ABSTRACT
Background: Mantle cell lymphoma (MCL) is a B-cell tumor which often relapses. BCR inhibitors (Ibrutinib, Acalabrutinib) and antiapoptotic BCL2-family members blockers BH3-mimetics (Venetoclax, ABT-199) are effective drugs to fight MCL. However, the disease remains incurable, due to therapy resistance, even to the promising Venetoclax and Ibrutinib combination. Therefore, there is a profound need to explore novel useful therapeutic targets. CK2 is a S/T kinase overexpressed in several solid and blood tumors. We demonstrated that CK2, operating through a 'non-oncogene addiction' mechanism promotes tumor cell survival, and counteracts apoptosis, by activating pro-survival signaling cascades, such as NF-κ B, STAT3 and AKT. CK2 could regulate also BCL2 family members. The CK2 chemical inhibitor CX-4945 (Silmitasertib, Sil) is already under scrutiny in clinical trials in relapsed multiple myeloma, solid tumors and COVID-19. Aims: In this work, we tested the effect of CK2 chemical inhibition or knock down on Venetoclax (Ven)-induced cytotoxicity in MCL pre-clinical models to effectively reduce MCL cell growth and clonal expansion. Methods: CK2 expression and BCR/BCL2 related signaling components were analyzed in MCL cells and control cells by Western blotting. CK2 and BCL2 inhibition was obtained with Sil and Ven, respectively and with CK2 gene silencing through the generation of anti-CK2 shRNA IPTG-inducible MCL cell clones. Survival, apoptosis, mitochondrial membrane depolarization and proliferation were investigated by FACS analysis of AnnexinV/PI and JC-10 staining. The synergic action of Ven and Sil was analyzed by the Chou-Talalay combination index (CI) method. CK2 knock down in vivo was obtained in xenograft NOD-SCID mouse models Results: CK2 inactivation (with Sil or CK2 silencing) determined a reduction in the activating phosphorylation of S529 p65/RelA and S473 and S129 AKT, important survival cascades for MCL. Sil or CK2 silencing caused BCL2 and related MCL1 protein reduction, causing cell death. Importantly, we confirmed these results also in an in vivo xenograft mouse model of CK2 knockdown in MCL. Sil +Ven combination increased MCL cell apoptosis, as judged by the augmented frequency of Annexin V positive cells and expression of cleaved PARP protein, and JC-10 mitochondrial membrane depolarization, with respect to the single treatments. Captivatingly, Sil or CK2 gene silencing led to a substantial reduction of the Ven-induced increase of MCL-1, potentially counteracting a deleterious Ven-induced drawback. Analysis of cell cycle distribution confirmed an increased frequency of apoptotic cells in the sub G1 phase in CK2-silenced cells and a modulation of the other phases of the cell cycle. Remarkably, the calculated CI less than 1 suggested a strong synergic cell-killing effect between Sil and Ven, on all the cell lines tested, including those less sensitive or resistant to Ven Summary/Conclusion: We demonstrated that the simultaneous inhibition/knock down of CK2 and BCL2 synergistically cooperates in inducing apoptosis and cell cycle arrest of MCL malignant B-lymphocytes and has the potential of reducing MCL clonal growth, also counterbalancing mechanism of resistance that may arise with Ven. Therefore, CK2 is a rational therapeutic target for the treatment of MCL to be tested in combination with Ibrutinib or Ven.
ABSTRACT
Purpose The need for accelerating innovation is exacerbated as organizations struggle to either adapt or perish in this unforgiving condition due to the COVID-19 disruption. To address this issue, many organizations have embraced employee-driven participatory innovation to survive and thrive albeit the uncertainties. This study aims to investigate the role of enterprise social media (ESM) in supporting and facilitating these efforts. Design/methodology/approach This study first identified the underlying mechanisms that allow ESM use to foster and maintain participatory innovation and then reexamined how these mechanisms played out during the COVID-19 lockdown restrictions. The data was collected through a questionnaire in two phases, before and during work-from-home mandates, and the results were analyzed and compared to capture similarities and differences. Findings The results revealed that innovation culture and management support mediated the effects of ESM use on three measures of innovation productivity in both conditions. Interestingly, the effect of ESM use was more prominent in driving innovation in the work-from-home condition. This effect was not limited to the direct effect of ESM use on innovation productivity but on innovation culture and management support as well. Originality/value The results suggest that ESM offer a potentially useful path to support and enable employees to participate in the innovation processes, especially when they work remotely or in a distributed team. More generally, this paper should be of interest to researchers and practitioners interested in understanding, implementing and evaluating enterprise social software applications and encouraging employee-driven participatory innovation.
ABSTRACT
K-12 education experienced an unprecedented disruption due to the COVID-19 pandemic. Classrooms moved from brick and mortar to online or hybrid classroom models with little training for teachers or students. During distance learning, students became disengaged learning through a computer screen. Collaborative learning, a key to engaging students in K-12 classrooms, was difficult or eliminated in online and hybrid models. This case study explores the experiences of K-12 teachers who implemented a social learning model during the COVID-19 pandemic. The case study supports the importance of authentic social learning as a new pedagogical approach for engaging students in collaborative social learning in K-12 hybrid and online classrooms. As a result, this paper proposes the Authentic Social Learning Model (ASLM) as a model for advancing the effective implementation of computer-supported collaborative learning (CSCL) in K-12 classrooms and provides recommendations for classroom technology to implement this model in current and future face-to-face, online, and hybrid classrooms. © AMCIS 2021.