Light-Activatable Red Blood Cell Membrane-Camouflaged Dimeric Prodrug Nanoparticles for Synergistic Photodynamic/Chemotherapy.
ACS Nano. 2018 Jan 18;:
Authors: Pei Q, Hu X, Zheng X, Liu S, Li Y, Jing X, Xie Z
Biomimetic approach offers numerous opportunities to design therapeutic platforms with enhanced antitumor performance and biocompatibility. Herein we report a novel red blood cell membrane-camouflaged nanoparticle (RBC(M(TPC-PTX))) for synergistic chemo- and photodynamic therapy (PDT). Specifically, the inner core is mainly constructed by reactive oxygen species (ROS)-responsive PTX dimer (PTX2-TK) and photosensitizer 5,10,15,20-tetraphenylchlorin (TPC). In vitro experiments show that the prepared RBC(M(TPC-PTX)) is readily taken up into endosomes. Under appropriate light irradiation, the TPC can generate ROS, not only for PDT, but also for triggering PTX2-TK cleavage and on-demand PTX release for chemotherapy. In vivo results show that the coating of RBC membrane prolongs blood circulation and improves tumor accumulation. The combination of chemo- and photodynamic therapy enhances anticancer therapeutic activity and light-triggered drug release reduces systematic toxicity. All these unique characteristics render the described technology extremely promising for cancer treatment.
PMID: 29346736 [PubMed - as supplied by publisher]
Two-Photon-Excited Silica and Organosilica Nanoparticles for Spatiotemporal Cancer Treatment.
Adv Healthc Mater. 2018 Jan 18;:
Authors: Croissant JG, Zink JI, Raehm L, Durand JO
Coherent two-photon-excited (TPE) therapy in the near-infrared (NIR) provides safer cancer treatments than current therapies lacking spatial and temporal selectivities because it is characterized by a 3D spatial resolution of 1 µm3 and very low scattering. In this review, the principle of TPE and its significance in combination with organosilica nanoparticles (NPs) are introduced and then studies involving the design of pioneering TPE-NIR organosilica nanomaterials are discussed for bioimaging, drug delivery, and photodynamic therapy. Organosilica nanoparticles and their rich and well-established chemistry, tunable composition, porosity, size, and morphology provide ideal platforms for minimal side-effect therapies via TPE-NIR. Mesoporous silica and organosilica nanoparticles endowed with high surface areas can be functionalized to carry hydrophobic and biologically unstable two-photon absorbers for drug delivery and diagnosis. Currently, most light-actuated clinical therapeutic applications with NPs involve photodynamic therapy by singlet oxygen generation, but low photosensitizing efficiencies, tumor resistance, and lack of spatial resolution limit their applicability. On the contrary, higher photosensitizing yields, versatile therapies, and a unique spatial resolution are available with engineered two-photon-sensitive organosilica particles that selectively impact tumors while healthy tissues remain untouched. Patients suffering pathologies such as retinoblastoma, breast, and skin cancers will greatly benefit from TPE-NIR ultrasensitive diagnosis and therapy.
PMID: 29345434 [PubMed - as supplied by publisher]
Characteristics of Patients Who Progress from Bridging to Long Term Oxygen Therapy.
Intern Med J. 2018 Jan 18;:
Authors: Levin K, Borg B, Miller B, Kee K, Dabscheck E
BACKGROUND AND OBJECTIVE: Patients with persistent hypoxia following an acute hospital admission may be discharged with "bridging" domiciliary oxygen as per criteria defined by the Thoracic Society of Australia and New Zealand. The need for continuous Long-Term Oxygen Therapy (LTOT) is then reassessed at a clinic review 1-2 months later. The aim of this study is to describe the characteristics of patients discharged from an acute hospital admission with continuous Short Term Oxygen Therapy (STOT), and subsequently to investigate for differences between subjects who proceeded to qualify for continuous LTOT versus those who were able to cease STOT at review.
METHODS: This is a retrospective cohort study involving all subjects discharged from Alfred Health between 2011 and 2015 inclusive with bridging domiciliary oxygen. Multiple biochemical, physiological and demographic characteristics were collated and analysed.
RESULTS: Of all patients prescribed continuous STOT at time of discharge, 53.7% qualified for LTOT at outpatient review. This cohort had a significantly lower PaO2 measurement at time of discharge, compared with those who no longer qualified.
CONCLUSION: PaO2 at time of discharge provides a signal with the potential to identify who will require continuous LTOT following an acute hospital admission. Additionally, this study highlights the need to re-evaluate patients' oxygen requirements during a period of clinical stability.
PMID: 29345397 [PubMed - as supplied by publisher]
Low NT-proBNP levels in overweight and obese patients do not rule out a diagnosis of heart failure with preserved ejection fraction.
ESC Heart Fail. 2018 Jan 18;:
Authors: Buckley LF, Canada JM, Del Buono MG, Carbone S, Trankle CR, Billingsley H, Kadariya D, Arena R, Van Tassell BW, Abbate A
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome that presents clinicians with a diagnostic challenge. The use of natriuretic peptides to exclude a diagnosis of HFpEF has been proposed. We sought to compare HFpEF patients with N-terminal pro-brain natriuretic peptide (NT-proBNP) level above and below the proposed cut-off.
METHODS: Stable patients (n = 30) with left ventricular (LV) ejection fraction ≥ 50% were eligible if they had a diagnosis of HF according to the European Society of Cardiology diagnostic criteria. Characteristics of patients with NT-proBNP below (≤125 pg/mL) and above (>125 pg/mL) the diagnostic criterion were compared.
RESULTS: There were 19 (66%) women with median age 54 years. Half were African American (16, 53%), and most were obese. There were no significant differences in clinical characteristics or medication use between groups. LV end-diastolic volume index was greater in high NT-proBNP patients (P = 0.03). Left atrial volume index, E/e' ratio, and E/e' ratio at peak exercise were not significantly different between NT-proBNP groups. Peak oxygen consumption (VO2 ), VO2 at ventilatory threshold, and ventilatory efficiency measures were impaired in all patients and were not significantly different between high and low NT-proBNP patients.
CONCLUSIONS: NT-proBNP was below the proposed diagnostic cut-off point of 125 pg/mL in half of this obese study cohort. Cardiac diastolic dysfunction and cardiorespiratory fitness were not significantly different between high and low NT-proBNP patients. These data indicate that excluding the diagnosis of HFpEF based solely on NT-proBNP levels should be discouraged.
PMID: 29345112 [PubMed - as supplied by publisher]
Association between values of preoperative 6-min walk test and surgical outcomes in lung cancer patients with decreased predicted postoperative pulmonary function.
Gen Thorac Cardiovasc Surg. 2018 Jan 17;:
Authors: Nakagawa T, Tomioka Y, Toyazaki T, Gotoh M
OBJECTIVE: We retrospectively investigated the possibility that the 6-min walk test (6MWT) could predict surgical outcomes in lung cancer patients with decreased predicted postoperative (ppo) lung function.
METHODS: Patients were enrolled based on their preoperative spirometry: <60% of the ppo forced expiratory volume in 1 s (FEV1.0) or < 60% of the ppo lung carbon monoxide diffusion capacity (DLco). Morbidity, oxygen inhalation required > 10 days, home oxygen therapy (HOT) requirement, unexpected readmission within 90 days, and 90-day mortality were included as surgical outcomes. The correlations with walking distance and the minimum SpO2 (SpO2min) and maximum decrease in SpO2 (ΔSpO2) during the 6MWT were analyzed using logistic regression analysis, adjusting for age, sex, and surgical procedure.
RESULTS: Altogether, 121 patients were analyzed. Logistic regression analysis revealed that higher ΔSpO2 and lower SpO2min were significantly correlated with a higher risk of prolonged need for oxygen inhalation and HOT, surgical morbidity, and 90-day mortality. Cut-off values of > 4% for ΔSpO2 were significant for prolonged oxygen inhalation and surgical morbidity. Cut-off values of < 89-91% for SpO2min were also significant for the need for prolonged oxygen inhalation, surgical morbidity, and HOT requirement. There were no significant correlations between walking distance and each surgical outcome.
CONCLUSIONS: Oxygen desaturation during 6MWT was a good predictor for poor surgical outcomes in lung cancer patients with decreased ppo pulmonary function.
PMID: 29344798 [PubMed - as supplied by publisher]
Underlying mechanism of the photodynamic activity of hematoporphyrin‑induced apoptosis in U87 glioma cells.
Int J Mol Med. 2018 Jan 18;:
Authors: Yuan SX, Li JL, Xu XK, Chen W, Chen C, Kuang KQ, Wang FY, Wang K, Li FC
Photodynamic therapy (PDT) is a relatively novel type of tumor therapy method with low toxicity and limited side‑effects. The aim of the present study was to investigate the underlying mechanism and potential microRNAs (miRNAs) involved in the treatment of glioma by PDT with hematoporphyrin, a clinical photosensitizer. The photodynamic activity of hematoporphyrin on the cell viability and apoptosis of gliomas was investigated by MTT, and flow cytometry and fluorescence microscopy, respectively. Alterations in singlet oxygen and mitochondrial membrane potential were detected. The differentially expressed miRNAs and proteins were evaluated by miRNA gene chip and apoptosis‑associated protein chip, respectively. The results demonstrated that cell viability significantly decreased with hematoporphyrin concentration. PDT with hematoporphyrin significantly increased cell apoptosis at a later stage, induced the content of reactive oxygen species (ROS) and decreased the mitochondrial membrane potential, indicating that PDT with hematoporphyrin inhibited cell growth via induction of radical oxygen, decreased the mitochondrial membrane potential and induced apoptosis. The upregulated miRNAs, including hsa‑miR‑7641, hsa‑miR‑9500, hsa‑miR‑4459, hsa‑miR‑21‑5p, hsa‑miR‑663a and hsa‑miR‑205‑5p may be important in PDT‑induced cell apoptosis in glioma. Transporter 1, ATP binding cassette subfamily B member‑ and nuclear factor‑κB‑mediated apoptosis signaling pathways were the most significant pathways. Thus, the current study presents PDT as a potential therapeutic approach for the treatment of malignant glioma, and identified miRNAs for the molecular design and development of a third‑generation photosensitizer (PS).
PMID: 29344634 [PubMed - as supplied by publisher]
Changes in contractile protein expression are linked to ventricular stiffness in infants with pulmonary hypertension or right ventricular hypertrophy due to congenital heart disease.
Open Heart. 2018;5(1):e000716
Authors: Bond AR, Iacobazzi D, Abdul-Ghani S, Ghorbel M, Heesom K, Wilson M, Gillett C, George SJ, Caputo M, Suleiman S, Tulloh RMR
Background: The right ventricle (RV) is not designed to sustain high pressure leading to failure. There are no current medications to help RV contraction, so further information is required on adaption of the RV to such hypertension.
Methods: The Right Ventricle in Children (RVENCH) study assessed infants with congenital heart disease undergoing cardiac surgery with hypertensive RV. Clinical and echocardiographic data were recorded, and samples of RV were taken from matched infants, analysed for proteomics and compared between pathologies and with clinical and echocardiographic outcome data.
Results: Those with tetralogy of Fallot (TOF) were significantly more cyanosed than those with ventricular septal defect (median oxygen saturation 83% vs 98%, P=0.0038), had significantly stiffer RV (tricuspid E wave/A wave ratio 1.95 vs 0.84, P=0.009) and had most had restrictive physiology. Gene ontology in TOF, with enrichment analysis, demonstrated significant increase in proteins of contractile mechanisms and those of calmodulin, actin binding and others associated with contractility than inventricular septal defect. Structural proteins were also found to be higher in association with sarcomeric function: Z-disc, M-Band and thin-filament proteins. Remaining proteins associated with actin binding, calcium signalling and myocyte cytoskeletal development. Phosphopeptide enrichment led to higher levels of calcium signalling proteins in TOF.
Conclusion: This is the first demonstration that those with an RV, which is stiff and hypertensive in TOF, have a range of altered proteins, often in calcium signalling pathways. Information about these alterations might guide treatment options both in terms of individualised therapy or inotropic support for the Right ventricle when hypertensive due to pulmoanry hypertension or congenital heart disease.
PMID: 29344379 [PubMed]
WST11 Vascular Targeted Photodynamic Therapy Effect Monitoring by Multispectral Optoacoustic Tomography (MSOT) in Mice.
Authors: Neuschmelting V, Kim K, Malekzadeh-Najafabadi J, Jebiwott S, Prakash J, Scherz A, Coleman JA, Kircher MF, Ntziachristos V
Objective: Monitoring emerging vascular-targeted photodynamic therapy (VTP) and understanding the time-dynamics of treatment effects remains challenging. We interrogated whether handheld multispectral optoacoustic tomography (MSOT) could noninvasively monitor the effect of VTP using WST11, a vascular-acting photosensitizer, on tumor tissues over time using a renal cell cancer mouse model. We also investigated whether MSOT illumination can induce VTP, to implement a single-modality theranostic approach. Materials and Methods: Eight BalB/c mice were subcutaneously implanted with murine renal adenocarcinoma cells (RENCA) on the flank. Three weeks later VTP was performed (10 min continuous illumination at 753 nm following intravenous infusion using WST11 or saline as control. Handheld MSOT images were collected prior to VTP administration and subsequently thereafter over the course of the first hour, at 24 and 48 h. Data collected were unmixed for blood oxygen saturation in tissue (SO2) based on the spectral signatures of deoxy- and oxygenated hemoglobin. Changes in oxygen saturation over time, relative to baseline, were examined by paired t-test for statistical significance (p < 0.05). In-vivo findings were corroborated by histological analyses of the tumor tissue. Results: MSOT is shown to prominently resolve changes in oxygen saturation in tumors within the first 20 min post WST11-VTP treatment. Within the first hour post-treatment, SO2 decreased by more than 60% over baseline (p < 0.05), whereas it remained unchanged (p > 0.1) in the sham-treated group. Moreover, unlike in the control group, SO2 in treated tumors further decreased over the course of 24 to 48 h post-treatment, concomitant with the propagation of profound central tumor necrosis present in histological analysis. We further show that pulsed MSOT illumination can activate WST11 as efficiently as the continuous wave irradiation employed for treatment. Conclusion: Handheld MSOT non-invasively monitored WST11-VTP effects based on the SO2 signal and detected blood saturation changes within the first 20 min post-treatment. MSOT may potentially serve as a means for both VTP induction and real-time VTP monitoring in a theranostic approach.
PMID: 29344301 [PubMed - in process]
DR2 blocker thioridazine: A promising drug for ovarian cancer therapy.
Oncol Lett. 2017 Dec;14(6):8171-8177
Authors: Yong M, Yu T, Tian S, Liu S, Xu J, Hu J, Hu L
Dopamine receptor 2 (DR2) may be a biomarker for various types of cancer. Ovarian cancer cells overexpress DR2; therefore, blocking DR2 may be a novel treatment strategy for ovarian cancer. Thioridazine, a DR2 blocker, has antineoplastic activity in a variety of cancer cells. In view of the requirement for novel therapeutic agents in ovarian cancer, the present study aimed to determine the potential effects of thioridazine in vitro and in vivo. It was revealed that the DR2 blocker thioridazine induced cell death in a dose-dependent manner in ovarian cancer cells. Thioridazine treatment induced apoptosis and autophagy, which may be attributed to an increased level of reactive oxygen species and associated DNA damage. Additionally, the expression of various proteins increased with oxidative stress, including nuclear factor E2-related factor 2, which is a pivotal transcriptional factor involved in cellular responses to oxidative stress. Heme oxygenase 1, NAPDH quinone dehydrogenase 1 and hypoxia inducible factor-1α and phosphorylated (p)-protein kinase B expression was significantly decreased, and the expression level of p-extracellular signal-related kinases and p-P38 was increased. Using 3-methyl adenine to inhibit autophagy caused the rate of apoptosis to increase. Thioridazine inhibited the growth of SKOV3 xenografts in nude mice. The present study demonstrated that the DR2 blocker thioridazine exhibited anticancer effects in vitro and in vivo, suggesting that thioridazine may be used as a potential drug in ovarian cancer therapy.
PMID: 29344260 [PubMed]
ZGDHu-1 for cancer therapy.
Oncol Lett. 2017 Dec;14(6):6334-6340
Authors: Liu J, Qiu L, Xia J, Chen S, Yu X, Zhou Y
N,N'-di-(m-methylphenyl)-3,6-dimethyl-1,4-dihydro-1,2,4,5-tetrazine-1,4-dicarboamide (ZGDHu-1) is a novel tetrazine derivative that was initially designed and produced by Professor W.X. Hu, and which has been reported by our group to exhibit antitumor activity. Accumulating evidence suggests that the anticancer mechanisms of ZGDHu-1 may be involved indifferent biological activities, particularly in acute myeloid leukemia (AML) cells. At a high concentration, ZGDHu-1 has been demonstrated to inhibit the proliferation of the leukemia cells by arresting the cell cycle at the G2/M phase, and by inducing cell apoptosis via inducing the accumulation of reactive oxygen species, the translocation of phosphatidylserine across the plasma membrane and the loss of mitochondrial membrane potential. Furthermore, at a low concentration, it was demonstrated to induce the differentiation and degrade the AML1-eight-twenty-one fusion protein in AML cells. Finally, results from a previous study indicate that ZGDHu-1 is a potential proteasome inhibitor. Overall, our preliminary research suggests that ZGDHu-1 may be a promising anticancer drug; however, further research is warranted to identify the exact drug target and potential clinical application in leukemia cells or solid tumors. In the present review, the application of ZGDHu-1 in cancer research, in addition to the specific underlying targets of ZGDHu-1, are discussed.
PMID: 29344112 [PubMed]
Understanding of COPD among final-year medical students.
Int J Chron Obstruct Pulmon Dis. 2018;13:131-139
Authors: Mohigefer J, Calero-Acuña C, Marquez-Martin E, Ortega-Ruiz F, Lopez-Campos JL
Objective: Several previous studies have shown a suboptimal level of understanding of COPD among different population groups. Students in their final year of Medicine constitute a population that has yet to be explored. The evaluation of their understanding provides an opportunity to establish strategies to improve teaching processes. The objective of the present study is to determine the current level of understanding of COPD among said population.
Methods: A cross-sectional observational study was done using digital surveys given to medical students in their final year at the Universidad de Sevilla. Those surveyed were asked about demographic data, smoking habits as well as the clinical manifestation, diagnosis and treatment of COPD.
Results: Of the 338 students contacted, responses were collected from 211 of them (62.4%). Only 25.2% had an accurate idea about the concept of the disease. The study found that 24.0% of students were familiar with the three main symptoms of COPD. Tobacco use was not considered a main risk factor for COPD by 1.5% of students. Of those surveyed, 22.8% did not know how to spirometrically diagnose COPD. Inhaled corticosteroids were believed to be part of the main treatment for this disease among 51.0% of the students. Results show that 36.4% of respondents believed that home oxygen therapy does not help COPD patients live longer. Only 15.0% considered the Body-mass index, airflow Obstruction, Dyspnea, and Exercise (BODE) index to be an important parameter for measuring the severity of COPD. Giving up smoking was not believed to prevent worsening COPD among 3.4% of students surveyed. Almost half of students (47.1%) did not recommend that those suffering from COPD undertake exercise.
Conclusion: The moderate level of understanding among the population of medical students in their final year shows some strengths and some shortcomings. Teaching intervention is required to reinforce solid knowledge among this population.
PMID: 29343952 [PubMed - in process]
[A study on the effects and safety of sequential humidified high flow nasal cannula oxygenation therapy on the COPD patients after extubation].
Zhonghua Yi Xue Za Zhi. 2018 Jan 09;98(2):109-112
Authors: Zhang JC, Wu FX, Meng LL, Zeng CY, Lu YQ
Objective: To investigate and compare the effect and safety of nasal high-flow oxygen therapy (HFNCO) and noninvasive ventilation (NIV) therapy after extubation in patients with chronic obstructive pulmonary disease (COPD). Methods: All COPD patients subjected to mechanical ventilation in the Emergency Intensive Unit of the First Affiliated Hospital of Zhejiang University during January 2015 to June 2016 were included in the study. The patients were divided into two groups after extubation and HFNCO and NIV were adopted on each group respectively. Clinical indexes including the patients' general condition, blood gas analysis and pulmonary function before and after extubation, ratio of re-intubation and CT grades were collected and analyzed. Results: There was no significant difference in the incidence of aspiration (4.8% vs 8.3%), pressure sores (0 vs 8.3%) and delirium (4.8% vs 12.5%) between the two groups (all P>0.05). At 12 h after extubation, the oxygenation index of NIV group was significantly higher than that of the HFNCO group (265±29 vs 297±33; P<0.05), while no significant difference in PCO(2) (P>0.05). For 24 h and 72 h after extubation, there was no statistically significant difference in oxygenation index and PCO(2) between the both groups (P>0.05). The intensive care unit (ICU) retention time in HFNCO group was significantly lower than that in NIV group (13.7±0.8 vs 15.2±0.5; P<0.05). In addition, no significant difference between the two groups in mortality and re-intubation rate at 28 d (P>0.05) was observed. Conclusion: HFNCO is effective and safe in the treatment of COPD patients after extubation, and it is hence valuable for further clinical application.
PMID: 29343034 [PubMed - in process]
Musashi1 Promotes Non-Small Cell Lung Carcinoma Malignancy and Chemoresistance via Activating the Akt Signaling Pathway.
Cell Physiol Biochem. 2017;44(2):455-466
Authors: Lang Y, Kong X, He C, Wang F, Liu B, Zhang S, Ning J, Zhu K, Xu S
BACKGROUND/AIMS: Lung cancer is one of the leading causes for cancer mortality. The poor therapeutic outcome of non-small cell lung carcinoma (NSCLC) is mainly due to late diagnosis and chemoresistance. In this study, we investigated the role of Musashi1 (MSI1) in NSCLC malignancy and chemoresistance.
METHODS: Colony formation, MTT, glucose uptake and lactate production assays were employed to study lung cancer cell malignancy and chemoresistance. RT-PCR and Western blotting were performed to detect mRNA and protein expressions of genes. We used immunohistochemistry and Pearson correlation analysis to study the relationship of gene expression.
RESULTS: We demonstrated that MSI1 was able to promote the proliferation and glucose metabolism of NSCLC cells, and to mediate the sensitivity to chemotherapy drugs in NSCLC cells. Importantly, we found that MSI1 could regulate the activity of Akt signaling. The regulation of NSCLC proliferation, glucose metabolism and chemoresistance by MSI1 was dependent on the modulation of the activity of the Akt signaling pathway. We also found that MSI1 was a target of miR-181a-5p, a microRNA involved in the regulation of cancer development. The expression levels of MSI1 and miR-181a-5p were negatively correlated in NSCLC.
CONCLUSION: MSI1 promotes non-small cell lung carcinoma malignancy and chemoresistance via activating the Akt signaling pathway, which provides a new strategy for the therapy of NSCLC.
PMID: 29141252 [PubMed - indexed for MEDLINE]
Airway Resistance in Patients with Obstructive Sleep Apnea Syndrome Following Robotic Prostatectomy.
J Endourol. 2017 May;31(5):489-496
Authors: Köhne W, Börgers A, Musch M, Kröpfl D, Groeben H
BACKGROUND: Because minimally invasive surgery can improve postoperative recovery, it became the preferred technique for patients with significant comorbidities. However, steep Trendelenburg position and abdominal CO2-insufflation can lead to a significant increase in upper airway resistance and an alteration of overall lung function. In particular, patients who already suffer from an obstructive airway disease like obstructive sleep apnea syndrome (OSAS) might be at risk for postoperative airway complications. Therefore, we perioperatively performed spirometric tests in patients with OSAS undergoing robotic surgery in steep Trendelenburg position.
METHODS: Twenty patients with OSAS were enrolled in the study. A day before surgery lung function measurements were performed and repeated preoperatively, 40, 120, and 240 minutes and 1 and 5 days postoperatively. We measured vital capacity (VC), forced expiratory volume in 1 second (FEV1), maximal mid expiratory and inspiratory flow (MEF50, MIF50), arterial oxygen saturation, and nasal flow.
RESULTS: The ratio of MEF50 to MIF50, as an indicator of upper airway resistance, was increased significantly postoperatively and normalized within 24 hours (p < 0.0001), while FEV1 and VC were significantly reduced and recovered only partially as much as the fifth postoperative day (p < 0.0001).
CONCLUSION: Airway resistance increased following robotic radical prostatectomy in Trendelenburg position in patients with OSAS. Two separate major effects can be observed. A significant increase of the upper airway resistance, which improved to preoperative conditions within 24 hours, and a reduction in FEV1 and VC, which recovered only partially as much as the fifth postoperative day.
PMID: 28355121 [PubMed - indexed for MEDLINE]
An "Unlikely" Pair: The Antimicrobial Synergy of Polymyxin B in Combination with the Cystic Fibrosis Transmembrane Conductance Regulator Drugs KALYDECO and ORKAMBI.
ACS Infect Dis. 2016 Jul 08;2(7):478-88
Authors: Schneider EK, Azad MA, Han ML, Tony Zhou Q, Wang J, Huang JX, Cooper MA, Doi Y, Baker MA, Bergen PJ, Muller MT, Li J, Velkov T
Novel combination therapies are desperately needed for combating lung infections caused by bacterial "superbugs". This study aimed to investigate the synergistic antibacterial activity of polymyxin B in combination with the cystic fibrosis (CF) drugs KALYDECO (ivacaftor) and ORKAMBI (ivacaftor + lumacaftor) against Gram-negative pathogens that commonly colonize the CF lung, in particular, the problematic Pseudomonas aeruginosa. The in vitro synergistic activity of polymyxin B combined with ivacaftor or lumacaftor was assessed using checkerboard and static time-kill assays against a panel of polymyxin-susceptible and polymyxin-resistant P. aeruginosa isolates from the lungs of CF patients. Polymyxin B, ivacaftor, and lumacaftor were ineffective when used individually against polymyxin-resistant (MIC ≥ 4 mg/L) isolates. However, when used together, the combination of clinically relevant concentrations of polymyxin B (2 mg/L) combined with ivacaftor (8 mg/L) or ivacaftor (8 mg/L) + lumacaftor (8 mg/L) displayed synergistic killing activity against polymyxin-resistant P. aeruginosa isolates as demonstrated by a 100-fold decrease in the bacterial count (CFU/mL) even after 24 h. The combinations also displayed excellent antibacterial activity against P. aeruginosa under CF relevant conditions in a sputum medium assay. The combination of lumacaftor (alone) with polymyxin B showed additivity against P. aeruginosa. The potential antimicrobial mode of action of the combinations against P. aeruginosa was investigated using different methods. Treatment with the combinations induced cytosolic GFP release from P. aeruginosa cells and showed permeabilizing activity in the nitrocefin assay, indicating damage to both the outer and inner Gram-negative cell membranes. Moreover, scanning and transmission electron micrographs revealed that the combinations produce outer membrane damage to P. aeruginosa cells that is distinct from the effect of each compound per se. Ivacaftor was also shown to be a weak inhibitor of the bacterial DNA gyrase and topoisomerase IV with no effect on either human type I or type IIα topoisomerases. Lumacaftor displayed the ability to increase the cellular production of damaging reactive oxygen species. In summary, the combination of polymyxin B with KALYDECO or ORKAMBI exhibited synergistic activity against highly polymyxin-resistant P. aeruginosa CF isolates and can be potentially useful for otherwise untreatable CF lung infections.
PMID: 27626100 [PubMed - indexed for MEDLINE]
FAILING TO IDENTIFY AND RESPOND TO THE DETERIORATING PATIENT: A CASE FOR THE CORONER.
Aust Nurs Midwifery J. 2016 07;24(1):31
Authors: Starr L
The Coroners Court is a unique court that fulfills an important function in our legal system--determining the manner and cause of death of those who have died in unexpected or unexplained circumstances. With broad powers of investigation the Coroner through the coronial process will make findings and recommendations regarding the death or suspected deaths of individuals in their particular circumstances.
PMID: 29236436 [PubMed - indexed for MEDLINE]
Chlorogenic acid protects against liver fibrosis in vivo and in vitro through inhibition of oxidative stress.
Clin Nutr. 2016 Dec;35(6):1366-1373
Authors: Shi H, Shi A, Dong L, Lu X, Wang Y, Zhao J, Dai F, Guo X
Liver fibrosis is a scaring process related to chronic liver injury of all causes and as yet no truly effective treatment is available. Chlorogenic acid (CGA) is a phenolic compound and exerts anti-inflammatory and anti-oxidant activities. Our former studies suggested that CGA could prevent CCl4-induced liver fibrosis through inhibition of inflammatory signaling pathway in rats. However, whether the anti-oxidant activity is involved in the anti-fibrotic effect of CGA on liver fibrosis is not yet fully understood. This study examined whether CGA may prevent CCl4-induced liver fibrosis by improving anti-oxidant capacity via activation of Nrf2 pathway and suppressing the PDGF-induced profibrotic action via inhibition of NOX/ROS/MAPK pathway. The studies in vivo showed that the liver fibrosis degree, hydroxyproline content and expression of α-SMA, Collagen Ⅰ, Collagen Ⅲ and TIMP-1 were increased in CCl4-injected rats and which were alleviated markedly by CGA. Furthermore, CGA significantly decreased CYP2E1 expression and increased the expression of nuclear Nrf2 and Nrf2-regulated anti-oxidant genes (HO-1, GCLC and NQO1). CGA decreased MDA level and increased GSH, SOD and CAT levels in liver tissues. In vitro studies PDGF could induce NOX subunits (p47phox and gp91phox) expression, ROS production, p38 and ERK1/2 phosphorylation, HSCs proliferation and profibrotic genes expression in HSCs, all of which were reduced by CGA treatment. In conclusion, the results suggest that CGA protects against CCl4-induced liver fibrosis, at least in part, through the suppression of oxidative stress in liver and hepatic stellate cells.
PMID: 27017478 [PubMed - indexed for MEDLINE]
Suppressive effects of sirtinol on human cytomegalovirus (hCMV) infection and hCMV-induced activation of molecular mechanisms of senescence and production of reactive oxygen species.
Mech Ageing Dev. 2016 Sep;158:62-9
Authors: Mao G, Li H, Ding X, Meng X, Wang G, Leng SX
Substantial evidence suggests that chronic human cytomegalovirus (hCMV) infection contributes significantly to T-cell immunosenescence and adverse health outcomes in older adults. As such, it is important to search for compounds with anti-hCMV properties. Studies have shown that resveratrol, a sirtuin activator, suppresses hCMV infection. Here we report suppressive effects of sirtinol, a sirtuin antagonist, on hCMV infection and its cellular and molecular consequences. Human diploid fibroblast WI-38 cells were infected by hCMV Towne strain in the absence or presence of sirtinol. hCMV replication was measured using qPCR. Senescent phenotype was determined by senescence-associated β galactosidase (SA-β-Gal) activity. Expression of hCMV immediate early (IE) and early (E) proteins and senescence-associated proteins (pRb and Rb, p16(INK4), and p53) and production of reactive oxygen species (ROS) were assessed using standard laboratory assays. The results demonstrated that sirtinol suppressed hCMV infection as well as hCMV-induced activation of molecular mechanisms of senescence and ROS production. While underlying molecular mechanisms remain to be elucidated, these findings indicate sirtinol as a novel and potent anti-hCMV agent with the potential to be developed as an effective treatment for chronic hCMV infection and its cellular and molecular consequences that are important to ageing and health of older adults.
PMID: 26763147 [PubMed - indexed for MEDLINE]
Feasibility and results of pull-percutaneous endoscopic gastrostomy for enteral nutrition in adults with severe cerebral palsy.
Clin Nutr. 2016 Aug;35(4):918-23
Authors: Davout A, Rech C, Hanachi M, Barthod F, Melchior JC, Crenn P
BACKGROUND & AIMS: Eating and swallowing impairments often get worse as patients with severe cerebral palsy (CP) get older, creating increased demand for percutaneous endoscopic gastrostomy (PEG) tube placement. Here we investigated the feasibility, safety, adverse events (AEs) and outcomes of PEG in adult CP.
METHODS: We performed a retrospective study of 26 consecutive severe adult (age: 28 [19-48] yrs) CP patients who underwent pull-PEG tube placement under general anesthesia between 2005 and 2012 (median follow-up: 23 [6-64] months) at the same tertiary hospital centre.
RESULTS: The procedure was a technical success for 19 patients (BMI: 13.8 [10.7-21.4]) with (n = 11) or without (n = 8) previous respiratory disorder. Indications were mainly swallowing disorders (n = 14) and inadequate oral intake (n = 8). Early AEs were 7 transient oxygen needs, 3 local wound infections and 2 transient ileus. Long-term AEs were 9 non-severe gastrostomy incidents. There was no significant improvement in neurological status but respiratory function was improved in 6 patients and enteral nutrition enabled a significant median weight gain of 4.2 [1-8.8] kg (P < 0.01). Quality-of-life assessed by relatives and the healthcare team was improved in 13/16 and 13/15 cases respectively. AEs and outcomes did not differ significantly with previous respiratory disorder or nutritional status.
CONCLUSIONS: PEG tube placement is feasible in adult CP, although the risk of failure is increased by anatomical specificities. Previous respiratory disorders and undernourishment did not increase AE rates or modify outcomes. There were positive changes over time for nutritional status and perceived quality-of-life, but no neurological improvement.
PMID: 26209255 [PubMed - indexed for MEDLINE]