Unleashing the power of NK cells in anticancer immunotherapy

Journal of Molecular Medicine - Due to their physiological role in removing damaged cells, natural killer (NK) cells represent ideal candidates for cellular immunotherapy in the treatment of...     

Precautionary allergen labelling: perspectives from key stakeholder groups

Precautionary allergen labelling (PAL) was introduced by the food industry to help manage and communicate the possibility of reaction from the unintended presence of allergens in foods. However, in its current form, PAL is counterproductive for consumers with food allergies. This review aims to summarize the perspectives of all the key stakeholders (including clinicians, patients, food industry and regulators), with the aim of defining common health protection and risk minimization goals. The lack of agreed reference doses has resulted in inconsistent application of PAL by the food industry and in levels of contamination that prompt withdrawal action by enforcement officers. So there is a poor relationship between the presence or absence of PAL and actual reaction risk. This has led to a loss of trust in PAL, reducing the ability of consumers with food allergies to make informed choices. The result has been reduced avoidance, reduced quality of life and increased risk‐taking by consumers who often ignore PAL. All contributing stakeholders agree that PAL must reflect actual risk. PAL should be transparent and consistent with rules underpinning decision‐making process being communicated clearly to all stakeholders. The use of PAL should indicate the possible, unintended presence of an allergen in a consumed portion of a food product at or above any proposed action level. This will require combined work by all stakeholders to ensure everyone understands the approach and its limitations. Consumers with food allergy then need to be educated to undertake individualized risk assessments in relation to any PAL present.     

Apolipoprotein genetic variation and human disease

Atherosclerosis is the major public health problem in much of the world today. The information summarized in this review, based on the recognized apolipoprotein structural variants appreciated at both the protein and gene levels, indicates that apolipoprotein genetic variation plays a major role in determining human genetic susceptibility to this disease. With the use of cloned apolipoprotein genes, it should, in the near future, be possible to determine how their expression is regulated; this should provide insight into other classes of mutations of a regulatory nature that might have clinical significance. In addition, the many association and linkage studies currently being undertaken will provide the rationale for cloning defective alleles and determining specific causative mutations. Both structural and regulatory mutations can then be described either with restriction enzymes and Southern blotting or by direct oligonucleotide hybridization techniques in the general population. This will allow the identification of presymptomatic atherosclerosis-susceptible individuals who would be targets for primary preventative therapy.     

A Vietnamese human genetic variation database

Large scale human genome projects have created tremendous human genome databases for some well‐studied populations. Vietnam has about 95 million people (the 14th largest country by population in the world) of which more than 86% are Kinh people. To date, genetic studies for Vietnamese people mostly rely on genetic information from other populations. Building a Vietnamese human genetic variation database is a must for properly interpreting Vietnamese genetic variants. To this end, we sequenced 105 whole genomes and 200 whole exomes of 305 unrelated Kinh Vietnamese (KHV) people. We also included 101 other previously published KHV genomes to build a Vietnamese human genetic variation database of 406 KHV people. The KHV database contains 24.81 million variants (22.47 million single nucleotide polymorphisms (SNPs) and 2.34 million indels) of which 0.71 million variants are novel. It includes more than 99.3% of variants with a frequency of >1% in the KHV population. Noticeably, the KHV database revealed 107 variants reported in the human genome mutation database as pathological mutations with a frequency above 1% in the KHV population. The KHV database (available at https://genomes.vn ) would be beneficial for genetic studies and medical applications not only for the Vietnamese population but also for other closely related populations.     

The effect of IL-10 genetic variation and interleukin 10 serum levels on Crohn's disease susceptibility in a New Zealand population

Interleukin (IL)-10 has important effects in immunoregulation and inflammation, and previous studies have provided evidence for the involvement of IL-10 in the pathogenesis of Crohn's disease (CD). In this study, we investigated whether genetic variants of the IL-10 gene were associated with CD in a New Zealand population. Three single nucleotide polymorphisms (SNPs) in the promoter region of IL-10 (rs1800871, rs1800872, and rs1800896) and a flanking SNP, rs3024505, were genotyped in a well-characterized New Zealand dataset consisting of 342 CD cases and 610 controls. Furthermore, we measured serum IL-10 levels in a number of the CD patients and controls and examined whether a relationship existed between these polymorphisms and serum IL-10 levels. We demonstrated an association with CD for SNPs rs3024505 and rs1800896, and phenotypic analysis indicated an association of rs3024505 with an early age at first diagnosis, stricturing CD behavior, and requirement for bowel resection. We also observed that IL-10 concentration was significantly higher in CD patients than in the controls and that the T allele of rs1800896, the A allele of rs1800871, and the T allele of rs1800872 were associated with increased serum IL-10 levels.     

A genetic interpretation of variation in human growth patterns

This research concerns the application of a previously developed methodology to some intergenerational human data, yielding a genetic interpretation of variation in growth patterns.The data used in this research came from two studies of the Institute of Human Development, University of California, Berkeley, which were begun with subjects born in 1928–29, and included, approximately 10,000 measurements on 78 Berkeley Growth Study subjects and 90 of their children, and 136 Guidance Study subjects.Many parent-offspring correlations for the two parameters interpreted as an overall size constant, and an average growth rate, respectively, are significantly different from zero at the five percent level. Evidence is also adduced for the presence of variation inY-linked factors strongly influencing leg length. Correlations between an index of Darwinian fitness and the absolute deviation from the sample mean of each growth parameter were generally negative in both the BGS and the Guidance Study, thereby indicating stabilizing selection for growth patterns in these two examples of natural populations.

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Zusammenfassung Diese Untersuchung beschäftigte sich mit der Anwendung einer zuvorentwickelten Methode auf Daten, die für Angehörige verschiedener Generationen ermittelt wurden. Es ergab sich eine genetische Interpretation von Schwankungen im Wachstumsablauf. Die Daten in dieser Untersuchung kamen von zwei Studien desInstitute of Human Development, University of California at Berkeley. Diese Studien wurden mit Personen unternommen, die in 1928–29 geboren waren, und umfasstenca. 10000 Messungen an 78Berkeley Growth Study Personen und 90 ihrer Kinder, und an 136Guidance Study Personen.Viele der Korrelationen für zwei Parameter, die als Konstante für Gesammtgrösse und als durchschnittliche Wachstumsrate interpretiert wurden, sind mit 95% Wahrscheinlichkeit nicht null.Es wird der Nachweiss erbracht dass Variation in Y-verbundenen Faktoren die Beinlänge stark beeinflussen kann. Korrelationen zwischen einem Index vonDarwinian fitness und der absoluten Abweichung vom Mittell der Untersuchung der beiden Wachstumsparameter waren im allgemeinen negativ sowohl in derBerkeley Growth Study als auch in derGuidance Study. Diese Korrelationen weisen auf stabilisierende Auswahl von Wachstumsabläufen in diesen zwei Proben natürlicher Bevölkerungsgruppen.

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Résumé Cette étude a pour sujet l'application d'une méthodologie mise au point antérieurement à des données de croissance humaine au cours de deux générations. Une interprétation génétique de la variation des modes de croissance en est le résultat.On employait pour cette recherche les données de deux études de l'Institut de Développement Humain de l'Université de Californie, Berkeley (institute of Human Development, University of California, Berkeley) qui commencèrent avec des sujets nés en 1928–29 et qui comprenaient à peu près 10,000 mensurations prises sur 78 des sujets de l'Étude de Croissance de Berkeley (Berkeley Growth Study) 90 des enfants de ces derniers et sur 136 sujets de l'Étude de Consultation (Guidance Study).Un grand nombre de corrélations parents-enfants pour les deux paramètres interprétés comme un constant de taille totale et un taux de croissance moyen, différent de manière significative de zéro, au niveau de cinq pour cent. L'existence de variation de facteurs linked au chromosome Y qui influent fortement sur la longueur de jambe est, d'autre part, mise en évidence. Les corrélations entre un index de fitness Darwinienne et la déviation absolue du moyen de l'échantillon de chaque paramètre de croissance ont généralement été négatives dans les BGS et Guidance Study, démontrant ainsi la présence d'une sélection stabilisante pour les modes de croissance dans ces deux examples de populations naturelles.

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This paper is based on an unpublished dissertation submitted in partial fulfillment of the requirements for the Ph.D. in Genetics, University of California, Berkeley. I wish to thank Drs. William Meredith, Everett Dempster, and Dorothy Eichorn for guidance and encouragement in this research, and Drs. Eichorn, Nancy Bayley, Marjorie Honzik, Norman Livson and numerous others for collecting and making available the data utilized in this research. This investigation was supported by NIH Training Grant #GM367 from the National Institute of General Medical Sciences.     

Impact of selection, mutation rate and genetic drift on human genetic variation

The accumulation of genome-wide information on single nucleotide polymorphisms in humans provides an unprecedented opportunity to detect the evolutionary forces responsible for heterogeneity of the level of genetic variability across loci. Previous studies have shown that history of recombination events has produced long haplotype blocks in the human genome, which contribute to this heterogeneity. Other factors, however, such as natural selection or the heterogeneity of mutation rates across loci, may also lead to heterogeneity of genetic variability. We compared synonymous and non-synonymous variability within human genes with their divergence from murine orthologs. We separately analyzed the non-synonymous variants predicted to damage protein structure or function and the variants predicted to be functionally benign. The predictions were based on comparative sequence analysis and, in some cases, on the analysis of protein structure. A strong correlation between non-synonymous, benign variability and non-synonymous human-mouse divergence suggests that selection played an important role in shaping the pattern of variability in coding regions of human genes. However, the lack of correlation between deleterious variability and evolutionary divergence shows that a substantial proportion of the observed non-synonymous single-nucleotide polymorphisms reduces fitness and never reaches fixation. Evolutionary and medical implications of the impact of selection on human polymorphisms are discussed.     

Holoprosencephaly-like phenotype: clinical and genetic perspectives

We report 22 patients with normal neuropsychological development and a holoprosencephaly-like (HPE-like) phenotype screened for SHH, SIX3, TGIF, and GLI2. These patients were divided into two groups: (1) 6 patients with SHH and GLI2 mutations and (2) 16 patients with no detectable mutations. We discuss the phenotypic manifestations, evolution of the phenotype, and neuroimaging in the two groups. Conclusions about the HPE-like phenotype include (1) initial appearance as an unusually wide, and very severe unilateral cleft lip-palate in some cases; (2) variability with the expression of minor anomalies in some cases, such as single maxillary central incisor; (3) identifiable mutations in some cases and absence of mutations in others; (4) essentially normal MRI in the most cases (pituitary tumor in two cases and choroid fissure cyst in one case in Group 1; empty sella turcica in one case in Group 2); (5) intelligence within the normal range; and (6) familial aggregation in some instances. Implications include (1) thorough examination of family members for minor anomalies; (2) MRI and developmental assessment for the proband; and (3) molecular analysis.     

Understanding human disease mutations through the use of interspecific genetic variation.

Data on replacement mutations in genes of disease patients exist in a variety of online resources. In addition, genome sequencing projects and individual gene sequencing efforts have led to the identification of disease gene homologs in diverse metazoan species. The availability of these two types of information provides unique opportunities to investigate factors that are important in the development of genetically based disease by contrasting long and short-term molecular evolutionary patterns. Therefore, we conducted an analysis of disease-associated human genetic variation for seven disease genes: the cystic fibrosis transmembrane conductance regulator, glucose-6-phosphate dehydrogenase, the neural cell adhesion molecule L1, phenylalanine hydroxylase, paired box 6, the X-linked retinoschisis gene and TSC2/tuberin. Our analyses indicate that disease mutations show definite patterns when examined from an evolutionary perspective. Human replacement mutations resulting in disease are overabundant at amino acid positions most conserved throughout the long-term history of metazoans. In contrast, human polymorphic replacement mutations and silent mutations are randomly distributed across sites with respect to the level of conservation of amino acid sites within genes. Furthermore, disease-causing amino acid changes are of types usually not observed among species. Using Grantham's chemical difference matrix, we find that amino acid changes observed in disease patients are far more radical than the variation found among species and in non-diseased humans. Overall, our results demonstrate the usefulness of evolutionary analyses for understanding patterns of human disease mutations and underscore the biomedical significance of sequence data currently being generated from various model organism genome sequencing projects.     

New perspectives in human stem cell therapeutic research

Human stem cells are in evaluation in clinical stem cell trials, primarily as autologous bone marrow studies, autologous and allogenic mesenchymal stem cell trials, and some allogenic neural stem cell transplantation projects. Safety and efficacy are being addressed for a number of disease state applications. There is considerable data supporting safety of bone marrow and mesenchymal stem cell transplants but the efficacy data are variable and of mixed benefit. Mechanisms of action of many of these cells are unknown and this raises the concern of unpredictable results in the future. Nevertheless there is considerable optimism that immune suppression and anti-inflammatory properties of mesenchymal stem cells will be of benefit for many conditions such as graft versus host disease, solid organ transplants and pulmonary fibrosis. Where bone marrow and mesenchymal stem cells are being studied for heart disease, stroke and other neurodegenerative disorders, again progress is mixed and mostly without significant benefit. However, correction of multiple sclerosis, at least in the short term is encouraging. Clinical trials on the use of embryonic stem cell derivatives for spinal injury and macular degeneration are beginning and a raft of other clinical trials can be expected soon, for example, the use of neural stem cells for killing inoperable glioma and embryonic stem cells for regenerating β islet cells for diabetes. The change in attitude to embryonic stem cell research with the incoming Obama administration heralds a new co-operative environment for study and evaluation of stem cell therapies. The Californian stem cell initiative (California Institute for Regenerative Medicine) has engendered global collaboration for this new medicine that will now also be supported by the US Federal Government. The active participation of governments, academia, biotechnology, pharmaceutical companies, and private investment is a powerful consortium for advances in health.     

Isozyme variation of Microsporum canis and M. cookei from New Zealand.

Fifty-four isolates of Microsporum canis (Arthroderma otae) from humans, cats and dogs obtained from Auckland, Palmerston North and Wellington, New Zealand and 18 M. cookei and two Diheterospori spp. from soils were examined for variation using eight isozyme loci. M. canis isolates were from infected and non-infected cases. Isozyme analysis separated the three species which were further subdivided into electrophoretic types (ETs). Clustering analysis using normalized percentage disagreement (PTC) average linkage method revealed two clusters for M. cookei with two subclusters in cluster 2. M. canis had three main divisions (clusters 3, 4 and 5) and Diheterospora formed a separate division. The presence of isolates from different sources in the same clusters and lack of statistical significance as measured by confidence intervals suggests the existence of isolates with common lineage.