indicates a better fit of the data and the preferred model. Recommended dosing regimens for pregnant WWE were selected using Monte Carlo simulation based on the established optimal model. In the refined PopPK model, the population mean of apparent LTG clearance (CL/F) in pregnant WWE was estimated to be 2.82 L/h, with an inter-individual variability of 23.6%. PopPK analysis indicated that changes in estrogen profile during pregnancy were the predominant reason for the significant variations in LTG-CL/F. Up to the 3rd trimester, the concentration accumulation effect of E2 increased LTG-CL/F by 5.109 L/h from baseline levels. Contrary to effect of E2, E3 as the main circulating estrogen in pregnancy with a peak value of 34.41 ng/mL is 1000-fold higher than that in non-pregnancy reduced LTG-CL/F by 1.413 L/h. In addition, the UGT2B7 rs4356975 C > T and ABCB1 rs1128503 A > G variants may contribute to a better understanding of the inter-individual variability in LTG-CL/F. LTG-CL/F was 1.66-fold higher in UGT2B7 rs4356975 CT or TT genotype carriers than in CC genotype carriers. In contrast, ABCB1 rs1128503 GG genotype carriers had only 71.9% of the LTG-CL/F of AA or AG genotype carriers. In the coarsened PopPK model, the gestational age was a promising predictor of changes in LTG-CL/F. When comparing these two models, the refined PopPK model was favored over the coarsened PopPK model (AIC = -30.899 vs. -20.017). Monte Carlo simulation based on optimal PopPK model revealed that the LTG dosage administered to carriers of the UGT2B7 rs4356975 CT or TT genotype required a 33-50% increase to reach the pre-pregnancy target concentration, and carriers of the ABCB1 rs1128503 GG genotype required a 33-66% lower dose of LTG than carriers of the ABCB1 rs1128503 AA or AG genotype. Changes in estrogen profile during pregnancy was a better predictor of variations in LTG-CL/F than gestational age. The developed model based on estrogen profile and pharmacogenetics can serve as a foundation for further optimization of dosing regimens of LTG in pregnant WWE.

Establishment of a tTA-dependent photoactivatable Cre recombinase knock-in mouse model for optogenetic genome engineering.

The Cre-loxP recombination system is widely used to generate genetically modified mice for biomedical research. Recently, a highly efficient photoactivatable Cre (PA-Cre) based on reassembly of split Cre fragments has been established. This technology enables efficient DNA recombination that is activated upon blue light illumination with spatiotemporal precision. In this study, we generated a tTA-dependent photoactivatable Cre-loxP recombinase knock-in mouse model (TRE-PA-Cre mice) using a CRISPR/Cas9 system. These mice were crossed with ROSA26-tdTomato mice (Cre reporter mouse) to visualize DNA recombination as marked by tdTomato expression. We demonstrated that external noninvasive LED blue light illumination allows efficient DNA recombination in the liver of TRE-PA-Cre:ROSA26-tdTomato mice transfected with tTA expression vectors using hydrodynamic tail vein injection. The TRE-PA-Cre mouse established here promises to be useful for optogenetic genome engineering in a noninvasive, spatiotemporal, and cell-type specific manner in vivo.

Postintubation Tracheal Stenosis Evaluated by Endobronchial Optical Coherence Tomography: A Canine Model Study.

BACKGROUND: The predictors and airway morphological changes during the development of postintubation tracheal stenosis (PITS) have not been well elucidated. OBJECTIVES: To elucidate the validation of endobronchial optical coherence tomography (EB-OCT) in assessing the airway morphological changes in PITS. METHODS: We performed oral endotracheal intubation in 12 beagles to establish the PITS model. EB-OCT was performed respectively before modeling and on the 1st, 7th, and 12th day after extubation in 9 canines, and was conducted consecutively in 3 canines during the development of PITS. Histological findings and the thickness and gray-scale value of the tracheal wall assessed by EB-OCT measurements were analyzed and compared. RESULTS: The tracheal wall edema, granulation tissue proliferation, cartilage destruction in PITS, and airway wall thickening detected by EB-OCT were in concordance with the histopathological measurements. The consecutive EB-OCT observation of the airway structure demonstrated the tracheal wall thickness significantly increased from 344.41 ± 44.19 µm before modeling to 796.67 ± 49.75 µm on the 9th day after modeling (p < 0.05). The airway wall gray-scale values assessed by EB-OCT decreased from 111.19 ± 14.71 before modeling to 74.96 ± 4.08 on the 9th day after modeling (p < 0.05). The gray-scale value was negatively correlated with the airway wall thickness (r = -0.945, p = 0.001). CONCLUSION: The EB-OCT imaging, in concordance with the histopathological finding, was validated for assessing the airway morphological changes during the development of PITS. The EB-OCT evaluation of cartilage damage and gray-scale value measurement might help predict the development and prognosis of PITS.

Protective effect of the glucagon-like peptide-1 analogue liraglutide on carbon tetrachloride-induced acute liver injury in mice.

Acute liver injury seriously endangers human health. Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, has antioxidative effects in addition to being widely used in the treatment of type 2 diabetes and was reported to ameliorate liver diseases. The aim of this study was to evaluate the hepatoprotective effects of liraglutide on carbon tetrachloride (CCl4)-induced acute liver injury in mice and to investigate the mechanisms involved in this protective effect. Male BALB/c mice were pre-treated with liraglutide (200 µg/kg/day) by hypodermic injection for 3 days before a 0.1% (v/v) CCl4 (10 ml/kg, dissolved in olive oil) intraperitoneal injection, or post-treated with liraglutide once immediately after a CCl4 intraperitoneal injection. The experimental data showed that liraglutide treatment significantly decreased the serum ALT and AST levels and ameliorated the liver histopathological changes induced by CCl4. In addition, liraglutide pre-treatment dramatically increased the number of proliferating cell nuclear antigen (PCNA)-positive hepatocytes and significantly reduced hepatocyte apoptosis after CCl4 treatment. As a consequence, liraglutide pre-treatment significantly prevented CCl4-induced malondialdehyde (MDA) production and increased the activity of the antioxidant superoxide dismutase (SOD) enzyme. In addition, liraglutide pre-treatment significantly ameliorated mitochondrial respiratory functions and ultrastructural features. Furthermore, liraglutide pre-treatment enhances the activation of the NRF2/HO-1 signaling pathway. In summary, liraglutide protects against CCl4-induced acute liver injury by protecting mitochondrial functions and inhibiting oxidative stress, which may partly involve the activation of NRF2/HO-1 signaling pathway.

Correlation between tumor glucose metabolism and multiparametric functional MRI (IVIM and R2*) metrics in cervical carcinoma: Evidence from integrated 18 F-FDG PET/MR.

BACKGROUND: Multiparameter, multimodality 18 F-FDG PET/MRI holds great potential for the diagnosis of cervical cancer based on the correlation between tumor glucose metabolism and imaging parameters. PURPOSE: To characterize the heterogeneity of tumor glucose metabolism by evaluating the correlation between 18 F-FDG uptake parameters and multiparametric functional MRI metrics in cervical carcinoma. STUDY TYPE: Retrospective. POPULATION: Fifty-four patients with cervical carcinoma. FIELD STRENGTH/SEQUENCE: Hybrid PET/MR (3T), multi-b DWI, and R2* mapping. ASSESSMENT: The maximum and mean standardized uptake values (SUVmax and SUVmean , respectively) from PET and functional MRI metrics (D, D*, f, and R2*) were obtained. Cervical carcinoma tissues also underwent HIF-1α, VEGF, and GLUT-1 immunohistochemical staining. STATISTICAL TESTS: Single-factor Spearman rank and Pearson correlation analysis and multiple linear regression (MLR) analysis were applied. RESULTS: R2*, D, and f have different degrees of correlation (moderate, weak, moderately strong correlation, respectively) with SUVmax and SUVmean (r = 0.530 and 0.527, and P < 0.001 for R2*; r = -0.292 and -0.291, and P < 0.05 for D; r = 0.539 and 0.520, and P < 0.001 for f, respectively). Immunohistochemical staining showed that HIF-1α expression has a moderate degree of correlation with R2* (r = 0.491; P < 0.001); GLUT-1 expression was significantly correlated with SUVmax and SUVmean (r = 0.633 and 0.622; P < 0.001), and VEGF expression had a moderately strong correlation with f (r = 0.457; P = 0.001). If SUVmax is the dependent variable, MLR yields an R-squared value after adjustment (adjusted R-squared) = 0.358, and F = 10.833 (P < 0.001), and the fitting linear equation is Y (SUVmax ) = 9.184 + 0.161X1 (R2*)+50.343X2 (f)-4.780 (D). Otherwise, MLR yields the adjusted R-squared = 0.342, and F = 10.187 (P < 0.001), and the linear regression equation is Y (SUVmean ) = 5.925 + 0.102X1 (R2*)+28.029X2 (f)-2.907X3 (D). DATA CONCLUSION: The functional MRI sequence parameters R2*, f, and D can provide information on the hypoxic condition, blood perfusion, and molecular diffusion of the tumor. 18 F-FDG PET/MR multi-imaging technique can be adopted to evaluate the heterogeneity of glucose metabolism in cervical carcinoma. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;49:1704-1712.

Vascular Hyperpermeability Response in Animals Systemically Exposed to Arsenic.

The mechanisms underlying cardiovascular diseases induced by chronic exposure to arsenic remain unclarified. The objectives of this study were to investigate whether increased vascular leakage is induced by inflammatory mustard oil in mice systemically exposed to various doses of arsenic and whether an increased vascular leakage response is still present in arsenic-fed mice after arsenic discontinuation for 2 or 6 months. ICR mice were fed water or various doses of sodium arsenite (10, 15, or 20 mg/kg/day; 5 days/week) for 8 weeks. In separate experiments, the mice were treated with sodium arsenite (20 mg/kg) for 2 or 8 weeks, followed by arsenic discontinuation for 2 or 6 months. Vascular permeability to inflammatory mustard oil was quantified using Evans blue (EB) techniques. Both arsenic-exposed and water-fed (control) mice displayed similar basal levels of EB leakage in the ears brushed with mineral oil, a vehicle of mustard oil. The levels of EB leakage induced by mustard oil in the arsenic groups fed with sodium arsenite (10 or 15 mg/kg) were similar to those of water-fed mice. However, increased levels of EB leakage in response to mustard oil stimulation were significantly higher in mice treated with sodium arsenite (20 mg/kg; high dose) than in arsenic-fed (10 or 15 mg/kg; low and middle doses) or control mice. After arsenic discontinuation for 2 or 6 months, mustard oil-induced vascular EB leakage in arsenic-fed (20 mg/kg) mice was similar to that in control mice. Dramatic increases in mustard oil-induced vascular leakage were only present in mice systemically exposed to the high arsenic dose, indicating the synergistic effects of the high arsenic dose and mustard oil.

Carbon-fiber-reinforced PEEK fixation system in the treatment of spine tumors: a preliminary report.

BACKGROUND: Protocols including combination of surgery and radiotherapy are more and more frequent in the treatment of bone tumors of the spine. In metastatic disease, combination of surgery and radiotherapy is since long time accepted, as based on clinical evidence. In primary tumors, combination of surgery and radiotherapy can be considered in all the cases in which a satisfactory oncological margin cannot be achieved: high-grade malignancies, recurrent tumors, huge tumors expanding in an extracompartimental area, and when tumor-free margin requires unacceptable functional sacrifices. However, metal implants are an obstacle in the collaboration between surgeons and radiation oncologists. Carbon-fiber-reinforced polyethil-ether-ether-ketone (CFR-PEEK) composite implants could make easier and more effective the treatment as radiolucent and not interfering with ionizing radiation and accelerated particles. The purpose of this article is to report the preliminary results from a cohort of patients treated with CFR-PEEK and to evaluate the safety and the non-inferiority of the device respect the commonly used titanium implants. MATERIALS AND METHODS: This study concerns an ambispective cohort series of 34 tumor patients (14 metastases and 20 primaries, most of them recurrent) submitted to thoracic and lumbar spine fixation with a CFR-PEEK composite implants. Oncologic surgery was palliative decompression and fixation in 9 cases, tumor excision in 21, and enbloc resection in 4. Data collected for this preliminary report were all intraoperative remarks, incidence of complications, changes in neurological status, local control, and survival. All the cases were followed 6-36 months (mean 13 months). RESULTS: Only one intraoperative screw breakage occurred out of 232 implanted screws. Pain control and neurological improvement were the early clinical results. Two sacral screws loosening were found at 9 and 12 months in multilevel constructs performed on multirecurrent tumors. Six local recurrences were early found thanks to the implant radiolucency. Radiation oncologists' opinion was favourable as concerning better treatment planning on CT and lacking of scattering effect during the treatment. CONCLUSIONS: No artifacts on imaging studies mean early local recurrence detection. For radiation oncologists, no artifacts on imaging studies mean easier planning and no scattering effect means more effective and safe radiotherapy, particularly when particles are used. Moreover, it seems that the clinical use of CFR-PEEK composite implants may be safe and at least comparable with the commonly used titanium implants in terms of intraoperative complications, stability at weight bearing and at functional recovery. Larger patient series and longer follow-up are required to confirm these data.

siRNA of DNA polymerase iota inhibits the migration and invasion in the lung cancer cell A549.

DNA polymerase iota (polɩ) is a member of low-fidelity Y-family of DNA polymerases. Our previous studies have demonstrated that the overexpression of polι is associated with the poorer prognosis in lung cancer patients. Here, we designed the small interfering RNA (siRNA) targeting polɩ gene (POLI) to investigate the effect of polɩ on the proliferation, apoptosis, and invasion of the lung cancer cell line A549 in order to reveal the role of polι in lung cancer progression. Our results showed that siRNA of POLI had no significant effect on the proliferation and apoptosis of the lung cancer cell line A549. However, siRNA of POLI could inhibit the migration and invasion of the lung cancer cell line A549 by upregulating the E-cadherin expression and downregulating the expressions of N-cadherin, MMP2, and MMP9. Together, our findings indicate that polι plays a positive role in lung cancer progression via promoting the migration and invasion of lung cancer cells. Therefore, polι might be a potential target for the clinical treatment of lung cancer in the future.

Ambient fine particles (PM2.5 ) attenuate collagen-induced platelet activation through interference of the PLCγ2/Akt/GSK3ß signaling pathway.

AIMS: It has been proven that carbon nanoparticles or diesel exhaust particles stimulate platelet activation. However, the effect of fine particle matter (PM2.5 ) on platelet activation remains unknown, which motivates this study. METHODS: PM2.5 samples were collected in an urban area of Zhengzhou, China. To study the morphological characteristics and the mass concentrations of trace elements of PM2.5 samples, a filed-emission scanning electron microscope, the Image-J software, and an inductively coupled plasma mass spectrometry were used. Washed human platelets or platelet-rich-plasma were used to study the effect of PM2.5 on platelet aggregation, P-selectin expression, or platelet signaling pathways. The cytotoxicity in platelets exposed to PM2.5 was evaluated by a lactate dehydrogenase assay kit. In addition, platelet adhesion and spreading were studied on collagen-coated surfaces in stable conditions. RESULTS: The filed-emission scanning electron microscope scanning showed that PM2.5 samples varied in shape and size distributions. The mean equivalent spherical diameter of these particles was 1.97 ± 0.04 µm, of which 82.40% were particles with equivalent spherical diameters of less than 2.5 µm. The mass concentration of Ca was higher than that of other elements. The other elements followed the trend of Al>Fe>Zn>Mg>Pb>K>Mn>Cu>Ti>Ba>As>Sr>Sn>Sb>Cd>B>Se>Mo>Ag>Ni>TI>V>Co. Furthermore, pretreatment of PM2.5 significantly inhibited rather than potentiated collagen-induced platelet aggregation and P-selectin expression, whereas it had no significant effect on ADP-induced platelet aggregation and P-selectin expression. The lactate dehydrogenase analysis showed trivial cytotoxic effect of PM2.5 exposure on platelets. Pretreatment of PM2.5 inhibited platelet adhesion on immobilized collagen-coated surfaces; however, it almost did not impact the platelet spreading. Immunoblotting analysis indicated that PM2.5 reduced collagen-induced phosphorylation of phospholipase C gamma-2 (PLCγ2) at Tyr759, Akt at Ser473, and glycogen synthase kinase 3ß (GSK3ß) at Ser9. CONCLUSIONS: PM2.5 attenuated collagen-induced platelet aggregation, α-granule secretion and adhesion, with the potential mechanism of impairing PLCγ2, Akt, and GSK3ß signaling. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 530-540, 2017.

A novel topical nano-propranolol for treatment of infantile hemangiomas.

Topical propranolol has been used for the therapy of superficial infantile hemangiomas (IH). A retrospective investigation was conducted in 50 patients to evaluate the clinical effect of a new type of topical nano-propranolol-dispersed hydrogel. Participants were treated 3 times per day for 2 weeks to 11 months. 68% of patients were female and 12% had received other treatments before therapy. The nano-propranolol 0.5% hydrogel was initiated at a mean age of 5.010 months and for a mean duration of 3.610 months. The response rate was 86%. No recurrence and rebound growth occurred after withdrawal of hydrogel. Slight side effects (application site itching, erosion and crusting) were observed in only 2 cases. All the local irritations were evaluated as mild and were tolerated without discontinuing the medication. We suggest that topical nano-propranolol hydrogel could be an alternative option for the treatment of uncomplicated superficial IH with satisfactory tolerability and optimal effectiveness. FROM THE CLINICAL EDITOR: The current recommended treatment for infantile hemangiomas is oral propranolol. Nonetheless, a small proportion of patients will have systemic side effects. In this article, the authors developed topical nano-propranolol hydrogel and tested this on clinical patients and found favorable response.

Variations in Depth and Chemical Composition of Groundwater During an Interval in Intermittent Water Delivery.

Based on monitoring data collected from 2006 to 2009 at the lower reaches of the Tarim River, tempo-spatial variations in groundwater depth and chemistry during an approximately 3-year interval of intermittent water delivery were studied. Results indicate that as the groundwater depth increased at the upper sector of the river's lower reaches from March 2007 to September 2009, so too did the main chemical composition of groundwater. Groundwater depth at the intermediate sector also increased, but major ions in groundwater declined. The groundwater depth at the lower sector started to decrease in August 2008, and the concentrations of main ions in the groundwater generally rose and fell along with the variations in groundwater depth. The groundwater depth and chemistry in the monitoring wells located at a distance from the aqueduct expressed complex changes at different sections. For instance, at the section near the Daxihaizi Reservoir Section B, groundwater depth increased gradually, but chemical composition changed little. In contrast, the groundwater depth of monitoring wells far from the Daxihaizi Reservoir (Section I) decreased and salt content in the groundwater increased. In sectors at a moderate distance from the reservoir, groundwater depth decreased and concentrations of main ions significantly increased.

Exercise prevents the increased anxiety-like behavior in lactational di-(2-ethylhexyl) phthalate-exposed female rats in late adolescence by improving the regulation of hypothalamus-pituitary-adrenal axis.

Both the detrimental effects of early life adversity and the beneficial effects of exercise on the hypothalamic-pituitary-adrenal (HPA) axis have been reported. Early life exposure to di-(2-ethylhexyl)-phthalate (DEHP) may impair the development of endocrine system. In this study, we investigated the effects of lactational DEHP exposure on stress responses in late adolescent female rats and examined the protective role of treadmill running. Sprague-Dawley dams were fed with DEHP (10mg/kg per day) or vehicle during lactation. After weaning, the female offspring rats were trained to exercise on a treadmill for 5 weeks and then stressed by exploring on an elevated plus maze. The activities of HPA axis were evaluated by measuring the plasma levels of ACTH and corticosterone, the expressions of adrenal enzymes cholesterol side-chain cleavage enzyme (CYP11A1) and cytochrome P-450 11ß-hydroxylase (CYP11B1), and the expression of hypothalamic glucocorticoid receptors (GR). The results demonstrate that DEHP-exposed rats exhibited enhanced anxiety-like behaviors. Increased hypothalamic GR and plasma ACTH levels, but decreased adrenal CYP11A1 and corticosterone levels, were observed in DEHP-exposed animals under stressed condition. Importantly, in DEHP-exposed animals, exercise during childhood-adolescence reduced anxiety-like behaviors by normalizing stress-induced alterations in ACTH level and adrenal CYP11A1 expression. The findings of this study suggest that treadmill running may provide beneficial effects on ameliorating the dysregulation of HPA axis in lactational DEHP-exposed adolescent female rats.