Women's experiences with Centering-Based Group Care in Zhejiang China: A pilot study.

BACKGROUND: The group prenatal care model, which caters to women with low medical needs but high support needs, has become a highly prevalent and innovative approach implemented globally. For Centering-Based Group Care (CBGC) to remain effective, women's evaluations of the quality of care and perspectives about the model are crucial. AIM: This study aimed to describe women's appraisal of CBGC quality and explore the experiences of women in the mixed-methods pilot study conducted in Zhejiang, China. METHODS: From August 2021 to December 2022, 20 women provided complete quantitative data using the Quality of Prenatal Care Questionnaire before hospital discharge. Semi-structured interviews were conducted at 6 months postpartum. Qualitative data were analysed using Colaizzi's method. FINDINGS: The mean (standard deviation) total score (of the 5) of the questionnaire was 4.43 (0.1) with a good quality of CBGC. Qualitative research identified five themes: motivations and concerns for participation, the appeal of interactive learning, the development of community ties and social support, healing from psychological trauma with CBGC, and suggestions for CBGC enhancement. DISCUSSION: Women rated CBGC quality as good and benefited significantly from it in the study. As a new alternative option, the women's accounts suggested that CBGC performed excellently in enhancing knowledge, strengthening social bonds, and providing psychological support. CONCLUSION: CBGC quality cannot be determined based on limited the sample size. This pilot study provides evidence regarding the beneficial effects of knowledge, socialization, and psychological healing on CBGC. Further research is suggested to measure CBGC effectiveness and quality.

The effect of in-hospital breast milk intake on the gut microbiota of preterm infants.

OBJECTIVE: The aim of this study was to explore the effect of in-hospital breast milk intake on the development of early gut microbiota in preterm infants in two dimensions: longitudinal over time and cross-sectional between groups. METHODS: Researchers collected preterm infants' general data baseline characteristics, recorded their daily breast milk intake, probiotics, and antibiotics use, and collected their stool specimens at 1st week, 2 nd week, 3rd week and 4th week after birth. The researchers analyzed the effect of breast milk on gut microbiota of preterm infants by bioinformatics methods of intra-group longitudinal variation of gut microbiota structure and diversity in preterm infants and cross-sectional differences between >70 % in-hospital breast milk intake (BM) group and ≤70 % (PF) group. RESULTS: A total of 60 preterm infants were included in this study, and a total of 213 stool specimens were retained. BM had statistically different Shannon and Simpson indices between the first and fourth week after admission (P < 0.05), both of them showed a lower diversity in the later week than in the previous week. The Shannon index and Simpson index of BM from week 3 onwards were statistically different from PF (P < 0.05), and the Shannon index and Simpson index of BM were lower than those of PF. Significantly statistical differences (P < 0.05) were found in the beta diversity of gut microbiota in preterm infants as time progressed, and both showed a lower beta diversity in the later week than in the preceding week. The dominant taxa of PF in the first postnatal week were Bifidobacterium animalis, etc., the dominant taxa of BM in the third postnatal week were Clostridium_sensu_stricto _1, etc. CONCLUSIONS: The development and evolution of gut microbiota in preterm infants' in-hospital period was a continuous, non-random process, and similar trends in species composition and changes in gut microbes emerged in preterm infants with different ratio of breast milk intake. In the NICU setting, alpha diversity was lower in preterm infants in the >70 % breast milk intake group than in the ≤70 % group when compared between groups at the same time, which may be related to delayed maturation of gut microbes and represents a more developmental gut time window.

NUPR1 packaged in extracellular vesicles promotes murine triple-negative breast cancer in a type 1 interferon-independent manner.

Aim: This study aims to elucidate the involvement of triple-negative breast cancer (TNBC)-derived extracellular vesicles in metastasis. The loss of components in the type 1 interferon (IFN1) signaling pathway has been linked to the promotion of metastasis. However, IFN1 signaling induces immunological dormancy and promotes tumorigenesis. Our hypothesis was that TNBC cells release tumor-derived extracellular vesicles (TEVs) that promote metastasis in an IFN1-independent manner. Methods: Two murine TNBC models and transgenic mice were used to examine the role of IFN1 in TNBC progression to metastasis. Reserpine was employed to determine the effect of TEV education on TNBC progression and overall survival. EVs from cancer cells treated with vehicle and reserpine and from the serum of tumor-bearing mice receiving reserpine were examined to determine changes in EV release and EV content. Results: TNBC cells progress to metastasis in mice lacking the IFN1-induced gene cholesterol-25 hydroxylase (CH25H) or expressing the IFNAR1S526 knock-in that cannot be downregulated. Reserpine suppresses EV release from TNBC cells in vitro and in vivo. Western blot analysis demonstrated reserpine decreased NUPR1 protein levels in EVs. RNAseq analysis demonstrated that endothelial cells lacking CH25H treated with TEVs exhibited increased NUPR1 expression that was decreased by adding reserpine with the TEVs. NUPR1 overexpression upregulated genes that mediate TEV biogenesis and incorporation. Knockdown of NUPR1 with shRNA decreased the release of TEVs. Conclusion: In conclusion, our study suggests that TNBC is driven by aberrant packaging of NUPR1 into TEVs which were transferred into recipient cells to activate pro-metastatic transcription driven by NUPR1.

Structural and functional characterization of triketone dioxygenase from Oryza Sativa.

The transgenic expression of rice triketone dioxygenase (TDO; also known as HIS1) can provide protection from triketone herbicides to susceptible dicot crops such as soybean. Triketones are phytotoxic inhibitors of plant hydroxyphenylpyruvate dioxygenases (HPPD). The TDO gene codes for an iron/2-oxoglutarate-dependent oxidoreductase. We obtained an X-ray crystal structure of TDO using SeMet-SAD phasing to 3.16 Å resolution. The structure reveals that TDO possesses a fold like that of Arabidopsis thaliana 2-oxoglutarate­iron-dependent oxygenase anthocyanidin synthase (ANS). Unlike ANS, this TDO structure lacks bound metals or cofactors, and we propose this is because the disordered flexible loop over the active site is sterically constrained from folding properly in the crystal lattice. A combination of mass spectrometry, nuclear magnetic resonance, and enzyme activity studies indicate that rice TDO oxidizes mesotrione in a series of steps; first producing 5-hydroxy-mesotrione and then oxy-mesotrione. Evidence suggests that 5-hydroxy-mesotrione is a much weaker inhibitor of HPPD than mesotrione, and oxy-mesotrione has virtually no inhibitory activity. Of the close homologues which have been tested, only corn and rice TDO have enzymatic activity and the ability to protect plants from mesotrione. Correlating sequence and structure has identified four amino acids necessary for TDO activity. Introducing these four amino acids imparts activity to a mesotrione-inactive TDO-like protein from sorghum, which may expand triketone herbicide resistance in new crop species.

LOC102549726/miR-760-3p network is involved in the progression of ISO-induced pathological cardiomyocyte hypertrophy via endoplasmic reticulum stress.

Pathological cardiac hypertrophy (CH) is featured by myocyte enlargement and cardiac malfunction. Multiple signaling pathways have been implicated in diverse pathological and physiological processes in CH. However, the function of LOC102549726/miR-760-3p network in CH remains unclear. Here, we characterize the functional role of LOC102549726/miR-760-3p network in CH and delineate the underlying mechanism. The expression of LncRNA LOC102549726 and hypertrophic markers was significantly increased compared to the control, while the level of miR-760-3p was decreased. Next, we examined ER stress response in a hypertrophic cardiomyocyte model. The expression of ER stress markers was greatly enhanced after incubation with ISO. The hypertrophic reaction, ER stress response, and increased potassium and calcium ion channels were alleviated by genetic downregulation of LOC102549726. It has been demonstrated that LOC102549726 functions as a competitive endogenous RNA (ceRNA) of miR-760-3p. Overexpression of miR-760-3p decreased cell surface area and substantially mitigated ER stress response; protein levels of potassium and calcium channels were also significantly up-regulated compared to the NC control. In contrast, miR-760-3p inhibition increased cell size, aggravated CH and ER stress responses, and reduced ion channels. Collectively, in this study we demonstrated that the LOC102549726/miR-760-3p network was a crucial regulator of CH development. Ion channels mediate the ER stress response and may be a downstream sensor of the LOC102549726/miR-760-3p network. Therefore, these findings advance our understanding of pathological CH and provide new insights into therapeutic targets for cardiac remodeling.

Characterization of histone chaperone MCM2 as a key regulator in arsenic-induced depletion of H3.3 at genomic loci.

Arsenic exposure is associated with an increased risk of many cancers, and epigenetic mechanisms play a crucial role in arsenic-mediated carcinogenesis. Our previous studies have shown that arsenic exposure induces polyadenylation of H3.1 mRNA and inhibits the deposition of H3.3 at critical gene regulatory elements. However, the precise underling mechanisms are not yet understood. To characterize the factors governing arsenic-induced inhibition of H3.3 assembly through H3.1 mRNA polyadenylation, we utilized mass spectrometry to identify the proteins, especially histone chaperones, with reduced binding affinity to H3.3 under conditions of arsenic exposure and polyadenylated H3.1 mRNA overexpression. Our findings reveal that the interaction between H3.3 and the histone chaperon protein MCM2 is diminished by both polyadenylated H3.1 mRNA overexpression and arsenic treatment in human lung epithelial BEAS-2B cells. The increased binding of MCM2 to H3.1, resulting from elevated H3.1 protein levels, appears to contribute to the reduced availability of MCM2 for H3.3. To further investigate the role of MCM2 in H3.3 deposition during arsenic exposure and H3.1 mRNA polyadenylation, we overexpressed MCM2 in BEAS-2B cells overexpressing polyadenylated H3.1 or exposed to arsenic. Our results demonstrate that MCM2 overexpression attenuates H3.3 depletion at several genomic loci, suggesting its involvement in the arsenic-induced displacement of H3.3 mediated by H3.1 mRNA polyadenylation. These findings suggest that changes in the association between histone chaperone MCM2 and H3.3 due to polyadenylation of H3.1 mRNA may play a pivotal role in arsenic-induced carcinogenesis.

A Hybrid Scheme for Disaster-Monitoring Applications in Wireless Sensor Networks.

Disaster monitoring is a primary task for wireless sensor networks. Systems for the rapid reporting of earthquake information are a crucial aspect of disaster monitoring. Furthermore, during emergency rescue after a large earthquake, wireless sensor networks can provide pictures and sound information to save lives. Therefore, when accompanied by multimedia data flow, the alert and seismic data sent by the seismic monitoring nodes must be sufficiently fast. We present herein the architecture of a collaborative disaster-monitoring system that can obtain seismic data in a highly energy-efficient manner. In this paper, a hybrid superior node token ring MAC scheme is proposed for disaster monitoring in wireless sensor networks. This scheme consists of set-up and steady-state stages. A clustering approach was proposed for heterogeneous networks during the set-up stage. The proposed MAC operates in the duty cycle mode at the steady-state stage and is based on the virtual token ring of ordinary nodes, the polling all the superior nodes in one period, and alert transmissions with a low-power listening and shortened preamble approach during the sleep state. The proposed scheme can simultaneously satisfy the requirements of three types of data in disaster-monitoring applications. Based on embedded Markov chains, a model of the proposed MAC was developed and the mean queue length, mean cycle time, and mean upper bound of the frame delay were obtained. Using simulations under various conditions, the clustering approach performed better than the pLEACH approach, and the theoretical results of the proposed MAC were verified. We found that alerts and superior data have outstanding delay and throughput performances even under heavy traffic intensity, and the proposed MAC can provide a data rate of several hundred kb/s for superior and ordinary data. Considering all three types of data, the frame delay performances of the proposed MAC are better than those of the WirelessHART and DRX schemes, and the alert data of the proposed MAC have a maximum frame delay of 15 ms. These satisfy the application requirements of disaster monitoring.

2,6-diazaspiro[3.4]octan-7-one derivatives as potent sigma-1 receptor antagonists that enhanced the antinociceptive effect of morphine and rescued morphine tolerance.

Opioids are efficacious analgesics for pain treatments. However, their repeated use in large doses often leads to analgesic tolerance, which limits the clinical application. Sigma-1 receptor (σ1R) antagonists were reported to synergistically enhance the analgesic effect of mu opioid receptor (MOR) agonists without amplifying the adverse effects. Therefore, the σ1R is considered a promising drug target for pain management. Based on the recently elucidated co-crystal structure of σ1R with 4-IBP, we designed and developed a series of σ1R antagonists harboring the 2,6-diazaspiro[3.4]octan-7-one scaffold. Through a detailed structure-activity relationship study, we identified compound 32 as a potent σ1R antagonist, which significantly enhanced the antinociceptive effect of morphine and rescued morphine-induced analgesic tolerance. Our results support σ1R antagonism as a promising strategy to develop novel analgesics and highlight the therapeutic potential of compound 32 to prevent morphine tolerance.

Development of a series of quinazoline-2,5-diamine derivatives as potent hematopoietic progenitor kinase 1 (HPK1) inhibitors.

Hematopoietic progenitor kinase 1 (HPK1) is a serine/threonine kinase that serves as the negative regulator of multiple immune signaling pathways. Genetic studies using HPK1 knockout and kinase-dead mice suggested that inhibiting HPK1 either alone or in combination with immune checkpoint blockade could be a promising strategy in cancer immunotherapy. Herein, we report the design, synthesis and structure-activity relationship (SAR) study of a series of potent HPK1 inhibitors bearing quinazoline-2,5-diamine scaffold. Three rounds of SAR exploration led to the identification of 9h, the most potent compound in this series which harbors a 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl substituent. Further biological assessments using human immune cells demonstrated that 9h could strongly inhibit downstream phosphorylation, augment interleukin-2 (IL-2) production and reverse prostaglandin E2 (PGE2)-induced immune suppression. Overall, our study on these quinazoline-2,5-diamine derivatives provided not only a tool compound for the community to help with elucidating the HPK1 pharmacology, but also a reliable reference for subsequent development of HPK1 inhibitors.

Design, synthesis and biological evaluation of 4-aminoquinoline derivatives as receptor-interacting protein kinase 2 (RIPK2) inhibitors.

Receptor-interacting protein kinase 2 (RIPK2) is an essential protein kinase mediating signal transduction by NOD1 and NOD2, which play an important role in regulating immune signalling. In this study, we designed and synthesised a novel series of 4-aminoquinoline-based derivatives as RIPK2 inhibitors. In vitro, compound 14 exhibited high affinity (IC50 = 5.1 ± 1.6 nM) and excellent selectivity to RIPK2 showing in a dendrogram view of the human kinome phylogenetic tree. Bearing favourable lipophilicity and eligible lipophilic ligand efficiency (LipE), compound 14 was selected to investigate cellular anti-inflammatory effect and was identified as a potent inhibitor to reduce the secretion of MDP-induced TNF-α with a dose-dependent manner. Moreover, compound 14 showed moderate stability in human liver microsome. Given these promising results, compound 14 could serve as a favourable inhibitor of RIPK2 for further physiological and biochemical research so as to be used in therapeutic treatment.

Experiences of mothers of NICU preterm infants in milk management out of the hospital: a qualitative study.

BACKGROUND: Human milk is important for the health and development of preterm infants. China's neonatal intensive care units (NICUs) have adopted the management system of maternal-infant separation. Human milk received and used by NICUs is managed by the infants' families in the out-of-hospital environment. There is scant publication on mothers' opinions on out-of-hospital human milk management. This study aimed to explore the experiences of Chinese mothers providing their infants in the NICUs with human milk expressed outside of the hospital. METHODS: Semi-structured interviews were conducted with 23 participants recruited from June 2020 to November 2020, who transported their human milk to the human milk bank of Women's Hospital School of Medicine Zhejiang University during the hospitalization of their preterm infants. This study adopted a qualitative research approach with thematic analysis. RESULTS: Three main themes were identified: 1) awareness of human milk management and a willingness to adopt it; 2) lack of standardization regarding expressing, storing, and transporting expressed human milk; and 3) the need for more external support. Theme 2 additionally has three sub-themes: I) differentiation of preparations before human milk expression; II) differentiation of devices for human milk expression; and III) insufficient knowledge and understanding. CONCLUSIONS: In this study, all participants who received health education showed enthusiasm for participating in out-of-hospital human milk management. However, most participants had questions during the implementation process. Medical staff should provide professional and continuous external support to support mothers in implementing human milk management.

What influences the implementation of kangaroo mother care? An umbrella review.

BACKGROUND: Kangaroo mother care (KMC) is an evidence-based intervention that reduces morbidity and mortality in preterm infants. However, it has not yet been fully integrated into health systems around the world. The aim of this study is to provide a cogent summary of the evidence base of the key barriers and facilitators to implementing KMC. METHODS: An umbrella review of existing reviews on KMC was adopted to identify systematic and scoping reviews that analysed data from primary studies. Electronic English databases, including PubMed, Embase, CINAHL and Cochrane Library, and three Chinese databases were searched from inception to 1 July 2022. Studies were included if they performed a review of barriers and facilitators to KMC. Quality assessment of the retrieved reviews was performed by at least two reviewers independently using the Joanna Briggs Institute (JBI) critical appraisal checklist and risk of bias was assessed with the Risk of Bias Assessment Tool for Systematic Reviews (ROBIS) tool. This umbrella review protocol was documented in the PROSPERO registry (CRD42022327994). RESULTS: We generated 531 studies, and after the removal of duplicates and ineligible studies, six eligible reviews were included in the analysis. The five themes identified were environmental factors, professional factors, parent/family factors, access factors, and cultural factors, and the factors under each theme were divided into barriers or facilitators depending on the specific features of a given scenario. CONCLUSIONS: Support from facility management and leadership and well-trained medical staff are of great significance to the successful integration of KMC into daily medical practice, while the parents of preterm infants and other family members should be educated and encouraged in KMC practice. Further research is needed to propose strategies and develop models for implementing KMC.

Effect of family-centred care on parental mental health and parent-infant interactions for preterm infants: a systematic review protocol.

INTRODUCTION: Unexpected premature delivery and separation from preterm infants are common problems that parents of preterm infants must handle with. Parents of preterm infants may suffer from severe psychological distress. Family-centred care (FCC) can effectively ease parents' psychological distress and strengthen connections between parents and their preterm infants. The purpose of this systematic review will be to systematically review and evaluate the impacts of FCC interventions on the mental health of parents of preterm infants and the parent-infant relationship. METHODS AND ANALYSIS: This protocol for this systematic review will be conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol. We will search databases including PubMed, Embase, The Cochrane Library, CINAHL, Web of Science, PsycINFO, Scopus and ProQuest, CNKI, SinoMed and Wanfang Data from 1 July 2012 to 1 July 2022. An additional search of OpenGrey will be conducted to identify grey literature. Randomised controlled trials related to FCC inventions for preterm infants≤37 weeks' gestational age and their parents will be included, and the outcome measures will be parental mental health and parent-infant interaction. Two reviewers will independently conduct title and abstract screening, full-text screening, data extraction and study quality assessment. Risk of bias for the studies will be evaluated using the Cochrane Collaboration Risk of Bias V.2.0. Any disagreements will be solved by a third reviewer to reach a consensus. If appropriate, a meta-analysis will be conducted to assess the effect of FCC on parental mental health and parent-infant relationship. ETHICS AND DISSEMINATION: Research ethics approval will not be required for this review since it will not involve the collection of primary data and will only use published literature. The results will be disseminated in a peer-reviewed journal through publication or by presentation at relevant academic conference. PROSPERO REGISTRATION NUMBER: CRD42022299203.

Downregulation of Stem-Loop Binding Protein by Nicotine via α7-Nicotinic Acetylcholine Receptor and Its Role in Nicotine-Induced Cell Transformation.

The use of electronic-cigarettes (e-cigs) has increased substantially in recent years, particularly among the younger generations. Liquid nicotine is the main component of e-cigs. Previous studies have shown that mice exposed to e-cig aerosols developed lung adenocarcinoma and bladder hyperplasia. These findings implicated a potential role for e-cig aerosols and nicotine in cancer development, although the underlying mechanisms are not fully understood. Here we report that exposure to liquid nicotine or nicotine aerosol generated from e-cig induces downregulation of Stem-loop binding protein (SLBP) and polyadenylation of canonical histone mRNAs in human bronchial epithelial cells and in mice lungs. Canonical histone mRNAs typically do not end in a poly(A) tail and the acquisition of such a tail via depletion of SLBP has been shown to causes chromosome instability. We show that nicotine-induced SLBP depletion is reversed by an inhibitor of α7-nicotinic acetylcholine receptors (α7-nAChR) or siRNA specific for α7-nAChR, indicating a nAChR-dependent reduction of SLBP by nicotine. Moreover, PI3K/AKT pathway is activated by nicotine exposure and CK2 and probably CDK1, 2 kinases well known for their function for SLBP phosphorylation and degradation, are shown to be involved, α7-nAChR-dependently, in nicotine-induced SLBP depletion. Importantly, nicotine-induced anchorage-independent cell growth is attenuated by inhibition of α7-nAChR and is rescued by overexpression of SLBP. We propose that the SLBP depletion and polyadenylation of canonical histone mRNAs via activation of α7-nAChR and a series of downstream signal transduction pathways are critical for nicotine-induced cell transformation and potential carcinogenesis.

Discovery of 4-cyclopropyl-3-(2-((1-cyclopropyl-1H-pyrazol-4-yl) amino) quinazolin-6-yl)-N-(3-(trifluoromethyl) phenyl) benzamides as potent discoidin domain receptor inhibitors for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease with a median survival time of 3-5 years. Inaccurate diagnosis, limited clinical therapy and high mortality together indicate that the development of effective therapeutics for IPF is an urgent need. In recent years, it was reported that DDRs are potential targets in anti-fibrosis treatment. Based on previous work we carried out further structure modifications and led to a more selective inhibitor 47 by averting some fibrosis-unrelated kinases, such as RET, AXL and ALK. Extensive profiling of compound 47 has demonstrated that it has potent DDR1/2 inhibitory activities, low toxicity, good pharmacokinetic properties and reliable in vivo anti-fibrosis efficacy. Therefore, we confirmed that discoidin domain receptors are promising drug targets for IPF, and compound 47 would be a promising candidate for further drug development.

PD-1/L1 With or Without CTLA-4 Inhibitors Versus Chemotherapy in Advanced Non-Small Cell Lung Cancer.

BACKGROUND: With the use of immune-checkpoint inhibitors (ICIs) in advanced or metastatic non-small cell lung cancer (NSCLC), whether ICIs or chemotherapy is more effective still remains controversial. This study was conducted to evaluate the efficacy of programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), cytotoxic T-lymphocyte protein 4 (CTLA-4) alone or in their combination vs chemotherapy in patients with advanced or metastatic NSCLC. METHODS: This meta-analysis was conducted from PubMed, Web of Science, Medline, Embase, and the Cochrane Library up to March 2021 to identify relevant randomized controlled trials. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoint was adverse events (AEs). This meta-analysis's Prospero registration number is CRD42022323570. RESULTS: The search process has identified 13 studies containing 7918 patients with advanced or metastatic NSCLC. The benefit of PD-1/L1 or CTLA-4 inhibitors alone or in combination compared with chemotherapy for advanced or metastatic NSCLC was elucidated in both OS [HR = .75, 95% CI (.70-.80), P < .001] and PFS [HR = .83, 95% CI (.73-.95), P < .001]. Besides, ICIs were associated with fewer AEs compared to chemotherapy. CONCLUSION: PD-1/L1 or CTLA-4 inhibitors alone or in combination, with fewer AEs, was associated with significant improvements in terms of OS and PFS than chemotherapy in advanced or metastatic NSCLC.

Design and development of a novel series of oral bivalent BET inhibitors with potent anticancer activities.

Bromodomain and extraterminal domain (BET) subfamily members are intriguing targets for cancer treatment. Most of the reported BET inhibitors were monovalent inhibitors. Recently, some bivalent inhibitors were disclosed, which bound to two bromodomains simultaneously. They had good activities, however, most of them also showed unsatisfactory pharmacokinetic properties, which were caused by long chain linkers. Based on our previous work on monovalent BRD4 inhibitors, we designed and synthesized a series of novel bivalent inhibitors with short and hydrophilic linkers. These compounds exhibited better activities than the corresponding monovalent inhibitors and good pharmacokinetic properties. Compound 21 showed excellent in vitro activities. And it also demonstrated potent in vivo antitumor efficacy under oral administration and was well tolerated in in vivo tests.

TRIP13, identified as a hub gene of tumor progression, is the target of microRNA-4693-5p and a potential therapeutic target for colorectal cancer.

Colorectal cancer (CRC) is one of the digestive tract malignancies whose early symptoms are not obvious. This study aimed to identify novel targets for CRC therapy, especially early-stage CRC, by reanalyzing the publicly available GEO and TCGA databases. Thyroid hormone receptor interactor 13 (TRIP13) correlated with tumor progression and prognosis of patients after several rounds of analysis, including weighted gene correlation network analysis (WGCNA), and further chosen for experimental validation in cancer cell lines and patient samples. We identified that mRNA and protein levels of TRIP13 increased in CRC cells and tumor tissues with tumor progression. miR-4693-5p was significantly downregulated in CRC tumor tissues and bound to the 3' untranslated region (3'UTR) of TRIP13, downregulating TRIP13 expression. DCZ0415, a small molecule inhibitor targeting TRIP13, induced anti-tumor activity in vitro and in vivo. DCZ0415 markedly suppressed CRC cell proliferation, migration, and tumor growth, promoted cell apoptosis, and resulted in the arrest of the cell cycle. Our research suggests that TRIP13 might play a crucial role in CRC progression and could be a potential target for CRC therapy.

Potential functions of histone H3.3 lysine 56 acetylation in mammals.

H3K56 acetylation (H3K56Ac) was first identified in yeast and has recently been reported to play important roles in maintaining genomic stability, chromatin assembly, DNA replication, cell cycle progression and DNA repair. Although H3.1K56Ac has been relatively well studied, the function of H3.3K56Ac remains mostly unknown in mammals. In this study, we used H3.3K56Q and H3.3K56R mutants to study the possible function of H3.3K56 acetylation. The K-to-Q substitution mimics a constitutively acetylated lysine, while the K-to-R replacement mimics a constitutively unmodified lysine. We report that cell lines harbouring mutation of H3.3K56R exhibit increased cell death and dramatic morphology changes. Using a Tet-Off inducible system, we found an increased population of polyploid/aneuploid cells and decreased cell viability in H3.3K56R mutant cells. Consistent with these results, the H3.3K56R mutant had compromised H3.3 incorporation into several pericentric and centric heterochromatin regions we tested. Moreover, mass spectrometry analysis coupled with label-free quantification revealed that biological processes regulated by the H3.3-associating proteins, whose interaction with H3.3 was markedly increased by H3.3K56Q mutation but decreased by H3.3K56R mutation, include sister chromatid cohesion, mitotic nuclear division, and mitotic nuclear envelope disassembly. These results suggest that H3.3K56 acetylation is crucial for chromosome segregation and cell division in mammals.

Discovery of a novel DDRs kinase inhibitor XBLJ-13 for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease characterized by destruction of lung parenchyma and deposition of extracellular matrix in interstitial and alveolar spaces. But known drugs for IPF are far from meeting clinical demands, validation of drug targets against pulmonary fibrosis is in urgent demand. Tyrosine kinase receptor DDRs has been considered as a potential therapeutic target for pulmonary fibrosis due to its pathological collagen binding property and the roles in regulating extracellular matrix remodeling. In this study we designed and synthesized a new indazole derivative XBLJ-13, and identified XBLJ-13 as a highly specific and potent DDRs inhibitor with anti-inflammation and anti-fibrosis activities. We first demonstrated that DDR1/2 was highly expressed in the lung tissues of IPF patients. Then we showed that XBLJ-13 potently inhibited DDR1 and DDR2 kinases with IC50 values of 17.18 nM and 15.13 nM, respectively. Among a panel of 34 kinases tested, XBLJ-13 displayed relatively high selectivity for DDRs with minimal inhibitory effect on PDGFR family and FGFR1, as well as Abl kinase that had high homology with DDRs. Extensive profiling of XBLJ-13 revealed that the new inhibitor had much lower toxicity than nintedanib and better pharmacokinetic properties in mice. Furthermore, pharmacodynamic evaluation conducted in bleomycin-induced pulmonary fibrosis mice showed that administration of XBLJ-13 (30, 60, 90 mg·kg-1·d-1, i.g.) for 12 days significantly and dose-dependently ameliorated lung inflammation and fibrosis. Together, this study confirms that DDRs kinase is a potential target for PF, Particularly, compound XBLJ-13 is a highly potent and specific DDRs inhibitor, along with good pharmacokinetics profiles, and preferable in vivo efficacy, suggesting that it is a potential candidate for the treatment of PF.