β-Catenin–induced melanoma growth requires the downstream target Microphthalmia-associated transcription factor

The transcription factor Microphthalmia-associated transcription factor (MITF) is a lineage-determination factor, which modulates melanocyte differentiation and pigmentation. MITF was recently shown to reside downstream of the canonical Wnt pathway during melanocyte differentiation from pluripotent neural crest cells in zebrafish as well as in mammalian melanocyte lineage cells. Although expression of many melanocytic/pigmentation markers is lost in human melanoma, MITF expression remains intact, even in unpigmented tumors, suggesting a role for MITF beyond its role in differentiation. A significant fraction of primary human melanomas exhibit deregulation (via aberrant nuclear accumulation) of β-catenin, leading us to examine its role in melanoma growth and survival. Here, we show that β-catenin is a potent mediator of growth for melanoma cells in a manner dependent on its downstream target MITF. Moreover, suppression of melanoma clonogenic growth by disruption of β-catenin–T-cell transcription factor/LEF is rescued by constitutive MITF. This rescue occurs largely through a prosurvival mechanism. Thus, β-catenin regulation of MITF expression represents a tissue-restricted pathway that significantly influences the growth and survival behavior of this notoriously treatment-resistant neoplasm

The Lantern Vol. 40, No. 2, Spring 1974

• Response • Roads • Ghost Dance • Natator • Make Believe • An English Sonnet • A Cinquain • Icarus • Alchemy • Pain • Love • Scramblen\u27 Zone • In the Gathering Wind • The Circus • Streams • The Showdown on the Corner of Main Street and Koscuisko Drive!!! • Fandango • Ode to an Orange Orangutan • Nauseahttps://digitalcommons.ursinus.edu/lantern/1104/thumbnail.jp

The Ursinus Weekly, May 22, 1975

Dr. Cope accepts history post at U. of Nebraska • Questionnaire summarized • UC faculty hears speaker from AAUP • U.C. Plans for Bicentennial • From the cluttered desk of the U.S.G.A. president • George Bause wins Scotland scholarship • Editorial: Last moments • Focus: Ms. Swanson • Wolsey Hall: British study • Alvarez attends seminar • Changes at library: Dr. Yost resigns post • Letters to the editor: Pets • Alumni elects • Intramural golf winners • Senior comments: Geoffery Higgins • Commencement • Earns degree • From the president • Cub and Key elects • Senior Spotlight: Dave McNamara • Reflections • Spring festival review • Study center success • New professors appointed • Ursinus bear squad • Volunteers needed at Pennhurst • Mulch queen contest • Concert review: Jesse Colin Young • Miller chosen • Dick Allen returns • Lacrosse wins 2 • Women\u27s tennis given team honors • Baseball: Season ends wrap-up • New results • Golf wins seven • Faculty-student net tournament • Intramural winnershttps://digitalcommons.ursinus.edu/weekly/1039/thumbnail.jp

The Ursinus Weekly, May 22, 1975

Dr. Cope accepts history post at U. of Nebraska • Questionnaire summarized • UC faculty hears speaker from AAUP • U.C. Plans for Bicentennial • From the cluttered desk of the U.S.G.A. president • George Bause wins Scotland scholarship • Editorial: Last moments • Focus: Ms. Swanson • Wolsey Hall: British study • Alvarez attends seminar • Changes at library: Dr. Yost resigns post • Letters to the editor: Pets • Alumni elects • Intramural golf winners • Senior comments: Geoffery Higgins • Commencement • Earns degree • From the president • Cub and Key elects • Senior Spotlight: Dave McNamara • Reflections • Spring festival review • Study center success • New professors appointed • Ursinus bear squad • Volunteers needed at Pennhurst • Mulch queen contest • Concert review: Jesse Colin Young • Miller chosen • Dick Allen returns • Lacrosse wins 2 • Women\u27s tennis given team honors • Baseball: Season ends wrap-up • New results • Golf wins seven • Faculty-student net tournament • Intramural winnershttps://digitalcommons.ursinus.edu/weekly/1039/thumbnail.jp

Targeting FLT3 in primary MLL-gene-rearranged infant acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) in infants is characterized by rearrangements of the mixed lineage leukemia (MLL) gene, drug resistance, and a poor treatment outcome. Therefore, novel therapeutic strategies are needed to improve prognosis. Recently, we showed that FLT3 is highly expressed in MLL rearranged ALL (MLL). Here we demonstrate FLT3 expression in infants with MLL (n = 41) to be significantly higher compared to both infant (n = 8; P < .001) and noninfant patients with ALL (n = 23; P = .001) carrying germline MLL genes. Furthermore, leukemic cells from infants with MLL were significantly more sensitive to the Fms-like tyrosine kinase 3 (FLT3) inhibitor PKC412 (N-benzoyl staurosporine) than noninfant ALL cells, and at least as sensitive as internal tandem duplication-positive (ITD+) AML cells. Surprisingly, activation loop mutations only occurred in about 3% (1 of 36) of the cases and no FLT3/ITDs were observed. However, measuring FLT3 phosphorylation in infants with MLL expressing varying levels of wild-type FLT3 revealed that high-level FLT3 expression is associated with ligand-independent FLT3 activation. This suggests that infant MLL cells displaying activated FLT3 as a result of overexpression can be targeted by FLT3 inhibitors such as PKC412. However, at concentrations of PKC412 minimall

Державне регулювання системи факторів оцінки та мінімізації ризиків легалізації коштів, одержаних злочинним шляхом в процесі фінансового моніторингу комерційних банків України

Основною ціллю данної статті є формулювання важливості впливу чітко визначених факторів, які впливають на процеси фінансового моніторингу в комерційних банків України. Виходячи з поставлених цілей, завданнями даної статті є розроблення моделі оцінки ризиків банківської установи щодо протидії легалізації коштів одержаних злочинним шляхом в системі внутрішньобанківського фінансового моніторингу, та використання в подальшому запропонованих стратегій управління наслідками даних ризиків

Cosmochemical and spectroscopic properties of Northwest Africa 7325 - A consortium study

This work is part of a project to build an infrared database in order to link IR data of planetary materials (and therefore possible Mercury material) with remote sensing observations of Mercury, which will probably be obtained by the MERTIS instrument on the forthcoming BepiColombo mission.The unique achondrite Northwest Africa (NWA) 7325, which has previously been suggested to represent the first sample from Mercury, was investigated by optical and electron microscopy, and infrared and Raman spectroscopy. In addition, the oxygen, strontium, xenon, and argon isotopes were measured and the abundance of selected trace elements determined. The meteorite is a cumulate rock with subchondritic abundances of HFSE and REE and elevated Sr contents, which underwent a second heating and partial remelting process. Oxygen isotope measurements show that NWA 7325 plots in the ureilite field, close to the ALM-A trachyandesitic fragment found in the unique Almahata Sitta meteorite breccia. On the other hand, mineralogical investigations of the pyroxenes in NWA 7325 provide evidence for similarities to the lodranites and acapulcoites. Furthermore, the rock is weakly shocked and argon isotope data record ancient (~4.5 Ga) plateau ages that have not been reset. The sample records a cosmogenic exposure age of ~19 Ma. Systematics of Rb-Sr indicate an extreme early volatile depletion of the precursor material, similar to many other achondrite groups. However, despite its compositional similarities to other meteorite groups, our results suggest that this meteorite is unique and unrelated to any other known achondrite group. An origin for NWA 7325 as a sample from the planet Mercury is not supported by the results of our investigation. In particular, the evidence from infrared spectroscopy indicates that a direct relationship between NWA 7325 and the planet Mercury can be ruled out: no acceptable spectral match between laboratory analyses and remote sensing observations from Mercury has been obtained. However, we demonstrate that infrared spectroscopy is a rapid and nondestructive method to characterize mineral phases and thus an excellent tool for planetary surface characterization in space missions

Impact of Cerebral Microbleeds in Stroke Patients with Atrial Fibrillation

OBJECTIVES: Cerebral microbleeds are associated with the risks of ischemic stroke and intracranial hemorrhage, causing clinical dilemmas for antithrombotic treatment decisions. We aimed to evaluate the risks of intracranial hemorrhage and ischemic stroke associated with microbleeds in patients with atrial fibrillation treated with Vitamin K antagonists, direct oral anticoagulants, antiplatelets, and combination therapy (i.e. concurrent oral anticoagulant and antiplatelet) METHODS: We included patients with documented atrial fibrillation from the pooled individual patient data analysis by the Microbleeds International Collaborative Network. Risks of subsequent intracranial hemorrhage and ischemic stroke were compared between patients with and without microbleeds, stratified by antithrombotic use. RESULTS: A total of 7,839 patients were included. The presence of microbleeds was associated with an increased relative risk of intracranial hemorrhage (aHR 2.74, 95% confidence interval 1.76 - 4.26) and ischemic stroke (aHR 1.29, 95% confidence interval 1.04 - 1.59). For the entire cohort, the absolute incidence of ischemic stroke was higher than intracranial hemorrhage regardless of microbleeds burden. However, for the subgroup of patients taking combination of anticoagulant and antiplatelet therapy, the absolute risk of intracranial hemorrhage exceeded that of ischemic stroke in those with 2-4 microbleeds (25 vs 12 per 1,000 patient-years) and ≥11 microbleeds (94 vs 48 per 1,000 patient-years). INTERPRETATION: Patients with atrial fibrillation and high burden of microbleeds receiving combination therapy have a tendency of higher rate of intracranial hemorrhage than ischemic stroke, with potential for net harm. Further studies are needed to help optimize stroke preventive strategies in this high-risk group. This article is protected by copyright. All rights reserved

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery