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Mackalister Silva: "No es que uno como jugador quiera hacer el juego lento"




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Debate: ¿Es alentador el panorama con los jugadores juveniles de Colombia?




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Iago Falque: "Tenemos un equipo con mucho talento"




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Jhon Vásquez: "Mi paso por el Deportivo Cali fue excelente, quedé campeón"




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¿Tendría jugadores problemáticos pero talentosos en su equipo?




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Arnulfo Valentierra sobre la situación del Once Caldas: “Estoy que me colocó los guayos”

Arnulfo Valentierra, uno de los máximos ídolos en la historia del Once Caldas, se refirió a la difícil situación que atraviesa el cuadro de Manizales, luchando por conservar la categoría y por enderezar su camino en el presente campeonato. En diálogo con El Alargue de Caracol Radio, Valentierra aseguró que la falta de confianza es el principal problema en lo deportivo del club.




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“Tuve la peor noche de mi vida”: concejal Julián Triana fue víctima de violento atraco

El concejal conversó con Caracol Radio sobre los angustiantes momentos de pánico que vivió.




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Jan 14: Exxon's excellent climate science, dolphins drowned out by noise, supersonic but boomless and more...

Climate change and insects, and designing Canada’s lunar rover



  • Radio/Quirks & Quarks

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Turn the Other Cheek: the radical case for nonviolent resistance

The Sermon on the Mount is one of the greatest gifts of scripture to humanity; just ask Mahatma Gandhi, Martin Luther King Jr., and Leo Tolstoy. In a time when an eye for an eye still seems to hold sway, IDEAS producer Sean Foley explores the logic of Christian non-violence, beginning with Jesus' counsel to 'turn the other cheek.'




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MAGA'S CRAVEN WAR ON DEMOCRACY & VIOLENT EMBRACE OF INSURRECTION

 

Eyewitness accounts regarding the events of January 6, 2021 give us the most reliable version of what happened that dark day. Particularly those eyewitnesses from the Republican Party who do not seek partisan advantage. For example:

"What happened here today was an insurrection incited by the President of the United States."

Republican Senator & former Presidential Nominee Mitt Romney, Jan. 6, 2021. 

"Today’s violent assault on our Capitol, an effort to subjugate American democracy by mob rule, was fomented by Mr. Trump. His use of the presidency to destroy trust in our election and to poison our respect for fellow citizens has been enabled by pseudo political leaders whose names will live in infamy as profiles in cowardice."

Former Trump Defense Secretary and Marine Corps General James Mattis, Jan. 6, 2021.

"The mob was fed lies. They were provoked by the president and other powerful people. And they tried to use fear and violence to stop a specific proceeding of the first branch of the federal government which they did not like."

GOP Senate Majority Leader Mitch McConnell, Jan. 19, 2021

"Today was a dark day in the history of the United States Capitol… We condemn the violence that took place here in the strongest possible terms… To those who wreaked havoc in our Capitol today, you did not win. Violence never wins. Freedom wins."

Trump Vice-President Mike Pence, January 6, 2021.

"These men and women in the uniform, they got overrun. One officer got killed…they got broken arms. You don’t understand what was transpiring at that moment and that time. . . . People brought ropes. . .[T]hey were well planned for it. They scaled walls. . . . They, they overtook the place.”

"Let me be clear: Last week’s violent attack on the Capitol was undemocratic, un-American and criminal…And make no mistake: Those who are responsible for Wednesday’s chaos will be brought to justice…The president bears responsibility for Wednesday’s attack on Congress by mob rioters."

GOP House Speaker Kevin McCarthy, Jan. 13, 2021 

"Today, the people's House was attacked, which is an attack on the Republic itself. There is no excuse for it. A women died. And people need to go to jail. And the President should never have spun up certain Americans to believe something that simply cannot be."

GOP Rep. Chip Roy, Jan. 6, 2021.

WOW!  The US Capitol became a combat zone on January 6.

The legal upshot of the above is Trump and his cultists levied war against the US in violation of 18 USC section 2381! They engaged in an insurrection in violation 18 USC section 2383!

These provisions carry severe criminal sanctions and section 2383 prohibits insurrectionists from ever holding federal office again. Trump also disqualified himself from federal office under the Fourteenth Amendment, section 3. As painful as it may be, the Biden Administration has little choice but to fully investigate these potential violations of law immediately. Donald Trump in particular must face swift justice. .

In his unending fantasy and lies of victory, President Donald Trump unleashed a violent coup on our democracy, our constitutional republic and ultimately our freedom in the lawless pursuit of autocracy, dictatorship, and dimwitted megalomania. 

This directly aided and abetted the ongoing efforts of Vladimir Putin to use Russian New Generation Warfare (RNGW) to weaken, undermine, subvert, and diminish the power of the USA to defend itself and its interests and allies across the world. As Lt. General H.R. McMaster explains RNGW aims to weaken the US and other democratic societies through the sustained use of misinformation. They seek to “disrupt, divide and weaken” American democracy. Yet, again the Trumpists continue to toss the nation and its people into bloody pitched battle with each other while doing the bidding of Putin.



Addendum:

"[T]here can be no soft-pedaling what happened and no absolution for those who planned, encouraged and aided the attempt to overthrow our democracy, Love of country demands nothing less. That’s true patriotism.” 

Karl Rove, writing in the Wall Street Journal, Former Republican Political Operative, January, 6, 2022.

"The importance of January 6th as an historic event cannot be overstated. I was honored and proud to join my daughter on the House floor to recognize this anniversary, to commend the heroic actions of law enforcement that day, and to reaffirm our dedication to the Constitution.  I am deeply disappointed at the failure of many members of my party to recognize the grave nature of the January 6 attacks and the ongoing threat to our nation.”

Former Republican Vice President Dick Cheney, January 6, 2022. 

January 6th, 2021 was a dark day for Congress and our country. The United States Capitol, the seat of the first branch of our federal government, was stormed by criminals who brutalized police officers and used force to try to stop Congress from doing its job. This disgraceful scene was antithetical to the rule of law. One year later, I am as grateful as ever for the brave men and women of the U.S. Capitol Police who served our institution bravely that day and every day since. I continue to support justice for those who broke the law.

GOP Senate Minority Leader Mitch McConnell, January 6, 2022. 

On the first anniversary of January 6, GOP Senator Ted Cruz and Trump-appointed FBI Director Christopher Wray called the violence "a violent terrorist attack on the Capitol" and "domestic terrorism," respectively.





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Talented teen has world at his feet

Football is in Kosta Grozos’ blood. The 15-year-old Kingsgrove footballer has been playing for about two thirds of his life and has no desire to stop any time soon.




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SLEEP TOKEN, KORN, BULLET FOR MY VALENTINE, SPIRITBOX & More Booked For Download 2025

Plus Cradle Of Filth, Lorna Shore, Sikth, Jinjer, Poppy, and more!




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Antron Brown, first Black drag racing champion, insists he’s still got plenty left in the tank: “I’m halfway through”

As a child, Antron Brown’s trips to Old Bridge Township Raceway Park in Englishtown, New Jersey, were a source of inspiration.




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Paige: Major talent Minor is one splendid sprinter

Major talent Minor is one splendid sprinter





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Kempe To Study At Solent University In UK

Sebastian Kempe, one of the top Bermudian sailing competitors, has secured his place to study yacht design and production at Solent University in Southampton. Kempe, who previously attended the Royal Hospital School in Suffolk, England, became the youth world sailing champion in the ILCA 6 class in 2021 and was named the Bermudian Junior Male […]




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Cumbermack Gears Up For Talent Cup Race

[Written by Stephen Wright] Bermudian motorcycle racer Jediah Cumbermack is ready to “make my country proud” as he gears up for the opening race of the North America Talent Cup in Austin, Texas, this coming weekend [April 8 to 10]. The 16-year-old is racing overseas for the first time against talented young riders from the United […]




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Jediah Cumbermack Ready For Talent Cup

[Written by Stephen Wright] Jediah Cumbermack admits he was surprised by the speed of his North American Talent Cup rivals during his race debut in Washington State last month. Cumbermack missed the first two rounds of the seven-race series after suffering a broken leg in a practice session before the opening race in Austin in April. […]




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Jediah Cumbermack Competes In Talent Cup

Jediah Cumbermack competed in the North American Talent Cup in Savannah, Georgia. Round four of the North America Talent Cup [NATC] produced the closest racing of the season so far, with the top eight riders finishing within .5 second of each other in race one. Race two was even closer, with the top four within […]




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Kde strávit dovolenou na Valentýna?

Zima je tu a dlouhé zimní měsíce přímo volají po troše tepla. Zejména období kolem svátku svatého Valentýna je ideální příležitostí jet se prokrvit na pláž u moře.




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Thoughts Of Love and Chocolate Brownies for St Valentines Day

With Valentines Day just around the corner … ones mind begins filling with thoughts of love, chocolate and chocolate lovers. If your someone special loves chocolate, think about making a batch of Ghirardelli Triple Chocolate Brownies to share with them on St. Valentines Day. Ghirardelli Brownies are delicious when served with a scoop of ice …




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talent quest




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36 tweets by Darryl Cooper aka @MartyrMade on July 8 2021 on why Trump supporters believe the 2020 election was fraudulent

Darryl Cooper, AKA @MartyrMade, is a podcaster who had a Twitter thread go viral with 13k retweets and 20k likes of the first Tweet alone. This one is 36-Tweets long. It makes very cogent arguments of not only why millions of Trump supporters believe the 2020 election was stolen, but also why we are justified to believe it. Continue reading




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BULLET FOR MY VALENTINE в студии

BULLET FOR MY VALENTINE опубликовали несколько студийных фотографий и подтвердили работу над новым материалом.
#Bullet_for_My_Valentine #BulletforMyValentine #MetalCore #Metal_Core


Full Article


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Happy Valentine's Day

My valentine understood me back in the early days when I didn't even understand myself. She taught me everything I know and helped me feel safe. She tolerates me even when I'm really bouncy. She lets me curl up next to her and use her ear as a blanket. I wouldn't be the dog I am without her.
Thank you for being my big sister, Lulu. I love you.

love,
Uba




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What To Do in Case of Psychic Attack or of Being the Victim of Malevolent Spell

Being a relatively visible public Witch, I get plenty of requests for spells, which I politely decline to do. I tell people two things: One is that it's best to create one's own spells rather than have someone else cast them. The other is a caution against performing any magic that would interfere with the free will of another. The exception to that would be a binding of someone else, making them unable to do further harm.

If you believe someone has put a negative spell on you (usually called a hex), here are a few things you can do to protect yourself, and possibly reverse the spell.


First, purify your person. Take a shower, or better yet, soak for a while in hot water containing sea salt, bath salts, or Epsom salts. Allow the salt and water to neutralize any negativity within yourself; think of this as you soak. Let any contamination be washed away with the water spiraling down the drain, out of your house and out of your life. Drink lots of water to wash out your insides. Wash your hair, brush your teeth, put on clean clothes. You may also wish to drink mint tea or another tea that you find refreshing.


Second, purify your dwelling. Dust, sweep, vacuum, tidy up, polish. Air out the rooms. Wash the windows with a mild solution of vinegar and water. This allows purifying sunlight and moonlight to illuminate the room as well as making the glass more reflective to deflect unwanted energies.[1]


Circulate through the rooms where you live with sage or other purifying incense, making sure to fumigate everywhere -- stairways, closets, underneath stairways, basement, attic, garage if attached. If your dwelling is one that you can circumnavigate, you may wish to walk all around the outside of the building wafting this smoke.


Then mix salt and water and sprinkle it around the house. As with the incense, do this around the outside of the home, too, if you can. Be sure to cense and sprinkle all openings to the outside -- doors and windows, of course, but also skylights, electrical outlets, heating vents, chimneys, ventilator hoods, toilets, and sink, tub and shower drains. Also do this to mirrors.


While you're doing these things, speak the words, "With Earth and Water I purify this space," and "with Fire and Air I consecrate this space," because that's exactly what you're doing.[2]


Third, ward your space. If you're the witchy sort, trace a protective pentacle with the salt water on all doors, windows and mirrors. Rosemary grows in abundance where I live, so I like to use a sprig of it to sprinkle the salt water. Then I like to leave rosemary sprigs on all the window sills.


When you've done all these things, take a step back, be very quiet, look around, listen and note how different your space feels to you now.


You may also wish to perform these acts at other places where you spend a lot of time, such as work, if you can.


One last thing you may want to do, although it's not as easy and practical as the rest. You may wish to hang little mirrors in the windows or on the outside of the building to reflect away negativity. The mirrors aren't really necessary; they're just extra insurance, if you will. You should be fine just doing the other things I've recommended.


Now envision yourself within a bubble. Project this bubble around you and around your home. Nothing can pass through the membrane that has not been invited by you. Anything unwelcome bounces off the bubble. Build a strong image of this bubble in your mind. If you have a small object, maybe a clear quartz crystal or a piece of rosemary, that reminds you of this visualization, carry it in your pocket or keep it someplace handy. You can't be expected to hold this image in your consciousness all the time. But if you have this object, then at times when the image has faded and you feel you need to reinforce your working, take it out and look at it and touch it to reawaken your sense of your protective bubble.


As with all magic spells, you needn't stick with the formula offered here. If other ingredients call to you or other actions spring from you, trust your intuition and go with them.


These are my recommendations. For another approach, here's a Lemon UncrossingSpell (to break a curse). I have never tried this so I can offer no assurance of its efficacy.


[1] For a super-duper heavy cleansing of a home, say if you're just moving in after someone else has been living there, and if you have the time, get some dragon's blood incense and burn it on a piece of charcoal in a container left in the bathtub or shower. As soon as you light it, leave and let it fumigate the entire house. You don't want to breathe much of this stuff. Then return a few hours later and open all the windows to let out the dragon's blood fumes.


[2] Some additional things you can do to cleanse a new or dirty home: Walk throughout the rooms with noisemakers, rattles, a drum to frighten off unwanted spirits. Do this before censing and sprinkling. After censing and sprinkling, ring a little bell at the windows and mirrors.




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What employers can learn from Wells Fargo’s failure to recruit and retain Black talent

We’ve all seen the quotes from Wells Fargo’s CEO in a June memo in which he blamed the bank’s failure in reaching diversity goals on a lack of qualified minority talent. “While it might sound like an excuse, the unfortunate reality is that there is a very limited pool of black talent to recruit from,” […]

The post What employers can learn from Wells Fargo’s failure to recruit and retain Black talent appeared first on DiversityJobs.com.




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Valentine Canvas – Easy Art Project for Kids

So this week, we decided to make a pretty Valentine's canvas for their playroom, that can stay up all year. My kids really love looking at art that they've created and declaring, "I'm the artist! I made that!"

The post Valentine Canvas – Easy Art Project for Kids appeared first on Joyful Abode.





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We're seeking a talented Service Designer

Iriss is seeking a Service Designer for its Pilotlight programme to support the continued development and delivery of self-directed support (SDS) in Scotland. 

Pilotlight works with co-design teams of people to design pathways to self-directed support.  Now in its fourth year, the Pilotlight programme uses a design approach to demonstrate how to design support for seldom heard groups, provide more personalised and appropriate services and increase the marketplace of support providers.

read more




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Violent and aggressive children. Caring for those who care

The topic of domestic violence is an emotive one conjuring visions of child abuse by parents or carers, or marital violence, in general abuse by men of their wives or partners. According to published police statistics in Scotland for the years of 2012 – 13 male violence of women accounted for 80% of all domestic abuse, and in 2014 over 2,600 children in Scotland were identified as needing protection from abuse. This is particularly concerning since the NSPCC suggests that, for every child who has been identified, there are 8 other children who are at risk but who are ‘under the radar’. These statistics, highlighting the underlying nature of inter-family abuse relationships, i.e. the abuse of less powerful and more vulnerable family members by more powerful adults, undoubtedly account for the majority of the abuse situations within family homes. However this is, sadly, not the whole story. Understanding abuse within a family means recognising the impact of sibling aggression on every family member. It also needs to encompass the growing recognition of child to parent aggression and it is this latter aspect of inter-family relationships with which this article is primarily concerned.




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Flagstaff, Arizona is an excellent vegan town to try

Flagstaff, Arizona draws outdoorsy folks and is known as one of Arizona’s more progressive and laidback towns — which bodes well for vegans. I spent a few days in Flagstaff and didn’t run out of delicious, plant-based places to eat. It’s an attractive town to visit in its own right, though many people find themselves here on their way to the Grand Canyon, which is an hour and a half away. Here are some of the top places for vegans to get a good meal.[...]




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New FakeCall Malware Variant Hijacks Android Devices for Fraudulent Banking Calls

Cybersecurity researchers have discovered a new version of a well-known Android malware family dubbed FakeCall that employs voice phishing (aka vishing) techniques to trick users into parting with their personal information. "FakeCall is an extremely sophisticated Vishing attack that leverages malware to take almost complete control of the mobile device, including the interception of incoming




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New Android Banking Malware 'ToxicPanda' Targets Users with Fraudulent Money Transfers

Over 1,500 Android devices have been infected by a new strain of Android banking malware called ToxicPanda that allows threat actors to conduct fraudulent banking transactions. "ToxicPanda's main goal is to initiate money transfers from compromised devices via account takeover (ATO) using a well-known technique called on-device fraud (ODF)," Cleafy researchers Michele Roviello, Alessandro Strino




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FBI says hackers are sending fraudulent police data requests ot tech giants to steal people's private information




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'Legendary' cognitive scientist Daniel Osherson, 'scientist of rare talent' and 'excellent and caring mentor,' dies at 73

Daniel Osherson, Princeton’s Henry R. Luce Professor in Information Technology, Consciousness, and Culture, Emeritus, known for his  creative scientific explorations with collaborators in many disciplines, died at home on Sept. 4. 




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'Generational' young England talents excite O'Shea

England have a "generational" crop of talent that has more potential than the squad that reached the 2019 World Cup final, says Rugby Football Union director of performance Conor O'Shea.




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News24 | Young opposition Mozambicans give Frelimo ultimatum to step down or face more violent protests

Young Mozambicans from opposition parties have given Frelimo until midday to relinquish power or face more unrest, after days of violence and looting in the country.




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On-Air Talent Will Not Be Spared as CNN Prepares Mass Layoffs in Wake of Election: Report

CNN reportedly will be making more cuts in the near future, including to its highly paid on-air personalities, following poor election ratings. The New York Post reported that Fox News […]

The post On-Air Talent Will Not Be Spared as CNN Prepares Mass Layoffs in Wake of Election: Report appeared first on The Western Journal.




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Building Resistance to Violent Extremism




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Undercurrents: Episode 63 - The Politics of Violent Images




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Multivalent feedback regulation of HMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth

MS Brown
Jul 1, 1980; 21:505-517
Reviews




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Ski resort announces immediate closure as relentless threat brings fewer visitors and increases debts: 'I feel like I'm in mourning'




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MMP activation-associated aminopeptidase N reveals a bivalent 14-3-3 binding motif [Protein Structure and Folding]

Aminopeptidase N (APN, CD13) is a transmembrane ectopeptidase involved in many crucial cellular functions. Besides its role as a peptidase, APN also mediates signal transduction and is involved in the activation of matrix metalloproteinases (MMPs). MMPs function in tissue remodeling within the extracellular space and are therefore involved in many human diseases, such as fibrosis, rheumatoid arthritis, tumor angiogenesis, and metastasis, as well as viral infections. However, the exact mechanism that leads to APN-driven MMP activation is unclear. It was previously shown that extracellular 14-3-3 adapter proteins bind to APN and thereby induce the transcription of MMPs. As a first step, we sought to identify potential 14-3-3–binding sites in the APN sequence. We constructed a set of phosphorylated peptides derived from APN to probe for interactions. We identified and characterized a canonical 14-3-3–binding site (site 1) within the flexible, structurally unresolved N-terminal APN region using direct binding fluorescence polarization assays and thermodynamic analysis. In addition, we identified a secondary, noncanonical binding site (site 2), which enhances the binding affinity in combination with site 1 by many orders of magnitude. Finally, we solved crystal structures of 14-3-3σ bound to mono- and bis-phosphorylated APN-derived peptides, which revealed atomic details of the binding mode of mono- and bivalent 14-3-3 interactions. Therefore, our findings shed some light on the first steps of APN-mediated MMP activation and open the field for further investigation of this important signaling pathway.




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Quels sont les aliments qui brûlent rapidement les graisses du ventre ?

Le ventre est l’une des parties du corps où il est plus difficile de perdre de la graisse. Souvent, la meilleure solution pour arriver à perdre de la graisse à cet endroit précis du corps consiste à manger sainement et équilibré. Cependant, quels sont les aliments qui brûlent les graisses du ventre sans danger pour la […]

L’article Quels sont les aliments qui brûlent rapidement les graisses du ventre ? est apparu en premier sur Ortho Doc France.




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Manny? Harper? Klentak satisfied but monitoring

General Manager Matt Klentak discussed the Phillies' offseason in a press conference on Thursday in Clearwater, Fla. The Phillies remain in contact with the agents for Bryce Harper and Manny Machado. The belief is that the front office still prefers Machado over Harper because of Machado's combination of offense and defense.




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Theranostic GPA33-Pretargeted Radioimmunotherapy of Human Colorectal Carcinoma with a Bivalent 177Lu-Labeled Radiohapten

Radiolabeled small-molecule DOTA-haptens can be combined with antitumor/anti-DOTA bispecific antibodies (BsAbs) for pretargeted radioimmunotherapy (PRIT). For optimized delivery of the theranostic - and β-emitting isotope 177Lu with DOTA-based PRIT (DOTA-PRIT), bivalent Gemini (DOTA-Bn-thiourea-PEG4-thiourea-Bn-DOTA, aka (3,6,9,12-tetraoxatetradecane-1,14-diyl)bis(DOTA-benzyl thiourea)) was developed. Methods: Gemini was synthesized by linking 2 S-2-(4-isothiocyanatobenzyl)-DOTA molecules together via a 1,14-diamino-PEG4 linker. [177Lu]Lu-Gemini was prepared with no-carrier-added 177LuCl3 to a molar-specific activity of 123 GBq/μmol and radiochemical purity of more than 99%. The specificity of BsAb-177Lu-Gemini was verified in vitro. Subsequently, we evaluated biodistribution and whole-body clearance for [177Lu]Lu-Gemini and, for comparison, our gold-standard monovalent [177Lu]Lu-S-2-(4-aminobenzyl)-DOTA ([177Lu]Lu-DOTA-Bn) in naïve (tumor-free) athymic nude mice. For our proof-of-concept system, a 3-step pretargeting approach was performed with an established DOTA-PRIT regimen (anti-GPA33/anti-DOTA IgG-scFv BsAb, a clearing agent, and [177Lu]Lu-Gemini) in mouse models. Results: Initial in vivo studies showed that [177Lu]Lu-Gemini behaved similarly to [177Lu]Lu-DOTA-Bn, with almost identical blood and whole-body clearance kinetics, as well as biodistribution and mouse kidney dosimetry. Pretargeting [177Lu]Lu-Gemini to GPA33-expressing SW1222 human colorectal xenografts was highly effective, leading to absorbed doses of [177Lu]Lu-Gemini for blood, tumor, liver, spleen, and kidneys of 3.99, 455, 6.93, 5.36, and 14.0 cGy/MBq, respectively. Tumor–to–normal tissue absorbed-dose ratios (i.e., therapeutic indices [TIs]) for the blood and kidneys were 114 and 33, respectively. In addition, we demonstrate that the use of bivalent [177Lu]Lu-Gemini in DOTA-PRIT leads to improved TIs and augmented [177Lu]Lu-Gemini tumor uptake and retention in comparison to monovalent [177Lu]Lu-DOTA-Bn. Finally, we established efficacy in SW1222 tumor-bearing mice, demonstrating that a single injection of anti-GPA33 DOTA-PRIT with 44 MBq (1.2 mCi) of [177Lu]Lu-Gemini (estimated tumor-absorbed dose, 200 Gy) induced complete responses in 5 of 5 animals and a histologic cure in 2 of 5 (40%) animals. Moreover, a significant increase in survival compared with nontreated controls was noted (maximum tolerated dose not reached). Conclusion: We have developed a bivalent DOTA-radiohapten, [177Lu]Lu-Gemini, that showed improved radiopharmacology for DOTA-PRIT application. The use of bivalent [177Lu]Lu-Gemini in DOTA-PRIT, as opposed to monovalent [177Lu]Lu-DOTA-Bn, allows curative treatments with considerably less administered 177Lu activity while still achieving high TIs for both the blood (>100) and the kidneys (>30).




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Preclinical Evaluation of 177Lu-OncoFAP-23, a Multivalent FAP-Targeted Radiopharmaceutical Therapeutic for Solid Tumors

Fibroblast activation protein (FAP) is abundantly expressed in the stroma of most human solid tumors. Clinical-stage radiolabeled FAP ligands are increasingly used as tools for the detection of various cancer lesions. To unleash the full therapeutic potential of FAP-targeting agents, ligands need to remain at the tumor site for several days after administration. We recently described the discovery of OncoFAP, a high-affinity small organic ligand of FAP with a rapid accumulation in tumors and low uptake in healthy tissues in cancer patients. Trimerization of OncoFAP provided a derivative (named TriOncoFAP, or OncoFAP-23) with improved FAP affinity. In this work, we evaluated the tissue biodistribution profile and the therapeutic performance of OncoFAP-23 in tumor-bearing mice. Methods: OncoFAP-23 was radiolabeled with the theranostic radionuclide 177Lu. Preclinical experiments were conducted on mice bearing SK-RC-52.hFAP (BALB/c nude mice) or CT-26.hFAP (BALB/c mice) tumors. 177Lu-OncoFAP and 177Lu-FAP-2286 were included in the biodistribution study as controls. Toxicologic evaluation was performed on Wistar rats and CD1 mice by injecting high doses of OncoFAP-23 or its cold-labeled counterpart, respectively. Results: 177Lu-OncoFAP-23 emerged for its best-in-class biodistribution profile, high and prolonged tumor uptake (i.e., ~16 percentage injected dose/g at 96 h), and low accumulation in healthy organs, which correlates well with its potent single-agent anticancer activity at low levels of administered radioactivity. Combination treatment with the tumor-targeted interleukin 2 (L19-IL2, a clinical-stage immunocytokine) further expands the therapeutic window of 177Lu-OncoFAP-23 by potentiating its in vivo antitumor activity. Proteomics studies revealed a potent tumor-directed immune response on treatment with the combination. OncoFAP-23 and natLu-OncoFAP-23 exhibited a favorable toxicologic profile, without showing any side effects or signs of toxicity. Conclusion: OncoFAP-23 presents enhanced tumor uptake and tumor retention and low accumulation in healthy organs, findings that correspond to a strongly improved in vivo antitumor efficacy. The data presented in this work support the clinical development of 177Lu-OncoFAP-23 for the treatment of FAP-positive solid tumors.




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Valentine's Day Got You Blue? There's an Upside

Unpleasant emotions like sadness and anger can feel overwhelming, but recent research suggests they can trigger behaviors that lead to something better




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Openbook’s autumn edition showcases diverse talents of Australia’s creative community

Wednesday 6 March 2024
Showcasing diverse talents of Australia’s creative community.