The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin ...(SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy.
We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral capecitabine 1000 mg/m2 twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral S-1 40–60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day one of each 21 day plus oral S-1 40–60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546.
Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5–56·3) in the adjuvant-CapOx group, 56·5% (51·0–61·7) in the adjuvant-SOX group, and 59·4% (53·8–64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61–0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68–1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3–4 adverse events was neutropenia (32 12% of 258 patients in the adjuvant-CapOx group, 21 8% of 249 patients in the adjuvant-SOX group, and 30 10% of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported.
Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer.
National Key Research and Development Program of China, Beijing Scholars Program 2018–2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical.
For the Chinese translation of the abstract see Supplementary Materials section.
Protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-related emergent zoonotic coronaviruses is urgently needed. We made homotypic nanoparticles displaying the ...receptor binding domain (RBD) of SARS-CoV-2 or co-displaying SARS-CoV-2 RBD along with RBDs from animal betacoronaviruses that represent threats to humans (mosaic nanoparticles with four to eight distinct RBDs). Mice immunized with RBD nanoparticles, but not soluble antigen, elicited cross-reactive binding and neutralization responses. Mosaic RBD nanoparticles elicited antibodies with superior cross-reactive recognition of heterologous RBDs relative to sera from immunizations with homotypic SARS-CoV-2-RBD nanoparticles or COVID-19 convalescent human plasmas. Moreover, after priming, sera from mosaic RBD-immunized mice neutralized heterologous pseudotyped coronaviruses as well as or better than sera from homotypic SARS-CoV-2-RBD nanoparticle immunizations, demonstrating no loss of immunogenicity against particular RBDs resulting from co-display. A single immunization with mosaic RBD nanoparticles provides a potential strategy to simultaneously protect against SARS-CoV-2 and emerging zoonotic coronaviruses.
It is usually assumed that each cooperator contributes equally to different public pools in spatial public goods game. However, it is more reasonable to invest differently according to individual ...investment preference. In this paper, an extended public goods game, in which cooperators contribute to the groups according to the investment preference, is developed. The investment preference of a cooperator is characterized by the fraction of the cooperator from his/her own memory about a group and the intensity of investment preference is represented by a tunable parameter α. The well-mixed population and the structured population are analyzed under this mechanism. It is shown that the investment preference can give rise to coordination. Moreover, the extensive numerical simulation results show that with the increasing of investment preference density or memory length, the proportion of cooperation can increase monotonously. This is because the investment preference could help cooperators resist the invasion from defectors. Compared with the basic version, the new mechanism is able to promote cooperation effectively. Our research may provide a valuable insight for further exploring the nature of cooperation in the real world.
Finding top-<inline-formula> <tex-math notation="LaTeX">k </tex-math></inline-formula> elephant flows in high-speed network is a crucial task for network traffic measurement. Since modern routers do ...not hold enough on-chip memory to precisely track all flow sizes, identifying elephant flows becomes more challenging than ever. Existing solutions mostly use compact data structures to fit in limited on-chip memory. However, they have to use large-size counters, i.e. , 20-bit counter, to prevent overflows when recording flow sizes. This wastes significant on-chip memory since flow size distribution is highly skewed. Most counters only require 8 bits to track mouse flows rather than 20 bits. In this letter, we propose ActiveKeeper, an efficient top-<inline-formula> <tex-math notation="LaTeX">k </tex-math></inline-formula> finding solution that uses two-mode active counter to record flow sizes, reducing memory usage while ensuring high accuracy. We also introduce dynamically exponential decay to increase the precision in expelling the small flows while holding the large ones. Experimental results based on real-world Internet traces show that our method outperforms the state-of-the-art by achieving high accuracy and higher precision with small on-chip memory usage.
Per-flow traffic measurement in the high-speed network plays an important role in many practical applications. Due to the limited on-chip memory and the mismatch between off-chip memory speed and ...line rate, sampling-based methods select and forward a part of flow traffic to off-chip memory, which complements sketch-based solutions in estimation accuracy and online query support. However, most current work uses the same sampling probability for all flows, leading to the waste in storage and communication resources. In practice, different flows often require different sampling rates to meet the same accuracy constraint. This paper presents self-adaptive sampling, a framework to sample each flow with a probability adapted to flow size/spread. Then we propose three algorithms, SAS-LC, SAS-LOG, and SAS-HYB. SAS-LC and SAS-LOG are geared towards per-flow spread estimation and per-flow size estimation by using different compression functions. SAS-HYB combines the advantages of SAS-LC and SAS-LOG, showing higher efficiency when both small flows and large flows are interested. We implement our estimators in hardware using NetFPGA. Experimental results based on real Internet traces show that, compared to the state-of-the-art in per-flow spread estimation, SAS-LC can save around 10% on-chip space and reduce up to 40% communication cost for large flows. In per-flow size estimation, SAS-LOG can save 40% on-chip space and reduce up to 96% communication costs for large flows. Moreover, SAS-HYB's on-chip memory usage will not be larger than SAS-LC or SAS-LOG and can save up to 19% on-chip space than SAS-LOG when both small flows and large flows are interested.
Data stream processing plays a critical role in providing fundamental statistics for various applications, such as anomaly detection. Still, the unbalanced distribution of data streams severely ...affects the performance of related algorithms, which motivates the recent studies on filter structure design to enhance the existing algorithms for a more precise estimation result. However, these filters are mainly designed for frequency-based filtration, while none of them can conduct universal filtration; apparently, frequency is not the only targeted metric in practical processing tasks, metrics like cardinality and persistence are of equal importance. To cope with the issue, we propose a novel filter framework to implement universal, lightweight, and accurate filtration. The filter framework is called Coupon Filter due to the interpretation of its flow-level filtration as a coupon collection process. We prove the filtration efficiency of our filter design and formally analyze its recording process. We deploy our filter on the three typical metrics (frequency, cardinality, and persistence) to illustrate its advantages. The experimental results on real Internet traces demonstrate the effectiveness of our filter in enhancing existing stream processing approaches in terms of accuracy and throughput. All source codes are available at Github https://github.com/duyang92/coupon-filter-paper.
An escapable (ES)/inescapable stress (IS) paradigm was used to study whether behavioral control and repeated footshock stressors may affect adult neurogenesis and related cognitive function. Male ...stressed mice having behavioral control (ES) had a short-term escalation in dorsal dentate gyrus (DG) neurogenesis, while similarly stressed mice having no such control had unaltered neurogenesis as compared to control mice receiving no stressors. Paradoxically, ES and IS mice had comparable stress-induced corticosterone elevations throughout the stress regimen. Appetitive operant conditioning and forced running procedures were used to model learning and exercise effects in this escapable/inescapable paradigm. Further, conditioning and running procedures did not seem to affect the mice's corticosterone or short-term neurogenesis. ES and IS mice did not show noticeable long-term changes in their dorsal DG neurogenesis, gliogenesis, local neuronal density, apoptosis, autophagic flux, or heterotypic stress responses. ES mice were found to have a greater number of previously labeled and functionally integrated DG neurons as compared to IS and control mice 6 weeks after the conclusion of the stressor regimen. Likewise, ES mice outperformed IS and non-stressed control mice for the first two, but not the remaining two, trials in the object location task. Compared to non-stressed controls, temozolomide-treated ES and IS mice having a lower number of dorsal DG 6-week-old neurons display poor performance in their object location working memory. These results, taken together, prompt us to conclude that repeated stressors, albeit their corticosterone secretion-stimulating effect, do not necessary affect adult dorsal DG neurogenesis. Moreover, stressed animals having behavioral control may display adult neurogenesis escalation in the dorsal DG. Furthermore, the number of 6-week-old and functionally-integrated neurons in the dorsal DG seems to confer the quality of spatial location working memory. Finally, these 6-week-old, adult-born neurons seem to contribute spatial location memory in a use-dependent manner.
Liquid biopsies based on blood samples have been widely accepted as a diagnostic and monitoring tool for cancers, but extremely high sensitivity is frequently needed due to the very low levels of the ...specially selected DNA, RNA, or protein biomarkers that are released into blood. However, routine blood indices tests are frequently ordered by physicians, as they are easy to perform and are cost effective. In addition, machine learning is broadly accepted for its ability to decipher complicated connections between multiple sets of test data and diseases.
The aim of this study is to discover the potential association between lung cancer and routine blood indices and thereby help clinicians and patients to identify lung cancer based on these routine tests.
The machine learning method known as Random Forest was adopted to build an identification model between routine blood indices and lung cancer that would determine if they were potentially linked. Ten-fold cross-validation and further tests were utilized to evaluate the reliability of the identification model.
In total, 277 patients with 49 types of routine blood indices were included in this study, including 183 patients with lung cancer and 94 patients without lung cancer. Throughout the course of the study, there was correlation found between the combination of 19 types of routine blood indices and lung cancer. Lung cancer patients could be identified from other patients, especially those with tuberculosis (which usually has similar clinical symptoms to lung cancer), with a sensitivity, specificity and total accuracy of 96.3%, 94.97% and 95.7% for the cross-validation results, respectively. This identification method is called the routine blood indices model for lung cancer, and it promises to be of help as a tool for both clinicians and patients for the identification of lung cancer based on routine blood indices.
Lung cancer can be identified based on the combination of 19 types of routine blood indices, which implies that artificial intelligence can find the connections between a disease and the fundamental indices of blood, which could reduce the necessity of costly, elaborate blood test techniques for this purpose. It may also be possible that the combination of multiple indices obtained from routine blood tests may be connected to other diseases as well.
Targeted therapeutics, such as those abrogating hypoxia inducible factor (HIF)/vascular endothelial growth factor signaling, are initially effective against kidney cancer (or renal cell carcinoma, ...RCC); however, drug resistance frequently occurs via subsequent activation of alternative pathways. Through genome-scale integrated analysis of the HIF-α network, we identified the major protein kinase C substrate MARCKS (myristoylated alanine-rich C kinase substrate) as a potential target molecule for kidney cancer. In a screen of nephrectomy samples from 56 patients with RCC, we found that MARCKS expression and its phosphorylation are increased and positively correlate with tumor grade. Genetic and pharmacologic suppression of MARCKS in high-grade RCC cell lines in vitro led to a decrease in cell proliferation and migration. We further demonstrated that higher MARCKS expression promotes growth and angiogenesis in vivo in an RCC xenograft tumor. MARCKS acted upstream of the AKT/mTOR pathway, activating HIF-target genes, notably vascular endothelial growth factor-A. Following knockdown of MARCKS in RCC cells, the IC50 of the multikinase inhibitor regorafenib was reduced. Surprisingly, attenuation of MARCKS using the MPS (MARCKS phosphorylation site domain) peptide synergistically interacted with regorafenib treatment and decreased survival of kidney cancer cells through inactivation of AKT and mTOR. Our data suggest a major contribution of MARCKS to kidney cancer growth and provide an alternative therapeutic strategy of improving the efficacy of multikinase inhibitors.
Crowdsensing has emerged as an efficient and inexpensive way to perform specialized tasks by leveraging external crowds. In some crowdsensing systems, different tasks may have different requirements, ...and there may be precedence constraints among them, such as the Unmanned Aerial Vehicle (UAV) crowdsensing systems. Moreover, minimizing the total execution time is a regular target for finishing the crowdsensing tasks with precedence constraints. As far as we know, only a few existing studies consider the precedence constraints among crowdsensing tasks, and none of them can minimize the total execution time simultaneously. To tackle this challenge, an efficient allocation mechanism for tasks with precedence constraints is first proposed, which can minimize the total execution time. Then, a case study is given to show how to fit our mechanism in the UAV crowdsensing system. Finally, the simulation results show that the proposed mechanisms have good approximate optimal ratios under different parameter settings and are efficient for the UAV crowdsensing system as well.
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