Synthesis and structure-activity optimization of azepane-containing derivatives as PTPN2/PTPN1 inhibitors.

Protein tyrosine phosphatases PTPN2 and PTPN1 (also known as PTP1B) have been implicated in a number of intracellular signaling pathways of immune cells. The inhibition of PTPN2 and PTPN1 has emerged as an attractive approach to sensitize T cell anti-tumor immunity. Two small molecule inhibitors have been entered the clinic. Here we report the design and development of compound 4, a novel small molecule PTPN2/N1 inhibitor demonstrating nanomolar inhibitory potency, good in vivo oral bioavailability, and robust in vivo antitumor efficacy.

Employment intention and career planning of male nursing students in different levels of colleges and universities: A qualitative study.

AIM: To explore the employment intention and career planning of male nursing students at different levels of colleges and universities and provide references for formulating individualized training content. DESIGN: Phenomenological research method in qualitative research. METHODS: Using a phenomenological research method, 15 male nursing students from three levels of colleges and universities were interviewed in a one-to-half structure, and the data were analysed using NVivo12.0 software and the Colaizzi seven-step analysis method. RESULTS: Four themes and 10 sub-themes were extracted. The four themes included professional identity experience, nursing learning experience, career expectation and planning and educational needs. The 10 sub-themes included the negative effects of traditional impressions, the gradual establishment of professional identity, public health events promote professional identity, negative experiences in learning, positive growth from learning, varied career plans, career expectations and influencing factors, a reasonable schedule, diversity of content requirements and the positive effect of teaching teachers. CONCLUSIONS: Influenced by many factors, the employment intention and career planning of male nursing students at different higher education levels are varied. Schools and clinical practice units should strengthen the training of employment intention and career planning and make reasonable time adjustments to the training content. PUBLIC CONTRIBUTION: In total, 15 male interns accepted our interview request. We utilized their break time to conduct the interviews, resulting in significant contributions to the content of the article.

Transcription Elongation Machinery Is a Druggable Dependency and Potentiates Immunotherapy in Glioblastoma Stem Cells.

Glioblastoma (GBM) is the most lethal primary brain cancer characterized by therapeutic resistance, which is promoted by GBM stem cells (GSC). Here, we interrogated gene expression and whole-genome CRISPR/Cas9 screening in a large panel of patient-derived GSCs, differentiated GBM cells (DGC), and neural stem cells (NSC) to identify master regulators of GSC stemness, revealing an essential transcription state with increased RNA polymerase II-mediated transcription. The YY1 and transcriptional CDK9 complex was essential for GSC survival and maintenance in vitro and in vivo. YY1 interacted with CDK9 to regulate transcription elongation in GSCs. Genetic or pharmacologic targeting of the YY1-CDK9 complex elicited RNA m6A modification-dependent interferon responses, reduced regulatory T-cell infiltration, and augmented efficacy of immune checkpoint therapy in GBM. Collectively, these results suggest that YY1-CDK9 transcription elongation complex defines a targetable cell state with active transcription, suppressed interferon responses, and immunotherapy resistance in GBM. SIGNIFICANCE: Effective strategies to rewire immunosuppressive microenvironment and enhance immunotherapy response are still lacking in GBM. YY1-driven transcriptional elongation machinery represents a druggable target to activate interferon response and enhance anti-PD-1 response through regulating the m6A modification program, linking epigenetic regulation to immunomodulatory function in GBM.This article is highlighted in the In This Issue feature, p. 275.

The effectiveness of the laid-back position on lactation-related nipple problems and comfort: a meta-analysis.

BACKGROUND: The importance of breastfeeding for maternal and child health is agreed upon worldwide. However, lactation-related nipple problems are common and are important factors affecting breastfeeding. Multiple studies recommended laid-back breastfeeding, but they are of various levels of quality, and the results are inconclusive. METHODS: We systematically searched the following twelve databases from inception to January 28,2020: Cochrane Library, EMBASE, Medline, Ovid, PubMed, Web of Science, CINAHL, Scopus, Chinese National Knowledge Infrastructure (CNKI), China Biology Medicine disc (CBM), WanFang, and VIP. All studies regarding laid-back breastfeeding or biological nurturing were considered, regardless of whether they were randomized controlled trials. Two trained investigators independently evaluated the quality of the selected articles and screened the data. All the data were analysed separately using Review Manager Version 5.3 and STATA/SE Version 15.1. RESULTS: A total of 12 studies involving 1936 groups of postpartum women and their newborns were included. The results of the meta-analysis showed that nipple pain (RR = 0.24; 95% CI 0.14, 0.40; p < 0.00001), nipple trauma (RR = 0.47; 95% CI 0.29, 0.75; p = 0.002) and correct latching position (RR = 1.22; 95% CI 1.11, 1.33; p < 0.0001) in the experimental groups were all better than those of the control groups, and the differences were statistically significant (p < 0.05), which indicates that the laid-back position has a positive effect on maternal breastfeeding. However, the results of position comfort showed that there was no statistical significance between the two groups (ES = 0.09; 95% CI -0.63, 0.81; p = 0.798). CONCLUSION: Compared with traditional breastfeeding positions, the laid-back position has been proven to be related to a decreased incidence of nipple pain and nipple trauma and is seemingly conducive to the use of the correct latching position. It is suggested that the laid-back position is helpful in solving lactation-related nipple problems and can be recommended as a position for breastfeeding. However, no significant difference in position comfort was found between the two groups based on the current evidence, and further studies are still needed to validate these results due to the limitations of the included studies.

Mediator MED23 regulates inflammatory responses and liver fibrosis.

Liver fibrosis, often associated with cirrhosis and hepatocellular carcinomas, is characterized by hepatic damage, an inflammatory response, and hepatic stellate cell (HSC) activation, although the underlying mechanisms are largely unknown. Here, we show that the transcriptional Mediator complex subunit 23 (MED23) participates in the development of experimental liver fibrosis. Compared with their control littermates, mice with hepatic Med23 deletion exhibited aggravated carbon tetrachloride (CCl4)-induced liver fibrosis, with enhanced chemokine production and inflammatory infiltration as well as increased hepatocyte regeneration. Mechanistically, the orphan nuclear receptor RAR-related orphan receptor alpha (RORα) activates the expression of the liver fibrosis-related chemokines C-C motif chemokine ligand 5 (CCL5) and C-X-C motif chemokine ligand 10 (CXCL10), which is suppressed by the Mediator subunit MED23. We further found that the inhibition of Ccl5 and Cxcl10 expression by MED23 likely occurs because of G9a (also known as euchromatic histone-lysine N-methyltransferase 2 [EHMT2])-mediated H3K9 dimethylation of the target promoters. Collectively, these findings reveal hepatic MED23 as a key modulator of chemokine production and inflammatory responses and define the MED23-CCL5/CXCL10 axis as a potential target for clinical intervention in liver fibrosis.

A Pharmacogenomic Landscape in Human Liver Cancers.

Liver cancers are highly heterogeneous with poor prognosis and drug response. A better understanding between genetic alterations and drug responses would facilitate precision treatment for liver cancers. To characterize the landscape of pharmacogenomic interactions in liver cancers, we developed a protocol to establish human liver cancer cell models at a success rate of around 50% and generated the Liver Cancer Model Repository (LIMORE) with 81 cell models. LIMORE represented genomic and transcriptomic heterogeneity of primary cancers. Interrogation of the pharmacogenomic landscape of LIMORE discovered unexplored gene-drug associations, including synthetic lethalities to prevalent alterations in liver cancers. Moreover, predictive biomarker candidates were suggested for the selection of sorafenib-responding patients. LIMORE provides a rich resource facilitating drug discovery in liver cancers.

Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin.

Understanding stage-dependent oncogenic mechanisms is critical to develop not only targeted therapies, but also diagnostic markers and preventive strategies. The mechanisms acting during cancer initiation remain elusive, largely owing to a lack of suitable animal models and limited availability of human precancerous lesions. Here we show using genetic mouse models specific for liver cancer initiation, that survival of initiated cancer cells is controlled by c-Jun, independently of p53, through suppressing c-Fos-mediated apoptosis. Mechanistically, c-Fos induces SIRT6 transcription, which represses survivin by reducing histone H3K9 acetylation and NF-κB activation. Importantly, increasing the level of SIRT6 or targeting the anti-apoptotic activity of survivin at the initiation stage markedly impairs cancer development. Moreover, in human dysplastic liver nodules, but not in malignant tumours, a specific expression pattern with increased c-Jun-survivin and attenuated c-Fos-SIRT6 levels was identified. These results reveal a regulatory network connecting stress response and histone modification in liver tumour initiation, which could be targeted to prevent liver tumorigenesis.

Sorafenib inhibits transforming growth factor ß1-mediated epithelial-mesenchymal transition and apoptosis in mouse hepatocytes.

Epithelial-mesenchymal transition (EMT) is a physiological process that has been recognized to occur during the progression of an increasingly large number of human diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. The activation of transforming growth factor ß (TGF-ß) signaling is considered a critical event during EMT, and efforts have been made to screen small molecules that interfere with the TGF-ß signaling pathway during EMT. Here we report the identification of sorafenib, a clinical agent that inhibits TGF-ß signaling. When applied to AML12 cells and primary hepatocytes, sorafenib strikingly suppressed TGF-ß1-induced EMT and apoptosis. Additionally, sorafenib inhibited TGF-ß1-induced signal transducer and activator of transcription 3 phosphorylation. We further present in vitro evidence that sorafenib ameliorates the proapoptotic and profibrotic effects of TGF-ß1 in mouse primary hepatocytes, suggesting that this drug exerts a protective effect on hepatocytes and has therapeutic potential for the treatment of liver fibrosis.

Mitogen-activated protein kinases in hepatocellular carcinoma development.

Hepatocellular carcinoma (HCC) is among the most frequently occurring cancers and the leading causes of cancer mortality worldwide. Identification of the signaling pathways regulating liver carcinogenesis is critical in developing novel chemoprevention and targeted therapies. Mitogen-activated protein kinases (MAPKs), comprising a family of serine and threonine kinases of ERK, JNK, and p38, are important signaling components which convert external stimuli into a wide range of cellular responses, such as proliferation, survival, differentiation and migration. Due to their essential roles in these cellular functions, deregulated MAPKs are often found to contribute to the development of many cancers, including HCC. Markedly, early studies on the ERK pathway have led to the development of the multikinase inhibitor Sorafenib, the first effective systemic drug for the targeted treatment of human HCC. Recently, the functions and molecular mechanisms of JNK and p38 in HCC development have also been addressed using mouse models. In this review, we discuss the latest findings regarding the ERK, JNK and p38 MAPK signaling pathways in HCC development and their potential roles as therapeutic targets for HCC.

Successful pregnancy following the transfer of vitrified blastocyst which developed from poor quality embryos on day 3.

BACKGROUND: The selection of pre-embryos for transferred is based on morphological appearance. But some poor quality cleaved embryos also can be cultured to the blastocyst stage and implanted. OBJECTIVE: To assess the clinical pregnancy outcomes of blastocyst transfer which developed from poor quality embryos. MATERIALS AND METHODS: A total of 109 cleaved embryos with poor quality were cultured to day 5/day 6 and 27 (24.8%) blastocysts were collected from the 15 cycles/patients undergoing conventional IVF. All the blastocysts were cooling with fast-freezing. Then the blastocysts were warmed for transfer. RESULTS: All of 25 vitrified blastocysts (92.6%) survived after warming and were transferred to 15 patients. Five of the women became pregnant. CONCLUSION: Our results suggest that vitrified human day 5/day 6 blastocyst transfer which develop from poor quality embryo at day 3 can contribute to increasing cumulative pregnancy rates in assisted reproduction.

Nitric oxide suppresses transforming growth factor-beta1-induced epithelial-to-mesenchymal transition and apoptosis in mouse hepatocytes.

UNLABELLED: Nitric oxide (NO) is a multifunctional regulator that is implicated in various physiological and pathological processes. Here we report that administration of NO donor S-nitroso-N-acetylpenicillamine (SNAP) inhibited transforming growth factor-beta1 (TGF-beta1)-induced epithelial-to-mesenchymal transition (EMT) and apoptosis in mouse hepatocytes. Overexpression of inducible NO synthase (iNOS) by transfection of the iNOS-expressing vector, which increased NO production, also inhibited the TGF-beta1-induced EMT and apoptosis in these cells. Treatment of cells with proinflammatory mediators, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and interferon (IFN)-gamma, which increased the endogenous NO production, produced the same inhibitory effect. Furthermore, exogenous NO donor SNAP treatment caused a decrease in the intracellular adenosine triphosphate (ATP) levels. Consistently, depletion of intracellular ATP by mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) inhibited the TGF-beta1-induced EMT and apoptosis, suggesting that an NO-induced decrease of ATP involved in the NO-mediated inhibition of TGF-beta1-induced EMT and apoptosis. NO and FCCP also inhibited TGF-beta1-induced STAT3 activation, suggesting that signal transducer and activator of transcription 3 inactivation is involved in the NO-induced effects on TGF-beta1-induced EMT and apoptosis. CONCLUSION: Our study indicates that NO plays an important role in the inhibition of TGF-beta1-induced EMT and apoptosis in mouse hepatocytes through the downregulation of intracellular ATP levels. The data provide an insight into the in vivo mechanisms on the function of NO during the processes of both EMT and apoptosis.

Effect of the size of zona pellucida thinning by laser assisted hatching on clinical outcome of human frozen-thawed embryo transfers.

Of 122 consecutive procedures, 31 were not assisted hatching (AH), which served as the control group, 34 were AH with 40 microm thinning of the zona, and 57 were AH with 80 microns of the zona thinning. The pregnancy and implantation rates were significantly higher in 80 microns thinning group compared to control group (40.3 vs. 16.1 percent, P=0.03; 21.5 vs. 7.5 percent, P=0.007, respectively). In addition, the implantation rate was signigicantly higher in 80 microns group than in 40 microns group (21.5 percent vs.9.4 percent, P=0.024). The results indicated that the size of the zona pellucida thinning by laser may influence the pregnancy and implantation rates following frozen-thawed cleaved embryo transfer.

Maternal confidence in China: association with infant neurobehaviors but not sociodemographic variables.

OBJECTIVE: To examine the relations of sociodemographic factors and infant neurobehaviors to maternal confidence in China. METHODS: The Brazelton Neonatal Behavioral Assessment Scale, Family APGAR, and Maternal Confidence in Caring for the Newborn scales were administered to 40 healthy, full-term neonates. RESULTS: Range and regulation of state, autonomic stability, and reflex cluster scores were positively correlated; the autonomic stability cluster score was negatively correlated with maternal confidence in meeting the infant's social and instrumental needs. Educational level, age, income, satisfaction with family conditions, and infant sex were not associated with maternal confidence. Range of state and autonomic stability cluster scores predicted maternal confidence. CONCLUSIONS: The infant's abilities to tolerate stimuli, and to be consoled, were associated with maternal confidence. Also, maternal confidence was related to the recognition of infant autonomic cues. Family and sociodemographic variables were not associated with maternal confidence. The sex of the newborn did not affect maternal confidence.