Discovery of Oxidized p-Terphenyls as Phosphodiesterase 4 Inhibitors from Marine-Derived Fungi.

Four new p-terphenyl derivatives, talaroterphenyls A-D (1-4), together with three biosynthetically related known ones (5-7), were obtained from the mangrove sediment-derived Talaromyces sp. SCSIO 41412. Compounds 1-3 are rare p-terphenyls, which are completely substituted on the central benzene ring by oxygen atoms; this is the first report of their isolation from natural sources. Their structures were elucidated through NMR spectroscopy, HRESIMS, and X-ray diffraction. Genome sequence analysis revealed that 1-7 were biosynthesized from tyrosine and phenylalanine, involving four key biosynthetic genes (ttpB-ttpE). These p-terphenyls (1-7) and 36 marine-derived terphenyl analogues (8-43) were screened for phosphodiesterase 4 (PDE4) inhibitory activities, and 1-5, 14, 17, 23, and 26 showed notable activities with IC50 values of 0.40-16 µM. The binding pattern of p-terphenyl inhibitors 1-3 with PDE4 were explored by molecular docking analysis. Talaroterphenyl A (1), with a low cytotoxicity, showed obvious anti-inflammatory activity in LPS-stimulated RAW264.7 cells. Furthermore, in the TGF-ß1-induced medical research council cell strain-5 (MRC-5) pulmonary fibrosis model, 1 could down-regulate the expression levels of FN1, COL1, and α-SMA significantly at concentrations of 5-20 µM. This study suggests that the oxidized p-terphenyl 1, as a marine-derived PDE4 inhibitor, could be used as a promising antifibrotic agent.

Structural optimization of Moracin M as novel selective phosphodiesterase 4 inhibitors for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high mortality lung disease. Although the antifibrotic drugs pirfenidone and nintedanib could slow the rate of lung function decline, the usual course of the condition is inexorably to respiratory failure and death. Therefore, new approaches and novel therapeutic drugs for the treatment of IPF are urgently needed. And the selective PDE4 inhibitor has in vivo and in vitro anti-fibrotic effects in IPF models. But the clinical application of most PDE4 inhibitors are limited by their unexpected and severe side effects such as nausea, vomiting, and diarrhea. Herein, structure-based optimizations of the natural product Moracin M resulted in a novel a novel series of 2-arylbenzofurans as potent PDE4 inhibitors. The most potent inhibitor L13 has an IC50 of 36 ± 7 nM with remarkable selectivity across the PDE families and administration of L13·citrate (10.0 mg/kg) exhibited comparable anti-pulmonary fibrosis effects to pirfenidone (300 mg/kg) in a bleomycin-induced IPF mice model, indicate that L13 is a potential lead for the treatment of IPF.

Laguerre Gaussian mode holography and its application in optical encryption.

Holography provides an approach to reconstructing both intensity and phase information, and has many applications for microscopic imaging, optical security, and data storage. Recently, the azimuthal Laguerre-Gaussian (LG) mode index, orbital angular momentum (OAM), has been implemented in holography technologies as an independent degree of freedom for high-security encryption. The radial index (RI) of LG mode, however, has not been implemented as an information carrier in holography. Here we propose and demonstrate the RI holography by using strong RI selectivity in the spatial-frequency domain. Furthermore, the LG holography is realized theoretically and experimentally with the (RI, OAM) spanning from (1, -15) to (7, 15), which leads to a 26bit LG-multiplexing hologram for high-security optical encryption. Based on LG holography, a high-capacity holographic information system can be constructed. In our experiments, a LG-multiplexing holography with a span of 217 independent LG channels has been realized, which is inaccessible at present for the OAM holography.

High-Dimensional Entanglement-Enabled Holography.

As an important imaging technique, holography has been realized with different physical dimensions of light, including polarization, wavelength, and time. Recently, quantum holography has been demonstrated by utilizing polarization entangled state with the advantages of high robustness and enhanced spatial resolution, comparing with classical holography. However, the polarization is only a two-dimensional degree of freedom, which greatly limits the capacity of quantum holography. Here, we propose a method to realize high-dimensional quantum holography by using high-dimensional orbital angular momentum (OAM) entanglement. A high-capacity OAM-encoded quantum holographic system can be obtained by multiplexing a wide range of OAM-dependent holographic images. Proof-of-principle experiments with four- and six-dimensional OAM entangled states have been implemented and verify the feasibility of our idea. Our experimental results also demonstrate that the high-dimensional quantum holography shows a high robustness to classical noise. What is more, the level of security of the holographic imaging encryption system can be greatly improved in our high-dimensional quantum holography.

FGF5 alleviated acute lung injury via AKT signal pathway in endothelial cells.

Acute lung injury (ALI), with high morbidity and mortality, is mainly resulted by infectious or non-infectious inflammatory stimulators, and it will further evolve into acute respiratory distress syndrome if not controlled. Fibroblast growth factors (FGFs) consist of more than 23 kinds of members, which are involved in various pathophysiological processes of body. However, the effect of FGF5, one member of FGFs, is still not certain in lipopolysaccharide (LPS)-induced ALI. In this study, we explored the possible impacts of FGF5 in LPS-induced ALI and primarily focused on endothelial cell, which was one of the most vulnerable cells in septic ALI. In the mouse group of FGF5 overexpression, LPS-induced lung injuries were mitigated, as well as the pyroptosis levels of pulmonary vascular endothelial cells. Additionally, in vitro human umbilical vein endothelial cells (HUVECs), our results showed that the level of cell pyroptosis was ameliorated with FGF5 overexpression, and AKT signal was activated with the overexpression of FGF5, whereas after administration of MK2206, an inhibitor of AKT signal, the protection of FGF5 was inhibited. Therefore, these results suggested that FGF5 exerted protective effects in endothelial cells exposed to LPS, and this protection of FGF5 could be attributed to activated AKT signal.

Correlations between serum levels of microRNA-148a-3p and microRNA-485-5p and the progression and recurrence of prostate cancer.

BACKGROUND: Unpredicted postoperative recurrence of prostate cancer, one of the most common malignancies among males worldwide, has become a prominent issue affecting patients after treatment. Here, we investigated the correlation between the serum miR-148a-3p and miR-485-5p expression levels and cancer recurrence in PCa patients, aiming to identify new biomarkers for diagnosis and predicting postoperative recurrence of prostate cancer. METHODS: A total of 198 male PCa cases treated with surgery, postoperative radiotherapy, and chemotherapy were involved in the presented study. Serum levels of miR-148a-3p and miR-485-5p were measured before the initial operation for the involved cases, which were then followed up for two years to monitor the recurrence of cancer and to split the cases into recurrence and non-recurrence groups. Comparison of the relative expressions of serum miR-148a-3p and miR-485-5p were made and related to other clinic pathological features. RESULTS: Pre-surgery serum levels of miR-148a-3p in patients with TNM stage cT1-2a prostate cancer (Gleason score < 7) were significantly lower (P < 0.05) than levels in patients with TNM Classification of Malignant Tumors (TNM) stage cT2b and higher prostate cancer (Gleason score ≥ 7). pre-surgery serum levels of miR-485-5p in patients with TNM stage cT1-2a prostate cancer (Gleason score < 7) were significantly higher (P < 0.05) than in patients with TNM stage cT2b and higher cancer (Gleason score ≥ 7). Serum miR-148a-3p level in recurrence group is higher than the non-recurrence group (P < 0.05) while serum miR-485-5p level in recurrence group is lower than non-recurrence group (P < 0.05). ROC curve analysis showed the AUCs of using miR-148a-3p, miR-485-5p, and combined detection for predicting recurrence of prostate cancer were 0.825 (95% CI 0.765-0.875, P < 0.0001), 0.790 (95% CI 0.726-0.844, P < 0.0001), and 0.913 (95% CI 0.865-0.948, P < 0.0001). CONCLUSION: Pre-surgery serum miR-148a-3p level positively correlates while miR-485-5p level negatively correlates with prostate cancer's progressing and postoperative recurrence. Both molecules show potential to be used for predicting postoperative recurrence individually or combined.

A new approach for reducing pollutants level: a longitudinal cohort study of physical exercises in young people.

BACKGROUND: The present study aimed to evaluate the elimination of three common pollutants (dimethoate, benzo(a)pyrene (BaP) and bisphenol A (BPA) by different physical exercises and to assess the possible factors which could affect the pollutants elimination. METHODS: A total of 200 individuals who chose different kinds of exercises in accordance to their own wish were recruited. The levels of urinary pollutants were measured using ß-glucuronidase hydrolysis followed by a high-performance liquid chromatography tandem mass spectrometry-based method. RESULTS: Totally, the levels of dimethoate, BaP and BPA were reduced after physical exercises. However, the elimination of BaP in male was higher than that in female but the elimination of BPA in female was higher than that in male. Multivariate logistic regression showed that the degree of heart rate (HR) change was a protective factor affecting the improvement effect of dimethoate, BaP and BPA while BMI (body mass index) was a risk factor. Nevertheless, sex was a risk factor affecting the improvement of dimethoate and BaP but had a lower efficacy on BPA improvement. CONCLUSION: The present findings indicate that physical exercises can be considered as a novel approach to eliminate pollutants level in human body and can also give suggestions for choosing specific physical exercises to male and female individuals. Moreover, those who are with higher BMI need to lose weight before eliminating pollutant level through physical exercises.

Baseline kidney function is associated with vancomycin-induced acute kidney injury in children: a prospective nested case-control study.

BACKGROUND: Children with kidney insufficiency are susceptible to vancomycin-induced acute kidney injury (VIAKI), but there is a lack of compelling clinical data. We conducted a nested case-control study to evaluate the relationship between kidney insufficiency and incidence of VIAKI in children. METHODS: Patients were considered to have VIAKI if they met the criteria for eGFR change according to pRIFLE-I or p-RIFLE-F. Case group comprised patients who developed VIAKI. Case-control ratio was 1:3; patients were matched for age, severity, and nature of illness and initial vancomycin dose. Primary endpoint was incidence of VIAKI at three levels of kidney function, calculated using Kaplan-Meier curve and log-rank test. Secondary endpoint was treatment-related in-hospital mortality amongst case and control groups. RESULTS: Amongst 386 children who fit study criteria, 31 developed VIAKI (8.03%). Thirty-one cases and 93 controls were selected from the observed cohort. Three risk factors were identified for VIAKI: moderate kidney insufficiency (OR 8.8, 2.4-32.8), vancomycin trough concentration ≥ 15 µg/mL (OR 7.7, 1.7-34.4), and furosemide use (OR 24.8, 6.4-98.2). A significant difference in time to VIAKI was noted between patients with moderate kidney insufficiency and patients with mild kidney insufficiency or normal kidney function (p < 0.001). In-hospital mortality rate in case group was 45.2%, compared to 18.3% in control group (p < 0.01). CONCLUSIONS: Children with moderate kidney insufficiency are more likely to develop VIAKI than those with normal and mild kidney insufficiency. Patients who develop VIAKI have higher in-hospital mortality than those who do not develop VIAKI.

Urinary levels of dimethoate, bisphenol A and benzo[a]pyrene in first-year students of Hohai University from different geographical regions.

BACKGROUND: The objective of this study was to detect the urinary levels of dimethoate, benzo(a) pyrene (BaP), and bisphenol A (BPA) in first-year Hohai University students with different geographic origins. METHODS: First-morning urine samples were collected from 540 healthy freshmen aged 17 to 19 years. Chemical levels were measured using ß-glucuronidase hydrolysis followed by a high-performance liquid chromatography-tandem mass spectrometry-based method. Geometric means (GMs) of these three chemicals are presented by body mass index (BMI) and location in a volume-based and creatinine-standardized way. RESULTS: GM concentrations of omethoate, BPA and 3-OHBaP were 9.47 µg/L (10.80 µg/g creatinine), 3.54 µg/L (4.04 µg/g creatinine) and 0.34 ng/L (0.39 ng/g creatinine), respectively. The GM concentration of omethoate in males was significantly higher than that in females. The individuals with a BMI higher than 23.9 had higher GM concentrations of omethoate, BPA, and 3-OHBaP. The inhabitants of Southwest China had significantly lower GM concentrations of omethoate, BPA, and 3-OHBaP than those who lived in other locations in China. CONCLUSION: The average level of environmental chemical accumulation in freshmen is lower in Southwest China and differs in youth who live in different regions. In addition, obesity is correlated with higher toxin levels in youth.

Laboratory markers associated with COVID-19 progression in patients with or without comorbidity: A retrospective study.

OBJECTIVES: To investigate laboratory markers for COVID-19 progression in patients with different medical conditions. METHODS: We performed a multicenter retrospective study of 836 cases in Hubei. To avoid the collinearity among the indicators, principal component analysis (PCA) followed by partial least squares discriminant analysis (PLS-DA) was performed to obtain an overview of laboratory assessments. Multivariable logistic regression analysis and multivariable Cox proportional hazards regression analysis were respectively used to explore risk factors associated with disease severity and mortality. Survival analysis was performed in patients with the most common comorbidities. RESULTS: Lactate dehydrogenase (LDH) and prealbumin were associated with disease severity in patients with or without comorbidities, indicated by both PCA/PLS-DA and multivariable logistic regression analysis. The mortality risk was associated with age, LDH, C-reactive protein (CRP), D-dimer, and lymphopenia in patients with comorbidities. CRP was a risk factor associated with short-term mortality in patients with hypertension, but not liver diseases; additionally, D-dimer was a risk factor for death in patients with liver diseases. CONCLUSIONS: Lactate dehydrogenase was a reliable predictor associated with COVID-19 severity and mortality in patients with different medical conditions. Laboratory biomarkers for mortality risk were not identical in patients with comorbidities, suggesting multiple pathophysiological mechanisms following COVID-19 infection.

Illustrating Interfacial Interaction between Honey Bee Venom Phospholipase A2 and Supported Negatively Charged Lipids with Sum Frequency Generation and Laser Scanning Confocal Microscopy.

Phospholipase A2 is an important enzyme species which can widely be found in animals, plants, bacteria, and so on. A large number of studies have shown that phospholipase A2 is highly catalytic toward the lipids. Here, sum frequency generation (SFG) vibrational spectroscopy and laser scanning confocal microscopy (LSCM) were applied to study the interaction between honey bee venom phospholipase A2 (bvPLA2) and the negatively charged DPPG bilayer. In both cases without and with the calcium ions (Ca2+), the bvPLA2 molecules were adsorbed onto the outer leaflet surface with the orientational order, and the adsorbed bvPLA2 molecules damaged the order of the packed outer leaflet. In comparison to the case without Ca2+, the addition of Ca2+ can accelerate the attaching process of bvPLA2 to the outer leaflet surface and decelerate the process of damaging the outer leaflet order. The experimental result also confirmed, with the help of the Ca2+, the DPPG molecules in the outer leaflet were hydrolyzed, with both hydrolysates, that is, lysophospholipids and fatty acids, remaining at the interface, showing a distinct difference from previous published literatures regarding neutral lipids [Phys. Chem. Chem. Phys. 2018, 20, 63-67] and PLA1 [Langmuir 2019, 35, 12831-12838].

Revealing Molecular-Level Interaction between a Polymeric Drug and Model Membrane Via Sum Frequency Generation and Microfluidics.

Body fluids flow all over the body and affect the biological processes at biointerfaces. To simulate such a case, sum frequency generation (SFG) vibrational spectroscopy and a self-designed microfluidic chip were combined together to investigate the interaction between a pH-responsive polymeric drug, poly(α-propylacrylic acid) (PPAAc), and the model cell membranes in different liquid environments. By examining the SFG spectra under the static and flowing conditions, the drug-membrane interaction was revealed comprehensively. The interfacial water layer was screened as the key factor affecting the drug-membrane interaction. The interfacial water layer can prevent the side propyl groups on PPAAc from inserting into the model cell membrane but would be disrupted by numerous ions in buffer solutions. Without flowing, at pH 6.6, the interaction between PPAAc and the model cell membrane was strongest; with flowing, at pH 5.8, the interaction was strongest. Flowing was proven to substantially affect the interaction between PPAAc and the model cell membranes, suggesting that the fluid environment was of key significance for biointerfaces. This work demonstrated that, by combining SFG and microfluidics, new information about the molecular-level interaction between macromolecules and the model cell membranes can be acquired, which cannot be obtained by collecting the normal static SFG spectra.

[Analysis and evaluation of dynamic accumulation of multiple bioactive constituents in Spatholobi Caulis].

A method was established for simultaneous determination of 21 active constituents including flavanols, isoflavones, flavonols, dihydroflavones, dihydroflavonols, chalcones, pterocarpan, anthocyanidins and phenolic acids in Spatholobi Caulis by ultra fast liquid chromatography with triple quadrupole linear ion trap mass spectrometry(UFLC-QTRAP-MS/MS). Then, it was employed to analyze and evaluate the dynamic accumulation of multiple bioactive constituents in Spatholobi Caulis. The chromatographic separation was performed on a XBridge®C_(18)(4.6 mm×100 mm, 3.5 µm) at 30 ℃ with a gradient elution of 0.3% formic acid aqueous solution-methanol, and the flow rate was 0.8 mL·min~(-1), using multiple-reaction monitoring(MRM) mode. A comprehensive evaluation of the multiple bioactive constituents was carried out by gray correlation analysis(GRA). The 21 target components showed good linearity(r>0.999 0) in the range of the tested concentrations. The average recovery rates of the 21 components were from 97.46% to 103.6% with relative standard deviations less than 5.0%. There were differences in the contents of 21 components in Spatholobi Caulis at diffe-rent harvest periods. Spatholobi Caulis had high quality from early November to early December, which is consistent with the local tradi-tional harvest period. This study reveals the rule of the dynamic accumulation of 21 components in Spatholobi Caulis and provides basic information for the suitable harvest time. At the same time, it provides a new method reference for the comprehensive evaluation of the internal quality of Spatholobi Caulis.

Revealing Interfacial Lipid Hydrolysis Catalyzed by Phospholipase A1 at Molecular Level via Sum Frequency Generation Vibrational Spectroscopy and Fluorescence Microscopy.

The interfacial hydrolysis of phospholipids catalyzed by phospholipase A1 (PLA1) was studied via sum frequency generation (SFG) vibrational spectroscopy and fluorescence microscopy. Both monolayer and bilayer setups were used to confirm the hydrolysis mechanism. During the hydrolysis, lysophospholipids, one of the hydrolysis products, were desorbed from the interface into the solution, while the other products, fatty acids, self-organized and accumulated with PLA1 at the interface to form the PLA1-induced regions, which can serve as nonspecific binding domains for proteins and thus lead to human vascular diseases. This experimental study provides the essential information on revealing the interfacial biochemical process related to the metabolism of the lipids, which is one of the basic building blocks for cells.

CmRAV1 shows differential expression in two melon (Cucumis melo L.) cultivars and enhances salt tolerance in transgenic Arabidopsis plants.

The growth and development of melon (Cucumis melo L.) are severely affected by soil salinization in many areas of the world, but the understanding of the molecular mechanisms underlying salt tolerance in melon remains limited. In this study, a new RAV (related to ABI3/VP1) gene, CmRAV1, was identified in melon. Protein structure homology analysis revealed that CmRAV1 contains an AP2 domain and a B3 domain, and subcellular localization assay revealed that CmRAV1 is localized in the nucleus. The transcript level of CmRAV1 was closely correlated with NaCl treatment, and the expression pattern of CmRAV1 differed between two cultivars (salt-tolerant and salt-sensitive cultivars) under NaCl treatment. In addition, yeasts transformed with CmRAV1 showed notably improved growth on medium containing 200 mM NaCl compared with wild-type ones. The overexpression of CmRAV1 in transgenic Arabidopsis thaliana resulted in enhanced salt tolerance at the seed germination and seedling growth stages. This study demonstrated that the expression of CmRAV1 was associated with saline stress and can potentially be utilized to improve plant salt tolerance.

A Method to Study the Distribution Patterns for Metabolites in Xylem and Phloem of Spatholobi Caulis.

Spatholobi Caulis (SC), the vine stem of Spatholobus suberectus Dunn, is a widely used traditional Chinese medicine (TCM) for the treatment of blood stasis syndrome and related diseases. Xylem and phloem are the main structures of SC and the color of xylem in SC is red brown or brown while the phloem with resin secretions is reddish brown to dark brown. They are alternately arranged in a plurality of concentric or eccentric rings. In order to investigate the distribution patterns of metabolites in xylem and phloem of SC, an analytical method based on UFLC-QTRAP-MS/MS was established for simultaneous determination of 22 constituents including four flavanols, nine isoflavones, two flavonols, two dihydroflavones, one flavanonol, one chalcone, one pterocarpan, one anthocyanidin and one phenolic acid in the samples (xylem and phloem) from Laos. Furthermore, according to the contents of 22 constituents, heat map, principal components analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA) and t-test were used to evaluate the samples and discover the differences between xylem and phloem of SC. The results indicated that the measured ingredients in xylem and phloem were significantly different. To be specific, the contents of flavonoids in xylem were higher than that in phloem, while the content of protocatechuic acid showed a contrary tendency. This study will not only reveal the distribution patterns of metabolites in xylem and phloem of SC but also facilitate further study on their quality formation.

Rare Shewanella spp. associated with pulmonary and bloodstream infections of cancer patients, China: a case report.

BACKGROUND: Members of Shewanella species are opportunistic pathogens that are found in marine environments. Currently more than sixty species have been identified, whereas the most commonly clinical cases associated with Shewanella species have involved only two species, i.e., S. algae and S. putrefaciens. We present two cases of pulmonary and bloodstream infections caused by two rare Shewanella spp. strains from patients of gastrointestinal cancer. CASE PRESENTATION: Two male patients with a history of gastrointestinal cancer presented to hospital with pulmonary and bloodstream infections, respectively. The infective pathogens of both cases were primarily isolated and identified as Shewanella algae (case I) and Shewanella putrefaciens (case II) by phenotypic features and VITEK 2 system, but they were further confirmed as Shewanella haliotis and Shewanella upenei by 16S rRNA gene sequence analysis. The major bacterial composition of the bronchoalveolar lavage in case I was also identified as Shewanella by 16S rRNA amplicon sequencing analysis. Antimicrobial susceptibility testing showed that the two strains had broad susceptibility, but S. haliotis in the case I was resistant to ciprofloxacin and levofloxacin and S. upenei in the case II was intermediate to imipenem, piperacillin/tazobactam and ciprofloxacin. CONCLUSIONS: To the best of our knowledge, this is the first cases of the pulmonary and bloodstream infections caused by Shewanella spp. from clinical patients in mainland China. Shewanella as a potential pathogen in China should not be ignored.

[Efficacy of analgesic and sedative treatments in children with mechanical ventilation in the pediatric intensive care unit].

OBJECTIVE: To compare the efficacy and safety of different analgesic and sedative treatments in children with mechanical ventilation in the pediatric intensive care unit (PICU). METHODS: Eighty children with mechanical ventilation in the PICU who needed analgesic and sedative treatments were equally and randomly divided into midazolam group and remifentanil+midazolam group. The sedative and analgesic effects were assessed using the Ramsay Scale and the Face, Legs, Activity, Cry and Consolability (FLACC) Scale. The following indices were recorded for the two groups: vital signs, ventilator parameters, organ function, total doses of remifentanil and midazolam, duration of mechanical ventilation, length of PICU stay, PICU cost, and incidence of adverse events. RESULTS: Satisfactory sedation was achieved in the two groups, but the remifentanil+midazolam group had a significantly shorter time to analgesia and sedation than the midazolam group. The remifentanil+midazolam group had a significantly higher percentage of patients with grade 3-4 on the Ramsay Scale and a significantly lower dose of midazolam than the midazolam group (P<0.05). Both groups showed decreases in heart rate (HR), mean arterial pressure (MAP), and spontaneous breathing frequency (RRs) after treatment. However, the remifentanil+midazolam group had significantly greater decreases in HR at 3-24 hours after treatment and MAP and RRs at 3-12 hours after treatment than the midazolam group (P<0.05). Compared with the midazolam group, the remifentanil+midazolam group had significantly higher ventilator tidal volume and transcutaneous oxygen saturation at 6 and 12 hours after treatment and significantly lower end-tidal carbon dioxide partial pressure at 6 and 12 hours after treatment (P<0.05). The remifentanil+midazolam group had significantly shorter time to awake, extubation time, duration of mechanical ventilation, and length of PICU stay than the midazolam group (P<0.05). There were no significant differences in PICU cost, incidence of adverse events, and hepatic and renal functions before and after treatment between the two groups (P>0.05). Both groups showed a significant decrease in fasting blood glucose level after treatment (P<0.05). CONCLUSIONS: For children with mechanical ventilation in the PICU, remifentanil+midazolam treatment can rapidly achieve analgesia and sedation, improve the effect of mechanical ventilation, and reduce the dose of sedative compared with midazolam alone, and is well tolerated.

High expression of Rad51c predicts poor prognostic outcome and induces cell resistance to cisplatin and radiation in non-small cell lung cancer.

Rad51c is critical for homologous recombination repair and genomic stability and may play roles in tumorigenesis and cancer therapy. We investigated the expression level and clinical significance of Rad51c in non-small cell lung cancer (NSCLC) and determined the effect of Rad51c on NSCLC cell chemosensitivity and radiosensitivity. Rad51c expression was detected using immunohistochemistry and was higher in NSCLC patient samples than in adjacent normal tissues. Kaplan-Meier analysis revealed that high Rad51c expression was an independent predictor of short overall survival (OS) and disease-free survival (DFS) in NSCLC patients receiving chemotherapy and/or radiotherapy. Furthermore, Rad51c knockdown increased the killing effect of ionizing radiation (IR) and enhanced cisplatin-induced apoptotic cells in NSCLC cells by disrupting the repair of cisplatin- and IR-induced DNA damage. In addition, ectopic expression of Rad51c dramatically enhanced NSCLC cell resistance to cisplatin and radiotherapy. These findings suggest that increased expression of Rad51c may confer resistance to chemotherapy and/or radiotherapy of NSCLC, and also be an independent prognostic factor for patient outcome. Therefore, targeting Rad51c may represent an improved therapeutic strategy for NSCLC patients with locally advanced disease.