A cluster analysis of the HSPC lineage output highlighted the existence of several stable, distinct differentiation programs, including myeloid-dominant, lymphoid-dominant and balanced cell subsets. Our study evidenced the heterogeneous nature of the cell lineage output from HSPCs, and provided methods for analyzing these complex data. Copyright © 2020 American Society of Hematology.Expression of the cell cycle regulatory gene CDK6 is required for Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) cell growth whereas expression of the closely related CDK4 protein is dispensable. Moreover, CDK6 silencing is more effective than treatment with the dual CDK4/6 inhibitor Palbociclib in suppressing Ph+ ALL in mice, suggesting that the growth-promoting effects of CDK6 are, in part, kinase-independent in Ph+ ALL. Accordingly, we developed CDK4/6-targeted proteolysis-targeting chimeras (PROTACs) that inhibit CDK6 enzymatic activity in vitro, promote the rapid and preferential degradation of CDK6 over CDK4 in Ph+ ALL cells, and markedly suppress S phase cells concomitant with inhibition of CDK6-regulated phospho-RB and FOXM1 expression. No such effects were observed in CD34+ normal hematopoietic progenitors, although CDK6 was efficiently degraded. Treatment with the CDK6-degrading PROTAC YX-2-107 markedly suppressed leukemia burden in mice injected with de novo or TKI-resistant primary Ph+ ALL cells and this effect was comparable or superior to that of the CDK4/6 enzymatic inhibitor Palbociclib. These studies provide "proof of principle" that targeting CDK6 with PROTACs that inhibit its enzymatic activity and promote its degradation represents an effective strategy to exploit the "CDK6 dependence" of Ph+ ALL and, perhaps, of other hematological malignancies. Moreover, they suggest that treatment of Ph+ ALL with CDK6-selective PROTACs would spare a high proportion of normal hematopoietic progenitors, preventing the neutropenia induced by treatment with dual CDK4/6 inhibitors. Copyright © 2020 American Society of Hematology.Increasing evidence suggests that platelets play a predominant role in colon and breast cancer metastasis but the underlying molecular mechanisms remain elusive.  https://www.selleckchem.com/products/sn-38.html  Glycoprotein VI (GPVI) is a platelet-specific receptor for collagen and fibrin that triggers platelet activation through immunoreceptor tyrosine-based activation motif (ITAM)-signaling and thereby regulates diverse functions including platelet adhesion, aggregation and procoagulant activity. GPVI has been proposed as a safe antithrombotic target as its inhibition is protective in models of arterial thrombosis with only minor effects on hemostasis. Here, we demonstrate that genetic deficiency of platelet GPVI in mice decreases experimental and spontaneous metastasis of colon and breast cancer cells. Similar results were obtained with mice lacking the spleen-tyrosine kinase Syk in platelets, an essential component of the ITAM-signaling cascade. In vitro and in vivo analyses show that mouse, as well as human GPVI, supports platelet adhesion to colon and breast cancer cells. Using a CRISPR/Cas9-based gene knock-out approach, we identified Galectin-3 as the major counter-receptor of GPVI on tumor cells. In vivo studies demonstrated that the interplay between platelet GPVI and tumor cell-expressed Galectin-3 utilizes ITAM-signaling components in platelets and favors the extravasation of tumor cells. Finally, we showed that JAQ1 F(ab)2-mediated inhibition of GPVI efficiently impairs platelet-tumor cell interaction and tumor metastasis. Our study reveals a new mechanism by which platelets promote the metastasis of colon and breast cancer cells and suggests that GPVI represents a promising target for antimetastatic therapies. Copyright © 2020 American Society of Hematology.The purpose of this study was to provide more insight into how the physical education (PE) context can be better tailored to the diverse motivational demands of secondary school students. Therefore, we examined how different constructs of student motivation in the context of PE combine into distinct motivational profiles, aiming to unveil motivational similarities and differences between students' PE experiences. Participants were 2,562 Dutch secondary school students, aged 12-18, from 24 different schools. Students responded to questionnaires assessing their perception of psychological need satisfaction and frustration, and perceived mastery and performance climate in PE. In order to interpret the emerging profiles additional variables were assessed (i.e. demographic, motivational and PE-related variables). Two-step cluster analysis identified three meaningful profiles labelled as negative perceivers, moderate perceivers and positive perceivers. These three profiles differed significantly with regard to perceived psychological need satisfaction and frustration and their perception of the motivational climate. This study demonstrates that students can be grouped in distinct profiles based on their perceptions of the motivational PE environment. Consequently, the insights obtained could assist PE teachers in designing instructional strategies that target students' differential motivational needs.INTRODUCTION Obstructed labour (OL) is an important clinical and public health problem because of the associated maternal and perinatal morbidity and mortality. Risk factors for OL and its associated obstetric squeal are usually context specific. No epidemiological study has documented the risk factors for OL in Eastern Uganda. This study was conducted to identify the risk factors for OL in Mbale Hospital. OBJECTIVE To identify the risk factors for OL in Mbale Regional Referral and Teaching Hospital, Eastern Uganda. METHODS We conducted a case control study with 270 cases of women with OL and 270 controls of women without OL. We consecutively enrolled eligible cases between July 2018 and February 2019. For each case, we randomly selected one eligible control admitted in the same 24-hour period. Data was collected using face-to-face interviews and a review of patient notes. Logistic regression was used to identify the risk factors for OL. RESULTS The risk factors for OL were, being a referral from a lower health facility (AOR 6.