Afatinib is an oral, irreversible ErbB family blocker that has shown activity in epidermal growth factor receptor (EGFR)-mutated lung cancer. We hypothesized that the agent would have greater ...antitumor activity compared with cetuximab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients, whose disease has progressed after platinum-containing therapy.
An open-label, randomized, phase II trial was conducted in 43 centers; 124 patients were randomized (1 : 1) to either afatinib (50mg/day) or cetuximab (250mg/m2/week) until disease progression or intolerable adverse events (AEs) (stage I), with optional crossover (stage II). The primary end point was tumor shrinkage before crossover assessed by investigator (IR) and independent central review (ICR).
A total of 121 patients were treated (61 afatinib, 60 cetuximab) and 68 crossed over to stage II (32 and 36 respectively). In stage I, mean tumor shrinkage by IR/ICR was 10.4%/16.6% with afatinib and 5.4%/10.1% with cetuximab (P = 0.46/0.30). Objective response rate was 16.1%/8.1% with afatinib and 6.5%/9.7% with cetuximab (IR/ICR). Comparable disease control rates were observed with afatinib (50%) and cetuximab (56.5%) by IR; similar results were seen by ICR. Most common grade ≥3 drug-related AEs (DRAEs) were rash/acne (18% versus 8.3%), diarrhea (14.8% versus 0%), and stomatitis/mucositis (11.5% versus 0%) with afatinib and cetuximab, respectively. Patients with DRAEs leading to treatment discontinuation were 23% with afatinib and 5% with cetuximab. In stage II, disease control rate (IR/ICR) was 38.9%/33.3% with afatinib and 18.8%/18.8% with cetuximab.
Afatinib showed antitumor activity comparable to cetuximab in R/M HNSCC in this exploratory phase II trial, although more patients on afatinib discontinued treatment due to AEs. Sequential EGFR/ErbB treatment with afatinib and cetuximab provided sustained clinical benefit in patients after crossover, suggesting a lack of cross-resistance.
Steady-state egress of hematopoietic progenitor cells can be rapidly amplified by mobilizing agents such as AMD3100, the mechanism, however, is poorly understood. We report that AMD3100 increased the ...homeostatic release of the chemokine stromal cell derived factor-1 (SDF-1) to the circulation in mice and non-human primates. Neutralizing antibodies against CXCR4 or SDF-1 inhibited both steady state and AMD3100-induced SDF-1 release and reduced egress of murine progenitor cells over mature leukocytes. Intra-bone injection of biotinylated SDF-1 also enhanced release of this chemokine and murine progenitor cell mobilization. AMD3100 directly induced SDF-1 release from CXCR4(+) human bone marrow osteoblasts and endothelial cells and activated uPA in a CXCR4/JNK-dependent manner. Additionally, ROS inhibition reduced AMD3100-induced SDF-1 release, activation of circulating uPA and mobilization of progenitor cells. Norepinephrine treatment, mimicking acute stress, rapidly increased SDF-1 release and progenitor cell mobilization, whereas β2-adrenergic antagonist inhibited both steady state and AMD3100-induced SDF-1 release and progenitor cell mobilization in mice. In conclusion, this study reveals that SDF-1 release from bone marrow stromal cells to the circulation emerges as a pivotal mechanism essential for steady-state egress and rapid mobilization of hematopoietic progenitor cells, but not mature leukocytes.
Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation in the absence of excess alcohol intake. NAFLD is the most common chronic liver disease, and ongoing research ...efforts are focused on understanding the underlying pathobiology of hepatic steatosis with the anticipation that these efforts will identify novel therapeutic targets. Under physiological conditions, the low steady-state triglyceride concentrations in the liver are attributable to a precise balance between acquisition by uptake of non-esterified fatty acids from the plasma and by de novo lipogenesis, versus triglyceride disposal by fatty acid oxidation and by the secretion of triglyceride-rich lipoproteins. In NAFLD patients, insulin resistance leads to hepatic steatosis by multiple mechanisms. Greater uptake rates of plasma non-esterified fatty acids are attributable to increased release from an expanded mass of adipose tissue as a consequence of diminished insulin responsiveness. Hyperinsulinemia promotes the transcriptional upregulation of genes that promote de novo lipogenesis in the liver. Increased hepatic lipid accumulation is not offset by fatty acid oxidation or by increased secretion rates of triglyceride-rich lipoproteins. This review discusses the molecular mechanisms by which hepatic triglyceride homeostasis is achieved under normal conditions, as well as the metabolic alterations that occur in the setting of insulin resistance and contribute to the pathogenesis of NAFLD.
Cortical layer 1 (L1) interneurons have been proposed as a hub for attentional modulation of underlying cortex, but the transformations that this circuit implements are not known. We combined ...genetically targeted voltage imaging with optogenetic activation and silencing to study the mechanisms underlying sensory processing in mouse barrel cortex L1. Whisker stimuli evoked precisely timed single spikes in L1 interneurons, followed by strong lateral inhibition. A mild aversive stimulus activated cholinergic inputs and evoked a bimodal distribution of spiking responses in L1. A simple conductance-based model that only contained lateral inhibition within L1 recapitulated the sensory responses and the winner-takes-all cholinergic responses, and the model correctly predicted that the network would function as a spatial and temporal high-pass filter for excitatory inputs. Our results demonstrate that all-optical electrophysiology can reveal basic principles of neural circuit function in vivo and suggest an intuitive picture for how L1 transforms sensory and modulatory inputs.
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•All-optical electrophysiology reveals synaptic excitation and inhibition, in vivo•Whisker stimuli evoke concurrent excitation and inhibition in L1 interneurons•Cholinergic inputs evoke winner-takes-all spiking in L1 interneurons•Lateral inhibition within L1 governs whisker and cholinergic responses
By simultaneously combining genetically targeted voltage imaging with optogenetic modulation of neuronal activity, Fan et al. demonstrate that all-optical electrophysiology in awake animals can be a powerful tool for revealing hidden principles of neural circuit function.
Using observations from the
High Energy Telescopes
(HETs) on the STEREO A and B spacecraft and similar observations from near-Earth spacecraft, we summarize the properties of more than 200 individual ...> 25 MeV solar proton events, some detected by multiple spacecraft, that occurred from the beginning of the STEREO mission in October 2006 to December 2013, and provide a catalog of these events and their solar sources and associations. Longitudinal dependencies of the electron and proton peak intensities and delays to onset and peak intensity relative to the solar event have been examined for 25 three-spacecraft particle events. Expressed as Gaussians, peak intensities fall off with longitude with
σ
=47±14
∘
for 0.7 – 4 MeV electrons, and
σ
=43±13
∘
for 14 – 24 MeV protons. Several particle events are discussed in more detail, including one on 3 November 2011, in which ∼ 25 MeV protons filled the inner heliosphere within 90 minutes of the solar event, and another on 7 March 2012, in which we demonstrate that the first of two coronal mass ejections that erupted from an active region within ∼ 1 hour was associated with particle acceleration. Comparing the current Solar Cycle 24 with the previous cycle, the first > 25 MeV proton event was detected at Earth in the current solar cycle around one year after smoothed sunspot minimum, compared with a delay of only two months in Cycle 23. Otherwise, solar energetic particle event occurrence rates were reasonably similar during the rising phases of Cycles 23 and 24. However, the rate declined in 2013, reflecting the decline in sunspot number since the peak in the northern-hemisphere sunspot number in November 2011. Observations in late 2013 suggest that the rate may be rising again in association with an increase in the southern sunspot number.
The 2019 novel coronavirus disease (COVID-19) has created unprecedented medical challenges. There remains a need for validated risk prediction models to assess short-term mortality risk among ...hospitalized patients with COVID-19. The objective of this study was to develop and validate a 7-day and 14-day mortality risk prediction model for patients hospitalized with COVID-19.
We performed a multicenter retrospective cohort study with a separate multicenter cohort for external validation using two hospitals in New York, NY, and 9 hospitals in Massachusetts, respectively. A total of 664 patients in NY and 265 patients with COVID-19 in Massachusetts, hospitalized from March to April 2020.
We developed a risk model consisting of patient age, hypoxia severity, mean arterial pressure and presence of kidney dysfunction at hospital presentation. Multivariable regression model was based on risk factors selected from univariable and Chi-squared automatic interaction detection analyses. Validation was by receiver operating characteristic curve (discrimination) and Hosmer-Lemeshow goodness of fit (GOF) test (calibration). In internal cross-validation, prediction of 7-day mortality had an AUC of 0.86 (95%CI 0.74-0.98; GOF p = 0.744); while 14-day had an AUC of 0.83 (95%CI 0.69-0.97; GOF p = 0.588). External validation was achieved using 265 patients from an outside cohort and confirmed 7- and 14-day mortality prediction performance with an AUC of 0.85 (95%CI 0.78-0.92; GOF p = 0.340) and 0.83 (95%CI 0.76-0.89; GOF p = 0.471) respectively, along with excellent calibration. Retrospective data collection, short follow-up time, and development in COVID-19 epicenter may limit model generalizability.
The COVID-AID risk tool is a well-calibrated model that demonstrates accuracy in the prediction of both 7-day and 14-day mortality risk among patients hospitalized with COVID-19. This prediction score could assist with resource utilization, patient and caregiver education, and provide a risk stratification instrument for future research trials.
Background Accurately estimating surgical risks is critical for shared decision making and informed consent. The Centers for Medicare and Medicaid Services may soon put forth a measure requiring ...surgeons to provide patients with patient-specific, empirically derived estimates of postoperative complications. Our objectives were to develop a universal surgical risk estimation tool, to compare performance of the universal vs previous procedure-specific surgical risk calculators, and to allow surgeons to empirically adjust the estimates of risk. Study Design Using standardized clinical data from 393 ACS NSQIP hospitals, a web-based tool was developed to allow surgeons to easily enter 21 preoperative factors (demographics, comorbidities, procedure). Regression models were developed to predict 8 outcomes based on the preoperative risk factors. The universal model was compared with procedure-specific models. To incorporate surgeon input, a subjective surgeon adjustment score, allowing risk estimates to vary within the estimate's confidence interval, was introduced and tested with 80 surgeons using 10 case scenarios. Results Based on 1,414,006 patients encompassing 1,557 unique CPT codes, a universal surgical risk calculator model was developed that had excellent performance for mortality (c-statistic = 0.944; Brier score = 0.011 where scores approaching 0 are better), morbidity (c-statistic = 0.816, Brier score = 0.069), and 6 additional complications (c-statistics > 0.8). Predictions were similarly robust for the universal calculator vs procedure-specific calculators (eg, colorectal). Surgeons demonstrated considerable agreement on the case scenario scoring (80% to 100% agreement), suggesting reliable score assignment between surgeons. Conclusions The ACS NSQIP surgical risk calculator is a decision-support tool based on reliable multi-institutional clinical data, which can be used to estimate the risks of most operations. The ACS NSQIP surgical risk calculator will allow clinicians and patients to make decisions using empirically derived, patient-specific postoperative risks.
Since the year 2000, a concerted campaign against malaria has led to unprecedented levels of intervention coverage across sub-Saharan Africa. Understanding the effect of this control effort is vital ...to inform future control planning. However, the effect of malaria interventions across the varied epidemiological settings of Africa remains poorly understood owing to the absence of reliable surveillance data and the simplistic approaches underlying current disease estimates. Here we link a large database of malaria field surveys with detailed reconstructions of changing intervention coverage to directly evaluate trends from 2000 to 2015, and quantify the attributable effect of malaria disease control efforts. We found that Plasmodium falciparum infection prevalence in endemic Africa halved and the incidence of clinical disease fell by 40% between 2000 and 2015. We estimate that interventions have averted 663 (542-753 credible interval) million clinical cases since 2000. Insecticide-treated nets, the most widespread intervention, were by far the largest contributor (68% of cases averted). Although still below target levels, current malaria interventions have substantially reduced malaria disease incidence across the continent. Increasing access to these interventions, and maintaining their effectiveness in the face of insecticide and drug resistance, should form a cornerstone of post-2015 control strategies.
Background
Mast cell localization within the airway smooth muscle (ASM)‐bundle plays an important role in the development of airway hyper‐responsiveness (AHR). Genomewide association studies ...implicate the ‘alarmin’ IL‐33 in asthma, but its role in mast cell–ASM interactions is unknown.
Objectives
We examined the expression and functional role of IL‐33 in bronchial biopsies of patients with and without asthma, ex vivo ASM, mast cells, cocultured cells and in a mouse model system.
Methods
IL‐33 protein expression was assessed in human bronchial tissue from 9 healthy controls, and 18 mild‐to‐moderate and 12 severe asthmatic patients by immunohistochemistry. IL‐33 and ST2 mRNA and protein expression in human‐derived ASM, epithelial and mast cells were assessed by qPCR, immunofluorescence and/or flow cytometry and ELISA. Functional assays were used to assess calcium signalling, wound repair, proliferation, apoptosis and contraction. AHR and inflammation were assessed in a mouse model.
Results
Bronchial epithelium and ASM expressed IL‐33 with the latter in asthma correlating with AHR. ASM and mast cells expressed intracellular IL‐33 and ST2. IL‐33 stimulated mast cell IL‐13 and histamine secretion independent of FcεR1 cross‐linking and directly promoted ASM wound repair. Coculture of mast cells with ASM activated by IL‐33 increased agonist‐induced ASM contraction, and in vivo IL‐33 induced AHR in a mouse cytokine installation model; both effects were IL‐13 dependent.
Conclusion
IL‐33 directly promotes mast cell activation and ASM wound repair but indirectly promotes ASM contraction via upregulation of mast cell‐derived IL‐13. This suggests that IL‐33 may present an important target to modulate mast cell–ASM crosstalk in asthma.
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