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Positively charged N-terminal histone tails play important roles in maintaining the nucleosome (and chromatin) structure and function. Charge alteration, including those imposed by post-translational modifications, impacts chromatin dynamics, protein binding, and the fate of DNA damage. There is evidence that N-terminal histone tails affect the local ionic environment within a nucleosome core particle (NCP), but this phenomenon is not well understood. Determining the modulation of the local ionic environment within an NCP by histone tails could help uncover the underlying mechanisms of their functions and effects. Utilizing bottom-up syntheses of NCPs containing wild-type or mutated histones and a fluorescent probe that is sensitive to the local ionic environment, we show that interaction with positively charged N-terminal tails increases the local ionic strength near nucleosomal DNA. The effect is diminished by replacing positively charged residues with neutral ones or deleting a tail in its entirety. Replacing the fluorescent probe with the major DNA methylation product

Currently, infections caused by drug-resistant bacteria have become a new challenge in anti-infective treatment, seriously endangering public health. In our continuous effort to develop new antimicrobials, a series of novel honokiol/magnolol amphiphiles were prepared by mimicking the chemical structures and antibacterial properties of cationic antimicrobial peptides. Among them, compound 5i showed excellent antibacterial activity against Gram-positive bacteria and clinical MRSA isolates (minimum inhibitory concentrations (MICs) = 0.5-2 μg/mL) with low hemolytic and cytotoxic activities and high membrane selectivity. Moreover, 5i exhibited rapid bactericidal properties, low resistance frequency, and good capabilities of disrupting bacterial biofilms. Mechanism studies revealed that 5i destroyed bacterial cell membranes, resulting in bacterial death. Additionally, 5i displayed high biosafety and potent in vivo anti-infective potency in a murine sepsis model. Our study indicates that these honokiol/magnolol amphiphiles shed light on developing novel antibacterial agents, and 5i is a potential antibacterial candidate for combating MRSA infections.

Colorectal cancer (CRC) is a frequently diagnosed cancer worldwide. Accumulating researches suggested that circular RNA 0007142 (circ_0007142) contributed to the progression and initiation of CRC. However, the molecular mechanism of circ_0007142 in CRC needs further research. Levels of circ_0007142, microRNA-455-5p (miR-455-5p), and serum- and glucocorticoid-induced protein kinase 1 (SGK1) were identified by quantitative real-time PCR. Cell proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazol-3-ium bromide assay. Flow cytometry assay was used to detect cell apoptosis in SW480 and HCT116 cells. The relative proteins expression was detected by western blot. Cell migration and invasion were evaluated using transwell assay. Moreover, dual-luciferase reporter and RNA immunoprecipitation assays were conducted to determine the relationship between miR-455-5p and circ_0007142 or SGK1. Finally, xenograft tumor model was established to confirm the effect of circ_0007142 on CRC progression in vivo. Circ_0007142 and SGK1 levels were clearly increased, while miR-455-5p level was reduced in CRC tissues and cell lines. Circ_0007142 silencing promoted cell apoptosis and inhibited cell proliferation, migration and invasion, while these effects of circ_0007142 were partially abolished by miR-455-5p inhibitor in CRC cells. Circ_0007142 could sponge miR-455-5p to regulate SGK1 expression. Moreover, the effects of miR-455-5p on cell proliferation, apoptosis, migration and invasion could be partially reversed by SGK1 overexpression. Besides, circ_0007142 knockdown also suppressed the progression of CRC in vivo. Collectively, Circ_0007142/miR-455-5p/SGK1 axis regulated cell proliferation, apoptosis, migration and invasion of CRC cells, providing a probable therapy target for CRC.

We aimed to investigate the effect of lymph node parameters on postoperative hypopharyngeal squamous cell carcinoma (HSCC) and to establish a nomogram to predict its prognosis and assist in adjuvant chemotherapy decisions. A retrospective analysis of postoperative HSCC in the Surveillance, Epidemiology, and End Results database (2004–2019) was performed. Cutoff points for continuous variables were determined by X-tile software. Univariate and multivariate analyses were performed to identify prognostic factors on overall survival (OS), and these variables were used to construct a nomogram. The nomogram’s accuracy was internally validated using concordance index, area under the curve, calibration plot, and decision curve analyses. Furthermore, the value of chemotherapy in each risk subgroup was assessed separately based on individualized scores from the nomogram. In total, 404 patients were eligible for analysis, and the median OS was 39 months. Age, origin, primary site, T stage, number of lymph nodes examined, lymph node ratio, and radiotherapy were identified as prognostic factors for OS and incorporated into the nomogram. In both the training and validation cohorts, favorable performance was exhibited compared with the other stage systems, and patients could be classified into low-, intermediate-, and high-risk subgroups. Chemotherapy significantly improved the OS in the high-risk subgroup, whereas chemotherapy did not confer a survival benefit in the low- or intermediate-risk groups. The lymph node parameter-based nomogram model can better stratify the prognosis of HSCC patients and screen out patients who would benefit from chemotherapy, suggesting that the model could be used as a reference for clinical decision making and to avoid overtreatment.

Currently, infections caused by drug-resistant bacteria have become a new challenge in anti-infective treatment, seriously endangering public health. In our continuous effort to develop new antimicrobials, a series of novel honokiol/magnolol amphiphiles were prepared by mimicking the chemical structures and antibacterial properties of cationic antimicrobial peptides. Among them, compound

e14568 Background: The incidence of NK-T cell lymphoma (NKTL) in Asia is significantly higher than that in European and American countries. The median survival time of EKTL is only 8-12 months, and the 5-year overall survival rate is still less than 30%. New therapies or combinations are warranted. Methods: The murine NKTL cell line EL4 and RMA were used to establish cell line xenograft models in transgenic humanized PD1 mice. Different dosages or sequential HDAC inhibitors were combined with humanized PD1 antibody in vivo to test whether the synergistic effect is existing. RNA-seq, qPCR, and IHC were performed to illustrate the potential mechanisms. Three NTKL patients who were treated with hPD1 and Chidamide in clinical were recorded in this study. Results: Romidepsin combined with hPD1 antibody is superior to hPD1 antibody alone in the treatment of two NKTL CDX models (EL4 and RMA), but it is similar with romidepsin single agent, either in different dosages or sequence. However, Chidamide combined with hPD1 antibody significantly inhibits the tumor growth compared to single agents in these two pre-clinical models. RNA-seq reveals Chidamide synergizes with humanized PD1 antibody to enhance T-cell chemokine expression, augment IFN-gamma response and increase CD8 T cell infiltration. String PPI analysis and ingenuity pathway analysis suggest IFN-gamma is the hub upstream regulator in the combination. On the contrary, the romidepsin combinations decrease the activity of T cell immune responses and the function of immune cell migration. The expression of IFN-gamma gene set signatures is decreased in the romidepsin combination. Three NKTL patients who received PD1 antibody and Chidamide are showed promising efficacy, and the progression-free survival is 26+ months, 8 months, and 9+ months respectively. Conclusions: Different HDAC inhibitor shows different combination effects with immunotherapy. Chidamide combination shows a synergistic effect with immunotherapy by enhancing INF-gamma response, but romidepsin combination antagonizes this effect significantly.

e15086 Background: Although anti-HER2 tyrosine kinase inhibitors (TKIs) have significantly prolonged survival and improved prognosis in HER2-positive breast cancer patients, resistance is a constant obstacle leading to TKIs treatment failure and tumor progression. Our previous research shows dual inhibition of HER2/CDK12 will prominently benefit the outcomes of patients with HER2-positive breast cancer by sensitizing the tumors to anti-HER2 TKIs treatment. Unfortunately, there is no high selective CDK12 inhibitor in clinical. This study sought to accelerate the CDK12 inhibitor discovery by a deep learning approach. Methods: We developed a large-scale self-supervised graph neural network to learn 11 million unlabelled compounds for molecular representation. And the model was trained with 233,823 kinase domain sequences by drug-target interaction datasets from the BindingDB database. Then, this transformer architecture was used to predict potential CDK12 inhibitors. The candidate hits compounds with diverse skeletons were divided into 50 clusters by clustering analysis. The representative hits with high transform scores and rational binding mode in each cluster were detected in the homogeneous time-resolved fluorescence CDK12 kinase assay. Candidate clusters with half-maximal inhibitory concentrations (IC50) lower than 200 nM were selected into expanded validation and kinase selective panel detection. xCELLigence RTCA system was adopted to monitor cell growth and sensitivity of breast cancer cells to CDK12 inhibitors in a real-time manner. Results: Our predictive transfer learning model yielded satisfactory predictions on various targets including CDK12. We screened a total of 4,527,236 compounds and recommended 50 clusters of potential CDK12 inhibitors for further enzyme activity detection. The IC50 of seven cluster representative compounds is lower than 10 uM. Expanded screening of 500 compounds in these clusters discovered a lot of hits with highly CDK12 selective inhibition. Half of the new compounds are showed promising proliferation inhibition in breast cancer cell lines. Conclusions: Our study provides a highly efficient and end-to-end deep learning approach to discover highly selective CDK12 inhibitors in breast cancer.

Natural products (NPs) are very important sources for the development of new drugs. Merrillianone and cycloparvifloralone, isolated from the roots, stems, and fruits of Illicium henryi Diels, are two natural sesquiterpene compounds. In continuation of our effort to discovery more effective neurotrophic compounds from NPs, a series of novel merrillianone/cycloparviforalone based esters 2a-i, 3a-g and 3i-q were prepared and their structures were characterized by 1H NMR, 13C NMR and IR spectral analyses. Furthermore, the spatial structure of compound 2h was unambiguously confirmed by X-ray crystallography. The neurite outgrowth-promoting activity results indicated that most of the target derivatives exhibited more potent neurite outgrowth-promoting activity than merrillianone and cycloparviforalone. Among all target derivatives, the neurite outgrowth-promoting activity of compounds 2a, 3a and 3b was about 2-fold stronger than that of their precursors merrillianone and cycloparviforalone, respectively. Besides, compounds 2a and 3a displayed relatively low cytotoxicity to normal GES-1 cells. Moreover, these derivatives had good hydrolytic stability. Finally, some interesting results of the structure-activity relationships (SARs) were also discussed. This work will pave the way for the development of merrillianone/cycloparviforalone derivatives as potential neurotrophic agents.

Electron backscattered diffraction was employed to observe the orientations of as-solidified Sn3.0Ag3.0Bi3.0In (SABI333) joints. Unlike other Sn-based solder joints consisting of only one grain or of tricrystals, the SABI333 joints typically consisted of polycrystals. The polycrystals were found to originate from Sn grains with deflections (> 15°) from the [110] and [ $$1\bar {1}0$$ ] directions, i.e., the directions in which nucleation tends to occur, and the Bi and In atoms dissolved in the SnAg melt significantly enhanced the deflection. In addition, the orientations of the SABI333 solder joints were highly related to the solidification temperature. Higher solidification temperatures were associated with higher degrees of deviation. Additionally, two types of double tricrystals of Sn formed during solder joint solidification in the SABI333 joints. Although the characteristics of the twinning differed, both types had 80°–90° misorientations. One system featured four orientations of Sn grain twinning with a [100] or [010] axis, while the other one featured perpendicular tricrystals.

Localized recrystallization occurs in Pb-free solder joints under thermomechanical fatigue stress (thermal fatigue). Scanning electronic microscopy and electron backscattered diffraction were used to obtain the microstructures and grain orientations, respectively, of Sn3.5Ag solder bumps after shear testing. At room temperature, recovery and continuous recrystallization tend to occur at the near-pad interface and near-shear edge regions of the solder bumps under shear stress. A (sub)grain rotation mechanism dominates the recrystallized (sub)grains, distinguishing them from the initial orientations. Additionally, the rotation axis and angle were investigated to further elucidate the recrystallized (sub)grain rotation behavior of Pb-free solder bumps. The results show the formation of a single rotation axis between a (sub)grain and its neighboring (sub)grain during recrystallization, indicating a relationship between continuous recrystallization and the Sn slip systems in Pb-free solder alloys.

DSN1 affects cell cycle progression and is associated with clinical-pathological features in colorectal and hepatocellular carcinomas. However, the biological function of DSN1 in breast cancer is still indistinct. In this study, we comprehensively analyzed the correlation between DSN1 expression in different molecular subtypes or stages of breast cancer and investigated the prognostic value of DSN1 in databases such as Oncomine, Cancer Cell Line Encyclopedia, UALCAN, Human Protein Atlas, Kaplan-Meier Plotter, OncoLnc, GEPIA. Moreover, we investigated the correlation of DSN1 with tumor-infiltrating immune cells in the different tumor microenvironments via Tumor Immune Estimation Resource database and explore DSN1 co-expression networks in breast cancer via LinkedOmics analysis, NetworkAnalyst database analysis. Finally, we also performed our immunohistochemical experiments to explore the expression of DSN1 in different stages or subtypes of breast cancer. The findings in this article shed light on the essential role of DSN1 in breast cancers as well as suggested that the upregulation of DSN1 expression was strongly associated with poor prognosis and decreased survival in breast cancer, and there were significant differences in its expression in different pathological subtypes and stages of breast cancer.

Infections caused by clinical methicillin-resistant Staphylococcus aureus (MRSA) are a serious public problem. Triphenyl-sesquineolignans from Illicium genus possess antibacterial activity, but few researches have reported their antibacterial spectrums, structure–activity relationships (SARs) and antibacterial mechanism. In this study, three triphenyl-sesquineolignans, dunnianol (1), macranthol (2) and isodunnianol (3) were isolated from the stems and leaves of I. simonsii Maxim, and seven dunnianol derivatives were prepared through esterification, etherification and halogenation reactions. Among all triphenyl-sesquineolignan analogues, compound 6 showed the best antibacterial activity against four Gram-positive bacteria (MICs = 1–2 µg/mL) and ten clinical MRSA strains (MICs = 2–8 µg/mL), and also exhibited characteristics of killing MRSA more rapidly than tigecycline. Meanwhile, compound 6 did not only show a low probability of drug resistance development, but also exhibited relatively low hemolysis, and good stability in 50% plasma. Further mechanism studies revealed that 6 could kill bacterial strains by disrupting bacterial membranes. These results suggested that 6 may be developed into a new antibacterial candidate for combating MRSA infections.

// Tingyu Wen 1 , Hai Xiao 2 , Chao Luo 3 , Li Huang 4 and Meimei Xiong 5 1 College of Basic Medical Sciences, Gannan Medical University, Ganzhou, China 2 Department of Pathology, Gannan Medical University, Ganzhou, China 3 Department of Urology, People’s Hosptial of Pingxiang, Pingxiang, China 4 Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China 5 Department of Nephrology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China Correspondence to: Hai Xiao, email: // Keywords : renal cell carcinoma, sorafenib, sunitinib, targeted agents, meta-analysis Received : November 10, 2016 Accepted : January 09, 2017 Published : January 15, 2017 Abstract The most efficient sequence of targeted agents for metastatic renal cell carcinoma patients has yet to be identified. Whether the sequence of sorafenib and sunitinib really matters is controversial and not answered clearly until now. This meta-analysis aims to estimate the efficacy of receptor tyrosine kinase inhibitors sorafenib-sunitinib and sunitinib-sorafenib for metastatic renal cell carcinoma, on the outcome of first-line progression-free survival, second-line progression-free survival, total progression-free survival and overall survival. We searched PubMed, Embase, Cochrane Library and ClinicalTrails.gov for eligible studies. Data were analyzed using random or fixed effects model depending on the heterogeneity of the eligible studies. Heterogeneity across studies were analyzed using Q and I2 statistics. Of 902 identified studies, ten were qualified in our analysis ( N = 1732 patients). Sorafenib-sunitinib yielded no statistically significant benefit in first-line progression-free survival (fixed effects; HR = 0.95; 95%CI 0.75-1.21; p = 0.702), total progression-free survival (random effects; HR = 0.92; 95%CI 0.71-1.19; p = 0.531) and overall survival (fixed effects; HR = 0.89; 95%CI 0.72-1.09; p = 0.257), compared with sunitinib-sorafenib. Second-line progression-free survival was longer for sorafenib-sunitinib than sunitinib-sorafenib (fixed effects; HR = 0.55; 95%CI 0.44-0.68; p = 0.000). Sequential therapies with sorafenib and sunitinib is well tolerated and efficient in mRCC. However, there are no evidence supported that sorafenib–sunitinib has the superiority to sunitinib-sorafenib in sequence. The ideal sequence of targeted agents requires further elucidation.

Submarine groundwater discharge (SGD) is now recognized as an important process of land/ocean interactions in coastal zones (LOICZ). In this study, the initial results of the SGD-derived nutrient fluxes into Sanggou Bay, Shandong, China, in June 2012 are reported. This bay is a typical multi-species culture ecosystem with aquaculture species, such as kelp, scallops, shrimp, and oysters. Using a 224Ra/228Ra activity ratio (AR) apparent age model, the average residence time of water in the bay was estimated to be 5.12 days, which was comparable with a flushing time of 6.08 days. Based on the non-conservative inventory of 226Ra and 228Ra in the water column, the average SGD fluxes into the bay were evaluated to be between 2.59 × 107 and 3.07 × 107 m3 d− 1, and the SGD-derived nutrient fluxes (mol/month) had DIN (dissolved inorganic nitrogen) value between 1.16 × 108 and 1.38 × 108, DIP (dissolved inorganic phosphorus) value between 4.17 × 105 and 4.92 × 105, and DSi (dissolved silicon) value between 6.33 × 106 and 7.50 × 106. Additionally, the riverine nutrient inputs to the bay were an order of magnitude lower than the SGD-derived inputs for the DIN and DIP. To balance the nutrient budget, a fertilizer input of N (approximately 4.76 × 107 mol/month) and P (approximately 5.58 × 106 mol/month) is required for aquaculture activities. The fertilizer is a major fraction of the DIP input compared to the SGD. SGD-driven nutrient fluxes may play an important role for nutrient recycling and are required to support the high density of aquaculture activities in the Sanggou Bay.

222Rn is one of the operative tracers for submarine groundwater discharge (SGD), which plays a significant role in the land–ocean interaction of the estuarine and coastal regions. By the distribution pattern of 222Rn in atmosphere, groundwater and surface seawater, in a full tidal period (25 h) in March 2012, SGD was estimated along the coast of Xiangshan, Zhejiang, China. 222Rn activity in Xiangshan coast was in range of 2.4 × 104–1.7 × 105 Bq/m3 with an average of 9.6 × 104 Bq/m3 for groundwater; 0.2 × 102–2.8 × 102 Bq/m3 with an average of 1.1 × 102 Bq/m3 for surface seawater. 222Rn activities in groundwater were much greater than those in surface water, suggesting that the major source of radon came from coastal groundwater discharge. Rn fluxes of atmospheric emissions, sediment, and of 226Ra in situ decay can be negligible in this study, but the tidal effects play a crucial role in Rn fluxes. Using a radon inventory equilibrium model, we estimated that the average SGD was 13.2 cm/day and the average terrestrial SGD flux was 1.8 × 108 m3/day. Furthermore, SGD may have a vital impact on the composition and structure of nutrients in seawater, and contribute to eutrophication events occurring in spring season along the coast of the East China Sea.

Our purpose was to discuss the biological function of Hpa gene and its regulatory network in invasion and metastasis of colon cancer. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes database were used to perform functional annotation and pathway analysis on Hpa gene. Gene Ontology analysis results showed that Hpa plays a significant role in cellular component, molecular function and biological process; and combined with Kyoto Encyclopedia of Genes and Genomes database, regulatory network of angiogenesis of colon cancer was drawn out. Through analysis of regulatory network linked to angiogenesis in invasion and metastasis of colon cancer, the study lays foundation for further prevention, diagnosis and treatment of colon cancer.

Through placement in a few hours after collecting radioaerosol samples (in Shanghai) after Fukushima nuclear power plant (NPP) accident, radionuclides with gamma-emitting rays can be found to be nuclides (132I/132Te, 129I/129Te) other than 131I, 134,137Cs because of the decrease in background baseline after the daughter nuclides (i.e. 214Bi, 214Pb and etc.) of radon makes decay sharply. Based on aerosol sample collected by passing through 1,300 M3 air in 24 h, the lower limit of detection (LLD) of 132I/132Te, 129I/129Te can be decreased from 6.11 × 10−5, 3.46 × 10−4 Bq m−3 after half an hour sampling to 1.64 × 10−5, 8.19 × 10−5 Bq m−3 after sampling 48 h sampling. Similarly, LLD can be decreased from 9.63 × 10−5 to 1.41 × 10−5 Bq m−3 for 131I, 7.72 × 10−5 to 9.96 × 10−6 Bq m−3 for 134Cs and 9.67 × 10−5 to 1.45 × 10−5 Bq m−3 for 137Cs after the same time sampling. In the same time, the activities of daughter nuclides such as 214Pb and 212Bi from the decay of their parent nuclides 222Rn and 220Rn can sharply decrease from 2.45 × 10−2, 2.57 × 10−2 Bq m−3 to be ~10−4 Bq m−3 while the activities of the concerned nuclides 132I/132Te, 129Te, 131I, 134,137Cs were almost constant. As our knowledge, it is the first time to report such case which is very helpful to monitor the leaked nuclides from NPP by aerosol sampling in both normal operation case and emergency case.

Background: Oncocytic carcinoma (OC) arising in the submandibular gland is an unusual malignant neoplasm, with