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Simple Summary: The adjuvant treatment for early-stage endometrial cancer (EC) has remained an intractable problem in clinical practice. Although several risk classification strategies have been proposed to guide precise treatment, a significant proportion of patients are still overtreated, especially patients with high-intermediate-risk (HIR) early-stage EC. Here, we compared the survival outcomes between different adjuvant radiotherapy modes in patients with HIR EC defined by three primarily-used criteria, based on multicenter data, to provide further evidence for the adjuvant treatment choices for HIR patients. This study revealed multicentric utilization trends for different radiotherapy (RT) modes for the first time. It confirmed that pelvic external beam radiation therapy (EBRT) showed a survival advantage over vaginal brachytherapy (VBT) alone only in selected patients with HIR. This study aimed to compare the outcomes of RT modalities among patients who met different HIR criteria based on multicentric real-world data over 15 years. The enrolled patients, who were diagnosed with FIGO I-II EC from 13 medical institutes and treated with hysterectomy and RT, were reclassified into HIR groups according to the criteria of GOG-249, PORTEC-2, and ESTRO-ESMO-ESGO, respectively. The trends in RT modes utilization were reviewed using the Man-Kendall test. The rate of VBT alone increased from zero in 2005 to 50% in 2015, which showed a significant upward trend (p < 0.05), while the rate of EBRT + VBT utilization declined from 87.5% to around 25% from 2005 to 2015 (p > 0.05). There were no significant differences in OS, DFS, LRFS, and DMFS between VBT alone and EBRT ± VBT in three HIR cohorts. Subgroup analyses in the GOG-249 HIR cohort showed that EBRT ± VBT had higher 5-year DFS, DMFS, and LRFS than VBT alone for patients without lymph node dissection (p < 0.05). Thus, VBT could be regarded as a standard adjuvant radiation modality for HIR patients. EBRT should be administrated to selected HIR patients who meet the GOG-249 criteria and did not undergo lymph node dissection. [ABSTRACT FROM AUTHOR]

While the close relationship between the brain system for speech processing and reading development is well‐documented in alphabetic languages, whether and how such a link exists in children in a language without systematic grapheme‐phoneme correspondence has not been directly investigated. In the present study, we measured Chinese children's brain activation during an auditory lexical decision task with functional magnetic resonance imaging. The results showed that brain areas distributed across the temporal and frontal lobes activated during spoken word recognition. In addition, the left occipitotemporal cortex (OTC) was recruited, especially under the real word condition, thus confirming the involvement of this orthographic‐related area in spoken language processing in Chinese children. Importantly, activation of the left temporoparietal cortex (TPC) in response to words and pseudowords was positively correlated with children's reading ability, thus supporting the salient role phonological processing plays in Chinese reading in the developing brain. Furthermore, children with higher reading scores also increasingly recruited the left anterior OTC to make decisions on the lexical status of pseudowords, indicating that higher‐skill children tend to search abstract lexical representations more deeply than lower‐skill children in deciding whether spoken syllables are real. In contrast, the precuneus was more related to trial‐by‐trial reaction time in lower‐skill children, suggesting that effort‐related neural systems differ among pupils with varying reading abilities. Taken together, these findings suggest a strong link between the neural correlates of speech processing and reading ability in Chinese children, thus supporting a universal basis underlying reading development across languages. [ABSTRACT FROM AUTHOR]

Background: Soil salinization is causing ecosystem degradation and crop yield reduction worldwide, and elucidation of the mechanism of salt-tolerant plants to improve crop yield is highly significant. Podocarpus macrophyllus is an ancient gymnosperm species with a unique environmental adaptation strategy that may be attributed to its lengthy evolutionary process. The present study investigated the physiological and molecular responses of P. macrophyllus plants to salt stress by analyzing its photosynthetic system and antioxidant enzyme activity. We also analyzed the differentially expressed genes (DEGs) in P. macrophyllus under salt stress using RNA sequencing and de novo transcriptome assembly. Results: Salt treatment significantly affected the photosynthetic system in P. macrophyllus seedlings, which decreased chlorophyll content, altered chloroplast ultrastructure, and reduced photosynthesis. The activities of antioxidant enzymes increased significantly following salt stress treatment. Transcriptome analysis showed that salt stress induced a large number of genes involved in multiple metabolic and biological regulation processes. The transcription levels of genes that mediate phytohormone transport or signaling were altered. K+ and Ca2+ transporter-encoding genes and the MYB transcription factor were upregulated under salt stress. However, the genes involved in cell wall biosynthesis and secondary metabolism were downregulated. Conclusion: Our research identified some important pathways and putative genes involved in salt tolerance in P. macrophyllus and provided clues for elucidating the mechanism of salt tolerance and the utilization of the salt tolerance genes of P. macrophyllus for crop improvement. [ABSTRACT FROM AUTHOR]

Background: For stage I to II high-risk endometrioid adenocarcinoma patients, the optimal adjuvant radiotherapy modality remains controversial. The present study sought to optimize the treatment of pelvic external beam radiation (EBRT) with/or vaginal brachytherapy (VBT) for high-risk endometrioid adenocarcinoma patients in multiple radiation oncology centers across China.Methods: This article retrospectively reviewed stage I to II patients with resected endometrioid adenocarcinoma treated at 13 radiation centers from 1999 to 2015. Patients were eligible if they had high-risk features (stage IB Grade 3 disease or stage II Grade 1-3 disease) on the basis of ESMO-ESGO-ESTRO risk group consensus.Results: A total of 218 patients were included. Fifty-one patients received EBRT, 25 patients received VBT, and 142 patients were administered EBRT combined with VBT. The three groups were comparable in baseline characteristics, except the proportion of stage IB and Grade 3 disease in the VBT group was significantly higher and their age was older. Survival analysis showed that OS, DFS, LRFS and DMFS were significantly different among the three groups. Two out of three groups were compared with each other, and results demonstrated that DFS, LRFS and DMFS were worse in the VBT group than in the EBRT or EBRT + VBT group. The 3-year OS rates were 95.2, 85.2 and 95.1% in the EBRT, VBT and EBRT + VBT groups, respectively (p = 0.043). There was no significant difference in survival outcomes between EBRT group and EBRT + VBT group. A propensity matching analysis was performed to eliminate group differences. The results demonstrated that DFS and LRFS were significantly improved in the pelvic radiation group compared to the VBT group. Distant failure accounted for most of the failure patterns. Patients in the VBT group had significantly increased local and regional recurrence rates than patients in the EBRT or EBRT + VBT group. Acute and chronic radiation-induced toxicities were well tolerated for all patients.Conclusion: For patients with postoperative stage I to II high-risk endometrioid adenocarcinoma, compared with VBT alone, radiotherapy modalities including EBRT significantly improved DFS, LRFS and DMFS with tolerable adverse effects. Overall survival was not significantly different between EBRT and EBRT + VBT modalities. [ABSTRACT FROM AUTHOR]

WRKY transcription factors are key regulators in regulating abiotic or biotic stress response in Arabidopsis. Previous studies showed that WRKY30 expression was induced by oxidative stress treatment, fungal elicitor, SA and ABA. However, functions of WRKY30 on viral defense are not well studied. Here, we found that Arabidopsis WRKY DNA binding protein 30 (WRKY30) plays essential roles in regulating Cucumber mosaic virus (CMV) resistance. The expression of WRKY30 was induced by CMV infection and wrky30 mutant displayed more susceptibility (including higher oxidative damages, induced reactive oxygen species synthesis and more PSII photochemistry compromise), while WRKY30 overexpression plants (WRKY30OX) exhibited more resistance to CMV infection. Moreover BRs-induced CMV tolerance is partly dependent on WRKY30. And WRKY30 expression increased after BL treatment. All these demonstrated that WRKY30 works as a positive regulator in plant CMV resistance process. • WRKY30 works as a positive regulator in plant CMV resistance process. • WRKY30 plays critical roles in alleviating photosystem damage after CMV infection. • Involvement of antioxidant system in WRKY30-mediated CMV defense. • WRKY30 regulates defense-associated genes expression in response to CMV. • BRs-induced CMV resistance is partially dependent on WRKY30. [ABSTRACT FROM AUTHOR]

Sepsis-induced ALI is marked by physiological, pathological, and biochemical irregularities caused by infection. Growth differentiation factor 3 (GDF3) is closely associated with the inflammatory response. Accumulating evidence has demonstrated a close relationship between GDF3 expression and the severity and prognosis of sepsis. However, the precise mechanism by which GDF3 protects against ALI induced by sepsis is still unclear. Following the intravenous administration of GDF3 in this research, we noted a rise in the survival rate, a decrease in the severity of histopathological damage as evaluated through HE staining, a decline in the count of inflammatory cells in bronchoalveolar lavage fluid (BALF), a reduction in the ratio of lung wet/dry (W/D) weight, and a noteworthy decrease in the levels of pro-inflammatory cytokines in both serum and BALF when compared to septic mice who underwent cecal ligation and puncture (CLP). These collective findings unequivocally indicate the protective effects of GDF3 against sepsis-induced ALI. In addition, the GDF3 group showed a significant reduction in the mRNA expression of Caspase-1 and NLRP3 when compared to the CLP group. Following this, we performed in vitro tests to confirm these discoveries and obtained comparable outcomes, wherein the administration of GDF3 notably decreased the levels of Caspase-1 and NLRP3 mRNA and protein in macrophages in comparison to the LPS group. Furthermore, GDF3 exhibited the capacity to reduce the secretion of inflammatory molecules from macrophages. By illuminating the mechanism by which GDF 3 regulates macrophages, this offers a theoretical basis for preventing and treating sepsis-induced ALI. [ABSTRACT FROM AUTHOR]

Summary: Mitochondrial alternative oxidase (AOX) is involved in a large number of plant physiological processes, such as growth, development and stress responses; however, the exact role of AOX in response to drought remains unclear. In our study, we provide solid evidences that the activated AOX capacity positively involved in ethylene‐induced drought tolerance, in tomato (Solanum lycopersicum), accompanied by the changing level of hydrogen peroxide (H2O2) and autophagy. In AOX1a‐RNAi plants, the ethylene‐induced drought tolerance was aggravated and associated with decreasing level of autophagy. The H2O2 level was relatively higher in AOX1a‐RNAi plants, whereas it was lower in AOX1a‐overexpressing (35S‐AOX1a‐OE) plants after 1‐(aminocarbonyl)‐1‐cyclopropanecarboxylic acid (ACC) pretreatment in the 14th day under drought stress. Interestingly, the accumulation of autophagosome was accompanied by the changing level of reactive oxygen species (ROS) in AOX transgenic tomato under drought stress whether or not pretreated with ACC. Pharmacological scavenging of H2O2 accumulation in AOX1a‐RNAi (aox19) stimulated autophagy acceleration under drought stress, and it seems that AOX‐dependent ROS signalling is critical in triggering autophagy. Lower levels of ROS signalling positively induce autophagy activity, whereas higher ROS level would lead to rapid programmed cell death (PCD), especially in ethylene‐mediated drought tolerance. Moreover, ethylene‐induced autophagy during drought stress also can be through ERF5 binding to the promoters of ATG8d and ATG18h. These results demonstrated that AOX plays an essential role in ethylene‐induced drought tolerance and also played important roles in mediating autophagy generation via balancing ROS level. [ABSTRACT FROM AUTHOR]

Objective: To investigate the combined predictive value of the preoperative serum cancer antigen 125 (CA125) level and age at diagnosis among patients with early‐stage endometrial cancer (EC) after initial treatment. Methods: We retrospectively analyzed data from patients with early‐stage EC from 1999 to 2015 in multiple institutions in China. All 447 patients received postoperative adjuvant radiotherapy for FIGO 2009 stage I and II EC with complete data on preoperative serum CA125 levels. All patients were divided into four groups according to the ESMO‐ESGO‐ESTRO risk classification. The predictive probability of 5‐year overall survival (OS) and the sensitivity and specificity of CA125 and age were calculated. Results: The median follow‐up time was 59 months (3–201 months). The 5‐year OS and disease‐free survival rates were 94.4% and 89.1%. Multivariate analysis showed that the preoperative CA125 level and age at diagnosis were independent prognostic factors for 5‐year OS. The area under the curve for CA125 combined with age at diagnosis for 5‐year OS was.692, and the corresponding sensitivity and specificity were 68.2% and 68.2% (p <.002), which were significantly better than the corresponding values for CA125 or age alone. After all 447 patients were divided into four groups according to CA125 combined with age, the 5‐year OS of the elderly and higher CA125 group was only 73.7%. Conclusions: Although preoperative CA125 had limited sensitivity in predicting the prognosis for early‐stage EC after initial treatment, it remains a useful serum marker for risk assessment of early‐stage EC. Combining CA125 with age may increase its predictive sensitivity. [ABSTRACT FROM AUTHOR]

Abstract: Orthographic influences in spoken word recognition have been previously examined in alphabetic languages. However, it is unknown whether orthographic information affects spoken word recognition in Chinese, which has a clean dissociation between orthography (O) and phonology (P). The present study investigated orthographic effects using event related potentials (ERPs) and an auditory lexical decision task. We manipulated the relationship between the phonology and orthography of the first syllable in each prime-target pair using the following four conditions: P+O+, P+O−, P−O+, P−O−. Importantly, we found significantly reduced N400 amplitudes when an item was preceded by an orthographically similar prime. In addition, these reduced N400 amplitudes were positively correlated with participants’ reading skill. The findings indicate that orthographic information is activated automatically during Chinese spoken word recognition, supporting the theory that there is a reciprocal connection between speech and print. [Copyright &y& Elsevier]

Abstract: The functional brain network of a bilingual''s first language (L1) plays a crucial role in shaping that of his or her second language (L2). However, it is less clear how L2 acquisition changes the functional network of L1 processing in bilinguals. In this study, we demonstrate that in bimodal (Chinese spoken-sign) bilinguals, the functional network supporting L1 production (spoken language) has been reorganized to accommodate the network underlying L2 production (sign language). Using functional magnetic resonance imaging (fMRI) and a picture naming task, we find greater recruitment of the right supramarginal gyrus (RSMG), the right temporal gyrus (RSTG), and the right superior occipital gyrus (RSOG) for bilingual speakers versus monolingual speakers during L1 production. In addition, our second experiment reveals that these regions reflect either automatic activation of L2 (RSOG) or extra cognitive coordination (RSMG and RSTG) between both languages during L1 production. The functional connectivity between these regions, as well as between other regions that are L1- or L2-specific, is enhanced during L1 production in bimodal bilinguals as compared to their monolingual peers. These findings suggest that L1 production in bimodal bilinguals involves an interaction between L1 and L2, supporting the claim that learning a second language does, in fact, change the functional brain network of the first language. [Copyright &y& Elsevier]

Abstract: Highly polar metabolites are abundant in human plasma. Analysis of these compounds by standard reverse-phase chromatography is difficult. Highly polar metabolites were extracted by a two-step method. They were analyzed by ultra-performance hydrophilic interaction chromatography (HILIC) coupled to quadrupole-time of flight mass spectrometer detection technology. The middle and low polar fraction were also analyzed using a standard C18 column. Data were extracted by Markerlynx, and analyzed by multivariate statistical methods to discriminate human plasma samples by sex and age. The results not only showed good classification of samples by sex and age, but also revealed new potential biomarkers not revealed by standard RPLC/MS analysis. This study showed that HILIC is an effective technique to analyze highly polar metabolites for metabonomic studies. [Copyright &y& Elsevier]

Nematanthus wettsteinii (Fritsch) H. E. Moore is one of the most popular ornamental species in China, and is known for its peculiar "goldfish" shape flower and is usually propagated by cuttings. This study aimed to establish in vitro protocols for N. wettsteinii regeneration. In this study, leaves and shoot-tips were used as explants, and the effects of adventitious shoot induction, rooting medium, and plant growth regulators (PGRs) on regeneration from explants were evaluated. Murashige and Skoog (MS) medium was used as the basic substrate. Among the PGRs tested, when leaves were used as explants, 0.1 mg L−1 α-naphthaleneacetic acid (NAA) and 2.0 mg L−1 thidiazuron (TDZ) induced the largest number of adventitious shoots (22.5 per leaf) with a 93.5% induction rate. When shoot-tips were used as explants, 3.0 mg L−1 benzyl adenine (BA) induced the fewest adventitious shoots (2.6 per shoot-tip), while 0.1 mg L−1 NAA and 2.0 mg L−1 TDZ yielded the largest number of adventitious shoot (20.3 per shoot-tip). The adventitious shoots were then transferred to MS medium containing NAA, BA, and gibberellin A3 (GA3) for shoot proliferation and elongation. When half-strength MS medium was supplemented with 0.3 mg L−1 indole-3-butyric acid (IBA), shoot rooting was essentially 100%. After transplanting the plantlets to garden soil mixed with river sand and vermiculite (1:1:1, v/v) substrate, 100% of the plantlets survived after 3 wk. These reliable regeneration protocols constitute a significant advance towards the large-scale propagation and conservation of this famous horticultural species. [ABSTRACT FROM AUTHOR]

Background: This study aimed to report clinical practice patterns of postoperative radiotherapy for stage I to II endometrial carcinoma (EC) patients treated in 13 Chinese medical centers. Methods: We included early stage EC patients treated by hysterectomy and adjuvant RT between 2003 and 2017 from 13 institutions. Patients were classified into 4 risk groups based on ESMO-ESGO-ESTRO recommendations (2014). Results: A total of 1,227 cases were analyzed. Along the 15 years of the study, an increasing tendency was found towards administration for vaginal brachytherapy (VBT) alone, while the proportion of external beam pelvic radiotherapy (EBRT) alone remained stable in the corresponding period. When radiation modalities were stratified by risk groups, proportion of VBT alone significantly increased in all risk groups. The higher the risk, the later VBT became the main adjuvant treatment modality. However, EBRT alone or with VBT remained the main adjuvant method for high-risk patients. There were 13 dose-fractionation schemes for VBT alone with the scheme of 30 Gy in 6 fractions prescribed at 0.5cm under the vaginal mucosa accounting for most. There were 17 schemes for VBT boost and the most common schedule was 10 Gy in 2 fractions. The upper 3–5cm part of vagina was the most frequent target. 89.6% of the practitioners performed two-dimensional VBT technique. The median dose for EBRT was 50 Gy. From 2003 to 2017, conventional radiotherapy was gradually replaced by three-dimensional conformal radiotherapy modality and intensity modulated radiotherapy. Conclusion: We report a significant shift from EBRT to VBT alone for high-intermediate-risk, intermediate-risk and low-risk EC patients from 2003 to 2017 while EBRT remained the main radiation modality for high-risk early stage patients. There has been remarkable heterogeneity among VBT dose fractionation schedules across China. Trial registration: The clinical trial ID was ChiCTR-PRC-17010712. It was authorized by the Institutional Review Board of Peking Union Medical College Hospital (N0. S-K139). [ABSTRACT FROM AUTHOR]

Purpose: To explore the prognostic factors and the optimal treatment modalities for patients with stage IVA laryngeal squamous cell carcinoma (LSCC), so as to improve the survival rate of patients. Methods: Patients with stage IVA LSCC between 2004 and 2019 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. We used competing risk models to build nomograms for predicting cancer-specific survival (CSS). The effectiveness of the model was assessed using the calibration curves and the concordance index (C-index). The above results were compared with the nomogram established by Cox regression analysis. The patients were grouped into low-risk and high-risk groups by competing risk nomogram formula. And the Kaplan–Meier (K–M) method and log-rank test were used to make sure that these groups had a survival difference. Results: Overall, 3612 patients were included. Older age, black race, a higher N stage, a higher pathological grade, and a larger tumor size were independent risk factors for CSS; married marital status, total/radical laryngectomy, and radiotherapy were protective factors. The C-index was 0.663, 0.633, and 0.628 in the train set and 0.674, 0.639, and 0.629 in the test set of the competing risk model, and 0.672, 0.640, and 0.634 in the traditional Cox nomogram for 1, 3, and 5 years. In overall survival and CSS, the prognosis of the high-risk group was poorer than that of the low-risk group. Conclusion: For patients with stage IVA LSCC, a competing risk nomogram was created to help screen risk population and guide clinical decision-making. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) represent a promising approach for the treatment of acute respiratory distress syndrome (ARDS). However, their low efficiency in homing to injured lung tissue limits their therapeutic effect. Prostaglandin E2 (PGE2) biosynthesis substantially enhances the inflammatory response of the tissue. Moreover, it also facilitates the migration of MSCs by activating the E-prostanoid 2 (EP2) receptor in vitro. Given these observations, it would seem reasonable that PGE2 might act as a chemokine to promote the migration of MSCs through activation of the EP2 receptor. Herein, we confirmed that PGE2 was significantly increased in lung tissue as a result of stimulation by LPS. In addition, we constructed a lentiviral vector carrying the EP2 gene, which was successfully transduced into MSCs (MSCs-EP2). Near-infrared imaging and immunofluorescence showed that compared with MSCs-GFP, MSCs-EP2 significantly enhanced MSC homing to injured lung tissue. Moreover, the diminished amounts of Evans blue in homogeneous lung parenchyma in vivo indicated, in comparison with MSCs-GFP, that MSCs-EP2 significantly decreased LPS-induced pulmonary vascular permeability. In addition, administration of MSCs-EP2 largely decreased the levels of interleukin-1β and tumor necrosis factor-α compared with that observed after administration of MSCs-GFP at both 24 and 72 hr. Our results suggested that treatment with MSCs-EP2 markedly enhanced MSC homing to damaged lung tissue and, in addition, improved both lung inflammation and permeability. Thus, MSCs and EP2 combination gene therapy could markedly facilitate MSC homing to areas of inflammation, representing a novel strategy for MSC-based gene therapy in inflammatory diseases. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is an acute and diffuse inflammatory lung injury in a short time, one of the common severe manifestations of the respiratory system that endangers human life and health. As an innate immune cell, macrophages play a key role in the inflammatory response. For a long time, the role of pulmonary macrophages in ARDS has tended to revolve around the polarization of M1/M2. However, with the development of single-cell RNA sequencing, fate mapping, metabolomics, and other new technologies, a deeper understanding of the development process, classification, and function of macrophages in the lung are acquired. Here, we discuss the function of pulmonary macrophages in ARDS from the two dimensions of anatomical location and cell origin and describe the effects of cell metabolism and intercellular interaction on the function of macrophages. Besides, we explore the treatments for targeting macrophages, such as enhancing macrophage phagocytosis, regulating macrophage recruitment, and macrophage death. Considering the differences in responsiveness of different research groups to these treatments and the tremendous dynamic changes in the gene expression of monocyte/macrophage, we discussed the possibility of characterizing the gene expression of monocyte/macrophage as the biomarkers. We hope that this review will provide new insight into pulmonary macrophage function and therapeutic targets of ARDS. [ABSTRACT FROM AUTHOR]

[Display omitted] • Melatonin can induce the downregulation of the MT 1 receptor. • MT 1 receptor internalization incurred by melatonin follows the canonical endolysosomal pathway. • The ubiquitin-specific protease 8 antagonizes the endocytic degradation of the MT 1 receptor. • The suppression of ubiquitin-specific protease 8 potentiates the cancer-inhibitory effects of melatonin in vitro. • Combination of USP8 inhibition and melatonin treatment effectively deters tumor growth in xenograft mouse models. The human genome encodes two melatonin receptors (MT 1 and MT 2) that relay melatonin signals to cellular interior. Accumulating evidence has linked melatonin to multiple health benefits, among which its anticancer effects have become well-established. However, the implications of its receptors in lung adenocarcinoma have so far remained incompletely understood. This study aims to investigate the response of the MT 1 receptor to melatonin treatment and its dynamic regulation by ubiquitin-specific protease 8 (USP8) in lung adenocarcinoma. The mRNA levels of MT 1 and MT 2 receptors were analyzed with sequencing data. The expression and localization of the MT 1 receptor with melatonin treatment were investigated by immunoblotting, immunofluorescence and confocal microscopy assays. Endocytic deubiquitylases were screened to identify MT 1 association. The effects of USP8 were assessed with shRNA-mediated knockdown and small molecule inhibitor. The combined efficacy of melatonin and USP8 suppression was also evaluated using xenograft animal models. Bioinformatic analysis revealed increased expression of the MT 1 receptor in lung adenocarcinoma tissues. Melatonin treatment leads to the downregulation of the MT 1 receptor in lung adenocarcinoma cells, which is attributed to receptor endocytosis and lysosomal degradation via the canonical endo -lysosomal route. USP8 negatively regulates the endocytic degradation of the MT 1 receptor incurred by melatonin exposure and thus protects lung adenocarcinoma cell growth. USP8 suppression by knockdown or pharmacological inhibition effectively deters cancer cell proliferation and sensitizes lung adenocarcinoma cells to melatonin in vitro. Furthermore, USP8 silencing significantly potentiates the anticancer effects of melatonin in xenograft tumor models. The MT 1 receptor responds to melatonin treatment and is endocytosed for lysosomal degradation that is counteracted by USP8. The inhibition of USP8 demonstrates tumor-suppressive effects and thus can be exploited as potential therapeutic strategy either as monotherapy or combined therapy with melatonin. [ABSTRACT FROM AUTHOR]

The metal tolerance protein (MTP) gene family plays an essential role in the transport of heavy metals, however the function of the MTP family in transporting lead (Pb) was still unclear in plants. In this study, we identified and characterized 12 ZmMTPs in the whole genome of maize. These ZmMTP genes were divided into three subfamilies in evolution, namely Zn-CDF, Zn/Fe-CDF, Mn-CDF subfamilies, which showed diverse expression patterns in different tissues of maize. Using gene-based association analyses, we identified a Pb accumulation-related MTP member in maize, ZmMTP11, which was located in plasma membrane and had the potential of transporting Pb ion. Under the Pb treatment, ZmMTP11 showed a generally decreased expression relative to the normal conditions. Heterologous expressions of ZmMTP11 in yeast, Arabidopsis, and rice demonstrated that ZmMTP11 enhanced Pb accumulation in the cells without affecting yeast and plant growth under Pb stress. Remarkably, the increased Pb concentration in the plant roots did not cause changes in Pb content in the shoots. Our study provides new insights into the genetic improvement of heavy metal tolerance in plants and contributes to bioremediation of Pb-contaminant soils. • Twelve ZmMTP genes were identified via whole-genome bioinformatics analysis in Zea mays L. • The ZmMTP11 was identified as a novel Pb accumulation-associated gene through gene-based association analysis. • The ZmMTP11 protein was identified to be localized in the plasma membrane. • Heterologous expression of ZmMTP11 increased Pb accumulation in yeast, Arabidopsis, and rice without affecting seedling growth under Pb stress. • Increased ZmMTP11 promoted maize adaption to Pb stress. [ABSTRACT FROM AUTHOR]

Previous neuroimaging studies have revealed that bilingualism induces both structural and functional neuroplasticity in the dorsal anterior cingulate cortex (dACC) and the left caudate nucleus (LCN), both of which are associated with cognitive control. Since these “control” regions should work together with other language regions during language processing, we hypothesized that bilingualism may also alter the functional interaction between the dACC/LCN and language regions. Here we tested this hypothesis by exploring the functional connectivity (FC) in bimodal bilinguals and monolinguals using functional MRI when they either performed a picture naming task with spoken language or were in resting state. We found that for bimodal bilinguals who use spoken and sign languages, the FC of the dACC with regions involved in spoken language (e.g. the left superior temporal gyrus) was stronger in performing the task, but weaker in the resting state as compared to monolinguals. For the LCN, its intrinsic FC with sign language regions including the left inferior temporo-occipital part and right inferior and superior parietal lobules was increased in the bilinguals. These results demonstrate that bilingual experience may alter the brain functional interaction between “control” regions and “language” regions. For different control regions, the FC alters in different ways. The findings also deepen our understanding of the functional roles of the dACC and LCN in language processing. [ABSTRACT FROM AUTHOR]

The dorso-lateral prefrontal cortex (DLPFC) and the anterior cingulate cortex (ACC) are two main regions that support bilingual language control during language production. Previous studies have suggested that the regions work together in language control processes. However, how they cooperate with each other during bilingual language production is far from clear. We addressed this issue by recruiting bimodal bilingual participants whose two languages could be separated at a neural level. Functional magnetic resonance imaging scans were acquired from the participants as they performed a dual-language production task and a spoken-production task. Dynamic causal modelling (DCM) was used to analyse the effective connectivity between the ACC and the DLPFC as well as the causal relationships among the control regions and language regions. We found that the ACC had positive effective connectivity to the DLPFC, left precentral gyrus and left superior temporal gyrus, while the DLPFC had negative effective connectivity to the other three regions. A similar pattern of effective connectivity between the control regions and language regions was also found in the spoken-production task. These results showed that the ACC may promote the production of the target language, while the DLPFC has an inhibitory effect in language production. The findings suggest an antagonistic relationship between the DLPFC and ACC that cooperatively ensures fluent language production in bilinguals. • We addressed how the control regions interact with the language regions during bilingual language production. •The anterior cingulate cortex promotes the production of the target language. •The dorso-lateral prefrontal cortex has inhibitory effects on other regions in the language control network. •Antagonistic and cooperative relationship between these control regions ensures fluent language production in bilinguals. [ABSTRACT FROM AUTHOR]

Background: This research aimed to provide an overview of the impact of adjuvant vaginal brachytherapy (VBT) and external beam pelvic radiotherapy (EBRT) with or without VBT on survival in stage I to II EC patients in China from a long-term multi-institutional analysis.Methods: We retrospectively analyzed stage I to II EC patients from 13 institutions treated between 2003 and 2015. All patients underwent surgical staging and received adjuvant RT. Patients were divided into groups of low-risk (LR), intermediate-risk (IR), high-intermediate-risk (HIR) and high-risk (HR). Survival statistics, failure pattern, and toxicity of different radiation modalities in different risk groups were analyzed.Results: A total of 1048 patients were included. HR disease represented 27.6%, HIR 17.7%, IR 27.7% and LR 27.1%, respectively. Endometrioid adenocarcinoma (EAC) and non-endometrioid carcinoma (NEC) accounted for 92.8 and 7.2%. A total of 474 patients received VBT alone and 574 patients received EBRT with or without VBT. As for EAC patients, the 5-year overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) rate was: 94.6, 90.4, 93.0 and 91.6%, respectively. For LR patients, EBRT (with or without VBT) seemed to be a risk factor. With the higher risk category, the survival benefit of EBRT gradually became remarkable. EBRT (with or without VBT) significantly increased DFS, LRFS and DMFS compared to VBT alone in the HR group (p < 0.05). Distant metastasis was the main failure pattern for all risk groups. As for NEC patients, the 5-year OS, DFS, LRFS and DMFS rate was: 93.4, 87.2, 91.7 and 89.3%, respectively. As for toxicity, EBRT (with or without VBT) significantly increased the incidence of grade 1-2 gastrointestinal, urinary, and hematological toxicity.Conclusions: For stage I to II EC patients, EAC accounted for the majority and had better prognosis than NEC. For EAC patients, VBT alone resulted in comparable survival to EBRT in the LR, IR and HIR groups, while EBRT significantly increased survival in the HR group. EBRT had higher rate of toxicity than VBT. [ABSTRACT FROM AUTHOR]

As a valuable medicinal plant, Salvia plebeia R. Brown (S. plebeia) belongs to the Lamiaceae family that has been subjected to over-exploitation in its natural habitat for phytochemical and pharmacological studies. The present study focuses on the development of a micropropagation protocol for sustainable propagation and conservation of S. plebeia. Direct organogenesis (from shoot tips and cotyledonary nodes explants) and globular bodies (GBs) induction (from hypocotyl explants) systems have been established in S. plebeia. Alternative collection methods need to be developed for the large-scale propagation of S. plebeia. In addition, roots as explants can also induce adventitious shoots via callus. The highest and number of regenerated shoots (7.0 ± 0.8) per shoot tips was obtained on Murashige and Skoog (MS) medium supplemented with a combination of 0.1 mg L−1 indole-3-acetic acid (IAA) and 1.0 mg L−1 6-benzyladenine (6-BA), the proliferation of shoots and shoots rooted were carried out on the same medium treatments almost synchronously. Similarly, MS medium supplemented with 0.1 mg L−1 IAA and 1.0 mg L−1 thidiazuron (TDZ) yielded the maximum number of shoots (37.5 ± 1.3) with 100% shoot sprouting frequency. Simultaneously, a protocol was developed for GB induction from hypocotyl explants, and it produced 17.4 GBs per explant with 82.7% response on MS medium supplemented with TDZ (1.0 mg L−1) and IAA (0.1 mg L−1), and produced GBs were characterized by globular, heart-shaped, and cotyledonary stages and successfully germinated on hormone-free MS medium, the developmental process of which was similar to that embryo. The acclimatized plantlets with well-developed root systems were successfully shifted to the natural soils with a 100% survival rate. Taken together, it is the foremost report on in vitro regeneration of S. plebeia; this work will facilitate in germplasm preservation and genetic transformation and provides necessary plant materials for various biotechnological and pharmaceutical applications. [ABSTRACT FROM AUTHOR]

Highlights: [•] HOXB9 is overexpressed in gliomas. [•] HOXB9 over expression had shorter survival time than down expression in gliomas. [•] HOXB9 stimulated the proliferation, migration and sphere formation of glioma cells. [•] Activation of TGF-β1 contributed to HOXB9-induced oncogenic activities. [ABSTRACT FROM AUTHOR]

Celosia argentea is a manganese (Mn) hyperaccumulator with high ornamental value and strong stress resistance. It is important to understand the molecular mechanism of tolerance to heavy metals of hyperaccumulators to improve the efficiency of phytoremediation. In this study, the effects of different Mn concentrations (0, 0.8, 3, and 10 mM) on physiological characteristics and molecular changes were determined. Low concentrations of Mn increased the growth of C. argentea , while high concentrations of Mn suppressed its growth, A concentration up to 3 mM did not affect the growth of C. argentea , and the highest transfer factor (TF) was 6.16. Oxidative damage of different Mn level treatments in C. argentea was verified through relative water content, electrolyte leakage, MDA content, H 2 O 2 content and superoxide contents. With an increase in Mn concentration, the contents of chlorophyll a, chlorophyll b, and carotenoids decreased. Our results indicated that low-concentration manganese treatment can reduce the reactive oxygen burst and MDA, soluble sugar and proline, making C. argentea have strong abiotic stress tolerance. The molecular mechanism of C. argentea after 10 mM Mn treatment was analysed through transcriptome analysis, and differentially expressed genes (DEGs) in these pathways were further verified by qRT PCR. Plant pathogen interactions, plant hormone signal transduction, the MAPK signalling pathway and the phenylpropanoid biosynthesis pathway were important in the response to Mn stress, and the heavy metal-associated isoprenylated plant protein, metal transporter Nramp, and zinc transporter play key roles in the strong ability of C. argentea to tolerate heavy metals. These results suggest that C. argentea exhibits strong manganese tolerance and provide new insight into the molecular mechanisms of plant responses to heavy metal stress. [Display omitted] • The physiology and transcriptome change of C. argentea under Mn stress were determined. • Low concentration of Mn treatment increased the growth while high concentration of Mn treatment suppressed the growth of C. argentea. • Mn stress induced oxidative and photosystem damage of C. argentea. • Nramp5, HIPP, zinc transport contribute to the excess Mn tolerance. [ABSTRACT FROM AUTHOR]

In vitro culture is employed as a means of producing plant materials from medicinal plants to meet the increasing demands of the market. Herein, we focused on an efficient protocol for organogenesis through two pathways in six explant types from Caryopteris terniflora Maxim (C. terniflora), a medicinal and ornamental plant. For direct organogenesis, the maximum number of shoots per internode explant (62.5) was achieved on Murashige and Skoog (MS) medium containing 3.0 mg L−1 thidiazuron (TDZ) and the maximum number of shoot tips per explant (45.5) was obtained by 1.5 mg L−1 TDZ, with 100% response. A protocol was also developed for indirect organogenesis from leaf, leaf-petiole, petiole, and root explants on MS basal medium containing a range of TDZ concentrations. Leaf-petiole explants induced more adventitious shoots (57.6 per explant) and leaves (31.4 per explant) than petioles (37.5 per explant) or roots (25.0 per explant), and the differentiation rate ranged from 87.2 to 100%. The regenerated shoots were elongated on MS medium containing 0.3 mg L−1α-naphthaleneacetic acid (NAA) and 1.0 mg L−1 gibberellic acid (GA3). The elongated shoots developed roots on ½ MS medium containing 0.3 mg L−1 NAA. Successful acclimatization of rooted plantlets in a greenhouse was achieved with 100% survival. Furthermore, the embryogenic-like structure was observed and the morphological characteristics of C. terniflora assessed at different stages of in vitro development. Our protocol offers, for the first time, an efficient, scalable propagation procedure for C. terniflora useful for large-scale cultivation for the purposes of conservation and genetic manipulation. [ABSTRACT FROM AUTHOR]

Plants sense the presence of competing neighboring vegetation as a change in light quality. These changes initiate shade avoidance syndrome (SAS) responses. PHYTOCHROME INTERACTING FACTORS (PIFs) are crucial factors in the SAS response. In particular, they mediate the expression of multiple phytohormones and cell expansion genes. Many positive regulatory factors in the SAS response have been identified, but the negative regulation of SAS transcription factors remains poorly understood. The functions of the short hypocotyl 2 (SHY2) transcription factor during the SAS response have not been established, although its roles in the participating hormone and stress responses are well documented. Here, the SHY2 loss-of-function (shy2-31) mutant had a longer hypocotyl, but the gain-of-function (shy2-2) hypocotyl was shorter than that of the wild type under white and shade conditions. We showed that the SHY2 expression level and its associated protein significantly accumulated under shade conditions. Furthermore, SHY2 transcript levels significantly increased in mutant pifQ , but decreased in PIF4OX compared to the wild type, which indicated that PIF4 is a transcriptional repressor of SHY2. ChIP assays have consistently shown that PIF4 directly binds to the promoters of SHY2. We further show that PIF4OX partially rescued the short hypocotyl characteristic of shy2-2 under white and shade conditions. Our results provide new insights into the regulatory mechanisms controlling SAS mediated elongation of the hypocotyl by PIF4-SHY2 modules in Arabidopsis. • SHY2 is a negative regulatory of hypocotyl elongation. • PIF4 binds to the promoter of SHY2. • PIF4OX partially rescued the shy2-2 hypocotyl length. [ABSTRACT FROM AUTHOR]

Background: Radiotherapy is regarded as a milestone for the cure of cervical cancer. However, clinical outcome heavily be hindered by radioresistance. So, exploring the underlying mechanism of radioresistance, and find potential target, well deserve fully emphasis. Methods: In this study, we developed two novel radiation resistance cervical cancer cell lines, which could mimic clinical radioresistance. In order to find new potential targets, RNA-Seq, database analysis, streptavidin-agarose and LC/MS were used. Pull-down, luciferase and rescue assays were conducted to explore the regulatory mechanisms. To further evaluate the correlation between therapeutic responses and HMGB3/hTERT expression, 172 cervical cancer patients were recruited. Results: Knockdown of HMGB3 significantly inhibit the DNA damage repair and induced more γH2AX foci, leading to enhanced chemo- and radio-sensitivity in vitro and in vivo, whereas HMGB3 overexpression has the opposite effects. HMGB3 promotes cell growth and radioresistance by transcriptionally up-regulating hTERT via the specifical binding of HMGB3 at the hTERT promoter region from − 902 to − 321. HMGB3 knockdown-mediated radiosensitization could be reversed by the overexpressed hTERT in both cervical cancer cell lines and xenograft tumor mouse model. Furthermore, clinical data from 172 cervical cancer patients proved that there was a positive correlation between HMGB3 and hTERT expression, and high expression of HMGB3/hTERT predicted poor response to radiotherapy, worse TNM stages and shorter survival time. Conclusion: Here, we have identified HMGB3/hTERT signaling axis as a new target for cervical cancer radioresistance. Our results provide new insights into the mechanism of cervical cancer radioresistance and indicate that targeting the HMGB3/hTERT signaling axis may benefit cervical cancer patients. [ABSTRACT FROM AUTHOR]

In multicellular organisms, the balance between cell division and differentiation determines organ size, and represents a central unknown in developmental biology. In Arabidopsis roots, this balance is mediated between cytokinin and auxin through a regulatory circuit converging on the IAA3/SHORT HYPOCOTYL 2 (SHY2) gene. Here, we show that crosstalk between brassinosteroids (BRs) and auxin occurs in the vascular transition zone to promote root meristem development. We found that BR increases root meristem size by up‐regulating expression of the PINFORMED 7 (PIN7) gene and down‐regulating expression of the SHY2 gene. In addition, BES1 could directly bind to the promoter regions of both PIN7 and SHY2, indicating that PIN7 and SHY2 mediate the BR‐induced growth of the root meristem by serving as direct targets of BES1. Moreover, the PIN7 overexpression and loss‐of‐function SHY2 mutant were sensitive to the effects of BR and could partially suppress the short‐root phenotypes associated with deficient BR signaling. Interestingly, BRs could inhibit the accumulation of SHY2 protein in response to cytokinin. Taken together, these findings suggest that a complex equilibrium model exists in which regulatory interactions among BRs, auxin, and cytokinin regulate optimal root growth. [ABSTRACT FROM AUTHOR]

Plant steroid hormones brassinosteroids (BRs) regulate plant growth and development at many levels. While negative regulatory factors that inhibit development and are counteracted by BRs exist in the root meristem, these factors have not been characterized. The functions of UPB1 transcription factor in BR-regulated root growth have not been established, although its role in regulating root are well documented. Here, we found that BIN2 interacts with and phosphorylates the UPB1 transcription factor consequently promoting UPB1 stability and transcriptional activity. Genetic analysis revealed that UPB1 deficiency could partially recover the short-root phenotype of BR-deficient mutants. Expression of a mutated UPB1S37AS41A protein lacking a conserved BIN2 phosphorylation sites can rescue shorter root phenotype of bin2-1 mutant. In addition, UPB1 was repressed by BES1 at the transcriptional level. The paclobutrazol-resistant protein family (PRE2/3) interacts with UPB1 and inhibits its transcriptional activity to promote root meristem development, and BIN2-mediated phosphorylation of UPB1 suppresses its interaction with PRE2/3, and subsequently impairing root meristem development. Taken together, our data elucidate a molecular mechanism by which BR promotes root growth via inhibiting BIN2-UPB1 module. Author summary: Various physiological and genetic researches have provided ample evidence in support of the role of plant hormones in root development. Brasinosteroids (BR) play important roles in controlling root growth and development, but the mechanism of negatively regulating factors in this process is less well studied. Here, we found BIN2 kinase, a negative component in BR signaling, interacted with and phosphorylated UPB1 to stabilize and promote its binding ability. The upb1-1 mutant was hypersensitive phenotype, while UPB1-overexpression lines showed opposite effects on BR regulated root meristem development, and defect of UPB1 partially suppressed the short-root phenotype in BR-deficient mutants. Moreover, the paclobutrazol-resistant protein family (PRE2/3) interacted with UPB1 and inhibited its transcriptional activity, and this interaction was also inhibited by BIN2 phosphorylation, thus impairing root meristem development. Our findings provide significant insights into BR signaling through BIN2-UPB1 in regulating root meristem. [ABSTRACT FROM AUTHOR]

Background: The most common chemotherapeutic drug for triple-negative breast cancer (TNBC) treatment is 5-fluorouracil (5-FU), but its therapeutic index is low due to its toxicity. β-Elemene (ELE) possesses antitumor activity against different cancers, but it has never been used in combination with 5-FU to improve its chemotherapeutic effect against TNBC. Materials and Methods: We treated MDA-MB-231 and BT549 cells of TNBC with ELE alone, 5-FU alone, or their combination to investigate their treatment effects on cell viability, proliferation, migration, invasion, and colony formation. We verified the molecular mechanisms of our results through confocal immunofluorescence, immunohistochemistry, and Western blot analysis in vitro and in vivo. Results: Our result revealed that ELE enhanced the 5-FU effect against cell viability, proliferation, migration, invasion, and colony formation through different mechanisms in MDA-MB-231 and BT549 cell lines. In molecular mechanisms, ELE and 5-FU in combination enhances apoptosis in both cell lines through Bl-2 family protein and caspase cascade modulation, thereby inhibiting NF-kB pathway through IKKβ, IKKα, and p65 downregulation in the cytoplasm and p50 and p65 downregulation in the nucleus. ELE and 5-FU in combination regulated the PI3K/AKT pathway through p-AKT, P-85, p110r, p-PDK1, and p110a protein and RAF-MEK-ERK pathway inhibition through the p-c-raf and p-ERK downregulation. The PI3K inhibitor LY294002 or RAF-MEK-ERK inhibitor U0126 in combination with ELE and 5-FU decreased cell viability in both cell lines significantly, thereby showing the involvement of these pathways in cell apoptosis. In mouse xenograft model, ELE and 5-FU in combination inhibited the tumor growth and modulated its molecular markers. Conclusion: The conclusion obtained, considering that the results suggest that the combination may be important specifically in the treatment of TNBC. [ABSTRACT FROM AUTHOR]

Thyroid cancer is the most common type of endocrine malignancy, and its incidence is increasing. Anaplastic thyroid cancer (ATC), referring to undifferentiated subtypes, is considered to be aggressive and associated with poor prognosis. Conventional therapies, including surgery, chemotherapy and radioiodine therapy, have been used for ATC, but these do not provide any significant reduction of the overall mortality rate. The tumorigenesis, development, dedifferentiation and metastasis of ATC are closely associated with the activation of various tyrosine cascades and inactivation of tumor suppressor genes, including B-Raf proto-oncogene, serine/threonine kinaseV600E, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α,tumor protein 53 mutations and telomerase reverse transcriptase mutation. These pathways exert their functions individually or through a complex network. Identification of these mutations may provide a deeper understanding of ATC. A variety of tyrosine kinase inhibitors have been successfully employed for controlling ATC growth in vitro and in xenografts. Certain novel compounds are still in clinical trials. Multi-kinase inhibitors provide a novel approach with great potential. This systematic review determined the prevalence of the major genetic alterations and their inhibitors in ATC. [ABSTRACT FROM AUTHOR]

Thyroid hormone receptor interactor 4 (TRIP4), a subunit of the tetrameric nuclear activating signal co-integrator 1 (ASC-1) complex, exerts pro-tumorigenic effects. The role for TRIP4 in the regulation of cervical cancer growth and radiation resistance is presently unknown. In this study, TRIP4 was found to be highly expressed in cervical cancer cells and tumor tissues. Knockdown of TRIP4 significantly suppressed cervical cancer cell proliferation and epithelial-mesenchymal transition (EMT), accompanied by inactivation of PI3K/AKT and MAPK/ERK signaling. TRIP4 was also found to target hTERT signaling by regulating its binding to the hTERT promoter. Moreover, the knockdown of TRIP4 increased cell sensitivity to radiation, concomitant with downregulation of Rad51 and p-H2AX. We also demonstrated in an in vivo study that the knockdown of TRIP4 effectively suppressed cervical cancer growth and progression in a xenograft tumor model, and these effects were concomitant with the downregulation of p-AKT, p-ERK, p-MEK1/2, MMP-9 and hTERT expression. Immunohistochemical analysis of tumor tissue microarrays showed that TRIP4 overexpression predicted poor prognosis in patients with cervical cancer. Collectively, these results show that TRIP4 plays an essential role in cervical cancer growth and survival. [ABSTRACT FROM AUTHOR]

Background: In cancers, tumor-associated macrophages (TAMs) play an important role in the progression, evasion of immunity and sensitivity to therapy. Unfortunately, radiation and hypoxia could induce the M2 macrophages infiltration and polarization. Materials and methods: In this study, we investigated the relevance of macrophage recruitment with radiation and hypoxia by transwell. We also evaluated the effect of β-elemene on the infiltration of M2 macrophages and explored its underlying molecular mechanism by a series of in vitro and in vivo experiments. Results: Irradiated or hypoxia lung cancer cells recruit macrophages, and the recruitment is MCP-1 dependent. We also found that radiation and hypoxia-induced MCP-1 secretion follows upregulation of Prx-1, which leads to nuclear accumulation of NF-κB and HIF-1α expression. In addition, β-elemene could effectively suppress this recruitment phenomenon through Prx-1/NF-κB/HIF-1α signaling. Conclusion:  Our study showed that radiation and hypoxia significantly promoted the macrophages recruitment. β-elemene could effectively suppress this recruitment phenomenon and MCP-1 expression via inhibiting Prx-1/NF-κB/HIF-1α pathways. [ABSTRACT FROM AUTHOR]

Background/Aims: PI3KCA and mutant p53 are associated with tumorigenesis and the development of cancers. NVP-BKM120, a selective pan-PI3K inhibitor, exerts the antitumor activity by suppressing the PI3K signaling pathway. Prima-1Met, a low molecular weight compound, can rescue the gain-of-function of mutant p53 by restoring its transcriptional function. In this study, we investigated whether PI3K inhibition combined with mutant p53 reactivation could enhance the antitumor effect in thyroid cancer cells. Methods: The effects of BKM120 and Prima-1Met on the proliferation, apoptosis, migration and invasion of thyroid cancer cells were measured by MTT, colony formation, flow cytometry, wound-healing and transwell assays, respectively. Thyroid differentiation was assessed by detecting the expression levels of specific markers using RT-PCR and Western blot. The in vivo antitumor efficacy was analyzed in a mouse xenograft model. Results: The combinational treatment of BKM120 and Prima-1Met significantly enhanced the inhibitions of cell viability, colony formation, migration and invasion, and the induction of apoptosis in thyroid cell lines, and synergistically suppressed tumor xenograft growth by inhibiting the PI3K/Akt/mTOR and EMT signaling pathways, up-regulating p53 targeted genes, and triggering the release of cytochrome c. Moreover, the combination of BKM120 and Prima-1Met suppressed the stemlike traits of thyroid cancer cells and promoted their differentiation by upregulating the expression of thyroid-specific differentiation markers and repressing the expression of cancer stem cell markers. Furthermore, the mechanism study demonstrated that the combinational treatment synergistically abrogated the binding of CPSF4 at the promoter of hTERT and thus suppressed hTERT expression. Consistently, overexpression of hTERT rescued the inhibitions of cell viability, invasion and stem-like traits mediated by the combination of BKM120 and Prima-1Met. Conclusion: Our results showed that the combination of BKM120 with Prima-1Met synergistically suppressed the growth of thyroid cancer cells and tumor xenografts via inhibiting PI3K/Akt/mTOR and CPSF4/hTERT signaling and reactivating mutant p53. [ABSTRACT FROM AUTHOR]

Background/Aims: ß-catenin is an integral component of the canonical Wnt signaling pathway, and its mutations are an autosomal recessive cause of colorectal cancer (CRC), medulloblastoma (MDB), and ovarian cancer. Nevertheless, little is known about its function in lung cancers. Methods: We first knocked down ß-catenin by siRNA to investigate its effects on lung cancer cell proliferation, migration and apoptosis. Then we verified the interaction between ß-catenin and CREB binding protein (CBP) by immunofluoresence and co-immunoprecipition assays. Finally, the expression of ß-catenin and CBP in human lung adenocarcinoma specimens were analyzed by immunohistochemistry assay. Results: ß-catenin knockdown inhibited cell proliferation, promoted apoptosis and suppressed cell migration in A549 and H460 cells accompanied by the decreased expression of Myc, PCNA, VEGF, CD44, MMP-9, MMP-13 and activated bax/caspase-3 pathway. Furthermore, co-immunoprecipition and immunofluoresence analyses revealed that CBP interacted with ß-catenin and contributed to ß-catenin-mediated lung cancer cell growth. Abolishment of their interaction by the Wnt/ß-catenin inhibitor ICG-001 remarkably suppressed cell proliferation. Immunohistochemistry assay of tissue microarrays from patients with lung cancer indicated that both CBP and ß-catenin were highly expressed in tumor tissues and predicted poor prognosis in lung adenocarcinoma patients. Conclusions: Our study has provided new evidence for the role of ß-catenin in promoting the growth of lung cancer cells through cooperation with CBP, and suggested that dual targeting of ß-catenin and CBP could be a potential therapeutic strategy in lung cancer treatment. [ABSTRACT FROM AUTHOR]

Macrophages in tumor are mostly M2-polarized and have been reported to promote tumorigenesis, which are also defined as tumor-associated macrophages (TAMs). β-elemene has therapeutic effects against several cancers, however, it remains unknown whether β-elemene could inhibit cancer by targeting TAMs. Herein, we examined the effect of β-elemene on macrophages to elucidate a novel mechanism of β-elemene in tumor therapy. We showed that the conditioned medium of M2 macrophages promoted lung cancer cells to migration, invasion and epithelial mesenchymal transition, which could be inhibited by β-elemene. Moreover, β-elemene regulated the polarization of macrophages from M2 to M1. β-elemene also inhibited the proliferation, migration, invasion of lung cancer cells and enhanced its radiosensitivity. These results indicate β-elemene suppresses lung cancer by regulating both macrophages and lung cancer cells, it is a promising drug for combination with chemotherapy or radiotherapy. [ABSTRACT FROM AUTHOR]

Bilingual experience can delay cognitive decline during aging. A general hypothesis is that the executive control system of bilinguals faces an increased load due to controlling two languages, and this increased load results in a more 'tuned brain' that eventually creates a neural reserve. Here we explored whether such a neuroprotective effect is independent of language modality, i.e., not limited to bilinguals who speak two languages but also occurs for bilinguals who use a spoken and a signed language. We addressed this issue by comparing bimodal bilinguals to monolinguals in order to detect age-induced structural brain changes and to determine whether we can detect the same beneficial effects on brain structure, in terms of preservation of gray matter volume (GMV), for bimodal bilinguals as has been reported for unimodal bilinguals. Our GMV analyses revealed a significant interaction effect of age × group in the bilateral anterior temporal lobes, left hippocampus/amygdala, and left insula where bimodal bilinguals showed slight GMV increases while monolinguals showed significant age-induced GMV decreases. We further found through cortical surface-based measurements that this effect was present for surface area and not for cortical thickness. Moreover, to further explore the hypothesis that overall bilingualism provides neuroprotection, we carried out a direct comparison of GMV, extracted from the brain regions reported above, between bimodal bilinguals, unimodal bilinguals, and monolinguals. Bilinguals, regardless of language modality, exhibited higher GMV compared to monolinguals. This finding highlights the general beneficial effects provided by experience handling two language systems, whether signed or spoken. Hum Brain Mapp 38:4109-4124, 2017. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

An offline two-dimensional chromatographic method based on the combination of hydrophilic interaction liquid chromatography (HILIC) and porous graphitized carbon (PGC) chromatography was developed for the separation and purification of glycopeptides. The high selectivity of HILIC and PGC isolated high-purity isomers ofN-glycopeptides from ribonuclease B.N-Glycopeptides were first separated from nonglycosylated peptides, andN-glycopeptides were sorted into fractions through the first-dimensional HILIC according to their monosaccharides. Further separation of the glycopeptide isomers in each fraction was achieved using second-dimensional PGC. Structural differences of the glycopeptide isomers were further enzymatically hydrolyzed with peptide-N-glycosidase F. The glycan structure were elucidated by matrix assisted laser desorption ionization tandem quadrupole time-of-flight mass spectrometry. The established procedure allows the isolation of glycopeptide or glycan standards from natural sources. [ABSTRACT FROM PUBLISHER]

Highlights: [•] A novel method was firstly developed for the extraction and cleanup of triptorelin from plasma. [•] The performance of the new sorbent Click XIon was excellent and satisfactory in terms of the matrix effect, recovery and overall process efficiency at the low, middle and high concentration levels of triptorelin. [•] The method was validated and successfully applied to determine triptorelin in rat plasma. [Copyright &y& Elsevier]

-elemene inhibits radiation and hypoxia-induced macrophages infiltration Potential targets for therapy and treatment protocols employed to. [Extracted from the article]

Background: ErbB2 overexpression identifies a subset of breast cancer as ErbB2-positive and is frequently associated with poor clinical outcomes. As a membrane-embedded receptor tyrosine kinase, cell surface levels of ErbB2 are regulated dynamically by membrane physical properties. The present study aims to investigate the influence of membrane cholesterol contents on ErbB2 status and cellular responses to its tyrosine kinase inhibitors. Methods: The cholesterol abundance was examined in ErbB2-positive breast cancer cells using filipin staining. Cellular ErbB2 localizations were investigated by immunofluorescence with altered membrane cholesterol contents. The inhibitory effects of the cholesterol-lowering drug lovastatin were assessed using cell proliferation, apoptosis, immunoblotting and immunofluorescence assays. The synergistic effects of lovastatin with the ErbB2 inhibitor lapatinib were evaluated using an ErbB2-positive breast cancer xenograft mouse model. Results: Membrane cholesterol contents positively correlated with cell surface distribution of ErbB2 through increasing the rigidity and decreasing the fluidity of cell membranes. Reduction in cholesterol abundance assisted the internalization and degradation of ErbB2. The cholesterol-lowering drug lovastatin significantly potentiated the inhibitory effects of ErbB2 kinase inhibitors, accompanied with enhanced ErbB2 endocytosis. Lovastatin also synergized with lapatinib to strongly suppress the in vivo growth of ErbB2-positive breast cancer xenografts. Conclusion: The cell surface distribution of ErbB2 was closely regulated by membrane physical properties governed by cholesterol contents. The cholesterol-lowering medications can hence be exploited for potential combinatorial therapies with ErbB2 kinase inhibitors in the clinical treatment of ErbB2-positive breast cancer. [ABSTRACT FROM AUTHOR]

Background/Aims: Activator protein-2 (AP-2) transcription factors have been proved to be essential in maintaining cellular homeostasis and regulating the transformation from normal growth to neoplasia. However, the role of AP-2β, a key member of AP-2 family, in breast cancer is rarely reported. Methods: The effect of AP-2 on cell growth, migration and invasion in breast cancer cells were measured by MTT, colony formation, wound-healing and transwell assays, respectively. The expression levels of AP-2β and other specific markers in breast cancer cell lines and tissue microarrays from the patients were detected using RT-PCR, Western blot and immunohistochemical staining. The regulation of AP-2β on tumor growth in vivo was analyzed in a mouse xenograft model. Results: We demonstrated the tumor-promoting function of AP-2β in breast cancer. AP-2β was found to be highly expressed in breast cancer cell lines and tumor tissues of breast cancer patients. The shRNA-mediated silencing of AP-2β led to the dramatic inhibition of cell proliferation, colony formation ability, migration and invasiveness in breast cancer cells accompanied by the down-regulated expression of some key proteins involved in cancer progression, including p75, MMP-2, MMP-9, C-Jun, p-ERK and STAT3. Overexpression of AP-2β markedly up-regulated the levels of these proteins. Consistent with the in vitro study, the silencing or overexpression of AP-2β blocked or promoted tumor growth in the mice with xenografts of breast cancers. Notably, the high AP-2β expression levels was correlated with poor prognosis and advanced malignancy in patients with breast cancer. Conclusions: Our study demonstrates that AP-2β promotes tumor growth and predicts poor prognosis, and may represent a potential therapeutic target for breast cancer. [ABSTRACT FROM AUTHOR]

Background: The epidermal growth factor receptor (EGFR) is closely implicated in cancer, and sequencing analyses have revealed a high mutation rate of EGFR in lung cancer. Recent advances have provided novel insights into the endocytic regulation of wild-type EGFR, but that of mutated EGFR remains elusive. In the present study, we aim to investigate the endocytic degradation of a frequently occurred exon 19-deleted mutant in lung cancer. Methods: The EGF-induced endocytic degradation of EGFR was examined in a panel of lung cancer cells using immunoblotting. The subcellular distribution of internalized EGFR was investigated using immunofluorescence and confocal microscopy. The effects of dynamin were assessed using its small molecule inhibitors, while the influence of RTN3 was tested using shRNA-mediated knockdown. Finally the ubiquitylation status of EGFR mutant was studied using immunoprecipitation under steady state and tyrosine kinase inhibitor-treated conditions. Results: EGF induced various rates of EGFR endocytic degradation in lung cancer cells. Interestingly, the exon 19 deletion mutant is constantly internalized and sorted to lysosome for degradation, and this process is independent of dynamin activity. EGF stimulation and HSP90 inhibition further enhance the endocytic degradation of the exon 19 deletion mutant, in a dynamin activity-dependent and -independent manner, respectively. Albeit with different modes of internalization, the uptake of the exon 19-deleted EGFR is mediated through receptor ubiquitylation. Conclusions: The internalized EGFR mutant is constantly routed through endosome to lysosome for degradation. The endocytosis of EGFR mutant occurs through both dynamin activity-dependent and -independent mechanisms. Our findings gain novel insights into the endocytic regulation of mutated EGFR and may have potential clinical implications. [ABSTRACT FROM AUTHOR]