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The field stress of the shale affects the proppant embedment, fracture conductivity, well production rate, and ultimately the recovery of hydrocarbons from reservoir formations. This paper presents, for the first time, an experimental study investigating the mechanical characteristics of a shale under confining pressures that simulate the in situ stress state in deep reservoirs. Bidirectional but equal confining pressures were applied to the shale sample to replicate its field stress state. Microindentation tests were conducted to assess the alterations of mechanical properties resulting from the application of confining pressures. The results demonstrate a significant increase in Young's modulus, hardness, and fracture toughness for the samples subjected to confining pressure. Considering the effect of confining pressure, the decrease in proppant embedment is proportional to Young's modulus of the shale. For larger-sized proppants (e.g., D = 2.50 mm), the influence of confining pressure on fracture conductivity is relatively minor. However, when smaller-sized proppants (e.g., D = 1.00 mm) are used, particularly in scenarios involving shale debris swelling due to prolonged interaction with fracturing fluid, there is a noticeable improvement in fracture conductivity. Importantly, previous computational models have tended to overestimate proppant embedment depth while underestimating fracture conductivity. The findings from this study contribute to advancing the understanding of shale's mechanical characteristics under in situ reservoir conditions and support the optimization of proppant embedment and fracture conductivity calculation models for the efficient extraction of shale gas. [ABSTRACT FROM AUTHOR]

The identification of novel age‐related biomarkers represents an area of intense research interest. Despite multiple studies associating DNA damage with aging, there is a glaring paucity of DNA damage‐based biomarkers of age, mainly due to the lack of precise methods for genome‐wide surveys of different types of DNA damage. Recently, we developed two techniques for genome‐wide mapping of the most prevalent types of DNA damage, single‐strand breaks and abasic sites, with nucleotide‐level resolution. Herein, we explored the potential of genomic patterns of DNA damage identified by these methods as a source of novel age‐related biomarkers using mice as a model system. Strikingly, we found that models based on genomic patterns of either DNA lesion could accurately predict age with higher precision than the commonly used transcriptome analysis. Interestingly, the informative patterns were limited to relatively few genes and the DNA damage levels were positively or negatively correlated with age. These findings show that previously unexplored high‐resolution genomic patterns of DNA damage contain useful information that can contribute significantly to both practical applications and basic science. [ABSTRACT FROM AUTHOR]

To rationally evaluate the seismic damage of RC structures comprehensively and multi-dimensionally, a damage index calculation method is proposed. This is a macroscopic global seismic damage model that considers torsional damage, damage in two perpendicular horizontal directions, as well as the overall damage, based on the modal characteristics of the three-dimensional structure and the multi-mode damage model. Formulas are derived, and the steps for damage evaluation are summarized. To better illustrate the results of the proposed method, an example of an asymmetric 6-story frame-shear wall structure is built using the OpenSees program. Thirteen ground motions are selected for incremental dynamic analysis. The structure's damage indexes are evaluated according to the proposed method and compared with the corresponding structural responses, He et al.'s index, and the Final Softening index. The results demonstrate that the proposed method can fully reflect the macroscopic damage state of the structure from different perspectives. Additionally, the results show that, despite the ground motion only acting in the y-direction, the structure exhibits responses and damage in both the x-direction and the torsional direction. The overall damage to the structure is primarily controlled by the torsional damage, attributed to the asymmetric arrangement of shear walls. The torsional effect is the key factor leading to the failure of asymmetric structures during earthquakes. Therefore, ensuring the torsional strength of the structure is crucial during the structural design process. [ABSTRACT FROM AUTHOR]

The effect of pulse characteristic of near-fault ground motions on multistory reinforced concrete frame structures is investigated by means of a synthetic broadband ground motion model (SBGM). A simplified analytical pulse model is used to describe the low-frequency components of ground motions, while a stochastic simulation method based on wavelet packet is adopted to simulate the high-frequency components of ground motions. First, the time histories, response spectrum, and structural response of synthetic ground motions are compared with those corresponding to recorded near-fault ground motions. The good agreement indicates that the SBGM model used in this article is a suitable and efficient tool for evaluating the structural response. Sensitivity analysis on structural response of 2-, 4-, 8-, and 12-story building models to the SBGM model input parameters is then performed to identify the key ground-motion parameters which control the main structural response indicators, that is, interstory drift ratio and maximum interstory drift ratio. Final results indicate that the amplitude of velocity pulse in the SBGM model has a significant influence on structural drift demands. Nevertheless, for low-rise buildings, the maximum drift demands would effectively decrease with increasing proportion of high-frequency components. Moreover, the ratio of pulse period to structural fundamental period and number of oscillations impose a large drift demands to the structure under near-fault pulse-like ground motions. [ABSTRACT FROM AUTHOR]

Progesterone is an important hormone for female reproduction, however, how the fluctuation of progesterone acts upon reproductive processes remains largely unknown. Mounting evidence indicates a pivotal role of the circadian clock in sensing hormone dynamics for homeostatic regulation of physiological functions. Therefore, we sought to determine whether clock genes respond to progesterone signaling in female reproductive system. In this study, we tested the hypothesis that the circadian system could respond to progesterone signaling during human endometrial decidual transformation. The expression of the circadian gene PER1 increased immediately and remained elevated during human endometrial decidualization. The progesterone receptor activated PER1 transcription by directly binding to its promoter from the onset of the stromal proliferation-differentiation transition. PER1 knockout significantly downregulated the expression of some PGR target genes, and attenuated human endometrial decidual transformation by expediting FOXO1 protein degradation. In conclusion, progesterone could control the female reproductive process through sustained feedback from the circadian gene PER1, which is probably involved to P4-PR signaling responsiveness in the initiation and maintenance of decidualization.

Purpose: Cetuximab in combination with chemotherapy is a standard-of-care first-line treatment regimen for patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC); however, the efficacy of cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX) has never before been proven in a controlled and randomized phase III trial. To our knowledge, the TAILOR trial ( ClinicalTrials.gov identifier: NCT01228734) is the first randomized, multicenter, phase III study of the addition of cetuximab to first-line FOLFOX prospectively choosing a RAS wt population and thus providing confirmative data for the efficacy and safety of cetuximab plus FOLFOX versus FOLFOX alone., Patients and Methods: TAILOR is an open-label, randomized (1:1), multicenter, phase III trial in patients from China comparing FOLFOX-4 with or without cetuximab in RAS wt ( KRAS / NRAS , exons 2 to 4) mCRC. The primary end point of TAILOR was progression-free survival time; secondary end points included overall survival time, overall response rate, and safety and tolerability., Results: In the modified intent-to-treat population of 393 patients with RAS wt mCRC, adding cetuximab to FOLFOX-4 significantly improved the primary end point of progression-free survival time compared with FOLFOX-4 alone (hazard ratio, 0.69; 95% CI, 0.54 to 0.89; P = .004; median, 9.2 v 7.4 months, respectively), as well as the secondary end points of overall survival time (current assessment after 300 events: hazard ratio, 0.76; 95% CI, 0.61 to 0.96; P = .02; median, 20.7 v 17.8 months, respectively) and overall response rate (odds ratio, 2.41; 95% CI, 1.61 to 3.61; P < .001; 61.1% v 39.5%, respectively). Treatment was well tolerated, and there were no new or unexpected safety findings., Conclusion: The TAILOR study met all of its objectives and relevant clinical end points, confirming cetuximab in combination with FOLFOX as an effective standard-of-care first-line treatment regimen for patients with RAS wt mCRC.

Purpose: There is currently no standard treatment strategy for patients with advanced metastatic gastric cancer experiencing progression after two or more lines of chemotherapy. We assessed the efficacy and safety of apatinib, a novel vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor, in patients with advanced gastric or gastroesophageal junction adenocarcinoma for whom at least two lines of prior chemotherapy had failed., Patients and Methods: This was a randomized, double-blind, placebo-controlled phase III trial. Patients from 32 centers in China with advanced gastric or gastroesophageal junction adenocarcinoma, for whom two or more prior lines of chemotherapy had failed, were enrolled. Patients were randomly assigned to oral apatinib 850 mg or placebo once daily. The primary end points were overall (OS) and progression-free survival (PFS)., Results: Between January 2011 and November 2012, 267 patients were enrolled. Median OS was significantly improved in the apatinib group compared with the placebo group (6.5 months; 95% CI, 4.8 to 7.6 v 4.7 months; 95% CI, 3.6 to 5.4; P = .0149; hazard ratio, 0.709; 95% CI, 0.537 to 0.937; P = .0156). Similarly, apatinib significantly prolonged median PFS compared with placebo (2.6 months; 95% CI, 2.0 to 2.9 v 1.8 months; 95% CI, 1.4 to 1.9; P < .001; hazard ratio, 0.444; 95% CI, 0.331 to 0.595; P < .001). The most common grade 3 to 4 nonhematologic adverse events were hand-foot syndrome, proteinuria, and hypertension., Conclusion: These data show that apatinib treatment significantly improved OS and PFS with an acceptable safety profile in patients with advanced gastric cancer refractory to two or more lines of prior chemotherapy., (© 2016 by American Society of Clinical Oncology.)