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Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683). High expression of Mcl-1 promotes tumorigenesis and resistance to anticancer therapies. Here they report a macrocyclic molecule with high selectivity and affinity for Mcl-1 that exhibits potent anti-tumor effects as single agent and in combination with bortezomib or venetoclax in preclinical models of multiple myeloma and acute myeloid leukemia.

The most damaging change during cancer progression is the switch from a locally growing tumour to a metastatic killer. This switch is believed to involve numerous alterations that allow tumour cells to complete the complex series of events needed for metastasis 1 . Relatively few genes have been implicated in these events 2 , 3 , 4 , 5 . Here we use an in vivo selection scheme to select highly metastatic melanoma cells. By analysing these cells on DNA arrays, we define a pattern of gene expression that correlates with progression to a metastatic phenotype. In particular, we show enhanced expression of several genes involved in extracellular matrix assembly and of a second set of genes that regulate, either directly or indirectly, the actin-based cytoskeleton. One of these, the small GTPase RhoC, enhances metastasis when overexpressed, whereas a dominant-negative Rho inhibits metastasis. Analysis of the phenotype of cells expressing dominant-negative Rho or RhoC indicates that RhoC is important in tumour cell invasion. The genomic approach allows us to identify families of genes involved in a process, not just single genes, and can indicate which molecular and cellular events might be important in complex biological processes such as metastasis.

Adhesive interactions play critical roles in directing the migration, proliferation, and differentiation of cells; aberrations in such interactions can lead to pathological disorders. These adhesive interactions, mediated by cell surface receptors that bind to ligands on adjacent cells or in the extracellular matrix, also regulate intracellular signal transduction pathways that control adhesion-induced changes in cell physiology. Though the extracellular molecular interactions involving many adhesion receptors have been well characterized, the adhesion-dependent intracellular signaling events that regulate these physiological alterations have only begun to be elucidated. This article will focus on recent advances in our understanding of intracellular signal transduction pathways regulated by the integrin family of adhesion receptors.

Tyrosine phosphorylation has been shown to play a critical role in the induction of cellular responses to extracellular stimuli in a wide variety of cell types. In platelets, activation by diverse agonists causes platelet aggregation and secretion and is associated with a rapid induction of multiple waves of tyrosine phosphorylation, suggesting a potential role for these protein modifications throughout the platelet activation process. Using various cellular, biochemical and immunological techniques we set out to identify the tyrosine kinases responsible for phosphorylation events which occur during three temporal phases of platelet activation. First, during the \"early\" wave of activation when proteins such as p21$\\sp{\\rm ras}$GAP and cortactin are tyrosine phosphorylated, the tyrosine kinases pp60$\\sp{\\rm c-src}$ and pp72$\\sp{\\rm syk}$ are activated by a mechanism independent of the platelet integrin receptor for fibrinogen, $\\alpha\\sb{\\rm IIb}\\beta\\sb3$. The activation of pp60$\\sp{\\rm c-src}$ appears to be regulated by dephosphorylation of its negative regulatory site and we were able to isolate a tyrosine phosphatase activity from platelets that was capable of activating pp60$\\sp{\\rm c-src}$ in vitro. Next, fibrinogen binding to $\\alpha\\sb{\\rm IIb}\\beta\\sb3$ triggers the phosphorylation and activation of Syk and initiates a second wave of tyrosine phosphorylation (of p140 and p50-68). Finally, platelet aggregation mediated by fibrinogen cross-linking of stirred platelets triggers the phosphorylation and activation of pp125$\\sp{\\rm FAK}$ and induces the tyrosine phosphorylation of still another set of proteins (p95/97). In addition, these studies show that membrane skeleton interactions with $\\alpha\\sb{\\rm IIb}\\beta\\sb3$ appear to play an important role in coupling tyrosine kinases and other signaling molecules with integrin-cytoskeletal complexes. Lastly, we used a unique disintegrin, contortrostatin, to analyze integrin-mediated signaling in platelets. Disintegrins not only inhibited platelet aggregation and aggregation-dependent tyrosine phosphorylation, contortrostatin also possesses a unique functional activity that allows it to activate an intracellular signaling pathway leading to integrin-dependent tyrosine phosphorylation. Therefore, a model is beginning to emerge in which multiple tyrosine kinases, phosphatases, and the cytoskeleton are involved in the three temporal waves of agonist-induced tyrosine phosphorylation. These studies have clearly demonstrated the role of agonist and integrin receptors in the regulation of signal transduction.

BEFORE every great era of drama, or following close upon its arrival, there has been an appreciative audience. Whether the audience was here first and created the demand for drama, or whether drama came first, may be another question; which came first, the chicken or the egg?

Background Genetic influence on DNA methylation is potentially an important mechanism affecting individual differences in humans. We use next-generation sequencing to assay blood DNA methylation at approximately 4.5 million loci, each comprising 2.9 CpGs on average, in 697 normal subjects. Methylation measures at each locus are tested for association with approximately 4.5 million single nucleotide polymorphisms (SNPs) to exhaustively screen for methylation quantitative trait loci (meQTLs). Results Using stringent false discovery rate control, 15 % of methylation sites show genetic influence. Most meQTLs are local, where the associated SNP and methylation site are in close genomic proximity. Distant meQTLs and those spanning different chromosomes are less common. Most local meQTLs encompass common SNPs that alter CpG sites (CpG-SNPs). Local meQTLs encompassing CpG-SNPs are enriched in regions of inactive chromatin in blood cells. In contrast, local meQTLs lacking CpG-SNPs are enriched in regions of active chromatin and transcription factor binding sites. Of 393 local meQTLs that overlap disease-associated regions from genome-wide studies, a high percentage encompass common CpG-SNPs. These meQTLs overlap active enhancers, differentiating them from CpG-SNP meQTLs in inactive chromatin. Conclusions Genetic influence on the human blood methylome is common, involves several heterogeneous processes and is predominantly dependent on local sequence context at the meQTL site. Most meQTLs involve CpG-SNPs, while sequence-dependent effects on chromatin binding are also important in regions of active chromatin. An abundance of local meQTLs resulting from methylation of CpG-SNPs in inactive chromatin suggests that many meQTLs lack functional consequence. Integrating meQTL and Roadmap Epigenomics data could assist fine-mapping efforts.

We present the first large-scale methylome-wide association studies (MWAS) for major depressive disorder (MDD) to identify sites of potential importance for MDD etiology. Using a sequencing-based approach that provides near-complete coverage of all 28 million common CpGs in the human genome, we assay methylation in MDD cases and controls from both blood (N = 1132) and postmortem brain tissues (N = 61 samples from Brodmann Area 10, BA10). The MWAS for blood identified several loci with P ranging from 1.91 × 10−8 to 4.39 × 10−8 and a resampling approach showed that the cumulative association was significant (P = 4.03 × 10−10) with the signal coming from the top 25,000 MWAS markers. Furthermore, a permutation-based analysis showed significant overlap (P = 5.4 × 10−3) between the MWAS findings in blood and brain (BA10). This overlap was significantly enriched for a number of features including being in eQTLs in blood and the frontal cortex, CpG islands and shores, and exons. The overlapping sites were also enriched for active chromatin states in brain including genic enhancers and active transcription start sites. Furthermore, three loci located in GABBR2, RUFY3, and in an intergenic region on chromosome 2 replicated with the same direction of effect in the second brain tissue (BA25, N = 60) from the same individuals and in two independent brain collections (BA10, N = 81 and 64). GABBR2 inhibits neuronal activity through G protein-coupled second-messenger systems and RUFY3 is implicated in the establishment of neuronal polarity and axon elongation. In conclusion, we identified and replicated methylated loci associated with MDD that are involved in biological functions of likely importance to MDD etiology.

HIV-related stigma is a frequently cited barrier to HIV testing and care engagement. A nuanced understanding of HIV-related stigma is critical for developing stigma-reduction interventions to optimize HIV-related outcomes. This qualitative study documented HIV-related stigma across eight communities in east Africa during the baseline year of a large HIV test-and-treat trial (SEARCH, NCT: 01864603), prior to implementation of widespread community HIV testing campaigns and efforts to link individuals with HIV to care and treatment. Findings revealed experiences of enacted, internalized and anticipated stigma that were highly gendered, and more pronounced in communities with lower HIV prevalence; women, overwhelmingly, both held and were targets of stigmatizing attitudes about HIV. Past experiences with enacted stigma included acts of segregation, verbal discrimination, physical violence, humiliation and rejection. Narratives among women, in particular, revealed acute internalized stigma including feelings of worthlessness, shame, embarrassment, and these resulted in anxiety and depression, including suicidality among a small number of women. Anticipated stigma included fears of marital dissolution, verbal and physical abuse, gossip and public ridicule. Anticipated stigma was especially salient for women who held internalized stigma and who had experienced enacted stigma from their partners. Anticipated stigma led to care avoidance, care-seeking at remote facilities, and hiding of HIV medications. Interventions aimed at reducing individual and community-level forms of stigma may be needed to improve the lives of PLHIV and fully realize the promise of test-and-treat strategies.

Postpartum depression (PPD) affects 1 in 7 women and has negative mental health consequences for both mother and child. However, the precise biological mechanisms behind the disorder are unknown. Therefore, we performed the largest transcriptome-wide association study (TWAS) for PPD (482 cases, 859 controls) to date using RNA-sequencing in whole blood and deconvoluted cell types. No transcriptional changes were observed in whole blood. B-cells showed a majority of transcriptome-wide significant results (891 transcripts representing 789 genes) with pathway analyses implicating altered B-cell activation and insulin resistance. Integration of other data types revealed cell type-specific DNA methylation loci and disease-associated eQTLs (deQTLs), but not hormones/neuropeptides (estradiol, progesterone, oxytocin, BDNF), serve as regulators for part of the transcriptional differences between cases and controls. Further, deQTLs were enriched for several brain region-specific eQTLs, but no overlap with MDD risk loci was observed. Altogether, our results constitute a convergence of evidence for pathways most affected in PPD with data across different biological mechanisms.