Retracted: Effect of Sham Acupuncture on Chronic Pain: A Bayesian Network Meta-Analysis.

BACKGROUND: Along with increasing research on acupuncture for chronic pain, the validity of sham acupuncture (SA) has also been argued. METHODS: Nine databases were searched for randomized controlled trials (RCTs) from the inception dates of the databases to July 5, 2022. With Markov Chain Monte Carlo methods, a Bayesian multiple-treatment network meta-analysis (NMA) with random-effects model was conducted. RESULTS: A total of 62 RCTs with 6,806 patients and four kinds of treatments (real acupuncture [RA], non-acupuncture [NA], penetrative SA [PSA], and non-penetrative SA [NPSA]) were included. The results indicated that both NPSA and PSA were not superior to NA in improving chronic pain (NPSA: mean difference [MD]= -4.77, 95% confidence interval [CI] -11.09 to 1.52; PSA: MD= -4.96, 95% CI -10.38 to 0.48). After NPSA and PSA were combined into the SA group, the weak trend of pain relief from SA was still not statistically significant (MD= -4.91, 95% CI -9.93 to 0.05). NPSA and PSA had similar effects (MD= 0.18, 95% CI -5.45 to 5.81). RA was significantly associated with pain relief, compared with NPSA and PSA (NPSA: MD= -12.03, 95% CI -16.62 to -7.41; PSA: MD= -11.85, 95% CI -15.48 to -8.23). The results were generally consistent regardless of pain phenotype, frequency, duration, acupuncture methods, analgesic intake, or detection bias. CONCLUSION: These results suggested that acupuncture was significantly associated with reduced chronic pain. The two kinds of placebo acupuncture, NPSA and PSA, have similar effects. Both NPSA and PSA, with a weak but not significant effect, are appropriate to be inert placebo controls in RCTs for chronic pain.

Comparative efficacy and safety of first-line treatments for advanced non-small cell lung cancer with ALK-rearranged: a meta-analysis of clinical trials.

BACKGROUND: Whereas there are many pharmacological interventions prescribed for patients with advanced anaplastic lymphoma kinase (ALK)- rearranged non-small cell lung cancer (NSCLC), comparative data between novel generation ALK-tyrosine kinase inhibitors (TKIs) remain scant. Here, we indirectly compared the efficacy and safety of first-line systemic therapeutic options used for the treatment of ALK-rearranged NSCLC. METHODS: We included all phase 2 and 3 randomised controlled trials (RCTs) comparing any two or three treatment options. Eligible studies reported at least one of the following outcomes: progression free survival (PFS), overall survival (OS), objective response rate (ORR), or adverse events of grade 3 or higher (Grade ≥ 3 AEs). Subgroup analysis was conducted according to central nervous system (CNS) metastases. RESULTS: A total of 9 RCTs consisting of 2484 patients with 8 treatment options were included in the systematic review. Our analysis showed that alectinib (300 mg and 600 mg), brigatinib, lorlatinib and ensartinib yielded the most favorable PFS. Whereas there was no significant OS or ORR difference among the ALK-TKIs. According to Bayesian ranking profiles, lorlatinib, alectinib 600 mg and alectinib 300 mg had the best PFS (63.7%), OS (35.9%) and ORR (37%), respectively. On the other hand, ceritinib showed the highest rate of severe adverse events (60%). CONCLUSION: Our analysis indicated that alectinib and lorlatinib might be associated with the best therapeutic efficacy in first-line treatment for major population of advanced NSCLC patients with ALK-rearrangement. However, since there is little comparative evidence on the treatment options, there is need for relative trials to fully determine the best treatment options as well as the rapidly evolving treatment landscape.

Genome-wide identification, characterization, and expression analysis of the TRAF gene family in Chinese tongue sole (Cynoglossus semilaevis).

Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) play crucial roles as signaling mediators for the TNF receptor (TNFR) superfamily and the interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) superfamily. TRAFs collectively play important roles in multiple biological processes and organismal immunity. However, systematic identification of the TRAF gene family in teleost fish has not yet been reported, and there is little available information about its roles in innate immunity in Chinese tongue sole (Cynoglossus semilaevis), an aquaculture fish of high economic value. In the present study, we identified and characterized seven TRAF genes, namely, CsTRAF2a, CsTRAF2b, CsTRAF3, CsTRAF4, CsTRAF5, CsTRAF6 and CsTRAF7, in Chinese tongue sole, and the complete ORFs of the CsTRAFs were cloned. Sequence analysis revealed various genomic structures of the CsTRAFs and showed that they contain typical conserved domains compared with mammalian TRAFs. Phylogenetic analysis indicated the evolutionary relationships of TRAF family members in teleost fish and revealed an absence of TRAF1 in most species and TRAF5 in some species of teleosts. Analysis of the gene structures and motifs showed the diversity and distribution of exon-intron structures and conserved motifs in Chinese tongue sole and several other teleost species. Real-time quantitative PCR was used to investigate the expression patterns of CsTRAF genes in tissues of healthy fish and in the gills, livers and spleens of fish after bacterial infection with Vibrio harveyi. The results indicate that only CsTRAF2a is relatively highly expressed in the brain and that the other CsTRAFs are highly expressed in immune-related tissues and may participate in the immune response after infection with pathogenic bacteria. Functional analysis of CsTRAF3, CsTRAF4 and CsTRAF6 revealed that only CsTRAF6 could strongly activate the NF-кB pathway after overexpression of CsTRAF3, CsTRAF4 and CsTRAF6 in HEK-293T cells. This systematic analysis provided valuable information about the diverse roles of TRAFs in the innate immune response to pathogenic bacterial infection in teleost fish and will contribute to the functional characterization of CsTRAF genes in further research.

pik3r3b, a novel immune-related gene in Nile tilapia (Oreochromis niloticus): Identification, expression and analysis of antibacterial activity.

A full-length cDNA encoding phosphatidylinositol 3-kinase regulatory subunit gamma b gene in Nile tilapia (Oreochromis niloticus), termed as On-pik3r3b, was identified and characterized in this study. The sequence analysis demonstrated that the full-length cDNA of On-pik3r3b was 2018 bp, containing a 5' untranslated region (UTR) of 171 bp, an open reading frame (ORF) of 1422 bp and a 3' UTR of 425 bp. Its protein sequence displayed a high degree of identity with other fish. Using qPCR, the expression patterns of On-pik3r3b were investigated. In healthy Nile tilapia, the transcripts of On-pik3r3b were detected in all examined tissues, except the skin. Upon the stimulation with Streptococcus agalactiae, the On-pik3r3b expression level in liver, spleen, kidney and gill were significantly increased at 12 h after infection. The recombinant On-pik3r3b showed in vitro antibacterial activity, against S. agalactiae and E. coli. Our observation strongly indicates that On-pik3r3b is involved in the innate immune response in Nile tilapia.

Cloning, characterization and functional analysis of dctn5 in immune response of Chinese tongue sole (Cynoglossus semilaevis).

In mammals, microtubule-dependent trafficking could participate the immune response, where the motor proteins are suggested to play an important role in this process, while the related study in fish was rare. In this study, dctn5, a subunit of dyactin complex for docking motor protein, was obtained by previous immune QTL screening. The full-length cDNAs of two dctn5 transcript variants were cloned and identified (named dctn5_tv1 and dctn5_tv2, respectively). Tissue distribution showed that dctn5_tv1 was widely distributed and high transcription was observed in immune tissue (skin), while dctn5_tv2 was predominantly detected in gonad and very low in other tissues. Time-course expression analysis revealed that dctn5_tv1 could be up-regulated in gill, intestine, skin, spleen, and kidney after Vibrio harveyi challenge. Moreover, recombinant Dctn5_tv1 exhibited high antimicrobial activity against Escherichia coli and Streptococcus agalactiae due to binding to bacteria cells. Taken together, these data suggest Dctn5_tv1 is involved in immune response of bacterial invasion in Chinese tongue sole.

Studies on [5,6]-Fused Bicyclic Scaffolds Derivatives as Potent Dual B-RafV600E/KDR Inhibitors Using Docking and 3D-QSAR Approaches.

Research and development of multi-target inhibitors has attracted increasing attention as anticancer therapeutics. B-RafV600E synergistically works with vascular endothelial growth factor receptor 2 (KDR) to promote the occurrence and progression of cancers, and the development of dual-target drugs simultaneously against these two kinds of kinase may offer a better treatment advantage. In this paper, docking and three-dimensional quantitative structure activity relationship (3D-QSAR) studies were performed on a series of dual B-Raf/KDR inhibitors with a novel hinge-binding group, [5,6]-fused bicyclic scaffold. Docking studies revealed optimal binding conformations of these compounds interacting with both B-Raf and KDR. Based on these conformations, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) 3D-QSAR models were constructed, and the best CoMFA (q²=0.542, r²=0.989 for B-Raf; q²=0.768, r²=0.991 for KDR) and CoMSIA models (q²=0.519, r²=0.992 for B-Raf; q²=0.849, r²=0.993 for KDR) were generated. Further external validations confirmed their predictability, yielding satisfactory correlation coefficients (r²pred=0.764 (CoMFA), r²pred=0.841 (CoMSIA) for B-Raf, r²pred=0.912 (CoMFA), r²pred=0.846 (CoMSIA) for KDR, respectively). Through graphical analysis and comparison on docking results and 3D-QSAR contour maps, key amino acids that affect the ligand-receptor interactions were identified and structural features influencing the activities were discussed. New potent derivatives were designed, and subjected to preliminary pharmacological evaluation. The study may offer useful references for the modification and development of novel dual B-Raf/KDR inhibitors.

The pivotal application of patient-derived organoid biobanks for personalized treatment of gastrointestinal cancers.

Gastrointestinal cancers (GICs) occupy more than 30% of the cancer-related incidence and mortality around the world. Despite advances in the treatment strategies, the long-term overall survival has not been improved for patients with GICs. Recently, the novel patient-derived organoid (PDO) culture technology has become a powerful tool for GICs in a manner that recapitulates the morphology, pathology, genetic, phenotypic, and behavior traits of the original tumors. Excitingly, a number of evidences suggest that the versatile technology has great potential for personalized treatment, suppling the clinical application of molecularly guided personalized treatment. In the paper, we summarize the literature on the topics of establishing organoid biobanks of PDOs, and their application in the personalized treatment allowing for radiotherapy, chemotherapy, targeted therapy, and immunotherapy selection for GICs. Despite the limitations of current organoid models, high-throughput drug screening of GIC PDO combined with next-generation sequencing technology represents a novel and pivotal preclinical model for precision medicine of tumors and has a great value in promoting the transformation from basic cancer research to clinical application.

Dissecting the ferroptosis-related prognostic biomarker and immune microenvironment of driver gene-negative lung cancer.

Despite significant advances in targeted and immune therapy for non-small cell lung cancer (NSCLC), effective therapies for wild-type epidermal growth factor receptor/anaplastic lymphoma kinase (EGFR/ALKWT) with low expression of programmed death ligand-1 (PD-L1) NSCLC remain elusive. Numerous studies have shown that ferroptosis plays an essential role in antitumor activity. To identify the molecular regulation patterns associated with ferroptosis, 351 EGFR/ALKWT NSCLC samples with low-level PD-L1 were extracted from The Cancer Genome Atlas (TCGA) and clustered using the k-means clustering technique. The two clusters associated with ferroptosis showed significantly different prognoses. In total, 169 differential expression genes (DEGs) were identified. Cluster differential analysis revealed that Cluster 1 had a significantly poorer overall survival (OS) and was associated with more negative immune regulation. In addition, TCGA samples were randomly assigned in a 7:3 ratio to a training group or testing group. A signature of eight genes associated with ferroptosis was established in the training cohort using DEGs and validated in the test cohort and three independent cohorts (GSE72049, GSE41271, and GSE50081). The 5-year area under the curve (AUC) was 0.713, which was significantly higher than that of other predictors, including TNM stage and age. Furthermore, the risk score was associated with immune function, immune infiltration, and immunotherapy response, with high-risk patients having a worse prognosis, an immune-suppressing phenotype, and a poor response to immune checkpoint inhibitors. This study aims to contribute to our understanding of the biological role of ferroptosis in EGFR/ALKWT NSCLC with low-level PD-L1, laying the groundwork for the development of novel therapeutic strategies.

Bone metastasis attenuates efficacy of immune checkpoint inhibitors and displays "cold" immune characteristics in Non-small cell lung cancer.

OBJECTIVES: This study aimed to assess the clinical characteristics affecting outcomes after immune checkpoint inhibitors (ICI) therapies in non-small cell lung cancer (NSCLC) patients, and the underlying mechanism in tumor immune micro-environment (TIME). MATERIALS AND METHODS: A total of 144 patients treated with ICI-based strategies were retrospectively analyzed. Expression of 10 immune antibodies in tumor tissues from other 60 untreated NSCLC patients were sequentially tested using multiplexed immunofluorescence (mIF) staining method. Correlation of clinical characteristics with ICI treatment outcomes and TIME characteristics were analyzed. RESULTS: Multivariate logistic and cox regression indicated that BoM negatively affected disease control rate (OR = 0.32, 95%CI: 0.13-0.82, P = 0.018), progression free survival (HR = 3.44, 95% CI:1.97-6.00, P < 0.001) and overall survival (HR = 3.24, 95% CI:1.62-6.50, P = 0.001), irrespective of programmed death-ligand 1 (PD-L1) expression. BoM patients were with significantly lower PD-L1, and this heterogeneity of TIME was then confirmed in the mIF staining, where 36 (61.0%) patients were clustered into immune-subtype A, with low expression of all the detected immune markers, similar to "cold" tumors, and 23 (39.0%) in cluster B with likely "hot" tumors. More patients in immune-subtype A were non-smokers (63.9% vs. 39.1% P = 0.063), with BoM (66.7% vs. 21.7%, P = 0.001), in stage IV(88.9% vs. 65.2%, P = 0.045), and with adenocarcinoma (91.7% vs. 69.6%, P = 0.037). Multivariate logistic regression indicated that BoM was independently associated with the "cold" immune characteristics (OR = 0.19, 95% CI:0.04-0.84, P = 0.028). Combination therapy with chemotherapy /antiangiogenesis or use of bisphosphonate during ICI treatment significantly improved clinical outcomes in BoM patients. CONCLUSIONS: BoM displays adverse impact on clinical outcomes after ICI treatments in NSCLC patients. The "cold" characteristics of TIME may be the underlying mechanism for the attenuated efficacy of ICIs in bone metastatic NSCLC patients.

Erratum to "Qing-Kai-Ling Injection Acts Better Than Shen-Fu Injection in Enhancing the Antitumor Effect of Gefitinib in Resistant Non-Small Cell Lung Cancer Models".

[This corrects the article DOI: 10.1155/2021/9911935.].

[Clinical observation on acupuncture for symptom burden in gastric cancer patients undergoing adjuvant chemotherapy after gastrectomy].

OBJECTIVE: To observe the efficacy of acupuncture on symptom burden in patients with gastric cancer during adjuvant chemotherapy after gastrectomy. METHODS: A total of 58 patients were randomized into a high-dose acupuncture group (19 cases, 5 cases dropped off), a low-dose acupuncture group (20 cases, 6 cases dropped off) and a control group (19 cases, 2 cases dropped off). Conventional chemotherapy and antiemetic treatment were adopted in the control group. On the basis of the treatment in the control group, acupuncture was applied 7 times each chemotherapy cycle for totally 21 times in the high-dose acupuncture group, and 3 times each chemotherapy cycle for totally 9 times in the low-dose acupuncture group. Baihui (GV 20), Zusanli (ST 36), Neiguan (PC 6), etc. were selected in the two acupuncture groups, as well as back-shu points selected by the meridian heat sensing technique. Electroacupuncture was connected to ipsilateral Zusanli (ST 36) and Neiguan (PC 6), with continuous wave, 2 Hz in frequency for 20 min. The Edmonton symptom assessment system (ESAS) score was observed on day 1-7, 14, and 21 of each cycle of chemotherapy respectively in the 3 groups. RESULTS: The symptom burden was worst within 7 days of each cycle of chemotherapy in the 3 groups. After the 3rd chemotherapy cycle, the total score of ESAS in the low-dose acupuncture group was lower than the control group (P<0.05), the total score and the scores of feeling of non-well being, pain and shortness of breath of ESAS in the acupuncture group (the high-dose acupuncture group combined with the low-dose acupuncture group) were lower than the control group (P<0.05). CONCLUSION: Acupuncture shows promising effect in controlling symptom burden during adjuvant chemotherapy in gastric cancer patients after gastrectomy.

Acupuncture for Quality of Life in Gastric Cancer Patients Undergoing Adjuvant Chemotherapy.

CONTEXT: Patients with gastric cancer experience health-related quality of life (HRQOL) decline during adjuvant chemotherapy following gastrectomy. OBJECTIVES: This pilot study aimed to evaluate the preliminary effect and feasibility of electro-acupuncture (EA) for HRQOL and symptom burden in these patients. METHODS: In this open-label, multicenter, parallel controlled trial, gastric cancer patients who planned to receive adjuvant chemotherapy were randomly assigned to receive high-dose EA (seven times each chemotherapy cycle for three cycles), low-dose EA (three times each chemotherapy cycle), or usual care only. The acupoints prescription consisted of bilateral ST36, PC6, SP4, and DU20, EX-HN3, and selected Back-shu points. Patients completed the Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) weekly, and the Edmonton Symptom Assessment System (ESAS). The primary outcome was the difference among the groups on the gastric cancer subscale (GaCS) of the FACT-Ga. RESULTS: Of the 66 randomized patients, 58 were analyzed according to intention-to-treat principle, and 45 were in the per-protocol set (PPS). The average scores in PPS of GaCS were 52.12±9.71, 51.85±12.36, and 45.37±8.61 in high-dose EA, low-dose EA, and control groups, respectively. EA was significantly associated with improved average GaCS scores when compared with control group (51.98±10.91 vs. 45.37±8.61, P = 0.039). EA treatment also produced ESAS relief at the end of intervention (14.36 ± 12.28 vs. 23.91 ± 15.52, P = 0.027). Participants in EA groups had fewer grade ≥3 leukopenia (0% vs. 15.79%, P = 0.031) and neutropenia (2.56% vs. 26.31%, P = 0.012). CONCLUSION: EA showed promising effects in improving HRQOL, controlling symptom burden, and reducing toxicity during adjuvant chemotherapy in gastric cancer patients. Future adequately powered trials are feasible and needed to confirm the specific effect of EA.

Rational design, synthesis, biological evaluation, homology and docking studies of coumarin derivatives as α1 -adrenoceptor antagonists.

According to a three-point pharmacophore for some uro-selective α(1) -adrenoceptor (AR) antagonists, a novel class of coumarin (=2H-1-benzopyran-2-one) derivatives have been successfully designed and synthesized with high efficacies for α(1) -AR. These synthesized coumarin derivatives exhibited high efficacies towards α(1) -AR in in vitro pharmacological assays. Compared with prazosin (pK(i) value of 8.77), among those coumarins, tolylpiperazine-substituted derivatives, 7 and 8, have comparable pK(i) values of 8.81 and 8.77, respectively. The trend in efficacies of these coumarin derivatives towards α(1A) -adrenoceptor was further rationalized by intensive molecular docking. Our work demonstrated that the designed coumarin derivatives can inhibit α(1) -AR in vitro. These findings will provide a guide for further studies of the medical therapy of benign prostatic hyperplasia (BPH).

Combined pharmacophore modeling, docking, and 3D-QSAR studies of PLK1 inhibitors.

Polo-like kinase 1, an important enzyme with diverse biological actions in cell mitosis, is a promising target for developing novel anticancer drugs. A combined molecular docking, structure-based pharmacophore modeling and three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on a set of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as PLK1 inhibitors. The common substructure, molecular docking and pharmacophore-based alignment were used to develop different 3D-QSAR models. The comparative molecular field analysis (CoMFA) and comparative molecule similarity indices analysis (CoMSIA) models gave statistically significant results. These models showed good q(2) and r(2) (pred) values and revealed a good response to test set validation. All of the structural insights obtained from the 3D-QSAR contour maps are consistent with the available crystal structure of PLK1. The contour maps obtained from the 3D-QSAR models in combination with the structure based pharmacophore model help to better interpret the structure-activity relationship. These satisfactory results may aid the design of novel PLK1 inhibitors. This is the first report on 3D-QSAR study of PLK1 inhibitors.

Qing-Kai-Ling Injection Acts Better Than Shen-Fu Injection in Enhancing the Antitumor Effect of Gefitinib in Resistant Non-Small Cell Lung Cancer Models.

Patients with EGFR gene mutation often obtain de novo resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) or develop secondary resistance to EGFR-TKIs after taking EGFR-TKI therapy. Traditional Chinese medicine (TCM) with different treatment principles, in combination with EGFR-TKIs, plays an important role in the treatment of cancers including resistant non-small cell lung cancer (NSCLC). However, inappropriate use of TCM herbs may induce resistance to gefitinib. Therefore, it is of a great value to evaluate which TCM treatment principle should be combined with EGFR-TKIs, and which one should be avoided, and find out the potential mechanisms. The lentiviral transfection assay was used for overexpression of PIK3CA mutation gene in PC-9 cells to construct PC-9-PIK3CA-mutation (PC-9-PIK3CA-M) cells. Cell proliferation, apoptosis, and the expression of EGFR/PI3K/AKT and EGFR/RAS/RAF/ERK in PC-9-PIK3CA-M and H1975 cells treated by the typical cooling-heat drug, Qing-kai-ling (QKL) and Tan-re-qing (TRQ), or the typical warming-yang drug, Shen-fu (SF) and gefitinib treatment, were detected by MTT, Annexin V/PI double labeling, and Western blot assays, respectively. Tumor xenograft and immunohistochemistry experiments were carried out to confirm the in vitro findings. PC-9-PIK3CA-M cells were less sensitive to gefitinib, when compared with PC-9 cells. QKL injection and TRQ injection, not SF injection, combined with gefitinib induced significantly increased cell growth inhibition and apoptosis in PC-9-PIK3CA-M and H1975 cells. SF injection antagonized the effect of gefitinib in promoting cancer cell apoptosis. QKL injection and TRQ injection increased the sensitivity of gefitinib by inhibiting the phosphorylation of AKT or ERK in H1975 and PC-9-PIK3CA-M cells. Similar findings were observed in vivo in H1975 xenograft mouse model. QKL and TRQ, with cooling-heat TCM treatment principle, should be combined with gefitinib in the treatment of NSCLC. Furthermore, warming-yang drug SF should be avoided to be used together with EGFR-TKIs.

[Structure and expression analysis of cbp gene in different natural colored-cocoon strains of Bombyx mori].

Carotenoid-binding protein (CBP) is the only key protein that has been characterized to be involved in yellow cocoon coloration of the domesticated silkworm (Bombyx mori). Gene structure and mRNA expression profiles of cbp along with UV-Vis spectrum profiles of carotenoids in silk glands were investigated among twelve strains to disclose their relationship with cocoon color. Yellow cocoon strains of B. mori contained two or three cbp gene types, which had different mRNA products with a longer form acting functionally to code CBP protein and the smaller one without exon 2. The structures of cbp were different among the green cocoon strains with the mRNA product lacking exon 2. Only one cbp gene structure existed in white cocoon strains of B. mori, which produced the mRNA product free of exon 2. A newly identified intron 1 sequence of cbp gene in this study may have cocoon color-specificity among strains. The UV-Vis spectrum profiles of carotenoids in the yellow cocoon strains' silk glands were significantly different from those in the green cocoon strains and white cocoon strains.Together, it can be concluded that the gene structure and expression profile of cbp was closely linked to cocoon colors of B. mori.

Improved Prediction of Aqueous Solubility of Novel Compounds by Going Deeper With Deep Learning.

Aqueous solubility is an important physicochemical property of compounds in anti-cancer drug discovery. Artificial intelligence solubility prediction tools have scored impressive performances by employing regression, machine learning, and deep learning methods. The reported performances vary significantly partly because of the different datasets used. Solubility prediction on novel compounds needs to be improved, which may be achieved by going deeper with deep learning. We constructed deeper-net models of ~20-layer modified ResNet convolutional neural network architecture, which were trained and tested with 9,943 compounds encoded by molecular fingerprints. Retrospectively tested by 62 recently-published novel compounds, one deeper-net model outperformed four established tools, shallow-net models, and four human experts. Deeper-net models also outperformed others in predicting the solubility values of a series of novel compounds newly-synthesized for anti-cancer drug discovery. Solubility prediction may be improved by going deeper with deep learning. Our deeper-net models are accessible at http://www.npbdb.net/solubility/index.jsp.

A potent CBP/p300-Snail interaction inhibitor suppresses tumor growth and metastasis in wild-type p53-expressing cancer.

The zinc finger transcription factor Snail is aberrantly activated in many human cancers and associated with poor prognosis. Therefore, targeting Snail is expected to exert therapeutic benefit in patients with cancer. However, Snail has traditionally been considered "undruggable," and no effective pharmacological inhibitors have been identified. Here, we found a small-molecule compound CYD19 that forms a high-affinity interaction with the evolutionarily conserved arginine-174 pocket of Snail protein. In aggressive cancer cells, CYD19 binds to Snail and thus disrupts Snail's interaction with CREB-binding protein (CBP)/p300, which consequently impairs CBP/p300-mediated Snail acetylation and then promotes its degradation through the ubiquitin-proteasome pathway. Moreover, CYD19 restores Snail-dependent repression of wild-type p53, thus reducing tumor growth and survival in vitro and in vivo. In addition, CYD19 reverses Snail-mediated epithelial-mesenchymal transition (EMT) and impairs EMT-associated tumor invasion and metastasis. Our findings demonstrate that pharmacologically targeting Snail by CYD19 may exert potent therapeutic effects in patients with cancer.

Virtual Screening Strategy Combined Bayesian Classification Model, Molecular Docking for Acetyl-CoA Carboxylases Inhibitors.

INTRODUCTION: Acetyl-CoA Carboxylases (ACC) have been an important target for the therapy of metabolic syndrome, such as obesity, hepatic steatosis, insulin resistance, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), type 2 diabetes (T2DM), and some other diseases. METHODS: In this study, virtual screening strategy combined with Bayesian categorization modeling, molecular docking and binding site analysis with protein ligand interaction fingerprint (PLIF) was adopted to validate some potent ACC inhibitors. First, the best Bayesian model with an excellent value of Area Under Curve (AUC) value (training set AUC: 0.972, test set AUC: 0.955) was used to screen compounds of validation library. Then the compounds screened by best Bayesian model were further screened by molecule docking again. RESULTS: Finally, the hit compounds evaluated with four percentages (1%, 2%, 5%, 10%) were verified to reveal enrichment rates for the compounds. The combination of the ligandbased Bayesian model and structure-based virtual screening resulted in the identification of top four compounds which exhibited excellent IC 50 values against ACC in top 1% of the validation library. CONCLUSION: In summary, the whole strategy is of high efficiency, and would be helpful for the discovery of ACC inhibitors and some other target inhibitors.

Pharmacophore identification of Raf-1 kinase inhibitors.

A three-dimensional pharmacophore model was developed based on 25 currently available Raf-1 kinase inhibitors. The best pharmacophore hypothesis (Hypo1), consisting of four chemical features (one hydrogen-bond acceptor, one hydrogen-bond donor, and two hydrophobic groups), has a correlation coefficient of 0.972. The results of our study provide a valuable tool in designing new leads with desired biological activity by virtual screening.