Oct 02 2012

obs overview  - Activators Patch

LGS obs. Issue /12/04 Update for P81, Phase 2; keyword II SINFONI: a detailed description of the instrument. 7 General description. Introduction to Global IT Asset Inventory API Paradigm - Get tips on using the Curl Asset Inventory asset identification updates. Just demonstrating how to use travelafter.us with OBS v25 on macOS. This requires the use of the Electron Capture app and the Blackhole (or.

You can watch a thematic video

(NEW VIDEO IN DESCRIPTION) How to Connect Zoom \u0026 OBS - The Right Way!


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PipeWire is a new low-level multimedia framework. It aims to offer capture and playback for both audio and video with minimal latency and support for PulseAudio, JACK, ALSA and GStreamer-based applications.

The daemon based on the framework can be configured to be both an audio server (with PulseAudio and JACK features) and a video capture server.

PipeWire also supports containers like Flatpak and does not rely on audio and videouser groups. Instead, it uses a Polkit-like security model, asking Flatpak or Wayland for permission to record screen or audio.


Install the pipewire package from the official repositories.

Pipewire uses systemd/User for management of the server and automatic socket activation.

Optionally, install pipewire-docs to review the documentation. Other packages, such as pipewire-alsa, pipewire-pulse, and pipewire-jack are normally not needed unless one wants to use PipeWire as a PulseAudio/JACK replacement. Also available are libpipewire and libpipewire-jack for multilib support.


  • Helvum &#; GTK-based patchbay for pipewire, inspired by the JACK tool catia.

StreamFX (for OBS® Studio) a8

It's finally time for the long awaited full and final release of StreamFX ! As the new baseline version for future updates and improvements, brings with it a lot of fixes, performance improvements, and even some new additions!

Support the StreamFX project!
If you rely on StreamFX for your streaming and recording needs and want StreamFX to continue existing, consider supporting me on Patreonor on Github Sponsors! Even a support as low as one dollar per month means a lot and helps keep the project afloat, and if every single user of the plugin was supporting me with just one dollar per month I could spend a lot more time working on the project than I do now. So what are you waiting for?

Help & Support
Before installing this plugin, please make sure to read the Installation Guidewhich includes the necessary prerequisites for succesfully getting StreamFX to run. If it still does not work, consider joining the official Discord.

Notable Changes (since )
Support for bit has been stopped!
With a1 I stopped officially supporting the use of the bit plugin and OBS Studio, and with this release it is now set in stone. If you are still stuck on bit, you will have to stick with older versions of the plugin, but the majority of you should already have a bit capable system and should be using the bit version of OBS Studio.

FFmpeg Encoders are now part of StreamFX
Yes, that's right: my old ffmpeg-encoders plugin is now fully merged into StreamFX. This is to reduce my effective work load in supporting two code bases with the same fixes, instead of just applying them to one. This also has the additional benefit that I can use any of the helper classes of StreamFX in the FFmpeg Encoders to improve their quality and UI/UX.

Custom Shaders are here!
With a3 custom shaders were introduced, and they are now here to stay. This release marks the first stable release of the Shaders, which can be added as a Source, Filter or Transition! They are incredibly powerful, and will recieve many new abilities later on into development. Just take a look at the page on the wikito see what they can do.

Keep your face in the frame with the NVIDIA Face Tracking filter!
Thanks to NVIDIA you now have a way to bypass all the annoying work of manually cropping your camera to fit in the travelafter.us add the filter, and it will take care of tracking the region that should be kept in the frame, so that you can focus on your content! (Requires an NVIDIA RTX GPU to be present and in use by OBS Studio.)

Added a new UI integration for StreamFX!
You can now find a new StreamFX menu in OBS Studio if you've installed it correctly. It contains many useful links, including links to the community and direct links to reporting issues, as well as the new 'About StreamFX' window. The 'About StreamFX' window shows all the people that have contributed towards the development, and contains information about the version of the plugin you are currently using.

Performance Improvements
There has been work to increase the effective performance of StreamFX through the use of more modern coding ways, including some compiler optimizations. These improvements should lead to a 10% reduction in CPU and GPU usage, more if you're using a Laptop or mobile APU.


  • Fixed a crash on closing OBS Studio caused by an Audio-enabled Source Mirror.
  • Fixed a possible scheduler collision between NVENC and NVIDIA Face Tracking causing sub-par performance.
  • Fixed Transition Shaders not getting their parameters in the correct order, causing some parameters to have no data.
  • Fixed a crash caused by FFmpeg encoders with no supported pixel formats.
  • Fixed incorrect colors when OBS is set to record sRGB content.
  • Fixed cases autodesk 2020 xforce keygen free download - Free Activators which the configuration file for StreamFX would not save and reset every time.
  • Fixed a flickering bug causing the 'About StreamFX' window to appear all the time or not appear at all.
  • Fixed support for the AppleClang compiler.
  • Fixed an uncommon out-of-order-lock freeze triggered by Source Mirror.
  • Fixed support for Boolean values in Shaders.
  • Improved performance of Shaders drastically by reusing existing memory and some additional compiler optimizations.
  • Improved tracking quality in NVIDIA Face Tracking by moving part of the update logic into the per-frame update instead of the per-track update.
  • Improved overall performance slightly by reusing existing memory.
  • Moved the StreamFX menu out of the 'Tools' menu into the main menu.
  • Added the new 'Thank You' images to the 'About StreamFX' window.
  • Added support for enumerations (int, float) to Shaders.
  • Added support for value suffixes to Shaders.
  • Added the currently used StreamFX version to the 'About StreamFX' window.
  • Fixed Linux being unable to load the plugin due to a missing Qt symbol.
  • Fixed vertex buffers not being initialized to 0, causing some effects to not render.
  • Fixed mip-mapping causing Browser Sources to render corrupted.
  • Fixed Dual-Filtering Blur causing excessive GPU usage due to miscalculated render target sizes, which also fixes Dual-Filtering looking weird.
  • Fixed the "Adaptive I-Frames" option being inverted in the NVENC FFmpeg Encoders.
  • Fixed that "Adaptive B-Frames" is not actually being applied in the NVENC FFmpeg Encoders.
  • Improved the performance of various rendering steps by using a single fullscreen tri instead of a quad (See #). The effects should be immediately noticable with mip-mapping and some of the Blur effects.
  • Added optional performance profiling which by default is not compiled in. Developers can choose to build StreamFX with it if they wish to check for possible optimizations.
  • Removed any currently broken shader examples.
  • (Hotfix 2) Actually fixed Shaders losing the ability to render transparency.
  • (Hotfix 1) Fixed Shaders losing the ability to render transparency.
  • Updated the StreamFX logo.
  • Updated translations from Crowdin again.
  • Updated help strings for Dynamic Mask and Blur.
  • Fixed the 'travelafter.us' example shader and added even worse options to it.
  • Fixed Shaders rendering larger or smaller than the specified size.
  • Fixed Shaders rendering once for each time they are drawn per tick instead of only once per tick.
  • Fixed Direct3D11 evicting important textures before encoders had a chance to work with them in high GPU usage situations.
  • Fixed "Look Ahead", "Adaptive I-Frames" and "Adaptive B-Frames" not being applied as expected.
  • Improved the performance of the Nvidia Face Tracking filter massively by moving almost all of it into worker threads.
  • Added a default path to the Shader file selection dialog.
  • Added various ShaderToy shaders (shadertoy-#####.effect) and a new travelafter.us which was used for the StreamFX logo.
  • Added an entry into the OBS Studio tools menu which links to important things such as where to get help and where to report bugs.
  • Added an "About StreamFX" window to thank all supporters, translators and contributors. This window opens once automatically when a new version of the plugin is installed, and otherwise is accessible via Tools -> StreamFX -> About StreamFX.
  • Updated translations from Crowdin, huge thanks to everyone submitting translations!
  • Fixed FFmpeg Encoders not respecting user selected color formats and instead always using YUV (#)
  • Fixed FFmpeg ProRes not correctly overriding color formats with the ones supported by the selected profile. (#, )
  • Fixed a lot of code issues by actually jumping ship to modern C++.
  • Fixed some sources not tagging the settings object with the current version, making migrating settings problematic.
  • Removed the lib prefix from the travelafter.us files on Linux. Make sure obs overview - Activators Patch delete the old version of the plugin first if you're using Linux!
  • Updated support for libOBS v and newer.
  • Added support for Ubuntu andtake a look at the platform parity wiki page to see what is missing.
  • Fixed potential memory corruption caused by FFmpeg Encoders.
  • Fixed a regression introduced in which causes 3D Transforms to suddenly invert. (#)
  • Added Custom Shader Filters, Sources and Transitions - and also added extra examples for them.
  • Added Nvidia Face Tracking filter which will be available at a later point in time.
  • Updated translations from Crowdin, many thanks to all the volunteer translators!
  • Updated support for libOBS v and newer.
  • Fixed 3D Transform causing discoloration in transparent sources. (#)
  • Fixed audio jitters caused by audio mirroring in Source Mirror happening out of order. (#)
  • Fixed a common freeze new to libOBS v25 caused by Source Mirror.
  • Fixed audio mirroring only working every second configuration update in Source Mirror.
  • Added FFmpeg Encoders which expose various encoders available in FFmpeg to you with a neat, easy to use UI (if you can read tooltips). You will find them available under either Streaming or Notezilla 8.0.33 Crack With Working Serial Key Free Download, depending on the codec you want to encode. This integration is slightly different from the one in obs-ffmpeg-encoder, so the two plugins will clash and you should remove obs-ffmpeg-encoder ahead of time using its uninstaller entry.
  • Improved Custom Shaders further, however these are still very experimental. Expect these to crash, corrupt or otherwise eat your setup in unexpected ways, and also expect these to change wildly.
  • Improved Audio Mirroring in Source Mirror by relying on a global thread pool instead of a thread per source, drastically reducing the total CPU load in massive setups.
  • Removed scaling from Source Mirror which was mostly broken anyway, so please use any of the available filters instead.
  • Fixed a possible crash in multi-core systems caused by event callbacks.
  • Fixed various crashes and corruptions caused by Source Mirror, Dynamic Mask and Blur.
  • Important: The plugin was renamed to StreamFX, users that manually installed this plugin (or manually built it) must ensure that the old obs-stream-effects files are removed before installing the new version.
  • Deprecated Bit versions of the plugin. You don't have an excuse to be on bit anymore, hardware has gotten dirt cheap thanks to AMD Ryzen. You can get a barebone modern PC for around €, or upgrade your existing one for around €.
  • Added additional options for Tint control to Color Grade, allowing fine tuning of what is Shadow, Midtone and Highlight.
  • Added GPU debug markers to most of the code which allow GPU debuggers like NVIDIA Nsight to show the exact time taken for each effect step.
  • Added a new example shader: Plasma. This effect simulates old school plasma effects and showcases some of the features of Custom Shaders.
  • Added a temporary workaround for a bug in OBS Studio to ensure that StreamFX does not crash or corrupt OBS Studio's memory. A fix to OBS Studio has already been submitted and is waiting on Review.
  • Updated translations from Crowdin: de-DE, es-Es, fr-FR, it-IT, ja-JP, nl-NL, pl-PL, ru-RU, sv-SE, zh-CN. Much thanks to all the contributors on Crowdin!
  • Improved Custom Shader Sources by adding support for automated file reloading, dynamic parameter updates, and various UI improvements.
  • Improved stability drastically by gracefully handling all unexpected exceptions and refactoring a lot of code.
  • Improved performance drastically by no longer always caching sources and ensuring that some code hotspots don't duplicate heap data on call.
  • Moved all examples from data/ to data/examples/.
  • Fixed a few crashes caused by the Graphics Subsystem Wrapper (GSW).
  • Fixed a freeze with Source Mirror when retrieving the size of a mirrored Source.
  • Fixed rescaling size in Source Mirror when "Use Original Size for Transform" is active.
  • Fixed filters messing with source sizes when they shouldn't be.
  • Fixed a freeze caused by Directional Gaussian Blur (#83, #85).
  • Removed Custom Shader Filters temporarily, they will return later.
  • Removed AppVeyor Continuous Integration in favor of GitHub Actions. You can now download bleeding edge builds from here obs overview - Activators Patch clicking on the commit, then clicking on Artifacts, and then selecting either windows (Windows 7) or windows (Windows 10 or up to date Windows 7).
Источник: travelafter.us%C2%AE-studio/updates?page=3
Neon question mark signs

All Windows 10 PCs have &#;Game Mode&#; enabled by default. Microsoft once touted this feature, but it&#;s now faded into the background. Bizarrely, some people report that disabling Game Mode boosts the performance of certain PC games!

What Does &#;Game Mode&#; Do on Windows 10?

First introduced in Windows 10&#;s Creators Update, which was released back in April&#;Game Mode&#; promises to boost the performance of many PC games.

Here&#;s the official description: Microsoft says that Game Mode &#;helps achieve a more stable frame rate depending on the specific game and system.&#;

Technically, it works by detecting games and giving them priority access to your computer&#;s resources. The game you&#;re focused on playing gets more CPU and GPU resources, while obs overview - Activators Patch applications and background processes get fewer resources. This only works Filmora Scrn License email Windows 10 detects that you&#;re playing a game.

Microsoft&#;s limited explanation of Game Mode also says that, in Game Mode, Windows Update won&#;t automatically install hardware drivers or notify you to restart your PC while you&#;re playing a game. This will reduce interruptions.

Does Game Mode Boost Performance?

The Performance widget window in Windows 10's Xbox Game Bar

Game Mode might boost your PC&#;s gaming performance, or it might not. Depending on the game, your PC&#;s hardware, and what you have running in the background, you may not see any difference.

You&#;ll see the greatest increase in gaming performance when a game is competing for resources with other running programs on your PC. If your PC has plenty of CPU and GPU resources to go around, Game Mode likely won&#;t do much.

A test from PC Gamer found that Game Mode boosted game performance a bit on low-end hardware. However, that came at the expense of background tasks&#;with Game Mode enabled, it wasn&#;t possible to play a YouTube video in the background while gaming without the video playback stuttering. It&#;s a trade-off&#;while gaming, resources are taken from background tasks and given to the game.

Why Is It on By Default?

Game Mode attempts to automatically detect when you&#;re playing a game, and it only takes action if Windows thinks you are. So, if you use web browsers and office software all day, Game Mode doesn&#;t do anything at all.

When you launch a game, however, Windows 10&#;s Game Mode takes effect and prioritizes that game over everything else on your PC. So why wouldn&#;t Game Mode be enabled by default? It doesn&#;t do anything unless Windows thinks you&#;re running a game.

Game Mode Can Sometimes Cause Problems

Some Windows users have reported that some games actually perform more slowly with Game Mode enabled. It sounds strange, and it certainly shouldn&#;t work this way&#;but it sometimes does.

For example, in MayGuru 3D wrote about reports of Game Mode leading to stutters and frozen screens with both NVIDIA and AMD graphics hardware.

Why could this happen? Well, all we have is speculation. However, in allocating more hardware resources to a PC game and deprioritizing background tasks, Game Mode could theoretically take resources away from important background tasks, causing system stutters or slowing the game itself down. Or perhaps there are just strange bugs in Game Mode with specific games or graphics drivers. Windows is very complicated.

Either way, if you encounter strange problems&#;stutters, freezes, crashes, or all-around low FPS&#;while playing a PC game, you might want to disable Game Mode and see if that solves your problem. It&#;s a useful troubleshooting step.

How to Enable and Disable Windows 10&#;s Game Mode

To control Game Mode, open the Settings window obs overview - Activators Patch the Start menu or by pressing Windows+i. Head to Settings > Gaming > Game Mode.

Here, you&#;ll find just a single setting: Game Mode, which you can turn on or off. By default, it&#;s on. If you&#;d like to disable Game Mode, just click the switch and set it to &#;Off.&#;

Game Mode settings on Windows 10

That&#;s it. In modern versions of Windows 10, there&#;s no way to manually enable or disable Game Mode for an individual game. In &#;s Creators Update, you could toggle Game Mode on or off for specific games in the Xbox Game Bar interface, but this option is now gone. As of Windows 10&#;s October Update, you won&#;t find it anywhere in the modern Xbox Game Bar.

All you can do is toggle Game Mode on or off system-wide. If Windows thinks that you&#;re playing a game, Windows will activate Game Mode&#;s tweaks. If Windows doesn&#;t detect that you&#;re playing a game, there&#;s no way to manually enable it.

Don&#;t worry, though: Even if Windows doesn&#;t notice that you&#;re playing a game and doesn&#;t activate Game Mode, you&#;re probably not missing out on much.

RELATED:6 Great Features in Windows 10's New Game Bar

Источник: travelafter.us

A highlight on Sonic hedgehog pathway

Hedgehog (Hh) is one of few of signaling pathways that is frequently used during development for intercellular communication. Hh is important for the organogenesis of almost all organs in mammals, as well as in regeneration and homeostasis. Further, Hh signaling is disrupted in diverse types of cancer [1, 2]. The vertebrate Hh signaling is not entirely dependent on an extremely specialized organelle, the primary cilium (PC), unlike other essential developmental signaling pathways. The PC is an organelle, microtubule-based, that emerges from the cell surface of most vertebrate cells. This organelle is important to process several cellular signals and/or extracellular environmental changes necessary for animal development, as Wingless (Wnt), Platelet-derived growth factor (PDGF), Shh, and Notch [3].

There are three mammalian Hh proteins, Shh, Indian-Hedgehog (Ihh), and Desert-Hedgehog (Dhh). Shh and Ihh have important, and sometimes coinciding, functions in several tissues. Shh has particularly marked roles in nervous system cell type specification and limbs patterning, whereas Ihh has important roles in skeletal development, mainly endochondral ossification. Dhh is restricted to the gonads including granulosa cells of ovaries and sertoli cells of testis [4,5,6]. The best-studied function of Shh, during mouse embryogenesis, is to instruct neural progenitors patterning, in which it is possible to distinguish six different cell types based on molecular markers, such as interneurons progenitors and motor neurons, that differentiate due to a gradient of Shh [7, 8].

Several evidences demonstrate that embryogenesis and tumorigenesis have common characteristics, where both processes depend on coordinated mechanisms of proliferation, differentiation and migration [9]. Vital signaling pathways for embryonic development and organogenesis are modulated in tumorigenesis. Aberrant activation of Hh signaling has been shown to be associated with the formation of brain tumors, as well as its cross talking with other pathways like transforming growth factor beta (TGFßs), Wnt, Notch and Shh [10,11,12]. Moreover, several studies have investigated the role of Hh-Gli (Gli means glioma-associated oncogene homologue) signaling in cancer initiating stem cells (CSCs) and suggested that it regulates self-renewal and tumorigenic potential [13]. This review focused on updating the role of these molecules in brain tumorigenesis as well as suggesting new therapeutic strategies/clinical trials using the Shh pathway as a potential future treatment.

Shh signaling pathway components in tumorigenesis

The canonical pathway

Activation of Shh pathway can happen in two major ways: 1. canonical signaling: by ligand-dependent interaction or through receptor-induced signaling and 2. non-canonical signaling, when there’s a mechanism of activation downstream of smoothened (Smo) (Fig. 1) [14].

The Canonical activation of Shh pathway in vertebrates. The activation occurs by ligand-dependent interaction when Shh binds to Ptch at the cell membrane. In response to this binding, Ptch no longer inhibits Smo, which accumulates at the PC and initiates the downstream signaling pathway cascade. So, Smo regulates the Gli processing and activation at the PC. When Gli is activated, it translocates to the nucleus, where it activates target genes. (Diagram by Carballo, VC). (Adapted from Robbins et al., ) [54]

Full size image

The Shh canonical signaling occurs when the glycoprotein Shh binds and inactivates the transmembrane protein Patched (Ptch1). In the lack of the ligand Shh, the activity of the 7-transmembrane protein Smo is inhibited by Ptch1, so Shh protein binding Ptch1 regulates Smo activity [15, 16]. Smo is a GPCR-like (G protein–coupled receptor) protein, and the translocation into the cilia membrane is a requisite for Gli activation [3, 17]. In response to Shh signaling, Ptch1 inhibition of Smo at the PC is abolished, when Ptch1 is internalized and degraded [18]. So, after Ptch1 degradation, Smo accumulates at the PC where is activated and stabilized by initiating the Shh downstream signaling cascade [18]. This downstream signaling cascade results in the translocation of Gli family proteins to the nucleus that begins the transcription of target genes, including Ptch1 and Obs overview - Activators Patch, in a negative and positive feedback loop, respectively (Fig. 1) [14]. Furthermore, Gli translocation to the nucleus also induces protein modulation of Wnt and Noggin [16, 19, 20]. Patched 2 (Ptch2) is another receptor for Shh that shares approximately 54% homology with Ptch1. However, the expression and signaling of Ptch2 is different from Ptch1, having decreased ability to inhibit Smo in absence of Shh ligand [21].

The Gli1 gene was initially cloned as an amplified oncogene of a malignant glioma and then characterized as a transcription factor of the hedgehog signaling pathway [22, 23]. Three Gli proteins (Gli1, Gli2 and Gli3) are zinc-finger transcription factors and are expressed in vertebrates, f.lux 4.75 Activation Code - Crack Key For U overlapping and partially redundant domains. These three proteins are Shh-dependent, where only Gli1 occurs as a full-length transcriptional activator, while Gli2 and Gli3 act as either a negative or positive regulators (Gli2A - Gli2 activated or Gli2R - Gli2 repressor and Gli3A - Gli3 activated or Gli3R - Gli3 repressor, respectively) of the pathway which is determined by post-transcriptional and post-translational processing [24, 25]. Moreover, the change of Gli3A to Gli3R form is favored Abelssoft CheckDrive Free Download respect to Gli2. Consequently, Gli2 has mainly an activator transcriptional behavior, while Gli3 acts as a repressor [26]. It has already been demonstrated that Gli2 can accumulate in the primary cilium and controls transcriptional activation, in response to Shh ligand binding, overcoming thereby the negative regulation of Gli3 [27].

The Gli3 has also a very important function in regulating Shh signaling. Without Shh, Gli3 has a repressor form (Gli3R). When Shh binds to Ptch and activates Smo, Smo converts Gli3R into an activated form (Gli3A). So, Gli3 works as a transcriptional factor with a dual function. The ratio kms activator windows 7 Gli3R/Gli3A is directly related to the control of several processes during organogenesis, such as digit types and number [28, 29].

Shh signaling pathway can also be controlled by Supressor of Fused (SUFU) (Fig. 2) [30]. SUFU is a negative regulator of the Shh signaling pathway, acting on the Gli transcription factors. When Shh ligand is not present, SUFU binds directly the Gli proteins and inhibits their translocation to the nucleus, preventing the pathway activation [31]. However, the specific mechanisms concerning Gli inactivation by SUFU are not completely understood, but the full-length Gli proteins are converted to a C-terminal shorten repressor form: Gli-R. This truncated form of Glis is then partially degraded after subsequent phosphorylation by glycogen synthase kinase 3 beta (GSK3β), casein kinase I (CK1) and protein kinase A (PKA) [26]. Gli proteins retained at the cytoplasm by SUFU are then degraded or processed and thereby inhibiting Shh signaling [32]. When Gli-R moves to the nucleus, it represses SHH target genes including Ptch1 and Gli1 itself. When Shh pathway is activated, it is necessary that SUFU inhibition of Glis occurs by hyper-phosphorilation of SUFU [33]. Therefore, it has been previously demonstrated that several protein kinases, such as PKA and protein kinase C (PKC), CK1, mitogen activated protein kinase kinase (Mek1), GSK3, Phosphoinositide-3 kinase (PI3K), or dual specificity Yak1-related kinase (DYRK1) can modulate this pathway at several levels [33,34,35,36,37,38,39] (Fig. 2). This mechanism of regulation of the Shh pathway by ubiquitination-related posttranslational modifications of the Gli transcription factors leads to massive protein degradation or a proteasome-dependent proteolytic cleavage [40]. This process was first identified in Drosophila, but it was also demonstrated in vertebrates [41]. It is important to note that mutations in Ptch and SUFU, which are the negative regulators of Shh signaling, are linked to tumorigenesis, although the exact mechanism is unknown [42]. It was demonstrated in knockout mice, that the loss of SUFU is enough to activate the pathway without the support of the receptors [43, 44]. This constitutive Shh signaling activation in medulloblastoma (MB) is not sufficient to induce tumorigenesis, because a second ARES Commander 2020.1 Build Crack + Keygen Key Free suppressor must be inactivated, such as p53 [45].

The non-canonical activation of Shh pathway. The non–canonical activation occurs through Gli-independent mechanisms and it can be of two types. A) Type I which modulates Ca2+ and actin cytoskeleton (left). When Shh binds the receptor Ptch, Smo is no longer inhibited and couple Gi proteins (G) and small GTPases RhoA and Rac1 activated. In addition, Smo stimulates calcium (Ca2+) release from the endoplasmic reticulum (ER) and PLC-γ-catalyzed the opening of IP3-dependent channels by the generation of IP3. B) Type II which is independent on Smo. When Shh binds Ptch, the interaction of Ptch with cyclin B1 is disrupted, leading to an increase in cell proliferation and survival (right). (Diagrams by Carballo, VC). (Adapted from Robbins et al., ) [54]

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The crosstalk between Shh pathway and others. Shh signaling pathway can crosstalk with several pathways, especially EGF, Wnt and TGF-β. Here we can observe the Shh signaling pathway in blue, the EGF pathway in orange, the Wnt pathway in, and TGF-β pathway in green. The crosstalk between these pathways and Shh occurs at different moments, and it becomes more important to understand this molecular interaction in order to search for new therapeutical drugs. (Diagrams by Carballo, VC). (Adapted from Matias et al., ; Berg and Soreide, and travelafter.us) [, ]

Full size image

Besides ubiquitination, mainly of Gli3, to control Shh pathway, it was also demonstrated that Gli1 and Gli2 can be acetylated at lysine andrespectively [46]. The mechanism of wise care 365 pro full version free download - Free Activators of these proteins is mediated by the enzyme histone deacetylase 1 (HDAC1), which promotes transcriptional activation of the pathway. This activation is turned off by the degradation of HDAC1, which sustains a positive autoregulatory loop, when Shh obs overview - Activators Patch present. This degradation is mediated through an E3 ubiquitin ligase complex [46].

Shh signaling pathway is a valid therapeutic goal in a broad range of cancers, such as pancreas, prostate, breast and brain tumors. We focus here on brain tumors. The transcriptomics data on clinical cases of The Cancer Genome Atlas-Glioblastoma (GBM) database showed a robust correlation between PTCH1 and GLI1 mRNA expression as an indication of the canonical Shh pathway activity in this malignancy. The expression of GLI1 mRNA varied in three orders of significance among the GBM patients of the same cohort, demonstrating a single continuous distribution different from the discrete high/low-GLI1 mRNA expressing clusters of MB [47]. Furthermore, it has already been well-established that tumor microenvironment plays an important role in controlling GBM pathology and their drug-resistance mechanisms [48]. Cells from the tumor microenvironment usually secrete inflammatory cytokines, growth factors [49,50,51] and other proteins that can activate Shh signaling in a typical or atypical manner (canonical or non-canonical) [52]. It was demonstrated that in the tumor microenvironment the endothelial cells provide Shh to activate the Hh signalling pathway in GBM cells, thereby promoting glioma stem cells (GSC) properties and tumor propagation [53].

Non-canonical Shh signaling

The “non-canonical Shh signaling” usually occurs through Gli-independent mechanisms. The Gli-independent mechanisms include two types: Type I is downstream of Smo, which modulates Ca2+ and actin cytoskeleton and type II is independent of Smo and increases cell proliferation and survival [54]. The non-canonical Shh signaling can regulate chemotaxis and cell migration through actin rearrangement. Additionally, it can stimulate cell proliferation via calcium-induced extracellular signal-regulated kinases (ERK) activation and activate Src family kinase, which is required axon guidance [54,55,56].

Some studies emerged mainly in tumor cells concerning the non-canonical Shh signaling in the ten last years. However it has not been completely elucidated how Smo selects between canonical or non-canonical routes. Usually the non-canonical route occurs when Smo couples to Gαi in vertebrates and modulates Ca2+ flux, Ras homolog gene family, member A (RhoA) and Rac activation and Warburg-like metabolism [56,57,58].

Interestingly, it was first believed that only Shh canonical signaling occurs when Smo enters the PC [59], and if Smo does not route through PC, it signals through a non-canonical pathway [17]. However, it was recently demonstrated that non-canonical Shh signaling leads to acetylation of α-tubulin via Smo-mediated calcium which increases in a primary cilia-dependent manner in mouse embryonic fibroblasts [17]. There are rare studies of this type of signaling associated with tumorigenesis and none with brain tumors. A ligand-independent Smo mutant resulted in tumors over-expressing Shh that show pronounced chromosomal instability and smoothened-independent up-regulation of Cyclin B1, a putative non-canonical branch of the Shh pathway in lung cancer. These results strongly support an autocrine, ligand-dependent model of Shh signaling in Small Cell Lung Cancer tumorigenesis and explain a new role for non-canonical Shh signaling through the induction of chromosomal instability [60]. Moreover, Hh signaling has an important role on the switch of hypoxia-induced pancreatic cancer epithelial audio amplifier pro v2.2.1 registration code mesenchymal transition and invasion in a ligand-independent manner [61].

Recently, it was demonstrated that the intraflagellar transport protein 80 (IFT80) promotes Hh canonical signaling via activation of Hh-Smo-Ptch1-Gli signaling pathway during osteoblasts (OBs) differentiation. On the other hand, when this occurs, the non-canonical Hh signaling is inhibited via Hh-Smo-Gαi-RhoA-stress fibre signaling, demonstrating that non-canonical Hh signaling negatively regulates OBs differentiation [62]. Moreover, this study demonstrated that at least in OBs differentiation and bone formation, IFT80 is essential for the balance of the non-canonical and canonical Hh signaling pathways [62].

However, the researchers are still unveiling the mystery of the non-canonical Smo signaling axis, as well as how Smo selects between canonical and non-canonical routes.

Shh interaction with others pathways

It is already known that Shh signaling is very important for embryonic development and in adults, deregulation or mutation of this pathway plays an important role in both differentiation and proliferation, inducing tumorigenesis [63, 64]. Furthermore, CSCs follow the same pathways than normal stem cells such as Wnt, Shh, Notch and others and are also present during embryonic development, organogenesis and tumorigenesis [10,11,12].

Emerging evidence suggests that Shh signaling pathway can interact with other signaling components, such as TGF-β, epidermal growth factor receptor (EGFR), K-Ras, PKA, Notch, and Wnt/β-catenin (Fig. 3) [65, 66]. Furthermore, it has been suggested that more than one of these pathways are active, in different types of tumors, at the same time [16].

The Shh and Wnt pathways could interact in two ways: 1. through Gli1 and Gli2, which have been shown to regulate positively the expression of secreted frizzled-related protein-1 (sFRP-1) and thus inhibiting Wnt ligands and/or their receptors [67] and 2. through downstream GSK3β (an essential component of complexes that inhibit Shh and WNT morphogenetic pathways) [68]. GSK3β, can act as a positive regulator of Shh signaling by phosphorylating SUFU and promoting the release of SUFU from Gli, at least when the pathway is active [69]. It has already been demonstrated that in mice without normal APC function (citoplasmatic degradation and nuclear exporting of β-catenin) that SUFU negatively regulates Tcf-dependent transcription by reducing nuclear β-catenin levels [70]. So, Shh can regulate Wnt signaling. This crosstalk between Shh and Wnt has also been demonstrated in medulloblastoma cells, where the loss of SUFU activates both pathways, inducing excessive proliferation and tumorigenesis [71]. Besides, Wnt signaling can also increase Shh pathway activity, as β-catenin may potentially affect the Gli1 transcriptional activity via TCF/LEF in an independent manner [66]. Interestingly, in gastric cancer, the Shh signaling pathway activation seems to be inversely correlated with the level of Wnt pathway activation. It was observed that Gli1 overexpression suppressed Wnt transcriptional activity, nuclear β-catenin accumulation and proliferation of gastric cancer cells [72].

It is well established that aberrant RAS activation has a protagonist role in tumorigenesis, and activating RAS mutation occurs in 30% of all human cancers [73]. It has been demonstrated that activation of the RAS/MAPK pathway (KRAS), induced by divers upstream signals and converging at the level of Gli transcription factors, is important in promoting cancer development during pancreatic tumorigenesis [74]. Another pathway that has been demonstrated to interact with Shh is the ERK signaling pathway, which controls Gli transcription factor function in Shh signaling, when stimulated by exogenous ligands (like basic fibroblast growth factor -bFGF) [39].

In addition to Wnt/βcatenin and KRAS, TGF-β/TGF-βR, EGFR, and platelet-derived growth factor receptor α (PDGFRα) can also cooperate with the canonical Shh pathway [39, 66, 75,76,77,78]. There is an important increase in Gli1 and Gli2 expression induced through the activation of TGF-β/TGF-βR/Smads in pancreatic cell lines. Furthermore, these cells were resistant to Shh inhibition, but the pharmacologic blockade of TGF-β signaling leads to repression of cell proliferation accompanied by a reduction in Gli2 expression [79].

Another signaling pathway that crosstalk with Shh and contributes to tumorigenesis is EGFR signaling. The stimulation of EGFR/RAS/RAF/MEK/ERK in different cancer cell lines such as gastric, and pancreatic cancer cell lines and was able to activate the Gli transcription factor and selective transcriptional modulation of Gli target gene expression [76,77,78, 80]. However, it was observed in MB cells, a crosstalk mechanism where EGFR signaling silences proteins acting as negative regulators of Hh signaling, as an ERK and AKT-signaling independent method. Reciprocally, a high-level synergism was also observed, due to a significant and strong up-regulation of several canonical EGF-targets. Synergistic outcomes between EGFR and Hh signaling can selectively promote a shift from a canonical HH/GLI profile to a gene profile specific target modulated. It indicates that there are more diffuse, yet context-dependent (i.e. cancer-dependent) interactions, between growth factor receptors and HH/GLI signaling in human tumorigenesis [81].

So, it is becoming more and more evident that the integration of these signaling pathways, which are important for embryonic morphogenesis, may support a more malignant behavior by tumor cells and consequently maintain the tumorigenesis of diverse aggressive tumors, such as pancreas, prostate, breast and brain [78, 80]. The need to understand the role of these pathways in tumorigenesis is becoming increasingly evident, mainly the molecular crosstalk between them, as it is an important consideration for the development of HH-targeting agents and the appropriate selection of a class of inhibitors for therapeutic intervention [82]. Furthermore, it is valid to be proposed in the future treatments of Shh-dependent tumors using inhibitors of Akt, PI3K, MEK, ERK, Wnt, EGFR and TGF-β [38, 66, 78,79,80].

Hh inhibitors and clinical trials

The importance of stem cells in brain tumors

Nowadays, several studies support the hypothesis that malignant tumors are initiated and maintained by CSCs. Although the origin of the CSCs in human tumors is not fully understood, it is already well established that these cells are responsible for the chemo and radioresistance of the most malignant tumors [49, 50]. The recurrence of the tumor is usually due the existence of these cells in the tumor bulk [49, 50]. Moreover, studies have demonstrated that CSCs could de-differentiate from a more differentiated cancer cell present in the tumor mass that acquires self-renewal properties, clonal tumor initiation capacity and clonal long-term repopulation potential, perhaps as a result of epithelial-to-mesenchymal transition (EMT) [83,84,85].

The hypothesis that the existence of CSCs initiates malignant tumor came from the observation that tumor cells, like adult tissues, originate from cells that can self-renew. Furthermore, that these cells also are able to differentiate into cell forming the tumor bulk [86]. In the adult tissue, these cells are the adult stem cells that are tissue-specific and multipotent, being able to differentiate between all cell types of the tissue of origin [86].

In the adult brain, it is already well established that the existence of a neurogenic niche, which is extremely dynamic and complex microenvironment where new glial cells and neurons are generated when necessary from the stem or progenitor cells [87]. This neurogenic niche has a very important role, as it provides signals that regulate whether the stem cells should differentiate, remain quiescent, or actively divide, controlling the self-renewal properties in this way and maintaining neural stem/progenitor cell populations [87]. These neural stem cells (NSCs) are found in two main niches in adult brain, in the lateral ventricles (ventricular-subventricular zone obs overview - Activators Patch and in the hippocampus (subgranular zone (SGZ)), and these microenvironments ensures the self-renew and multipotent properties [88, 89].

It is interesting to note that Shh is very important for determining cell fate and patterning during embryo development, having a mitogenic effect on proliferative cells throughout development [90]. Recently it was demonstrated that in the adulthood, the level of Shh signaling pathway activation played an important role to regulate the balance between quiescent and activated NSCs. Moreover, when the Shh pathway was genetically activated the number of quiescent NSCs increased and the pool of activated NSCs decreased [91]. However, there was an initial transitory period over the short term when activated NSCs are actively proliferating, apparently when their G1 and S-G2/M phases were short [91].

Taking into account that in GBM, the Shh pathway is usually upregulated, affecting GBM CSC proliferation and self-renewal [87, 92], this discovery opened an avenue for clinical trials that managed not only to stop the tumor to growth but also the tumor to relapse after surgery.

The importance of Shh and MGMT interaction in clinical trials

Nowadays, the standard treatment for most brain tumors comprises resection of the majority of the tumor mass, followed by chemo- and radiotherapy [49, 93], being Temozolmide (TMZ) and radiotherapy being the gold standard treatment [94]. TMZ is an alkylating agent prodrug, and its effect on tumor cells is to methylate the O6 residues of guanine preventing DNA duplication during cell proliferation and inducing cell death and apoptosis [95]. However, the DNA repair enzyme Omethylguanine-DNA methyltransferase (MGMT) is able to reverse the effects of alkylating agents as TMZ [96,97,98]. The MGMT promoter methylation is directly related to patient’s prognosis, as low promoter methylation status induces a high MGMT expression and a shorter survival due to a remarkable chemoresistance. On the other hand, a higher promoter methylation status predicts a good response to TMZ chemotherapy, as the MGMT enzyme is downregulated, resulting in longer survival for the patients [99, ]. Therefore, studies are being done in order to control and impairs the MGMT enzyme activity in chemoresitant tumors It is interestingly to note that many DNA repair proteins could be potential targets for inhibiting cancer cells without affecting normal cells; as they usually are upregulated in several chemorresistant cells and cancers [].

The most malignant tumors are also highly mutated and present CSCs, which make them difficult to treat. So efforts are being made in order to bypass the chemoresitance in tumors. As written above, the Shh pathway is upregulated in CSCs [87, ]. Moreover, these cells express also usually high levels of MGMT, and therefore they are involved in chemotherapy resistance and are responsible for tumor recurrence []. Emerging evidences are demonstrating that Shh signaling pathway could regulate MGMT expression and chemoresistance to TMZ in human GBM. Moreover, this regulation occurred independently from MGMT promoter methylation status, offering a probable target to reestablish chemosensitivity to TMZ in tumor that developed chemoresitance []. Furthermore, it is believed that Gli1 expression is also responsible for chemoresistance in gliomas and that it’s overexpression is related to tumor recurrence after treatment. So in the other hand, when Shh pathway is inhibited, [] the sensitivity to chemotherapy improves by down-regulating many genes related to apoptosis, cell survival, multi-drug resistance, and especially MGMT [, ,,].

Smo-based inhibitors

Presently, there are several Hh inhibitors employed in clinical trials for different types of brain tumors (travelafter.us) (see Table 1). SMO is the principal target for the development of Shh-pathway inhibitors; however preclinical and clinical studies have demonstrated that the use of Smo inhibitors induces the development of mutations that lead to treatment resistance [, ].

Full size table

The first clinical trial, targeting Smo and so using Shh pathway inhibitor as therapy, considered several patients with recurrent or metastatic basal cell carcinoma (BCC). At that time, a preliminary study was performed with cyclopamine in a topical application and cream formulation. This study has revealed that the tumors rapidly regressed in all cases without adverse effects, and the normal skin and putative stem cells exposed to cyclopamine were preserved []. Cyclopamine is a natural steroidal alkaloid derived from Veratrum californicum which inhibits the cellular response to Shh signaling by antagonizing the proto-oncogene SMO []. The histological and immunohistochemical analyses from this study have also indicated that the topical cyclopamine application resulted in an inhibition of the proliferation and induced the apoptotic death of tumor cells []. InHerman started a Phase III clinical trial to assess cyclopamine as a chemo-preventive agent to inhibit the recurrence of BCC following surgical resection. At that moment, neither a phase I nor a phase II clinical trials have evaluated the possible side effects of cyclopamine in human subjects, so the patients may choose not to take part in the study. It is important to note that in both clinical trials, the cyclopamine was administered topically that diminished the side effects of the drug [, ].

However, cyclopamine has never been used orally in clinical trials. Test using animal models demonstrated that cyclopamine besides being poorly soluble orally, at high doses, it has a potential teratogenic effect, causing many potential side effects, including weight loss, dehydration, and death [], which limits its clinical use. Therefore, some other potent SMO inhibitors have also reached the clinical trials, such as: the orally active IPI, a semi-synthetic derivative of cyclopamine and different synthetic compounds, such as GDC (vismodegib), Cur, and NVPLDE (Erismodegib or Sonidegib or Odomzo) [,,].

Presently some ongoing and completed clinical trials used Shh inhibitors to treat brain tumors (see Tables 2 and 3). The first clinical trial performed using a Shh inhibitor to treat a brain tumor was conducted in At the time, a year-old man with metastatic MB that was refractory to multiple therapies was treated with a novel Hh pathway inhibitor, GDC []. Interestingly, the group did molecular analyses of the patient’s tumor specimens obtained before treatment which suggested activation of Shh pathway, as there was a high expression of Hh target genes including GLI1, PTCH1, PTCH2 and sFRP1. So, the treatment resulted in rapid regression of the tumor and reduction of symptoms, but unfortunately, this effect was transient and the patient died after five months of treatment []. It was observed that the Hh pathway inhibition with GDC induced the malignant transformation in MB which induced the tumor regrowth and the rapid progress of the disease [].

Full size table

Full size table

Only inthe US Food and Drug Administration (FDA) approved GDC as a standard therapy in patients with locally advanced and metastatic BCC []. Then few phase I and II clinical trials emerged with the objective to define the pediatric maximum tolerated dose and the efficacy of GDC in SHH-MB. Some studies evaluated the use of GDC in combination with TMZ. The studies were performed through the Pediatric Brain Tumor Consortium. These were phase II studies which evaluated the efficacy of GDC in younger patients, as well as in adult patients with recurrent or refractory MB []. Many other collaborative studies using GDC are still ongoing which directs therapy based on both clinical and molecular risk stratification (see Table 2 and see travelafter.us). GDC has an advantage for the use in clinical trials since it has low toxicity and high specificity for the Shh pathway. Additionally, this drug may also be used together with other pathway inhibitors or chemotherapy []. Moreover, GDC usually is well tolerated because of a lack of Smo receptor in most normal tissues []. It is believed that the use of Winx hd video converter deluxe 5.15.2 license key - Free Activators pathway inhibitors in MB treatment may offer an adequate therapeutic option. However, it is important to note that, as Shh pathway is very important during development, the adverse effect of blocking Shh pathway in prepubescent children is not completely understood []. Recently a study demonstrated that the used of GDC in pediatric oncologic patients induces short stature and growth abnormalities as they developed physeal fusion []. So, the use of Hh inhibitors in skeletally immature patients should be widely discussed and may be limited to those patients whom treatment options are limited or absent.

Gli-based inhibitors

Shh-MBs as GBMs are highly mutated tumors, and it is not uncommon for those tumors to demonstrate primary resistance to SMO inhibition, as they present alterations in downstream SHH pathway genes such as SUFU, GLI2, or MYCN []. As described above, it is typical for those tumors to acquire secondary resistance to Shh inhibition, and in this case, a Shh inhibition monotherapy is not efficient []. This is why, several pharmaceutical companies such as Exelixis/Bristol-Myers Squibb, Novartis, Infinity, and Pfizer developed alternative Shh antagonists that act directly in Gli (see Table 1). Some of these inhibitors are already being tested in the brain and central nervous system tumors as coadjuvant therapy with TMZ (see Tables 2 and 3 and travelafter.us).

So, besides GDC, NVPLDE and BMS (XL) were also tested in brain tumors. There were some phase I and phase II clinical trials completed with the purpose of testing the efficacy tolerability, pharmacokinetics, pharmaco-dynamics, and safety of these drugs orally [65].

Another drug that Winrar 5.50 Crack + Serial Key Full Version Download Free being tested for gliomas in phase I and II clinical trials is the arsenic trioxide (ATO). ATO is an FDA-approved drug that has been shown to inhibit Gli-dependent growth in MB mouse model, obs overview - Activators Patch was first used for the treatment of patients with acute promyelocytic leukemia (APL) []. Recently, a study demonstrated that apparently, the treatment of patients in combination with ATO, TMZ, and radiation does not improve the overall outcome in GBM patients; however, it might have some benefit in anaplastic astrocytoma patients [].

Most of Hh inhibitors that have entered clinical trials targeted Smo, although several mechanisms of resistance to Smo inhibitors have been identified. Therefore, the discovery of new Hh pathway inhibitors may be crucial to bypass these resistance mechanisms and control tumorigenesis.

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