The a-2 adrenergic receptor agonists have been used for decades to treat common medical conditions such as hypertension; attention-deficit/hyperactivity disorder; various pain and panic disorders; symptoms of opioid, benzodiazepine, and alcohol withdrawal; and cigarette craving.1 However, in more recent years, these drugs have been used as adjuncts for sedation and to reduce anesthetic requirements. This review will provide an historical perspective of this drug class, an understanding of pharmacological mechanisms, and an insight into current applications in clinical anesthesiology.

Multidrug-resistant bacteria are spreading at alarming rates, and despite extensive efforts no new class of antibiotic with activity against Gram-negative bacteria has been approved in over fifty years. Natural products and their derivatives have a key role in combating Gram-negative pathogens. Here we report chemical optimization of the arylomycins-a class of natural products with weak activity and limited spectrum-to obtain G0775, a molecule with potent, broad-spectrum activity against Gram-negative bacteria. G0775 inhibits the essential bacterial type I signal peptidase, a new antibiotic target, through an unprecedented molecular mechanism. It circumvents existing antibiotic resistance mechanisms and retains activity against contemporary multidrug-resistant Gram-negative clinical isolates in vitro and in several in vivo infection models. These findings demonstrate that optimized arylomycin analogues such as G0775 could translate into new therapies to address the growing threat of multidrug-resistant Gram-negative infections.

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The Hippo pathway remains a central focus in both basic and translational research and is a key modulator of developmental biology. Dysregulation of the pathway is associated with a plethora of human cancers and there are multiple efforts to target key components of the pathway for disease intervention. In this review, we briefly highlight the latest research advances around the core components of the Hippo pathway in cancer. More specifically, we discuss several genetic aberrations of these factors as mechanisms for the development of cancers, including genetic amplification, deletion, and gene fusions. Additionally, we highlight the role of the Hippo pathway in cancer therapy resistance and tumor immunogenicity. Last, we summarize the ongoing efforts to target the pathway in cancers. The Hippo Pathway The Hippo pathway is a highly conserved signaling pathway across higher-order vertebrates that modulates key target genes to regulate a multitude of biological processes including cellular proliferation, survival, differentiation, cellular fate determination, organ size, and tissue homeostasis (Figure 1). At the core of the pathway are serine/threonine kinases, sterile 20-like kinase 1/2 (MST1/2), and large tumor suppressor 1/2 (LATS1/2). Recently, MAP4K and TAOK kinases have been shown to directly phosphorylate LATS1/2, thus acting in parallel with MST1/2 [1]. These kinases, along with the adaptor proteins, Salvador homolog 1 (SAV1) and MOB kinase activator 1A/B (MOB1A/B), phosphorylate and inhibit downstream effector proteins, Yesassociated protein (YAP1), and its paralog transcriptional coactivator with PDZ-binding motif (TAZ) (also known as WWTR1) and sequestrates them in the cytoplasm by binding to 14-3-3 proteins [2]. Notably, the tumor suppressor neurofibromin 2 (NF2) (also known as Merlin) participates upstream of these kinases to inhibit YAP and TAZ activity by promoting the activation of the pathway. Additional phosphorylation of YAP/TAZ leads to proteasome-mediated degradation facilitated by binding to β-TrCP [3,4]. Such regulation prevents YAP/TAZ from accumulating in the nucleus and from binding to a family of sequence-specific transcription factors called TEA DNA-binding proteins (TEAD1-4) that mediate proliferative and prosurvival genes such as CTGF, CRY61, BIRC5, ANKRD1, and AXL (Figure 2). Besides TEADs, YAP/TAZ also cooperates with RUNT-related transcription factors (RUNX1 and 2), T-box transcription factor 5 (TBX5), and SMADs as among others [2,5]. Hippo Pathway Deregulation in Cancer Overexpression of Hippo Pathway Effector Proteins Aberration of the Hippo pathway is associated with the hallmarks of oncogenesis and, more recently, has been linked to other cellular processes such as regulation of T cell functionality [6]. These hallmarks include the induction of hyperproliferation, cellular invasion, and metastasis, as well as a role in cancer cell maintenance and chemotherapeutic resistance mechanisms. Analysis of over 9000 tumors showed that YAP and TAZ are frequently amplified in head and nec...

Bruton's tyrosine kinase (Btk) is a nonreceptor cytoplasmic tyrosine kinase involved in B-cell and myeloid cell activation, downstream of B-cell and Fcγ receptors, respectively. Preclinical studies have indicated that inhibition of Btk activity might offer a potential therapy in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Here we disclose the discovery and preclinical characterization of a potent, selective, and noncovalent Btk inhibitor currently in clinical development. GDC-0853 (29) suppresses B cell- and myeloid cell-mediated components of disease and demonstrates dose-dependent activity in an in vivo rat model of inflammatory arthritis. It demonstrates highly favorable safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in preclinical and Phase 2 studies ongoing in patients with rheumatoid arthritis, lupus, and chronic spontaneous urticaria. On the basis of its potency, selectivity, long target residence time, and noncovalent mode of inhibition, 29 has the potential to be a best-in-class Btk inhibitor for a wide range of immunological indications.