Summary Background Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. We aimed to assess efficacy and safety of treatment with docetaxel plus ...ramucirumab or placebo as second-line treatment for patients with stage IV non-small-cell-lung cancer (NSCLC) after platinum-based therapy. Methods In this multicentre, double-blind, randomised phase 3 trial (REVEL), we enrolled patients with squamous or non-squamous NSCLC who had progressed during or after a first-line platinum-based chemotherapy regimen. Patients were randomly allocated (1:1) with a centralised, interactive voice-response system (stratified by sex, region, performance status, and previous maintenance therapy yes vs no) to receive docetaxel 75 mg/m2 and either ramucirumab (10 mg/kg) or placebo on day 1 of a 21 day cycle until disease progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was overall survival in all patients allocated to treatment. We assessed adverse events according to treatment received. This study is registered with ClinicalTrials.gov , number NCT01168973. Findings Between Dec 3, 2010, and Jan 24, 2013, we screened 1825 patients, of whom 1253 patients were randomly allocated to treatment. Median overall survival was 10·5 months (IQR 5·1–21·2) for 628 patients allocated ramucirumab plus docetaxel and 9·1 months (4·2–18·0) for 625 patients who received placebo plus docetaxel (hazard ratio 0·86, 95% CI 0·75–0·98; p=0·023). Median progression-free survival was 4·5 months (IQR 2·3–8·3) for the ramucirumab group compared with 3·0 months (1·4–6·9) for the control group (0·76, 0·68–0·86; p<0·0001). We noted treatment-emergent adverse events in 613 (98%) of 627 patients in the ramucirumab safety population and 594 (95%) of 618 patients in the control safety population. The most common grade 3 or worse adverse events were neutropenia (306 patients 49% in the ramucirumab group vs 246 40% in the control group), febrile neutropenia (100 16% vs 62 10%), fatigue (88 14% vs 65 10%), leucopenia (86 14% vs 77 12%), and hypertension (35 6% vs 13 2%). The numbers of deaths from adverse events (31 5% vs 35 6%) and grade 3 or worse pulmonary haemorrhage (eight 1% vs eight 1%) did not differ between groups. Toxicities were manageable with appropriate dose reductions and supportive care. Interpretation Ramucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC. Funding Eli Lilly.
Background and Aims EUS-guided drainage using plastic stents may be inadequate for treatment of walled-off necrosis (WON). Recent studies report variable outcomes even when using covered metal ...stents. The aim of this study was to evaluate the efficacy of a dedicated covered biflanged metal stent (BFMS) when adopting an endoscopic “step-up approach” for drainage of symptomatic WON. Methods We retrospectively evaluated consecutive patients with symptomatic WON who underwent EUS-guided drainage using BFMSs over a 3-year period. Reassessment was done between 48 and 72 hours for resolution. Endoscopic reinterventions were tailored in nonresponders in a stepwise manner. Step 1 encompassed declogging the blocked lumen of the BFMS. In step 2, a nasocystic tube was placed via BFMSs with intermittent irrigation. Step 3 involved direct endoscopic necrosectomy (DEN). BFMSs were removed between 4 and 8 weeks of follow-up. The main outcome measures were technical success, clinical success, adverse events, and need for DEN. Results Two hundred five WON patients underwent EUS-guided drainage using BFMSs. Technical success was achieved in 203 patients (99%). Periprocedure adverse events occurred in 8 patients (bleeding in 6, perforation in 2). Clinical success with BFMSs alone was seen in 153 patients (74.6%). Reintervention adopting the step-up approach was required in 49 patients (23.9%). Incremental success was achieved in 10 patients with step 1, 16 patients with step 2, and 19 patients with step 3. Overall clinical success was achieved in 198 patients (96.5%), with DEN required in 9.2%. Four patients failed treatment and required surgery (2) or percutaneous drainage (2). Conclusions The endoscopic step-up approach using BFMSs was safe, effective, and yielded successful outcomes in most patients, reducing the need for DEN.
Daily variations in nutrients were monitored for 15 months (September 2007–November 2008) in the Godavari estuary, Andhra Pradesh, India, at two fixed locations. River discharge has significant ...influence on nutrients loading to the estuary, which peaks during June–August (peak discharge period; monsoon) whereas exchanges at the sediment–water interface, groundwater and rainwater contribute significantly during other period. Despite significant amount of nutrients brought by discharge to the study region, phytoplankton biomass, in terms of chlorophyll-
a (Chl
a), did not increase significantly due to high suspended load and shallow photic depth. Nutrients showed downward gradient towards downstream of the estuary from upstream due to dilution by nutrient poor seawater and biological uptake. The N:P ratios were higher than Redfield ratio in both upstream and downstream of the estuary during no discharge period suggesting PO
4 to be a limiting nutrient for phytoplankton production, at levels <0.10
μmol
L
−1. On the other hand, Si:N ratios were always more than unity during entire study period at both the stations indicating that Si(OH)
4 is not a limiting nutrient. Our results suggest that suspended matter limits phytoplankton biomass during peak discharge period whereas PO
4 during no discharge period.
Surface measurements of aerosol physical properties were made at Anantapur （14.62°N, 77.65°E, 331 m a.s.l）, a semiarid rural site in India, during August 2008-July 2009. Measurements included the ...segregated sizes of aerosolsas as well as total mass concentration and size distributions of aerosols measured at low relative humidity （RH〈75%） using a Quartz Crystal Microbalance （QCM） in the 25-0.05 um aerodynamic diameter range. The hourly average total surface aerosol mass concentration in a day varied from 15 to 70 ug m-3, with a mean value of 34.02±9.05 ug m-3 for the entire study period. A clear diurnal pattern appeared in coarse, accumulation and nucleation-mode particle concentrations, with two local maxima occurring in early morning and late evening hours. The concentration of coarse-mode particles was high during the summer season, with a maximum concentration of 11.81±0.98 ug m-3 in the month of April, whereas accumulationmode concentration was observed to be high in the winter period contributed 〉68% to the total aerosol mass concentration. Accumulation aerosol mass fraction, Af （= Ma/Mt） was highest during winter （mean value of Af -0.80） and lowest （Af - 0.64） during the monsoon season. The regression analysis shows that both Reff and Rm are dependent on coarse-mode aerosols. The relationship between the simultaneous measurements of daily mean aerosol optical depth at 500 nm （AOD500） and PM2.5 mass concentration （PM2.5） shows that surface-level aerosol mass concentration increases with the increase in columnar aerosol optical depth over the observation period.
Myc oncoproteins are commonly upregulated in human cancers of different organ origins, stabilized by Aurora A, degraded through ubiquitin-proteasome pathway-mediated proteolysis, and exert oncogenic ...effects by modulating gene and protein expression. Histone deacetylases are emerging as targets for cancer therapy. Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. Affymetrix gene array studies revealed that the gene most significantly repressed by SIRT2 was the ubiquitin-protein ligase NEDD4. Consistent with this finding, SIRT2 repressed NEDD4 gene expression by directly binding to the NEDD4 gene core promoter and deacetylating histone H4 lysine 16. Importantly, NEDD4 directly bound to Myc oncoproteins and targeted Myc oncoproteins for ubiquitination and degradation, and small-molecule SIRT2 inhibitors reactivated NEDD4 gene expression, reduced N-Myc and c-Myc protein expression, and suppressed neuroblastoma and pancreatic cancer cell proliferation. Additionally, SIRT2 upregulated and small-molecule SIRT2 inhibitors decreased Aurora A expression. Our data reveal a novel pathway critical for Myc oncoprotein stability, and provide important evidences for potential application of SIRT2 inhibitors for the prevention and therapy of Myc-induced malignancies.
The difficult computer vision task of low-light image augmentation tries to raise the standard of photographs taken in low light. Deep learning-based low-light picture enhancing systems have recently ...attained modern outcomes. In this article, we compare the effectiveness of two cutting-edge deep learning-based algorithms-DCE-Net and MirNetv2-to enhance the quality of images in low light. A deep cross-enhancement network called DCE-Net uses a cutting-edge cross-connection module to take advantage of the complementing data that exists between the network's various tiers. A multi-scale feature extraction module is used by the multi-scale illumination recovery network MirNetv2 to extract features from various scales of the picture. On the LOLdataset benchmark Datasets for enhancing low-light images, we compare the execution of DCE-Net and MirNetv2. The outcomes demonstrate that DCE-Net and MirNetv2 provides cutting-edge outcomes. On the LOLdataset, DCE-Net performs better than MirNetv2 in terms of improving contrast and brightness. The findings of this study indicate that the deep learning-based Improving visibility in low-light images method DCE-Net- a promising one. In a wide range of applications, including surveillance, night photography, and medical imaging, DCE-Net can be utilized to improve low-light photos.
In order to examine the influence of forcing (river flow and tides) and anthropogenic activities (dredging and dam regulation) on stratification, a study was conducted over a period of 19 months ...(June 2008–December 2009) in the Gautami–Godavari estuary (G–GE) during spring and neap tide periods covering entire spectrum of discharge over a distance of 36 km from the mouth. The bathymetry of the estuary was recently changed due to dredging of ∼20 km of the estuary from the mouth for transportation of barges. This significantly changed the mean depth and salinity of the estuary from its earlier state. The variations in the distribution of salinity in the Godavari estuary are driven by river discharge during wet period (June–November) and tides during dry period (December–May). The weak stratification was observed during high discharge (July–August) and no discharge (January–June) periods associated with dominant fresh water and marine water respectively. The strong stratification was developed associated with decrease in discharge during moderate discharge period (October–December). Relatively stronger stratification was noticed during neap than spring tides. The 15 psu isohaline was observed to have migrated ∼2–3 km more towards upper estuary during spring than neap tide suggesting more salt enters during former than latter period. Total salt content was inversely correlated with river discharge and higher salt of about 400×10
6
m
3
psu was observed during spring than neap tide. Flushing times varied between less than a day and more than a month during peak and no discharge periods respectively with lower times during spring than neap tide. The flushing times are controlled by river discharge during high discharge period, tides during dry period and both (river discharge and tides) under moderate discharge period. This study suggests that modification of discharge, either natural due to weak monsoon, or artificial such as dam constructions and re-routing the river flow, may have significant impact on the stratification and biogeochemistry of the Godavari estuary.
The present study identifies the potential of highly biocompatible SF-GNP nano-conjugate to enhance the chemotherapeutic response to combat drug resistance in cancer cells. We developed a stable ...colloidal suspension of sorafenib-gold nanoconjugate (SF-GNP) of <10 nm size in aqueous medium for reverting the cancer drug resistance in SF-resistant HepG2 cells in a 3D ex-vivo model system. In-vivo biocompatibility assay of SF-GNPs showed absence of systemic toxicological effects including hematological, biochemical and histological parameters. More importantly, the histopathological analysis of vital organs such as liver, brain, lung, kidney and heart showed very least or no sign of inflammation, cell infiltration, necrosis, tissue disorganization or fibrotic reactions after intra-peritoneal administration of SF-GNP nanoconjugates in animals. However, SF-GNP nanoconjugates significantly reduced (>80%) the percentage cell survival and the size and number of SF resistant solid tumor colonies of HepG2 cells in 3D model system. The exposure of SF-GNP nanoconjugate to SF resistant HepG2 cell colonies also provided evidence for anti-proliferative effect and reversal of drug resistance by elucidating the molecular regulatory mechanisms of extracellular matrix factor (CD147), tumor growth factor (TGF-β), hepatoma upregulated protein (hURP) and drug transporter (ABCG-2).
Abstract Importance In most low- and middle-income countries (LMICs), the resources to accurately quantify injury severity using traditional injury scoring systems are limited. Novel injury scoring ...systems appear to have adequate discrimination for mortality in LMIC contexts, but they have not been rigorously compared where traditional injury scores can be accurately calculated. Objective To determine whether novel injury scoring systems perform as well as traditional ones in a HIC with complete and comprehensive data collection. Setting Data from an American level-I trauma registry collected 2008-2013 were used to compare three traditional injury scoring systems: Injury Severity Score (ISS); Revised Trauma Score (RTS); and Trauma Injury Severity Score (TRISS); and three novel injury scoring systems: Kampala Trauma Score (KTS); Mechanism, GCS, Age and Pressure (MGAP) score; and GCS, Age and Pressure (GAP) score. Main Outcomes and Measures Logistic regression was used to assess the association between each scoring system and mortality. Standardized regression coefficients ( β 2 ) , Akaike information criteria, area under the receiver operating characteristics curve, and the calibration line intercept and slope were used to evaluate the discrimination and calibration of each model. Results Among 18,746 patients, all six scores were associated with hospital mortality. GAP had the highest effect size, and KTS had the lowest median Akaike information criteria. Although TRISS discriminated best, the discrimination of KTS approached that of TRISS and outperformed GAP, MGAP, RTS, and ISS. MGAP was best calibrated, and KTS was better calibrated than RTS, GAP, ISS, or TRISS. Conclusions and Relevance The novel injury scoring systems (KTS, MGAP, and GAP), which are more feasible to calculate in low-resource settings, discriminated hospital mortality as well as traditional injury scoring systems (ISS and RTS) and approached the discrimination of a sophisticated, data-intensive injury scoring system (TRISS) in a high-resource setting. Two novel injury scoring systems (KTS and MGAP) surpassed the calibration of TRISS. These novel injury scoring systems should be considered when clinicians and researchers wish to accurately account for injury severity. Implementation of these resource-appropriate tools in LMICs can improve injury surveillance, guiding quality improvement efforts, and supporting advocacy for resource allocation commensurate with the volume and severity of trauma.
Adverse local tissue reaction (ALTR) is a recognized complication of total hip arthroplasty (THA) with metal-on-polyethylene (MoP) bearing surface implants. Specific models of THA implants have been ...identified as having a higher incidence of ALTR. The purpose of this study is to determine if serum metal levels, patient symptoms, implant factors, and imaging findings can be predictive of ALTR within this high-risk population.
We retrospectively reviewed an observational cohort of 474 patients who underwent MoP THA and were at increased risk of having ALTR. Patients were stratified based on the presence or absence of ALTR. Patient symptoms, serum metal ions, implant head offset, and imaging findings were compared.
Patients with ALTR were more likely to be symptomatic (52.9% vs 9.9%, P < .0001). The presence of ALTR was associated with significantly higher serum cobalt and chromium levels (6.2 ppb vs 3.6 ppb, P < .0001; 2.3 ppb vs 1.2 ppb, P < .0001). Head offsets greater than 4 mm were associated with a higher prevalence of ALTR (53% vs 38%, P = .05). On metal artifact reduction sequence magnetic resonance imaging, patients with ALTR had larger effusions (4.7 cm vs 2.1 cm, P < .001) and a higher incidence of trochanteric bursitis (47% vs 16%, P < .001).
In high-risk MoP implants, serum cobalt and chromium levels are elevated, even in patients without ALTR. A larger femoral head offset is a risk factor for the development of ALTR. Our study suggests that patients presenting with painful THA and elevated metal ions require risk stratification based on patient symptoms, metal artifact reduction sequence magnetic resonance imaging findings, and implant factors.
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