Development of novel polymeric nanoagents and their potential in cancer diagnosis and therapy runing title: Polymeric nanoagents for cancer theranostics

Cancer has been one of the leading factors of death around the world. Cancer patients usually have low 5-year survival rates and poor life quality requiring substantial improvement. In clinic, the presenting diagnostic strategies lack sensitivity with only a small proportion of patients can be accurately identified. For diagnosed patients, most of them are at the advanced stages thus being delayed to receive treatment. Therefore, it is eager to investigate and develop highly effective and accurate techniques for cancer early diagnosis and individualized therapy. Various nanoplatforms are emerging as imaging agents and drug carriers for cancer theranostics recently. Novel polymeric nanoagents, as a potent exemplar, have extraordinary merits, such as good stability, high biosafety and high drug loading efficacy, showing the great prospect for cancer early diagnosis and precise treatment. Herein, we review the recent advances in novel polymeric nanoagents and elucidate their synthesis procedures. We further introduce the applications of novel polymeric nanoagents in cancer diagnosis, treatment, and theranostics, as well as associated challenges and prospects in this field

Methylation Profile of Single Hepatocytes Derived from Hepatitis B Virus-Related Hepatocellular Carcinoma

BACKGROUND: With the development of high-throughput screening, a variety of genetic alterations has been found in hepatocellular carcinoma (HCC). Although previous studies on HCC methylation profiles have focused on liver tissue, studies using isolated hepatocytes are rare. The heterogeneity of liver composition may impact the genuine methylation status of HCC; therefore, it is important to clarify the methylation profile of hepatocytes to aid in understanding the process of tumorigenesis. METHODS AND FINDINGS: The global methylation profile of single hepatocytes isolated from liver tissue of hepatitis B virus (HBV) related HCC (HBHC) was analyzed using Illumina Infinium Human Methylation27 BeadChips, and combined bisulfite restriction analysis (COBRA) and bisulfite sequencing were used to validate the 20 significant hypermethylated genes identified. In this study, we found many noteworthy differences in the genome-wide methylation profiles of single hepatocytes of HBHC. Unsupervised hierarchical clustering analysis showed that hepatocyte methylation profiles could be classified according to three cell types: hepatocytes of HCC, adjacent hepatocytes and normal hepatocytes. Among the 20 most hypermethylated genes in the hepatocytes of HBHC, 7 novel genes (WNK2, EMILIN2, TLX3, TM6SF1, TRIM58, HIST1H4Fand GRASP) were found to be hypermethylated in HBHC and hypomethylated in paired adjacent liver tissues; these findings have not been reported in previous studies on tissue samples. CONCLUSION: The genome-wide methylation profile of purified single hepatocytes of HBHC was aided in understanding the process of tumorigenesis, and a series of novel methylated genes found in this study have the potential to be biomarkers for the diagnosis and prognosis of HBHC

OR-029 Effects of BCAA Plus Glucose Supplement Timing on Inflammatory Response Indicators after a Resistant Exercise

Objective A single bout of high-intensity exercise (such as resistant exercise) may result in oxidative stress and impaired immunity, for example, excessive-inflammation and compensatory immunosuppression during the recovery period. BCAA supplement has been reported that it can reduce immunosuppression and excessive inflammation after high-intensity resistant exercise. The purpose of this study was conducted to compare the effects of one-time BCAA plus glucose supplement at two different points of time, two hours before exercise and after it immediately, then figure out a better timing for improving human's impaired immune function after resistant exercise. Methods The study was a randomized, controlled, one-blind crossover trial. The entire test lasted two weeks. It recruited 16 non-trained healthy male college students. They were divided into two groups (each group contained 8 people), pre-exercise supplement group (group A) and post-exercise supplement group (group B). All subjects have not had other high-intensity exercises at least 1week before this study. Also, they did not have any exercise-induced injury or physical discomfort. All subjects needed to ingest BCAA plus glucose and placebo supplement in 2 weeks respectively and they consumed them at 2 different timing (group A or B). Because of digestion time of the capsule, subjects of group A consumed supplements 0.5h before exercise, group B need to consume them after exercise immediately. At the test day, subjects were asked not to eat anything 3 hours before their resistant exercise. Besides, subjects' diets were recorded for 2 weeks experience, to make sure if they consumed other excessive essential amino-acid which may influence this study. And the study compared each subject's 2 different results and figured out whether one-time BCAA plus glucose supplement could improve human's impaired immune function after resistant exercise and which timing was better. This exercise was designed to be a circular centrifugal movement which contained 3 different training subjects, including 5 sets of 95%10RM seated leg curl machine training, 3 sets of the maximum Drop-jumps and 2 sets of the maximum strength continuous 20m frog jump. The whole resistant exercise lasted about 1 hour. All subjects went through the same exercise and rest 7 days, then they repeated it in next week. All subjects were taken 8 blood samples in vein in 2 weeks. In other words, there were 4 timing of taking subjects’ blood samples in each test. Samples would be placed on a shaker for 1h at-20℃, before being centrifuged for 10 mins at 3,000 g. The test indicators of this study included serum interleukin-6 (IL-6), serum C-reactive protein (CRP), serum immunoglobulin a (Iga) and DOMS soreness. Among them, the level serum IL-6 was tested using a human interleukin 6 ELISA kit in a double antibody one-step sandwich enzyme-linked immunosorbent assay. The serum C-reactive protein index was tested by a human C-reactive protein (CRP) ELISA kit, which is an experimental method for enzyme-linked immunosorbent assay. Serum Iga was analyzed by collecting peripheral anticoagulation and then using an automated biochemical analyzer. The degree of muscle soreness was evaluated using a visual simulation evaluation method. Participants will be asked to perform and hold a squat (90°knee angle) whilst they rated their perceived muscle soreness on a 200 mm visual analog scale The scale consisted of a line from 0 mm (no pain) to 200mm. Supplement protocol: The pure BCAA supplement contained a ratio of 2:1:1 (leucine, isoleucine, and valine, respectively), a dose of 40 mg per kilogram of body weight and glucose supplement was designed to a dose of 24 mg per kilogram of body weight. The form of BCAA was the capsule, and the glucose supplement was in the powder form; each serving was mixed with 300 ml of water. The placebo was the same dose of oligosaccharides in capsule, and artificial sweetener in 300ml of water to match the taste of glucose supplement. Data analysis was performed using the PC version of SPSS 19.0 software. All indicators were statistically analyzed using repeated measures analysis. If the interaction of supplement x timing was significant, the independent sample t test was performed between the groups, and the paired sample t test or one-way ANOVA was performed in the group. Results In this study, all the data from the two weeks were divided into four groups according to the timing of supplementation and the supplementary category. They were the pre-exercise , placeco  group(called A- group), the post-exercise, placeco group (called B- group), the pre-exercise, BCAA plus glucose group(A+ group), the post-exercise, BCAA plus glucose group(B+ group). The data of A- group and A+ group were compared to determine the effectiveness of BCAA plus glucose supplement on anti-inflammatory response. Also, it’s the same goal to compare the data of B- group and B+ group. Then, through comparison between the the pre-exercise, BCAA plus glucose group and the post-exercise, BCAA plus glucose group, it is determined which supplemental timing IS better for lower resistant exercise-induced inflammatory response. The results showed that serum IL-6 levels were 208.35±11.34 pg/ml in the pre-exercise, BCAA plus glucose group and 273.08±4.76 pg /ml in the pre-exercise, placeco group at 24 h after exercise. There was significantly lower in A+ group(p<0.05); the serum IL-6 level in the post-exercise, BCAA plus glucose group was 169.99±10.85 pg/ml, while the serum IL-6 value of 303.78±8.79 pg/ml in the post-exercise, placeco group. There was a significant decrease in B+ group comparing with the level of B- group (p < 0.05). Besides, the serum IL-6 level in the post-exercise, placeco group was lower than that in the pre-exercise, BCAA plus glucose group, and there was a significant difference at 24 h after exercise (p<0.05). Serum CRP at 24 h after exercise, the serum CRP value of the pre-exercise, BCAA plus glucose group was 4.26 ± 0.29 mg /L ,significantly lower than the data of CRP in pre-exercise, placeco group (4.64 ± 0.35 mg/L,p < 0.05). Similarly, the supplement The serum CRP level of post-exercise, BCAA plus glucose group was 3.75±0.44 mg/L, which was significantly different from it in post-exercise, placeco group (p<0.05). At timing of 48h after exercise, the serum CRP level of the B+ group was 3.92±0.24mg/L, which was significantly lower than the serum CRP value of the B- group after 48h (4.4±0.29 mg/L), and there was a significant difference (p<0.05). ). In addition, at the timing of 24 hour after exercise, the serum CRP level of the post-exercise, BCAA plus glucose group was significantly lower than it in pre-exercise, placeco group, and there was a significant difference (p<0.05). There was no significant difference in the data of exercise–induced immunoglobulin of each group after centrifugation. As a direct indicator of the systemic inflammatory response, serum IL-6 and CRP can significantly reflect the inflammatory response induced by BCAA combined with glucose supplementation at 24 and 48 hours after exercise. And instead of Supplement before exercise, it is better for lowering resistant exercise-induced inflammatory response to supply it after exercise immediately. The degree of delayed onset muscle soreness is considered to be a clear indicator of the local inflammatory response. The Visual Analogue Scale(VAS) of delayed onset muscle soreness (DOMS) was 2.63±1.55 in A+ group at 24 h after exercise, was significantly lower than it (3.31±1.54) in the A- group (p<0.05). And the level of VAS in the B+ group was 1.27±0.72, which was significantly lower than it in the B- group at 24 h after exercise (2.86±1.77, p<0.05). At 48 h after exercise, the DOMS level in the post-exercise, BCAA plus glucose group(1.36±0.85) was significantly lower than the 48-hour DOMS level in the post-exercise, placeco group (4.4±0.29 mg/L). In addition, at the timing of 24 hour after exercise, the VAS of DOMS in the post-exercise, BCAA plus glucose group was significantly lower than it in pre-exercise, placeco group(p<0.05). Conclusions Acute and one-time BCAA plus glucose supplement can reduce the exercise-induced systemic inflammatory response (serum IL-6 and serum CRP) and local inflammatory response (DOMS) 24 h and/or 48 h after a resistant exercise. Besides, compared with a supplementation before a resistant exercise, it’s more effective to supply BCAA plus glucose after the exercise immediately for reducing body’s exercise-induced inflammatory response damage

OR-027 Research about Training Monitoring during Different training periods in Chinese Elite Swimmers

Objective Training monitoring has become an integral component of total athlete training. Systematically monitoring the physiological and biochemical variables related to performance helps coaches and athletes to measure the effectiveness of their training programs and decide how to revise or update those programs, especially in swimming training. The key purpose of this study is to evaluate the physical function characteristics during preparation season and stress response during competition training sessions in 2017, and provides the helpful data for scientific training for the implementation of the preparation process. Methods During the preparation period, the National Swimming Team athletes were planed to screen and test the physical function characteristics. There are 39 male athletes and 37 female athletes to participate in the study. Body composition was assessed with dual energy X-ray (DXA). Anthropometric characteristics were assessed using Anthroscan 3D VITUS body scanner, and pulmonary function test using CHEST portable lung function meter(HI-101). During the competition period, the training load monitoring targets were 2 elite players who participated in XVII World Aquatics Championship in Budapest-2017 and the National Games 2017. The monitoring methods mainly included: blood tests (including Hb, CK, BU, testosterone, cortisol and ferritin etc.) were used to monitor the athlete's fitness functional status, and the Z-score method was used to express the index changes of two athletes; blood lactate was used to monitor the training load of athletes, and urine indexes were used to monitor body fluid balance and fatigue. Results 1. During the preparation period, the weight of male athletes is 78.4±8.2kg, the percentage of body fat is 15.9±2.8%, the weight of female athletes is 64.8±6.6kg, and the percentage of body fat is 24.2±3.5%. The vital capacity(VC) was 6.65±0.87 L for males and 4.86±0.69 L for females, the value of forced vital capacity(FVC) was 4.29±1.33 L for males and 3.43±0.96 L for females, and the mean value of ventilation per minute was 148.1±23.12 L for males and 110.4 ± 19.67 L for females. 2. During the competition preparation period, Z score was used to express the blood indicators of two athletes, before the XVII World Aquatics Championship in Budapest-2017, the Z score of Hb, T, T/C ratio and ferritin were (-0.5, 0, -0.4, 1.1) and (-0.8, -0.1, -1.0, 0), respectively. Before the competition of the National Games, the Z scores were (1.0, 0.3, 0.7, 0.6) and (1.4, 1.0, 0.1, -0.6) respectively. 3. Training load monitoring was carried out using the blood lactate control test, as the training load increased, the athletes' performance improved and the lactate level increased slightly. 4. The urine indicator test is used to observe the athlete's dehydration and recovery. On the second morning after the intensive training day, both athletes were negative for urine protein and with normal urine specific gravity. Conclusions 1. The screen and tests about the physical function characteristics of swimming athletes during preparation period is useful to develop a personalized training plan; 2. Z-score is easy and feasible for the elite swimmers to monitoring physical fitness capabilities, and higher Z-score is related with better athletic performance; 3. Blood lactate control test can be used for the training intensity monitoring of swimmers, athletes show higher levels of lactic acid metabolism and higher athletic performance before the competition

HBV infection-induced liver cirrhosis development in dual-humanized mice with human bone mesenchymal stem cell transplantation

疾病动物模型是现代医学发展的基石，尤其是重大、突发传染病暴发时，适宜的疾病动物模型可为及时发现病原体、制定防控策略提供强大保障，原创的疾病动物模型已成为衡量一个国家生物医药科研水平的标志。我校夏宁邵教授团队和浙江大学附属第一医院李君教授团队历经5年的协同攻关，终于建立了国际上首个高度模拟人类乙肝病毒（HBV）自然感染诱发的慢乙肝肝硬化小鼠模型。厦门大学公共卫生学院袁伦志博士生、浙江大学医学院附属第一医院江静博士和厦门大学公共卫生学院刘旋博士生为该论文共同第一作者。厦门大学夏宁邵教授、浙江大学附属第一医院李君教授和厦门大学程通副教授为该论文共同通讯作者。【Abstract】Objective： Developing a small animal model that accurately delineates the natural history of hepatitis B virus (HBV) infection and immunopathophysiology is necessary to clarify the mechanisms of host-virus interactions and to identify intervention strategies for HBV-related liver diseases. This study aimed to develop an HBV-induced chronic hepatitis and cirrhosis mouse model through transplantation of human bone marrow mesenchymal stem cells (hBMSCs). Design： Transplantation of hBMSCs into Fah -/- Rag2 -/- IL-2Rγc -/- SCID (FRGS) mice with fulminant hepatic failure (FHF) induced by hamster-anti-mouse CD95 antibody JO2 generated a liver and immune cell dual-humanized (hBMSC-FRGS) mouse. The generated hBMSC-FRGS mice were subjected to assessments of sustained viremia, specific immune and inflammatory responses and liver pathophysiological injury to characterize the progression of chronic hepatitis and cirrhosis after HBV infection. Results： The implantation of hBMSCs rescued FHF mice, as demonstrated by robust proliferation and transdifferentiation of functional human hepatocytes and multiple immune cell lineages, including B cells, T cells, NK cells, dendritic cells (DCs) and immune cell lineages, including B cells, T cells, NK cells, dendritic cells (DCs) and viremia and specific immune and inflammatory responses and showed progression to chronic hepatitis and liver cirrhosis at a frequency of 55% after 54 weeks. Conclusion： This new humanized mouse model recapitulates the liver cirrhosis induced by human HBV infection, thus providing research opportunities for understanding viral immune pathophysiology and testing antiviral therapies in vivo.this work was supported by the national Science and technology Major Project (grant nos. 2017ZX10304402, 2017ZX10203201 and 2018ZX09711003-005-003), the national natural Science Foundation of china(grant nos. 81672023, 81571818 and 81771996), the Scientific research Foundation of the State Key laboratory of Molecular Vaccinology and Molecular Diagnostics (grant no 2016ZY005), Zhejiang Province and State's Key Project of the research and Development Plan of china (grant nos 2017c01026 and 2016YFc1101304/3).该研究获得了传染病防治国家科技重大专项、新药创制国家科技重大专项和国家自然科学基金的资助

Breast cancer-derived K172N, D301V mutations abolish Na+/H+ exchanger regulatory factor 1 inhibition of platelet-derived growth factor receptor signaling

AbstractNa+/H+ exchanger regulatory factor 1 (NHERF1) is a scaffold protein known to interact with a number of cancer-related proteins. nherf1 Mutations (K172N and D301V) were recently identified in breast cancer cells. To investigate the functional properties of NHERF1, wild-type and cancer-derived nherf1 mutations were stably expressed in SKMES-1 cells respectively. NHERF1-wt overexpression suppressed the cellular malignant phenotypes, including proliferation, migration, and invasion. nherf1 Mutations (K172N and D301V) caused complete or partial loss of NHERF1 functions by affecting the PTEN/NHERF1/PDGFRβ complex formation, inactivating NHERF1 inhibition of PDGF-induced AKT and ERK activation, and attenuating the tumor-suppressor effects of NHERF1-wt. These results further demonstrated the functional consequences of breast cancer-derived nherf1 mutations (K172N and D301V), and suggested the causal role of NHERF1 in tumor development and progression

Comparative analysis of the efficacies of probiotic supplementation and glucose-lowering drugs for the treatment of type 2 diabetes: A systematic review and meta-analysis

The aim of this systematic review and meta-analysis was to evaluate the effects of probiotics and glucose-lowering drugs (thiazolidinedione [TZD], glucagon-like pep-tide-1 receptor agonists [GLP-1 RA], dipeptidyl peptidase IV inhibitors, and sodium glucose co-transporter 2 inhibitors [SGLT-2i]) in patients with type 2 diabetes from randomized con-trolled trials (RCTs). The PubMed, Web of science, Embase, and Cochrane Library databases were searched on the treatment effects of probiotics and glucose-lowering drugs on glycemia, lipids, and blood pressure metabolism published between Jan 2015 and April 2021. We performed meta-analyses using the random-effects model. We included 25 RCTs (2,843 participants). Overall, GLP-1RA, SGLT-2i, and TZD significantly reduce fasting blood sugar (FBS) and glycated hemoglobin (HbA1c), whereas GLP-1 RA increased the risk of hypoglycaemia. Multispecies probiotics decrease FBS, total cholesterol (TC), and systolic and diastolic blood pressure (SBP, DBP). Moreover, subgroup analyses indicated that participants aged >55 years, BMI ≥30 kg/m2, longer duration of intervention, and subjects from Eastern countries, showed significantly higher reduction in FBS and HbA1c, TC, TG and SBP. This meta-analysis revealed that including multiple probiotic rather than glucose-lowering drugs might be more beneficial regarding T2D prevention who suffering from simultaneously hyperglycemia, hypercholesterolemia, and hypertension

Another chiral crystal structure of 1-[4-(Dimethylamino)benzylidene]-4-phenylthiosemicarbazide

Another chiral crystal of 1-[4-(dimethylamino)benzylidenel-4-phenylthiosemicarbazide (DMB) was obtained, and its absolute structure was determined by X-ray single crystal diffraction and the solid circular dichroism (CD) spectrum. The crystal belongs to orthorhombic system with space group P2(1)2(1)2(1) and a = 0.7870(2), b = 1. 1560(2), c = 1.6668(3) nm(3), V = 1.5164(5) nm, Z= 4, D-c=1.307 g/cm(3), F(000)=632, mu=0.213 mm(-1), the final R=0.0409 and wR=0.1061 for 2577 observed reflections [I > 2 sigma(I)]. The absolute structure can be determined well with the Flack parameter 0.00(9). The crystal structure and CD spectrum show that an enantiomer of the compound packs into the chiral crystal