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Owing to the high rates of relapse and migration, ovarian cancer (OC) has been recognized as the most lethal gynecological malignancy worldwide. The activity of the epidermal growth factor receptor (EGFR) signaling pathway is frequently associated with OC cell proliferation and migration. Despite this knowledge, inhibition of EGFR signaling in OC patients failed to achieve satisfactory therapeutic effects. In this study, we identified that bruceine D (BD) and EGFR inhibitor, afatinib, combination resulted in synergistic anti-OC effects. The results indicated that compared with one of both drugs alone, the combination of BD and afatinib slowed the DNA replication rate, inhibition of cell viability, and proliferation and clone formation. This resulted in cell cycle arrest and cell apoptosis. In addition, the combination of BD and afatinib possessed a stronger ability to inhibit the OC cell adhesion and migration than treatment with BD or afatinib alone. Mechanistically, the combined treatment triggered intense DNA damage, suppressed DNA damage repair, and enhanced the inhibition of the EGFR pathway. These results demonstrated that compared with each pathway inhibition, combined blocking of both DNA damage repair and the EGFR pathway appears to more effective against OC treatment. The results support the potential of BD and afatinib combination as a therapeutic strategy for OC patients.

Biothiols play essential roles in balancing the redox state and modulating cellular functions. Fluorescent probes for monitoring/labelling biothiols often suffer from slow reaction rates, strong background fluorescence and cytotoxic byproduct release. Thus, developing facile and versatile probes to overcome the challenges is still in high demand. Here, we report four coumarin-maleimides as fast responding and fluorogenic probes to detect GSH or label peptides/proteins. The probes quantitatively and selectively react with GSH

Being a critical factor affecting the maintainability and reusability of the software, code readability is growing crucial in modern software development, where a metric for classifying code readability levels is both applicable and desired. However, most prior research has treated code readability classification as a binary classification task due to the lack of labeled data. To support the training of multi-class code readability classification models, we propose an enhanced data augmentation approach that could be used to generate sufficient readability data and well train a multi-class code readability model. The approach includes the use of domain-specific data transformation and GAN-based data augmentation. We conduct a series of experiments to verify our augmentation approach and gain a state-of-the-art multi-class code readability classification performance with 69.5% Micro-F1, 54.0% Macro-F1 and 67.7% Macro-AUC. Compared to the results where no augmented data is used, the improvements on Micro-F1, Macro-F1 and Macro-AUC are significant with 6.9%, 11.3% and 11.2%, respectively. As an innovative work of proposing multi-class code readability classification and an enhanced code readability data augmentation approach, our method is proved to be effective.

APOBEC and AICDA expression after exposure to gefitinb.

PDF file - 90K, Notch pathway genes categorized based on function.

Uracil-DNA glycosylase (UDG) hydrolysis assay.

PDF file - 467K, Representative immunohistochemical staining for Hes-1 protein, in primary NSCLC tissue micro array and NCI-H1299 xenograft.

PDF file - 357K, NSCLC cell lines transduced with Notch reporter.

PDF file - 184K, Supporting data for Notch reporter specificity, Notch activity and MRK003 specific targeting of Notch pathway.

AICDA CRISPR1 and CRISPR2 mutations.

XLSX file - 63K, Microarray Notch pathway components gene expression data on 443 human lung adenocarcinomas.

Patients' clinical data.

Sensitivity of T790M ddPCR assay.

AICDA and RELB expression after TKI exposure was inhibited upon pretreatment with BAY11-7802.

PDF file - 196K, Stable transduction of NCI-H1299 with Notch reporter, where GFP-bright cells regenerate GFP-dim cells, while GFP-dim cells are unable to generate GFP-bright cells.

PDF file - 84K, Immunohistochemistry and PCR assays methodology.

Almost all patients with EGFR-driven lung cancer who are treated with EGFR tyrosine kinase inhibitors (TKI) develop resistance to treatment. A single base (c.2369C>T) transition mutation, EGFR T790M, is the most frequent resistance event after first-generation exposure to EGFR TKIs. Whether T790M mutation is acquired or is selected from a preexisting clone has been a matter of significant debate. In this study, we show that treatment with EGFR TKIs leads to activation of the NFκB pathway, which in turn induces expression of activation-induced cytidine deaminase (AICDA). In turn, AICDA causes deamination of 5-methylcytosine to thymine at position c.2369 to generate the T790M mutation. Pharmacologic inhibition of the NFκB pathway or knockout of AICDA decreased the frequency or prevented the development of T790M mutation, respectively. In addition, patients treated with first-line EGFR TKI displayed increased expression of AICDA and detection of the T790M mutation upon progression. These results identify the mechanism of T790M acquisition and present an opportunity to target the process to delay or prevent it.Significance:These findings identify the mechanism behind acquisition of a common resistance mutation to TKI treatment in lung cancer.

Purpose: The cancer stem cell theory postulates that tumors contain a subset of cells with stem cell properties of self-renewal, differentiation, and tumor initiation. The purpose of this study is to determine the role of Notch activity in identifying lung cancer stem cells.Experimental Design: We investigated the role of Notch activity in lung adenocarcinoma using a Notch GFP reporter construct and a γ-secretase inhibitor (GSI), which inhibits Notch pathway activity.Results: Transduction of lung cancer cells with Notch GFP reporter construct identified a subset of cells with high Notch activity (GFP-bright). GFP-bright cells had the ability to form more tumor spheres in serum-free media and were able to generate both GFP-bright and GFP-dim (lower Notch activity) cell populations. GFP-bright cells were resistant to chemotherapy and were tumorigenic in serial xenotransplantation assays. Tumor xenografts of mice treated with GSI had decreased expression of downstream effectors of Notch pathway and failed to regenerate tumors upon reimplantation in NOD/SCID mice. Using multivariate analysis, we detected a statistically significant correlation between poor clinical outcome and Notch activity (reflected in increased Notch ligand expression or decreased expression of the negative modulators), in a group of 443 patients with lung adenocarcinoma. This correlation was further confirmed in an independent group of 89 patients with adenocarcinoma in which Hes-1 overexpression correlated with poor overall survival.Conclusions: Notch activity can identify lung cancer stem cell–like population and its inhibition may be an appropriate target for treating lung adenocarcinoma. Clin Cancer Res; 19(8); 1972–80. ©2013 AACR.

PDF file - 82K, Relative expression of Notch receptors and ligands in multiple NSCLC cell lines transduced with Notch reporter.

PDF file - 89K, Relative gene expression of cancer stem cell related genes based on Notch activity.

Deamination of Cytosine or 5-methylcytosine to Uracil or Thymine respectively.

PDF file - 59K, Notch1 receptor mutation analysis in multiple NSCLC cell lines.

PDF file - 102K, Xenograft tumor growth curves of NCI-H1299 cell lines, in mice treated with MRK003, docetaxel, and combination with evidence of blocking Notch activity with MRK003 treatment.

PDF file - 76K, Clinical variables of the lung adenocarcinoma patients.

Immune checkpoint inhibitors (ICI) have dramatically transformed the treatment landscape for metastatic colorectal cancer (mCRC) with deficient DNA mismatch repair (dMMR) or high microsatellite instability (MSI-H). Envafolimab, a novel programmed death-1 ligand 1 (PD-L1) inhibitor, has been reported to be efficient and safe for the management of advanced MSI-H/dMMR solid tumors. Here, we report the case of a 35-year-old female patient with MSI-H/dMMR mCRC who was treated with envafolimab following mFOLFOX6 (oxaliplatin, leucovorin, and fluorouracil) plus bevacizumab. While suffering from interstitial pneumonia after chemotherapy, the patient achieved a complete clinical response with the use of envafolimab without additional adverse events. Thus, PD-L1 inhibitors may be potential candidates for treating patients with MSI-H/dMMR mCRC.

To identify the genetic characteristics and local adaptation mechanism of the snail Neptunea cumingii in different sea areas of China, specimens from six coastal areas of the Yellow Sea and Bohai Sea were collected. Simplified genome technology was used to study the population genetic structure and genetic diversity level of N. cumingii and to infer the genetic variation pattern of environmental adaptation of this species. In total, 1992 discrete loci with high quality were obtained used for population genomics analysis. The observed heterozygosity was 0.1551–0.1612, and the expected heterozygosity was 0.1064–0.1117. Nucleotide diversity ranged from 0.1120 to 0.1241, and fixation index values ranged from −0.04683 to −0.02041. A total of 330 discrete loci were screened based on two fixation index values and a method associated with environmental factors. Functional annotation showed that the genes of discrete loci were involved in the three major functions of cell composition, biological process, and molecular function, including growth and development and cell metabolism and catalytic activity. These results suggested that different populations of N. cumingii had loci that may be related to local adaptation. The results of this study helped to clarify the level of genetic diversity and the germplasm genetic background of N. cumingii. They also provided information about the genetic mechanism of environmental adaptation of N. cumingii that can be applied to the restoration and management of N. cumingii resources.

Various kinds of optical structured surface have been widely used in different fields, such as imaging and illumination. However, the machining process of the optical structured surface usually leaves tool marks, burs, debris and defects on the structured surface. Currently, it is still a challenging problem to remove these kinds of defects and further improve the surface quality effectively, to obtain better functional performance. In this paper, maskless fluid jet polishing (MFJP) is innovatively presented which is an attempt to solve this problem. In MFJP, low pressure micro abrasive water jet slurry is impinged on the structured surface to implement tiny material removal without using a mask. Experimental investigations on the polishing of sinusoidal structured surface and V-groove structured surface were performed to realize the technical feasibility of MFJP on structured surface, based on the analysis of surface roughness, form maintainability, and surface smoothness. A computational fluid dynamics (CFD) model was also developed to simulate the MFJP process on V-groove surface to demonstrate the fluid flow movement and material removal characteristics. In addition, the effect of the key polishing parameters was also studied and discussed. The results indicate that MFJP can significantly improve the surface quality of optical structured surface, while possessing high form maintainability under certain conditions. It may become a competitive method for the precision polishing of optical structured surfaces. And this study also sheds some light on the application of MFJP for the polishing of other kinds of surfaces with small or micrometer scale cavities or channels, such as microfluidic chips, etc.

BACKGROUND As the most common cancer in women, breast cancer is the leading cause of death. Most patients are initially diagnosed as stage I-III. Among those without distant metastases, 64% are local tumors and 27% are regional tumors. Patients in stage IIA-IIIC and those who meet the breast-conserving criterion with the exception of tumor size can consider neoadjuvant chemotherapy (NACT). It is worth noting that the status of tumor cell biomarkers is not consistently static. Endocrine-related estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) encoded by erythroblastic leukemia viral oncogene homolog 2 gene can all alter from positive to negative or vice versa, especially in luminal B subtype after NACT. In addition, determination of HER2 status currently mainly relies on immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), but FISH is commonly used when the result of IHC is uncertain. HER2 is regarded as negative when the IHC result is 0/1+ without the addition of FISH. To the best of our knowledge, this is the first report of a case harboring HER2 status transformation and IHC1+ with positive amplification by FISH after NACT. CASE SUMMARY A 49-year-old woman discovered a mass in her right breast and underwent diagnostic workup. Biopsies of the right breast lesion and axillary lymph nodes were obtained. The results pointed to invasive ductal carcinoma with the IHC result for ER (80%), PR (60%), Ki-67 (20%) and ambiguous expression of HER2 (IHC 2+) with negative amplification by FISH (HER2/CEP17 ratio of 1.13). She underwent surgery after NACT. The pathological findings of the surgically resected sample supported invasive ductal carcinoma with the tumor measuring 1.1 cm × 0.8 cm × 0.5 cm and had spread to one of fifteen dissected lymph nodes. Retesting of the specimen showed that the tumor was positive for ER (2+, 85%) and PR (2+, 10%) but negative for HER2 by IHC (1+). Also Ki-67 had dropped to 2%. The patient was regularly monitored every 3 mo without evidence of recurrence. CONCLUSION Biomarker status should be reassessed after NACT especially in luminal subtypes.

Sustainability has become a critical concern for the textile and apparel industry. Over years, a variety of initiatives and practices have been implemented in the industry to reduce the impact to the environment. Offering sustainable products has been an endeavor for many companies in the apparel industry, including the outdoor wear segment. While Consumers are increasingly aware of and interested in buying sustainable products, much research is still needed in terms of important attributes influencing consumers’ purchase decision as well as tradeoffs consumers make when important attributes conflicting against each other. Employing a conjoint analysis approach, this study aims to investigate how different product attributes (i.e., type of fabric, type of down, eco-label certification, and price) jointly affect consumers’ sustainable apparel purchase decision in more realistic settings. As a result of a full profile fractional factorial design, a parsimonious orthogonal array of eight profiles were generated, representing eight different realistic combinations of product attributes. Four hundred and four participants were recruited to participate in this study to evaluate and indicate their purchase intention toward each product profile. Results suggest that price, as expected, is still the most important attribute to consumers, followed by type of fabric(recycled), availability of eco-labels, and type of down (traceable). Moreover, the results reveal that the tradeoffs consumers made varied due to their demographics in terms of gender, education, income, and past purchase experience. This research provides insightful managerial implications to fashion practitioners in their efforts in formulating strategies for product development and marketing by identifying preferred product attributes from the consumer-centric perspective.

Excessive cadmium (Cd) accumulation in vegetables due to farmland pollution constitutes a serious threat to human health. Eggplant has a tendency to accumulate Cd. To investigate the mechanism of the differences in Cd accumulation levels between high-Cd (BXGZ) and low-Cd (MYQZ) eggplant cultivar, physiological and biochemical indicators and mRNA expression of eggplant were examined using photosynthetic apparatus, biochemical test kits, Fourier transform infrared (FTIR) spectroscopy and transcriptome sequencing, etc. The results of biochemical test kits and FTIR revealed that MYQZ enhanced pectin methylesterase (PME) activity, and lignin and pectin content in the root cell wall, which was associated with the upregulation of PME, cinnamyl-alcohol dehydrogenase and peroxidase (PODs). Higher levels of cysteine and glutathione (GSH) contents and upregulation of genes associated with sulfur metabolism, as well as higher expression of ATP-binding cassette transporters (ABCs), cation exchangers (CAX) and metal tolerance proteins (MTPs) were observed in MYQZ. In BXGZ, the higher stomatal density and stomatal aperture as well as higher levels of Ca2+ binding protein-1 (PCaP1) and aquaporins and lower levels of A2-type cyclins (CYCA2-1) are consistent with an enhanced transpiration rate in BXGZ. Furthermore, a more developed root system was shown to be associated with higher levels of auxin response factor (ARF19), GATA transcription factors (GATA4, 5 and 11) and auxin efflux carrier component (PIN5) in BXGZ. In conclusion, highly active PME, and higher levels of lignin and pectin in MYQZ are expected to reduce Cd toxicity, while Cd translocation can be inhibited with the help of ABC and other Cd transporters. As for BXGZ, the uptake and translocation of Cd were enhanced by the developed root system and stronger transpiration.

Advanced or recurrent mucinous carcinoma of the ovary minimally responds to current cytotoxic treatments and has a poor prognosis. Despite multimodal treatment with chemotherapy and surgery, most patients ultimately progress and require palliative systemic therapy. Anti-HER2 therapy has been demonstrated to be an effective strategy for the treatment of HER2-positive breast cancer. However, the role of anti-HER2 therapy in ovarian cancer remains largely unknown. Here, we report the case of a young woman with FIGO Stage IIIc recurrent mucinous ovarian carcinoma (MOC) who developed trastuzumab resistance and disease progression following cross-treatment with trastuzumab combined with pertuzumab. HER2 amplification was discovered using next-generation sequencing (NGS). The patient then received bevacizumab, and pyrotinib (an irreversible HER2 antagonist) plus capecitabine treatment, and achieved a long-term clinical benefit for 22 months. Pyrotinib combined with bevacizumab is a potential treatment for MOC patients who are heavily pretreated and harbor a HER2 amplification. Our case may provide valuable treatment information for patients with advanced or recurrent MOC.

An investigation of changes in lake diatom assemblages and diversity with water depth can help determine whether the biodiversity of a single sediment core is representative of that of the entire lake, as well as can improve our understanding of the relationship between diatom assemblages and water depth. In this study, Huguang Maar Lake in Southern China was investigated in order to explore the spatial patterns of diatom diversity and diatom assemblages of 95 surface sediment samples from different locations and depth zones within the lake. The results show an essentially constant diatom diversity, dominated by planktonic diatoms, in the open deep water zone (OD), and consistent diatom diversity in the northern gently-sloping shallow water zone (NS). However, there is a much higher diatom diversity in different microhabitats in the southern and western shallow water zone (SWS), where the bathymetry is much steeper. This difference may reflect the influence of the bathymetry on the occurrence of sediment slumping. In the steeply-sloping SWS zone, frequently influenced by wave action and sediment slumping, diatom diversity is less representative of that of the entire lake, possibly due to the presence of diatoms from different sources and of different depositional ages. The results indicate that for relatively strongly mixed lakes with a simple morphometry, water depth has little influence on diatom diversity; however, the possible influence of local lake basin topography should be considered when reconstructing past diatom diversity changes from sediment cores.

Far-travelled ash layers from explosive volcanic eruptions can provide invaluable marker horizons for dating and correlating regional to global sedimentary archives. Here, we present a new cryptotephra associated with the ~5.9 cal ka bp Towada-Chuseri eruption (To-Cu) in a peat sediment record from northeast China. This tephra exhibits a rhyolitic glass composition that can be distinguished from other widespread tephra layers around the region of Japan and northeast China. Our findings extend the known range of this ash significantly, making it now traceable about 1200 km from its source, Towada volcano, Japan. Notably, this tephra provides an important isochron for synchronising palaeoenvironmental studies during the mid-Holocene period from the western Pacific, central Japan, Japan Sea and northeast China.

Crusade preaching in the twelfth and thirteenth centuries has often been studied as a centralised programme devised and deployed by the papacy for reform purposes. This article examines the career of John of Cantimpré, a relatively low-profile priest operating at the local level, who none the less was deeply engaged in crusade campaigns as integral to the moral reform of European society. This study first analyses an unusually sophisticated ritual performance in which a usurer was transformed into a crusader as part of a preaching event orchestrated by John of Cantimpré on the eve of the Fourth Crusade, and then investigates the representation of him as a methodical preacher who associated local concerns, such as usury and predatory lordship, with the crusading enterprise.

By coupling parametric modelling, building performance (like energy efficiency) simulation, and algorithmic optimization, performance-based generative architectural design (PGAD) can automatically generate lots of high-performance architectural design solutions. Although it is ‘performance-based’, the final selection of a real design project still needs to consider the aesthetics of design choices. However, due to the overwhelming number of design choices generated by PGAD, it is difficult for designers to choose the most favourable one from them. Therefore, the current study tries to integrate the technology of sketch-based image retrieval (SBIR) into the selecting stage of PGAD. Rather than navigating alternatives one from another and getting lost, designers can directly find the most aesthetically preferred one by inputting his/her hand-drawn design. A design project of fenestrating a multiple-floor office building is used to demonstrate this method and test three SBIR algorithms: Angular radial partitioning (ARP), Angular radial orientation partitioning (AROP), and Sketch-A-Net model (SAN). Test results show that AROP performs the best among these three algorithms. Its retrievals are most similar to inquiry images drawn by architects. Meanwhile, performances of AROP with different template combinations are also rated. After that, AROP with the best template is also tested with incompletely drawn inquiry images. In the end, investigation results are validated by another building facade design case. The current study automates the PGAD process stepwise, making it more applicable to real design projects.

The pandemic of coronavirus disease 2019 (COVID-19) has had a serious impact on global health. COVID-19 vaccines may be one of the most effective measure to end the pandemic. High infection risk and higher serious incident and mortality rates have been shown in cancer patients with COVID-19. Therefore, cancer patients should be the priority group for COVID-19 prevention. Until now, data of COVID-19 vaccination for cancer patients is lacking. We review the interim data of safety and immune-efficacy of COVID-19 vaccination in cancer patients based on the latest studies. Due to the complicated immune systems of cancer patients caused by the malignancy and anticancer treatments, we proposed preliminary specific COVID-19 vaccination recommendations for cancer patients with different anticancer treatments and at different stages of the disease. Preventing COVID-19 with vaccinations for cancer patients is crucial, and we call for more large-scale clinical trials and real-world studies, for further COVID-19 vaccination recommendations development.