Cytotoxic natural antibodies against human tumours: an option for anti-cancer immunotherapy?

Healthy individuals may contain in their peripheral blood antibodies which are able to destroy human tumour cells mediated either by complement-dependent cytotoxicity or by apoptosis. The largest proportion of these antibodies is of IgM isotype and directed against distinct tumour associated carbohydrate epitopes. Although the origin of these antibodies is not clear they seem to belong to the class of natural antibodies because they are not affinity matured and are encoded by distinct germ-line restricted gene families. It is most likely that this class of natural antibodies has in vivo an anti-tumour protective effect which may contribute to so-called tumour surveillance. On the other hand malignant tumour cells exert mechanisms to counteract such an antibody attack. These comprise soluble factors as well as cell surface expressed membrane complement regulatory proteins (mCRP). Further studies are needed to elucidate molecular mechanisms leading to either tumour destruction induced by natural antibodies or to overcome the protective strategies of the tumour against antibody attack.     

Is the mouse a clinically relevant model for human fertilization failures?

This study compares failed fertilization oocytes from patients participating in an in-vitro fertilization (IVF) programme with failed fertilization oocytes from B6SJLF(1)/J mice, in order to characterize and describe the distribution of DNA in oocytes that do not undergo normal fertilization. Our goal is to evaluate the mouse IVF system as a model to gain insight into reasons for human fertilization failures. All oocytes were stained with the vital fluorescent dye, Hoechst 33342, which rapidly stains double-stranded DNA. Of the 237 human oocytes that had been scored as failed fertilization by brightfield microscopy, 61 (25.7%) showed the presence of at least one spermatozoon within the oocyte cytoplasm. In contrast, out of 69 failed fertilization mouse oocytes, only one oocyte showed the presence of a spermatozoon within its cytoplasm. Mouse failed fertilization oocytes exhibited a significantly lower internal sperm rate (P < 0.0001) than human failed fertilization oocytes. Human failed fertilization oocytes show a higher incidence of sperm penetration, but the cytoplasm fails to support pronuclear development, whereas, at least in this strain, mouse failed fertilization oocytes arise from an inability of the spermatozoa to penetrate the oocyte. This study suggests that the mouse is not a clinically relevant model for human fertilization failures.     

Are we ready for genome editing in human embryos for clinical purposes?

Perhaps the two most significant pioneering biomedical discoveries with immediate clinical implications during the past forty years have been the advent of assisted reproductive technologies (ART) and the genetics revolution. ART, including in vitro fertilization (IVF), intracytoplasmic sperm injection and preimplantation genetic testing, has resulted in the birth of more than 8 million children, and the pioneer of IVF, Professor Bob Edwards, was awarded the 2010 Nobel Prize. The genetics revolution has resulted in our genomes being sequenced and many of the molecular mechanisms understood, and technologies for genomic editing have been developed. With the combination of nearly routine ART protocols for healthy conceptions together with almost error-free, inexpensive and simple methods for genetic modification, the question “Are we ready for genome editing in human embryos for clinical purposes?” was debated at the 5th congress on controversies in preconception, preimplantation and Prenatal Genetic Diagnosis, in collaboration with the Ovarian Club Meeting, in November 2018 in Paris. The co-authors each presented scientific, medical and bioethical backgrounds, and the debate was chaired by Professor Alan Handyside. In this paper, we consider whether genome editing is safe and ethical. We conclude that we are currently not ready for genome editing to be used in human embryos for clinical purposes, and we call for a global debate to determine if and when this technology could be used in ART. ‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬     

Muscle agonist–antagonist interactions in an experimental joint model

The experiments presented here and performed in anaesthetized cats aimed at studying the dynamics of interactions between antagonist muscle groups. The tendons of triceps surae muscles of both hindlimbs were connected with an artificial joint (a pulley installed on a shaft). The muscles were activated by the distributed stimulation of five filaments of cut ventral roots L7–S1 on both sides of the spinal cord; movements were evoked by the rate-modulation of the stimulation trains. The study mostly compared programs of reciprocal activation and co-activation, including different changes in stimulation rates of muscle antagonists. The most common feature of the movements in both activation modes was hysteresis of the joint angle changes in dependence on stimulus rate. Reciprocal activation appeared suitable for a precise regulation of both amplitude and velocity of the movements in direction of the agonist shortening; maximal effectiveness was achieved during full switching off the antagonist stimulation at plateaus of the movement traces. The reverse movements during decrease of the agonist’s stimulation rate demonstrated an explicit nonlinear form with pronounced initial phase of the joint angle fixation. The co-activation pattern distinctly reduced the hysteresis of joint movements and suppressed the stimulation after-effects, such as the lasting residual movements after fixation of the stimulation rates.     

Lymphangiogenesis in malignant tumours: does it occur?

The development of a vascular bed is essential for solid tumour growth and metastasis. In many tumours, mean vascular density can be related to the rate of metastasis and, therefore, to prognosis. In other tumour types, such as cutaneous melanoma and head-and-neck squamous cell carcinoma, this relation is absent. Until now, the reason for this has been unclear, but since these particular tumour types are also known for their propensity to spread via the lymphatic system, it may be speculated that the presence of a pre-existing lymphatic bed and the formation of new lymphatics (lymphangiogenesis) are important factors. Growth factors involved in lymphangiogenesis during embryogenesis have been recently identified and these are also expressed in many tumour types, but the existence of tumour-induced lymphangiogenesis has not so far been reported. Partly, this could be due to the lack of reliable endothelial markers, thereby hampering a consistent evaluation of lymphatic vasculature. This editorial discusses the role of the lymphatic bed in mediating the metastasis of solid tumours, summarizes known methods to detect lymphatics, and proposes a hypothetical mechanism of tumour-induced lymphangiogenesis.     

Establishment of animal model for potency evaluationof inactivated SARS virus experimental vaccine

The SARS outbreak in China has made governmentto organize a comprehensive collaborative study forevery aspect of SARS. A great progress has beenmade in the research of SARS basically, clinicallyand epidemiologically. Meanwhile, thanks to in ternational cooperation, we have now known thatSARS is caused by a human coronavirus (HCoV).The classical method for the development of vac cine by inactivating virus in tissue culture is afastest, safe and effective one [1,2]. SARS HCoV…     

Alone in the dark? Modeling the conditions for visual experience in human fetuses

It is commonly assumed that, whereas auditory and olfactory learning take place already during fetal development, visual experience and learning are not possible before birth. This paper explores the conditions for visual experience in the last two months of human gestation, when the fetal visual system is mature enough to permit directed vision if a sufficient amount of light is available. Light transmission from the external environment to the uterine cavity is modeled, based on the measured transmission coefficients of biological tissues. Results indicate that illumination in the uterine cavity is highly variable, depending on factors such as external illumination and the mother's abdominal thickness. At least some fetuses can be predicted to develop in conditions allowing for ample visual experience before birth. This finding could have intriguing implications for the ontogeny of early visuo-motor abilities in newborns and infants.     

Locating voices in space: A perceptual model for auditory hallucinations?

Introduction. Auditory hallucinations are often perceived as being located in external auditory space (“outside the head”), like real auditory perceptions, but in the absence of a speaker or other external stimulus. Method. A selective literature review of the spatial phenomenology of auditory hallucinations and the cognitive neuroscience of locating real voices in external space was undertaken. An auditory-perceptual model of external auditory hallucinations was developed in healthy right-handed subjects using functional magnetic resonance imaging and the presentation of speech in virtual acoustic space. Results. Karl Jaspers inextricably linked “reality” and “externality” of auditory hallucinations. Although these two properties do not always occur simultaneously in hallucinating patients, the issue of “externality” is important from both a clinical and neuroscientific perspective. In an auditory-perceptual model of auditory hallucinations, association cortex in the left planum temporale is critically involved in the perception of real voices as located in external space. Right-sided voice stimuli are associated with greater neural response in the dominant (left) auditory cortex than left-sided stimuli. Subjects are better at identifying the spatial location of voices presented on the right than on the left. Conclusion. The auditory-perceptual model described helps identify candidate brain systems likely to be involved in the pathogenesis of auditory hallucinations in schizophrenia, and is distinct from other models, which use concepts of “internal monitoring” and “inner speech”. Its application, in the cognitive neuroscientific investigation of the phenomenology of auditory hallucinations, may shed further light on the mechanisms underlying this distressing experience.     

What future for dissection in courses of human topographical anatomy in universities in the UK?

In the United Kingdom most medical schools have traditionally included dissection as a major component of their anatomy courses. There is a dearth of substantive literature which can be used to demonstrate the educational values of dissection, although many authors have expressed opinions. Current scrutiny of the role of dissection has been prompted by many influences acting on medical schools in the UK, including changes in the medical curriculum promoted by the General Medical Council, changes in the mechanisms of funding for universities and their courses, and the introduction of research assessments and appraisal of teaching. It is probable that in the UK dissection will continue to decline but that its reduced role will be prompted by the interactions of many complicated processes, only some of which will be educationally driven. © 1995 WiIey-Liss, Inc.     

Is the mouse a good model for the human with respect to the development of the preimplantation embryo in vitro?

A comparison has been made of various aspects of preimplantation development of mouse and human embryos in vitro. Changes in substrate utilization follow similar patterns in both species. This similarity in metabolic parameters between the two species has facilitated the use of the mouse as a model to study the formulation of culture media to be used at different stages over the preimplantation period from fertilization to the fully expanded blastocyst stage. It has also prescribed the mouse embryo as a practical tool for quality control testing of the laboratory system in human in-vitro fertilization. Aspects of the physiology of both species that require further study are the physiological levels of endogenous inorganic phosphate in the female reproductive tract, the requirement for inorganic phosphate in culture medium, the specificity of the amino acid requirements for optimal development before and after compaction and the importance of including EDTA in culture medium.     

Demented flies? using Drosophila to model human neurodegenerative diseases

The success of biomedical research in the past few decades has led to dramatic improvements in human health and, as a result, increased life expectancy. An unexpected consequence, however, has been an increase in the number of age-related diseases and, in particular, neurodegenerative diseases. Despite their prevalence, a therapeutic void exists in part due to an incomplete understanding of the biochemical pathogenesis of these diseases. A powerful method that can be used to understand the basic mechanisms underlying neurodegenerative diseases is to generate animal models based on manipulating the expression of single genes that are disease causative. This approach has been facilitated by the fact that many neurodegenerative diseases are inherited as autosomal dominant traits such that expression of the mutant gene in a model organism might be expected to recapitulate the disease. During the past few years, the fruit fly, Drosophila melanogaster, has emerged as a powerful tool to model human neurodegenerative diseases. Here, we describe the various approaches utilized to create fly models of human neurodegenerative disease, and how they can aid in our understanding of disease pathogenesis and facilitate drug discovery and testing.     

Development of the immune system in the cynomolgus monkey: the appropriate model in human targeted toxicology?

Toxicological research for humans requires model animals that are physiologically and/or developmentally closely related to one another. The development of the immune system (IS) in the cynomolgus monkey (Macaca fascicularis) was assessed and compared with selected data of humans and mice with the aim of contributing arguments to the discussion of the most appropriate animal model in toxicological research. Details of the developing IS in the cynomolgus monkey from embryonic day 35 to birth are investigated utilizing cluster development (CD) antibodies. Early immunoreactivity with CD 68, CD 117, and HLA-DR antibody is apparent from days 40 and 45 onward. All principal cell lines-T-, B-, and NK-cells-are present on day 100 in both thymus and peripheral organs. We discuss investigations of the cynomolgus monkey IS development with the reported development in humans and mice and stress 4 topics of significant interspecies differences to be considered in the decision for the appropriate animal model in a toxicological study.     

Shape perception in human vision: specialized detectors for concentric spatial structures?

It has been suggested that second-order shape integration mechanisms in human spatial vision (e.g. the neurons at V2 and V4 cortical areas) may contain specialized detectors for concentric shapes [Vision Res. 37 (1997) 2325; Vision Res. 38 (1998) 2933]. We tested this notion using psychophysical techniques in which the observers' task was to detect orientation noise (randomly oriented dot pairs) in concentric and linear Glass patterns. Our results showed that the detection of orientation noise was easier in concentric Glass patterns, thus supporting the notion of specialized detectors.