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Computationally identifying new targets for existing drugs has drawn much attention in drug repurposing due to its advantages over de novo drugs, including low risk, low costs, and rapid pace. To facilitate the drug repurposing computation, we constructed an automated and parameter-free virtual screening server, namely DrugRep, which performed molecular 3D structure construction, binding pocket prediction, docking, similarity comparison and binding affinity screening in a fully automatic manner. DrugRep repurposed drugs not only by receptor-based screening but also by ligand-based screening. The former automatically detected possible binding pockets of the receptor with our cavity detection approach, and then performed batch docking over drugs with a widespread docking program, AutoDock Vina. The latter explored drugs using seven well-established similarity measuring tools, including our recently developed ligand-similarity-based methods LigMate and FitDock. DrugRep utilized easy-to-use graphic interfaces for the user operation, and offered interactive predictions with state-of-the-art accuracy. We expect that this freely available online drug repurposing tool could be beneficial to the drug discovery community. The web site is http://cao.labshare.cn/drugrep/ .

Aging is characterized by a progressive deterioration of physiological integrity, leading to impaired functional ability and ultimately increased susceptibility to death. It is a major risk factor for chronic human diseases, including cardiovascular disease, diabetes, neurological degeneration, and cancer. Therefore, the growing emphasis on "healthy aging" raises a series of important questions in life and social sciences. In recent years, there has been unprecedented progress in aging research, particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes. In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases, we review the descriptive, conceptual, and interventive aspects of the landscape of aging composed of a number of layers at the cellular, tissue, organ, organ system, and organismal levels.

The utilization of high-throughput sequencing (HTS) for B-cell receptor (BCR) immune repertoire analysis has become widespread in the fields of adaptive immunity and antibody drug development. However, the sheer volume of sequences generated by these experiments presents a challenge in data processing. Specifically, multiple sequence alignment (MSA), a critical aspect of BCR analysis, remains inadequate for handling massive BCR sequencing data and lacks the ability to provide immunoglobulin-specific information. To address this gap, we introduce Abalign, a standalone program specifically designed for ultrafast MSA of BCR/antibody sequences. Benchmark tests demonstrate that Abalign achieves comparable or even better accuracy than state-of-the-art MSA tools, and shows remarkable advantages in terms of speed and memory consumption, reducing the time required for high-throughput analysis from weeks to hours. In addition to its alignment capabilities, Abalign offers a broad range of BCR analysis features, including extracting BCRs, constructing lineage trees, assigning VJ genes, analyzing clonotypes, profiling mutations, and comparing BCR immune repertoires. With its user-friendly graphic interface, Abalign can be easily run on personal computers instead of computing clusters. Overall, Abalign is an easy-to-use and effective tool that enables researchers to analyze massive BCR/antibody sequences, leading to new discoveries in the field of immunoinformatics. The software is freely available at http://cao.labshare.cn/abalign/.

Protein-ligand blind docking is a powerful method for exploring the binding sites of receptors and the corresponding binding poses of ligands. It has seen wide applications in pharmaceutical and biological researches. Previously, we proposed a blind docking server, CB-Dock, which has been under heavy use (over 200 submissions per day) by researchers worldwide since 2019. Here, we substantially improved the docking method by combining CB-Dock with our template-based docking engine to enhance the accuracy in binding site identification and binding pose prediction. In the benchmark tests, it yielded the success rate of ∼85% for binding pose prediction (RMSD

Protein–ligand docking is an essential method in computer-aided drug design and structural bioinformatics. It can be used to identify active compounds and reveal molecular mechanisms of biological processes. A successful docking usually requires thorough conformation sampling and scoring, which are computationally expensive and difficult. Recent studies demonstrated that it can be beneficial to docking with the guidance of existing similar co-crystal structures. In this work, we developed a protein–ligand docking method, named FitDock, which fits initial conformation to the given template using a hierarchical multi-feature alignment approach, subsequently explores the possible conformations and finally outputs refined docking poses. In our comprehensive benchmark tests, FitDock showed 40%–60% improvement in terms of docking success rate and an order of magnitude faster over popular docking methods, if template structures exist (> 0.5 ligand similarity). FitDock has been implemented in a user-friendly program, which could serve as a convenient tool for drug design and molecular mechanism exploration. It is now freely available for academic users at http://cao.labshare.cn/fitdock/.

Esophageal squamous cell carcinoma (ESCC) is a cancer type with limited treatment options. The present study aimed to screen for small molecules that may inhibit ESCC cell viability. The small‑molecule‑perturbed signatures were extrapolated from the library of integrated network‑based cellular signatures (LINCS) database. Since LINCS does not include small‑molecule‑perturbed signatures of ESCC cells, it was hypothesized that non‑ESCC cell lines that display transcriptome profiles similar to those of ESCC may have similar small‑molecule‑perturbated responses to ESCC cells and that identifying small molecules that inhibit the viability of these non‑ESCC cells may also inhibit the viability of ESCC cells. The transcriptomes of1,000 cancer cell lines from the Cancer Cell Line Encyclopedia database were analyzed and 70 non‑ESCC cell lines exhibiting similar transcriptome profiles to those of ESCC cells were identified. Among them, six cell lines with transcriptome signatures upon drug perturbation were available in the LINCS, which were used as reference signatures. A total of 20 ESCC datasets were analyzed and 522 downregulated and 461 upregulated differentially expressed genes (DEGs) that were consistently altered across50% of the datasets were identified. These DEGs together with the reference signatures were then used as inputs of the ZhangScore method to score small molecules that may reverse transcriptome alterations of ESCC. Among the top‑ranked 50 molecules identified by the ZhangScore, four candidates that may inhibit ESCC cell viability were experimentally verified. Furthermore, 2‑[(aminocarbonyl)amino]‑5‑(4‑fluorophenyl)‑3‑-thiophenecarboxamide (TPCA‑1), an inhibitor of the NF‑κB pathway, was able to preferentially inhibit the viability of ESCC cells compared with non‑tumorigenic epithelial Het‑1A cells. Mechanistically, TPCA‑1 induced ESCC KYSE‑450 cell apoptosis by inhibiting the phosphorylation of inhibitor of NF‑κB kinase subunit β, leading to IκBα stabilization and NF‑κB signaling pathway inhibition. Collectively, these results demonstrated that LINCS‑based drug repositioning may facilitate drug discovery and that TPCA‑1 may be a promising candidate molecule in the treatment of ESCC.

Since the outbreak of SARS-CoV-2, numerous compounds against COVID-19 have been derived by computer-aided drug design (CADD) studies. They are valuable resources for the development of COVID-19 therapeutics. In this work, we reviewed these studies and analyzed 779 compounds against 16 target proteins from 181 CADD publications. We performed unified docking simulations and neck-to-neck comparison with the solved co-crystal structures. We computed their chemical features and classified these compounds aiming to provide insights for subsequent drug design. Through detailed analyses, we recommended a batch of compounds that are worth further study. Moreover, we organized all the abundant data and constructed a freely available database, DrugDevCovid19 (http://clab.labshare.cn/covid/php/index.php), to facilitate the development of COVID-19 therapeutics.

Testicular germ cell tumors and closely related embryonal stem cells are exquisitely sensitive to cisplatin, a feature thought to be linked to their pluripotent state and p53 status. It remains unclear whether and how cellular state is coordinated with p53 to confer cisplatin sensitivity. Here, we report that positive transcription elongation factor b (P-TEFb) determines cell fate upon DNA damage. We find that cisplatin rapidly activates P-TEFb by releasing it from inhibitory 7SK small nuclear ribonucleoprotein complex. P-TEFb directly phosphorylates pluripotency factor estrogen-related receptor beta (ESRRB), and induces its proteasomal degradation to enhance pro-survival glycolysis. On the other hand, P-TEFb is required for the transcription of a substantial portion of p53 target genes, triggering cell death during prolonged cisplatin treatment. These results reveal previously underappreciated roles of P-TEFb to coordinate the DNA damage response. We discuss the implications for using P-TEFb inhibitors to treat cancer and ameliorate cisplatin-induced ototoxicity.

Ligand-similarity-based virtual screening is one of the most applicable computer-aided drug design techniques. The current methodology relies heavily on several descriptors of molecular features, including atoms (zero-dimensional, 0D), the presence or absence of structural features (one-dimensional, 1D), topological descriptors (two-dimensional, 2D), geometry and volume (three-dimensional, 3D), or stereoelectronic and stereodynamic properties (four-dimensional, 4D). These descriptors have been frequently used in virtual screening; however, they are usually used independently without integration, which may hinder effective and precise virtual screening. In this study, we developed a multifeature integration algorithm named LigMate, which employs a Hungarian algorithm-based matching and a machine learning-based nonlinear combination of various descriptors, including the new relevant descriptors focusing on the maximum common substructures (maximum common substructure score, MCSS), the relative distance of atoms from the ligand mass center (intraligand distance score, ILDS), as well as the ring differences (ring score, RS). In the benchmark tests, LigMate achieved an overall enrichment factor of the first percent (EF1) of 36.14 and an area under the curve (AUC) value of 0.81 on the DUD-E data set, as well as an EF1 of 15.44 and an AUC of 0.69 on the maximum unbiased validation (MUV) data set, outperforming the control methods that are based on single descriptors. Thus, our study provides a new framework for multiple feature integration, which can benefit ligand-similarity-based virtual screening. LigMate is freely available for noncommercial users at http://cao.labshare.cn/ligmate/.

Identifying the types of body fluids left at the crime scene can be essential to reconstructing the crime scene and inferring criminal behavior. MicroRNA (miRNA) molecule extracted from the trace of body fluids is one of the most promising biomarkers for the identification due to its high expression, extreme stability and tissue specificity. However, the detection of miRNA markers is not the answer to a yes–no question but the probability of an assumption. Therefore, it is a crucial task to develop complicated methods combining multi-miRNAs as well as computational algorithms to achieve the goal. In this study, we systematically analyzed the expression of 10 most probable body fluid-specific miRNA markers (miR-451a, miR-205-5p, miR-203a-3p, miR-214-3p, miR-144-3p, miR-144-5p, miR-654-5p, miR-888-5p, miR-891a-5p and miR-124-3p) in 605 body fluids-related samples, including peripheral blood, menstrual blood, saliva, semen and vaginal secretion. We introduced the kernel density estimation (KDE) method and six well-established methods to classify the body fluids in order to find the most optimal combinations of miRNA markers as well as the corresponding classifying method. The results show that the combination of miR-451a, miR-891a-5p, miR-144-5p and miR-203a-3p together with KDE can achieve the most accurate and robust performance according to the cross-validation, independent tests and random perturbation tests. This systematic analysis suggests a reference scheme for the identification of body fluids in an accurate and stable manner.

A tunable optoelectronic oscillator (OEO) employing a directly modulated microsquare laser is proposed and experimentally demonstrated without using any external modulator and electrical bandpass filter. In our scheme, the OEO oscillates near the relaxation oscillation frequency at which the microsquare laser has the highest modulation efficiency. Microwave signals with the frequency tuned from 3.51 to 8.16 GHz are generated by tuning the bias current of the microsquare laser. Single sideband phase noise of -112.5 dBc/Hz is obtained at a frequency offset of 10 kHz for the generated 7.48 GHz microwave signal.

The assembly of prereplicative complex (pre-RC) during G1 phase must be tightly controlled to sustain cell proliferation and maintain genomic stability. Mechanisms to prevent pre-RC formation in G2/M and S phases are well appreciated, whereas how cells ensure efficient pre-RC assembly during G1 is less clear. Here we report that cyclin K regulates pre-RC formation. We find that cyclin K expression positively correlates with cell proliferation, and knockdown of cyclin K or its cognate kinase CDK12 prevents the assembly of pre-RC in G1 phase. Mechanistically we uncover that cyclin K promotes pre-RC assembly by restricting cyclin E1 activity in G1. We identify a cyclin K-dependent, novel phosphorylation site in cyclin E1 that disrupts its interaction with CDK2. Importantly, this antagonistic relationship is largely recapitulated in cyclin E1-overexpressing tumors. We discuss the implications of our findings in light of recent reports linking cyclin K and CDK12 to human tumorigenesis., Prereplicative complex (pre-RC) formation during G1 is fundamental for cell replication. Here the authors report a role for cyclin K in regulating pre-RC formation in mammalian cells by affecting cyclin E1 activity.

As a member of tumor suppressor p53 family, p63, a gene encoding versatile protein variant, has been documented to correlate with cancer formation and progression, though it is rarely mutated in cancer patients. However, it has long been controversial on whether p63 is an oncogene or a tumor suppressor. Here, we comprehensively reviewed reports on roles of p63 in development, tumorigenesis and tumor progression. According to data from molecular cell biology, genetic models and clinic research, we conclude that p63 may act as either an oncogene or a tumor suppressor gene in different scenarios: TA isoforms of p63 gene are generally tumor-suppressive through repressing cell proliferation, survival and metastasis; ΔN isoforms, however, may initiate tumorigenesis via promoting cell proliferation and survival, but inhibit tumor metastasis and progression; effects of p63 on tumor formation and progression depend on the context of the whole p53 family, and either amplification or loss of p63 gene locus can break the balance to cause tumorigenesis.

Comprehensive genomic analyses of cancers have revealed substantial intrapatient molecular heterogeneities that may explain some instances of drug resistance and treatment failures. Examination of the clonal composition of an individual tumor and its evolution through disease progression and treatment may enable identification of precise therapeutic targets for drug design. Multi-region and single-cell sequencing are powerful tools that can be used to capture intratumor heterogeneity. Here, we present a database we’ve named CancerTracer (http://cailab.labshare.cn/cancertracer): a manually curated database designed to track and characterize the evolutionary trajectories of tumor growth in individual patients. We collected over 6000 tumor samples from 1548 patients corresponding to 45 different types of cancer. Patient-specific tumor phylogenetic trees were constructed based on somatic mutations or copy number alterations identified in multiple biopsies. Using the structured heterogeneity data, researchers can identify common driver events shared by all tumor regions, and the heterogeneous somatic events present in different regions of a tumor of interest. The database can also be used to investigate the phylogenetic relationships between primary and metastatic tumors. It is our hope that CancerTracer will significantly improve our understanding of the evolutionary histories of tumors, and may facilitate the identification of predictive biomarkers for personalized cancer therapies.

Supplemental Digital Content is available in the text, Cervical cancer is among the most frequent cancer types in women worldwide. Radiotherapy, including external beam radiation and brachytherapy, is one of the commonly used treatment options for cervical cancer. However, the adverse effects of radiation therapy on cervical cancer survival have been poorly investigated with inconclusive results. Therefore, the aim of this study was to determine the suitable radiotherapy modality according to patients’ characteristics. A retrospective survival analysis of 44,602 patients was performed using the Surveillance, Epidemiology, and End Results (SEER) database. Multivariate proportional hazard Cox model was used to evaluate the prognostic impact of different radiotherapy modalities, primary surgery, age, TNM stage, and tumor size. Our results indicated that patients without primary surgery, diagnosed at older age (≥45 years’ old), at advanced TNM stages (III/IV) or with larger tumor size (≥3 cm) could benefit from radiotherapy. However, radiotherapy was detrimental in patients with primary surgery, diagnosed at younger age (

The remarkable progress in cancer immunotherapy in recent years has led to the heat of great development for therapeutic antibodies. Antibody numbering, which standardizes a residue index at each position of an antibody variable domain, is an important step in immunoinformatic analysis. It provides an equivalent index for the comparison of sequences or structures, which is particularly valuable for antibody modeling and engineering. However, due to the extremely high diversity of antibody sequences, antibody-numbering tools cannot work in all cases. This article introduces a new antibody-numbering tool named AbRSA, which integrates heuristic knowledge of region-specific features into sequence mapping to enhance the robustness. The benchmarks demonstrate that, AbRSA exhibits robust performance in numbering sequences with diverse lengths and patterns compared with the state-of-the-art tools. AbRSA offers a user-friendly interface for antibody numbering, complementarity-determining region delimitation, and 3D structure rendering. It is freely available at http://cao.labshare.cn/AbRSA.

p53-related p63 plays a critical role in regulation of cell proliferation, survival and cell differentiation. Dysregulation of p63 functions results in a disruption of a variety of normal biological processes, including stem cell biology, embryonic development, aging and tumorigenesis. ΔNp63α, a predominantly expressed p63 protein isoform in epithelial cells, plays a crucial role in regulation of cell cycle progression and cell growth. p38 MAP kinases (p38MAPK) are the members of mitogen-activated protein kinases family and are critical in regulation of cell survival in response to stress signals. In this study, we show that ectopic expression of ΔNp63α inhibited phosphorylation of p38MAPK. Acute knockdown of p63 led to a significant upregulation of p38MAPK phosphorylation, resulting in increased p21cip1/waf1 expression, reduced phosphorylation of retinoblastoma protein (RB), cell cycle G1 arrest and cell growth retardation. Restoration of ΔNp63α expression reversed cell cycle arrest and growth inhibition induced by p63 ablation. Pharmacological inhibition of p38MAPK significantly suppressed ΔNp63α ablation-induced cell cycle G1/S arrest. In addition, MAP Kinase Phosphatase 3 (MKP3) was responsible for ΔNp63α-mediated regulation of p38MAPK phosphorylation. Together, these results suggest that ΔNp63α-MPK3-p38MAPK signaling pathway plays an important role in cell cycle progression and cell growth.

Summary Embryonic stem cells (ESCs) are fast proliferating cells capable of differentiating into all somatic cell types. In somatic cells, it is well documented that p53 is rapidly activated upon DNA damage to arrest the cell cycle and induce apoptosis. In mouse ESCs, p53 can also be functionally activated, but the precise biological consequences are not well characterized. Here, we demonstrated that doxorubicin treatment initially led to cell-cycle arrest at G2/M in ESCs, followed by the occurrence of massive apoptosis. Neither p53 nor its target gene p73 was required for G2/M arrest. Instead, p53 and p73 were fully responsible for apoptosis. p53 and p73 were also required for differentiation-induced apoptosis in mouse ESCs. In addition, doxorubicin treatment induced the expression of retinoblastoma protein in a p53-dependent manner. Therefore, both p53 and p73 are critical in apoptosis induced by DNA damage and differentiation., Highlights • p53/p73 are key for DNA damage-induced apoptosis but not G2/M arrest in mESCs • Both p53 and p73 are required for differentiation-induced apoptosis in mESCs • Doxorubicin induces RB via p53-mediated suppression of miR-17-92 and miR-106a-363 • p73 expression is induced upon differentiation in mESCs, In this article, Xiao, Li, and colleagues show that p53 and p73 are pivotal for DNA-damage-induced apoptosis but not for G2/M arrest in mESCs. In addition, doxorubicin induces RB via p53-mediated suppression of miR-17-92 and miR-106a-363. During differentiation, p73, but not p53, is induced, and both p53 and p73 are critical for differentiation-induced apoptosis.

Both p53-related p63 and c-Myc are transcription factors playing key roles in cell proliferation, survival, development and tumorigenesis. In the present study, we identified that MM1, a c-Myc inhibitor, specifically binds to C-termini of p63α (including ΔNp63α and TAp63α). Further study demonstrates that p63α facilitates MM1 protein degradation via proteasomal pathway, resulting in elevation of c-Myc transactivation activity. Knockdown of ΔNp63α leads to decrease in c-Myc protein levels, concomitant with reduced expression of CDK4 and Cyclin D1, and impaired cell cycle progression, both of which are effectively reversed by simultaneous knockdown of MM1. Moreover, expression of p63 and CDK4 is concomitantly up-regulated in B-cell acute lymphoblastic leukemia. Together, this study reveals a novel crosstalk between p63 and c-Myc that may play an important role in cell cycle progression and tumorigenesis.

Metformin has been used as therapy for type 2 diabetes for many years. Clinical and basic evidence as indicated that metformin has anti-cancer activities. It has been well-established that metformin activates AMP-activated protein kinase (AMPK), which in turn regulates energy homeostasis. However, the mechanistic aspects of metformin anti-cancer activity remain elusive. p53 family proteins, including p53, p63 and p73, have diverse biological functions, including regulation of cell growth, survival, development, senescence and aging. In this review, we highlight the evidence and mechanisms by which metformin inhibits cancer cell survival and tumor growth. We also aimed to discuss the role of p53 family proteins in metformin-mediated suppression of cancer growth and survival.

AlGaInAs/InP waveguide-coupled deformed hexagonal resonator microlasers with enhanced mode quality (Q)-factors are demonstrated for realizing single-transverse-mode operation. A circular hole is introduced to the center of the hexagonal resonators with rounded corners to enhance the mode Q-factors and suppress high-order transverse modes simultaneously. Single-mode lasing with side-mode suppression ratios up to 40 dB is obtained for the 10-μm-sidelength hexagonal microlasers with a center hole. All the lasing spectra demonstrate pure single-transverse-mode properties within the whole tuning range of injection current, and mode hopping with one, two, and three longitudinal-mode intervals is observed due to the mode Q-factor modification by the center holes. To further reduce the device size and threshold current, the deformed hexagonal resonator microlasers with the flat sides replaced by circular arcs are analyzed and demonstrated experimentally. The Q-factors of the fundamental transverse modes can be enhanced by two orders of magnitude due to the convergence effect of the circular sides by optimizing the deformation amplitude, while the single-transverse-mode property is still maintained. A threshold current of 2.4 mA is realized for a circular-side hexagonal microlaser with the side length of 8.5 μm and the deformation amplitude of 0.55 μm.

We have realized a dual-transverse-mode microlaser. The nonlinear dynamics including chaos, four-wave mixing, and high-order oscillations states are observed based on the laser. Random bits are generated based on the same laser without external optical injection or feedback.

Summary: When the core body temperature is higher than 40°C, life is threatened due to heatstroke. Tumor repressor p53 is required for heat-induced apoptosis at hyperthermia conditions (>41°C). However, its role in sub-heatstroke conditions (≤40°C) remains unclear. Here, we reveal that both zebrafish and human p53 promote survival at 40°C, the heatstroke threshold temperature, by preventing a hyperreactive heat shock response (HSR). At 40°C, both Hsf1 and Hsp90 are activated. Hsf1 upregulates the expression of Hsc70 to trigger Hsc70-mediated protein degradation, whereas Hsp90 stabilizes p53 to repress the expression of Hsf1 and Hsc70, which prevents excessive HSR to maintain cell homeostasis. Under hyperthermia conditions, ATM is activated to phosphorylate p53 at S37, which increases BAX expression to induce apoptosis. Furthermore, growth of p53-deficient tumor xenografts, but not that of their p53+/+ counterparts, was inhibited by 40°C treatment. Our findings may provide a strategy for individualized therapy for p53-deficient cancers. : Gong et al. report that in contrast to promoting apoptosis in hyperthermia conditions, both zebrafish and human tumor repressor p53 protect cells from death by preventing a hyperreactive heat shock response at 40°C, the heatstroke threshold temperature (HTT). They may provide a strategy for individualized therapy for p53-deficient cancers. Keywords: p53, heatstroke threshold temperature, hyperthermia temperature, cell death, Hsf1, Hsc70, Hsp90, ATM, zebrafish, human cell

p63 and c-Myc are key transcription factors controlling genes involved in the cell cycle and cellular senescence. We previously reported that p63α can destabilize MM1 protein to derepress c-Myc, resulting in cell cycle progress and tumorigenesis. However, how the proteasomal degradation of MM1 is facilitated remains unclear. In the present study, we identified a novel E3 ligase, HERC3, which can mediate ubiquitination of MM1 and promote its proteasome-dependent degradation. We found that ΔNp63α transcriptionally up-regulates HERC3 and knockdown of HERC3 abrogates ΔNp63α-induced down-regulation of MM1. Either overexpression of MM1 or ablation of HERC3 induces cell senescence, while knockdown of MM1 rescues cell senescence induced by deficiency of either ΔNp63α or HERC3, implicating the involvement of the ΔNp63α/HERC3/MM1/c-Myc axis in the modulation of cell senescence. Additionally, our Oncomine analysis indicates activation of the ΔNp63α/HERC3/MM1/c-Myc axis in invasive breast carcinoma. Together, our data illuminate a novel axis regulating cell senescence: ΔNp63α stimulates transcription of E3 ligase HERC3, which mediates ubiquitination of c-Myc modulator MM1 and targets it to proteasomal degradation; subsequently, c-Myc is derepressed by ΔNp63α, thereby cell senescence is modulated by this axis. Our work provides a new interpretation of crosstalk between p63 and c-Myc, and also sheds new light on ΔNp63α-controlled cell senescence and tumorigenesis.

Background The integration of DNA methylation and copy number alteration data promises to provide valuable insight into the underlying molecular mechanisms responsible for cancer initiation and progression. However, the generation and processing of these datasets are costly and time-consuming if carried out separately. The Illumina Infinium HumanMethylation450 BeadChip, initially designed for the evaluation of DNA methylation levels, allows copy number variant calling using bioinformatics tools. Results A substantial amount of Infinium HumanMethylation450 data across various cancer types has been accumulated in recent years and is a valuable resource for large-scale data analysis. Here we present MethCNA, a comprehensive database for genomic and epigenomic data integration in human cancer. In the current release, MethCNA contains about 10,000 tumor samples representing 37 cancer types. All raw array data were collected from The Cancer Genome Atlas and NCBI Gene Expression Omnibus database and analyzed using a pipeline that integrated multiple computational resources and tools. The normalized copy number aberration data and DNA methylation alterations were obtained. We provide a user-friendly web-interface for data mining and visualization. Conclusions The Illumina Infinium HumanMethylation450 BeadChip enables the interrogation and integration of both genomic and epigenomic data from exactly the same DNA specimen, and thus can aid in distinguishing driver from passenger mutations in cancer. We expect MethCNA will enable researchers to explore DNA methylation and copy number alteration patterns, identify key oncogenic drivers in cancer, and assist in the development of targeted therapies. MethCNA is publicly available online at http://cgma.scu.edu.cn/MethCNA. Electronic supplementary material The online version of this article (10.1186/s12864-018-4525-0) contains supplementary material, which is available to authorized users.

Stable dual-mode lasing deformed square microcavity lasers and single mode deformed hexagonal microlasers are reported, where flat-sides are replaced by circular sides for enhancing mode Q factors due to the reduction of vertex radiation loss.

PTEN is one of the most frequently mutated tumour suppressors and reduction in PTEN protein stability also plays a role in tumorigenesis. Although several ubiquitin ligases for PTEN have been identified, the deubiquitylase for de-polyubiquitylation and stabilization of PTEN is less defined. Here, we report OTUD3 as a deubiquitylase of PTEN. OTUD3 interacts with, de-polyubiquitylates and stabilizes PTEN. Depletion of OTUD3 leads to the activation of Akt signalling, induction of cellular transformation and cancer metastasis. OTUD3 transgenic mice exhibit higher levels of the PTEN protein and are less prone to tumorigenesis. Reduction of OTUD3 expression, concomitant with decreased PTEN abundance, correlates with human breast cancer progression. Furthermore, we identified loss-of-function OTUD3 mutations in human cancers, which either abolish OTUD3 catalytic activity or attenuate the interaction with PTEN. These findings demonstrate that OTUD3 is an essential regulator of PTEN and that the OTUD3-PTEN signalling axis plays a critical role in tumour suppression.

Inactivation of the retinoblastoma protein (RB) has a major role in the development of human malignancies. We have previously shown that MDM2, an ubiquitin E3 ligase and major negative regulator of p53, binds to and promotes proteasome-mediated degradation of RB. MDMX, a homolog of MDM2, also binds to and inhibits p53 transactivation activity, yet it does not possess intrinsic ubiquitin ligase activity. Here, we show that MDMX binds to and promotes RB degradation in an MDM2-dependent manner. Specifically, the MDMX C-terminal ring domain binds to the RB C-pocket and enhances MDM2-RB interaction. Silencing MDMX induces RB accumulation, cell cycle arrest and senescence-like phenotypes, which are reverted by simultaneous RB knockdown. Furthermore, MDMX ablation leads to significant retardation of xenograft tumor growth, concomitant with RB accumulation. These results demonstrate that MDMX exerts oncogenic activity via suppression of RB, and suggest that both MDM2 and MDMX could be chemotherapeutic targets.

Modulation bandwidth enhancements are investigated for coupled twin-square microcavity lasers due to photon-photon resonance effect. For a coupled twin-square microcavity laser with the square side length of 20 μm, we demonstrate the increase of 3-dB modulation bandwidth from 9.6 GHz to 19.5 GHz, by adjusting the resonance mode wavelength interval between two square microcavities. The enhanced modulation bandwidth is explained by rate equation analysis, and numerical simulations are conducted for large signal modulation with improved eye-diagrams at 40 Gbit/s.

We demonstrate electrically pumped continuous-wave (CW) lasing near 1.5 pm at room temperature in microcylinder lasers with InAs quantum dot active regions. The microcylinder radius can reduce to 4μm at room temperature and contentious-wave lasing.

Knowledge absorptive capacity is essential for the development of enterprises in the era of knowledge economy. Trust relationship is the key influencing factor of knowledge absorptive capacity in the service outsourcing enterprises. Building a trust relationship between service outsourcing enterprises must meet four conditions: understanding, profitable, predictable and faithworthy. Above all, this paper proposes two dimensions of trust relationship: interpersonal communication and organizational commitment. Then this paper discusses the impact of the interpersonal communication and organizational commitment on the knowledge absorption capacity. Finally this paper does an empirical research as example of service outsourcing enterprises by using the structural equation model. The results of empirical study show that interpersonal communication, organizational commitment and knowledge absorptive capacity is positive correlation. The conclusion of study has an important role to improve the knowledge absorptive capacity of enterprises.

HER2 (human epidermal growth factor receptor 2) activation is critical in breast cancer development. HER2 promotes cell proliferation, angiogenesis, survival, and metastasis by activation of PI3K/Akt, Ras/MEK/ERK, and JAK/STAT pathways. However, beyond these signaling molecules, the key proteins underlining HER2-mediated metastasis remain elusive. ATF4 (Activating transcription factor 4), a critical regulator in unfolded protein response (UPR), is implicated in cell migration and tumor metastasis. In this study, we demonstrate that HER2 upregulated ATF4 expression at both mRNA and protein levels, resulting in cell migration increased. In addition, ATF4 upregulated ZEB1 (Zinc finger E-box-binding homeobox 1) and suppressed E-cadherin expression resulting in promoting cell migration. Restoration of E-cadherin expression effectively inhibited HER2- or ATF4-mediated cell migration. In addition, upregulated expression of ATF4 was found in HER2-positive breast cancer specimens. Together, this study demonstrates that ATF4-ZEB1 is important for HER2-mediated cell migration and suggests that ATF4-ZEB1 may be potential therapeutic targets for breast cancer metastasis.

Whispering-gallery-mode (WGM) hexagonal optical micro-/nanocavities can be utilized as high-quality (Q) resonators for realizing compact-size low-threshold lasers. In this paper, the progress in WGM hexagonal micro-/nanocavity lasers is reviewed comprehensively. High-Q WGMs in hexagonal cavities are divided into two kinds of resonances propagating along hexagonal and triangular periodic orbits, with distinct mode characteristics according to theoretical analyses and numerical simulations; however, WGMs in a wavelength-scale nanocavity cannot be well described by the ray model. Hexagonal micro-/nanocavity lasers can be constructed by both bottom-up and top-down processes, leading to a diversity of these lasers. The ZnO- or nitride-based semiconductor material generally has a wurtzite crystal structure and typically presents a natural hexagonal cross section. Bottom-up growth guarantees smooth surface faceting and hence reduces the scattering loss effectively. Laser emissions have been successfully demonstrated in hexagonal micro-/nanocavities synthesized with various materials and structures. Furthermore, slight deformation can be easily introduced and precisely controlled in top-down fabrication, which allows lasing-mode manipulation. WGM lasing with excellent single-transverse-mode property was realized in waveguide-coupled ideal and deformed hexagonal microcavity lasers.

Cell–cell adhesion plays an important role in regulation of cell proliferation, migration, survival, and drug sensitivity. Metformin, a first line drug for type 2 diabetes, has been shown to possess anti-cancer activities. However, whether cell–cell adhesion affects metformin anti-cancer activity is unknown. In this study, Microscopic and FACS analyses showed that metformin induced cancer cell–cell adhesion exemplified by cell aggregation and anoikis under glucose restriction. Furthermore, western blot and QPCR analyses revealed that metformin dramatically upregulated integrin β1 expression. Silencing of integrin β1 significantly disrupted cell aggregation and reduced anoikis induced by metformin. Moreover, we showed that p53 family member ΔNp63α transcriptionally suppressed integrin β1 expression and is responsible for metformin-mediated upregulation of integrin β1. In summary, this study reveals a novel mechanism for metformin anticancer activity and demonstrates that cell–cell adhesion mediated by integrin β1 plays a critical role in metformin-induced anoikis.

The MUC1 transmembrane glycoprotein is aberrantly overexpressed in diverse human carcinomas and has been shown to inhibit apoptosis induced by genotoxic agents. In the present work, we report that MUC1 binds to and activates JNK1, an important member of the mitogen-activated protein kinases (MAPK) superfamily. The physical interaction between MUC1 cytoplasmic domain (MUC1-CD) and JNK1 was established by GST-pull-down assay in vitro and co-immunoprecipitation assay in vivo. We show that MUC1 activates JNK1 and inhibits cisplatin-induced apoptosis in human colon cancer HCT116 cells. Pharmacological inhibition of JNK or knockdown of JNK significantly reduces the ability of MUC1 to inhibit cisplatin-induced apoptosis. Together, our data indicate that MUC1 can inhibit apoptosis via activating JNK1 pathway in response to genotoxic anticancer agents.

The blood glucose modifier metformin is used to treat type II diabetes and has also been shown to possess anticancer activities. Recent studies indicate that glucose deprivation can greatly enhance metformin-mediated inhibition of cell viability, but the molecular mechanism involved in this inhibition is unclear. In this study, we report that, under glucose deprivation, metformin inhibited expression of ΔNp63α, a p53 family member involved in cell adhesion pathways, resulting in disruption of cell matrix adhesion and subsequent apoptosis in human squamous carcinoma cells. We further show that metformin promoted ΔNp63α protein instability independent of AMP-activated protein kinase and that WWP1, an E3 ligase of ΔNp63α, was involved in metformin-mediated down-regulation of ΔNp63α levels. In addition, we demonstrate that a combination of metformin and the glycolysis inhibitor 2-deoxy-d-glucose significantly inhibited ΔNp63α expression and also suppressed xenographic tumor growth in vivo. In summary, this study reveals a new mechanism for metformin-mediated anticancer activity and suggests a new strategy for treating human squamous cell carcinoma.

Lasing mode control and direct modulation characteristics have been investigated for waveguide-coupled unidirectional-emission square microcavity lasers. A quasi-analytical model is introduced to analyze the mode field distributions and quality (Q) factors for the confined modes inside the square optical microcavities with directly coupled waveguide, where high-Q whispering-gallery-like (WG-like) modes are induced by the mode coupling between doubly-degenerate modes. AlGaInAs/InP waveguide-coupled unidirectional-emission square microcavity lasers are fabricated by using standard planar technology, and electrically-injected lasing is realized at room temperature. The lasing modes are controlled by properly designing the lasing cavity, output waveguide and injection pattern. Dual-transverse-mode lasing with a tunable wavelength interval from 0.25 to 0.39 nm is realized by using a spatially selective current injection to modulate the refractive index, as the mode field distributions of different transverse are spatially separated. The wavelength interval can be further increased to a few nanometers by reducing the cavity size and replacing the flat sidewalls with circular arcs. The field distributions of WG-like modes distribute uniformly in square microcavity, which avoid the burning-induced carrier diffusion in high-speed direct modulation. A small-signal modulation 3dB bandwidth exceeding 16 GHz, and an open eye diagram at 25 Gb/s are demonstrated for the high-speed direct modulated square microcavity laser.

A circular-side hexagonal microresonator with an output waveguide is proposed for realizing single-transverse-mode microlaser with unidirectional emission. Single-transverse-mode lasing with a threshold current of 2mA and side-mode-suppression ratios of more than 36dB is demonstrated.

Hybrid square-rectangular lasers capable of mode control are proposed and fabricated. Single mode and unidirectional emission operation are obtained with a side-mode suppression-ratio up to 46 dB and single-mode-fiber coupling loss of 3.2 dB.