The expression and localization of Kappa Myeloma antigen on malignant and normal B cells

University of Technology, Sydney. Faculty of Science.Kappa Myeloma Antigen (KMA) is a plasma membrane associated form of free immunoglobulin kappa light chain (FkLC) expressed on malignant B cells from patients with multiple myeloma (MM), Waldenstrom’s macroglobulinaema (WM) and non- Hodgkin’s lymphoma (Walker et al. 1985). KMA is recognized by the murine monoclonal antibody (mAb) mKap, and its human-mouse chimeric equivalent, cKap, which is currently undergoing clinical trials as a therapy for kappa type MM (Boux et al. 1983; Raison et al. 2005). Earlier expression studies on KMA suggested that the antigen is not expressed by normal B cells in vivo. However, in vitro activation of tonsillar B cells induced expression of KMA on a subset of cells. Like their KMA expressing malignant counterparts, these were presumed to be FkLC secreting plasma cells or plasmablasts but, due to the lack of B cell lineage specific markers at the time, these cells were not phenotyped (Walker et al. 1985). Furthermore, given the extremely low frequency of plasmablasts and plasma cells in normal tissues, it was not possible to exclude the presence of a ‘normal’ KMA positive cell population in vivo. The first section of this thesis expands upon this earlier work. By utilizing in vitro activation protocols on peripheral blood CD 19+ B cells, KMA expression was induced on a subset of cells. Phenotypic analysis revealed that the majority of KMA positive cells were CD27++ CD38+/- plasmablasts and CD38++ plasma cells. Analysis from normal human tissues found that a subset of plasma cells in the tonsils expressed the antigen. These cells co-expressed CD45, indicating that they are at an immature stage of plasma cell differentiation. In contrast, peripheral plasma cells, considered to be more fully mature cells in transit from secondary lymphoid organs to plasma cell niches in bone marrow or spleen, did not express KMA. This implies that KMA expression, in vivo, is limited to a small subset of immature plasma cells in secondary lymphoid organs such as the tonsils. Despite cKap’s current assessment in clinical trials for the treatment of MM, very little is known about its molecular target KMA. Previous studies have showed that KMA is comprised of FkLC (Goodnow and Raison 1985); however it was never determined as to how FkLC is associated with the plasma membrane. Since FkLC is a secreted molecule, it was initially presumed that it associated with a proteinaceous ‘membrane receptor’ (Goodnow and Raison 1985). However membrane extraction studies, as described in the second part of this thesis, reveal that FkLC directly associates with the plasma membrane through a combination of hydrophobic and electrostatic forces to form KMA. Further investigations confirmed that FkLCs can bind directly to cellular and artificial membranes. Moreover, this binding is likely dependent on self-association processes, which suggest that KMA consists of aggregated, membrane associated FkLCs. Lipid binding studies revealed that FkLCs associate specifically with saturated phosphocholine species such as sphingomyelin in membranes, and KMA expression was positively correlated with sphingomyelin expression in FkLC secreting cell lines. The final section of this thesis examines how FkLCs might interact with saturated phosphocholine lipids. Molecular modeling of dimeric FkLC suggests they are able to weakly associate with phosphocholine in the conventional antigen binding pocket formed by the kLC variable domain (V-domain). Since FkLC aggregation is a feature of KMA, then the avidity effects of multi-valent binding likely increases the strength of the proposed FicLC-phosphocholine interaction. This hypothesis explains the observation of both electrostatic and hydrophobic interactions by FkLC, as KMA, with the plasma membrane - the electrostatic component, governed by single FkLC molecules interacting with the charged phosphocholine headgroups, and the hydrophobic component, due to selfassociation of adjacent FkLC molecules. Finally, a model of KMA expression by FkLC secreting cells is proposed. FkLC is synthesized in the endoplasmic reticulum (ER) then transported to the golgi-apparatus and encapsulated into vesicles destined for secretion. There FkLCs interact with saturated phosphocholine lipids, such as sphingomyelin, and undergo aggregation resulting in stable association on the inner vesicular membrane. Fusion of the vesicle with the plasma membrane during exocytosis allows for membrane associated FkLC to become exposed on the extracellular face as KMA

The relationship of wellness factors to work performance and job satisfaction among managers

The purpose of this study was (a) to assess whether components of holistic wellness were more predictive than physical wellness variables in predicting work performance and job satisfaction in managers, and (b) to assess the utility of components of holistic wellness in predicting work performance and job satisfaction in managers. A sample of 161 American managers comprised the sample. Participants were administered the Wellness Evaluation of Lifestyle-Revised (WELR; Witmer, Sweeney, & Myers, 1995), four scales from the Physical Self-Description Questionairre (PSDQ; Marsh, Richards, Johnson, Roche, & Tremayne, 1994), the Job Satisfaction Blank (Hoppock, 1977), and the Work Performance Scale (WPS) created by the researcher. The WEL-R is designed to measure components of holistic wellness. The four scales from PSDQ (Physical Activity, Endurance, Strength, and Health) measure physical fitness and physical wellness. The JSB measures global job satisfaction. The WPS measures eight managerial job performance functions. All instruments were determined to be useful with this sample after undergoing statistical analysis. Multiple regression analyses of the hypotheses revealed that components of holistic wellness predicted work performance and job satisfaction better than physical wellness variables. Occupational wellness was the best predictor, accounting for 12% of the variance of work performance, and 35% of the variance of job satisfaction. One scale from the WEL-R, "Intellectual Stimulation, Problem-Solving, and Creativity." produced statistically significant beta weights in the regression equation for both dependent variables

A parasite-derived 68-mer peptide ameliorates autoimmune disease in murine models of Type 1 diabetes and multiple sclerosis

© 2016 cThe Author(s). Helminth parasites secrete molecules that potently modulate the immune responses of their hosts and, therefore, have potential for the treatment of immune-mediated human diseases. FhHDM-1, a 68-mer peptide secreted by the helminth parasite Fasciola hepatica, ameliorated disease in two different murine models of autoimmunity, type 1 diabetes and relapsing-remitting immune-mediated demyelination. Unexpectedly, FhHDM-1 treatment did not affect the proliferation of auto-antigen specific T cells or their production of cytokines. However, in both conditions, the reduction in clinical symptoms was associated with the absence of immune cell infiltrates in the target organ (islets and the brain tissue). Furthermore, after parenteral administration, the FhHDM-1 peptide interacted with macrophages and reduced their capacity to secrete pro-inflammatory cytokines, such as TNF and IL-6. We propose this inhibition of innate pro-inflammatory immune responses, which are central to the initiation of autoimmunity in both diseases, prevented the trafficking of autoreactive lymphocytes from the periphery to the site of autoimmunity (as opposed to directly modulating their function per se), and thus prevented tissue destruction. The ability of FhHDM-1 to modulate macrophage function, combined with its efficacy in disease prevention in multiple models, suggests that FhHDM-1 has considerable potential as a treatment for autoimmune diseases

Potential Geographic Distribution of Brown Marmorated Stink Bug Invasion (Halyomorpha halys)

BACKGROUND: The Brown Marmorated Stink Bug (BMSB), Halyomorpha halys (Stål) (Hemiptera: Pentatomidae), native to Asia, is becoming an invasive species with a rapidly expanding range in North America and Europe. In the US, it is a household pest and also caused unprecedented damage to agriculture crops. Exploring its climatic limits and estimating its potential geographic distribution can provide critical information for management strategies. METHODOLOGY/PRINCIPALS: We used direct climate comparisons to explore the climatic niche occupied by native and invasive populations of BMSB. Ecological niche modelings based on the native range were used to anticipate the potential distribution of BMSB worldwide. Conversely, niche models based on the introduced range were used to locate the original invasive propagates in Asia. Areas with high invasion potential were identified by two niche modeling algorithms (i.e., Maxent and GARP). CONCLUSIONS/SIGNIFICANCE: Reduced dimensionality of environmental space improves native model transferability in the invade area. Projecting models from invasive population back to native distributional areas offers valuable information on the potential source regions of the invasive populations. Our models anticipated successfully the current disjunct distribution of BMSB in the US. The original propagates are hypothesized to have come from northern Japan or western Korea. High climate suitable areas at risk of invasion include latitudes between 30°-50° including northern Europe, northeastern North America, southern Australia and the North Island of New Zealand. Angola in Africa and Uruguay in South America also showed high climate suitability

Alien Invasive Slider Turtle in Unpredicted Habitat: A Matter of Niche Shift or of Predictors Studied?

BACKGROUND: Species Distribution Models (SDMs) aim on the characterization of a species' ecological niche and project it into geographic space. The result is a map of the species' potential distribution, which is, for instance, helpful to predict the capability of alien invasive species. With regard to alien invasive species, recently several authors observed a mismatch between potential distributions of native and invasive ranges derived from SDMs and, as an explanation, ecological niche shift during biological invasion has been suggested. We studied the physiologically well known Slider turtle from North America which today is widely distributed over the globe and address the issue of ecological niche shift versus choice of ecological predictors used for model building, i.e., by deriving SDMs using multiple sets of climatic predictor. PRINCIPAL FINDINGS: In one SDM, predictors were used aiming to mirror the physiological limits of the Slider turtle. It was compared to numerous other models based on various sets of ecological predictors or predictors aiming at comprehensiveness. The SDM focusing on the study species' physiological limits depicts the target species' worldwide potential distribution better than any of the other approaches. CONCLUSION: These results suggest that a natural history-driven understanding is crucial in developing statistical models of ecological niches (as SDMs) while "comprehensive" or "standard" sets of ecological predictors may be of limited use

Cost-effectiveness of HBV and HCV screening strategies:a systematic review of existing modelling techniques

Introduction: Studies evaluating the cost-effectiveness of screening for Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) are generally heterogeneous in terms of risk groups, settings, screening intervention, outcomes and the economic modelling framework. It is therefore difficult to compare cost-effectiveness results between studies. This systematic review aims to summarise and critically assess existing economic models for HBV and HCV in order to identify the main methodological differences in modelling approaches. Methods: A structured search strategy was developed and a systematic review carried out. A critical assessment of the decision-analytic models was carried out according to the guidelines and framework developed for assessment of decision-analytic models in Health Technology Assessment of health care interventions. Results: The overall approach to analysing the cost-effectiveness of screening strategies was found to be broadly consistent for HBV and HCV. However, modelling parameters and related structure differed between models, producing different results. More recent publications performed better against a performance matrix, evaluating model components and methodology. Conclusion: When assessing screening strategies for HBV and HCV infection, the focus should be on more recent studies, which applied the latest treatment regimes, test methods and had better and more complete data on which to base their models. In addition to parameter selection and associated assumptions, careful consideration of dynamic versus static modelling is recommended. Future research may want to focus on these methodological issues. In addition, the ability to evaluate screening strategies for multiple infectious diseases, (HCV and HIV at the same time) might prove important for decision makers

Consistent phenological shifts in the making of a biodiversity hotspot: the Cape flora

Background The best documented survival responses of organisms to past climate change on short (glacial-interglacial) timescales are distributional shifts. Despite ample evidence on such timescales for local adaptations of populations at specific sites, the long-term impacts of such changes on evolutionary significant units in response to past climatic change have been little documented. Here we use phylogenies to reconstruct changes in distribution and flowering ecology of the Cape flora - South Africa's biodiversity hotspot - through a period of past (Neogene and Quaternary) changes in the seasonality of rainfall over a timescale of several million years. Results Forty-three distributional and phenological shifts consistent with past climatic change occur across the flora, and a comparable number of clades underwent adaptive changes in their flowering phenology (9 clades; half of the clades investigated) as underwent distributional shifts (12 clades; two thirds of the clades investigated). Of extant Cape angiosperm species, 14-41% have been contributed by lineages that show distributional shifts consistent with past climate change, yet a similar proportion (14-55%) arose from lineages that shifted flowering phenology. Conclusions Adaptive changes in ecology at the scale we uncover in the Cape and consistent with past climatic change have not been documented for other floras. Shifts in climate tolerance appear to have been more important in this flora than is currently appreciated, and lineages that underwent such shifts went on to contribute a high proportion of the flora's extant species diversity. That shifts in phenology, on an evolutionary timescale and on such a scale, have not yet been detected for other floras is likely a result of the method used; shifts in flowering phenology cannot be detected in the fossil record

A Tale of Four “Carp”: Invasion Potential and Ecological Niche Modeling

. We assessed the geographic potential of four Eurasian cyprinid fishes (common carp, tench, grass carp, black carp) as invaders in North America via ecological niche modeling (ENM). These “carp” represent four stages of invasion of the continent (a long-established invader with a wide distribution, a long-established invader with a limited distribution, a spreading invader whose distribution is expanding, and a newly introduced potential invader that is not yet established), and as such illustrate the progressive reduction of distributional disequilibrium over the history of species' invasions.We used ENM to estimate the potential distributional area for each species in North America using models based on native range distribution data. Environmental data layers for native and introduced ranges were imported from state, national, and international climate and environmental databases. Models were evaluated using independent validation data on native and invaded areas. We calculated omission error for the independent validation data for each species: all native range tests were highly successful (all omission values <7%); invaded-range predictions were predictive for common and grass carp (omission values 8.8 and 19.8%, respectively). Model omission was high for introduced tench populations (54.7%), but the model correctly identified some areas where the species has been successful; distributional predictions for black carp show that large portions of eastern North America are at risk.ENMs predicted potential ranges of carp species accurately even in regions where the species have not been present until recently. ENM can forecast species' potential geographic ranges with reasonable precision and within the short screening time required by proposed U.S. invasive species legislation

Noninvasive prenatal screening in twin pregnancies with cell-free DNA using the IONA test: a prospective multicenter study.

BACKGROUND: In singleton pregnancies, studies investigating cell-free DNA in maternal blood have consistently reported high detection rate and low false-positive rate for the 3 common fetal trisomies (trisomies 21, 18, and 13). The potential advantages of noninvasive prenatal testing in twin pregnancies are even greater than in singletons, in particular lower need for invasive testing and consequent fetal loss rate. However, several organizations do not recommend cell-free DNA in twin pregnancies and call for larger prospective studies. OBJECTIVE: In response to this, we undertook a large prospective multicenter study to establish the screening performance of cell-free DNA for the 3 common trisomies in twin pregnancies. Moreover, we combined our data with that reported in published studies to obtain the best estimate of screening performance. STUDY DESIGN: This was a prospective multicenter blinded study evaluating the screening performance of cell-free DNA in maternal plasma for the detection of fetal trisomies in twin pregnancies. The study took place in 6 fetal medicine centers in England, United Kingdom. The primary outcome was the screening performance and test failure rate of cell-free DNA using next generation sequencing (the IONA test). Maternal blood was taken at the time of (or after) a conventional screening test. Data were collected at enrolment, at any relevant invasive testing throughout pregnancy, and after delivery until the time of hospital discharge. Prospective detailed outcome ascertainment was undertaken on all newborns. The study was undertaken and reported according to the Standards for Reporting of Diagnostic Accuracy Studies. A pooled analysis was also undertaken using our data and those in the studies identified by a literature search (MEDLINE, Embase, CENTRAL, Cochrane Library, and ClinicalTrials.gov) on June 6, 2020. RESULTS: A total of 1003 women with twin pregnancies were recruited, and complete data with follow-up and reference data were available for 961 (95.8%); 276 were monochorionic and 685 were dichorionic. The failure rate was 0.31%. The mean fetal fraction was 12.2% (range, 3%-36%); all 9 samples with a 3% fetal fraction provided a valid result. There were no false-positive or false-negative results for trisomy 21 or trisomy 13, whereas there was 1 false-negative and 1 false-positive result for trisomy 18. The IONA test had a detection rate of 100% for trisomy 21 (n=13; 95% confidence interval, 75-100), 0% for trisomy 18 (n=1; 95% confidence interval, 0-98), and 100% for trisomy 13 (n=1; 95% confidence interval, 3-100). The corresponding false-positive rates were 0% (95% confidence interval, 0-0.39), 0.10% (95% confidence interval, 0-0.58), and 0% (95% confidence interval, 0-0.39), respectively. By combining data from our study with the 11 studies identified by literature search, the detection rate for trisomy 21 was 95% (n=74; 95% confidence interval, 90-99) and the false-positive rate was 0.09% (n=5598; 95% confidence interval, 0.03-0.19). The corresponding values for trisomy 18 were 82% (n=22; 95% confidence interval, 66-93) and 0.08% (n=4869; 95% confidence interval, 0.02-0.18), respectively. There were 5 cases of trisomy 13 and 3881 non-trisomy 13 pregnancies, resulting in a computed average detection rate of 80% and a false-positive rate of 0.13%. CONCLUSION: This large multicenter study confirms that cell-free DNA testing is the most accurate screening test for trisomy 21 in twin pregnancies, with screening performance similar to that in singletons and very low failure rates (0.31%). The predictive accuracy for trisomies 18 and 13 may be less. However, given the low false-positive rate, offering first-line screening with cell-free DNA to women with twin pregnancy is appropriate in our view and should be considered a primary screening test for trisomy 21 in twins

Pregnant women’s awareness, knowledge and beliefs about pelvic floor muscles: a cross-sectional survey

Introduction and hypothesis: Pregnant women benefit from completing pelvic floor muscle exercises (PFMEs). The aims of the study were to evaluate pregnant women’s levels of awareness, knowledge, and beliefs about the pelvic floor muscles (PFMs) and PFMEs. Methods: A cross-sectional survey was conducted. Respondents were pregnant women over the age of 18 years who attended antenatal clinics in Western Australia (WA). Questionnaire items measured awareness and knowledge about PFMs, confidence and beliefs about engaging in PFMEs, and attendance at antenatal education (ANE) classes. Chi-squared tests examined potential associations between questionnaire items and respondent characteristics. Results: Mean gestation of respondents (n = 633 out of 850; 74% response rate) was 28.7 (+7.8) weeks and 50% were giving birth for the first time. Although 76% of respondents knew that PFMs can prevent urinary incontinence, only 27% knew that they prevented faecal incontinence and 41% thought it was normal to leak urine when pregnant. Only n = 72 (11%) were practicing PFMEs. Respondents who had attended ANE (28%) were significantly more knowledgeable about pelvic floor function (p &lt; .001) and significantly less likely to believe that leaking urine during pregnancy was normal (p = 0.02), compared with those who had not attended ANE. Respondents who did not speak English at home (18%) were significantly less knowledgeable about PFMs and PFMEs, and significantly less likely to have attended, or planned to attend, ANE classes. Conclusion: Pregnant women require more health education regarding PFMs. Education should be provided using diverse modes, especially for women from migrant backgrounds and women who do not plan to attend formal ANE classes