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In this work, CoCrFeNiMo0.35 high entropy alloy was hot-rolled at 900 °C by varying different reductions (10%, 20%, 30%, 40%, 50%) and the impact of hot rolling on the structure and mechanical properties of this alloy has been investigated. It is found that the phase composition of CoCrFeNiMo0.35 high entropy alloy after hot rolling has not been changed, and it still consists of FCC phase and σ phase (Cr and Mo-rich phase), which is the same as the as-cast state alloy. Besides, the grain size becomes finer after hot rolling and is stretched to a flat shape in the rolling direction, and the grain orientation gradually changes from and direction to direction with the increase of reduction. At the same time, as the increase of rolling reduction, the volume fraction of σ phase increases, and the yield strength (∼817.8 MPa), tensile strength (∼891.7 MPa) and hardness of the alloy are improved. The comprehensive influence of fine grain strengthening, second phase strengthening and dislocation strengthening is the main reason for this result. Besides, the fracture mode of the tensile sample changes from mixed tough-brittle fracture to brittle fracture. The research results can be used as a reference for hot rolling strengthening of CoCrFeNiMo0.35 high entropy alloy.

The NiCoCrFeAlW eutectic high-entropy alloy exhibits a balanced combination of ductility and strength. This study examines the microstructure evolution and mechanical properties of the Ni30Co30Cr10Fe10Al18W2 alloy at varying growth velocities (10, 20, 50, 100, and 200 μm/s), which in its as-cast state, features a microstructure that includes both coarse dendrites and lamellar eutectic. The structure of the coarse dendrites is characterized by an ordered body-centered cubic (B2) phase, while the lamellar eutectic, features a combination of face-centered cubic (FCC) and ordered B2 phases. The microstructure, characterized by lamellar and dendritic structures that are parallel to the growth direction after directional solidification, undergoes a morphological transition at the solid-liquid interface from a planar to a dendritic form as growth velocity increases. The tensile fracture strength initially increases with the growth velocity, reaching a peak of 1286 MPa at a velocity of 50 μm/s, and then subsequently decreases as the growth velocity continues to increase. Directional solidification results in an increase in sample elongation with increasing growth velocity, achieving an elongation of 22.5% at 200 μm/s. An examination of the deformation mechanism reveals that the lamellar structure, composed of the more ductile FCC phase and the harder B2 phase, effectively harmonizes the plasticity and strength of the alloy. Therefore, directional solidification significantly adjusts the eutectic microstructure's orientation, thereby enhancing the mechanical properties along the direction of solidification.

Abstract To date, the types of fuels used in pottery kilns during the Western Zhou Dynasty have not been adequately addressed. Samples from updraft kilns and semi-downdraft kilns at the Fengjing site, the capital in the late Western Zhou period, were selected for analysis. Through phytolith and wood charcoal analysis, various grasses mainly Panicoideae, Pooideae, and Eragrostidoideae, as well as millet, rice, and wheat crops were identified. Additionally, wood primarily from trees of the Quercus, Ulmus, and Liquidambar taxa was found. These findings suggest that different pottery kilns used similar fuels, demonstrating a broad-spectrum rather than specialized fuel utilization during the Zhou period.

Autonomous navigation systems often struggle in dynamic, complex environments due to challenges in safety, intent prediction, and strategic planning. Traditional methods are limited by rigid architectures and inadequate safety mechanisms, reducing adaptability to unpredictable scenarios. We propose SafeMod, a novel framework enhancing safety in autonomous driving by improving decision-making and scenario management. SafeMod features a bidirectional planning structure with two components: forward planning and backward planning. Forward planning predicts surrounding agents’ behavior using text-based environment descriptions and reasoning via large language models, generating action predictions. These are embedded into a transformer-based planner that integrates text and image data to produce feasible driving trajectories. Backward planning refines these trajectories using policy and value functions learned through Actor–Critic-based reinforcement learning, selecting optimal actions based on probability distributions. Experiments on CARLA and nuScenes benchmarks demonstrate that SafeMod outperforms recent planning systems in both real-world and simulation testing, significantly improving safety and decision-making. This underscores SafeMod’s potential to effectively integrate safety considerations and decision-making in autonomous driving.

Abstract The Beibai’e cemetery is a high-status noble tomb group from the early Spring–Autumn period (770 B.C–476 B.C). Three sealed bronze vessels with mud and liquid residues were excavated from the M1 tomb. In a previous investigation, it was concluded that the residues were fruit wine since syringic acid was detected. However, this finding contradicts the grain-based brewing traditions prevalent in the central plains region of China since the Neolithic era. In the previous study, syringic acid was considered a unique biomarker for fruit wine. In this study, multiple analytical techniques, including microfossil analysis, HPLC‒MS and FTIR were applied. The results indicated that the residue was beer rather than fruit wine. This study demonstrated that comprehensive analysis and multiple pieces of evidence are necessary in wine residue research.

Abstract Tumor budding (TB) is a small tumor cell cluster with highly aggressive behavior located ahead of the invasive tumor front. However, the molecular and biological characteristics of TB and the regulatory mechanisms governing TB phenotypes remain unclear. This study reveals that TB exhibits a particular dynamic gene signature with stemness and partial epithelial‐mesenchymal transition (p‐EMT). Importantly, nuclear expression of CYTOR is identified to be the key regulator governing stemness and the p‐EMT phenotype of TB cells, and targeting CYTOR significantly inhibits TB formation, tumor growth and lymph node metastasis in head and neck squamous cell carcinoma (HNSCC). Mechanistically, CYTOR promotes tumorigenicity and metastasis of TB cells by facilitating the formation of FOSL1 phase‐separated condensates to establish FOSL1‐dependent super enhancers (SEs). Depletion of CYTOR leads to the disruption of FOSL1‐dependent SEs, which results in the inactivation of cancer stemness and pro‐metastatic genes. In turn, activation of FOSL1 promotes the transcription of CYTOR. These findings indicate that CYTOR is a super‐lncRNA that controls the stemness and metastasis of TB cells through facilitating the formation of FOSL1 phase separation and SEs, which may be an attractive target for therapeutic interventions in HNSCC.

The influence of normal rolling and cross-rolling on the microstructure, mechanical properties, and anisotropy of Al-3Li-1Cu-0.4Mg-0.1Er-0.1Zr alloy was investigated. With an increase in the rolling reduction amount, both the strength and plasticity of the alloy are enhanced. Among them, the alloy in the normal rolling state with a deformation amount of 90% exhibits the best properties, with a tensile strength of 362 MPa and an elongation of 19.1% along the rolling direction. During the rolling process, the intergranular Cu-containing phase in the alloy is continuously broken and dissolved, leading to a decrease in both size and quantity, turning from continuous distribution along grain boundaries to a granular distribution. Moreover, a large quantity of the Al3Li phase and Al3(Er, Zr, Li) core–shell composite phase are precipitated in the alloy. Recrystallization occurs mainly through the particle stimulated nucleation (PSN) mechanism. Cross-rolling eliminates the brass-type texture produced by normal rolling and enhances the brass R-type texture {111}. The index of plane anisotropy (IPA) of the strength decreases from 10.1% for normal rolling to 5.5% for cross-rolling, and the IPA of elongation decreases from 12.8% to 3.3%. Cross-rolling provides an effective method to reduce the anisotropy of Al-Li alloys.

Little is known on the transcriptional mechanisms that control cancer stem cell (CSC) self-renewal and stemness. Here the authors show superenhancers (SEs) play a role in the transcription of cancer stemness genes as well as prometastatic genes, thereby controlling their tumorigenic potential; disrupting SEs inhibited CSC self-renewal and eliminated CSCs.

The diet of prehistoric humans in the Qijia period (4,400–3,500 BP) was significantly changed by the advent of dry agriculture and food globalization. However, it is yet to be proven whether wild plants were exploited despite the cultivation of millet, and whether wheat crops, cattle, and sheep originating from southwestern Asia were adopted into the regional human diet. This study presents stable isotope, starch grain, and phytolith analyses of 24 human teeth from the Lajia site in Qinghai, which is a representative Qijia culture settlement site. The carbon and nitrogen isotope results show that the subjects primarily ate C4 plants and had a high protein diet. Starch grain and phytolith results showed that the inhabitants consumed broomcorn millet (Panicum miliaceum), foxtail millet (Setaria italica), Triticeae, tubers and roots, along with other Pooideae and Poaceae plants. This data proves that although broomcorn and foxtail millet formed the mainstay of the Qijia diet, it also included a wide range of plants, such as the tribe Triticeae, tubers and roots, which would have been foraged rather than grown. Compared with the other three contemporaneous sites in Northern China, the proportion of millet starches was highest at the Lajia site, while the type and proportion of foraged plants were the lowest. This was probably because of the arid environment in the region, which could not have supported sufficient plant resources for foraging, which in turn might have led to enhanced millet cultivation and/or a greater reliance on hunting. No wheat or barley traces were found in human teeth in Lajia, and the high proportion of nitrogen was possibly related to the consumption of sheep because sheep bones were found in a zooarchaeological study. This study enhances our understanding of the subsistence strategies present in Qijia culture and of prehistoric food globalization, which is of pivotal significance for a deeper understanding of interactions between east and west Asia during the Neolithic and Bronze ages.

From 6,000 calendar years before the present (cal BP) onward, grooved pottery vessels occurred in the lower and middle reaches of the Yangtze River in succession. After a thousand years, it was introduced into central China and became popularized there around 4,000 years ago. It has been proposed that the function of the grooved vessels was to process plant foods, replacing the previously used stone slabs and rollers in terms of ethnographic investigation, but there is a lack of solid and direct evidence although little evidence of starches has been provided. Here we report our study on the sherds of grooved vessels from the Meishan site in central China (late Longshan and Erlitou period). The combined starch and phytolith analyses were first used together to examine the residues on the sherds. Starches from geophytes, millets (Setaria italica and Panicum miliaceum), wheat (Triticum aestivum), and phytoliths from the glumes and leaves of these crops plus rice (Oryza sativa), seem to suggest that the grooved pottery vessels were likely to be used to grind geophytes and dehusk grain seeds. But, incorporating the extremely low proportion of grooved vessels to entire pottery tools at the site, we hypothesize that the invention of grooved vessels may have been related to the success of rice domestication and may have been used as tools to pound by-products of crops, leaves, and husks somehow.

In undertaking a functional study of ceramic Li tripods, a common archaeological artifact in Northeast China during the Bronze Age, this study provides a crucial insight into both the function of these ceramics, plant resource strategies and human diets during this period. The precise function of the Li tripod has to date been controversial due to a lack of direct contextual evidence. Hence, this paper presents analyses of 10 Li tripods from six sites in the Chifeng area of Northeast China, all of which can be dated from their excavation contexts to the Lower Xiajiadian cultural period (3,900–3,400 cal a B.P.). The interior and exterior surfaces of the tripods were analyzed using starch grain analysis, phytolith analysis and microfossil charcoal analysis. A total of 133 starch grains were recovered, of which 111 (83.46%) were found on 80% of the interior surfaces examined. Further analysis found that these starch grains had damage features specifically gelatinised characteristics, which were consistent with the starch grains that had been boiled in our cooking simulations. In addition, there were obvious soot traces on the surfaces of the tripods, 2,835 microfossil charcoal grains not completely burned were identified, and 70% of the exterior surface samples had a higher frequency of contact with fire. These findings serve to confirm that Li tripods were used in the cooking of food. Of the 133 starch grains found, only 62 could be identified to species level. These were foxtail millet (Setaria italica) and broomcorn millet (Panicum milliaceum) and plants from Triticeae taxa, as well as roots and tubers. The 3,424 phytoliths recovered from the 10 tripods were found to belong to the Panicoideae and Pooideae genera, of which the husks from foxtail and broomcorn millets from the Panicoideae genus accounted for 6.19% of the total. These results indicate that millets, the Triticeae, roots, and tubers, in addition to plants from Panicoideae and Pooideae genera, were utilized in the Chifeng area of Northeast China during the Bronze Age. This study deepens our understanding of the local subsistence patterns and the social context of early Bronze age civilization in the region.

Northern Shaanxi is important in understanding the ancient use and northward spread of foxtail millet (Setaria italica) and broomcorn millet (Panicum miliaceum). Nonetheless, due to the lack of millet remains, AMS radiocarbon data, and environmental background, the emergence, crop structure, and environmental factors of millet use in northern Shaanxi remain ambiguous. To address this knowledge gap, a systematic survey was conducted along the Beiluo River. Forty-two relic units at 19 Neolithic sites were selected for analysis through phytolith, AMS radiocarbon dating, and spatio-temporal approaches. Phytolith and AMS radiocarbon dating analyses traced the utilization of millets in the Beiluo River to 6280 cal. BP. In addition, broomcorn millet was more prevalent than foxtail millet during the Neolithic period, although the prevalence of the latter increased during the late Longshan period. Spatio-temporal analysis demonstrated that millets initially appeared in the Beiluo River during the Yangshao period, gradually moving away during the Longshan period, which was probably first related to the nearest rivers and then the spread of cattle and sheep. However, the millet cultivation altitude remained at 1400 m throughout the Yangshao and Longshan periods. Collectively, these findings provide evidence for the use and northward spread of millets in northwest China.

MiR-21-5p is one of the most common oncogenic miRNAs that is upregulated in many solid cancers by inhibiting its target genes at the posttranscriptional level. However, the upstream regulatory mechanisms of miR-21-5p are still not well documented in cancers. Here, we identify a super-enhancer associated with the MIR21 gene (MIR21-SE) by analyzing the MIR21 genomic regulatory landscape in head and neck squamous cell carcinoma (HNSCC). We show that the MIR21-SE regulates miR-21-5p expression in different HNSCC cell lines and disruption of MIR21-SE inhibits miR-21-5p expression. We also identified that a key transcription factor, FOSL1 directly controls miR-21-5p expression by interacting with the MIR21-SE in HNSCC. Moreover, functional studies indicate that restoration of miR-21-5p partially abrogates FOSL1 depletion-mediated inhibition of cell proliferation and invasion. Clinical studies confirmed that miR-21-5p expression is positively correlated with FOSL1 expression. These findings suggest that FOSL1-SE drives miR-21-5p expression to promote malignant progression of HNSCC

Abstract Although ErbB2-targeted therapeutics have significantly improved ErbB2+ breast cancer patient outcomes, therapeutic resistance remains a significant challenge. Therefore, the development of novel ErbB2-targeting strategies is necessary. Importantly, ErbB2 is a sensitive client protein of heat shock protein 90 (HSP90), which regulates client protein folding, maturation, and stabilization. HSP90 inhibition provides an alternative therapeutic strategy for ErbB2-targeted degradation. In particular, ganetespib, a novel HSP90 inhibitor, is a promising agent for ErbB2+ cancers. Nevertheless, the anti-cancer efficacy and clinical application of ganetespib for ErbB2+ breast cancer is largely unknown. In our study, we examined the anti-cancer effects of ganetespib on ErbB2+ BT474 and SKBR3 breast cancer cells, and isogenic paired cancer cell lines with lentivirus-mediated ErbB2 overexpression. Ganetespib potently inhibited cell proliferation, cell cycle progression, survival, and activation/phosphorylation of ErbB2 and key downstream effectors in ErbB2+ breast cancer cells. Moreover, ganetespib decreased the total protein levels of HSP90 client proteins and reduced ErbB2 protein half-life. ErbB2-overexpressing cancer cells were also more sensitive to ganetespib-mediated growth inhibition than parental cells. Ganetespib also strikingly potentiated the inhibitory effects of lapatinib in BT474 and SKBR3 cells. Ultimately, our results support the application of ganetespib-mediated HSP90 inhibition as a promising therapeutic strategy for ErbB2+ breast cancer.

Resistance to CDK4/6 inhibitors (CDKis) is emerging as a clinical challenge. Identification of the factors contributing to CDKi resistance, with mechanistic insight, is of pivotal significance. Recent studies linked aberrant FGFR signaling to CDKi resistance. However, detailed mechanisms are less clear. Based on control and FGFR1 overexpressing luminal A cell line models, we demonstrated that FGFR1 overexpression rendered the cells resistant to palbociclib. FGFR1 overexpression abolished palbociclib-mediated cell cycle arrest, as well as the attenuated palbociclib-induced inhibition of G1/S transition regulators (pRb, E2F1, and cyclin D3) and factors that promote G2/M transition (cyclin B1, cdc2/CDK1, and cdc25). Importantly, FGFR1-induced palbociclib resistance was associated with promotion of cancer cell stemness and the upregulation of Wnt/β-catenin signaling. We found that palbociclib may function as an ER agonist in MCF-7/FGFR1 cells. Upregulation of the ER-mediated transcription in MCF-7/FGFR1 cells was associated with ERα phosphorylation and enhanced receptor tyrosine kinase signaling. The combination of palbociclib with FGFR-targeting AZD4547 resulted in remarkable synergistic effects on MCF-7/FGFR1 cells, especially for the inhibition of cancer cell stemness. Our findings of FGFR1-induced palbociclib resistance, promotion of cancer stem cells and associated molecular changes advance our mechanistic understanding of CDKi resistance, which will facilitate the development of strategies targeting CDKi resistance in breast cancer treatment.

Our studies investigating the existence of tumor-initiating cell (TIC) populations in human esophageal squamous cell carcinoma (ESCC) had identified a subpopulation of cells isolated from ESCC patient-derived tumor specimens marked by an ALDHbri+ phenotype bear stem cell-like features. Importantly, KDM4C, a histone demethylase was enhanced in ALDHbri+ subpopulation, suggesting that strategies interfering with KDM4C may be able to target these putative TICs. In the present study, by genetic and chemical means, we demonstrated that, KDM4C blockade selectively decreased the ESCC ALDHbri+ TICs population in vitro and specifically targeted the TICs in ALDHbri+-derived xenograft, retarding engraftment. Subsequent studies of the KDM4C functional network identified a subset of pluripotency-associated genes (PAGs) and aldehyde dehydrogenase family members to be preferentially down-regulated in KDM4C inhibited ALDHbri+ TICs. We further supported a model in which KDM4C maintains permissive histone modifications with a low level of H3K9 methylation at the promoters of several PAGs. Moreover, ectopic expression of SOX2 restored KDM4C inhibition-dependent ALDHbri+ TIC properties. We further confirmed these findings by showing that the cytoplasmic and nuclear KDM4C staining increased with adverse pathologic phenotypes and poor patient survival. Such staining pattern of intracellular KDM4C appeared to overlap with the expression of SOX2 and ALDH1. Collectively, our findings provided the insights into the development of novel therapeutic strategies based on the inhibition of KDM4C pathway for the eliminating of ESCC TIC compartment.

Exposure to bisphenol A (BPA), an endocrine-disrupting compound, is associated with increased risk of estrogen-related diseases, including estrogen receptor-positive (ER+) breast cancer. Although bisphenol analogs, i.e. bisphenol AF (BPAF), have replaced BPA in industrial settings, increasing data indicate that these alternatives may have similar or even more potent estrogenic effects. As such, BPAF exhibits increased ER binding affinities than BPA in biochemical assays. However, preclinical studies exploring the effects of BPAF on ER+ breast cancer are missing mechanistic data. Thus, we aimed to characterize the effects of BPAF on MCF-7 and T47D ER+ breast cancer cells with mechanistic insight. We found that BPAF promoted cell growth and cell cycle progression concurrently with BPAF-induced ERα transcriptional activity and ER-RTK signaling activation. ER signaling blockage revealed that BPAF-induced cell proliferation and ER-RTK crosstalk were ER-dependent. Gene expression data demonstrated that AREG is a sensitive target of BPAF in our in vitro models. Importantly, we determined that AREG upregulation is necessary for BPAF-induced cellular responses. Ultimately, our novel finding that AREG mediates BPAF-induced ER-RTK crosstalk in ER+ breast cancer cells supports future studies to characterize the impact of BPAF on human ER+ breast cancer risk and to assess the safety profile of BPAF.

The process of rice domestication has been studied for decades based on changing morphological characteristics in assemblages of both macroremains, such as charred seeds and spikelet bases, and microremains, such as phytoliths, esp. bulliform and double-peaked phytoliths. The applicability of these indicators in determining if a specific assemblage is wild or domesticated, however, is rarely discussed. To understand the significance of these indicators in the determination of domestication, we collected 38 archaeological samples from eight Neolithic sites, dating from 10-2ka BP, in the lower Yangtze River region to analyze and compare the changes of these different indicators over eight thousand years. The data demonstrate that the comprehensive analysis of multiple indicators may be the best method to study the process of rice domestication developed thus far. An assemblage of rice remains can be identified as domesticated forms if they meet the following criteria simultaneously: 1) the proportion of domesticated-type bulliform phytoliths is more than 73%; and 2) the proportion of domesticated-type rice spikelet bases is higher than 75%. Furthermore, we found that each indicator tends to change steadily and gradually over time, and each stabilized at a different time, suggesting that the characteristics of domesticated rice developed slowly and successively. Changes of multiple indicators during the period between 10,000-2,000 yr BP indicate that the process of rice domestication in the lower Yangtze River region lasted as long as ca. 6,000 years during the Neolithic, and can be divided into three stages with the turning points in the middle Hemudu-late Majiabang culture (6,500-5,800yr BP) and the late Liangzhu culture (4,600-4,300yr BP).

Poor preservation of plant macroremains in the acid soils of southern subtropical China has hampered understanding of prehistoric diets in the region and of the spread of domesticated rice southwards from the Yangtze River region. According to records in ancient books and archaeological discoveries from historical sites, it is presumed that roots and tubers were the staple plant foods in this region before rice agriculture was widely practiced. But no direct evidences provided to test the hypothesis. Here we present evidence from starch and phytolith analyses of samples obtained during systematic excavations at the site of Xincun on the southern coast of China, demonstrating that during 3,350-2,470 aBC humans exploited sago palms, bananas, freshwater roots and tubers, fern roots, acorns, Job's-tears as well as wild rice. A dominance of starches and phytoliths from palms suggest that the sago-type palms were an important plant food prior to the rice in south subtropical China. We also believe that because of their reliance on a wide range of starch-rich plant foods, the transition towards labour intensive rice agriculture was a slow process.

While p73 overexpression has been associated with increased apoptosis in cancer tissues, p73 overexpressing tumors appear to be of high grade malignancy. Why this putative tumor suppressor is overexpressed in cancer cells and what the function of overexpressed p73 is in breast cancers are critical questions to be addressed. By investigating the effect of p53 inactivation on p73 expression, we found that both protein and mRNA levels of TAp73 were increased in MCF-7/p53siRNA cells, MCF-7/p53mt135 cells and HCT-116/p53-/- cells, as compared to wild type control, suggesting that p53 inactivation by various forms upregulates p73. We showed that p53 knockdown induced p73 was mainly regulated at the transcriptional level. However, although p53 has a putative binding site in the TAp73 promoter, deletion of this binding site did not affect p53 knockdown mediated activation of TAp73 promoter. Chromatin immuno-precipitation (ChIP) data demonstrated that loss of p53 results in enhanced occupancy of E2F-1 in the TAp73 promoter. The responsive sequence of p53 inactivation mediated p73 upregulation was mapped to the proximal promoter region of the TAp73 gene. To test the role of E2F-1 in p53 inactivation mediated regulation of p73 transcription, we found that p53 knockdown enhanced E2F-1 dependent p73 transcription, and mutations in E2F-1 binding sites in the TAp73 promoter abrogated p53 knockdown mediated activation of TAp73 promoter. Moreover, we demonstrated that p21 is a mediator of p53-E2F crosstalk in the regulation of p73 transcription. We concluded that p53 knockdown/inactivation may upregulate TAp73 expression through E2F-1 mediated transcriptional regulation. p53 inactivation mediated upregulation of p73 suggests an intrinsic rescuing mechanism in response to p53 mutation/inactivation. These findings support further analysis of the correlation between p53 status and p73 expression and its prognostic/predictive significance in human cancers.

The microstructure and mechanical properties of Al-Cu-Li alloy with different aging processes have been investigated. The experimental results indicate that increasing aging temperature enhances the precipitation kinetics of the alloy, which is beneficial for T1 phase precipitation. The average size of δ' phase is decreased from 18.2 to 11.6 nm when aging process changes from 200 °C singlestage aging to 150 °C/200 °C two-stage aging. The two-stage aging can effectively suppress the coarsening of δ' phase because T1 phase competes with δ' phase for Li atoms. The past researches have pointed out that T1 phase thickens when aging temperature exceeds 190 °C. However, the results indicate that two-stage aging can not only retard thickening but also increase number density of T1 phase. The alloy reaches maximum strength in two-stage aging, and the ultimate tensile strength, yield strength, and elongation are 415 MPa, 376 MPa, and 5.9%, respectively. When the diameter of T1 phase reaches a critical value, the strengthening mechanism of T1 phase has changed from shear mechanism to bypass mechanism. The diameter distribution range of T1 phase is large in this paper, and the strengthening mechanism of T1 phase is a mixed strengthening mechanism of shear mechanism and bypass mechanism. [ABSTRACT FROM AUTHOR]

The present study aimed to assess the expression of endoplasmic reticulum oxidoreductin-1-like (ERO1L) in gastric cancer and determine its association with patient prognosis. A total of 105 patients with gastric cancer undergoing radical gastrectomy were selected for the current study. Gastric cancer tissues (the observation group) and normal gastric tissue adjacent to the carcinoma (the control group) were resected from patients. Levels of ERO1L mRNA and protein in tumor tissues and adjacent tissues were detected using reverse transcription-quantitative polymerase chain reaction, western blotting and immunohistochemistry. Patients were divided into two groups: A positive group and negative group, according to the expression of ERO1. The expression of ERO1L in gastric cancer and its association with patient prognosis was analyzed. Levels of ERO1 mRNA and protein in gastric cancer were significantly higher than those of adjacent tissues (P<0.05). Immunohistochemical analysis demonstrated that there were 22 patients exhibiting negative expression of ERO1L and 83 patients exhibiting positive expression of ERO1L. The cumulative recurrence rates over 3 years in patients with positive expression of ERO1L were significantly higher than in patients with negative expression of ERO1L (P<0.05); the cumulative survival rates over 3 years in patients with positive expression of ERO1L were significantly lower than those of patients with negative expression of ERO1L (P<0.05). Thus, the current study determined that ERO1L was highly expressed in gastric cancer tissue. The high expression of ERO1L was associated with adverse prognoses in patients with gastric cancer. ERO1L may therefore be a therapeutic target for the prevention of gastric cancer. [ABSTRACT FROM AUTHOR]

While the possibility of indigenous rice cultivation cannot be entirely ruled out, there is increasing evidence suggesting that rice farming was introduced to South China during the late-Holocene. However, determination of the exact timing of the spread of rice farming to South China is fraught with the lack of reliable radiocarbon dates. In this article, we present 15 new AMS 14C dates of charred plant remains recovered from late-Holocene sites of Shixia and Guye in Guangdong Province of South China. Our new AMS 14C dates suggest a later arrival of rice farming in the Pearl River Delta than previously thought. These new AMS 14C dates will shed new lights to an improved understanding of the environmental background and ecology of the southward spread of rice farming. [ABSTRACT FROM AUTHOR]

The potential contamination of ancient residues from both modern plant sources and sediments adjacent to archaeological contexts can complicate interpretation in the field of starch grain analysis, thus affecting the sustainable use of the method in archaeobotany. In this study, we examined two potential sources of contamination at a wheat field in Shandong Province and a maize field in Beijing, the Nanzhuangtou site in Hebei Province and the Zhuannian site in Beijing in Northern China. Surface soils from active farmland and its surrounds, as well as deposits from clearly-defined cultural layers, overlying layers, and underlayers at the archaeological sites were subjected to starch grain analysis. No starches were recovered from any of the 16 surface soil samples from fields of wheat and maize, or their environs. This outcome indicates that starches do not preserve well in active surface soils. Further results from the analysis of 33 samples from the two sites demonstrate that starches do not occur in either the overlying layers or underlayers of cultural deposits. Thus, starch grains extracted from the surface residues of artifacts were not deposited from adjacent sediments after the artifacts were abandoned or buried. Further, cultural sediments contained fewer starch grains than the surfaces of artifacts in the same horizon. Thus, if any starch grains on the surfaces of tools are the result of contamination, ancient cultural sediments are the primary source. In conclusion, we offer insights for the prevention of misinterpretation of extraneous residues and sustainable development for the use of starch grain analysis. [ABSTRACT FROM AUTHOR]

Background: Metformin, an FDA-approved drug for the treatment of Type II diabetes, has emerged as a promising anti-cancer agent. Other biguanide analogs, including buformin and phenformin, are suggested to have similar properties. Although buformin was shown to reduce mammary tumor burden in carcinogen models, the anti-cancer effects of buformin on different breast cancer subtypes and the underlying mechanisms remain unclear. Therefore, we aimed to investigate the effects of buformin on erbB-2-overexpressing breast cancer with in vitro and in vivo models. Methods: MTT, cell cycle, clonogenic/CFC, ALDEFLUOR, tumorsphere, and Western blot analyses were used to determine the effects of buformin on cell growth, stem cell populations, stem cell-like properties, and signaling pathways in SKBR3 and BT474 erbB-2-overexpressing breast cancer cell lines. A syngeneic tumor cell transplantation model inoculating MMTV-erbB-2 mice with 78617 mouse mammary tumor cells was used to study the effects of buformin (1.2 g buformin/kg chow) on tumor growth in vivo. MMTV-erbB-2 mice were also fed buformin for 10 weeks, followed by analysis of premalignant mammary tissues for changes in morphological development, mammary epithelial cell (MEC) populations, and signaling pathways. Results: Buformin significantly inhibited SKBR3 and BT474 cell growth, and in vivo activity was demonstrated by considerable growth inhibition of syngeneic tumors derived from MMTV-erbB-2 mice. In particular, buformin suppressed stem cell populations and self-renewal in vitro, which was associated with inhibited receptor tyrosine kinase (RTK) and mTOR signaling. Consistent with in vitro data, buformin suppressed mammary morphogenesis and reduced cell proliferation in MMTV-erbB-2mice. Importantly, buformin decreased MEC populations enriched with mammary reconstitution units (MRUs) and tumor-initiating cells (TICs) from MMTV-erbB-2 mice, as supported by impaired clonogenic and mammosphere formation in primary MECs. We further demonstrated that buformin-mediated in vivo inhibition of MEC stemness is associated with suppressed activation of mTOR, RTK, ER, and β-catenin signaling pathways. Conclusions: Overall, our results provide evidence for buformin as an effective anti-cancer drug that selectively targets TICs, and present a novel prevention and/or treatment strategy for patients who are genetically predisposed to erbB-2-overexpressing breast cancer. [ABSTRACT FROM AUTHOR]

Background: Although chemopreventative agents targeting the estrogen/estrogen receptor (ER) pathway have been effective for ER+ breast cancers, prevention of hormone receptor-negative breast cancers, such as Her2/erbB-2 + breast cancers, remains a significant issue. Previous studies have demonstrated that administration of EGFR/ erbB-2-targeting lapatinib to MMTV-erbB-2 transgenic mice inhibited mammary tumor development. The prevention, however, was achieved by prolonged high dose exposure. The tolerance to high dose/long-term drug administration may hinder its potential in clinical settings. Therefore, we aimed to test a novel, short-term chemopreventative strategy using lapatinib during the premalignant risk window in MMTV-erbB-2 mice. Methods: We initially treated cultured cells with lapatinib to explore the anti-proliferative effects of lapatinib in vitro. We used a syngeneic tumor graft model to begin exploring the in vivo anti-tumorigenic effects of lapatinib in MMTV-erbB-2 mice. Then, we tested the efficacy of brief exposure to lapatinib (100 mg/kg/day for 8 weeks), beginning at 16 weeks of age, in the prevention of mammary tumor development in MMTV-erbB-2 mice. Results: In the syngeneic tumor transplant model, we determined that lapatinib significantly inhibited tumor cell proliferation. Furthermore, we demonstrated that short-term lapatinib exposure resulted in life-long protective effects, as supported by increased tumor latency in lapatinib-treated mice compared to the control mice. We further established that delayed tumor development in the treated mice was preceded by decreased BrdU nuclear incorporation and inhibited mammary morphogenesis. Molecular analysis indicated that lapatinib inhibited phosphorylation and expression of EGFR, erbB-3, erbB-2, Akt1, and Erk1/2 in premalignant mammary tissues. Also, lapatinib drastically inhibited the phosphorylation and expression of ERa and the transcription of ER target genes in premalignant mammary tissues. We also determined that lapatinib suppressed the stemness of breast cancer cell lines, as evidenced by decreased tumorsphere formation and ALDH+ cell populations. Conclusions: Taken together, these data demonstrate that brief treatment with EGFR/erbB-2-targeting agents before the onset of tumors may provide lifelong protection from mammary tumors, through the concurrent inhibition of erbB-2 and ER signaling pathways and consequential reprogramming. Our findings support further clinical testing to explore the benefit of shorter lapatinib exposure in the prevention of erbB-2-mediated carcinogenesis. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the expression of Golgi phosphoprotein/3 (GOLPH3) protein in colon cancer tissues and the association with the prognosis of patients. In total, 98 patients with colon cancer admitted to The First Affiliated Hospital of Henan University of Science and Technology for surgery between June 2011 and June 2013 were taken as the observation group. In addition, 15 healthy individuals, determined by enteroscopy, were taken as the control group. The expressions of GOLPH3 mRNA and protein were detected by reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. The patients were divided into GOLPH3-positive and GOLPH3-negative groups according to the expression of GOLPH3. The expression of GOLPH3 in colon cancer and its association with the prognosis of patients was analyzed. The expression of GOLPH3 mRNA and protein in colon cancer tissues was significantly increased compared with normal colon mucosa (P<0.05); among the tissues, GOLPH3 was not expressed in 29 patients and positively expressed in 69 patients. The expression of GOLPH3 was negatively associated with the tumor differentiation degree, and positively associated with tumor invasion depth, lymph node metastasis and clinical stages in GOLPH3-positive patients. The cumulative recurrence rates at 1, 2 and 3 years were significantly lower in GOLPH3-negative patients (P<0.05). The survival rates at 1, 2 and 3 years in the GOLPH3-positive group were significantly higher than that of the GOLPH3-negative patients (P<0.05). In conclusion, the positive expression of GOLPH3 mRNA and protein in colon cancer tissue was significantly increased compared with the control group. GOLPH3 expression was closely associated with the pathological features, consisting of tissue typing, clinical stage, degree of tumor invasion and lymph node metastasis, and GOLPH3 expression. Patients with GOLPH3 overexpression also had a poor prognosis. [ABSTRACT FROM AUTHOR]

Background: Mounting evidence suggests a causal relationship between specific bacterial infections and the development of certain malignancies. However, the possible role of the keystone periodontal pathogen, Porphyromonas gingivalis, in esophageal squamous cell carcinoma (ESCC) remains unknown. Therefore, we examined the presence of P. gingivalis in esophageal mucosa, and the relationship between P. gingivalis infection and the diagnosis and prognosis of ESCC. Methods: The presence of P. gingivalis in the esophageal tissues from ESCC patients and normal controls was examined by immunohistochemistry using antibodies targeting whole bacteria and its unique secreted protease, the gingipain Kgp. qRT-PCR was used as a confirmatory approach to detect P. gingivalis 16S rDNA. Clinicopathologic characteristics were collected to analyze the relationship between P. gingivalis infection and development of ESCC. Results: P. gingivalis was detected immunohistochemically in 61 % of cancerous tissues, 12 % of adjacent tissues and was undetected in normal esophageal mucosa. A similar distribution of lysine-specific gingipain, a catalytic endoprotease uniquely secreted by P. gingivalis, and P. gingivalis 16S rDNA was also observed. Moreover, statistic correlations showed P. gingivalis infection was positively associated with multiple clinicopathologic characteristics, including differentiation status, metastasis, and overall survival rate. Conclusion: These findings demonstrate for the first time that P. gingivalis infects the epithelium of the esophagus of ESCC patients, establish an association between infection with P. gingivalis and the progression of ESCC, and suggest P. gingivalis infection could be a biomarker for this disease. More importantly, these data, if confirmed, indicate that eradication of a common oral pathogen could potentially contribute to a reduction in the overall ESCC burden. [ABSTRACT FROM AUTHOR]

Background: An increasing body of evidence indicates that miRNAs have a critical role in carcinogenesis and cancer progression; however, the role of miRNAs in the tumorigenesis of adencarcinoma of gastric esophageal junction (AGEJ) remains largely unclear. Methods: The SGC7901 and BGC-823 gastric cancer cell lines were used. The expressions of miR-645 and IFIT2 (Interferon-induced protein with tetratricopeptide repeats 2) were examined by qRT-PCR, The expressions of IFIT2 was examined by western blotting and immunohistochemistry assay. The cell apoptosis was determined by FACS. MiR-645 inhibitor, mimics and plasmid-IFIT2 transfections were performed to study the loss- and gain-function. Caspase-3/7 activity was examined by caspase-3/7 assay. Results: In the present study, we have reported an increased expression of miR-645 in AGEJ clinical specimens compared with paired non-cancerous tissues. We also observed a significant miR-645 up-regulation in two gastric cancer (GC) cell lines, SGC7901 and BGC-823, which were used as cell models because there was no available AGEJ cell lines established to date. We found that inhibition of miR-645 could sensitize dramatically SGC7901 and BGC-823 cells to both serum starvation- and chemotherapeutic drug-induced apoptosis by up-regulating IFIT2, a mediator of apoptosis via a mitochondrial pathway, with a potential binding site for miR-645 in its mRNA's 3'UTR. Further investigation exhibited that IFIT2 expression decreases in SGC7901 and BGC-823 cells and AGEJ tissues. IFIT2 ectopic expression leads to promotion of cell apoptosis, indicating that IFIT2 may function as a suppressor in the development of AGEJ. Furthermore, inhibition of miR-645 induces up-regulation of IFIT2 and increased caspase-3/7 activity compared with control groups. Conclusions: Our data suggest that miR-645 functions as an oncogene in human AGEJ by, at least partially through, targeting IFIT2 [ABSTRACT FROM AUTHOR]

While p73 overexpression has been associated with increased apoptosis in cancer tissues, p73 overexpressing tumors appear to be of high grade malignancy. Why this putative tumor suppressor is overexpressed in cancer cells and what the function of overexpressed p73 is in breast cancers are critical questions to be addressed. By investigating the effect of p53 inactivation on p73 expression, we found that both protein and mRNA levels of TAp73 were increased in MCF- 7/p53siRNA cells, MCF-7/p53mt135 cells and HCT-116/p532/2 cells, as compared to wild type control, suggesting that p53 inactivation by various forms upregulates p73. We showed that p53 knockdown induced p73 was mainly regulated at the transcriptional level. However, although p53 has a putative binding site in the TAp73 promoter, deletion of this binding site did not affect p53 knockdown mediated activation of TAp73 promoter. Chromatin immuno-precipitation (ChIP) data demonstrated that loss of p53 results in enhanced occupancy of E2F-1 in the TAp73 promoter. The responsive sequence of p53 inactivation mediated p73 upregulation was mapped to the proximal promoter region of the TAp73 gene. To test the role of E2F-1 in p53 inactivation mediated regulation of p73 transcription, we found that p53 knockdown enhanced E2F-1 dependent p73 transcription, and mutations in E2F-1 binding sites in the TAp73 promoter abrogated p53 knockdown mediated activation of TAp73 promoter. Moreover, we demonstrated that p21 is a mediator of p53-E2F crosstalk in the regulation of p73 transcription. We concluded that p53 knockdown/inactivation may upregulate TAp73 expression through E2F-1 mediated transcriptional regulation. p53 inactivation mediated upregulation of p73 suggests an intrinsic rescuing mechanism in response to p53 mutation/inactivation. These findings support further analysis of the correlation between p53 status and p73 expression and its prognostic/predictive significance in human cancers. [ABSTRACT FROM AUTHOR]

Electric-field control of magnetism is now an attractive trend to approach a new kind of fast, low-power-cost memory device. In this work, we report a strong non-volatile electric control of magnetism in an Fe–Al/Pb(Mg1/3Nb2/3)O3–PbTiO3 heterostructure. In this system, a 90° rotation of the in-plane uniaxial magnetic anisotropy is exhibited during the increase of the external electric field, which means the easy axis turns into a hard axis and the hard axis turns into an easy one. Additionally, a non-volatile switch of the remanence is observed after a sweeping of the electric field from 0 kV cm−1 to  ±  10 kV cm−1, then back to 0 kV cm−1. More interestingly, a 20% non-volatile magnetic state tuning driven by individual pulse electric fields is shown in contrast to large tuning up to 120% caused by pulse electric fields with small assistant pulse magnetic fields, which means a 180° reverse of the magnetization. These remarkable behaviors demonstrated in this heterostructure reveal a promising potential application in magnetic memory devices mediated by electric fields. [ABSTRACT FROM AUTHOR]