Transmorphic phage-guided systemic delivery of TNFα gene for the treatment of human pediatric medulloblastoma

Medulloblastoma is the most common childhood brain tumor with an unfavorable prognosis and limited options of harmful treatments that are associated with devastating long-term side effects. Therefore, the development of safe, noninvasive, and effective therapeutic approaches is required to save the quality of life of young medulloblastoma survivors. We postulated that therapeutic targeting is a solution. Thus, we used a recently designed tumor-targeted bacteriophage (phage)-derived particle, named transmorphic phage/AAV, TPA, to deliver a transgene expressing the tumor necrosis factor-alpha (TNFα) for targeted systemic therapy of medulloblastoma. This vector was engineered to display the double-cyclic RGD4C ligand to selectively target tumors after intravenous administration. Furthermore, the lack of native phage tropism in mammalian cells warrants safe and selective systemic delivery to the tumor microenvironment. In vitro RGD4C.TPA.TNFα treatment of human medulloblastoma cells generated efficient and selective TNFα expression, subsequently triggering cell death. Combination with the chemotherapeutic drug cisplatin used clinically against medulloblastoma resulted in augmented effect through the enhancement of TNFα gene expression. Systemic administration of RGD4C.TPA.TNFα to mice-bearing subcutaneous medulloblastoma xenografts resulted in selective tumor homing of these particles and consequently, targeted tumor expression of TNFα, apoptosis, and destruction of the tumor vasculature. Thus, our RGD4C.TPA.TNFα particle provides selective and efficient systemic delivery of TNFα to medulloblastoma, yielding a potential TNFα anti-medulloblastoma therapy while sparing healthy tissues from the systemic toxicity of this cytokine

White Matter Hyperintensity Associations with Cerebral Blood Flow in Elderly Subjects Stratified by Cerebrovascular Risk

Objective: This study aims to add clarity to the relationship between deep and periventricular brain white matter hyperintensities (WMHs), cerebral blood flow (CBF), and cerebrovascular risk in older persons. Methods: Deep white matter hyperintensity (dWMH) and periventricular white matter hyperintensity (pWMH) and regional gray matter (GM) and white matter (WM) blood flow from arterial spin labeling were quantified from magnetic resonance imaging scans of 26 cognitively normal elderly subjects stratified by cerebrovascular disease (CVD) risk. Fluidattenuated inversion recovery images were acquired using a high-resolution 3-dimensional (3-D) sequence that reduced partial volume effects seen with slicebased techniques. Results: dWMHs but not pWMHs were increased in patients at high risk of CVD; pWMHs but not dWMHs were associated with decreased regional cortical (GM) blood flow. We also found that blood flow in WM is decreased in regions of both pWMH and dWMH, with a greater degree of decrease in pWMH areas. Conclusions: WMHs are usefully divided into dWMH and pWMH regions because they demonstrate differential effects. 3-D regional WMH volume is a potentially valuable marker for CVD based on associations with cortical CBF and WM CBF

Data on cytotoxic and antibacterial activity of synthesized Fe3O4 nanoparticles using Malva sylvestris

The biosynthesis of materials using medicinal plants can be a low-cost and eco-friendly approach due to their extraordinary properties. Herein, we reported a facile synthesis of Fe3O4 nanoparticles using Malva sylvestris. The surface morphology, functional groups, and elemental analysis were done to characterize the synthesized nanoparticles. The cytotoxicity performance of the synthesized nanoparticles was analyzed by exposing nanoparticles to MCF-7 and Hep-G2 cancer cell lines through MTT colorimetric assay and the IC50 value was defined as 100 μg/mL and 200 μg/mL, respectively. The antibacterial performance of synthesized nanoparticles against four different bacterial strains including Staphylococcus aureus, Corynebacterium, Pseudomonas aeruginosa, and Klebsiella pneumoniae were assessed through microdilution broth method. The synthesized Fe3O4 nanoparticles using Malva sylvestris demonstrated higher antibacterial effects against Gram-positive strains with MIC values of 62.5 μg/mL and 125 μg/mL which increase the inhibitory percentage to more than 90%

A clinician’s guide to management of intra-abdominal hypertension and abdominal compartment syndrome in critically ill patients

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2020. Other selected articles can be found online at . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901

Systemically targeted cancer immunotherapy and gene delivery using transmorphic particles

Immunotherapy is a powerful tool for cancer treatment, but the pleiotropic nature of cytokines and immunological agents strongly limits clinical translation and safety. To address this unmet need, we designed and characterised a systemically targeted cytokine gene delivery system through transmorphic encapsidation of human recombinant adeno-associated virus DNA using coat proteins from a tumour-targeted bacteriophage (phage). We show that Transmorphic Phage/AAV (TPA) particles provide superior delivery of transgenes over current phage-derived vectors through greater diffusion across the extracellular space and improved intracellular trafficking. We used TPA to target the delivery of cytokine-encoding transgenes for interleukin-12 (IL12), and novel isoforms of IL15 and tumour necrosis factor alpha (TNFα) for tumour immunotherapy. Our results demonstrate selective and efficient gene delivery and immunotherapy against solid tumours in vivo, without harming healthy organs. Our transmorphic particle system provides a promising modality for safe and effective gene delivery, and cancer immunotherapies through cross-species complementation of two commonly used viruses

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Detection of Plant DNA in the Bronchoalveolar Lavage of Patients with Ventilator-Associated Pneumonia

BACKGROUND: Hospital-acquired infections such as nosocomial pneumonia are a serious cause of mortality for hospitalized patients, especially for those admitted to intensive care units (ICUs). Despite the number of the studies reported to date, the causative agents of pneumonia are not completely known. Herein, we found by molecular technique that vegetable and tobacco DNA may be detected in the bronchoalveolar lavage from patients with ventilator-associated pneumonia (VAP). METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we studied bronchoalveolar lavage (BAL) from patients admitted to ICUs with ventilator-associated pneumonia. BAL fluids were assessed with molecular tests, culture and blood culture. We successfully identified plant DNA in six patients out of 106 (6%) with ventilator-associated pneumonia. Inhalation was confirmed in four cases and suspected in the other two cases. Inhalation was significantly frequent in patients with plant DNA (four out of six patients) than those without plant DNA (three out of 100 patients) (P<0.001). Nicotiana tabacum chloroplast DNA was identified in three patients who were smokers (cases 2, 3 and 6). Cucurbita pepo, Morus bombycis and Triticum aestivum DNA were identified in cases 1, 4 and 5 respectively. Twenty-three different bacterial species, two viruses and five fungal species were identified from among these six patients by using molecular and culture techniques. Several of the pathogenic microorganisms identified are reported to be food-borne or tobacco plant-associated pathogens. CONCLUSIONS/SIGNIFICANCE: Our study shows that plants DNA may be identified in the BAL fluid of pneumonia patients, especially when exploring aspiration pneumonia, but the significance of the presence of plant DNA and its role in the pathogenesis of pneumonia is unknown and remains to be investigated. However, the identification of these plants may be a potential marker of aspiration in patients with pneumonia

Language in India www.languageinindia.com 12 : 2 February 2012 Taher Bahrani and Rahmatollah Soltani An Overview on How to Utilize Authentic Language Input for Language Teaching 800 LANGUAGE IN INDIA Strength for Today and Bright Hope for Tomorrow An Over

Abstract Today, the application of various audiovisual mass media programs such as films and cartoons has gone beyond the boundaries of entertainment. As a matter of fact, various types of audiovisual programs can be used as a rich source of authentic language input for language teaching. The pedagogical values of authentic materials have been emphasized by many researchers. In fact, many researchers agree on the fact that authentic language input from various audiovisual programs has the potential to provide the necessary language input for language learning. In the same line, the present paper aims at highlighting the pedagogical values of films and cartoons as two types of programs which have the optimal potential to enhance language learning if they are utilized properly in language classrooms

Predictive model of biliocystic communication in liver hydatid cysts using classification and regression tree analysis

<p>Abstract</p> <p>Background</p> <p>Incidence of liver hydatid cyst (LHC) rupture ranged 15%-40% of all cases and most of them concern the bile duct tree. Patients with biliocystic communication (BCC) had specific clinic and therapeutic aspect. The purpose of this study was to determine witch patients with LHC may develop BCC using classification and regression tree (CART) analysis</p> <p>Methods</p> <p>A retrospective study of 672 patients with liver hydatid cyst treated at the surgery department "A" at Ibn Sina University Hospital, Rabat Morocco. Four-teen risk factors for BCC occurrence were entered into CART analysis to build an algorithm that can predict at the best way the occurrence of BCC.</p> <p>Results</p> <p><b>I</b>ncidence of BCC was 24.5%. Subgroups with high risk were patients with jaundice and thick pericyst risk at 73.2% and patients with thick pericyst, with no jaundice 36.5 years and younger with no past history of LHC risk at 40.5%. Our developed CART model has sensitivity at 39.6%, specificity at 93.3%, positive predictive value at 65.6%, a negative predictive value at 82.6% and accuracy of good classification at 80.1%. Discriminating ability of the model was good 82%.</p> <p>Conclusion</p> <p>we developed a simple classification tool to identify LHC patients with high risk BCC during a routine clinic visit (only on clinical history and examination followed by an ultrasonography). Predictive factors were based on pericyst aspect, jaundice, age, past history of liver hydatidosis and morphological Gharbi cyst aspect. We think that this classification can be useful with efficacy to direct patients at appropriated medical struct's.</p

Serum levels of cytokines and C-reactive protein in acute ischemic stroke patients, and their relationship to stroke lateralization, type, and infarct volume

There is increasing evidence that inflammation plays an important role in the progression of acute ischemic stroke (AIS). The primary aims of this study were to examine the serum levels of 13 cytokines, C-reactive protein (CRP), glucose, and hemoglobin in AIS patients, and their relationship to stroke lateralization, type, and infarct volume. Forty-five patients with AIS were evaluated. Blood samples were taken within 72 h, and volumetric analyses performed within 1–7 days after AIS onset. Cytokines were measured in serum from all patients and from 40 control subjects using Luminex Bio-Plex XMap technology. The levels of interleukin (IL)-1ra (p < 0.001), IL-6 (p < 0.001), IL-8 (p < 0.001), IL-9 (p = 0.038), IL-10 (p = 0.001), IL-12 (p = 0.001), IL-18 (p < 0.001), and GRO-α (CXCL1) (p = 0.017) were significantly higher in the AIS patients than in the controls. The IL-8 level was significantly correlated with age in the patient group (r = 0.52, p < 0.001). None of the variables were found to be associated with stroke lateralization. Infarct volume was significantly positively correlated with CRP level (r = 0.47, p = 0.005). Patients with radiologically confirmed infarctions had significantly elevated serum levels of GRO-α (p = 0.023). The cytokine profile of the AIS patients supports not only earlier findings of a proinflammatory response but also early activation of endogenous immunosuppressive mechanisms. Novel findings of this study are elevated serum levels of IL-9 and GRO-α. Elevated GRO-α in AIS patients with radiologically confirmed infarctions suggests that GRO-α is specific for stroke of known etiology. Our results indicate that CRP plays an important role in the progression of cerebral tissue injury