Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy

New Dual Mode Gadolinium Nanoparticle Contrast Agent for Magnetic Resonance Imaging

BACKGROUND: Liposomal-based gadolinium (Gd) nanoparticles have elicited significant interest for use as blood pool and molecular magnetic resonance imaging (MRI) contrast agents. Previous generations of liposomal MR agents contained gadolinium-chelates either within the interior of liposomes (core-encapsulated gadolinium liposomes) or presented on the surface of liposomes (surface-conjugated gadolinium liposomes). We hypothesized that a liposomal agent that contained both core-encapsulated gadolinium and surface-conjugated gadolinium, defined herein as dual-mode gadolinium (Dual-Gd) liposomes, would result in a significant improvement in nanoparticle-based T1 relaxivity over the previous generations of liposomal agents. In this study, we have developed and tested, both in vitro and in vivo, such a dual-mode liposomal-based gadolinium contrast agent. METHODOLOGY/PRINCIPAL FINDINGS: THREE TYPES OF LIPOSOMAL AGENTS WERE FABRICATED: core-encapsulated, surface-conjugated and dual-mode gadolinium liposomes. In vitro physico-chemical characterizations of the agents were performed to determine particle size and elemental composition. Gadolinium-based and nanoparticle-based T1 relaxivities of various agents were determined in bovine plasma. Subsequently, the agents were tested in vivo for contrast-enhanced magnetic resonance angiography (CE-MRA) studies. Characterization of the agents demonstrated the highest gadolinium atoms per nanoparticle for Dual-Gd liposomes. In vitro, surface-conjugated gadolinium liposomes demonstrated the highest T1 relaxivity on a gadolinium-basis. However, Dual-Gd liposomes demonstrated the highest T1 relaxivity on a nanoparticle-basis. In vivo, Dual-Gd liposomes resulted in the highest signal-to-noise ratio (SNR) and contrast-to-noise ratio in CE-MRA studies. CONCLUSIONS/SIGNIFICANCE: The dual-mode gadolinium liposomal contrast agent demonstrated higher particle-based T1 relaxivity, both in vitro and in vivo, compared to either the core-encapsulated or the surface-conjugated liposomal agent. The dual-mode gadolinium liposomes could enable reduced particle dose for use in CE-MRA and increased contrast sensitivity for use in molecular imaging

Prospective randomized study comparing the Teleflex Medical SaphLITE Retractor to the Ethicon CardioVations Clearglide Endoscopic System

BACKGROUND: Several minimally invasive saphenous vein harvesting techniques have been developed to reduce morbidities associated with coronary artery bypass grafting. This prospective, randomized study was designed to compare two commonly used minimally invasive saphenous vein harvesting techniques, the SaphLITE Retractor System (Teleflex Medical) and the Clearglide Endoscopic Vessel Harvesting System (Ethicon CardioVations, Inc.). METHODS: Between January 2003 and March 2004, a total of 200 patients scheduled for primary, nonemergent coronary artery bypass grafting, with or without concomitant procedures were randomized into two groups: SaphLITE (n = 100) and Clearglide (n = 100). Pre-, intra- and postoperative data was collected and subjected to statistical analysis. Randomization provided homogenous groups with respect to preoperative risk factors. RESULTS: Harvest location for the SaphLITE group was thigh (n = 40), lower leg (n = 5) and both lower leg and thigh (n = 55). The location of harvest for the Clearglide group was thigh (n = 3), lower leg (n = 16) and both lower leg and thigh (n = 81). The mean incision length was 3.6 cm (range, 2–6) in the SaphLITE group versus 2.1 cm (range, 1–4) in the Clearglide group (p < 0.05). The total incision length was 12.9 cm versus 8.9 (p < 0.05) in the SaphLITE and Clearglide groups. Conversion to the open technique occurred in 5 SaphLITE patients and 7 Clearglide patients. Intraoperative leg exploration for bleeding occurred in two of the Clearglide patients and none of the SaphLITE patients. Post-operative complications specifically related to minimally invasive harvesting technique, including a two-week post-discharge visit, were not statistically different between the groups. CONCLUSION: The saphenous vein can be safely harvested utilizing the SaphLITE and Clearglide systems. While the Clearglide system allows for fewer incisions (number and length) and less harvest time, these benefits may be outweighed by the increased cost of the Clearglide system compared to the SaphLITE retractor

The Procedural Index for Mortality Risk (PIMR): an index calculated using administrative data to quantify the independent influence of procedures on risk of hospital death

<p>Abstract</p> <p>Background</p> <p>Surgeries and other procedures can influence the risk of death in hospital. All published scales that predict post-operative death risk require clinical data and cannot be measured using administrative data alone. This study derived and internally validated an index that can be calculated using administrative data to quantify the independent risk of hospital death after a procedure.</p> <p>Methods</p> <p>For all patients admitted to a single academic centre between 2004 and 2009, we estimated the risk of all-cause death using the Kaiser Permanente Inpatient Risk Adjustment Methodology (KP-IRAM). We determined whether each patient underwent one of 503 commonly performed therapeutic procedures using Canadian Classification of Interventions codes and whether each procedure was emergent or elective. Multivariate logistic regression modeling was used to measure the association of each procedure-urgency combination with death in hospital independent of the KP-IRAM risk of death. The final model was modified into a scoring system to quantify the independent influence each procedure had on the risk of death in hospital.</p> <p>Results</p> <p>275 460 hospitalizations were included (137,730 derivation, 137,730 validation). In the derivation group, the median expected risk of death was 0.1% (IQR 0.01%-1.4%) with 4013 (2.9%) dying during the hospitalization. 56 distinct procedure-urgency combinations entered our final model resulting in a Procedural Index for Mortality Rating (PIMR) score values ranging from -7 to +11. In the validation group, the PIMR score significantly predicted the risk of death by itself (c-statistic 67.3%, 95% CI 66.6-68.0%) and when added to the KP-IRAM model (c-index improved significantly from 0.929 to 0.938).</p> <p>Conclusions</p> <p>We derived and internally validated an index that uses administrative data to quantify the independent association of a broad range of therapeutic procedures with risk of death in hospital. This scale will improve risk adjustment when administrative data are used for analyses.</p

Distinct Temporal and Anatomical Distributions of Amyloid-β and Tau Abnormalities following Controlled Cortical Impact in Transgenic Mice

Traumatic brain injury (TBI) is a major environmental risk factor for Alzheimer's disease. Intracellular accumulations of amyloid-β and tau proteins have been observed within hours following severe TBI in humans. Similar abnormalities have been recapitulated in young 3xTg-AD mice subjected to the controlled cortical impact model (CCI) of TBI and sacrificed at 24 h and 7 days post injury. This study investigated the temporal and anatomical distributions of amyloid-β and tau abnormalities from 1 h to 24 h post injury in the same model. Intra-axonal amyloid-β accumulation in the fimbria was detected as early as 1 hour and increased monotonically over 24 hours following injury. Tau immunoreactivity in the fimbria and amygdala had a biphasic time course with peaks at 1 hour and 24 hours, while tau immunoreactivity in the contralateral CA1 rose in a delayed fashion starting at 12 hours after injury. Furthermore, rapid intra-axonal amyloid-β accumulation was similarly observed post controlled cortical injury in APP/PS1 mice, another transgenic Alzheimer's disease mouse model. Acute increases in total and phospho-tau immunoreactivity were also evident in single transgenic TauP301L mice subjected to controlled cortical injury. These data provide further evidence for the causal effects of moderately severe contusional TBI on acceleration of acute Alzheimer-related abnormalities and the independent relationship between amyloid-β and tau in this setting

Requirements for generic anti-epileptic medicines: a regulatory perspective

Contains fulltext : 81660.pdf (publisher's version ) (Closed access

Seroepidemiology of coxsackievirus A6, coxsackievirus A16, and Enterovirus 71 infections among children and adolescents in Singapore, 2008-2010

10.1371/journal.pone.0127999PLoS ONE105e012799

Upcycling spent brewery grains through the production of carbon adsorbents: application to the removal of carbamazepine from water

Spent brewery grains, a by-product of the brewing process, were used as precursor of biochars and activated carbons to be applied to the removal of pharmaceuticals from water. Biochars were obtained by pyrolysis of the raw materials, while activated carbons were produced by adding a previous chemical activation step. The influence of using different precursors (from distinct fermentation processes), activating agents (potassium hydroxide, sodium hydroxide, and phosphoric acid), pyrolysis temperatures, and residence times was assessed. The adsorbents were physicochemically characterized and applied to the removal of the antiepileptic carbamazepine from water. Potassium hydroxide activation produced the materials with the most promising properties and adsorptive removals, with specific surface areas up to 1120 m2 g-1 and maximum adsorption capacities up to 190 ± 27 mg g-1 in ultrapure water. The adsorption capacity suffered a reduction of < 70% in wastewater, allowing to evaluate the impact of realistic matrices on the efficiency of the materials.publishe

In Their Own Words: Assessment of Satisfaction with Residential Location among Migrants in Nairobi Slums

Using qualitative data collected from a sample of rural-urban migrants over the age of 15 in two Nairobi slums interviewed in 2008, this paper discusses the migrants’ extent of satisfaction with their residential location and decision to migrate. The study sheds light on why people continue to migrate to, and stay in, the rapidly growing slum settlements despite the high levels of poverty and poor health conditions in these areas. Tenure status is related to satisfaction for all ages. Environmental factors were frequently mentioned as a source of dissatisfaction. Life cycle and ‘age-cohort effects’ may also affect satisfaction for different age groups in terms of who is satisfied as well as the issues that are considered for satisfaction. High levels of dissatisfaction with slum life may be responsible for high out-migration in slum areas, although it does not mean that those who remain do so because they are satisfied. At the same time, challenges associated with slum life do not automatically signify dissatisfaction. Perceived success, as well as conditions in the area of origin can be used to explain and understand satisfaction/dissatisfaction with slum life. Satisfaction with migration and residential location may be related not only to the destination place, but also to events in the area of origin