Background: To compare capecitabine/cisplatin with 5-fluorouracil/cisplatin as first-line treatment for advanced gastric cancer (AGC). Patients and methods: In this randomised, open-label, phase III ...study, patients received cisplatin (80 mg/m2 i.v. day 1) plus oral capecitabine (1000 mg/m2 b.i.d., days 1–14) (XP) or 5-FU (800 mg/m2/day by continuous infusion, days 1–5) (FP) every 3 weeks. The primary end point was to confirm noninferiority of XP versus FP for progression-free survival (PFS). Results: A total of 316 patients were randomised to XP (n = 160) or FP (n = 156). In the per-protocol population, median PFS for XP (n = 139) versus FP (n = 137) was 5.6 versus 5.0 months. The primary end point was met with an unadjusted hazard ratio (HR) of 0.81 95% confidence interval (CI) 0.63–1.04, P < 0.001 versus noninferiority margin of 1.25. Median overall survival was 10.5 versus 9.3 months for XP versus FP (unadjusted HR = 0.85, 95% CI 0.64–1.13, P = 0.008 versus noninferiority margin of 1.25). The most common treatment-related grade 3/4 adverse events in XP versus FP patients were as follows: neutropenia (16% versus 19%), vomiting (7% versus 8%), and stomatitis (2% versus 6%). Conclusions: XP showed significant noninferiority for PFS versus FP in the first-line treatment of AGC. XP can be considered an effective alternative to FP.
Nivolumab is approved as an option for third- or later-line treatment of advanced gastric/gastroesophageal junction (G/GEJ) cancer in several countries after ATTRACTION-2. To further improve the ...therapeutic efficacy of first-line therapy, exploration of a nivolumab-chemotherapy combination is warranted. In part 1 (phase II) of ATTRACTION-4, the safety and efficacy of nivolumab combined with S-1 plus oxaliplatin (SOX) or capecitabine plus oxaliplatin (CapeOX) as first-line therapy for unresectable advanced or recurrent human epidermal growth factor receptor 2 (HER2)-negative G/GEJ cancer were evaluated.
Patients were randomized (1 : 1) to receive nivolumab (360 mg intravenously every 3 weeks) plus SOX (S-1, 40 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) or CapeOX (capecitabine, 1000 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal.
Of 40 randomized patients, 39 (nivolumab plus SOX, 21; nivolumab plus CapeOX, 18) and 38 (21 and 17, respectively) comprised the safety and efficacy populations, respectively. Most frequent (>10%) grade 3/4 treatment-related adverse events were neutropenia (14.3%) in the nivolumab plus SOX group, and neutropenia (16.7%), anemia, peripheral sensory neuropathy, decreased appetite, type 1 diabetes mellitus, and nausea (11.1% each) in the nivolumab plus CapeOX group. No treatment-related death occurred. Objective response rate was 57.1% (95% confidence interval 34.0–78.2) with nivolumab plus SOX and 76.5% (50.1–93.2) with nivolumab plus CapeOX. Median overall survival was not reached (NR) in both groups. Median progression-free survival was 9.7 months (5.8–NR) and 10.6 months (5.6–12.5), respectively.
Nivolumab combined with SOX/CapeOX was well tolerated and demonstrated encouraging efficacy for unresectable advanced or recurrent HER2-negative G/GEJ cancer. ATTRACTION-4 has proceeded to part 2 (phase III) to compare nivolumab plus SOX/CapeOX versus placebo plus SOX/CapeOX.
NCT02746796.
We systematically study how diverse physiologic systems in the human organism dynamically interact and collectively behave to produce distinct physiologic states and functions. This is a fundamental ...question in the new interdisciplinary field of Network Physiology, and has not been previously explored. Introducing the novel concept of Time Delay Stability (TDS), we develop a computational approach to identify and quantify networks of physiologic interactions from long-term continuous, multi-channel physiological recordings. We also develop a physiologically-motivated visualization framework to map networks of dynamical organ interactions to graphical objects encoded with information about the coupling strength of network links quantified using the TDS measure. Applying a system-wide integrative approach, we identify distinct patterns in the network structure of organ interactions, as well as the frequency bands through which these interactions are mediated. We establish first maps representing physiologic organ network interactions and discover basic rules underlying the complex hierarchical reorganization in physiologic networks with transitions across physiologic states. Our findings demonstrate a direct association between network topology and physiologic function, and provide new insights into understanding how health and distinct physiologic states emerge from networked interactions among nonlinear multi-component complex systems. The presented here investigations are initial steps in building a first atlas of dynamic interactions among organ systems.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background and Objective
Resistin was recently reported to play a role in inflammation‐related diseases such as arthritis. However, the precise role of resistin in chronic inflammatory diseases, such ...as periodontal disease, remains unclear. The aim of this study was to investigate the combined effects of nicotine and lipopolysaccharide (LPS) on the expression of resistin and to assess whether resistin expression influences the levels of inflammatory cytokines, extracellular matrix (ECM) molecules and MMPs in human periodontal ligament cells (PDLCs) stimulated with both nicotine and LPS.
Material and Methods
PDLCs were pretreated with isoproterenol or resistin‐specific small interfering RNA (siRNA), stimulated with LPS plus nicotine for 24 h, and then monitored for the production of inflammatory mediators. The concentrations of prostaglandin E2 (PGE2) and nitric oxide (NO) were measured by radioimmunoassay and the Griess method, respectively. RT‐PCR and western blot analysis were used to measure the levels of mRNA and protein, respectively. Western blot analysis was also used to assess the activation of various signal‐transduction pathways.
Results
Treatment with nicotine plus LPS up‐regulated the expression of resistin mRNA and the production of resistin protein in PDLCs in a time‐ and concentration‐dependent manner. Isoproterenol‐mediated interference with the function of resistin, or siRNA‐mediated knockdown of resistin expression, markedly attenuated the LPS plus nicotine‐mediated stimulation of PGE2 and NO production, the production of cyclooxygenase‐2 (COX‐2) and inducible nitric oxide synthase proteins and the expression of proinflammatory cytokines tumor necrosis factor‐α, interleukin (IL)‐1β, IL‐6 and IL‐12 and MMPs (MMP‐1, MMP‐2 and MMP‐9); however, these treatments restored the expression of ECM molecules. Furthermore, pretreatment with isoproterenol or resistin‐specific siRNA blocked nicotine plus LPS‐induced activation of phosphoinositide‐3‐kinase, glycogen synthase kinase‐3 beta, β‐catenin, p38, ERK, JNK and nuclear factor‐κB.
Conclusion
This is the first study to show that the inhibition of resistin, by either a pharmacological or a genetic silencing approach, has anti‐inflammatory effects. These effects include decreased levels of inflammatory cytokines and the prevention of ECM breakdown in a nicotine plus LPS‐stimulated PDLC model.
Effects of chordwise, spanwise, and isotropic flexibility on the force generation and propulsive efficiency of flapping wings are elucidated. For a moving body immersed in viscous fluid, different ...types of forces, as a function of the Reynolds number, reduced frequency (k), and Strouhal number (St), acting on the moving body are identified based on a scaling argument. In particular, at the Reynolds number regime of $O(1{0}^{3} \ensuremath{-} 1{0}^{4} )$ and the reduced frequency of $O(1)$, the added mass force, related to the acceleration of the wing, is important. Based on the order of magnitude and energy balance arguments, a relationship between the propulsive force and the maximum relative wing-tip deformation parameter ($\gamma $) is established. The parameter depends on the density ratio, St, k, natural and flapping frequency ratio, and flapping amplitude. The lift generation, and the propulsive efficiency can be deduced by the same scaling procedures. It seems that the maximum propulsive force is obtained when flapping near the resonance, whereas the optimal propulsive efficiency is reached when flapping at about half of the natural frequency; both are supported by the reported studies. The established scaling relationships can offer direct guidance for micro air vehicle design and performance analysis.
AIMS: In this report, we characterized the probiotic potential of Lactobacillus mucosae LM1, focusing on its in vitro mucin‐adhesion abilities. METHODS AND RESULTS: Screening assays were used to ...evaluate LM1. Previous studies on Lact. mucosae species have been performed, but few have examined the ability of this species to adhere to and colonize the intestinal mucosa. Thus, adhesion, aggregation and pathogen inhibition assays of LM1 along with microbial adhesion to solvents (MATS) assay were carried out in comparison with another putative probiotic, Lactobacillus johnsonii PF01, and the commercial strain, Lactobacillus rhamnosus GG. Based on MATS assay, the cell surfaces of the lactobacilli strains were found to be hydrophobic and highly electron‐donating, but the average hydropathy (GRAVY) index of predicted surface‐exposed proteins in the LM1 genome indicated that most were hydrophilic. LM1 showed the highest adhesion, aggregation and hydrophobicity among the strains tested and significantly inhibited the adhesion of Escherichia coli K88 and Salmonella enterica serovar Typhimurium KCCM 40253. Correlations among adhesion, aggregation and hydrophobicity, as well as between coaggregation and displacement of E. coli, were observed. CONCLUSIONS: Increased adhesion may not always correlate with increased pathogen inhibition due to various strain‐specific mechanisms. Nevertheless, LM1 has promising probiotic properties that can be explored further using a genomics approach. SIGNIFICANCE AND IMPACT OF THE STUDY: Our data on adhesion of LM1 strain showed a significant correlation between adhesion, hydrophobicity of cell surface and autoaggregation. This study gives basic knowledge for the elucidation of the adhesion mechanism of Lactobacillus sp. and prediction of its adherence in specific host models.
Objectives: Histone deacetylase (HDAC) is an important therapeutic target in cancer. Two of the main anticancer mechanisms of HDAC inhibitors are induction of terminal differentiation and inhibition ...of cell proliferation. To investigate the role of HDAC in maintenance of self‐renewal and cell proliferation, we treated mesenchymal stem cells (MSCs) that originated from adipose tissue or umbilical cord blood with valproic acid (VPA) and sodium butyrate (NaBu).
Materials and methods: Human MSCs were isolated from mammary fat tissue and cord blood. We performed MTT assay and flow cytometry‐based cell cycle analysis to assess self‐renewal of MSCs. In vitro differentiation assays into osteogenic, adipogenic, neurogenic and chondrogenic lineages were conducted to investigate MSC multipotency. Immunocytochemistry, Western blot and reverse transcription‐polymerase chain reaction were used to interrogate molecular pathways.
Results: VPA and NaBu flattened the morphology of MSCs and inhibited their growth. VPA and NaBu activated the transcription of p21CIP1/WAF1 by increasing the acetylation of histone H3 and H4 and eventually blocked the cell cycle at G2/M phase. The expression level of p16INK4A, a cdk inhibitor that is closely related to cellular senescence, was not changed by HDAC inhibitor treatment. We performed controlled differentiation into bone, fat, cartilage and nervous tissue to elucidate the role of HDAC in the pluripotency of MSC to differentiate into functional tissues. VPA and NaBu decreased the efficiency of adipogenic, chondrogenic, and neurogenic differentiation as visualized by specific staining and reverse transcription‐polymerase chain reaction. In contrast, osteogenic differentiation was elevated by HDAC inhibitor treatment.
Conclusion: HDAC activity is essential for maintaining the self‐renewal and pluripotency of MSCs.
The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are prognostic factors for various types of cancer. In this study, we assessed the association of NLR and PLR with the ...prognosis of small-cell lung cancer (SCLC) in patients who received the standard treatment.
We retrospectively reviewed patients who were diagnosed with SCLC and treated with platinum-based chemotherapy between July 2006 and October 2013 in Gyeongsang National University Hospital Regional Cancer Center and Changwon Samsung Hospital.
In total, 187 patients were evaluated. Compared with low NLR (<4), high NLR (⩾4) at diagnosis was associated with poor performance status, advanced stage, and lower response rate. Median overall survival (OS) and progression-free survival (PFS) were worse in the high-NLR group (high vs low, 11.17 vs 9.20 months, P=0.019 and 6.90 vs 5.49 months, P=0.005, respectively). In contrast, PLR at diagnosis was not associated with OS or PFS (P=0.467 and P=0.205, respectively). In multivariate analysis, stage, lactate dehydrogenase, and NLR at diagnosis were independent prognostic factors for OS and PFS.
NLR is easily measurable and reflects the SCLC prognosis. A future prospective study is warranted to confirm our results.
Micro air vehicles (MAVs) have the potential to revolutionize our sensing and information gathering capabilities in areas such as environmental monitoring and homeland security. Flapping wings with ...suitable wing kinematics, wing shapes, and flexible structures can enhance lift as well as thrust by exploiting large-scale vortical flow structures under various conditions. However, the scaling invariance of both fluid dynamics and structural dynamics as the size changes is fundamentally difficult. The focus of this review is to assess the recent progress in flapping wing aerodynamics and aeroelasticity. It is realized that a variation of the Reynolds number (wing sizing, flapping frequency, etc.) leads to a change in the leading edge vortex (LEV) and spanwise flow structures, which impacts the aerodynamic force generation. While in classical stationary wing theory, the tip vortices (TiVs) are seen as wasted energy, in flapping flight, they can interact with the LEV to enhance lift without increasing the power requirements. Surrogate modeling techniques can assess the aerodynamic outcomes between two- and three-dimensional wing. The combined effect of the TiVs, the LEV, and jet can improve the aerodynamics of a flapping wing. Regarding aeroelasticity, chordwise flexibility in the forward flight can substantially adjust the projected area normal to the flight trajectory via shape deformation, hence redistributing thrust and lift. Spanwise flexibility in the forward flight creates shape deformation from the wing root to the wing tip resulting in varied phase shift and effective angle of attack distribution along the wing span. Numerous open issues in flapping wing aerodynamics are highlighted.
Summary
The use of lactobacilli as probiotics in swine has been gaining attention due to their ability to improve growth performance and carcass quality, prevent gastrointestinal infection and most ...importantly, their ‘generally recognized as safe’ status. Previous studies support the potential of lactobacilli to regulate host immune systems, enhance gut metabolic capacities and maintain balance in the gut microbiota. Research on swine gut microbiota has revealed complex gut microbial community structure and showed the importance of Lactobacillus to the host's health. However, the species‐ and strain‐specific characteristics of lactobacilli that confer probiotic benefits are still not well understood. The diversity of probiotic traits in a complex gut ecosystem makes it challenging to infer the relationships between specific functions of Lactobacillus sp. and host health. In this review, we provide an overview of how lactobacilli play a pivotal role in the swine gut ecosystem and identify key characteristics that influence gut microbial community structure and the health of pigs. In addition, based on recent and ongoing meta‐omics and omics research on the gut microbiota of pigs, we suggest a workflow combining culture‐dependent and culture‐independent approaches for more effective selection of probiotic lactobacilli.
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