The B-cell receptor signaling pathway as a therapeutic target in CLL

Targeted therapy with imatinib and other selective tyrosine kinase inhibitors has transformed the treatment of chronic myeloid leukemia. Unlike chronic myeloid leukemia, chronic lymphocytic leukemia (CLL) lacks a common genetic aberration amenable to therapeutic targeting. However, our understanding of normal B-cell versus CLL biology points to differences in properties of B-cell receptor (BCR) signaling that may be amenable to selective therapeutic targeting. The applica-tion of mouse models has further expanded this understanding and provides information about targets in the BCR signaling pathway that may have other important functions in cell development or long-term health. In addition, overexpression or knockout of selected targets offers the potential to validate targets genetically using new mouse models of CLL. The initial success of BCR-targeted therapies has promoted much excitement in the field of CLL. At the present time, GS-1101, which reversibly inhibits PI3Kδ, and ibrutinib (PCI-32765), an irreversible inhibitor of Bruton tyrosine kinase, have generated the most promising early results in clinical trials including predominately refractory CLL where durable disease control has been observed. This review provides a summary of BCR signaling, tools for studying this pathway relevant to drug development in CLL, and early progress made with therapeutics targeting BCR-related kinases.     

Complex karyotype predicts for inferior outcomes following reduced-intensity conditioning allogeneic transplant for chronic lymphocytic leukaemia

Complex karyotype (CK) on metaphase cytogenetics discriminates poor outcome in chronic lymphocytic leukaemia (CLL) patients undergoing salvage treatment; we hypothesized that it might provide prognostic information for patients undergoing allogeneic stem cell transplant. Fifty‐one CLL patients were analysed following transplant; 18‐month overall survival (OS), event‐free survival (EFS) and cumulative incidence of progression estimates were 35%, 14% and 63%, respectively, in patients with CK (n = 19) versus 83%, 68% and 29% in patients without (n = 32) (P ≤ 0·0001, P ≤ 0·0001, and P = 0·02). In patients with high‐risk interphase cytogenetics, CK remained predictive of worse OS (P = 0·02) and EFS (P = 0·009). These findings support further evaluation of metaphase karyotype in transplant risk assessment.     

HIV-related cognitive impairment shows bi-directional association with dopamine receptor DRD1 and DRD2 polymorphisms in substance-dependent and substance-independent populations

It has been postulated that drugs of abuse act synergistically with HIV, leading to increased neurotoxicity and neurocognitive impairment. The CNS impacts of HIV and drug use converge on the mesocorticolimbic dopamine (DA) system, which contains two main receptor subtypes: dopamine receptors 1 (DRD1) and 2 (DRD2). DRD1 and DRD2 have been linked to substance dependence; whether they predict HIV-associated neurocognitive disorder (HAND) is unclear. Using an advanced-stage HIV+ population, we sought to determine if drug dependence impacts the contribution of DA receptor polymorphisms on neurocognition. We observed that both DRD1 and DRD2 polymorphisms were associated with opiate and cocaine dependence (P?<?0.05) in Caucasian subjects, but not African-American individuals. Using linear regression analysis, we examined the polymorphisms for associations with neuropsychological performance in global and cognitive domain T-scores (Motor, Processing Speed, Verbal Fluency, Learning, Memory, Executive Functioning, Working Memory) while controlling for opiate and cocaine dependency. In the Motor domain, we observed an association for two DRD2 polymorphisms (P?<?0.05) in Caucasian subjects. The effects differed for substance dependence groups as the direction of the correlations with DRD2 were opposite to what was seen in subjects without these dependencies. In African-American subjects, associations were observed in nearly every domain, and again, the direction of the correlation differed between substance-dependent and substance-independent groups. We conclude that studies to examine genetic risk for HAND must carefully account for substance dependence patterns when assaying dopaminergic systems, as the neurobiological substrates of cognition in HIV populations may vary with tonic alterations secondary to chronic substance exposures.     

Segmental and metrical complexity during non-word repetition in adults who stutter

Non-word repetition is weaker for adults who stutter (AWS) compared to adults who do not stutter (AWNS) as phonological demands increase. However, non-word stimuli used in previous studies varied by length, but did not vary with regard to segmental or metrical complexity. The purpose of the present study was to examine the unique influence of these two distinct types of complexity on non-word repetition in AWS and AWNS via administration of the Test of Phonological Structure (TOPhS). Twenty-four adults (12 AWNS, 12 AWS) repeated 96 non-words within a soundproof booth immediately after auditory presentation. All 96 non-word targets included on the TOPhS were one to four syllables in length and ranked based on segmental complexity (simple, moderate and complex) and metrical complexity (simple, moderate and complex). No main effect of metrical complexity was detected between groups, and no differences in accuracy were observed for non-words with simple or moderate segmental complexity. However, AWS were significantly more likely to produce a phonemic error when repeating words with complex segmental structure than AWNS, irrespective of metrical complexity. Segmental complexity may contribute to the differences in phonological working memory in AWS when controlling for metrical complexity and length.     

The mechanism of appearance of specific antibody-forming cells in lungs of inbred mice after intratracheal immunization with sheep erythrocytes

Immunization, ablation, and adoptive transfer studies were performed in inbred mice to define in vivo the cellular mechanisms for the appearance of specific antibody-forming cells (AFC) in pulmonary parenchyma. Mice were immunized locally or systemically with sheep erythrocytes (SRBC), and the concentrations of IgM- and IgG-producing AFC were measured in lung and extrapulmonary lymphoid tissues with a hemolytic-plaque assay. Splenectomized mice and recipients of adoptively transferred, sensitized lymphocytes were examined. We found that primary intratracheal (IT) immunization regularly failed to induce the appearance of AFC in lungs, whereas IT boosting of primed animals consistently succeeded. Immunization experiments showed that mice could be primed by any of a variety of local or systemic routes, but that the IT route of boosting was an absolute requirement for the induction of pulmonary AFC in primed mice. Recruitment of AFC into lungs by IT boosting of systemically primed and boosted animals was antigen-specific. Splenectomy performed prior to priming reduced, but did not ablate, the pulmonary AFC-response to IT boosting. Adoptive transfer of sensitized lymphocytes to naive recipient mice substituted for antigen-priming, which is required for induction of pulmonary AFC by IT challenge. Results of adoptive transfer studies demonstrate that IT challenge with specific antigen recruits systemically administered sensitized lymphocytes into the lung. We conclude that local primary immunization of mice results in the generation of AFC in extrapulmonary lymphoid tissues and that the major mechanism for the appearance of AFC in lungs is through recruitment of sensitized cells from systemic sources by intrapulmonary boosting with specific antigen.     

Dietary acculturation of Hispanic immigrants in Mississippi

OBJECTIVE: Assisting Hispanic immigrants in making culturally acceptable food choices may affect their health for generations. As a relatively new enclave of Hispanics, Scott County, Mississippi, was chosen to study dietary acculturation and health concerns of immigrants. MATERIAL AND METHODS: The research method consisted of interviews with community representatives (N=11), a focus group (N=6), and interviews with Hispanic immigrants (N=18). RESULTS: Community representatives mentioned availability influenced immigrants' food choices and suggested promoting cultural awareness and offering nutrition classes on local ingredients. Food cost, health concepts, food selection, and eating habits of children were salient themes from the focus group and interviews with Hispanics. Hispanic participants mentioned long work hours affect food selection and that U.S. produce lacks freshness and flavor. CONCLUSIONS: Results indicate that an intervention must be formulated that preserves healthful dietary practices and minimizes the negative health aspects of acculturation to the "American diet"     

Flavopiridol Induces Apoptosis in Chronic Lymphocytic Leukemia Cells Via Activation of Caspase-3 Without Evidence of bcl-2 Modulation or Dependence on Functional p53

Flavopiridol has been reported to induce apoptosis in lymphoid celllines via downregulation of bcl-2. The in vitro activity offlavopiridol against human chronic lymphocytic leukemia (CLL) cells andpotential mechanisms of action for inducing cytotoxicity were studied.The in vitro viability of mononuclear cells from CLL patients (n = 11) was reduced by 50% at 4 hours, 24 hours, and 4 days at aflavopiridol concentration of 1.15 µmol/L (95% confidence interval[CI] ±0.31), 0.18 µmol/L (95% CI±0.04), and 0.16 µmol/L (95% CI ±0.04), respectively. Loss ofviability in human CLL cells correlated with early induction ofapoptosis. Exposure of CLL cells to 0.18 µmol/L of flavopiridolresulted in both decreased expression of p53 protein and cleavage ofthe caspase-3 zymogen 32-kD protein with the appearance of its 20-kD subunit. Contrasting observations of others in tumor cell lines, flavopiridol cytotoxicity in CLL cells did not correlate with changesin bcl-2 protein expression alterations. We evaluated flavopiridol'sdependence on intact p53 by exposing splenocytes from wild-type(p53^+/+) and p53 null (p53^/) micethat demonstrated no preferential cytotoxicity as compared with amarked differential with F-ara-a and radiation. Incubation of CLL cellswith antiapoptotic cytokine interleukin-4 (IL-4) did not alter theLC₅₀ of flavopiridol, as compared with a marked elevationnoted with F-ara-a in the majority of patients tested. These datademonstrate that flavopiridol has significant in vitro activity againsthuman CLL cells through activation of caspase-3, which appears to occurindependently of bcl-2 modulation, the presence of IL-4, or p53 status.Such findings strongly support the early introduction of flavopiridolinto clinical trials for patients with B-CLL.     

Cholesterol starvation induces differentiation of the intestinal parasite Giardia lamblia.

Giardia lamblia, like most human intestinal parasitic protozoa, sustains fundamental morphological and biochemical changes to survive outside the small intestine of its mammalian host by differentiating into an infective cyst. However, the stimulus that triggers this differentiation remains totally undefined. In this work, we demonstrate the induction of cyst formation in vitro when trophozoites are starved for cholesterol. Expression of cyst wall proteins was detected within encystation-specific secretory vesicles 90 min after the cells were placed in lipoprotein-deficient TYI-S-33 medium. Four cloned lines derived from two independent Giardia isolates were tested, and all formed cysts similarly. Addition of cholesterol, low density or very low density lipoproteins to the lipoprotein-deficient culture medium, inhibited the expression of cyst wall proteins, the generation of encystation-specific vesicles, and cyst wall biogenesis. In contrast, high density lipoproteins, phospholipids, bile salts, or fatty acids had little or no effect. These results indicate that cholesterol starvation is necessary and sufficient for the stimulation of Giardia encystation in vitro and, likely, in the intestine of mammalian hosts.     

Profiles of ethnic-racial socialization from family,school, neighborhood,and the Internet: Relations to adolescent outcomes

Given that ecological models of development highlight the interacting influences of multiple environments, further research is needed that explores ethnic-racial socialization from multiple contexts. The current study explores how families, schools, neighborhoods, and the Internet jointly impact academic outcomes, critical consciousness, and psychological well-being in adolescents, both through socialization messages and experiences with racial discrimination. The research questions were: (a) What profiles of multiple contexts of socialization exist? and (b) How are the different profiles associated with academic outcomes, critical consciousness, and psychological well-being? The sample consisted of 1,084 U.S. adolescents aged 13–17 (M = 14.99, SD = 1.37; 49% girls) from four ethnic-racial groups: 25.6% Asian American, 26.3% Black/African American, 25.3% Latinx, and 22.9% White. The participants completed online surveys of socialization and discrimination from four contexts and three types of outcomes: academic outcomes, critical consciousness, and well-being. A latent profile analysis revealed three profiles: Average, High Discrimination, and Positive School. The Positive School class had the most positive academic outcomes and well-being. The High Discrimination class reported the highest critical consciousness. Their academic outcomes and well-being were similar to the Average group. The findings support complexity in perceptions of socialization from different contexts and the associations of socialization with youth outcomes.