Explore the vast range of titles available.

Hyer et al . generate a potent and specific small-molecule inhibitor of the E1 ubiquitin-activating enzyme UBE1 that has antitumor activity in mice against a wide variety of tumor types. The ubiquitin–proteasome system (UPS) comprises a network of enzymes that is responsible for maintaining cellular protein homeostasis. The therapeutic potential of this pathway has been validated by the clinical successes of a number of UPS modulators, including proteasome inhibitors and immunomodulatory imide drugs (IMiDs). Here we identified TAK-243 (formerly known as MLN7243) as a potent, mechanism-based small-molecule inhibitor of the ubiquitin activating enzyme (UAE), the primary mammalian E1 enzyme that regulates the ubiquitin conjugation cascade. TAK-243 treatment caused depletion of cellular ubiquitin conjugates, resulting in disruption of signaling events, induction of proteotoxic stress, and impairment of cell cycle progression and DNA damage repair pathways. TAK-243 treatment caused death of cancer cells and, in primary human xenograft studies, demonstrated antitumor activity at tolerated doses. Due to its specificity and potency, TAK-243 allows for interrogation of ubiquitin biology and for assessment of UAE inhibition as a new approach for cancer treatment.

An inhibitor of the SUMO-activating (E1) enzyme SAE blocks enzyme activity and total SUMOylation in cells—thereby defining roles for SAE in mitotic progression and chromosome segregation—and also decreases cancer cell proliferation. Small ubiquitin-like modifier (SUMO) family proteins regulate target-protein functions by post-translational modification. However, a potent and selective inhibitor targeting the SUMO pathway has been lacking. Here we describe ML-792, a mechanism-based SUMO-activating enzyme (SAE) inhibitor with nanomolar potency in cellular assays. ML-792 selectively blocks SAE enzyme activity and total SUMOylation, thus decreasing cancer cell proliferation. Moreover, we found that induction of the MYC oncogene increased the ML-792-mediated viability effect in cancer cells, thus indicating a potential application of SAE inhibitors in treating MYC -amplified tumors. Using ML-792, we further explored the critical roles of SUMOylation in mitotic progression and chromosome segregation. Furthermore, expression of an SAE catalytic-subunit (UBA2) S95N M97T mutant rescued SUMOylation loss and the mitotic defect induced by ML-792, thus confirming the selectivity of ML-792. As a potent and selective SAE inhibitor, ML-792 provides rapid loss of endogenously SUMOylated proteins, thereby facilitating novel insights into SUMO biology.

SUMOylation is a post-translational ubiquitin-like protein modification pathway that regulates important cellular processes including chromosome structure, kinetochore function, chromosome segregation, nuclear and sub-nuclear organization, transcription and DNA damage repair. There is increasing evidence that the SUMO pathway is dysregulated in cancer, raising the possibility that modulation of this pathway may have therapeutic potential. To investigate the importance of the SUMO pathway in the context of cancer cell proliferation and tumor growth, we applied lentivirus-based short hairpin RNAs (shRNA) to knockdown SUMO pathway genes in human cancer cells. shRNAs for SAE2 and UBC9 reduced SUMO conjugation activity and inhibited proliferation of human cancer cells. To expand upon these observations, we generated doxycycline inducible conditional shRNA cell lines for SAE2 to achieve acute and reversible SAE2 knockdown. Conditional SAE2 knockdown in U2OS and HCT116 cells slowed cell growth in vitro, and SAE2 knockdown induced multiple terminal outcomes including apoptosis, endoreduplication and senescence. Multinucleated cells became senescent and stained positive for the senescence marker, SA-β Gal, and displayed elevated levels of p53 and p21. In an attempt to explain these phenotypes, we confirmed that loss of SUMO pathway activity leads to a loss of SUMOylated Topoisomerase IIα and the appearance of chromatin bridges which can impair proper cytokinesis and lead to multinucleation. Furthermore, knockdown of SAE2 induces disruption of PML nuclear bodies which may further promote apoptosis or senescence. In an in vivo HCT116 xenograft tumor model, conditional SAE2 knockdown strongly impaired tumor growth. These data demonstrate that the SUMO pathway is required for cancer cell proliferation in vitro and tumor growth in vivo, implicating the SUMO pathway as a potential cancer therapeutic target.

How Did Poetry Survive? traces the emergence of modern American poetry at the turn of the nineteenth century. American poetry had stalled: a small group of recently deceased New England poets still held sway, and few outlets existed for living poets. However, the United States' quickly accelerating urbanization in the early twentieth century opened new opportunities, as it allowed the rise of publications focused on promoting the work of living writers of all kinds. The urban scene also influenced the work of poets, shifting away from traditional subjects and forms to reflect the rise of buildings and the increasingly busy bustle of the city. Change was everywhere: new forms of architecture and transportation, new immigrants, new professions, new tastes, new worries. This urbanized world called for a new poetry, and a group of new magazines entirely or chiefly devoted to exploring modern themes and forms led the way. Avant-garde little magazines succeeded not by ignoring or rejecting the busy commercial world that surrounded them, but by adapting its technologies of production and strategies of marketing for their own purposes. With a particular focus on four literary magazines-- Poetry, The Masses, Others, and The Seven Arts --John Timberman Newcomb shows how each advanced ambitious agendas combining urban subjects, stylistic experimentation, and progressive social ideals. All four were profoundly affected by World War I, and the poetry on their pages responded to the war and its causes with clarity and strength. While subsequent literary history has favored the poets whose work made them distinct--individuals singled out usually on the basis of a novel technique--Newcomb provides a denser, richer view of the history that hundreds of poets made.

Despite significant progress in the treatment of multiple myeloma (MM), relapsed/refractory patients urgently require more effective therapies. We here describe the discovery, mechanism of action, and preclinical anti‐MM activity of engineered toxin body MT‐0169, a next‐generation immunotoxin comprising a CD38‐specific antibody fragment linked to a de‐immunized Shiga‐like toxin A subunit (SLTA) payload. We show that specific binding of MT‐0169 to CD38 on MM cell lines triggers rapid internalization of SLTA, causing cell death via irreversible ribosome inhibition, protein synthesis blockade, and caspase 3/7 activation. In co‐culture experiments, bone marrow mesenchymal stromal cells did not induce drug resistance against MT‐0169. In the preclinical setting, MT‐0169 effectively lysed primary MM cells from newly diagnosed and heavily pretreated MM patients, including those refractory to daratumumab, with minimal toxicity against nonmalignant hematopoietic cells. MM cell lysis showed a significant correlation with their CD38 expression levels but not with cytogenetic risk, tumor load, or number of prior lines of therapy. Finally, MT‐0169 showed efficient in vivo anti‐MM activity in various mouse xenograft models, including one in which MM cells are grown in a humanized bone marrow‐like niche. These findings support clinical investigation of MT‐0169 in relapsed/refractory MM patients, including those refractory to CD38‐targeting immunotherapies.

American poets became modernist in the 1910s not merely by embracing a new set of formal techniques, but by immersing themselves in the milieu of the machine-age metropolis. Poetry's turn in subject matter has always been neglected because it contravenes the long-consensual view that modernism was defined by its repudiation of urban-industrial modernity. But one of the salient facts of early modernism is this: beginning suddenly around 1911, a vast range of American poets, whose predecessors had largely shunned modern subjects, took up the industrial city as a challenge, and an opportunity, to reimagine poetry's value for the twentieth century. Their willingness to engage with urban modernity may have been crucial to the very continuation of poetry in the United States.

THE invariant chain, which associates with the major histocompatibility complex (MHC) class II molecules in the endoplasmic reticulum, serves two functions important in antigen processing. First, it prevents class II molecules from binding peptides in the early stages of intracellular transport 1–3 . Second, it contains a cytoplasmic signal that targets the class II-invariant chain complex to an acidic endosomal compartment 4–6 . Proteolytic cleavage and subsequent dissociation of the invariant chain then occurs 7,8 , allowing peptides derived from endocytosed proteins to bind to released class II molecules before their expression at the cell surface 3 . Certain human cell lines that are mutant in one or more MHC-linked genes are defective in class II-restricted antigen processing 9–11 . Here we show that in transfectants of one of these cell lines, T2, this deficiency results in the association of a large proportion of class II molecules with a nested set of invariant-chain-derived peptides (class II-associated invariant chain peptides, or CLIP). HLA-DR3 molecules isolated from T2 transfectants can be efficiently loaded with antigenic peptides by exposure to a low pH in vitro , perhaps reflecting the in vivo conditions in which peptides associate with class II molecules 12–14 . Addition of synthetic CLIP inhibits the loading process, indicating that CLIP may define the region of the invariant chain responsible for obstructing the class II binding site.

Victoria, BC, incorporated as a city in 1862, population 85,792 (2016c), 80,017 (2011c). The capital of British Columbia, the City of Victoria is situated on the southern tip of Vancouver Island, about 100 km south of Vancouver. Occupying a peninsular site, Victoria is bordered by the Juan de Fuca and Haro straits. In addition, the Olympic Mountains lie to the south, the San Juan Islands to the east, and the fjord-like Saanich Inlet and richly forested Malahat Ridge and Sooke Hills to the west. Greater Victoria lies within the Capital Regional District (CRD), a federation comprising the following incorporated areas: the cities of Victoria, Colwood and Langford; the towns of Sidney and View Royal; and the municipalities of Saanich, Oak Bay, Esquimalt, Central Saanich, North Saanich, Sooke, Metchosin and Highlands. The CRD also includes the electoral areas of Juan de Fuca, the Southern Gulf Islands and Saltspring Island.