Induction of carbohydrate‐specific antibodies in HLA‐DR transgenic mice by a synthetic glycopeptide: a potential anti cancer vaccine for human use

Abstract: Over the last few years, anticancer immunotherapy has emerged as a new exciting area for controlling tumors. In particular, vaccination using synthetic tumor‐associated antigens (TAA), such as carbohydrate antigens hold promise for generating a specific antitumor response by targeting the immune system to cancer cells. However, development of synthetic vaccines for human use is hampered by the extreme polymorphism of human leukocyte‐associated antigens (HLA). In order to stimulate a T‐cell dependent anticarbohydrate response, and to bypass the HLA polymorphism of the human population, we designed and synthesized a glycopeptide vaccine containing a cluster of a carbohydrate TAA B‐cell epitope (Tn antigen: α‐GalNAc‐Ser) covalently linked to peptides corresponding to the Pan DR ‘universal’ T‐helper epitope (PADRE) and to a cytotoxic T lymphocyte (CTL) epitope from the carcinoembryonic antigen (CEA). The immunogenicity of the construct was evaluated in outbred mice as well as in HLA transgenic mice (HLA‐DR1, and HLA‐DR4). A strong T‐cell dependent antibody response specific for the Tn antigen was elicited in both outbred and HLA transgenic mice. The antibodies induced by the glycopeptide construct efficiently recognized a human tumor cell line underlying the biological relevance of the response. The rational design and synthesis of the glycopeptide construct presented herein, together with its efficacy to induce antibodies specific for native tumor carbohydrate antigens, demonstrate the potential of a such synthetic molecule as an anticancer vaccine candidate for human use.     

Let bone and muscle talk together: a study of real and virtual dissection and its implications for femoral musculoskeletal structure of chimpanzees

Proximal femoral morphology and associated musculature are of special relevance to the understanding of hominoid locomotor systems. Knowledge of bone–muscle correspondence in extant hominoids forms an important comparative basis for inferring structure–function relationships in fossil hominids. However, there is still a lack of consensus on the correspondence between muscle attachment sites and surface morphology of the proximal femoral diaphysis in chimpanzees. Two alternative observations have been proposed regarding the attachment site positions of gluteus maximus (GM) and vastus lateralis (VL) relative to two prominent surface features of the proximal femoral diaphysis, the lateral spiral pilaster and the inferolateral fossa. Here, we use a combination of virtual and physical dissection in an attempt to identify the exact correspondence between muscle attachment sites and osteological features in two specimens of Pan troglodytes verus. The results show that the insertion of the GM tendon is consistently inferolateral to the lateral spiral pilaster, and that a part of the inferolateral fossa consistently forms the attachment site of the VL muscular fibers. While overall musculoskeletal features are similar in the two specimens examined in this study, GM and VL exhibit different degrees of segregation at the level of the inferolateral fossa. One specimen exhibited tendinous GM fibers penetrating the posteromedial part of VL, with both GM and VL inserting at the inferolateral fossa. In the other specimen, GM and VL were separated by a lateral intermuscular septum, which inserted into the inferolateral fossa. Variation of proximal femoral muscle attachments in chimpanzees is thus greater than previously thought. Our results indicate that a conspicuous osteological feature such as the inferolateral fossa does not necessarily correspond to the attachment site of a single muscle, but could serve as a boundary region between two muscles. Caution is thus warranted when interpreting the surface topography of muscle attachment sites and inferring locomotor functions.     

Translating vaccine policy into action: A report from the Bill & Melinda Gates Foundation Consultation on the prevention of maternal and early infant influenza in resource-limited settings

Immunization of pregnant women against influenza is a promising strategy to protect the mother, fetus, and young infant from influenza-related diseases. The burden of influenza during pregnancy, the vaccine immunogenicity during this period, and the robust influenza vaccine safety database underpin recommendations that all pregnant women receive the vaccine to decrease complications of influenza disease during their pregnancies. Recent data also support maternal immunization for the additional purpose of preventing disease in the infant during the first six months of life.     

Extensive X-linked adaptive evolution in central chimpanzees

Surveying genome-wide coding variation within and among species gives unprecedented power to study the genetics of adaptation, in particular the proportion of amino acid substitutions fixed by positive selection. Additionally, contrasting the autosomes and the X chromosome holds information on the dominance of beneficial (adaptive) and deleterious mutations. Here we capture and sequence the complete exomes of 12 chimpanzees and present the largest set of protein-coding polymorphism to date. We report extensive adaptive evolution specifically targeting the X chromosome of chimpanzees with as much as 30% of all amino acid replacements being adaptive. Adaptive evolution is barely detectable on the autosomes except for a few striking cases of recent selective sweeps associated with immunity gene clusters. We also find much stronger purifying selection than observed in humans, and in contrast to humans, we find that purifying selection is stronger on the X chromosome than on the autosomes in chimpanzees. We therefore conclude that most adaptive mutations are recessive. We also document dramatically reduced synonymous diversity in the chimpanzee X chromosome relative to autosomes and stronger purifying selection than for the human X chromosome. If similar processes were operating in the human-chimpanzee ancestor as in central chimpanzees today, our results therefore provide an explanation for the much-discussed reduction in the human-chimpanzee divergence at the X chromosome.     

Morphometrics and inertial properties in the body segments of chimpanzees (Pan troglodytes)

Inertial characteristics and dimensions of the body and body segments form an integral part of a biomechanical analysis of motion. In primate studies, however, segment inertial parameters of non-human hominoids are scarce and often obtained using varying techniques. Therefore, the principal aim of this study was to expand the existing chimpanzee inertial property data set using a non-invasive measuring technique. We also considered age- and sex-related differences within our sample. By means of a geometric model based on Crompton et al. (1996; Am J Phys Anthropol 99, 547-570) we generated inertial properties using external segment length and diameter measurements of 53 anaesthetized chimpanzees (Pan troglodytes). We report absolute inertial parameters for immature and mature subjects and for males and females separately. Proportional data were computed to allow the comparison between age classes and sex classes. In addition, we calculated whole limb inertial properties and we discuss their potential biomechanical consequences. We found no significant differences between the age classes in the proportional data except for hand and foot measures where juveniles exhibit relatively longer and heavier distal segments than adults. Furthermore, most sex-related differences can be directly attributed to the higher absolute segment masses in male chimpanzees resulting in higher moments of inertia. Additionally, males tend to have longer upper limbs than females. However, regarding proportional data we discuss the general inertial properties of the chimpanzee. The described segment inertial parameters of males and females, and of the two age classes, represent a valuable data set ready for use in a range of biomechanical locomotor models. These models offer great potential for improving our understanding of early hominin locomotor patterns.     

过氧化氢溶液声学造影进行子宫输卵管通畅性检查的临床价值

目的：探讨超声下过氧化氢溶液声学造影对子宫输卵管通畅性的临床价值。方法选择2011年1月~2013年6月在河南省军区直属医院妇科收治的确诊为输卵管性不孕症的患者65例,按照入院顺序将其随机分为对照组和实验组,对照组32例(输卵管61条),其中3例为单侧输卵管切除,实验组33例(输卵管64条),其中2例单侧输卵管切除。对照组患者采用传统输卵管通液法进行诊断,实验组采用超声下3%过氧化氢造影法进行诊断,术后所有患者均采用泛影葡胺X线造影作为诊断标准,观察两组的诊断结果并分别与泛影葡胺X线下造影结果进行比较。结果对照组输卵管通畅44条,阻塞17条,采用泛影葡胺X线造影诊断输卵管通畅58条,阻塞3条,诊断结果比较,差异有统计学意义(字2=6.1,P<0.05);实验组输卵管通畅59条,阻塞5条,采用泛影葡胺X线造影诊断输卵管通畅62条,阻塞2条,诊断结果比较,差异无统计学意义(字2=3.6,P>0.05)。对照组诊断输卵管通畅符合率为72.13%,阻塞符合率为27.87%;实验组诊断输卵管通畅符合率为92.19%,阻塞符合率为7.81%;两组诊断符合率比较,差异有统计学意义(字2=7.45,P<0.05)。结论超声下过氧化氢溶液声学造影诊断子宫输卵管通畅情况方法操作简单,在诊治输卵管性不孕症方面具有临床价值,值得推广。     

Bidirectional association between depressive symptoms and type 2 diabetes mellitus: The China Health and Retirement Longitudinal Study

ObjectiveTo prospectively examine the bidirectional relationship between depressive symptoms and type 2 diabetes mellitus (T2DM) among middle-aged and elderly Chinese.MethodsParticipants were enrolled in 2011–2012 (Wave 1) and followed up in 2013–2014 (Wave 2) and 2015–2016 (Wave 3) in the China Health and Retirement Longitudinal Study. Depressive symptoms were evaluated by the Chinese language version of 10-item Center for Epidemiological Studies Depression Scale (CESD-10) at three waves. T2DM was assessed by biochemical biomarkers at Wave 1 and reported physician-diagnosis at Wave 2 and 3. Cox proportional hazards regression was applied to calculate hazard ratio (HR) and 95% confidence intervals (CIs) for the bidirectional association.ResultsParticipants with baseline depressive symptoms were 1.33 times as likely to develop T2DM (HR, 1.33; 95% CI: 1.06, 1.66), compared to their counterparts after adjusting for demographic characteristics and T2DM risk factors. The risk of T2DM increased linearly with higher severity of depression as determined by a higher CESD-10 score (P for trend ? 0.001). In addition, baseline T2DM was associated with increased risk of incident depressive symptoms (1.15; 1.00, 1.31) and persistent depressive symptoms (1.35; 1.03, 1.77).ConclusionThere is a positive bidirectional association between depressive symptoms and T2DM in middle-aged and elderly Chinese.     

Identifying signatures of the impact of rotavirus vaccines on hospitalizations using sentinel surveillance data from Latin American countries

BackgroundPassive surveillance data are often the only available source of data that can be used to evaluate the population-level impact of vaccination, but such data often suffer from important limitations such as changes in surveillance efforts. This study provides an example of how to identify important signatures of rotavirus vaccine impact, including evaluating the overall effectiveness and changes in rotavirus seasonal dynamics.MethodsWe used data from a standardized sentinel rotavirus surveillance network in six Latin American countries (Bolivia, El Salvador, Guatemala, Honduras, Paraguay, and Venezuela) from 2004 to 2017. A random-effects model was used to evaluate changes in the proportion of rotavirus-associated hospitalizations following vaccine introduction. Harmonic regression models were used to estimate vaccine impact on the number of rotavirus hospitalizations, controlling for trends in rotavirus-negative cases. Changes to rotavirus seasonality were evaluated using center of gravity analysis, wavelet analysis, and harmonic regression.ResultsAll countries observed declines in the proportion of rotavirus-positive acute diarrhea samples with a mean reduction of 16% (95% confidence interval: 10–22%). We estimate that each 10% increase in vaccine coverage was associated with declines in the number of rotavirus-positive cases, ranging from 4.3% (1.3–7.2%) in Honduras to 21.4% (16.8–25.9%) in Venezuela. The strength of the seasonal peak in rotavirus incidence became smaller after vaccine introduction in Guatemala, Honduras, and Venezuela. Seasonal peaks also shifted later in the surveillance year, especially in higher-mortality countries.ConclusionsThe combination of methods we applied have different strengths that allow us to identify common signatures of rotavirus vaccine impact.