Targeted inhibition of the HNF1A/SHH axis by triptolide overcomes paclitaxel resistance in non-small cell lung cancer.

Paclitaxel resistance is associated with a poor prognosis in non-small cell lung cancer (NSCLC) patients, and currently, there is no promising drug for paclitaxel resistance. In this study, we investigated the molecular mechanisms underlying the chemoresistance in human NSCLC-derived cell lines. We constructed paclitaxel-resistant NSCLC cell lines (A549/PR and H460/PR) by long-term exposure to paclitaxel. We found that triptolide, a diterpenoid epoxide isolated from the Chinese medicinal herb Tripterygium wilfordii Hook F, effectively enhanced the sensitivity of paclitaxel-resistant cells to paclitaxel by reducing ABCB1 expression in vivo and in vitro. Through high-throughput sequencing, we identified the SHH-initiated Hedgehog signaling pathway playing an important role in this process. We demonstrated that triptolide directly bound to HNF1A, one of the transcription factors of SHH, and inhibited HNF1A/SHH expression, ensuing in attenuation of Hedgehog signaling. In NSCLC tumor tissue microarrays and cancer network databases, we found a positive correlation between HNF1A and SHH expression. Our results illuminate a novel molecular mechanism through which triptolide targets and inhibits HNF1A, thereby impeding the activation of the Hedgehog signaling pathway and reducing the expression of ABCB1. This study suggests the potential clinical application of triptolide and provides promising prospects in targeting the HNF1A/SHH pathway as a therapeutic strategy for NSCLC patients with paclitaxel resistance. Schematic diagram showing that triptolide overcomes paclitaxel resistance by mediating inhibition of the HNF1A/SHH/ABCB1 axis.

A temporary-sustainable team: A new multidisciplinary team model for severe trauma.

The treatment of severe trauma, especially multiple injuries, requires multidisciplinary collaboration. The current study aims to highlight the challenges of consultation mode for severe trauma in general hospitals and emphasizes the need to create a new temporary-sustainable team. It suggests developing an information consultation mode and enforcing the fine management to improve the quality and safety of the medical treatment. The management mode of a temporary-sustainable team will reduce the cost and improve the treatment efficiency. Overall, a temporary-sustainable team has significant advantages over a traditional multidisciplinary team for severe trauma treatment.

A nomogram prediction model for recurrent laryngeal nerve lymph node metastasis in thoracic oesophageal squamous cell carcinoma.

BACKGROUND: The metastasis rate to the recurrent laryngeal nerve lymph node (RLN LN) is high, but resection of it is challenging and increases complications. This study explored the risk factors for the RLN LN metastasis in thoracic oesophageal squamous cell carcinoma and developed a novel scoring system to predict it. METHODS: We retrospectively analysed the clinicopathological data of 265 patients between 2015 and 2018. Univariate and multivariate analyses were performed to screen for risk factors and establish a logistic regression model to predict the risk of RLN LN metastasis. A nomogram was constructed accordingly. Further analyses were conducted regarding right and left RLN LN metastasis alone. RESULTS: (I) The metastatic rates of the left and right RLN LN were 15.1% and 20.4%, respectively. (II) Multivariate logistic regression analysis showed that the short axis diameter of the left RLN LN, short axis diameter of the right RLN LN, maximum diameter of the tumor, tumor location, subcarinal lymph node status and paraoesophageal lymph node status were all independent risk factors for RLN LN metastasis. (III) Multivariate logistic regression analysis showed that the short axis diameter of right RLN LN, tumor location and subcarinal lymph node status were independent risk factors for right RLN LN metastasis. (IV) Multivariate logistic regression analysis showed that short axis diameter of left RLN LN was an independent risk factor for left RLN LN metastasis. CONCLUSIONS: The metastatic rates of the left and right RLN LNs were high and can be predicted according to these nomograms.

Alterations of fecal bacterial communities in patients with lung cancer.

Emerging evidence suggests the microbiome may affect a number of diseases, including lung cancer. However, the direct relationship between gut bacteria and lung cancer remains uncharacterized. In this study, we directly sequenced the hypervariable V1-V2 regions of the 16S rRNA gene in fecal samples from patients with lung cancer and healthy volunteers. Unweighted principal coordinate analysis (PCoA) revealed a clear difference in the bacterial community membership between the lung cancer group and the healthy control group. The lung cancer group had remarkably higher levels of Bacteroidetes, Fusobacteria, Cyanobacteria, Spirochaetes, and Lentisphaerae but dramatically lower levels of Firmicutes and Verrucomicrobia than the healthy control group (P < 0.05). Despite significant interindividual variation, eight predominant genera were significantly different between the two groups. The lung cancer group had higher levels of Bacteroides, Veillonella, and Fusobacterium but lower levels of Escherichia-Shigella, Kluyvera, Fecalibacterium, Enterobacter, and Dialister than the healthy control group (P < 0.05). Most notably, correlations between certain specific bacteria and serum inflammatory biomarkers were identified. Our findings demonstrated an altered bacterial community in patients with lung cancer, providing a significant step in understanding the relationship between gut bacteria and lung cancer. To our knowledge, this is the first study to evaluate the correlations between certain specific bacteria and inflammatory indicators. To better understand this relationship, further studies should investigate the underlying mechanisms of gut bacteria in lung cancer animal models.

Efficacy of betahistine plus cognitive behavioral therapy on residual dizziness after successful canalith repositioning procedure for benign paroxysmal positional vertigo.

BACKGROUND: Some patients still complain of residual dizziness after successful canalith repositioning procedure (CRP) for benign paroxysmal positional vertigo (BPPV). Previous study found that compared to the low-dose betahistine, the high-dose betahistine could yield better efficacy in treating residual dizziness. Therefore, this study was conducted to assess whether the addition of cognitive behavioral therapy (CBT) could make low-dose betahistine produce similar results to high-dose betahistine in treating residual dizziness. METHODS: The recruited patients were randomly assigned to receive either low-dose betahistine (6 mg/time, three times/day) or high-dose betahistine (12 mg/time, three times/day). Patients in the low-dose group also received CBT (twice a week, 1 hour per time). The treatment was continued for 4 weeks. The duration of residual dizziness, 25-item Dizziness Handicap Inventory (DHI), Hamilton Anxiety Rating Scale (HARS), and Hamilton Depression Rating Scale (HDRS) were recorded and analyzed. The duration of residual dizziness and DHI score were the primary outcomes, and the HARS and HDRS scores were the secondary outcomes. RESULTS: Each group had 50 patients. After treatment, the average DHI scores, HDRS scores, and HARS scores were significantly decreased in both groups. The duration of residual dizziness and average DHI score were nonsignificantly different (P=0.08; P=0.06) between the two groups, although they were lower in the low-dose group. Compared to the high-dose group, the low-dose group had the significantly lower average HDRS score (P=0.007) and HARS score (P=0.02). Meanwhile, four patients in the high-dose group experienced intolerable stomach upset. CONCLUSION: These results demonstrated that the addition of CBT could make low-dose beta-histine produce similar results to high-dose betahistine in treating residual dizziness. Moreover, the low-dose betahistine plus CBT showed some advantages over high-dose betahistine in relieving depressive and anxiety symptoms and should be further explored.

Effect of spleen tyrosine kinase on nonsmall cell lung cancer.

AIM OF STUDY: To investigate the anti.tumor effect of spleen tyrosine kinase. (Syk) on the human nonsmall cell lung cancer cells in vitro and its mechanism. MATERIALS AND METHODS: In this study, we constructed a eukaryotic expression vector pcDNA3.1D/V5-His-TOPO/Syk and transfected it into human nonsmall cell lung cancer cells A549. Then, we not only analyzed the expression of Syk in transfected cells and its invasion but also the expression of matrix metalloproteinase-9 (MMP-9). RESULTS: The results showed that overexpressed Syk significantly inhibited A549 cell invasive ability by decreasing the expression of MMP-9. CONCLUSION: The overexpressed Syk plays an important role in tumor invasion and metastasis, and a negative role in human nonsmall cell lung cancer cells.

Current trauma care system and trauma care training in China.

Trauma is a life-threatening "modern disease". The outcomes could only be optimized by cost-efficient and prompt trauma care, which embarks on the improvement of essential capacities and conceptual revolution in addition to the disruptive innovation of the trauma care system. According to experiences from the developed countries, systematic trauma care training is the cornerstone of the generalization and the improvement on the trauma care, such as the Advance Trauma Life Support (ATLS). Currently, the pre-hospital emergency medical services (EMS) has been one of the essential elements of infrastructure of health services in China, which is also fundamental to the trauma care system. Hereby, the China Trauma Care Training (CTCT) with independent intellectual property rights has been initiated and launched by the Chinese Trauma Surgeon Association to extend the up-to-date concepts and techniques in the field of trauma care as well to reinforce the generally well-accepted standardized protocols in the practices. This article reviews the current status of the trauma care system as well as the trauma care training.

Atrial Natriuretic Peptide: A Potential Early Therapy for the Prevention of Multiple Organ Dysfunction Syndrome Following Severe Trauma.

Trauma remains a tremendous medical burden partly because of increased expenditure for the management of multiple organ dysfunction syndrome (MODS) developed during hospital stay. The intestinal barrier injury continues to be a second insult resulting in MODS which currently lacks efficient strategies for prevention. Recent studies have uncovered multi-organ protective benefits of atrial natriuretic peptide (ANP) in cardiovascular disease. However, the role of ANP in the prevention of MODS following severe trauma has not been understood. In our laboratory study, 1-h infusion of exogenous ANP during hemorrhagic shock following severe trauma induced high-level expression of endogenous serum ANP after 24 h, this effect was related to the improved level of functional biomarkers in multiple organs. Such phenomenon has not been found in other laboratories. A thorough literature review consequently was performed to uncover the potential mechanisms, to appraise therapy safety, and to propose uncertainties. In severe trauma, short-term exogenous ANP therapy during hemorrhagic shock may promote sustained endogenous expression of ANP from intestinal epithelium through activating a positive feedback loop mechanism involving phospholipase C-γ1 and reactive oxygen species crosstalk. This feedback loop may prevent MODS through multiple signaling pathways. Administration of ANP during hemorrhagic shock is thought to be safe. Further studies are required to confirm our proposed mechanisms and to investigate the dose, duration, and timing of ANP therapy in severe trauma.

Retraction: Origin of colossal permittivity in (In1/2Nb1/2)TiO2via broadband dielectric spectroscopy.

Retraction of 'Origin of colossal permittivity in (In1/2Nb1/2)TiO2via broadband dielectric spectroscopy' by Xiao-gang Zhao et al., Phys. Chem. Chem. Phys., 2015, 17, 23132-23139.

Aggressive re-warming at 38.5 °C following deep hypothermia at 21 °C increases neutrophil membrane bound elastase activity and pro-inflammatory factor release.

BACKGROUND: Cardiopulmonary bypass (CPB) is often performed under hypothermic condition. The effects of hypothermia and re-warming on neutrophil activity are unclear. This study aimed to compare the effects of different hypothermia and re-warming regimens on neutrophil membrane bound elastase (MBE) activity and the release of pro-inflammatory factors from neutrophils. METHODS: Human neutrophils were exposed to different hypothermia and re-warming regimens. MBE activity and the release of interleukin (IL)-ß1, IL-6, IL-8, and tumor necrosis factor (TNF)-α were measured. RESULTS: Neutrophil MBE activity was significantly reduced after 60-min moderate (28 °C) or deep (21 °C) hypothermic treatment. Compared with normothermic (37 °C) re-warming, aggressive re-warming (38.5°) for 120 min following deep hypothermia (21 °C) dramatically increased neutrophil MBE activity (P < 0.05). Co-incubation of neutrophils with platelet-rich plasma further increased MBE activity significantly under all the tested temperature regimens. IL-ß1 release from neutrophils was significantly higher after deep hypothermia (21 °C) followed by normothermic (37 °C) re-warming than after moderate hypothermia (28 °C) followed by normothermic re-warming (P < 0.05). Aggressive re-warming (38.5°) following deep hypothermia significantly increased the release of IL-ß1, IL-8, and TNF-α from neutrophil compared with moderate re-warming (37 °C) (all P < 0.05). CONCLUSION: Aggressive re-warming following deep hypothermia may contribute to CPB-associated tissue injury by increasing neutrophil MBE activity and stimulating pro-inflammatory factor release, thus, should be avoided. The optimal hypothermic temperature of CPB should be determined based on patient clinical characteristics and surgery type.

Triptolide reverses the Taxol resistance of lung adenocarcinoma by inhibiting the NF-κB signaling pathway and the expression of NF-κB-regulated drug-resistant genes.

Paclitaxel (or Taxol®) is a first-line chemotherapeutic drug for the treatment of non-small cell lung cancer; however, resistance to the drug is an important factor, which influences the outcome of chemotherapy. The present study aimed to investigate the role of triptolide (TPL) in reversing Taxol­resistant human lung adenocarcinoma and to elucidate the underlying molecular mechanism of resistance reversal mediated by TPL. It was hypothesized that this experimental approach would assist in solving the problem of chemotherapeutic resistance in non­small cell lung cancer, thereby improving the clinical outcomes. The human Taxol­resistant lung adenocarcinoma cell line, A549/Taxol, was established. The resistance index of the cell line was calculated, according to the half maximal inhibitory concentration (IC50) of A549/Taxol IC50 of A549, to be 51.87. The levels of apoptosis and the cell cycle in the A549/Taxol cell line were assessed to confirm the effects of TPL at three different concentrations (0.03, 0.3 and 3 µmol/l) and treatment durations (2, 4, 6 and 12 h) by flow cytometric analysis, and the inhibition of the NF­κB signaling pathway and the expression of NF­κB­regulated drug­resistant proteins were determined by immunofluorescence and western blotting, respectively. The administration of TPL promoted cell apoptosis in the A549/Taxol lung adenocarcinoma Taxol­resistant cell line and also promoted cell cycle regulation. The drug was also able to elicit a reversal of the drug resistance. TPL inhibited the nuclear factor­κB (NF­κB) signaling pathway and the expression of NF­κB­regulated drug­resistant genes, including those for FLICE­like inhibitory protein, X­linked inhibitor of apoptosis protein, Bcl­2, Bcl­xL and cyclo­oxygenase­2. TPL exerted a marked drug­resistance­reversal effect on human lung adenocarcinoma Taxol resistance, and the effect was revealed to be dose­ and time­dependent. In conclusion, TPL exerted its role in the process of resistance reversal by inhibiting the NF­κB signaling pathway, and the transcription and expression of NF-κB-regulated drug-resistant genes.

Correction: Origin of colossal permittivity in (In1/2Nb1/2)TiO2via broadband dielectric spectroscopy.

Correction for 'Origin of colossal permittivity in (In1/2Nb1/2)TiO2via broadband dielectric spectroscopy' by Xiao-gang Zhao et al., Phys. Chem. Chem. Phys., 2015, 17, 23132-23139.

Origin of colossal permittivity in (In1/2Nb1/2)TiO2via broadband dielectric spectroscopy.

(In1/2Nb1/2)TiO2 (IN-T) ceramics were prepared via a solid-state reaction route. X-ray diffraction (XRD) and Raman spectroscopy were used for the structural and compositional characterization of the synthesized compounds. The results indicated that the sintered ceramics have a single phase of rutile TiO2. Dielectric spectroscopy (frequency range from 20 Hz to 1 MHz and temperature range from 10 K to 270 K) was performed on these ceramics. The IN-T ceramics showed extremely high permittivities of up to ∼10(3), which can be referred to as colossal permittivity, with relatively low dielectric losses of ∼0.05. Most importantly, detailed impedance data analyses of IN-T demonstrated that electron-pinned defect-dipoles, interfacial polarization and polaron hopping polarization contribute to the colossal permittivity at high temperatures (270 K); however, only the complexes (pinned electron) and polaron hopping polarization are active at low temperatures (below 180 K), which is consistent with UDR analysis.

Ideal target arterial pressure after control of bleeding in a rabbit model of severe traumatic hemorrhagic shock: results from volume loading-based fluid resuscitation.

BACKGROUND: Previously reported ideal target mean arterial pressure (MAP) after control of bleeding in traumatic hemorrhagic shock (THS) requires further verification in more clinically related models. The authors explored this issue via gradient volume loading without vasopressor therapy. As certain volume loading can induce secretion of atrial natriuretic peptide (ANP), which has been shown to be protective, the authors also observed its potential role. MATERIALS AND METHODS: Fifty male New Zealand rabbits were submitted to 1.5 h of uncontrolled THS (with another eight rabbits assigned to the sham group). After bleeding control, treated rabbits were randomly (n = 10, respectively) resuscitated with blood and Ringer lactate (1:2) to achieve target MAP of 50, 60, 70, 80, and 90 mm Hg within 1 h. During the following 2 h, they were resuscitated toward baseline MAP. Rabbits were observed until 7 h. RESULTS: After resuscitation, infused fluid was lower and oxidative stress injury was milder in the 70 mm Hg group. Fluid volume loaded during the initial hour after hemostasis was negatively correlated with pH, oxygen saturation, and base excess at the end of resuscitation. It also correlated positively with proinflammatory responses in bronchoalveolar lavage fluid at 7 h and 7-h mortality. Moreover, after volume loading, the 80 mm Hg group showed significantly increased serum ANP level, which correlated with the expression of Akt protein in the jejunum at 7 h. CONCLUSIONS: In rabbits the ideal target MAP during the initial resuscitation of severe THS after hemostasis was 70 mm Hg. ANP may have a critical role in gut protection.

Inhibitory effects of syk transfection on lung cancer cell invasion.

OBJECTIVE: Spleen tyrosine kinase (Syk) is closely related to tumor invasion and metastasis, and has been shown to have potential inhibitory effects in tumors. In this study, we constructed a eukaryotic expression vector for Syk and analyzed its effects on invasive ability of the A549 non-small cell lung cancer cell line in vitro. METHODS: A fragment of Syk was obtained by RT-PCR from human lung cancer cells and cloned into the expression vector pLNCXSyk. After restriction endonuclease digestion, PCR and DNA sequencing confirmation, the recombinant Syk expression plasmid was transfected into A549 human lung cancer cells using lipofectamine protocols. After selection, the cells stably expressed Syk. Detection of Syk expression of the cells by RT-PCR, and invasive ability were examined. RESULTS: The eukaryotic expression plamid pLNCXSyk was constructed and expressed stably in the A549 human lung cancer cells. The RT-PCR results showed that Syk mRNA expression was upregulated significantly (P<0.05). Lower invasion through a basal membrane were apparent after transfection (P<0.05). CONCLUSIONS: A eukaryotic expression plasmid to cause Syk expression in lung cancer cells can obviously inhibit their invasive ability in vitro.

Endostar combined with cisplatin inhibits tumor growth and lymphatic metastasis of lewis lung carcinoma xenografts in mice.

OBJECTIVE: To investigate the effects of endostar, a recombined humanized endostatin, plus cisplatin on the growth, lymphangiogenesis and lymphatic metastasis of the Lewis lung carcinoma (LLC) in mice. METHODS: A tumor model were established in C57BL/6 mice by intravenious transplantation of LLC cells. Then the mice were randomized to receive administration with NS, endostar, cisplatin, or endostar plus cisplatin. After the mice were sacrificed, tumor multiplicity, tumor size and lymph node metastasis were assessed. Then the expression of vascular endothelial growth factor-c (VEGF-C) and podoplanin were determined by immunohistochemical staining. RESULTS: Endostar plus cisplatin significantly suppressed tumor growth. lymphatic metastasis and prolonged survival time of the mice without obvious toxicity. The inhibition of lymphatic metastasis was associated with decreased microlymphatic vessel density (MLVD) and expression of VEGF-C. CONCLUSIONS: Endostar combined with cisplatin was more effective to suppress tumor growth and lymphatic metastasis than either agent alone. Thus this may provide a rational alternative for lung carcinoma treatment.

Potential role of therapeutic hypothermia in the salvage of traumatic hemorrhagic shock.

Although therapeutic hypothermia could serve as a potential therapeutic strategy for treatment of traumatic hemorrhagic shock, significant controversy exists regarding its safety and feasibility. The current resuscitation strategy in traumatic hemorrhagic shock may also require updating. In this article, we have carried out an extensive literature search in this field and propose an initial algorithm for use of therapeutic hypothermia in traumatic hemorrhagic shock. This work lays essential groundwork for future investigations in this field.

[Study of the expression and function of Syk and VEGF-C in the development of non-small cell lung cancer].

OBJECTIVE: To explore the role of Syk and VEGF-C in the development of NSCLC. METHODS: Transfered these genes(eukaryotic expression vector pcDNA3.1-VEGF-C and pLNCX-syk)into A549 cells with the liposomes. Tested the expression of VEGF-C mRNA and Syk mRNA with RT-PCR.Investigated the cell invasion assay with transwell chamber in vitro. Analysis the expression of VEGF-C proteins in A549 cells and detect Syk and VEGF-C proteins of 81 NSCLC tissue samples with immunohistochemical staining. RESULTS: Higher expression of VEGF-C was revealed in VEGF-C-construct-transfected A549 cell than that in controls through RT-PCR (P < 0.05) and immunohistochemistry(P < 0.01).RT-PCR also revealed that Syk expression was higher in Syk-construct-transfected cells than in controls (P < 0.05). The cell invading experiments showed that there was more invaded cells in both transfected terms than in controls (P < 0.05). The expression of Syk protein in NSCLC tissue were significantly lower than that in the normal lung tissue (P < 0.05), while the expression of VEGF-C protein in NSCLC tissue were significantly higher than that in the normal lung tissue(P < 0.05). The expression of Syk and VEGF-C has a negative correlationship (r = -1.000, P = 0.019). CONCLUSION: The expression of Syk and VEGF-C has a negative correlationship in NSCLC tissue, VEGF-C-construct-transfected A549 cells are more aggressive than Syk-construct-transfected cells. And they may cooperated with each other in the development of NSCLC.