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Astrocytes, a type of glial cell in the brain, are thought to be functionally and morphologically diverse cells that regulate brain homeostasis. Cell immortalization is a promising technique for the propagation of primary human astrocytes. The immortalized cells retain their astrocytic marker mRNA expression at lower levels than the primary cells. Therefore, improvement of the differentiation status is required. The use of a 3D formation technique to mimic structural tissue is a good strategy for reflecting physiological cell–cell interactions. Previously, we developed a spheroid formation method using highly viscous methyl cellulose (MC) medium. In this study, we applied this formation method to the well-established immortalized human astrocyte cell line HASTR/ci35. Stable HASTR/ci35 spheroids were successfully formed in MC medium, and laminin deposition was detected inside of the spheroids. Their functional markers were enhanced compared to conventional spheroids formed in U-bottom plates. The inflammatory response was moderately sensitive, and the ability to support neurite growth was confirmed. The HASTR/ci35 spheroid in the MC medium demonstrated the differentiation phenotype and could serve as a potent in vitro model for matured astrocytes.

Adoptive cell therapy with T cells reprogrammed to express chimeric antigen receptors (CAR-T cells) has been highly successful in patients with hematological neoplasms. However, its therapeutic benefits have been limited in solid tumor cases. Even those patients who respond to this immunotherapy remain at risk of relapse due to the short-term persistence or non-expansion of CAR-T cells; moreover, the hostile tumor microenvironment (TME) leads to the dysfunction of these cells after reinfusion. Some research has shown that, in adoptive T-cell therapies, the presence of less differentiated T-cell subsets within the infusion product is associated with better clinical outcomes. Naive and memory T cells persist longer and exhibit greater antitumor activity than effector T cells. Therefore, new methods are being studied to overcome the limitations of this therapy to generate CAR-T cells with these ideal phenotypes. In this paper, we review the characteristics of T-cell subsets and their implications in the clinical outcomes of adoptive therapy with CAR-T cells. In addition, we describe some strategies developed to overcome the reduced persistence of CAR T-cells and alternatives to improve this therapy by increasing the expansion ability and longevity of modified T cells. These methods include cell culture optimization, incorporating homeostatic cytokines during the expansion phase of manufacturing, modulation of CAR-T cell metabolism, manipulating signaling pathways involved in T-cell differentiation, and strategies related to CAR construct designs.

Background Up to date, investigation of the prognostic value of differentiation status mainly focused on signet ring cell and mucinous gastric cancer. Thus, the present study aims to investigate the clinicopathological features and prognosis of gastric cancer patients with well, moderately and poorly differentiation status. Methods From September 2008 to March 2015, a total of 3090 gastric cancer patients treated with radical D2 gastrectomy were enrolled in the present study. Clinicopathological characteristics and prognosis of gastric cancer patients with well, moderately and poorly differentiation status were analyzed. Results There were 2422 male (78.4%) and 668 female (21.6%). The median age was 58 (20–90) years. There were 370 (12.0%) well differentiated tumors, 836 (27.0%) moderately differentiated tumors and 1884 (61.0%) poorly differentiated tumors. Well and moderately differentiation status were associated with older age, male gender, smaller tumor, shallower invasion, less lymph node involvement and earlier tumor stage (all p  < 0.001). Inversely, poorly differentiation status was associated with younger age, female gender, larger tumor, deeper invasion, more lymph node involvement and later tumor stage (all p  < 0.001). With respect to prognosis, well differentiation status was associated with favorable overall survival and poorly differentiation status was associated with unfavorable overall survival ( p  < 0.001). However, after matching with age, tumor size, T and N stage, there was no significant difference among the overall survival of the three groups ( p  = 0.415). Conclusions Well, moderately and poorly differentiation status was significantly associated with clinicopathological features of gastric cancer patients. However, it was not associated with the prognosis of gastric cancer patients.

We develop a conceptual model to theorize the impact of high versus low power distance cultural contexts on group creativity and individual group member creativity. High power distance cultural contexts manifest in group social environments where status differentiation among individuals is expected and accepted. This hierarchical social environment is substantially different from the relatively equal social environment in low power distance cultural contexts. Building on this premise, we theorize how and why power distance cultural contexts may (1) impact group creativity by influencing the divergent and convergent processes at the group level and (2) impact the creativity of individual group members by influencing an individual’s cognitive task involvement and impression management motives. Further, we identify contextual factors and individual differences that may moderate the impact of power distance. This conceptual model advances our understanding of how creative processes in groups may differ in different cultural contexts as well as suggests ways to foster group creativity in non-Western high power distance cultural contexts.

Advancing age is characterized by functional and phenotypic alterations in the distribution of circulating T-cell subsets, some of which are exacerbated by a latent infection with the persistent herpesvirus, cytomegalovirus (CMV). The influence of age, sex and CMV-infection on T-cell subpopulations in the peripheral blood remains incompletely understood. Here, T cells from 157 participants of the Berlin Aging Study II (BASE-II) were characterized at 21–34 (n = 59) and 62–85 (n = 98) years of age. We found that the frequency of naïve CD8 + T cells was significantly lower in the older group than in the young, and was different in men and women. Elderly men had a significantly lower proportion of naïve CD8 + T cells than younger men, regardless of their CMV-status, but in older women, this was seen only in the CMV-seropositive group. Reciprocally, older men had a higher proportion of late-differentiated, potentially “senescent” CD57 + T cells. Thus, T-cell senescence may be more pronounced in older men than women. Within the CD4 + population, in the elderly of both sexes there was a significantly higher proportion of late-differentiated TEMRA cells (T effector memory cells re-expressing CD45RA), but these were present exclusively in CMV-positive subjects. Finally, for the first time, we examined the so-called TSCM cell (T-stem cell-like memory) subpopulations in both CD4 + and CD8 + subsets and found that neither CMV-seropositivity nor age or sex affected their frequencies. This study confirms significant cross-sectional age-associated differences of T-cell subset distribution in a representative German urban population and emphasizes the impact of both sex and CMV-infection on T-cell naïve and memory phenotypes, but unaffected frequencies of T-stem cell-like memory cells.

Background: Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies in fair-skinned populations worldwide and its incidence is increasing. Despite previous observations of multiple genetic abnormalities in cSCC, the oncogenic process remains elusive. The purpose of this study was to elucidate key molecular events associated with progression from premalignant actinic keratoses (AKs) to invasive cSCC by transcriptome profiling. Methods: We combined laser capture microdissection with the Affymetrix HGU133 Plus 2.0 microarrays to profile 30 cSCC and 10 AKs. Results: We identified a core set of 196 genes that are differentially expressed between AK and cSCC, and are enriched for processes including epidermal differentiation, cell migration, cell-cycle regulation and metabolism. Gene set enrichment analysis highlighted a key role for the mitogen activated protein kinase (MAPK) pathway in cSCC compared with AK. Furthermore, the histological subtype of the tumour was shown to influence the expression profile. Conclusion: These data indicate that the MAPK pathway may be pivotal to the transition from AK to cSCC, thus representing a potential target for cSCC prevention. In addition, transcriptome differences identified between cSCC subtypes have important implications for future development of targeted therapies for this malignancy.

Prior research on status has focused primarily on the cognitive perspective, exploring the effects of status and offering a limited understanding of the impact of positive status change and its emotional mechanisms. This study draws upon the two-facet model of pride to examine how positive status change influences the behaviors of new status holders. Specifically, we propose that when status differentiation is low, positive status change enhances new status holders' prosocial behavior through their authentic pride, while in cases of high status differentiation, it increases their self-interested behavior through their hubristic pride. To test our hypotheses, we conducted a series of studies, including a laboratory experiment, a scenario experiment, and a time-lagged multilevel and multisource field study. Our multilevel analyses of the data provided strong support for our hypotheses. Our findings shed light on when and why positive status change triggers different behaviors among new status holders, offering important insights into the emotional mechanisms that underlie the effects of status change.

The expression of PD-L1 by tumor cells is mainly associated with its immunosuppressive effect. In fact, PD-1/PD-L1 immune checkpoint inhibitors demonstrated remarkable effects in advanced cancer patients including HNSCC. In this context, irradiation is currently being investigated as a synergistic treatment modality to immunotherapy. However, the majority of HNSCC patients still show little improvement or even hyperprogression. Interestingly, there is increasing evidence for additional cell-intrinsic functions of PD-L1 in tumor cells. In previous studies, we showed that PD-L1 has a strong influence on proliferation, migration, invasion, and survival after irradiation. We demonstrated that cellular expression and localization of PD-L1 differed depending on sensitivity to irradiation. Here, we show that PD-L1 is also differentially expressed during cell cycle progression of HNSCC. Furthermore, cellular localization of PD-L1 also changes depending on a particular cell cycle phase. Moreover, distinct observations occurred depending on the general differentiation status. Overall, the function of PD-L1 cannot be generalized. Rather, it depends on the differentiation status and microenvironment. PD-L1 expression and localization are variable, depending on different factors. These findings may provide insight into why differential response to PD-1/PD-L1 antibody therapy can occur. Detailed understanding of cell-intrinsic PD-L1 functions will further allow antibody-based immunotherapy to be optimized.

Based on social-cognitive theory, this article proposes a model that seeks to explain why high status organizational members engage in unethical behavior. We argue that status differentiation in organizations creates social isolation which initiates activation of high status group identity and a deactivation of moral identity. We further argue that high status group identity results in insensitivity to the needs of out-group members which, in turn, results in lessened motivation to selfregulate ethical decision making. As a result of this identity activation, we demonstrate how high status individuals will be more vulnerable to engaging in unethical activities. Individual-level moderators of the relationships are also discussed.

Objectives Differentiation hierarchies in myeloid malignancies influence therapeutic response and prognosis. Acute myeloid leukaemia (AML) with t(8;21) is one of the most recurrent genetic subtypes of AML and is considered a distinct entity with shared characteristics. However, clinical outcomes remain markedly heterogeneous. This study aimed to investigate the relationship between leukaemic arrest at specific differentiation stages, genomic profiles and clinical outcomes in t(8;21) AML. Methods We conducted a retrospective study involving 338 patients with t(8;21) AML from three clinical centres in China. Patients received either chemotherapy alone (49.11%, n = 166) or chemotherapy followed by allogeneic haematopoietic stem cell transplantation (allo‐HSCT; 41.72%, n = 141). Immunophenotypic profiling classified patients into progenitor subgroups: MPP (20.12%, n = 68), lymphoid‐primed multi‐potent progenitor (14.50%, n = 49), CMP (12.72%, n = 43), GMP (24.85%, n = 84) and GP/MP (10.36%, n = 35). Based on differentiation stage, patients were categorised as primitive (Immuno‐Prim; 47.34%, n = 160) or monocytic (Immuno‐Mono; 35.21%, n = 119). Results The Immuno‐Mono group was associated with lower 2‐year overall survival (OS) and a higher 2‐year cumulative incidence of relapse (CIR) compared to the Immuno‐Prim group. Patients with a KIT mutation had poorer 2‐year OS and higher 2‐year CIR than those without the mutation. In the allo‐HSCT cohort, the Immuno‐Mono group continued to show lower 2‐year OS and higher 2‐year CIR relative to the Immuno‐Prim group. Neither gene mutations (aside from KIT) nor chromosomal losses significantly affected OS or CIR. Conclusions Leukaemic differentiation stage independently predicts post‐treatment outcomes in t(8;21) AML. Arrest at specific myeloid stages correlates significantly with genetic aberrations, clinical presentation, therapeutic response and survival. In this multi‐centre study of 338 t(8;21) acute myeloid leukaemia patients, we demonstrate that leukaemic arrest at monocytic differentiation stages (Immuno‐Mono) predicts significantly worse 2‐year survival and higher relapse rates than primitive‐stage arrest (Immuno‐Prim), independent of therapy. We further identify KIT mutations as compounding adverse factors and show that allogeneic transplantation fails to overcome Immuno‐Mono‐associated risk, establishing differentiation arrest as a key prognostic determinant.