Longer Survival in Patients with Breast Cancer with Cyclin D1 Over-Expression after Tumor Recurrence: Longer,but Occupied with Disease

Purpose

The effect of cyclin D1 overexpression on breast cancer outcomes and prognosis is controversial, even though amplification of the cyclin D1 gene, CCND1, has been shown to be associated with early relapse and poor prognosis. In this study, we examined the relationship between cyclin D1 overexpression and disease-specific survival (DSS). We also analyzed survival in patients who experienced recurrence.

Methods

We retrospectively analyzed data from patients diagnosed with ductal carcinoma between April 2005 and December 2010. We examined clinicopathologic factors associated with cyclin D1 overexpression and analyzed the influence of cyclin D1 on recurrence-free survival and DSS.

Results

We identified 236 patients diagnosed with primary breast cancer who completed all phases of their primary treatment. Cyclin D1 overexpression was significantly associated with longer DSS (5-year DSS, 89.9% in patients without cyclin D1 overexpression vs. 98.9% in patients with cyclin D1 overexpression; p=0.008). Multivariate analysis also found that patients with cyclin D1 overexpressing tumors had significantly longer disease-specific survival than patients whose tumors did not overexpress cyclin D1, with a hazard ratio for disease-specific mortality of 7.97 (1.17-54.22, p=0.034). However, in the group of patients who experienced recurrence, cyclin D1 overexpression was not significantly associated with recurrence-free survival. Cyclin D1 overexpression was significantly associated with increased survival after disease recurrence, indicating that cyclin D1 overexpression might be indicative of more indolent disease progression after metastasis.

Conclusion

Cyclin D1 overexpression is associated with longer DSS, but not recurrence-free survival, in patients with breast cancer. Longer postrecurrence survival could explain the apparent inconsistency between DSS and recurrence-free survival. Patients with cyclin D1-overexpressing tumors survive longer, but with metastatic disease after recurrence. This information should spark the urgent development of tailored therapies to cure these patients.     

Adolescent subthreshold‐depression and anxiety: psychopathology,functional impairment and increased suicide risk

Background: Subthreshold‐depression and anxiety have been associated with significant impairments in adults. This study investigates the characteristics of adolescent subthreshold‐depression and anxiety with a focus on suicidality, using both categorical and dimensional diagnostic models. Methods: Data were drawn from the Saving and Empowering Young Lives in Europe (SEYLE) study, comprising 12,395 adolescents from 11 countries. Based on self‐report, including Beck Depression Inventory‐II (BDI‐II), Zung Self‐Rating Anxiety Scale (SAS), Strengths and Difficulties Questionnaire (SDQ) and Paykel Suicide Scale (PSS) were administered to students. Based on BDI‐II, adolescents were divided into three groups: nondepressed, subthreshold‐depressed and depressed; based on the SAS, they were divided into nonanxiety, subthreshold‐anxiety and anxiety groups. Analyses of Covariance were conducted on SDQ scores to explore psychopathology of the defined groups. Logistic regression analyses were conducted to explore the relationships between functional impairments, suicidality and subthreshold and full syndromes. Results: Thirty‐two percent of the adolescents were subthreshold‐anxious and 5.8% anxious, 29.2% subthreshold‐depressed and 10.5% depressed, with high comorbidity. Mean scores of SDQ of subthreshold‐depressed/anxious were significantly higher than the mean scores of the nondepressed/nonanxious groups and significantly lower than those of the depressed/anxious groups. Both subthreshold and threshold‐anxiety and depression were related to functional impairment and suicidality. Conclusions: Subthreshold‐depression and subthreshold‐anxiety are associated with an increased burden of disease and suicide risk. These results highlight the importance of early identification of adolescent subthreshold‐depression and anxiety to minimize suicide. Incorporating these subthreshold disorders into a diagnosis could provide a bridge between categorical and dimensional diagnostic models.     

Lattice Boltzmann Modeling of Advection-Diffusion-Reaction Equations: Pattern Formation Under Uniform Differential Advection

A lattice Boltzmann model for the study of advection-diffusion-reaction (ADR) problems is proposed. Via multiscale expansion analysis, we derive from the LB model the resulting macroscopic equations. It is shown that a linear equilibrium distribution is sufficient to produce ADR equations within error terms of the order of the Mach number squared. Furthermore, we study spatially varying structures arising from the interaction of advective transport with a cubic autocatalytic reaction-diffusion process under an imposed uniform flow. While advecting all the present species leads to trivial translation of the Turing patterns, differential advection leads to flow induced instability characterized with traveling stripes with a velocity dependent wave vector parallel to the flow direction. Predictions from a linear stability analysis of the model equations are found to be in line with these observations.     

A disintegrin and metalloproteinase (ADAM)-10 as a predictive factor for tocilizumab effectiveness in rheumatoid arthritis

Objectives: A disintegrin and metalloproteinase (ADAM)-10 is expressed in rheumatoid arthritis (RA). In this study, we focused on ADAM-10 as a predictive factor for the treatment with biologics in RA.

Methods: The levels of ADAM-10 and fractalkine/CX3CL1 in RA and healthy controls serum were measured using enzyme-linked immunosorbent assays. Fifteen patients were treated with adalimumab (ADA), and 20 patients were treated with tocilizumab (TCZ).

Results: ADAM-10 positively correlated with fractalkine/CX3CL1 in the sera of RA patients and was presented at a significantly higher level compared to that in normal serum (487?±?80?pg/ml and 85?±?33?pg/ml, respectively, p?Conclusions: ADAM-10 may be a predictor of the effectiveness of TCZ in treating RA.     

Long-term outcome of inflammatory bowel disease patients with deep remission after discontinuation of TNFα-blocking agents

Background: Little data exist on the long-term prognosis of patients with inflammatory bowel disease (IBD) after stopping TNFα-blocking therapy in deep remission. Existing data indicate that approximately 50% of patients on combination therapy who discontinued TNFα-blockers are still in remission 24 months later. The aims of this follow-up analysis were to evaluate the long-term remission rate after cessation of TNFα-blocking therapy, the predicting factors of a relapse and the response to restarting TNFα blockers.

Methods: The first follow-up data of 51 IBD patients (17 Crohn’s disease [CD], 30 ulcerative colitis [UC] and four inflammatory bowel disease type unclassified [IBDU]) in deep remission at the time of cessation of TNFα-blocking therapy have been published earlier. The long-term data was collected retrospectively after the first follow-up year to evaluate the remission rate and risk factors for the relapse after a median of 36 months.

Results: After the first relapse-free year, 14 out of the remaining 34 IBD patients relapsed (41%; 5/12 [42%] CD and 9/22 [41%] UC/IBDU). Univariate analysis indicated no associations with any predictive factors. Re-treatment was effective in 90% (26/29) of patients.

Conclusion: Of IBD patients in deep remission at the time of cessation of TNFα-blocking therapy, up to 60% experience a clinical or endoscopic relapse after a median follow-up time of 36 months (95% CI 31–41 months). No individual risk factors predicting relapse could be identified. However, the initial response to a restart of TNFα-blockers seems to be effective and well tolerated.     

Reconstitution of huPBL-NSG Mice with Donor-Matched Dendritic Cells Enables Antigen-Specific T-cell Activation

Humanized mouse models provide a unique opportunity to study human immune cells in vivo, but traditional models have been limited to the evaluation of non-specific T-cell interactions due to the absence of antigen-presenting cells. In this study, immunodeficient NOD/SCID/IL2r-??^null (NSG) mice were engrafted with human peripheral blood lymphocytes alone or in combination with donor-matched monocyte-derived dendritic cells (DC) to determine whether antigen-specific T-cell activation could be reconstituted. Over a period of 3 weeks, transferred peripheral blood lymphocytes reconstituted the spleen and peripheral blood of recipient mice with predominantly human CD45-positive lymphocytes. Animals exhibited a relatively normal CD4/CD8 ratio (average 1.63:1) as well as reconstitution of CD3/CD56 (averaging 17.8%) and CD20 subsets (averaging 4.0%). Animals reconstituted with donor-matched CD11c+ DC also demonstrated a CD11c+ population within their spleen, representing 0.27% to 0.43% of the recovered human cells with concurrent expression of HLA-DR, CD40, and CD86. When immunized with adenovirus, either as free replication-incompetent vector (AdV) or as vector-transduced DC (DC/AdV), there was activation and expansion of AdV-specific T-cells, an increase in Th1 cytokines in serum, and skewing of T-cells toward an effector/memory phenotype. T-cells recovered from animals challenged with AdV in vivo proliferated and secreted a Th1-profile of cytokines in response to DC/AdV challenge in vitro. Our results suggest that engrafting NSG mice with a combination of lymphocytes and donor-matched DC can reconstitute antigen responsiveness and allow the in vivo assessment of human immune response to viruses, vaccines, and other immune challenges.     

Vertical and horizontal coding of space in the monkey dorsolateral prefrontal cortex

Single cell activity in the dorsolateral prefrontal cortex was recorded in a monkey performing a delayed alternation (DA) task in 3 directions, to the left, to the right, and upwards. Among the 127 units studied in all three directions, 18 neurons were spatially selective in one direction (to the left, to the right or upwards), 37 neurons in two directions and 8 neurons in each 3 directions during the performance of the DA task. Of the 9 neurons that were spatially selective upwards, 8 had a specific pattern of activity during the delay period and one during the response period. When several spatial directions are studied in a DA task, as in this work, it becomes evident that the prefrontal cortex contains a large number of spatially selective neurons. The results of this study suggest that there is a spatial memory map in the prefrontal cortex which is needed not only when a DA task is performed to the left and to the right but also in the upward direction.     

The role of extracellular vesicles throughout normal pregnancy and in relation to oral bacteria

BackgroundRecently, the relationship between the maternal oral environment and complicated pregnancies has been discussed in depth. The depletion of all bacterial flora, including oral bacteria, significantly decreased the size of the maternal placenta and suppressed fetal bone reabsorption. Furthermore, bacterial flora DNA of the host placenta has been reported to be remarkably similar to that of oral flora DNA. These findings indicate that maternal oral flora has a considerable effect on the formation of the placenta and fetus.HighlightPlacenta is a sophisticated tissue, in which the fetus and mother exchange substance. Placental homeostasis affects the maternal and fetal health; therefore, any disorder in this context is directly linked to serious health issues for the mother and developmental inhibition of the fetus. Extracellular vesicles (EVs) possess and deliver various factors (i.e., nucleic acids, proteins, and lipids) to distant organs through intercellular crosstalk. EVs are released during natural physiological events as well as under stress conditions. EVs derived from reproductive tissues, such as the placenta, are deeply involved in all stages of pregnancy, including the maturation and survival of sperm and egg, various events during fertilization, implantation, spiral artery remodeling, and immunomodulation.ConclusionTo date, the precise role of EVs in oral diseases, including periodontal disease, is not well understood. Nonetheless, placental EVs are likely to attract attention, in the future, to objectively evaluate the effects of periodontal disease on maternal and fetal health. Therefore, the role of EVs throughout normal pregnancy will be discussed in this review.     

Regulation of Cell Surface CB<Subscript>2</Subscript> Receptor during Human B Cell Activation and Differentiation

Cannabinoid receptor type 2 (CB₂) is the primary receptor pathway mediating the immunologic consequences of cannabinoids. We recently reported that human peripheral blood B cells express CB₂ on both the extracellular membrane and at intracellular sites, where-as monocytes and T cells only express intracellular CB₂. To better understand the pattern of CB₂ expression by human B cells, we examined CD20⁺ B cells from three tissue sources. Both surface and intracellular expression were present and uniform in cord blood B cells, where all cells exhibited a naïve mature phenotype (IgD⁺/CD38^Dim). While naïve mature and quiescent memory B cells (IgD^?/CD38^?) from tonsils and peripheral blood exhibited a similar pattern, tonsillar activated B cells (IgD^?/CD38⁺) expressed little to no surface CB₂. We hypothesized that regulation of the surface CB₂ receptor may occur during B cell activation. Consistent with this, a B cell lymphoma cell line known to exhibit an activated phenotype (SUDHL-4) was found to lack cell surface CB₂ but express intracellular CB₂. Furthermore, in vitro activation of human cord blood resulted in a down-regulation of surface CB₂ on those B cells acquiring the activated phenotype but not on those retaining IgD expression. Using a CB₂ expressing cell line (293 T/CB₂-GFP), confocal microscopy confirmed the presence of both cell surface expression and multifocal intracellular expression, the latter of which co-localized with endoplasmic reticulum but not with mitochondria, lysosomes, or nucleus. Our findings suggest a dynamic multi-compartment expression pattern for CB₂ in B cells that is specifically modulated during the course of B cell activation.