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Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, is critical for membrane targeting and cell signaling. Because cancer cells often have increased N-myristoyltransferase (NMT) expression, NMTs were proposed as anti-cancer targets. To systematically investigate this, we performed robotic cancer cell line screens and discovered a marked sensitivity of hematological cancer cell lines, including B-cell lymphomas, to the potent pan-NMT inhibitor PCLX-001. PCLX-001 treatment impacts the global myristoylation of lymphoma cell proteins and inhibits early B-cell receptor (BCR) signaling events critical for survival. In addition to abrogating myristoylation of Src family kinases, PCLX-001 also promotes their degradation and, unexpectedly, that of numerous non-myristoylated BCR effectors including c-Myc, NFκB and P-ERK, leading to cancer cell death in vitro and in xenograft models. Because some treated lymphoma patients experience relapse and die, targeting B-cell lymphomas with a NMT inhibitor potentially provides an additional much needed treatment option for lymphoma. N-myristoyltransferases (NMTs) target many signaling proteins to membranes. Here the authors show an NMT inhibitor named PCLX-001 selectively kills lymphoma cells by shutting down their main survival signaling pathway and offers an additional treatment strategy for lymphoma patients.

Smart city construction, as a new model of urban development, has become a crucial means to encourage residents’ participation in physical exercise. However, there is still a lack of systematic exploration regarding the mechanisms by which smart city construction specifically affects residents’ engagement in physical activity. This paper analyzes the impact of smart city construction on residents’ participation in physical activity using a Difference-in-Differences (DID) model, based on data from the 2010 to 2020 China Family Panel Studies (CFPS). Data processing involved removing missing values, addressing outliers, and introducing control variables at the individual, household, and city levels. The study found that smart city construction significantly promotes residents’ participation in physical activity. Smart city policies have a notable positive effect on this participation, and there are significant differences in the responses of various resident groups to physical activity engagement. The results of the mediation analysis indicate that the built environment, information access channels, and enjoyment of consumption play significant mediating roles between smart city policies and residents’ participation in physical activity. Smart city construction influences residents’ participation in physical activity both directly or indirectly by enhancing urban infrastructure, expanding access to information, and fostering enjoyable consumption experiences. In the future, smart city initiatives should prioritize the equitable distribution of resources, strengthen infrastructure development in rural and western regions, and further enhance the national fitness level.

PurposeN-myristoyltransferases 1 and 2 (NMT1 and NMT2) catalyze the addition of 14-carbon fatty acids to the N-terminus of proteins. Myristoylation regulates numerous membrane-bound signal transduction pathways important in cancer biology and the pan-NMT inhibitor PCLX-001 is approaching clinical development as a cancer therapy. The tissue distribution, relative abundances, and prognostic value of the two human NMTs remain poorly understood.MethodsWe generated and validated mutually exclusive monoclonal antibodies (mAbs) specific to human NMT1 and NMT2. These mAbs were used to perform immunohistochemical analysis of the abundance and distribution of NMT1 and NMT2 in normal breast epithelial samples and a large cohort of primary breast adenocarcinomas from the BCIRG001 clinical trial (n = 706).ResultsNMT1 protein was readily quantified in normal and most transformed breast epithelial tissue and was associated with higher overall histologic grade, higher Ki67, and lower hormone receptor expression. While NMT2 protein was readily detected in normal breast epithelial tissue, it was undetectable in the majority of breast cancers. Detectable NMT2 protein correlated with significantly poorer overall survival (hazard ratio 1.36; P = 0.029) and worse biological features including younger age, higher histologic grade, lower hormone receptor expression, higher Ki67, and p53 positivity. Treatment of cultured breast cancer cells with PCLX-001 reduced cell viability in vitro. Daily oral administration of PCLX-001 to immunodeficient mice bearing human MDA-MB-231 breast cancer xenografts produced significant dose-dependent tumor growth inhibition in vivo.ConclusionsThese results support further evaluation of NMT immunohistochemistry for patient selection and clinical trials of NMT inhibition in breast cancer patients.

To analyze the correlation between the level of physical activity and the risk of cognitive impairment in Chinese older adults aged 60 years and above, and to provide correlational evidence for the development of targeted strategies to prevent cognitive impairment. This study used five rounds of longitudinal data from the China Health and Retirement Longitudinal Study (CHARLS) conducted between 2011 and 2020, which included 3,583 older adults aged 60 years and above. Multiple regression models were employed to evaluate the association between varying intensities of physical activity (low-intensity, moderate-intensity, and high-intensity) and the risk of developing cognitive impairment (HR). In models that were not adjusted for any variables, the risk of cognitive impairment was reduced by 25.3% in the moderate-intensity physical activity group compared to the low-intensity group (HR = 0.747, 95%CI: 0.617-0.903), and by 11.0% in the high-intensity group (HR = 0.890, 95%CI: 0.798-0.992). In the model that fully controlled for all confounding variables, the risk ratio was further reduced to 30.7% (HR = 0.693, 95%CI: 0.571-0.841) in the moderate-intensity physical activity group and 9.7% (HR = 0.903, 95% CI: 0.809-1.007) in the high-intensity group. Dose-response analysis revealed an optimal strength of association between moderate-intensity physical activity (approximately 2,800 MET-minutes per week) and cognitive health. Moderate-intensity physical activity can significantly reduce the risk of cognitive impairment among older adults in China. It is recommended that health management and cognitive impairment prevention strategies for this population incorporate moderate-intensity physical activity.

IntroductionNeoadjuvant chemotherapy for breast cancer treatment is prescribed to facilitate surgery and provide confirmation of drug-sensitive disease, and the achievement of pathological complete response (pCR) predicts improved long-term outcomes. Docosahexaenoic acid (DHA) has been shown to reduce tumour growth in preclinical models when combined with chemotherapy and is known to beneficially modulate systemic immune function. The purpose of this trial is to investigate the benefit of DHA supplementation in combination with neoadjuvant chemotherapy in patients with breast cancer.Methods and analysisThis is a double-blind, phase II, randomised controlled trial of 52 women prescribed neoadjuvant chemotherapy to test if DHA supplementation enhances chemotherapy efficacy. The DHA supplementation group will take 4.4 g/day DHA orally, and the placebo group will take an equal fat supplement of vegetable oil. The primary outcome will be change in Ki67 labelling index from prechemotherapy core needle biopsy to definitive surgical specimen. The secondary endpoints include assessment of (1) DHA plasma phospholipid content; (2) systemic immune cell types, plasma cytokines and inflammatory markers; (3) tumour markers for apoptosis and tumour infiltrating lymphocytes; (4) rate of pCR in breast and in axillary nodes; (5) frequency of grade 3 and 4 chemotherapy-associated toxicities; and (6) patient-perceived quality of life. The trial has 81% power to detect a significant between-group difference in Ki67 index with a two-sided t-test of less than 0.0497, and accounts for 10% dropout rate.Ethics and disseminationThis study has full approval from the Health Research Ethics Board of Alberta - Cancer Committee (Protocol #: HREBA.CC-18-0381). We expect to present the findings of this study to the scientific community in peer-reviewed journals and at conferences. The results of this study will provide evidence for supplementing with DHA during neoadjuvant chemotherapy treatment for breast cancer.Trial registration number NCT03831178

Gastric cancer is a deadly disease. Some microRNAs are involved in tumor invasion and metastasis. Underexpression of miR-375 has been correlated with tumorigenesis, treatment resistance, and poor prognosis. In this study, we first analyzed the profiles and prognostic values of miR-375 expression in gastric cancer tissues from a public database, and the expression level of miR-375 in gastric cancer samples and gastric cancer cell lines was then analyzed by quantitative real- time polymerase chain reaction. Significant underexpression of miR-375 was seen in all the gastric cancer samples compared to paired paracarcinoma tissues, and the expression level of miR-375 in the gastric cancer cell lines was negatively associated with the cell migration ability. A Cell proliferation (CCK-8) assay was performed to examine cell viability. Overexpression of miR-375 suppressed the proliferation of gastric cancer cells. A Western blot analysis was carried out to test protein expression. Overexpression of miR-375 inhibited autophagy through the AKT/ mammalian target of rapamycin signaling pathway. MiR-375 regulated invasion and migration via AKT/ mammalian target of rapamycin pathway-mediated epithelial-to-mesenchymal transition. Wound healing and migration assays were used to determine the motility of gastric cancer cells. A gastric cancer xenograft nude mouse model was used for an in vivo efficacy evaluation. Overexpression of miR-375 significantly suppressed cell proliferation in the established gastric cancer xenograft nude mouse model. Our results demonstrate that increasing the expression level of miR-375 suppresses proliferation in vitro and in vivo, and they provide a mechanistic and applicable rationale for the future clinical evaluation of miR-375 in gastric cancer treatment. Our findings provide not only new information about the molecular mechanism of microRNAs in regulating invasion and migration in gastric cancer but also a theoretical principle for a potential targeted therapy for gastric cancer.

MicroRNA-182 (miR-182) is significantly downregulated in human gastric tissue samples. Overexpression of miR-182 suppresses the proliferation and colony formation of gastric cancer cells. However, new aspects of the mechanism are still emerging in gastric cancer. ANUBL1, also known as ZFAND4 (zinc finger, AN1-type domain 4), its roles are scarely reported in cancer. In this study, we not only showed that ANUBL1 as an oncogene was upregulated and could promote proliferation of SGC-7901 cells, but also demonstrated that its overexpression led to a strong decrease of miR-182 expression and expression of ANUBL1 was in turn directly downregulated by miR-182, thereby establishing a negative feedback loop between miR-182 and ANUBL1. The elucidation of the mechanisms of miR-182 targeting ANUBL1 in gastric cancer helps us to further understand the mechanism of gastric cancer initiation and progression.

Novel and efficient synthetic strategies are developed for the first synthesis of two new impurities found in obeticholic acid. The synthetic routes to the impurities are designed without column purification using 4-nitrobenzoyl chloride as a selective protecting group. The impurities, which are obtained in good yields and high purity, are identified and characterized using high-resolution mass spectrometry, Fourier transform infrared, one-dimensional nuclear magnetic resonance (1H, 13C, distortionless enhancement by polarization transfer), and two-dimensional nuclear magnetic resonance (Correlated Spectroscopy, heteronuclear single quantum coherence, heteronuclear multiple bond correlation, and rotating-frame Overhauser effect spectroscopy) techniques.

The effect of panel shape on hydrodynamic performances of a vertical v-shaped double-slotted cambered otter-board was investigated using engineering models in a wind tunnel. Three different shape panels (rhomboid, left trapezoid and isosceles trapezoid) were evaluated at a wind speed of 28 m/s. Parameters measured included: drag coefficient C x , lift coefficient C y , pitch moment coefficient C m , center of pressure coefficient C p , over a range of angle of attack (0° to 70°). These coefficients were used in analyzing the differences in the performance among the three otter-board models. Results showed that the maximum lift coefficient C y of the otter-board model with the isosceles trapezoid shape panels was highest (2.103 at α=45°). The maximum C y /C x of the otter-board with the rhomboid shape panels was highest (3.976 at α=15°). A comparative analysis of C m and C p showed that the stability of otter-board model with the isosceles trapezoid shape panels is better in pitch, and the stability of otter-board model with the left trapezoid shape panels is better in roll. The findings of this study can offer useful reference data for the structural optimization of otter-boards for trawling.

Three known impurities of cefoxitin have been prepared and characterised. One is a double-bond isomer of cefoxitin, Δ3-cefoxitin, which was easily prepared by base-catalysed isomerisation of cefoxitin. The second is a side-chain methoxylated derivative, methoxycefoxitin, which required a four-step synthesis from cephalothin. The last impurity is a lactone lacking the carbamyl grouping in cefoxitin, cefoxitin lactone, which was also prepared in four steps from cephalothin. The accessibility of these three impurities and methods for their analysis could be important for quality control in the manufacture of cefoxitin.