Data-independent acquisition (DIA) is a promising technique for the proteomic analysis of complex protein samples. A number of studies have claimed that DIA experiments are more reproducible than ...data-dependent acquisition (DDA), but these claims are unsubstantiated since different data analysis methods are used in the two methods. Data analysis in most DIA workflows depends on spectral library searches, whereas DDA typically employs sequence database searches. In this study, we examined the reproducibility of the DIA and DDA results using both sequence database and spectral library search. The comparison was first performed using a cell lysate and then extended to an interactome study. Protein overlap among the technical replicates in both DDA and DIA experiments was 30% higher with library-based identifications than with sequence database identifications. The reproducibility of quantification was also improved with library search compared to database search, with the mean of the coefficient of variation decreasing more than 30% and a reduction in the number of missing values of more than 35%. Our results show that regardless of the acquisition method, higher identification and quantification reproducibility is observed when library search was used.
In this article, a tensor-based angle estimation algorithm is proposed for bistatic multiple-input multiple-output (MIMO) radar systems with a multislot gain-phase error (MSGPE). First, the received ...signals are constructed into a complex-valued third-order parallel factor model that contains information, such as transmit MSGPE, receive MSGPE, directions of departure (DODs), and directions of arrival (DOAs). Then, a two-stage tensor-based angle algorithm is proposed for antenna arrays with the MSGPE. In the first stage, the MSGPE information part and angle information part are separated by the least-squares Khatri–Rao factorization. In the second stage, the DODs and DOAs are obtained jointly based on spatial smoothing and real-valued processing techniques under eliminating the influence of MSGPE. Compared with the existing competitive algorithms, the proposed algorithm achieves an improved performance and is applicable for both the coherent and noncoherent targets. Simulation results show the superiority of the proposed tensor-based angle estimation algorithm.
Lung Cancer with a High Tumor Mutational Burden VanderLaan, Paul A; Rangachari, Deepa; Costa, Daniel B
The New England journal of medicine,
2018-Sep-13, Letnik:
379, Številka:
11
Journal Article
Given the pivotal role of epidermal growth factor receptor (EGFR) inhibitors in advanced EGFR-mutant non-small-cell lung cancer (NSCLC), we tested adjuvant erlotinib in patients with EGFR-mutant ...early-stage NSCLC.
In this open-label phase II trial, patients with resected stage IA to IIIA (7
edition of the American Joint Committee on Cancer staging system) EGFR-mutant NSCLC were treated with erlotinib 150 mg per day for 2 years after standard adjuvant chemotherapy with or without radiotherapy. The study was designed for 100 patients and powered to demonstrate a primary end point of 2-year disease-free survival (DFS) greater than 85%, improving on historic data of 76%.
Patients (N = 100) were enrolled at seven sites from January 2008 to May 2012; 13% had stage IA disease, 32% had stage IB disease, 11% had stage IIA disease, 16% had stage IIB disease, and 28% had stage IIIA disease. Toxicities were typical of erlotinib; there were no grade 4 or 5 adverse events. Forty percent of patients required erlotinib dose reduction to 100 mg per day and 16% to 50 mg per day. The intended 2-year course was achieved in 69% of patients. The median follow-up was 5.2 years, and 2-year DFS was 88% (96% stage I, 78% stage II, 91% stage III). Median DFS and overall survival have not been reached; 5-year DFS was 56% (95% CI, 45% to 66%), 5-year overall survival was 86% (95% CI, 77% to 92%). Disease recurred in 40 patients, with only four recurrences during erlotinib treatment. The median time to recurrence was 25 months after stopping erlotinib. Of patients with recurrence who underwent rebiopsy (n = 24; 60%), only one had T790M mutation detected. The majority of patients with recurrence were retreated with erlotinib (n = 26; 65%) for a median duration of 13 months.
Patients with EGFR-mutant NSCLC treated with adjuvant erlotinib had an improved 2-year DFS compared with historic genotype-matched controls. Recurrences were rare for patients receiving adjuvant erlotinib, and patients rechallenged with erlotinib after recurrence experienced durable benefit.
Stellar streams are excellent probes of the underlying gravitational potential in which they evolve. In this work, we fit dynamical models to five streams in the Southern Galactic hemisphere, ...combining observations from the Southern Stellar Stream Spectroscopic Survey (S 5), Gaia EDR3, and the Dark Energy Survey, to measure the mass of the Large Magellanic Cloud (LMC). With an ensemble of streams, we find a mass of the LMC ranging from ∼14–19 × 1010 M ⊙, probed over a range of closest approach times and distances. With the most constraining stream (Orphan–Chenab), we measure an LMC mass of \({18.8}_{-4.0}^{+3.5}\times {10}^{10}\,{M}_{\odot }\), probed at a closest approach time of 310 Myr and a closest approach distance of 25.4 kpc. This mass is compatible with previous measurements, showing that a consistent picture is emerging of the LMC’s influence on structures in the Milky Way. Using this sample of streams, we find that the LMC’s effect depends on the relative orientation of the stream and LMC at their point of closest approach. To better understand this, we present a simple model based on the impulse approximation and we show that the LMC’s effect depends both on the magnitude of the velocity kick imparted to the stream and the direction of this kick.
Highlights • EGFR mutations are identified concurrently with other genomic events. • The impact of concurrent mutations ( TP53 , PIK3CA , PTEN etc) on inhibitor response is unknown. • TP53 mutations ...commonly co-occur with EGFR mutations, and may affect clinical outcomes.
Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the ...therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase.
After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy.
Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects.
The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
The paper presents a comprehensive closed-form performance analysis framework for multihop communications over Weibull fading channels. This framework may be of interest in different applications in ...the contexts of beyond-5G (B5G) and Internet of Things (IoT) use cases. The analyzed scheme consists generally of multiple regenerative relays, and we also consider generalized high-order quadrature amplitude modulation (M-QAM) transmissions. To take into consideration the channel fading, we adopt the Weibull model for its largely flexible ability to cover different channel conditions in different application contexts. The end-to-end performance is evaluated in terms of outage probability, bit error probability (BER), symbol error probability (SER), block error rate (BLER), ergodic capacity, and energy efficiency (EE). For all the metrics, we present exact closed-form expressions—along with their asymptotic behavior—capitalizing on the powerful generalized hypergeometric functions. To illustrate the utility of the obtained analytical results, we derive two BER- and EE-optimal transmit power allocation strategies, and we discuss the resulting performance gains. The exactness of our analysis is illustrated by numerical examples, and assessed via Monte-Carlo simulations for different system and channel parameters. Finally, as a secondary contribution, and noting the increasing popularity of single and bivariate Fox’s H-function, we provide generalized Matlab codes for computing these functions which are of practical utility in many fields.
Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how and when obesity contributes to PDAC progression is not well understood. Leveraging an autochthonous ...mouse model, we demonstrate a causal and reversible role for obesity in early PDAC progression, showing that obesity markedly enhances tumorigenesis, while genetic or dietary induction of weight loss intercepts cancer development. Molecular analyses of human and murine samples define microenvironmental consequences of obesity that foster tumorigenesis rather than new driver gene mutations, including significant pancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identify aberrant beta cell expression of the peptide hormone cholecystokinin (Cck) in response to obesity and show that islet Cck promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression is driven by local obesity-associated changes in the tumor microenvironment and implicate endocrine-exocrine signaling beyond insulin in PDAC development.
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•Obesity accelerates oncogenic Kras-driven pancreatic ductal tumorigenesis in mice•Genetic or dietary weight loss intercepts pancreatic cancer progression•Obesity is associated with aberrant pancreatic islet cholecystokinin expression•Islet cholecystokinin overexpression drives pancreatic ductal cancer development
Obesity is an intrinsic driver of PDAC in mice, leading to a remodeling of beta cells to increase CCK secretion and playing a role early in pancreatic cancer development that can be intercepted by weight loss.
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