Purpose: Recent studies have found that KRAS mutations predict resistance to monoclonal antibodies targeting the epidermal growth factor receptor in metastatic colorectal cancer (mCRC). A ...polymorphism in a let-7 microRNA complementary site (lcs6) in the KRAS 3′ untranslated region (UTR) is associated with an increased cancer risk in non-small-cell lung cancer and reduced overall survival (OS) in oral cancers. We tested the hypothesis whether this polymorphism may be associated with clinical outcome in KRAS wild-type (KRASwt) mCRC patients treated with cetuximab monotherapy.
Patients and methods: The presence of KRAS let-7 lcs6 polymorphism was evaluated in 130 mCRC patients who were enrolled in a phase II study of cetuximab monotherapy (IMCL-0144). Genomic DNA was extracted from dissected formalin-fixed paraffin-embedded tumor tissue, KRAS mutation status and polymorphism were assessed using direct sequencing and PCR restriction fragment length polymorphism technique.
Results:KRAS let-7 lcs6 polymorphism was found to be related to object response rate (ORR) in mCRC patients whose tumors had KRASwt. The 12 KRASwt patients harboring at least a variant G allele (TG or GG) had a 42% ORR compared with a 9% ORR in 55 KRASwt patients with let-7 lcs6 TT genotype (P = 0.02, Fisher’s exact test). KRASwt patients with TG/GG genotypes had trend of longer median progression-free survival (3.9 versus 1.3 months) and OS (10.7 versus 6.4 months) compared to those with TT genotypes.
Conclusions: These results are the first to indicate that the KRAS 3’UTR polymorphism may predict for cetuximab responsiveness in KRASwt mCRC patients, which warrants validation in other clinical trials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Knowledge of the mechanical properties of clathrate hydrates is central for studying the mechanical properties of hydrate-bearing sediments, their associated applications in wellbore stability, ...exploitation in stratum deformation, geological disaster prevention, and risk assessment of CO
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buried in oceans. However, because of the limited understanding of hydrate formation conditions and limited methods to investigate these, the understanding of the mechanical properties of hydrates is still poor and even controversial to some extent. This paper reviews current experimental and theoretical results on mechanical properties of hydrates, and discusses the typical difficulties faced in this area. On the experimental side, the most important problem is obtaining pure hydrate samples. Theoretically, the essential origin of the mechanical properties has not been explained in terms of molecular interactions. The hope is to resolve these issues by combining novel macroscopic experiments and microscopic methods. In order to avoid difficulties caused by impurities, it is proposed to use molecular dynamics simulations. This technique can be used to reveal the nature of the mechanical characteristics of hydrates at the molecular and nanometre scale. The goals of this paper are to establish a bridge between the micromechanical nature and the macromechanical properties of hydrates, and to lay a solid theoretical basis for the study of the mechanical properties of hydrate-bearing sediments. These goals are important for the future safe and efficient exploitation of natural hydrates, hydrate-induced seabed geological disaster prevention, the safety of CO
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geological burial, and the deployment of a reliable long-term seabed-borehole coupled hydrate observation system in the integrated Ocean Drilling Program.
Molecular dynamics simulations may provide new insight into the microscopic nature of gas hydrates and bridge this insight with their macro-mechanical behaviour.
This paper reports on the observation of the sidereal large-scale anisotropy of cosmic rays using data collected by the ARGO-YBJ experiment over 5 years (2008-2012). This analysis extends previous ...work limited to the period from 2008 January to 2009 December, near the minimum of solar activity between cycles 23 and 24. With the new data sample, the period of solar cycle 24 from near minimum to maximum is investigated. A new method is used to improve the energy reconstruction, allowing us to cover a much wider energy range, from 4 to 520 TeV. Below 100 TeV, the anisotropy is dominated by two wide regions, the so-called "tail-in" and "loss-cone" features. At higher energies, a dramatic change of the morphology is confirmed. The yearly time dependence of the anisotropy is investigated. Finally, no noticeable variation of cosmic-ray anisotropy with solar activity is observed for a median energy of 7 TeV.
The study of neuron interactions and hardware implementations are crucial research directions in neuroscience, particularly in developing large-scale biological neural networks. The FitzHugh-Nagumo ...(FHN) model is a popular neuron model with highly biological plausibility, but its complexity makes it difficult to apply at scale. This paper presents a cost-saving and improved precision approximation algorithm for the digital implementation of the FHN model. By converting the computational data into floating-point numbers, the original multiplication calculations are replaced by adding the floating-point exponent part and fitting the mantissa part with piecewise linear. In the hardware implementation, shifters and adders are used, greatly reducing resource overhead. Implementing FHN neurons by this approximation calculations on FPGA reduces the normalized root mean square error (RMSE) to 3.5% of the state-of-the-art (SOTA) while maintaining a performance overhead ratio improvement of 1.09 times. Compared to implementations based on approximate multipliers, the proposed method achieves a 20% reduction in error at the cost of a 2.8% increase in overhead.This model gained additional biological properties compared to LIF while reducing the deployment scale by only 9%. Furthermore, the hardware implementation of nine coupled circular networks with eight nodes and directional diffusion was carried out to demonstrate the algorithm's effectiveness on neural networks. The error decreased to 60% compared to the single neuron of the SOTA. This hardware-friendly algorithm allows for the low-cost implementation of high-precision hardware simulation, providing a novel perspective for studying large-scale, biologically plausible neural networks.
Herpes zoster (HZ) is a prevalent viral disease that inflicts substantial morbidity and associated healthcare and socioeconomic burdens. Current treatments are not fully effective, especially among ...the most vulnerable patients. Although widely recommended, vaccination against HZ is not routine; barriers in Asia-Pacific include long-standing neglect of adult immunisation and sparse local data. To address knowledge gaps, raise awareness, and disseminate best practice, we reviewed recent data and guidelines on HZ from the Asia-Pacific region.
We searched PubMed, Scopus, and World Health Organization databases for articles about HZ published from 1994 to 2014 by authors from Australia, China, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, New Zealand, the Philippines, Singapore, Taiwan, Thailand, and Vietnam. We selected articles about epidemiology, burden, complications, comorbidities, management, prevention, and recommendations/guidelines. Internet searches retrieved additional HZ immunisation guidelines.
From 4007 retrieved articles, we screened-out 1501 duplicates and excluded 1264 extraneous articles, leaving 1242 unique articles. We found guidelines on adult immunisation from Australia, India, Indonesia, Malaysia, New Zealand, the Philippines, South Korea, and Thailand. HZ epidemiology in Asia-Pacific is similar to elsewhere; incidence rises with age and peaks at around 70 years - lifetime risk is approximately one-third. Average incidence of 3-10/1000 person-years is rising at around 5% per year. The principal risk factors are immunosenescence and immunosuppression. HZ almost always causes pain, and post-herpetic neuralgia is its most common complication. Half or more of hospitalised HZ patients have post-herpetic neuralgia, secondary infections, or inflammatory sequelae that are occasionally fatal. These disease burdens severely diminish patients' quality of life and incur heavy healthcare utilisation.
Several countries have abundant data on HZ, but others, especially in South-East Asia, very few. However, Asia-Pacific countries generally lack data on HZ vaccine safety, efficacy and cost-effectiveness. Physicians treating HZ and its complications in Asia-Pacific face familiar challenges but, with a vast aged population, Asia bears a unique and growing burden of disease. Given the strong rationale for prevention, most adult immunisation guidelines include HZ vaccine, yet it remains underused. We urge all stakeholders to give higher priority to adult immunisation in general and HZ in particular.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Recycled concrete fines (RCF) are activated through a thermal treatment method.•RCF can be used in mortar samples up to 20% cement replacement.•800°C-treated RCF had mechanical performances ...equivalent to fly ash.•Thermally treated RCF showed an activation effect on ground blast furnace slag.•A calcium silicate phase is formed during the treatment of RCF at 800°C.
Cement is the most energy-consuming component of concrete, leading to a high CO2 release during its fabrication. Therefore, a reduction of the cement amount used in concrete mixtures would be beneficial from an environmental point of view. One way to do this is by replacing cement with a suitable material; in this research, recycled concrete fines obtained from crushed concrete (RCF) is used to replace part of the cement in new mortar recipes. RCF subjected to various thermal treatments were used to replace part of the cement in the standard mortar samples containing either OPC or slag- or fly-ash blended cements. Both untreated and thermally-treated RCF were characterized in terms of density, PSD, composition (XRF and XRD, as well as SEM), calorimetric behavior and mechanical strength when added into mortars. Mortar samples were tested and the results show that RCFs can be a beneficial addition, especially in the case of blended cements.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Using structure-guided design, several cell based assays, and microdosed positron emission tomography (PET) imaging, we identified a series of highly potent, selective, and brain-penetrant ...oxazole-4-carboxamide-based inhibitors of glycogen synthase kinase-3 (GSK-3). An isotopologue of our first-generation lead, 3HPF-367, demonstrates selective and specific target engagement in vitro, irrespective of the activation state. We discovered substantial ubiquitous GSK-3-specific radioligand binding in Tg2576 Alzheimer’s disease (AD), suggesting application for these compounds in AD diagnosis and identified 11COCM-44 as our lead GSK-3 radiotracer, with optimized brain uptake by PET imaging in nonhuman primates. GSK-3β-isozyme selectivity was assessed to reveal OCM-51, the most potent (IC50 = 0.030 nM) and selective (>10-fold GSK-3β/GSK-3α) GSK-3β inhibitor known to date. Inhibition of CRMP2T514 and tau phosphorylation, as well as favorable therapeutic window against WNT/β-catenin signaling activation, was observed in cells.
Based on 10 billion J/psi events collected at the BESIII experiment, a search for CP violation in Lambda decay is performed in the difference between CP-odd decay parameters alpha_ for Lambda -> p ...pi(-) and alpha(+) for (Lambda) over bar -> (p) over bar pi(+) by using the process e(+)e(-) -> J/psi -> Lambda(Lambda) over bar. With a five-dimensional fit to the full angular distributions of the daughter baryon, the most precise values for the decay parameters arc determined to be a_ = 0.7519 +/- 0.0036 +/- 0.0024 and alpha(+) = -0.7559 +/- 0.0036 +/- 0.0030, respectively. The Lambda and (Lambda) over bar averaged value of the decay parameter is extracted to be a(avg) = 0.7542 +/- 0.0010 +/- 0.0024 with unprecedented accuracy. The CP asymmetry A(CP) = (alpha_ + alpha(+))/(a_-alpha(+)) is determined to be -0.0025 +/- 0.0046 +/- 0.0012, which is one of the most precise measurements in the baryon sector. The reported results for the decay parameter will play an important role in the studies of the polarizations and CP violations for the strange, charmed and beauty baryons.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM
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