Clonal origin of KMT2A wild-type lineage-switch leukemia following CAR-T cell and blinatumomab therapy.

Children with acute lymphoblastic leukemia (ALL) undergoing anti-CD19 therapy occasionally develop acute myeloid leukemia (AML). The clonal origin of such lineage-switch leukemias1-4 remains unresolved. Here, we reconstructed the phylogeny of multiple leukemias in a girl who, following multiply relapsed ALL, received anti-CD19 cellular and antibody treatment and subsequently developed AML. Whole genome sequencing unambiguously revealed the AML derived from the initial ALL, with distinct driver mutations that were detectable before emergence. Extensive prior diversification and subsequent clonal selection underpins this fatal lineage switch. Genomic monitoring of primary leukemias and recurrences may predict therapy resistance, especially regarding anti-CD19 treatment.

Occupational health-related experiences in rural Tasmania.

This descriptive, explorative study sought to identify the occupational-related health experiences of community nurses in their workday within rural North West Tasmania. Tasmania is one of eight states and territories that form Australia. The findings indicate the majority of community nurses consider their health average or better, although 30% reported being overweight; 5% reported smoking; 60% reported feeling tense, anxious or depressed sometimes during the week. In the 12 months prior to survey 48% of participants had experienced a work-related injury or illness. At least two thirds of participants spent an average of 1.5 hours teaching nursing students and 2 hours teaching medical students, per week. Hazards (needlestick injury, items obstructing passageways, debris within homes), dogs and use of mobile telephones were regularly associated with weekly work incidents. Interestingly, more time was spent in a day on documentation than with clients or professional development.

Self-socialization: a case study of a parachute child.

The theoretical concept of self-socialization suggests that an individual is able to reflect on the self, formulate a vision of a future self, set goals, and take actions that create or alter the developmental trajectory. This case study of a parachute child illustrates how a person constructs her life from a very young age, drawing on a profound capacity for personal agency to overcome obstacles, identify resources, and internalize values to build a life structure. A model of the psychosocial process of self-socialization emerges from this case. Following the disruption of a well-defined trajectory, self-socialization is observed as a sequence of actions, reflection, correction, and new actions. Self-socialization is possible when a strong sense of self-efficacy is applied to attaining internalized values and goals.

Challenging convention: symbolic interactionism and grounded theory.

Not very much is written in the literature about decisions made by researchers and the justifications on method as a result of a particular clinical problem, together with an appropriate and congruent theoretical perspective, particularly for Glaserian grounded theory. I contend the utilisation of symbolic interactionism as a theoretical perspective to inform and guide the evolving research process and analysis of data when using classic or Glaserian grounded theory (GT) method, is not always appropriate. Within this article I offer an analysis of the key issues to be addressed when contemplating the use of Glaserian GT and the utilisation of an appropriate theoretical perspective, rather than accepting convention of symbolic interactionism (SI). The analysis became imperative in a study I conducted that sought to explore the concerns, adaptive behaviours, psychosocial processes and relevant interactions over a 12-month period, among newly diagnosed persons with end stage renal disease, dependent on haemodialysis in the home environment for survival. The reality of perception was central to the end product in the study. Human ethics approval was granted by six committees within New South Wales Health Department and one from a university.

The relationship of social support to depressive symptoms during the transition to high school.

The transition to high school is studied as a time when students may experience disruptions in their social support systems. Peer support, family support, and school belonging were hypothesized to be associated with adolescent adjustment, specifically depressive symptoms. Participants included 104 eighth graders and 101 ninth graders from a middle- to high-income, predominantly white community in southern Rhode Island. In year 2, 60 of the original 8th graders were surveyed as 9th graders. Three hypotheses were examined: Social support declines from 8th to 9th grade; depressive symptoms increase from 8th to 9th grade; and social support is significantly associated with depressive symptoms. The hypotheses were tested using cross-sectional and longitudinal analyses. Results indicated that 9th graders experienced more depressive symptoms and lower levels of school belonging as compared to the 8th graders. Changes in parent support and peer support were significantly associated with depressive symptoms in the transition to high school. Implications for increasing school belonging in the 9th grade are discussed.

Peer group membership and a sense of belonging: their relationship to adolescent behavior problems.

This study explored three aspects of peer group membership in adolescence: peer group affiliation, the importance of group membership, and a sense of peer group belonging. Each is considered in relationship to adolescents' behavior problems as measured by the Achenbach Youth Self-Report. Participants included an ethnically and socioeconomically diverse sample of 733 adolescents ranging in age from 11 to 18 years. Girls reported more internalizing problems and boys reported more externalizing problems. Girls also reported a higher sense of peer group belonging than boys. When controlling for adolescent age, gender, ethnicity, parent's educational level, and family structure, a sense of peer group belonging was negatively related to internalizing and externalizing behavior problems. Adolescents who viewed peer group membership as very important to them and had a positive sense of peer group belonging had significantly fewer behavior problems than those who viewed peer group membership as very important but did not have a positive sense of peer group belonging.

Models of systemic lupus erythematosus: development of autoimmunity following peptide immunizations of noninbred pedigreed rabbits.

Reported in this study are the initial results from studies to develop rabbit models of systemic lupus erythematosus (SLE) by immunizations using two distinct peptides on branched polylysine backbones (multiple Ag peptide)-peptides. Eleven rabbits received a peptide from the Sm B/B' spliceosomal complex previously shown to be immunogenic in rabbits, and 13 rabbits received a peptide from the rabbit N-methyl-d-aspartate receptor NR2b. All 24 animals in different generations of pedigreed, noninbred rabbits produced peptide-specific responses. Anti-nuclear autoantibody responses, including anti-dsDNA, were seen in 17 of 24 rabbits. To date, two rabbits have been observed to have seizure-like events and a third nystagmus. A model for eliciting development of SLE in genetically related yet heterogeneous rabbits may more closely resemble development of human SLE than do some models in inbred mice. Through selective breeding, it may also ultimately provide additional information about the genetics and etiology of SLE and serve as a model for assessing new treatment options.

Activation-induced deaminase cloning, localization, and protein extraction from young VH-mutant rabbit appendix.

Studies in mouse, human, and chicken suggest that activation-induced deaminase (AID) is involved in three known processes leading to antibody diversification: somatic hypermutation, gene conversion, and class-switch recombination. Developing rabbit appendix provides a particularly good site for studying all three of these B cell maturation events. We report here successful cloning of rabbit AID and isolation of AID protein from rabbit appendix-cell nuclear and cytoplasmic extracts. We succeeded in identifying and locating AID protein in cells by immunohistochemical and immunofluorescent staining techniques and examined colocalization of AID and other molecules important for Ab diversification. This report extends our knowledge about AID to a mammalian species that uses gene conversion to diversify rearranged Ig genes. Although much work remains to understand fully the mechanism of action of AID and its association with other cellular components, the rabbit system now offers a particularly useful model for future studies of these dynamics.

Translational regulation of MOS messenger RNA in pig oocytes.

The temporal and spatial translation control of stored mRNA in oocytes is regulated by elements in their 3'-untranslated region (3'-UTR). The MOS 3'-UTR in pig oocytes is both heterogeneous (180, 480, or 530 nucleotides), and it contains multiple U-rich elements and extensive A-rich sequences (CA13CA5CA5CA6). We have examined the role of these potential regulatory elements by fusing wild-type or mutant MOS 3'-UTRs to luciferase mRNA and then injecting these chimeric transcripts into oocytes. We draw six main conclusions. First, the length of the MOS 3'-UTR tightly controls the level of translation of luciferase during oocyte maturation. Second, two U-rich (U5A) elements and the hexanucleotide signal (AAUAAA) are required for translation. Third, mutations, duplications, or relocations of the A-rich sequence reduce or block translation. Fourth, the relative importance of the A-rich and U-rich elements in controlling the level of translation differs. Fifth, none of our MOS 3'-UTR manipulations relieved translational repression before germinal vesicle breakdown. Sixth, all the MOS mRNA variants underwent polyadenylation during maturation. Whereas mutations to the hexanucleotide signal block both polyadenylation and translation, mutations to either the A-rich sequence or the U-rich elements block translation without fully blocking polyadenylation. We conclude that MOS mRNA translation in pig oocytes is subject to a more extensive series of controls than that in lower vertebrates.

The Nogo-66 receptor homolog NgR2 is a sialic acid-dependent receptor selective for myelin-associated glycoprotein.

The Nogo-66 receptor (NgR1) is a promiscuous receptor for the myelin inhibitory proteins Nogo/Nogo-66, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp). NgR1, an axonal glycoprotein, is the founding member of a protein family composed of the structurally related molecules NgR1, NgR2, and NgR3. Here we show that NgR2 is a novel receptor for MAG and acts selectively to mediate MAG inhibitory responses. MAG binds NgR2 directly and with greater affinity than NgR1. In neurons NgR1 and NgR2 support MAG binding in a sialic acid-dependent Vibrio cholerae neuraminidase-sensitive manner. Forced expression of NgR2 is sufficient to impart MAG inhibition to neonatal sensory neurons. Soluble NgR2 has MAG antagonistic capacity and promotes neuronal growth on MAG and CNS myelin substrate in vitro. Structural studies have revealed that the NgR2 leucine-rich repeat cluster and the NgR2 "unique" domain are necessary for high-affinity MAG binding. Consistent with its role as a neuronal MAG receptor, NgR2 is an axonassociated glycoprotein. In postnatal brain NgR1 and NgR2 are strongly enriched in Triton X-100-insoluble lipid rafts. Neural expression studies of NgR1 and NgR2 have revealed broad and overlapping, yet distinct, distribution in the mature CNS. Taken together, our studies identify NgRs as a family of receptors (or components of receptors) for myelin inhibitors and provide insights into how interactions between MAG and members of the Nogo receptor family function to coordinate myelin inhibitory responses.

Stable expression of the extracellular domains of rabbit recombinant CD5: development and characterization of polyclonal and monoclonal antibodies.

Previous studies in our laboratory suggested that there was positive selection of B cells during early development in the appendix of normal and V(H) mutant (ali/ali) rabbits. Preferential expansion and survival of B lymphocytes was affected by the Ig V(H) frameworks 1 and 3 sequences expressed on the cell surface. We demonstrated a specific interaction between rabbit CD5 and the V region of rabbit heavy chains and suggested that CD5 is a potential selecting ligand for B-cell surface immunoglobulin framework region sequences. To further investigate the role of CD5 in rabbit B-cell selection and survival we prepared recombinant constructs and obtained stable expression of the three scavenger receptor cysteine-rich (SRCR) extracellular domains of rabbit CD5. Here we describe the production and purification of this expressed recombinant CD5 protein, polyclonal antibody obtained by immunization of a goat and initial production and characterization of specific mAbs against peptides selected from each sequenced SRCR domain.