A novel fully human anti-NT-ANGPTL3 antibody from phage display library exhibits potent ApoB, TG, and LDL-C lowering activities in hyperlipidemia mice.

Dyslipidemia is characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and TG-rich lipoprotein (TGRLs) in circulation, and is closely associated with the incidence and development of cardiovascular disease. Angiopoietin-like protein 3 (ANGPTL3) deficiency has been identified as a cause of familial combined hypolipidemia in humans, which allows it to be an important therapeutic target for reducing plasma lipids. Here, we report the discovery and characterization of a novel fully human antibody F1519-D95aA against N-terminal ANGPTL3 (NT-ANGPTL3), which potently inhibits NT-ANGPTL3 with a KD as low as 9.21 nM. In hyperlipidemic mice, F1519-D95aA shows higher apolipoprotein B (ApoB) and TG-lowering, and similar LDL-C reducing activity as compared to positive control Evinacumab (56.50% vs 26.01% decrease in serum ApoB levels, 30.84% vs 25.28% decrease in serum TG levels, 23.32% vs 22.52% decrease in serum LDLC levels, relative to vehicle group). Molecular docking and binding energy calculations reveal that the F1519-D95aA-ANGPTL3 complex (10 hydrogen bonds, -65.51 kcal/mol) is more stable than the Evinacumab-ANGPTL3 complex (4 hydrogen bonds, -63.76 kcal/mol). Importantly, F1519-D95aA binds to ANGPTL3 with different residues in ANGPTL3 from Evinacumab, suggesting that F1519-D95aA may be useful for the treatment of patients resistant to Evinacumab. In conclusion, F1519-D95aA is a novel fully human anti-NT-ANGPTL3 antibody with potent plasma ApoB, TG, and LDL-C lowering activities, which can potentially serve as a therapeutic agent for hyperlipidemia and relevant cardiovascular diseases.

Long-term variations of urban-Rural disparities in infectious disease burden of over 8.44 million children, adolescents, and youth in China from 2013 to 2021: An observational study.

BACKGROUND: An accelerated epidemiological transition, spurred by economic development and urbanization, has led to a rapid transformation of the disease spectrum. However, this transition has resulted in a divergent change in the burden of infectious diseases between urban and rural areas. The objective of our study was to evaluate the long-term urban-rural disparities in infectious diseases among children, adolescents, and youths in China, while also examining the specific diseases driving these disparities. METHODS AND FINDINGS: This observational study examined data on 43 notifiable infectious diseases from 8,442,956 cases from individuals aged 4 to 24 years, with 4,487,043 cases in urban areas and 3,955,913 in rural areas. The data from 2013 to 2021 were obtained from China's Notifiable Infectious Disease Surveillance System. The 43 infectious diseases were categorized into 7 categories: vaccine-preventable, bacterial, gastrointestinal and enterovirus, sexually transmitted and bloodborne, vectorborne, zoonotic, and quarantinable diseases. The calculation of infectious disease incidence was stratified by urban and rural areas. We used the index of incidence rate ratio (IRR), calculated by dividing the urban incidence rate by the rural incidence rate for each disease category, to assess the urban-rural disparity. During the nine-year study period, most notifiable infectious diseases in both urban and rural areas exhibited either a decreased or stable pattern. However, a significant and progressively widening urban-rural disparity in notifiable infectious diseases was observed. Children, adolescents, and youths in urban areas experienced a higher average yearly incidence compared to their rural counterparts, with rates of 439 per 100,000 compared to 211 per 100,000, respectively (IRR: 2.078, 95% CI [2.075, 2.081]; p < 0.001). From 2013 to 2021, this disparity was primarily driven by higher incidences of pertussis (IRR: 1.782, 95% CI [1.705, 1.862]; p < 0.001) and seasonal influenza (IRR: 3.213, 95% CI [3.205, 3.220]; p < 0.001) among vaccine-preventable diseases, tuberculosis (IRR: 1.011, 95% CI [1.006, 1.015]; p < 0.001), and scarlet fever (IRR: 2.942, 95% CI [2.918, 2.966]; p < 0.001) among bacterial diseases, infectious diarrhea (IRR: 1.932, 95% CI [1.924, 1.939]; p < 0.001), and hand, foot, and mouth disease (IRR: 2.501, 95% CI [2.491, 2.510]; p < 0.001) among gastrointestinal and enterovirus diseases, dengue (IRR: 11.952, 95% CI [11.313, 12.628]; p < 0.001) among vectorborne diseases, and 4 sexually transmitted and bloodborne diseases (syphilis: IRR 1.743, 95% CI [1.731, 1.755], p < 0.001; gonorrhea: IRR 2.658, 95% CI [2.635, 2.682], p < 0.001; HIV/AIDS: IRR 2.269, 95% CI [2.239, 2.299], p < 0.001; hepatitis C: IRR 1.540, 95% CI [1.506, 1.575], p < 0.001), but was partially offset by lower incidences of most zoonotic and quarantinable diseases in urban areas (for example, brucellosis among zoonotic: IRR 0.516, 95% CI [0.498, 0.534], p < 0.001; hemorrhagic fever among quarantinable: IRR 0.930, 95% CI [0.881, 0.981], p = 0.008). Additionally, the overall urban-rural disparity was particularly pronounced in the middle (IRR: 1.704, 95% CI [1.699, 1.708]; p < 0.001) and northeastern regions (IRR: 1.713, 95% CI [1.700, 1.726]; p < 0.001) of China. A primary limitation of our study is that the incidence was calculated based on annual average population data without accounting for population mobility. CONCLUSIONS: A significant urban-rural disparity in notifiable infectious diseases among children, adolescents, and youths was evident from our study. The burden in urban areas exceeded that in rural areas by more than 2-fold, and this gap appears to be widening, particularly influenced by tuberculosis, scarlet fever, infectious diarrhea, and typhus. These findings underscore the urgent need for interventions to mitigate infectious diseases and address the growing urban-rural disparity.

Second messenger 2'3'-cyclic GMP-AMP (2'3'-cGAMP): the cell autonomous and non-autonomous roles in cancer progression.

Cytosolic double-stranded DNA (dsDNA) is frequently accumulated in cancer cells due to chromosomal instability or exogenous stimulation. Cyclic GMP-AMP synthase (cGAS) acts as a cytosolic DNA sensor, which is activated upon binding to dsDNA to synthesize the crucial second messenger 2'3'-cyclic GMP-AMP (2'3'-cGAMP) that in turn triggers stimulator of interferon genes (STING) signaling. The canonical role of cGAS-cGAMP-STING pathway is essential for innate immunity and viral defense. Recent emerging evidence indicates that 2'3'-cGAMP plays an important role in cancer progression via cell autonomous and non-autonomous mechanisms. Beyond its role as an intracellular messenger to activate STING signaling in tumor cells, 2'3'-cGAMP also serves as an immunotransmitter produced by cancer cells to modulate the functions of non-tumor cells especially immune cells in the tumor microenvironment by activating STING signaling. In this review, we summarize the synthesis, transmission, and degradation of 2'3'-cGAMP as well as the dual functions of 2'3'-cGAMP in a STING-dependent manner. Additionally, we discuss the potential therapeutic strategies that harness the cGAMP-mediated antitumor response for cancer therapy.

Associations of school physical activity environment with comorbid obesity and myopia in children and adolescents: Findings from a Chinese national follow-up study.

BACKGROUND: Overweight and obesity (OWOB) and myopia have become two of the most important issues affecting the health of children and adolescents worldwide. Despite the recognition that the school physical activity (PA) environment is a critical factor for preventing and controlling overweight, obesity (OWOB), and myopia in children and adolescents, research on OWOB and myopia as a comorbidity remains unexplored, with evidence for effective strategies still being inconclusive. Hence, this study aimed to assess the prevalence and progression of comorbid OWOB/myopia and each condition alone, and to explore the association with school PA environment. METHODS: A total of 9814 children and adolescents aged 6-18 years were included from the Chinese National Survey on Students' Constitution and Health follow-up survey conducted from November 2019 to November 2020 in China. Anthropometric measurements, unaided distance vision acuity and non-cycloplegic refraction data were collected to assess OWOB and myopia, while eight indicators from questionnaires for children and adolescents aged 9-18 years were investigated to assess school PA environment. We calculated the one-year incidence and progression rates of comorbid OWOB/myopia, OWOB alone, and myopia alone. Mixed effect logistic regression was evaluated the association between school PA environment and incidence and progression of comorbid OWOB/myopia, OWOB, and myopia. RESULTS: The prevalence of comorbid OWOB/myopia increased from 11.1% in 2019 to 17.9% in 2020, and the incidence of comorbid OWOB/myopia was 10.9%. Children and adolescents experiencing an unfavorable school PA environment had a higher risk of the incidence of comorbid OWOB/myopia compared to a favorable school environment (OR = 1.85, 95% CI: 1.42-2.42). Similar findings were seen in the incidence of obesity (OR = 1.86, 95% CI: 1.26-2.75). Children and adolescents in an unfavorable school PA environment had a higher risk of myopia progression (OR = 1.29, 95% CI: 1.01-1.65). CONCLUSIONS: Obesity and myopia and their comorbidity have been serious among children and adolescents in China. A favorable school PA environment might mitigate the risk of comorbid OWOB/myopia, OWOB, and myopia progression.

Effects of continuous low-speed biogas agitation on anaerobic digestion of high-solids pig manure: Performance and microbial community.

This study aimed to investigate effects of continuous low-speed biogas agitation on the anaerobic digestion (AD) performance and microbial community of high-solids pig manure (total solids content of 10%). Our results reveal that at a biogas agitation intensity of 1.10 L/g feed VS/d, CH4 production increased by 16.67% compared to the non-agitated condition, the removal efficiency of H2S reached 63.18%, and the abundance of Methanosarcina was the highest. The presence of Hungateiclostridiaceae was associated with H2S concentrations. An increasing biogas agitation intensity led to an elevated pH and a decreased oxidation-reduction potential (ORP). Acetate concentrations, pH, and ORP values indicated changes in H2S concentrations. Sedimentibacter demonstrates the potential to indicate biogas agitation intensity and pH. We demonstrate that continuous low-speed biogas agitation effectively increases CH4 production and reduces H2S concentrations in AD of high-solids pig manure, offering a potential technical pathway for developing AD processes for high-solids pig manure, it also demonstrates that AD process can reduce the risk of pathogen and parasite transmission.

Long-term exposure to exogenous phthalate, masculinity and femininity trait, and gender identity in children: a Chinese 3-year longitudinal cohort study.

BACKGROUND: Phthalate esters (PAEs) are known to have hormone-like properties, and there is a growing trend of children expressing a gender identity different from assigned sex. However, there has been limited research in the potential links between PAEs exposure and gender identity. METHODS: A total of 571 children (278 boys) completed the follow-up from Oct 2017 to Oct 2020 in Childhood Blood Pressure and Environmental Factors (CBPEF) cohort in Xiamen, China. Urinary PAE metabolites were measured at three time of visits using ultraperformance liquid chromatography-tandem mass spectrometry. The Children's Sex Role Inventory scale was used to assess gender identity (masculinity, femininity, androgyny and undifferentiated), and Tanner definition was used to define puberty timing. Generalized linear models and log-binomial regression were used to assess the relationships between PAEs exposure, gender trait scores and gender identity. RESULTS: Overall, the concentration of most PAEs in more than 90% of participants was above the limit of detection values. In visit 1, there were 10.1% boys with femininity and 11.3% girls with masculinity; while these figures increased to 10.8% and 12.3% during follow-up, respectively. Early puberty onset accounted for 24.8% and 25.6% among boys and girls. Long-term exposure to mono-2-ethylhexyl phthalate (MEHP) (ß = 1.20, 95%CI = 0.13, 2.28), mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP) (ß = 1.25, 95%CI = 0.22, 2.28) and mono-2-ethyl-5-oxohexyl phthalate (MEOHP) (ß = 1.40, 95%CI = 0.24, 2.56) was associated with the increased differences of femininity trait scores in boys who enter puberty earlier, prolonged exposure to di(2-ethylhexyl) phthalate (DEHP) might also have such a positive impact (ß = 1.38, 95%CI = 0.36, 2.41). For gender identity, persistent exposure to low molecular weight phthalates (LMWP) was negatively associated with undifferentiated type among boys entering puberty earlier (RR = 0.18, 95%CI = 0.05, 0.75, P < 0.05), and most of the PAE metabolites exposures showed risk ratios > 1 for their femininity. CONCLUSION: Long-term exposure to PAEs increase the femininity trait scores in boys with early onset of puberty. Although the mechanisms remain to be determined, environmental pollution might have subtle, yet measurable effects on childhood gender identity. Reducing these chemicals exposure has important public implications on gender development.

Weight self-misperception and obesity-related knowledge, attitudes, lifestyle behaviours and cardio-metabolic markers among Chinese school-aged children and adolescents.

OBJECTIVE: The relationships between childhood weight self-misperception and obesity-related factors particularly health markers have not been extensively discussed. This study aims to examine the associations between weight self-misperception and obesity-related knowledge, attitudes, lifestyles and cardio-metabolic markers among Chinese paediatric population. DESIGN: Cross-sectional study. SETTING: Data sourced from a national survey in Chinese seven provinces in 2013. PARTICIPANTS: Children and adolescents aged 5-19 years. RESULTS: Of the total 14 079 participants, there were 14·5 % and 2·2 % participants over-estimated and under-perceived their weight, respectively. Multi-variable logistic regression was applied to calculate OR and 95 % CI (95 % Cl) of obesity-related behaviours and cardio-metabolic markers by actual and perceived weight status. Individuals who perceived themselves as overweight/obese were more likely to have prolonged screen time, insufficient dairy intake and over sugar-sweetened beverages consumption (all P < 0·05), regardless of their weight. Furthermore, actual overweight/obese individuals had higher odds of abnormal cardio-metabolic markers, but a smaller magnitude of association was found among weight under-estimators. Among non-overweight/obese individuals, weight over-estimation was positively associated with abdominal obesity (OR: 10·49, 95 % CI: 7·45, 14·76), elevated blood pressure (OR: 1·30, 95 % CI: 1·12, 1·51) and dyslipidemia (OR: 1·43, 95 % CI: 1·29, 1·58). CONCLUSIONS: Weight over-perception was more prevalent than under-estimation, particularly in girls. Weight over-estimators tended to master better knowledge but behave more unhealthily; both weight over-perception and actual overweight/obesity status were associated with poorer cardio-metabolic markers. Future obesity intervention programmes should additionally pay attention to the population with inaccurate estimation of weight who were easily overlooked.

Enhancing the effectiveness of infectious disease health education for children and adolescents in China: a national multicenter school-based trial.

BACKGROUND: Infectious diseases pose a significant risk to the health and well-being of children and adolescents, and can even be life-threatening. Thus, our study aimed to explore the effectiveness of health education based on the social-ecological model in improving the knowledge of infectious diseases among this vulnerable population. METHODS: This study was a school-based intervention conducted in seven Chinese provinces in 2013, involving a total of 26,591 children and adolescents in the intervention group and 24,327 in the control group. The intervention group received a comprehensive health intervention based on the social-ecological model (SEM) over six months, which included a supportive environment, health education on infectious diseases, guidance on self-monitoring infectious disease-related behaviors, and other measures. Data on infectious disease-related knowledge and other characteristics were collected through questionnaires. The main outcome measure will be the difference in the effectiveness of health education regarding infectious diseases in children and adolescents between baseline and post-intervention. A mixed-effects regression model was used to calculate the odds ratio (OR) and 95% confidence interval (95% CI) to assess the impact of infectious disease-related interventions on the participants. RESULTS: We utilized a socioecological model as the foundation for a six-month health education program on infectious diseases targeting children and adolescents in the intervention group. At the individual and community levels, the correct rate of health behavior related to infectious diseases in the intervention group was higher than that in the control group (P < 0.05), the ORs (95% CI) were 0.94 (0.90-0.99) and 0.94 (0.89-0.99), respectively. But the intervention effect was not significant at the interpersonal level. The intervention effect at the organizational level was obvious, with an increase in opportunities for children and adolescents to acquire knowledge of infectious diseases from courses and lectures, teachers, and doctors, (all P < 0.05), with the ORs (95% CI) of 0.92 (0.87-0.97) and 0.86 (0.83-0.94), respectively. However, there was no significant difference between the intervention group and the control group in school infectious disease health education policy. CONCLUSION: Enhancing health education regarding infectious diseases is crucial in promoting comprehensive prevention and control measures among children and adolescents. Nevertheless, it remains imperative to reinforce health education on infectious diseases at the interpersonal and policy levels. This holds significant reference value for mitigating childhood infectious diseases in the post-COVID-19 era.

Lean body mass positively associate with blood pressure in Chinese adults: the roles of ages and body fat distribution.

BACKGROUND: The relationship between lean body mass (LBM) and blood pressure (BP) is controversial and limited. This study investigated the associations between LBM indexes and BP in adults of different ages and with varying body fat distribution. METHODS: The data for the present analysis was obtained from a cross-sectional survey of 1,465 adults (50.7% males) aged 18-70 years conducted in Beijing, China. Regional LBM and fat distribution, including fat mass (FM) and android to gynoid fat ratio (AOI), were assessed using a dual-energy X-ray bone densitometer. Generalized Liner Model (GLM) was employed. Confounders, including age, sex, height, weight, smoking, and alcohol use, were evaluated through questionnaires and physical examinations. RESULTS: Males had higher rates of hypertension (11.19% vs. 4.92%) and prehypertension (21.57% vs. 14.59%) than females. The mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) were 122.04 mmHg and 76.68 mmHg. There were no significant associations between LBM and DBP (p > 0.05). However, arms LBM (ß = 1.86, 95% CI: 0.77, 2.94) and trunk LBM (ß = 0.37, 95% CI: 0.01, 0.73) were significantly associated with SBP. The association of LBM on DBP was stronger with increasing ages, and stronger in females than in males (p < 0.001). The association between adults' arms LBM and SBP was stronger in the high level FM group (ß = 2.74 vs. ß = 1.30) and high level AOI group (ß = 1.80 vs. ß = 2.08). CONCLUSION: The influence of LBM on SBP increases with age, particularly after the age twenty years in females. For adults with high FM or high AOI, LBM in the arms, showed a stronger positive predictive association with SBP. This suggests that, in addition to controlling fat content, future efforts to improve cardiovascular health in adults should include the management of LBM (especially in the upper body).

Persistent high exposure to exogenous phthalates and endogenous sex hormones associated with early pubertal onset among children: A 3.5-year longitudinal cohort study in China.

BACKGROUND: Early onset of puberty could have significant impacts on childhood health, but the extent to which it was affected by phthalate esters (PAEs) and sex hormone disruption was not understood. The aim of this study is to investigate the associations between exposure to PAEs and sex hormone disruption and early onset of puberty in children. METHODS: A longitudinal cohort study was conducted in China from May 2017 to Oct 2020, involving 740 children during consecutive visits. The onset of puberty was evaluated using Tanner definition, and early puberty was defined as an onset age less than the first 25 %, with cut-offs of 10.33 and 8.97 years for boys and girls, respectively. Serum testosterone (TT), estradiol (E2) and urinary PAE metabolites were measured during three visits. Generalized linear models were used to explore the associations between PAE and sex hormones with the age of puberty onset, while log-binomial regressions were applied to assess the associations of persistent exposure to PAEs and sex hormones with early pubertal onset. RESULTS: Approximately 86.0 % of boys and 90.2 % of girls completed puberty onset from pre-puberty, and more than 95 % of participants had PAE concentrations higher than the limit of detection. Boys showed higher exposure to PAE pollutants and higher TT levels. Persistent exposure to PAEs was positively associated with early pubertal onset in girls (ARR = 1.97, 95 %CI = 1.12, 3.46). Moreover, persistent exposure to PAEs and E2 had synergistic associations with early pubertal onset in both boys (ARR = 4.77, 95 %CI = 1.06, 21.54) and girls (ARR = 7.07, 95 %CI = 1.51, 33.10). However, PAEs and TT had antagonistic associations only in boys (ARR = 0.44, 95 %CI = 0.07, 2.58). CONCLUSION: Long-term exposure to PAEs might increase the risk of early pubertal onset, and it appears to work in synergy with E2, while in antagonism with TT in boys' early pubertal onset. Reducing PAEs exposure might promote pubertal health.

Sarcopenia in Patients with Cirrhosis after Transjugular Intrahepatic Portosystemic Shunt Placement.

Background Sarcopenia is frequently found in patients with cirrhosis and is associated with liver dysfunction, cirrhosis-related complications, and poorer quality of life. Purpose To evaluate changes in skeletal muscle and fat mass at CT and to evaluate the relationship of sarcopenia to mortality in patients with cirrhosis after transjugular intrahepatic portosystemic shunt (TIPS) placement. Materials and Methods Patients who underwent TIPS between August 2016 and May 2020 were included in this retrospective study. Skeletal muscle and fat mass were evaluated at CT at the L3 vertebra at baseline and at 2 months, 5 months, and 1 year after TIPS. Sarcopenia was defined as L3 skeletal muscle index (SMI) less than 50 cm2/m2 for men and less than 39 cm2/m2 for women. The primary end point was change in skeletal muscle and fat mass, and secondary end points included survival and the predictive factors for survival. Changes in skeletal muscle and fat mass over time were analyzed by generalized estimating equations. Results A total of 224 patients (159 men [113 with and 46 without sarcopenia] and 65 women [32 with and 33 without sarcopenia]) were included. In male patients with sarcopenia, the mean L3 SMI increased from 41.8 cm2/m2 (baseline) to 49.1 cm2/m2 (at 5-month follow-up; P < .001) and 49.6 cm2/m2 (at 1-year follow-up; P < .001) after TIPS. In female patients with sarcopenia, SMI increased from 33.7 cm2/m2 (at baseline) to 40.6 cm2/m2 (at 5-month follow-up; P < .001) and 42.0 cm2/m2 (at 1-year follow-up; P < .001) after TIPS. Sarcopenia (hazard ratio, 3.0; 95% CI: 1.2, 7.8) was identified as an independent risk factor for mortality after TIPS, and the patients who converted from sarcopenic to nonsarcopenic had higher cumulative survival rate than those who did not (96.4% vs 82.1%; log-rank P = .04). Conclusion In patients with sarcopenia, both skeletal muscle and fat mass increased after transjugular intrahepatic portosystemic shunt placement. The reversal of sarcopenia could reduce the risk of death. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Lee in this issue.

Association between healthy lifestyle pattern and early onset of puberty: based on a longitudinal follow-up study.

The present study aimed to explore the association between healthy lifestyle pattern and childhood early onset of puberty. Based on a cohort study in Xiamen of China, a total of 1294 children was followed for three and a half years. Children's lifestyles, including dietary behaviour, physical activity, sleep duration, smoking and drinking behaviour and sedentary behaviour, were collected by questionnaires. Healthy lifestyle pattern was determined mainly according to the recommendations by the Dietary Guidelines for Chinese school-age children and Canadian Guidelines for children and youth. The pubertal development was assessed by clinical examination according to Tanner stages. The association between pre-pubertal lifestyle and early onset of puberty was estimated using linear regression and log-binomial regression. We found that children who adhered to a healthy lifestyle had a 0·36-year delay of the age of puberty onset (coef = 0·36, 95 % CI (0·08, 0·65)) and 53 % lower risk of early onset of puberty (risk ratio = 0·47, 95 % CI (0·27, 0·80)), compared with those who had a poor lifestyle. However, the beneficial effect of favourable lifestyles on the early onset of puberty was found only in boys with normal weight. Boys who adhered to active physical activity and low sedentary behaviour had a relatively delayed age of puberty onset (coef = 0·49, 95 % CI (0·26, 0·72)). This is the first time to find that healthy lifestyle pattern was associated with a substantially lower risk of early onset of puberty, especially in boys with normal weight. Advocating an integrated healthy lifestyle is essential for the development of children.

The double faced role of xanthine oxidoreductase in cancer.

Xanthine oxidoreductase (XOR) is a critical, rate-limiting enzyme that controls the last two steps of purine catabolism by converting hypoxanthine to xanthine and xanthine to uric acid. It also produces reactive oxygen species (ROS) during the catalytic process. The enzyme is generally recognized as a drug target for the therapy of gout and hyperuricemia. The catalytic products uric acid and ROS act as antioxidants or oxidants, respectively, and are involved in pro/anti-inflammatory actions, which are associated with various disease manifestations, including metabolic syndrome, ischemia reperfusion injury, cardiovascular disorders, and cancer. Recently, extensive efforts have been devoted to understanding the paradoxical roles of XOR in tumor promotion. Here, we summarize the expression of XOR in different types of cancer and decipher the dual roles of XOR in cancer by its enzymatic or nonenzymatic activity to provide an updated understanding of the mechanistic function of XOR in cancer. We also discuss the potential to modulate XOR in cancer therapy.

Efficacy of Endoscopic Posterior Nasal Neurectomy in Treating Eosinophilic Chronic Rhinosinusitis.

OBJECTIVES: Recent guidelines have revealed that eosinophilic chronic rhinosinusitis (ECRS) exhibits a strong tendency for recurrence after surgery and impairs quality of life. Neuropeptides play an important neuroimmunological role. The aim of this study was to determine the efficacy of posterior nasal neurectomy (PNN) for the treatment of ECRS by inhibiting type 2 cytokine expression. METHODS: Forty-six patients were divided into group A and group B according to a random number table. Group A underwent conventional functional endoscopic sinusitis surgery (FESS) combined with PNN, and group B underwent conventional FESS alone. The subjective and objective symptoms included a 10-cm visual analog scale (VAS), 22-item SinoNasal Outcome Test (SNOT-22) score, nasal speculum Lund-Kennedy score, and paranasal sinus computed tomography (CT) Lund-Mackay score at the 1-year postoperative follow-up. RESULTS: Postoperative VAS (10.33 ± 2.18 vs. 8.38 ± 2.11, p < 0.01) and Lund-Kennedy score (1.95 ± 1.32 vs. 3.14 ± 1.35, p < 0.01) were significantly improved. The rhinorrhea score (1.76 ± 0.83 vs. 2.90 ± 1.14, p < 0.001) in the VAS and the discharge (0.43 ± 0.51, vs. 0.95 ± 0.67, p < 0.01) and edema (0.57 ± 0.60 vs. 0.95 ± 0.59, p < 0.05) scores in the Lund-Kennedy score were observed to have improved significantly in group A compared with those in group B. CONCLUSIONS: FESS combined with PNN suppresses edema symptoms, which might significantly decrease the surgical recurrence rate of ECRS in the long term.

Comparative anatomical and transcriptomic insights into Vaccinium corymbosum flower bud and fruit throughout development.

BACKGROUND: Blueberry (Vaccinium spp.) is characterized by the production of berries that are smaller than most common fruits, and the underlying mechanisms of fruit size in blueberry remain elusive. V. corymbosum 'O'Neal' and 'Bluerain' are commercial southern highbush blueberry cultivars with large- and small-size fruits, respectively, which mature 'O'Neal' fruits are 1 ~ 2-fold heavier than those of 'Bluerain'. In this study, the ontogenetical patterns of 'O'Neal' and 'Bluerain' hypanthia and fruits were compared, and comparative transcriptomic analysis was performed during early fruit development. RESULTS: V. corymbosum 'O'Neal' and 'Bluerain' hypanthia and fruits exhibited intricate temporal and spatial cell proliferation and expansion patterns. Cell division before anthesis and cell expansion after fertilization were the major restricting factors, and outer mesocarp was the key tissue affecting fruit size variation among blueberry genotypes. Comparative transcriptomic and annotation analysis of differentially expressed genes revealed that the plant hormone signal transduction pathway was enriched, and that jasmonate-related TIFYs genes might be the key components orchestrating other phytohormones and influencing fruit size during early blueberry fruit development. CONCLUSIONS: These results provided detailed ontogenetic evidence for determining blueberry fruit size, and revealed the important roles of phytohormone signal transductions involving in early fruit development. The TIFY genes could be useful as markers for large-size fruit selection in the current breeding programs of blueberry.

AZn4Ga5Se12 (A = K, Rb, or Cs): Infrared Nonlinear Optical Materials with Simultaneous Large Second Harmonic Generation Responses and High Laser-Induced Damage Thresholds.

Despite the fact that nonlinear optical (NLO) crystals such as AgGaS2 and AgGaSe2 have been widely used in the infrared (IR) range due to their large second harmonic generation (SHG) coefficients and wide range of IR transparency windows, the small laser-induced damage threshold (LIDT) remains a great issue hindering their high-power applications. Herein, three noncentrosymmetric (NCS) chalcogenides AZn4Ga5Se12 (A = K, Rb, or Cs) are successfully obtained through an appropriate flux method after the extensive design and synthesis of the A/Zn/Ga/Q system. Single-crystal X-ray diffraction data demonstrate that they adopt trigonal space group R3 (No. 146) with three-dimensional diamond-like frameworks composed of [M9Se24] layers (M = Zn or Ga) stacking in the same direction and filled by charge-balancing A+ cations. Noticeably, they all exhibit strong powder SHG responses (2.8-3.7 × AgGaS2) and amazing LIDTs (19.2-23.4 × AgGaS2). In addition, theoretical calculations are performed to further determine the relationship between NCS structures and NLO properties. This work provides effective solutions for overcoming the trade-off between strong SHG and high LIDT in IR-NLO materials.

Berberine attenuates Aß-induced neuronal damage through regulating miR-188/NOS1 in Alzheimer's disease.

Alzheimer's disease (AD) is a public health issue worldwide. Berberine (Ber) acts as the neuroprotective role in an animal experiment of AD. MicroRNA-188 (miRNA-188) was reported to be decreased in primary hippocampal neurons of mice. However, the roles and molecular basis of Ber and miRNA-188 in the treatment of AD need to be further explored. In this study, 5 µM Ber treatment has little effect on cell viability. Ber treatment or miR-188 overexpression expedited proliferation and inhibited caspase-3 activity and apoptotic rate in amyloid-beta (Aß)-treated BV2 and N2a cells. MiR-188 was downregulated, and nitric oxide synthase 1 (NOS1) was upregulated in Aß-induced BV2 and N2a cells. NOS1 worked as the target of miR-188. NOS1 overturned miR-188-induced effects on cell viability, caspase-3 activity, and apoptotic rate in Aß-induced BV2 and N2a cells. Ber mitigated neuronal damage in Aß-induced BV2 and N2a cells by miR-188/NOS1 axis. These results suggested that Ber accelerated cell viability and suppressed caspase-3 activity and apoptotic rate possible by miR-188/NOS1 pathway, implying the treatment of Ber as an underlying effective drug for AD patients.

Comparison of Quality of Life and Nutritional Status of Between Roux-en-Y and Billroth-I Reconstruction After Distal Gastrectomy: A Systematic Review and Meta-Analysis.

Background: This paper purports to use a meta-analysis to compare the postoperative quality of life (QoL) and nutritional status of between Roux-en-Y (R-Y) and Billroth-I (B-I) reconstruction after distal gastrectomy.Methods: For this study, the following databases were searched for articles published from inception until December 2018: PubMed, Web of Science, EBSCO, and Cochrane library.Results: A total of 13 eligible studies, covering 3645 patients, were selected for a meta-analysis. The analysis showed that compared with B-I group in term of short-term outcomes, patients undergoing R-Y reconstruction did not only have significantly better physiological function (P = 0.02), but had significantly less pain (P = 0.04). In the long-term outcomes, the dyspnea and constipation in the B-I group were worse than that in the R-Y group (P = 0.004; P = 0.04, respectively). Patients in the B-I group had higher cholesterol than those in the R-Y group at 5 years postoperatively (P = 0.003). There were no significant differences in termof other nutritional indicators including total protein, cholesterol, albumin, hemoglobin and weight in short-term outcomes.Conclusions: The final conclusion was that R-Y may be superior to the B-I reconstruction in some aspects of QoL. Besides, R-Y reconstruction could reduce the patient's cholesterol level for a long time. For the short-term outcomes, there were no significant differences in other common nutritional indicators.

Effect of posterior nasal neurectomy on the suppression of allergic rhinitis.

OBJECTIVES: Recent guidelines have revealed that allergic rhinitis (AR) impairs quality of life. Neuropeptides play a central role in AR. The aim of this study was to determine the efficacy of posterior nasal neurectomy (PNN) for the treatment of AR and for the suppression of neuropeptides and type 2 cytokine expression. METHODS: In total, 77 patients undergoing PNN were recruited. Subjective symptoms, including sneezing and rhinorrhea, were elicited with a questionnaire using a 10 cm visual analogue scale (VAS). Nasal lavage fluid taken from a random sample of 17 patients both preoperatively and 1 year postoperatively was screened with enzyme-linked immunosorbent assays. RESULTS: Postoperative rhinorrhea (6.03 ± 1.31vs 2.12 ± 1.40, P < 0.001) and sneezing (5.53 ± 1.25vs 2.04 ± 1.29, P < 0.001) were significantly improved relative to the preoperative levels; the mean SP and NPY concentrations in the nasal lavage fluid were 91.6 ± 20.9 pg/ml and 71.5 ± 10.5 pg/ml, which decreased significantly to 52.9 ± 16.7 pg/ml and 31.8 ± 8.2 pg/ml, respectively, and the mean periostin and IL-5 concentrations were 215.2 ± 87.7 pg/ml and 984.5 ± 181.8 pg/ml, which decreased significantly to 146.1 ± 70.1 pg/ml and 281.6 ± 74.0 pg/ml, respectively. CONCLUSIONS: PNN was safe and well tolerated, and the symptom (sneezing and rhinorrhea) scores were significantly decreased by 1 year postoperatively.

The safety and tolerability of combined immune checkpoint inhibitors (anti-PD-1/PD-L1 plus anti-CTLA-4): a systematic review and meta-analysis.

BACKGROUND: The future of combined immunotherapy (a PD-1/PD-L1 plus a CTLA-4 antagonist) is very bright. However, besides improving efficacy, combined therapy increases treatment-related adverse events (TRAEs). Also, the clinical application is limited in some solid tumors. METHODS: This paper purports to investigate the TRAEs for the combined immunotherapy aiming for a more appropriate utilization of immune checkpoint inhibitors (ICIs) in clinical practice through a meta-analysis. RESULTS: A total of 17 eligible studies covering 2626 patients were selected for a meta-analysis based on specified inclusion and exclusion criteria. The incidence rates of any grade and grade 3 or higher TRAEs were 88% (95%CI, 84-92%) and 41% (95%CI, 35-47%), respectively. The overall incidence of any grade TRAEs leading to discontinuation of treatment was 20% (95%CI, 16-24%). The incidence rate of treatment related deaths was 4.3‰ (95%CI, 1.4‰-8.4‰). Analysis showed that NIVO1 + IPI3 cohort had higher incidences of grade 3 or higher TRAEs (RR = 1.77, 95%CI, 1.34-2.34, p < 0.0001) and any grade TRAEs leading to discontinuation of treatment (RR = 1.81, 95%CI, 1.08-3.04, P = 0.02), compared with NIVO3 + IPI1 regimen. CONCLUSIONS: The combined therapy had high TRAEs. The TRAEs, especially grade 3 or higher, led to discontinuation of the treatment. Furthermore, the incidence of treatment-related deaths was rare. Moreover, the NIVO3 + IPI1 regimen, regardless of efficacy, is more recommended because of better tolerance and lower adverse events.