Immunogenicity of mAbs in non-human primates during nonclinical safety assessment

The immunogenicity of biopharmaceuticals used in clinical practice remains an unsolved challenge in drug development. Non-human primates (NHPs) are often the only relevant animal model for the development of monoclonal antibodies (mAbs), but the immune response of NHPs to therapeutic mAbs is not considered to be predictive of the response in humans because of species differences. In this study, we accessed the drug registration files of all mAbs registered in the European Union to establish the relative immunogenicity of mAbs in NHPs and humans. The incidence of formation of antidrug-antibodies in NHPs and patients was comparable in only 59% of the cases. In addition, the type of antidrug-antibody response was different in NHP and humans in 59% of the cases. Humanization did not necessarily reduce immunogenicity in humans. Immunogenicity interfered with the safety assessment during non-clinical drug development when clearing or neutralizing antibodies were formed. While important to interpret the study results, immunogenicity reduced the quality of NHP data in safety assessment. These findings confirm that the ability to compare relative immunogenicity of mAbs in NHPs and humans is low. Furthermore, immunogenicity limits the value of informative NHP studies.     

失代偿期肝硬化患者感染的危险因素及临床特点分析

目的：分析失代偿期肝硬化患者感染的相关危险因素和临床特点。方法：回顾性分析我院2012年4月--2013年4月住院的197例肝硬化失代偿期患者,比较感染患者与非感染患者的年龄、性别、肝功能分级、白细胞水平、门静脉内径、肝硬化并发症、侵入性操作措施、应用抗菌药物、住院时间等差异。结果：197例患者中发生感染的56例,其中以呼吸道和腹部感染为主。统计发现肝功能分级、白细胞水平、侵入性操作、住院时间及抗菌药的运用等与感染因素有关（P〈0．05）。结论：引起失代偿期肝硬化感染的危险因素是多方面的,临床特点也较突出,需要我们采取防措施去避免。     

THE LAKE ST. LUCIA SYSTEM—A RESEARCH ASSESSMENT

SUMMARY

This paper assesses the research undertaken at Lake St. Lucia over the past 25 years based on over 300 documents from that period. Trends related to both time and subject matter are evident, and these are considered in relation to the gaps in our current knowledge concerning the system.

A feature evident throughout the period under consideration is that the major portion of documented material available relates to reports and contributions to workshops (77%) with only 23% from scientific publications. Contributions by these two sources to the subject group being considered for St. Lucia are markedly different with research publications dominating the biological field and reports dominating in physical aspects, catchment characteristics, man's activities, management, dredging and hydrological modelling. However, some 55% of all unpublished data related to reviews or assessments of the state of research on St. Lucia.

The importance of the scientific publications group as an indicator of the state of research into the system is considered in the light of an apparent decline in the number of completed projects being published. It is also considered in the light of the recent establishment of a co-ordinated Lake St. Lucia Research Programme, which may provide the impetus for a more concentrated and directed research effort on the Lake System.     

2型糖尿病患者下肢血管病变的危险因素分析

目的:探讨2型糖尿病患者发生下肢血管病变的危险因素.方法:回顾性分析我院2009年12月～2011年12月收治的98例2型糖尿病患者的临床资料,通过彩色多普勒超声检查其下肢血管,按下肢血管有无病变将其分为单纯2型糖尿病租和2型糖尿病合并下肢血管病变组,通过非条件Logistic回归分析导致2型糖尿病患者发生下肢血管病变的危险因素.结果:彩色多普勒超声检查结果显示,98例2型糖尿病患者中,61例发生不同程度下肢血管病变,占62.24％.与单纯2型糖尿病组比较,下肢血管病变组患者年龄、病程、收缩压及低密度脂蛋白胆固醇的差异均有统计学意义(P＜0.05),经非条件Logistic回归分析,患者的年龄、病程、SBP及LDL-L是下肢血管病变的独立危险因素(P＜0.05).结论:2型糖尿病患者下肢血管病变的发生与患者的年龄、病程、血压及血脂情况密切相关.     

SRSF1-dependent alternative splicing attenuates BIN1 expression in non–small cell lung cancer

Decreased bridging integrator 1 (BIN1) expression has great significance in promoting the progression of malignant tumors. Reduced messenger RNA expression is partly due to aberrant alternative splicing (AS). However, the AS status of BIN1 and its correlation with BIN1 inactivation in non–small cell lung cancer (NSCLC) remains poorly defined. Here we reported that BIN1 inactivation was not related to DNA methylation in NSCLC. Importantly, BIN1 with exon 12A inclusion (BIN1+12A isoform), the most frequent aberrant splicing variant in tumors was also observed in NSCLC, and might be accounted for BIN1 inactivation. Furthermore, we showed that the aberrant splicing of BIN1 was under the control of serine and arginine-rich factor 1 (SRSF1) in NSCLC. In addition, colony formation assay showed that BIN1+12A isoform could abolish the tumor-inhibiting ability of BIN1 in NSCLC cells. Meanwhile, transwell, wound healing and apoptosis experiments demonstrated that the occurrence of BIN1+12A could abrogate the invasion suppressing activity and proapoptotic property of BIN1 in NSCLC. Significantly, we also found that BIN1+12A isoform neutralized the tumor-suppressing functions of BIN1 via affecting its subcellular localization. Altogether, these data revealed an aberrant splicing phenomenon which abated the expression and tumor-inhibiting activity of BIN1 in NSCLC, and the related mechanisms were associated with SRSF1.     

Evening chronotype is associated with poor cardiovascular health and adverse health behaviors in a diverse population of women

ABSTRACT

Chronotype reflects time of day preferences for performing daily activities. Previous research within Asian and European cohorts indicates evening chronotype is associated with elevated cardiometabolic risk. However, evidence is limited from population-based US cohorts, particularly among women in whom evening chronotype prevalence may become higher after middle-age, coinciding with life stages associated with higher cardiovascular disease (CVD) risk. This cross-sectional study evaluated associations of chronotype with overall cardiovascular health (CVH), health behaviors, and cardiometabolic risk factors among 506 women (mean age = 37 ± 16y, 62% racial/ethnic minority) in the American Heart Association (AHA)’s Go Red for Women Strategically-Focused Research Network cohort at Columbia University (New York City, NY, USA). Chronotype was assessed using the validated Morningness-Eveningness Questionnaire (MEQ) and categorized as “evening”, “intermediate”, and “morning” chronotypes. Health behaviors (diet, physical activity, and sleep) were assessed using validated questionnaires. Anthropometrics, clinical blood pressure, and blood biomarkers were assessed at the clinic visit. CVH was evaluated using the AHA Life’s Simple 7 (LS7) metrics; LS7 scores of 0–8 and 9–14 were considered indicative of poor and moderate-to-high CVH, respectively. Linear and logistic regression models adjusted for age, race/ethnicity, education, health insurance, and menopausal status were used to examine associations of MEQ scores and chronotype categories with overall CVH, clinical cardiometabolic risk factors, and health behaviors. Overall, 13% of women identified as evening chronotypes, while 55% and 32% reported being intermediate and morning types. In linear models, higher MEQ scores were associated with higher AHA LS7 scores (β(SE) = 0.02(0.01); p = .014), indicative of more favorable CVH, and with health behaviors not included in the LS7. Higher MEQ scores were also associated with lower Pittsburgh Sleep Quality Index, i.e. better sleep quality, (β(SE) = ?0.07(0.02), p < .0001), lower insomnia severity (β(SE) = ?0.14(0.01), p < .0001), shorter time to fall asleep (β(SE) = ?0.28(0.14), p = .044), and less sedentary time (β(SE) = ?0.11(0.03), p = .001). In logistic regression models, evening chronotype, compared to intermediate/morning type, was associated with higher odds of having poor CVH (OR(95%CI):2.41(1.20–4.85)), not meeting AHA diet (OR(95%CI):2.89(1.59–5.23)) and physical activity guidelines (OR(95%CI):1.78(1.03–3.07)), and having short sleep (OR(95%CI):2.15(1.24–3.73)) or insomnia (OR(95%CI):2.69(1.53–4.75)). The evening type compared to morning type was also associated with being a current smoker (OR(95%CI):2.14(1.02–4.52)) and having poor sleep quality (OR(95%CI:2.35(1.27–4.37)) and long sleep onset latency (OR(95%CI:1.89(1.00–3.56)). In our cohort of women, evening chronotype was related to poor CVH, likely driven by its influence on health behaviors. These findings, although warranting confirmation prospectively in other populations, suggest chronotype is an important factor to consider and possibly target when designing lifestyle interventions for CVD prevention.     

Residency and abundance of sperm whales (Physeter macrocephalus) in Nemuro Strait,Hokkaido, Japan

We examined the trend in residence patterns and abundance of male sperm whales in Nemuro Strait, Japan, based on long-term photo-identification (1,513 survey days, total 2,969 photos) between 2006 and 2017. A total of 225 unique individuals were identified during this study, with an average of 36 (SE = 2.55) new individuals identified in each season. The model chosen by maximum likelihood suggests that residence time around Nemuro Strait is 769 (SE = 372.4) days, with individuals staying in the strait about 48 days (SE = 8.36) per year. While the migration patterns of male sperm whales visiting this area are still unclear, these findings along with previous studies suggest that males move from one breeding area to another neighboring area every several weeks, shifting their home ranges gradually over a period of a few years. The abundance of sperm whales in Nemuro Strait varied greatly from year to year; from 28 (95%CI: 24–44) in 2015 and (95%CI: 22–48) in 2016 to 66 (95%CI: 57–84) in 2011. This study provides important knowledge of abundance and residency for Nemuro Strait, information which will contribute to further research on the social structure and movement pattern of male sperm whales.     

Southern right whales show no behavioral response to low noise levels from a nearby unmanned aerial vehicle

Unmanned aerial vehicles (UAVs) are increasingly used for wildlife research and monitoring, but little information exists on their potential effect on marine mammals. We assessed the effects of a UAV on the behavior of southern right whales (Eubalaena australis) in Australia. Focal follows of ten right whale mother-calf pairs were conducted using a theodolite. Control data were recorded for 30 min, and then a DJI Inspire 1 Pro was flown above the whales for 10 min at 5 m altitude. Potential changes to horizontal behavior (swim speed and turning angle) and surfacing pattern (interbreath intervals) were investigated by comparing mother-calf behavior before and during UAV approaches. Changes in respiration rate were used to quantify energetic effects. We also explored acoustic cue perceptibility of the UAV at 5, 10, and 30 m altitude, by measuring the received UAV underwater noise level on whales equipped with acoustic tags (DTAGs). The received noise levels were 86.0 ± 3.9 dB re 1 μPa, while the measured ambient noise was 80.7 ± 7.3 dB re 1 μPa in the same frequency band (100–1,500 Hz). No behavioral response to the UAV was observed. This provides support for UAVs as a noninvasive tool to study baleen whale behavior and ecophysiology.     

Plasticity of Least Tern and Piping Plover nesting behaviors in response to sand temperature

Birds that nest on the ground in open areas, such as Piping Plovers (Charadrius melodus) and Interior Least Terns (Sternula antillarum athalassos), are exposed to high temperatures in thermally stressful environments. As a result, some ground-nesting avian species have adapted behavioral strategies to maintain thermal regulation of eggs and themselves. We assessed the impact of sand temperature on shorebird nesting behaviors by installing video cameras and thermocouples at 52 Least Tern and 55 Piping Plover nests on the Missouri River in North Dakota during the 2014–2015 breeding seasons. Daily duration and frequency of shading behaviors exhibited a nonlinear relationship with temperature; therefore, we used segmented regressions to determine at what threshold temperature (mean temperature = 25.7^⸰C for shading behavior daily frequency and mean temperature = 25.1^⸰C for shading behavior daily duration) shorebird adults exhibited a behavioral response to rising sand temperatures. Daily nest attendance of both species decreased with increasing sand temperatures in our system. Frequency and duration of daily shading behaviors were positively correlated with sand temperatures above the temperature threshold. Piping Plovers exhibited more and longer shading behaviors above and below the temperature thresholds (below: frequency = 10.30 ± 1.69 se, duration = 7.29 min ± 2.35 se; above: frequency = 59.27 ± 6.87 se) compared to Least Terns (below: frequency = −1.37 ± 1.98 se, duration = −0.73 min ± 1.51 se; above: frequency = 31.32 ± 7.29 se). The effects of sand temperature on avian ground-nesting behavior will be critical to understand in order to adapt or develop recovery plans in response to climate change.     

NBPF1 independently determine the risk stratification and prognosis of patients with neuroblastoma

Neuroblastoma is the most frequent extracranial malignant solid tumor in children, and the 5 year OS of high risk neuroblastoma patients was less than 15%. This study aimed to identify biomarkers for risk stratification and prognosis prediction in neuroblastoma.149 low risk samples, 108 intermediate risk samples and 619 high risk samples were included in our study, and NBPF1 gene was found to be significantly correlated with risk levels and OS. Significant negative correlations between NBPF1 and the expression of MYCN and AKT1S1, and positive correlations between NBPF1 and KIF1B expression were found, but only NBPF1 was an independent biomarker based on the construct of PPI for MYCN, NBPF1, KIF1B and AKT1S1 by STRING enrichment.