Early sorting endosomes are responsible for the trafficking and function of transferrin receptor (TfR) and EGFR. These receptors play important roles in iron uptake and signaling and are critical for breast cancer development. However, the role of morphology, receptor composition, and signaling of early endosomes in breast cancer remains poorly understood. A novel population of enlarged early endosomes was identified in breast cancer cells and tumor xenografts but not in noncancerous MCF10A cells. Quantitative analysis of endosomal morphology, cargo sorting, EGFR activation, and Rab GTPase regulation was performed using super-resolution and confocal microscopy followed by 3D rendering. MDA-MB-231 breast cancer cells have fewer, but larger EEA1-positive early endosomes compared with MCF10A cells. Live-cell imaging indicated dysregulated cargo sorting, because EGF and Tf traffic together via enlarged endosomes in MDA-MB-231, but not in MCF10A. Large EEA1-positive MDA-MB-231 endosomes exhibited prolonged and increased EGF-induced activation of EGFR upon phosphorylation at tyrosine-1068 (EGFR-p1068). Rab4A overexpression in MCF10A cells produced EEA1-positive enlarged endosomes that displayed prolonged and amplified EGF-induced EGFR-p1068 activation. Knockdown of Rab4A lead to increased endosomal size in MCF10A, but not in MDA-MB-231 cells. Nevertheless, Rab4A knockdown resulted in enhanced EGF-induced activation of EGFR-p1068 in MDA-MB-231 as well as downstream signaling in MCF10A cells. Altogether, this extensive characterization of early endosomes in breast cancer cells has identified a Rab4-modulated enlarged early endosomal compartment as the site of prolonged and increased EGFR activation.

Approximately 40% of patients with diabetic macular edema (DME) are resistant to anti–vascular endothelial growth factor (VEGF) therapy (rDME). Here, we demonstrate that significant correlations between inflammatory cytokines and VEGF, as observed in naive DME, are lost in patients with rDME. VEGF overexpression in the mouse retina caused delayed inflammatory cytokine upregulation, monocyte/macrophage infiltration (CD11b⁺ Ly6C⁺ CCR2⁺ cells), macrophage/microglia activation (CD11b⁺ CD80⁺ cells), and blood-retinal barrier disruption due to claudin-5 redistribution, which did not recover with VEGF blockade alone. Phosphorylated protein analysis of VEGF-overexpressed retinas revealed rho-associated coiled-coil–containing protein kinase (ROCK) activation. Administration of ripasudil, a selective ROCK inhibitor, attenuated retinal inflammation and claudin-5 redistribution. Ripasudil also contributed to the stability of claudin-5 expression by both transcriptional enhancement and degradation suppression in inflammatory cytokine–stimulated endothelium. Notably, the anti-VEGF agent and the ROCK inhibitor were synergic in suppressing cytokine upregulation, monocyte/macrophage infiltration, macrophage/microglia activation, and claudin-5 redistribution. Furthermore, in vitro analysis confirmed that claudin-5 redistribution depends on ROCK2 but not on ROCK1. This synergistic effect was also confirmed in human rDME cases. Our results suggest that ROCK-mediated claudin-5 redistribution by inflammation is a key mechanism in the anti-VEGF resistance of DME.

Purpose:

Currently, an optimal therapeutic strategy comprising molecularly targeted agents for treating EGFR-mutated non–small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib is not available. Therefore, the initial therapeutic intervention is crucial for the prolonged survival of these patients. The activation of anexelekto (AXL) signaling is known to be associated with intrinsic and acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). In this study, we investigated the best therapeutic strategy to combat AXL-induced tolerance to EGFR-TKIs using the novel AXL inhibitor ONO-7475.

The MaMTH-DS assay detected inhibitors of mutant EGFR in non–small cell lung cancer cells.

Roy Horn, half of the iconic magician duo Siegfried and Roy, has died from complications of the new coronavirus in Las Vegas. He was 75.

Together with Siegfried Fischbacher, Horn, born Uwe Ludwig Horn, created one of the most widely known magic acts in the world, staging shows filled with sleights of hand and exotic animals for packed audiences in Las Vegas for more than a decade. At its height, the glitzy show grossed $45 million per year, according to The Hollywood Reporter, among the highest ever in Las Vegas.

“Today, the world has lost one of the greats of magic, but I have lost my best friend,” Fischbacher said in a statement. “There could be no Siegfried without Roy, no Roy without Siegfried.” Fischbacher thanked the doctors and nurses who cared for his friend.

Read more at The Daily Beast.

“Today, the world has lost one of the greats of magic, but I have lost my best friend,” Siegfried Fischbacher said in a statement.

Half of the legendary Las Vegas magic duo died on Friday following complications from COVID-19.

The magician survived an attack by a 380-pound tiger, who bit his neck during a show at the Mirage Las Vegas in 2003.

Magician Roy Horn, who alongside Siegfried Fischbacher starred in a popular, long-running Las Vegas act built around rare tigers, died on Friday from of complications of COVID-19, the Las Vegas Review-Journal newspaper reported. He was 75.

'Today, the world has lost one of the greats of magic, but I have lost my best friend,' Siegfried Fischbacher said in a statement

Roy Uwe Ludwig Horn, whose collaboration with Siegfried Fischbacher created the well-known animal training and magic duo Siegfried & Roy, died of complications from COVID-19 Friday in Las Vegas. He was 75. Horn had revealed on April 28 that he had tested positive for coronavirus. “Today, the world has lost one of the greats of […]

Roy Horn of the famous Siegrfried & Roy duo has died at the age of 75 from complications caused by the coronavirus. According to a press release, the legendary performer succumbed to...

'Roy was a fighter his whole life including during these final days,' his partner Siegfried Fischbacher said

Roy Horn of the famous Siegrfried & Roy duo has died at the age of 75 from complications caused by the coronavirus. According to a press release, the legendary performer succumbed to...

Roy Horn, who thrilled Las Vegas crowds as part of the big-cats-and-magic act Siegfried & Roy until a tiger attack ended his career in 2003, died today of coronavirus at Mountain View Hospital in Las Vegas. He was 75. Horn’s publicist said on April 28 that the magician had tested positive for COVID-19. “Today, the […]

Roy Horn of Siegfried & Roy, the duo whose extraordinary magic tricks astonished millions until Horn was critically injured in 2003 by one of the act's famed white tigers, has died. He was 75.

Roy Horn of the famous Siegrfried & Roy duo has died at the age of 75 from complications caused by the coronavirus. According to a press release, the legendary performer succumbed to...

Magician Roy Horn, best known as part of the Las Vegas performing duo of Siegfried & Roy, has died at the age of 75 after contracting coronavirus.

Roy Horn, one half of the famous Siegfried & Roy magic and entertainment act in Las Vegas, is dead after being infected with the coronavirus ... TMZ has learned. We just got a statement from Siegfried, who told us, "Today, the world has lost…

US-based drugmaker Mylan and partner India-based biologicals specialist Biocon have announced the launch of their pegfilgrastim biosimilar, Fulphila, in Australia. The drug can be used to treat neutropenia (a lack of white blood cells) in cancer patients.

US-based drugmaker Mylan and partner, India-based biologicals specialist Biocon, announced on 28 April 2020 the launch of their pegfilgrastim biosimilar, Fulphila, in Canada. This is the second biosimilar from the pair to be launched in the country.

Roy Horn, the dark-haired half of Siegfried & Roy, raised the white tigers and other animals in the duo's extravagant shows that were one of the biggest draws on the Las Vegas Strip.

Zebrafish studies suggest VEGFR inhibitors could help treat tuberculosis.

Tumor cell and mouse studies suggest tetravalent antibodies that target four different antigens could help treat cancers resistant to HER-targeted therapies.

Roy Horn met Siegfried Fischbacher on a cruise ship.

Horn was famed for introducing a pet cheetah to the magic show and was mauled on stage by a tiger in 2003

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Roy Horn of Siegfried & Roy, the duo whose extraordinary magic tricks astonished millions until Horn was critically injured in 2003 by one of the act’s famed white tigers, has died from coronavirus complications. He was 75.

Horn died of on Friday in a Las Vegas hospital, according to a statement released by his publicist Dave Kirvin.

Legendary magician Roy Horn has died. He was 75. Horn,one half of the longtime Las Vegas illusionist duo Siegfried & Roy, had tested positive for COVID-19.

Roy Horn, one half of the Las Vegas magic duo Siegfried & Roy, has died aged 75 due to coronavirus complications.Horn's publicist Dave Kirvin confirmed that he died in a Las Vegas hospital on Friday after testing positive for the coronavirus last week."Today, the world has lost one of the greats of magic, but I have lost my best friend," read a statement from Siegfried Fischbacher.Visit Insider's homepage for more stories.Roy Horn of the iconic Siegfried & Roy magic duo has died aged 75 from complications related to the coronavirus.The legendary magician died at Mountain View Hospital in Las Vegas on Friday, his publicist Dave Kirvin confirmed. He added that Horn had tested positive for the coronavirus last week, according to the New York Times.The German-born double act, Horn and Siegfried

Roy Horn, half of Las Vegas illusionist duo Siegfried and Roy, died Friday of complications from the coronavirus. He was 75.Known for his work with big cats,...

Legendary magician Roy Horn has died. He was 75. Horn,one half of the longtime Las Vegas illusionist duo Siegfried & Roy, had tested positive for COVID-19.

Roy Horn of Siegfried & Roy, the duo whose extraordinary magic tricks astonished millions until Horn was critically injured in 2003 by one of the act's famed white tigers, has died. He was 75. Horn died of complications from the coronavirus on Friday in a Las Vegas hospital, according to a statement released by publicist Dave Kirvin. Today, the world has lost one of the greats of magic, but I have lost my best friend, Siegfried Fischbacher said in the statement. From the moment we met, I knew Roy and I, together, would change the world. There could be no Siegfried without Roy, and no Roy without Siegfried. He was injured in October 2003 when a tiger named Montecore attacked him on stage at the Mirage hotel-casino in Las Vegas. He had severe neck injuries, lost a lot of blood and later suffered a stroke. He underwent lengthy rehabilitation, but the attack ended the long-running Las Vegas Strip production. The darker-haired of the flashy duo, Horn was credited with the idea of ...

Magician Roy Horn, who alongside Siegfried Fischbacher starred in a popular, long-running Las Vegas act built around rare tigers, died on Friday from of complications of COVID-19, the Las Vegas Review-Journal newspaper reported. He was 75.

Magician Roy Horn, who alongside Siegfried Fischbacher starred in a popular, long-running Las Vegas act built around rare tigers, died on Friday from of complications of COVID-19, the Las Vegas Review-Journal newspaper reported. He was 75.

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