Large-scale array for radio astronomy on the farside (LARAF).

At the Royal Society meeting in 2023, we have mainly presented our lunar orbit array concept called DSL, and also briefly introduced a concept of a lunar surface array, LARAF. As the DSL concept had been presented before, in this article, we introduce the LARAF. We propose to build an array in the far side of the Moon, with a master station which handles the data collection and processing, and 20 stations with maximum baseline of 10 km. Each station consists of 12 membrane antenna units, and the stations are connected to the master station by power line and optical fibre. The array will make interferometric observation in the 0.1-50 MHz band during the lunar night, powered by regenerated fuel cells. The whole array can be carried to the lunar surface with a heavy rocket mission, and deployed with a rover in eight months. Such an array would be an important step in the long-term development of lunar-based ultralong wavelength radio astronomy. It has a sufficiently high sensitivity to observe many radio sources in the sky, though still short of the dark age fluctuations. We discuss the possible options in the power supply, data communication, deployment etc. This article is part of a discussion meeting issue 'Astronomy from the Moon: the next decades (part 2)'.

PRDX2 regulates stemness contributing to cisplatin resistance and metastasis in bladder cancer.

BACKGROUND: Cisplatin (CDDP)-based chemotherapy has emerged as the primary treatment for muscle-invasive bladder cancer and metastatic bladder cancer. Nevertheless, a significant proportion of patients experience rapidly developed chemoresistance, leading to treatment ineffectiveness. Existing evidence suggests that chemoresistance is governed by various factors, including tumor stem cells, epithelial mesenchymal transition, and reactive oxygen species (ROS). However, limited research has been conducted on the role of PRDX2, a crucial ROS scavenger, in the modulation of chemoresistance in bladder cancer. METHODS: Cisplatin-resistant cell lines were established using the concentration gradient overlay method, and differentially expressed genes in resistant cells were screened through RNA sequencing. The expression of PRDX2 in cells and tissues was assessed using RT-qPCR, Western Blot, and immunohistochemistry. The expression of PRDX2 in bladder cancer and adjacent tissues was evaluated using a bladder cancer tissue microarray. Furthermore, the impact of PRDX2 knockdown on tumor formation and metastasis was investigated in vivo by applying subcutaneous tumor xenografts tail vein metastasis assays. RESULTS: We demonstrated that PRDX2 is significantly upregulated in bladder tumors and cisplatin-resistant bladder tumor cell lines. Overexpression of PRDX2 can promote tumor proliferation, migration, and invasion both in vitro and in vivo. We have found that knockdown of PRDX2 expression can effectively reverse cell resistance to cisplatin. Mechanistically, our findings suggest that PRDX2 is involved in regulating tumor stemness and epithelial-mesenchymal transition (EMT). Knockdown of PRDX2 affects the PI3K-AKT and mTOR signaling pathways, thereby influencing tumor stemness and EMT, ultimately impacting the chemotherapy resistance of the tumor. CONCLUSIONS: This study provides a new insight into the regulation of chemotherapy resistance in bladder cancer by PRDX2. Targeting PRDX2 can serve as a potent therapeutic target for chemotherapy resistance.

The baseline metabolism parameters of 18F­FDG PET/CT as promising prognostic biomarkers in pediatric Langerhans cell histiocytosis.

Background: Langerhans cell histiocytosis (LCH) is a rare myeloid precursor cell inflammatory neoplasia, which agonizes, maims, and even kills patients. Although clinical outcomes have steadily improved over the past decades, the progression/relapse rate of LCH remains high. The purpose of this study was to evaluate the prognostic value of the pre-treatment metabolism parameters of baseline 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F­FDG PET/CT) in children with LCH. Methods: This cross-sectional study retrospectively and consecutively included 37 children (24 males and 13 females; median age, 5.1 years; range, 2.4-7.8 years) with pre-treatment 18F-FDG PET/CT from September 2020 to September 2022 in Nuclear Medicine Department, Beijing friendship hospital, Capital Medical University, Beijing, China. These patients were then all admitted to the hospital and diagnosed with LCH by biopsy, in Hematology Center, Beijing Children's Hospital, Capital Medical University, Beijing, China. Five metabolism parameters of 18F-FDG PET/CT were analyzed, including maximum standardized uptake, tumor-to-normal liver standard uptake value ratio, tumor-to-normal bone marrow standard uptake value ratio, sum of metabolic tumor volume (sMTV), and sum of total lesion glycolysis (sTLG) of all lesions. Patients were followed up for at least 1 year or until disease progression/relapse. Univariate and multivariate analyses of progression-free survival was performed. Results: During follow-up, 11 (29.7%) patients had disease progression/relapse. Univariate analysis revealed that the risk organ involvement, the treatment response at the 5th or 11th week, pre-treatment sMTV, and sTLG were significantly associated with progression-free survival (P=0.024, 0.018, 0.006, 0.006, and 0.042, respectively). Multivariate COX analysis revealed that non-response at the 11th week, pre-treatment sMTV >32.55 g/cm3, and sTLG >98.86 g (P=0.002, 0.020, 0.026, respectively) were risk factors for progression-free survival. Conclusions: The baseline metabolism parameters of 18F-FDG PET/CT could be promising imaging biomarkers for predicting prognosis in children with LCH.

Advances in molecular characterization of pediatric acute megakaryoblastic leukemia not associated with Down syndrome; impact on therapy development.

Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia (AML) in which leukemic blasts have megakaryocytic features. AMKL makes up 4%-15% of newly diagnosed pediatric AML, typically affecting young children (less than 2 years old). AMKL associated with Down syndrome (DS) shows GATA1 mutations and has a favorable prognosis. In contrast, AMKL in children without DS is often associated with recurrent and mutually exclusive chimeric fusion genes and has an unfavorable prognosis. This review mainly summarizes the unique features of pediatric non-DS AMKL and highlights the development of novel therapies for high-risk patients. Due to the rarity of pediatric AMKL, large-scale multi-center studies are needed to progress molecular characterization of this disease. Better disease models are also required to test leukemogenic mechanisms and emerging therapies.

Combination of epidrugs with immune checkpoint inhibitors in cancer immunotherapy: From theory to therapy.

Immunotherapy based on immune checkpoint inhibitors (ICIs) has revolutionized treatment strategies in multiple types of cancer. However, the resistance and relapse as associated with the extreme complexity of cancer-immunity interactions remain a major challenge to be resolved. Owing to the epigenome plasticity of cancer and immune cells, a growing body of evidence has been presented indicating that epigenetic treatments have the potential to overcome current limitations of immunotherapy, thus providing a rationalefor the combination of ICIs with epigenetic agents (epidrugs). In this review, we first make an overview about the epigenetic regulations in tumor biology and immunodevelopment. Subsequently, a diverse array of inhibitory agents under investigations targeted epigenetic modulators (Azacitidine, Decitabine, Vorinostat, Romidepsin, Belinostat, Panobinostat, Tazemetostat, Enasidenib and Ivosidenib, etc.) and immune checkpoints (Atezolizmab, Avelumab, Cemiplimab, Durvalumb, Ipilimumab, Nivolumab and Pembrolizmab, etc.) to increase anticancer responses were described and the potential mechanisms were further discussed. Finally, we summarize the findings of clinical trials and provide a perspective for future clinical studies directed at investigating the combination of epidrugs with ICIs as a treatment for cancer.

Regional Differences, Dynamic Evolution and Convergence of Public Health Level in China.

People's health is a necessary condition for the country's prosperity. Under the background of the COVID-19 pandemic and frequent natural disasters, exploring the spatial and temporal distribution, regional differences and convergence of China's provincial public health level is of great significance to promoting the coordinated development of China's regional public health and achieving the strategic goal of a "healthy China". Based on China's provincial panel data from 2009 to 2020, this paper constructs an evaluation index system for China's public health level from five dimensions: the popularization of a healthy life, optimization of health services, improvement of health insurance, construction of a healthy environment, and development of a health industry. In this paper, the entropy method, Dagum Gini coefficient, Kernel density function and spatial econometric model are used to analyze the spatiotemporal distribution, regional differences, dynamic evolution and convergence of China's public health level since the new medical reform. The study found that, first, China's public health level is generally low, structural contradictions are prominent and the construction of a healthy environment has become a shortcoming hindering the improvement of China's public health level since the new medical reform. The public health level of the four major regions showed a spatial distribution pattern of "high in the eastern, low in the northeastern, central and western" areas. Second, the overall Gini coefficient of China's public health level showed a "V-shaped" trend of first decreasing and then rising, but the overall decrease was greater than the increase, among which the regional difference was the main source of regional differences in China's public health level, but its contribution rate showed a downward trend. Third, except for the basic maintenance of a healthy environment, the Kernel density curves of China's public health level and its sub-dimensions have shifted to the right to a certain extent, and there is no polarization phenomenon. Finally, the level of public health in China has a significant spatial correlation. Except for the northeast region, the growth rate of low-level public health provinces in China and the other three major regions is higher than that of high-level public health provinces, showing a certain convergence trend. In addition, the impact of economic development, financial pressure, and urbanization on the convergence of public health levels in the four major regions is significantly heterogeneous.

Deregulated calcium signaling in blood cancer: Underlying mechanisms and therapeutic potential.

Intracellular calcium signaling regulates diverse physiological and pathological processes. In solid tumors, changes to calcium channels and effectors via mutations or changes in expression affect all cancer hallmarks. Such changes often disrupt transport of calcium ions (Ca2+) in the endoplasmic reticulum (ER) or mitochondria, impacting apoptosis. Evidence rapidly accumulates that this is similar in blood cancer. Principles of intracellular Ca2+ signaling are outlined in the introduction. We describe different Ca2+-toolkit components and summarize the unique relationship between extracellular Ca2+ in the endosteal niche and hematopoietic stem cells. The foundational data on Ca2+ homeostasis in red blood cells is discussed, with the demonstration of changes in red blood cell disorders. This leads to the role of Ca2+ in neoplastic erythropoiesis. Then we expand onto the neoplastic impact of deregulated plasma membrane Ca2+ channels, ER Ca2+ channels, Ca2+ pumps and exchangers, as well as Ca2+ sensor and effector proteins across all types of hematologic neoplasms. This includes an overview of genetic variants in the Ca2+-toolkit encoding genes in lymphoid and myeloid cancers as recorded in publically available cancer databases. The data we compiled demonstrate that multiple Ca2+ homeostatic mechanisms and Ca2+ responsive pathways are altered in hematologic cancers. Some of these alterations may have genetic basis but this requires further investigation. Most changes in the Ca2+-toolkit do not appear to define/associate with specific disease entities but may influence disease grade, prognosis, treatment response, and certain complications. Further elucidation of the underlying mechanisms may lead to novel treatments, with the aim to tailor drugs to different patterns of deregulation. To our knowledge this is the first review of its type in the published literature. We hope that the evidence we compiled increases awareness of the calcium signaling deregulation in hematologic neoplasms and triggers more clinical studies to help advance this field.

The Spatiotemporal Evolution and Influencing Factors of the Chinese Cities' Ecological Welfare Performance.

In the "full world" where natural capital is scarce, within the limits of the ecological environment, the improvement of welfare is a fundamental requirement for sustainable development. The ecological wellbeing performance (EWP) of 284 cities in China from 2007 to 2020 was measured by the superefficient SBM-DEA model, considering undesirable output, and analyzing the evolutionary trends of overall comprehensive technical efficiency, pure technical efficiency, and scale efficiency. The Theil index was used to explore the source and distribution of the Chinese cities' EWP differences. Exploratory spatial data analysis (ESDA) and the spatial Durbin model (SDM) were applied to analyze the spatial distribution characteristics and driving factors of cities' EWP. The results showed the following: (1) Regarding spatial and temporal distribution, the EWP of Chinese cities showed a fluctuating upward trend, in which pure technical efficiency > scale efficiency. (2) Considering regional differences, the differences in cities' EWP were mainly intraregional rather than interregional. The contribution rates of distinct regions to the differences in EWP varied, i.e., western region > eastern region > central region > northeastern region. (3) In terms of spatial correlation, China's EWP showed positive spatial correlation, i.e., high-high agglomeration and low-low agglomeration. (4) Concerning influencing factors, the level of financial development, the structure of secondary industries, the level of opening-up, and the degree of urbanization significantly improved EWP. Decentralization of fiscal revenue significantly inhibited improvement of EWP. Decentralization of fiscal expenditure and technological progress had no significant impact on the EWP. In the future, to improve cities' EWP, China should focus on reducing differences in intraregional EWP, overcoming administrative regional limitations, encouraging regions with similar locations to formulate coordinated development plans, promoting economic growth, reducing levels of environmental pollution, and paying attention to the improvement of social welfare.

Evaluation and Obstacle Analysis of Emergency Response Capability in China.

Emergency response capability evaluation is an essential means to strengthen emergency response capacity-building and improve the level of government administration. Based on the whole life cycle of emergency management, the emergency capability evaluation index system is constructed from four aspects: prevention and emergency preparedness, monitoring and early warning, emergency response and rescue, and recovery and reconstruction. Firstly, the entropy method is applied to measure the emergency response capability level of 31 Chinese provinces from 2011 to 2020. Second, the Theil index and ESDA (Exploratory Spatial Data Analysis) are applied in exploring the regional differences and spatial-temporal distribution characteristics of China's emergency response capacity. Finally, the obstacle degree model is used to explore the obstacle factors and obstacle degrees that affect the emergency response capability. The results show that: (1) The average value of China's emergency response capacity is 0.277, with a steady growth trend and a gradient distribution of "high in the east, low in the west, and average in center and northeast" in the four major regions. (2) From the perspective of spatial distribution characteristics, the unbalanced regional development leads to the obvious aggregation effect of "high-efficiency aggregation and low-efficiency aggregation", and the interaction of the "centripetal effect" and "centrifugal effect" finally forms the spatial clustering result of emergency response capability level in China. (3) Examining the source of regional differences, inter-regional differences are the decisive factor affecting the overall differences in emergency response capability, and the inter-regional differences show a reciprocating fluctuation of narrowing-widening-narrowing from 2011 to 2020. (4) Main obstacles restricting the improvement of China's emergency response capabilities are "the business volume of postal and telecommunication services per capita", "the daily disposal capacity of city sewage" and "the general public budget revenue by region". The extent of the obstacles' impacts in 2020 are 12.19%, 7.48%, and 7.08%, respectively. Based on the evaluation results, the following countermeasures are proposed: to realize the balance of each stage of emergency management during the holistic process; to strengthen emergency coordination and balanced regional development; and to implement precise measures to make up for the shortcomings of emergency response capabilities.

Advances in molecular characterization of myeloid proliferations associated with Down syndrome.

Myeloid leukemia associated with Down syndrome (ML-DS) has a unique molecular landscape that differs from other subtypes of acute myeloid leukemia. ML-DS is often preceded by a myeloproliferative neoplastic condition called transient abnormal myelopoiesis (TAM) that disrupts megakaryocytic and erythroid differentiation. Over the last two decades, many genetic and epigenetic changes in TAM and ML-DS have been elucidated. These include overexpression of molecules and micro-RNAs located on chromosome 21, GATA1 mutations, and a range of other somatic mutations and chromosomal alterations. In this review, we summarize molecular changes reported in TAM and ML-DS and provide a comprehensive discussion of these findings. Recent advances in the development of CRISPR/Cas9-modified induced pluripotent stem cell-based disease models are also highlighted. However, despite significant progress in this area, we still do not fully understand the pathogenesis of ML-DS, and there are no targeted therapies. Initial diagnosis of ML-DS has a favorable prognosis, but refractory and relapsed disease can be difficult to treat; therapeutic options are limited in Down syndrome children by their stronger sensitivity to the toxic effects of chemotherapy. Because of the rarity of TAM and ML-DS, large-scale multi-center studies would be helpful to advance molecular characterization of these diseases at different stages of development and progression.

Association of Nucleostemin Polymorphisms with Chronic Hepatitis B Virus Infection in Chinese Han Population.

Background: Chronic hepatitis B virus infection (CHB) is a common infectious disease that poses a global economic and health burden due to its high morbidity and mortality. Studies have demonstrated that host genetic factors play critical roles in the susceptibility and outcome of CHB. Aims: In this study, we aimed to assess the potential role of genetic variants of the nucleostemin (NS) gene with respect to CHB susceptibility. Materials and Methods: Four single nucleotide polymorphisms (SNPs) in the NS gene were genotyped in 446 patients with CHB and 399 healthy controls all of Chinese Han origin using the polymerase chain reaction-ligation detection reaction method. Results: The results showed that the three SNPs, rs3733039, rs1866268, and rs11177, were significantly associated with CHB. After a Bonferroni correction, the positive association of the rs3733039 SNP with CHB remained significant. Further analyses based on gender demonstrated that these SNPs are associated with CHB in both the female and male subgroups. After correction for multiple comparisons, all three SNPs in the female group were associated with CHB, whereas only the rs1866268 SNP in the male group was associated with CHB. Haplotype analysis showed that the C-C-G and T-T-T haplotypes in the block consisting of rs3733039-rs1866268-rs11177 were significantly associated with CHB. Conclusion: Our study demonstrated a genetic association between SNPs in the NS gene and the risk of CHB in the Chinese Han population for the first time. Thus, variations in the NS gene might serve as potential genetic biomarkers of CHB.

Prediction of MYCN Amplification, 1p and 11q Aberrations in Pediatric Neuroblastoma via Pre-therapy 18F-FDG PET/CT Radiomics.

Purpose: This study aimed to assess the predictive ability of 18F-FDG PET/CT radiomic features for MYCN, 1p and 11q abnormalities in NB. Method: One hundred and twenty-two pediatric patients (median age 3. 2 years, range, 0.2-9.8 years) with NB were retrospectively enrolled. Significant features by multivariable logistic regression were retained to establish a clinical model (C_model), which included clinical characteristics. 18F-FDG PET/CT radiomic features were extracted by Computational Environment for Radiological Research. The least absolute shrinkage and selection operator (LASSO) regression was used to select radiomic features and build models (R-model). The predictive performance of models constructed by clinical characteristic (C_model), radiomic signature (R_model), and their combinations (CR_model) were compared using receiver operating curves (ROCs). Nomograms based on the radiomic score (rad-score) and clinical parameters were developed. Results: The patients were classified into a training set (n = 86) and a test set (n = 36). Accordingly, 6, 8, and 7 radiomic features were selected to establish R_models for predicting MYCN, 1p and 11q status. The R_models showed a strong power for identifying these aberrations, with area under ROC curves (AUCs) of 0.96, 0.89, and 0.89 in the training set and 0.92, 0.85, and 0.84 in the test set. When combining clinical characteristics and radiomic signature, the AUCs increased to 0.98, 0.91, and 0.93 in the training set and 0.96, 0.88, and 0.89 in the test set. The CR_models had the greatest performance for MYCN, 1p and 11q predictions (P < 0.05). Conclusions: The pre-therapy 18F-FDG PET/CT radiomics is able to predict MYCN amplification and 1p and 11 aberrations in pediatric NB, thus aiding tumor stage, risk stratification and disease management in the clinical practice.

Development and Validation of 18F-FDG PET/CT-Based Multivariable Clinical Prediction Models for the Identification of Malignancy-Associated Hemophagocytic Lymphohistiocytosis.

OBJECTIVE: 18F-fluorodeoxyglucose (FDG) PET/CT is often used for detecting malignancy in patients with newly diagnosed hemophagocytic lymphohistiocytosis (HLH), with acceptable sensitivity but relatively low specificity. The aim of this study was to improve the diagnostic ability of 18F-FDG PET/CT in identifying malignancy in patients with HLH by combining 18F-FDG PET/CT and clinical parameters. MATERIALS AND METHODS: Ninety-seven patients (age ≥ 14 years) with secondary HLH were retrospectively reviewed and divided into the derivation (n = 71) and validation (n = 26) cohorts according to admission time. In the derivation cohort, 22 patients had malignancy-associated HLH (M-HLH) and 49 patients had non-malignancy-associated HLH (NM-HLH). Data on pretreatment 18F-FDG PET/CT and laboratory results were collected. The variables were analyzed using the Mann-Whitney U test or Pearson's chi-square test, and a nomogram for predicting M-HLH was constructed using multivariable binary logistic regression. The predictors were also ranked using decision-tree analysis. The nomogram and decision tree were validated in the validation cohort (10 patients with M-HLH and 16 patients with NM-HLH). RESULTS: The ratio of the maximal standardized uptake value (SUVmax) of the lymph nodes to that of the mediastinum, the ratio of the SUVmax of bone lesions or bone marrow to that of the mediastinum, and age were selected for constructing the model. The nomogram showed good performance in predicting M-HLH in the validation cohort, with an area under the receiver operating characteristic curve of 0.875 (95% confidence interval, 0.686-0.971). At an appropriate cutoff value, the sensitivity and specificity for identifying M-HLH were 90% (9/10) and 68.8% (11/16), respectively. The decision tree integrating the same variables showed 70% (7/10) sensitivity and 93.8% (15/16) specificity for identifying M-HLH. In comparison, visual analysis of 18F-FDG PET/CT images demonstrated 100% (10/10) sensitivity and 12.5% (2/16) specificity. CONCLUSION: 18F-FDG PET/CT may be a practical technique for identifying M-HLH. The model constructed using 18F-FDG PET/CT features and age was able to detect malignancy with better accuracy than visual analysis of 18F-FDG PET/CT images.

Experimental study on creep properties prediction of reed bales based on SVR and MLP.

BACKGROUND: Reed has high lignin content, wide distribution and low cost. It is an ideal raw material for replacing wood in the paper industry. Reeds are rich in resources, but the density of reeds is low, leading to high transportation and storage costs. This paper aims to study the compression process of reeds and the creep behaviour of compressed reeds, and provide theoretical guidance for the reed compressor management, bundling equipment and the stability of compressed reed bales. RESULTS: We have established a multi-layer perceptron network prediction model for the creep characteristics of reeds, and the prediction rate R2 of this model is greater than 0.997. The constitutive equation, constitutive coefficient and creep quaternary model of the reed creep process were established by using the prediction model. The creep behaviour of the reed bale is positively correlated with the initial maximum compressive stress (σ0). During the creep of the reed, the elastic power and the viscous resistance restrict each other. The results show that the proportion of elastic strain in the initial stage is the largest, and gradually decreases to 99.19% over time. The viscoelastic strain increases rapidly with time, then slowly increases, and finally stabilizes to 0.69%, while the plastic strain accounts for the proportion of the total strain. The specific gravity of the reed increases linearly with the increase of creep time, and finally accounts for 0.39%, indicating that as time increases, the damage of the reed's own structure gradually increases. CONCLUSIONS: We studied the relationship between the strain and time of the reed and the strain and creep behaviour of the reed bag under different holding forces under constant force. It is proved that the multi-layer perceptron network is better than the support vector machine regression in predicting the characteristics of reed materials. The three stages of elasticity, viscoelasticity and plasticity in the process of reed creep are analysed in detail. This article opens up a new way for using machine learning methods to predict the mechanical properties of materials. The proposed prediction model provides new ideas for the characterization of material characteristics.

Hypoglycemic and Hypolipidemic Activity of Polygonatum sibiricum Fermented with Lactobacillus brevis YM 1301 in Diabetic C57BL/6 Mice.

Polygonatum sibiricum (PS) has been used as herbal medicine to treat type 2 diabetes mellitus (T2DM). However, how lactic acid fermentation of PS influences glucose and lipid metabolism remains unclear. The current study was undertaken to evaluate the hypoglycemic and hypolipidemic effects of PS fermented with Lactobacillus brevis YM 1301 (YM 1301) in streptozotocin and high-fat diet-induced T2DM mice. Biochemical analysis revealed that supplementation with metformin, PS, or fermented Polygonatum sibiricum (FPS) lowered the fasting blood glucose, insulin, total cholesterol, triglyceride, and low-density lipoprotein cholesterol of diabetic mice. FPS showed relatively more potency to reduce the homeostasis model assessment-insulin resistance and glycated hemoglobin than PS. Moreover, a high dosage of FPS protected against glucose intolerance and insulin resistance by increasing the ratio of phosphor-AKT/AKT. Histological examination and quantitative polymerase chain reaction results showed that dietary FPS ameliorated the lipid accumulation in liver and white adipose tissue (WAT) by inhibiting lipogenesis, enhancing lipolysis, and fatty acid oxidation. FPS exhibited greater efficacy than PS on improving the transcriptional expression of adipose triacylglyceride lipase, carnitine palmitoyltransferase 1, and uncoupling protein 1. In addition, FPS exerted a striking anti-inflammatory effect by suppressing the expression of interleukin 6, interleukin 1ß, tumor necrosis factor-α, and transforming growth factor-ß in WAT of diabetic C57BL/6 mice. Finally, FPS supplementation enhanced the activation of AMPK. In conclusion, these results suggest that the FPS may be more promising than PS as a potential therapeutic agent for diabetes and obesity.

Development and Validation of a Nomogram Based on 18F-FDG PET/CT Radiomics to Predict the Overall Survival in Adult Hemophagocytic Lymphohistiocytosis.

Purpose: Hemophagocytic lymphohistiocytosis (HLH) is a rare and severe disease with a poor prognosis. We aimed to determine if 18F-fluorodeoxyglucose (18F-FDG) PET/CT-derived radiomic features alone or combination with clinical parameters could predict survival in adult HLH. Methods: This study included 70 adults with HLH (training cohort, n = 50; validation cohort, n = 20) who underwent pretherapeutic 18F-FDG PET/CT scans between August 2016 and June 2020. Radiomic features were extracted from the liver and spleen on CT and PET images. For evaluation of 6-month survival, the features exhibiting p < 0.1 in the univariate analysis between non-survivors and survivors were selected. The least absolute shrinkage and selection operator (LASSO) regression analysis was used to develop a radiomics score (Rad-score). A nomogram was built by the multivariate regression analysis to visualize the predictive model for 3-month, 6-month, and 1-year survival, while the performance and usefulness of the model were evaluated by calibration curves, the receiver operating characteristic (ROC) curves, and decision curves. Results: The Rad-score was able to predict 6-month survival in adult HLH, with area under the ROC curves (AUCs) of 0.927 (95% CI: 0.878-0.974) and 0.869 (95% CI: 0.697-1.000) in the training and validation cohorts, respectively. The radiomics nomogram combining the Rad-score with the clinical parameters resulted in better performance for predicting 6-month survival than the clinical model or the Rad-score alone. Moreover, the nomogram displayed superior discrimination, calibration, and clinical usefulness in both the cohorts. Conclusion: The newly developed Rad-score is a powerful predictor for overall survival (OS) in adults with HLH. The nomogram has great potential for predicting 3-month, 6-month, and 1-year survival, which may timely guide personalized treatments for adult HLH.

Regional Differences and Influencing Factors of Allocation Efficiency of Rural Public Health Resources in China.

In the face of increasingly growing health demands and the impact of various public health emergencies, it is of great significance to study the regional differences in the allocation efficiency of the rural public health resources and its improvement mechanism. In this paper, the game competition relationship is included in the evaluation model, and the game cross-efficiency model is used to measure the allocation efficiency of the rural public health resources in 31 provinces of China from 2008 to 2017. Then, the Theil index model and the Gini index model are applied in exploring the regional differences in the allocation efficiency of rural public health resources and its sources. Finally, the bootstrap truncated regression model is used to analyze the influencing factors of the allocation efficiency of the rural public health resources in China. The results show that, first, the total allocation efficiency level of the rural public health resources in China from 2008 to 2017 is relatively low, and it presents a U-shaped trend, first falling and then rising. Second, the changing trend of the allocation efficiency of the rural public health resources in the eastern, central, and western regions of China is similar to that in the nationwide region, and it shows a gradient trend that "the allocation efficiency in the eastern region is high, the allocation efficiency in the western region is low, and the allocation efficiency in the Central region is at the medium level". However, the gap among the three regions is continually narrowing. Third, the calculation results of the Theil index and the Gini index show that intra-regional differences are the major source of the regional differences in the allocation efficiency of the rural public health resources in China, and the inter-regional differences demonstrate an expansion trend. Finally, the improvement of the education level and the social support level will generally improve the allocation efficiency of the rural public health resources in China and its three regions. The increased governmental financial support and urbanization level will reduce the allocation efficiency of the rural public health resources in China and its three regions. The economic development level, the living conditions and the population density are the important influencing factors of the allocation efficiency differences of the rural public health resources in the three regions. Therefore, on the basis of ensuring the increase of the total supply of the rural public health resources, more attention should be paid to the improvement of the allocation efficiency. Moreover, on the basis of continually narrowing the inter-regional differences among the eastern, central, and western regions, more attention should be paid to the intra-regional differences of the allocation efficiency of the rural public health resources among the different provinces. The various economic and social policies should be constantly optimized to jointly improve the allocation efficiency of the rural public health resources.

Quercetin­3­methyl ether suppresses human breast cancer stem cell formation by inhibiting the Notch1 and PI3K/Akt signaling pathways.

Breast cancer is a leading cause of mortality among women with cancer worldwide. Quercetin­3­methyl ether, a natural compound occurring in various plants, has been indicated to have potent anticancer activity. Breast cancer cell growth and survival were examined by CCK­8 and colony formation assay, whilst cell cycle and apoptosis were determined by flow cytometry. Cell invasion and migration were assessed by wound­healing assay and Transwell assay. Cancer stem cell formation was analyzed by mammosphere formation assay and related signaling pathways were detected by western blotting. In the present study, it was observed that treatment with quercetin­3­methyl ether significantly inhibited cell growth, induced apoptosis and cell cycle arrest at the G2­M phase, and suppressed invasion and migration in human breast cancer cells, including the triple negative MDAMB­231 cell line, and the estrogen receptor­positive/progesterone receptor­positive/human epidermal growth factor receptor 2­negative MCF­7 and T47D cell lines. This compound also markedly suppressed the epithelial­mesenchymal transition process as evidenced by the upregulated expression of E­cadherin, and the concomitant downregulated expression of vimentin and MMP­2. Furthermore, it was demonstrated that quercetin­3­methyl ether treatment inhibited mammosphere formation and the expression of the stemness­related genes, SRY­box 2 and Nanog. Mechanistically, this compound decreased the expression of Notch1, and induced the phosphorylation of phosphoinositide 3­kinase (PI3K) and Akt. It also attenuated the human insulin growth factor 1­induced phosphorylation of PI3K, Akt and glycogen synthase kinase ß. Additionally, the combination of quercetin­3­methyl ether and a secretase inhibitor (DAPT) exhibited additive suppression of the expression of Notch1, PI3K, Akt and mammalian target of rapamycin and a more marked inhibitory effect on cell proliferation and colony formation compared with either drug alone. Treatment with quercetin­3­methyl ether alone markedly suppressed the levels of tri­methyl histone H3 (Lys27), but had no effect on the expression of enhancer of zeste homolog 2. Overall, these findings indicated that quercein­3­methyl ether may be a potential therapeutic compound for the treatment of triple negative and hormone­sensitive breast cancer.

Targeted photodynamic therapy of cancer using a novel gallium (III) tris (ethoxycarbonyl) corrole conjugated-mAb directed against cancer/testis antigens 83.

Photodynamic therapy (PDT) is a noninvasive, highly selective approach to the treatment of tumors. However, its therapeutic effect is limited by long-lasting skin phototoxicity. Therefore, to compromise this shortcoming, it is preferable to deliver photosensitizers selectively to tumor cells with the aid of antibodies specific against tumor-associated antigens. Cancer/testis antigens 83 (CT83), also called KK-LC-1 or CXorf61, recognized by cytotoxic T lymphocytes (CTL), has become a promising target for immunotherapy. Herein, we developed and characterized a novel mouse CT83 mAb 7G4 with a high affinity with Gallium (III) 5, 10, 15-tris (ethoxycarbonyl) corrole (1-Ga), a new and promising photosensitizer in PDT. The enzyme-linked immunosorbent assay (ELISA), flow cytometry and cytotoxicity activity assays revealed that 7G4-1-Ga was able to recognize human CT83 with high specificity. Furthermore, 7G4-1-Ga showed greater cytotoxicity to CT83-expressing human cancer cells in vitro than 1-Ga. These results suggest that the antibody-conjugated photosensitizer between anti-CT83 mAb and 1-Ga may have a good application in PDT, where the destruction of CT83-expressing tumor is required.

Development and validation of immortalized bovine mammary epithelial cell line as an in vitro model for the study of mammary gland functions.

This study aimed to develop a bovine mammary epithelial (BME) cell line model, which provides a possibility to determine functional properties of the bovine mammary gland. The primary cell culture was derived from bovine mammary gland tissues and processed enzymatically to obtain cell colonies with epithelial-like morphology. The cultures of BME cells were purified and optimally cultured at 37 °C in DMEM/F12 medium supplemented with 10% fetal bovine serum. The BME cells were identified as epithelial cell line by the evaluating the expression of keratin-18 using immunofluorescence staining. A novel gene expression system strongly enhances the expression of telomerase, has been used to immortalize BME cell line termed hTBME cell line. Interestingly, telomerase remained active even after over 60 passages of hTBME cell line, required for immortalization of BME cells. In addition, the hTBME cell line was continuously subcultured with a spontaneous epithelial-like morphology, with a great proliferation activity, and without evidence of apoptotic and necrotic effects. Further characterization showed that hTBME cell line can be continuously propagated in culture with constant chromosomal features and without tumorigenic properties. Finally, established hTBME cell line was evaluated for mammary gland specific functions. Our results demonstrated that the hTBME cell line was able to retain functional-morphological structure, and functional differentiation by expression of beta (ß)-casein as in the bovine mammary gland in vivo. Taken together, our findings suggest that the established hTBME cell line can serve as a valuable tool for the study of bovine mammary gland functions.