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Tuesday, March 12, 2024

Neural mechanisms involved in progression from aggressive motivation to action

 The social behaviors of humans and animals often unfold over two distinct phases, namely a motivational and an action phase. The first of these phases entails instinctual and reward-seeking mental states, characterized by sexual or aggressive drives to perform specific actions. The second phase entails acting on these motivations and drives.

While many neuroscience studies investigated social behaviors and these two "phases," their underlying neural underpinnings are not yet fully understood. A deeper understanding of these phases, particularly the processes behind the progression from motivation to action, could offer valuable insight into mental health disorders marked by dysregulated social interactions, such as aggressive tendencies or hypersexual behaviors.

Researchers at Princeton Neuroscience Institute recently carried out a study investigating the neural underpinnings of the progression from aggressive motivation to action. Their paper, published in Nature Neuroscience, highlights the potential role of neurons in a subregion of the hypothalamus in encoding the sequence leading from hostile intentions to aggressive behaviors.

"We show that neurons in the  ventrolateral area (VMHvl) of mice encode the temporal sequence of aggressive motivation to action," Tomohito Minakuchi, Eartha Mae Guthman and their colleagues wrote in their paper. "The VMHvl receives local inhibitory input (VMHvl shell) and long-range input from the medial preoptic area (MPO) with functional coupling to neurons with specific temporal profiles."

The VMHv1 is a nucleus located in the front-middle part of the hypothalamus, which has been previously linked to the regulation of glucose, as well as various motivation-driven behaviors, including those aimed at eating to stop hunger, sexually driven behaviors and other social behaviors.

As part of their study, Minakuchi, Guthman and their colleagues set to specifically explore the role of neurons in the VMHv1 in aggression-driven behaviors. To do this, they carried out a series of experiments on mice, during which the male mice were trained to complete a task and were rewarded by the ability to freely express their aggression towards other male mice.

The researchers observed the  of the mice and monitored the activity of individual neurons in the VMHv1 region throughout the experiments. Their analyses unveiled a relationship between the patterns of activity of neurons in this region and the progression from aggressive motivation to action.

"Encoding models reveal that during aggression, VMHvl shellvgat+ activity peaks at the start of an attack, whereas activity from the MPO–VMHvlvgat+ input peaks at specific interaction endpoints," Minakuchi, Guthman and their colleagues wrote. "Activation of the MPO–VMHvlvgat+ input promotes and prolongs a low motivation state, whereas activation of VMHvl shellvgat+ results in action-related deficits, acutely terminating attack. Moreover, stimulation of MPO–VMHvlvgat+ input is positively valenced and anxiolytic."

This recent work by Minakuchi, Guthman and their collaborators gathered new insight about the neural underpinnings of the shift from aggressive motivation to aggressive behavior in .

In the future, if validated in primates, humans, and other mammals, these findings could contribute to the understanding of psychiatric and behavioral disorders marked by anti-social tendencies, particularly by the poor inhibitory control of aggressive impulses.

More information: Tomohito Minakuchi et al, Independent inhibitory control mechanisms for aggressive motivation and action, Nature Neuroscience (2024). DOI: 10.1038/s41593-023-01563-6


https://medicalxpress.com/news/2024-03-insights-neural-mechanisms-involved-aggressive.html

Restaurants, bars still serving alcohol to intoxicated patrons

 Nearly every state has laws that ban restaurants and bars from serving alcohol to visibly intoxicated customers. But, at least in one region, few establishments seem to be complying, according to a new study in the Journal of Studies on Alcohol and Drugs.

Researchers found that across 300 bars and restaurants in the San Francisco Bay area, staff only rarely made the right call when confronted with a clearly intoxicated person ordering alcohol: Just 21% of establishments refused service.

Fortunately, in this case, the customers were actually "pseudo-patrons" working with the researchers and pretending to be inebriated. But the implications are still disquieting.

"It's discouraging to think that these laws have had so little effect," said Robert Saltz, Ph.D., a senior scientist with the Prevention Research Center at Pacific Institute for Research & Evaluation, in Berkeley, Calif.

In all U.S. states except two (Florida and Nevada), it's illegal to serve alcohol to obviously intoxicated customers. But one challenge has been putting the laws into action. Some studies have found that training servers in responsible beverage service can help. Yet not all states require such training, Saltz said, and even when they do, the quality of that training may vary widely.

It's an important issue, Saltz said, because if the laws on the books were enforced, that could potentially prevent a lot of harm. Almost one-third of traffic accidents in the United States are alcohol-related, and research has found that drivers coming home from bars are often involved.

For their study, Saltz and his colleagues wanted to see not only whether establishments would serve  to "drunk" pseudo-patrons but also whether any factors made that more or less likely: Would a busy, noisy bar be less likely to refuse service than a quieter , for example?

Over the course of a year, eight young adults trained for the study visited 300 bars and restaurants. They worked in pairs, with one portraying behaviors typical of an intoxicated patron and the other serving as an observer who recorded specific details.

Overall, servers only rarely refused to serve the pseudo-patron, although they were more likely to say no to women than to men: 31% of female patrons were refused versus 8% of men. The only other factor that seemed to correlate with refusals was whether the establishment was "upscale." Almost one third of fine-dining restaurants refused service—still clearly a disappointing rate, Saltz pointed out.

There is no single solution to the problem. More and better training for servers would likely help but will likely not be enough on its own, Saltz said. Some combination of laws, , police enforcement and community awareness may be needed to move the needle, the researchers say.

More information: Saltz, R., Paschall, M. J., O'Hara, S., Buller, D. B., Woodall, W. G., & Martinez, L. (2024). Serving alcohol to an "obviously intoxicated" patron. Journal of Studies on Alcohol and Drugs, 85(2), 168–174. doi.org/10.15288/jsad.23-00253


https://medicalxpress.com/news/2024-03-restaurants-bars-alcohol-intoxicated-patrons.html

Walgreens settles New York charges it grossly inflated prices of infant formula

  Walgreens has settled charges by New York Attorney General Letitia James that it grossly inflated prices on at least 20 infant formula products after a recall by Abbott Labs led to a nationwide shortage in early 2022.

The largest U.S. pharmacy chain did not admit or deny wrongdoing in entering an assurance of discontinuance with James' office, including a $50,000 payment covering civil penalties and costs, that was made public on Monday.

James said Walgreens raised prices on the 20 products, including Abbott's Similac and Reckitt Benckiser's Enfamil, by 10% or more following the February 2022 recall, and in at least one case boosted formula prices by more than 70%.

Walgreens allegedly sold more than 3,400 cans or bottles or formula at the "unconscionably" inflated prices.

Without admitting or denying wrongdoing, Walgreens agreed not to charge excessive prices on consumer goods and services vital and necessary to people's health and safety.

The Deerfield, Illinois-based company also agreed to donate 9,564 canisters of formula to benefit low-income New Yorkers with infant children.

Walgreens declined to comment.

"During the formula shortage, families were panicked and struggling about how to feed their babies," James said in a statement. "For Walgreens to take advantage of this crisis and jack up formula prices is not only illegal, but downright shameful.

"My office will not tolerate any company that attempts to price gouge our state's consumers," she added.

The settlement was effective as of March 7, and signed by a Walgreens representative on Monday.

Abbott recalled its infant formula and closed its Sturgis, Michigan plant following reports that infants became sick after being fed formula that was produced there. The company reopened the plant that July. 

https://finance.yahoo.com/news/1-walgreens-settles-york-charges-230352389.html

Alkermes and Jazz: Two Different Approaches to Neuroscience, Oncology Portfolios

 Dublin-based Alkermes is one of the industry’s most recent examples of a global biopharma spinning off a business as part of its strategy to generate profitability and cash flow. Alkermes entered 2024 as a pure-play neuroscience company focused on difficult-to-treat psychiatric and neurological disorders, having completed the separation of its oncology business into a new company, Mural Oncology, in November 2023.  

Founded in 1987, Alkermes decided a couple of years ago to “clean up and clarify” the company’s business for investors, CEO Richard Pops told BioSpace.

“Alkermes has always been so multivalent, so complicated. We had a legacy drug delivery royalty business—with large cash flows coming from that. We had a neuroscience business, a commercial business. We had an oncology business. And we didn’t fit in a particular category,” Pops said.

The CEO compared Alkermes’ evolution over the years to a tree with two trunks: neuroscience and oncology. “When you plant the tree and it’s growing, for a while it’s no problem. But pretty soon they get big, and you’ve got to decide how you’re going to support both of them,” Pops said.

Spinning off Alkermes’ oncology business by creating Mural Oncology, a public company, was a big undertaking given the IRS and SEC regulations, Pops said, but the cancer business deserved its own capital, instead of sharing with the neuroscience arm of the business.  

Moreover, Alkermes now has “a really clear story,” Pops said. “It’s a pure-play neuroscience company that has a billion dollars of revenue and growing.” It’s important to have that division for oncology-focused investors and analysts and those following the neuroscience market, he said.

Jazz Pharmaceuticals, on the other hand, has opted not to divorce its neuroscience and oncology pipelines. Bruce Cozadd, co-founder and CEO, told BioSpace that the Dublin-based company has been in the neuroscience space since its founding in 2003, only beginning to target oncology nine years later. Today, about half of Jazz’s revenues currently come from its oncology portfolio.

“Both of those businesses are growing and have robust pipelines,” Cozadd said. He added that while he’s aware of companies like Alkermes that have separated their neuroscience and oncology businesses, Jazz was not considering such a move. Cozadd pointed to his company’s financial strength as one reason for that decision.

Jazz reported late last month that its oncology revenue surpassed $1 billion in 2023, while total neuroscience revenue came in at $2.8 billion. By comparison, Alkermes last month announced total 2023 revenues of $1.66 billion. As of Dec. 31, 2023, Jazz had $1.6 billion in cash, cash equivalents and investments, while Alkermes reported about half that.

“We’re in the fortunate position that we can fund our key growth drivers commercially . . . while at the same time making pipeline investments,” Cozadd said.  

To expand its early-stage oncology pipeline, Jazz last month bought Redx Pharma’s KRAS inhibitor program in a potential $880 million deal, including preclinical-stage drug candidates, with the companies working to advance assets through IND-enabling studies.

However, it hasn’t been smooth sailing for Jazz’s neuroscience business. In December 2023, Jazz reported top-line Phase II results for JZP150—a small molecule being studied in patients with post-traumatic stress disorder—showing that the investigational candidate fell short of its primary efficacy endpoint and failed to meet key secondary endpoints.

“We’re not in both oncology and neuroscience because of some mechanistic scientific medical reason,” Cozadd said. “We’re in these two areas because we look for areas where there’s significant unmet medical need and we can offer a differentiated product that really benefits patients in a unique way.”

While Jazz’s neuroscience portfolio currently generates more revenue than its oncology business, the nearer term “larger” potential opportunities are in the oncology pipeline, according to Cozadd. “We don’t have a particular goal of a ratio,” he added. “I’d like both of them to be as big as possible.” 

https://www.biospace.com/article/alkermes-and-jazz-two-different-approaches-to-dealing-with-neuroscience-oncology-portfolios/

Four Years Ago This Week, Freedom Was Torched

 by Jeffrey Tucker via The Brownstone Institute,

"Beware the Ides of March,” Shakespeare quotes the soothsayer’s warning Julius Caesar about what turned out to be an impending assassination on March 15. The death of American liberty happened around the same time four years ago, when the orders went out from all levels of government to close all indoor and outdoor venues where people gather. 

It was not quite a law and it was never voted on by anyone. Seemingly out of nowhere, people who the public had largely ignored, the public health bureaucrats, all united to tell the executives in charge – mayors, governors, and the president – that the only way to deal with a respiratory virus was to scrap freedom and the Bill of Rights. 

And they did, not only in the US but all over the world. 

The forced closures in the US began on March 6 when the mayor of Austin, Texas, announced the shutdown of the technology and arts festival South by Southwest. Hundreds of thousands of contracts, of attendees and vendors, were instantly scrapped. The mayor said he was acting on the advice of his health experts and they in turn pointed to the CDC, which in turn pointed to the World Health Organization, which in turn pointed to member states and so on. 

There was no record of Covid in Austin, Texas, that day but they were sure they were doing their part to stop the spread. It was the first deployment of the “Zero Covid” strategy that became, for a time, official US policy, just as in China. 

It was never clear precisely who to blame or who would take responsibility, legal or otherwise. 

This Friday evening press conference in Austin was just the beginning. By the next Thursday evening, the lockdown mania reached a full crescendo. Donald Trump went on nationwide television to announce that everything was under control but that he was stopping all travel in and out of US borders, from Europe, the UK, Australia, and New Zealand. American citizens would need to return by Monday or be stuck. 

Americans abroad panicked while spending on tickets home and crowded into international airports with waits up to 8 hours standing shoulder to shoulder. It was the first clear sign: there would be no consistency in the deployment of these edicts. 

There is no historical record of any American president ever issuing global travel restrictions like this without a declaration of war. Until then, and since the age of travel began, every American had taken it for granted that he could buy a ticket and board a plane. That was no longer possible. Very quickly it became even difficult to travel state to state, as most states eventually implemented a two-week quarantine rule. 

The next day, Friday March 13, Broadway closed and New York City began to empty out as any residents who could went to summer homes or out of state. 

On that day, the Trump administration declared the national emergency by invoking the Stafford Act which triggers new powers and resources to the Federal Emergency Management Administration. 

In addition, the Department of Health and Human Services issued a classified document, only to be released to the public months later. The document initiated the lockdowns. It still does not exist on any government website.

The White House Coronavirus Response Task Force, led by the Vice President, will coordinate a whole-of-government approach, including governors, state and local officials, and members of Congress, to develop the best options for the safety, well-being, and health of the American people. HHS is the LFA [Lead Federal Agency] for coordinating the federal response to COVID-19.

Closures were guaranteed:

Recommend significantly limiting public gatherings and cancellation of almost all sporting events, performances, and public and private meetings that cannot be convened by phone. Consider school closures. Issue widespread ‘stay at home’ directives for public and private organizations, with nearly 100% telework for some, although critical public services and infrastructure may need to retain skeleton crews. Law enforcement could shift to focus more on crime prevention, as routine monitoring of storefronts could be important.

In this vision of turnkey totalitarian control of society, the vaccine was pre-approved: “Partner with pharmaceutical industry to produce anti-virals and vaccine.”

The National Security Council was put in charge of policy making. The CDC was just the marketing operation. That’s why it felt like martial law. Without using those words, that’s what was being declared. It even urged information management, with censorship strongly implied.

The timing here is fascinating. This document came out on a Friday. But according to every autobiographical account – from Mike Pence and Scott Gottlieb to Deborah Birx and Jared Kushner – the gathered team did not meet with Trump himself until the weekend of the 14th and 15th, Saturday and Sunday. 

According to their account, this was his first real encounter with the urge that he lock down the whole country. He reluctantly agreed to 15 days to flatten the curve. He announced this on Monday the 16th with the famous line“All public and private venues where people gather should be closed.”

This makes no sense. The decision had already been made and all enabling documents were already in circulation. 

There are only two possibilities. 

One: the Department of Homeland Security issued this March 13 HHS document without Trump’s knowledge or authority. That seems unlikely. 

Two: Kushner, Birx, Pence, and Gottlieb are lying. They decided on a story and they are sticking to it. 

Trump himself has never explained the timeline or precisely when he decided to greenlight the lockdowns. To this day, he avoids the issue beyond his constant claim that he doesn’t get enough credit for his handling of the pandemic.

With Nixon, the famous question was always what did he know and when did he know it? When it comes to Trump and insofar as concerns Covid lockdowns – unlike the fake allegations of collusion with Russia – we have no investigations. To this day, no one in the corporate media seems even slightly interested in why, how, or when human rights got abolished by bureaucratic edict. 

As part of the lockdowns, the Cybersecurity and Infrastructure Security Agency, which was and is part of the Department of Homeland Security, as set up in 2018, broke the entire American labor force into essential and nonessential.

They also set up and enforced censorship protocols, which is why it seemed like so few objected. In addition, CISA was tasked with overseeing mail-in ballots. 

Only 8 days into the 15, Trump announced that he wanted to open the country by Easter, which was on April 12. His announcement on March 24 was treated as outrageous and irresponsible by the national press but keep in mind: Easter would already take us beyond the initial two-week lockdown. What seemed to be an opening was an extension of closing. 

This announcement by Trump encouraged Birx and Fauci to ask for an additional 30 days of lockdown, which Trump granted. Even on April 23, Trump told Georgia and Florida, which had made noises about reopening, that “It’s too soon.” He publicly fought with the governor of Georgia, who was first to open his state. 

Before the 15 days was over, Congress passed and the president signed the 880-page CARES Act, which authorized the distribution of $2 trillion to states, businesses, and individuals, thus guaranteeing that lockdowns would continue for the duration. 

There was never a stated exit plan beyond Birx’s public statements that she wanted zero cases of Covid in the country. That was never going to happen. It is very likely that the virus had already been circulating in the US and Canada from October 2019. A famous seroprevalence study by Jay Bhattacharya came out in May 2020 discerning that infections and immunity were already widespread in the California county they examined. 

What that implied was two crucial points: there was zero hope for the Zero Covid mission and this pandemic would end as they all did, through endemicity via exposure, not from a vaccine as such. That was certainly not the message that was being broadcast from Washington. The growing sense at the time was that we all had to sit tight and just wait for the inoculation on which pharmaceutical companies were working. 

By summer 2020, you recall what happened. A restless generation of kids fed up with this stay-at-home nonsense seized on the opportunity to protest racial injustice in the killing of George Floyd. Public health officials approved of these gatherings – unlike protests against lockdowns – on grounds that racism was a virus even more serious than Covid. Some of these protests got out of hand and became violent and destructive. 

Meanwhile, substance abuse rage – the liquor and weed stores never closed – and immune systems were being degraded by lack of normal exposure, exactly as the Bakersfield doctors had predicted. Millions of small businesses had closed. The learning losses from school closures were mounting, as it turned out that Zoom school was near worthless. 

It was about this time that Trump seemed to figure out – thanks to the wise council of Dr. Scott Atlas – that he had been played and started urging states to reopen. But it was strange: he seemed to be less in the position of being a president in charge and more of a public pundit, Tweeting out his wishes until his account was banned. He was unable to put the worms back in the can that he had approved opening. 

By that time, and by all accounts, Trump was convinced that the whole effort was a mistake, that he had been trolled into wrecking the country he promised to make great. It was too late. Mail-in ballots had been widely approved, the country was in shambles, the media and public health bureaucrats were ruling the airwaves, and his final months of the campaign failed even to come to grips with the reality on the ground. 

At the time, many people had predicted that once Biden took office and the vaccine was released, Covid would be declared to have been beaten. But that didn’t happen and mainly for one reason: resistance to the vaccine was more intense than anyone had predicted. The Biden administration attempted to impose mandates on the entire US workforce. Thanks to a Supreme Court ruling, that effort was thwarted but not before HR departments around the country had already implemented them. 

As the months rolled on – and four major cities closed all public accommodations to the unvaccinated, who were being demonized for prolonging the pandemic – it became clear that the vaccine could not and would not stop infection or transmission, which means that this shot could not be classified as a public health benefit. Even as a private benefit, the evidence was mixed. Any protection it provided was short-lived and reports of vaccine injury began to mount. Even now, we cannot gain full clarity on the scale of the problem because essential data and documentation remains classified. 

After four years, we find ourselves in a strange position. We still do not know precisely what unfolded in mid-March 2020: who made what decisions, when, and why. There has been no serious attempt at any high level to provide a clear accounting much less assign blame. 

Not even Tucker Carlson, who reportedly played a crucial role in getting Trump to panic over the virus, will tell us the source of his own information or what his source told him. There have been a series of valuable hearings in the House and Senate but they have received little to no press attention, and none have focus on the lockdown orders themselves. 

The prevailing attitude in public life is just to forget the whole thing. And yet we live now in a country very different from the one we inhabited five years ago. Our media is captured. Social media is widely censored in violation of the First Amendment, a problem being taken up by the Supreme Court this month with no certainty of the outcome. The administrative state that seized control has not given up power. Crime has been normalized. Art and music institutions are on the rocks. Public trust in all official institutions is at rock bottom. We don’t even know if we can trust the elections anymore. 

In the early days of lockdown, Henry Kissinger warned that if the mitigation plan does not go well, the world will find itself set “on fire.” He died in 2023. Meanwhile, the world is indeed on fire. The essential struggle in every country on earth today concerns the battle between the authority and power of permanent administration apparatus of the state – the very one that took total control in lockdowns – and the enlightenment ideal of a government that is responsible to the will of the people and the moral demand for freedom and rights. 

How this struggle turns out is the essential story of our times. 

CODA: I’m embedding a copy of PanCAP Adapted, as annotated by Debbie Lerman. You might need to download the whole thing to see the annotations. If you can help with research, please do.

*  *  *

Jeffrey Tucker is the author of  new book 'Life After Lock-Down'

https://www.zerohedge.com/covid-19/four-years-ago-week-freedom-was-torched

France & Estonia State Agencies Hit By 'Intense' Cyberattacks

 On Monday the government of France said several of its agencies were hit by 'intense' cyberattacks. "Many ministerial services were targeted" from Sunday "using familiar technical means but of unprecedented intensity," Prime Minister Gabriel Attal's office said.

The PM's staff announced that a "crisis cell has been activated to deploy countermeasures", meaning "the impact of these attacks has been reduced for most services and access to state websites restored." The statement didn't directly accuse Russia, but officials have implied it. It comes after Defense Minister Sebastien Lecornu last month said that protection against "sabotage and cyberattack" by Russia should be a top priority.

While little in the way of specific details were initially given as to the targets of Monday's intrusions, the attacks come days after newly appointed French Minister Delegate for Europe Jean-Noël Barrot charged that Russia is ramping up its cyberattacks and disinformation campaigns targeting Europe.

"We’ve been seeing over the past few months aggressivity towards European countries through cyberattacks, through disinformation, misinformation campaigns," Barrot said of the Kremlin in a Friday interview with state-run France24.

"And this suggests that we need in Europe to display unity and strength and send this signal to Vladimir Putin that we will support Ukraine whatever it takes, and that we will stand alongside the Ukrainian resistance," Barrot continued. He said this soon after French President Emmanuel Macron floated the possibility of sending Western troops to Ukraine, which has unleashed immense controversy even within NATO alliance countries.

This past weekend saw one of the largest cyber attacks ever launched against the Baltic state of Estonia, which has also been an outspoken supporter of Ukraine.

Regional media pointed to pro-Kremlin hackers for a devastating DDoS attack:

Over the weekend, the websites of numerous Estonian government institutions were targeted by the largest wave of DDoS (Distributed Denial of Service) attacks in the country’s history. The attacks, claimed by pro-Kremlin hackers, were reported by the Postimees newspaper on Monday.

"Thanks to the quick actions taken, the impact of the attack on the functioning of institutions was not significant," the newspaper emphasized.

Dozens of public sector websites were reportedly targeted Saturday and Sunday, including sites for the Estonian Police and Border Guard Board (PPA), the tax and customs board, and the Ministry of Justice. 

Just days ago...

"Pro-Kremlin hacker groups have been primarily claiming responsibility for the attacks, as was the case last weekend," said the Estonian agency. Ukraine itself has also long been directly subject of Russian cyber warfare, however, NATO countries have assisted Kiev and have been largely successful in defending the country's information systems.

https://www.zerohedge.com/geopolitical/france-estonia-state-agencies-hit-intense-cyberattacks

Monday, March 11, 2024

Aprea gets go-ahead for cancer therapy study

 Monday, Aprea Therapeutics Inc 

+ Free Alerts
 announced that the FDA has cleared its Investigational New Drug (IND) application for APR-1051.

“APR-1051 is a next-generation inhibitor of WEE1 kinase, and based on its unique characteristics, we believe it will be best in class,” said Oren Gilad, President and CEO of Aprea.

“We look forward to evaluating therapeutic activity in patients, focusing on Cyclin E overexpressing cancers, including ovarian and breast cancers,” Gilad added.

Clearance of the IND application will allow Aprea to initiate the Phase 1 ACESOT-1051 dose escalation trial to evaluate the safety, tolerability, and preliminary efficacy of APR-1051. 

Enrollment of the first patient in this study is expected in the first half of 2024, with an update expected in the fourth quarter of the year.

Concurrently, Aprea Therapeutics has announced a private placement of up to $34 million, including initial upfront funding of $16.0 million and up to an additional $18.0 million upon cash exercise of accompanying warrants at the election of the investors.

Aprea will use the net proceeds from the private placement for general corporate purposes and to fund the clinical development of APR-1051, the Company’s WEE1 inhibitor product candidate. 

The aggregate net proceeds (assuming the cash exercise of all accompanying warrants) are expected to be sufficient to fund the company into 2026.

https://www.benzinga.com/general/biotech/24/03/37586418/why-is-precision-oncology-focused-aprea-therapeutics-stock-trading-higher-on-monday