Link between lung cancer and chronic pain—and a druggable pathway for both

 Scientists have uncovered a link between chronic pain and lung cancer—a link that also offers a potentially druggable pathway for both conditions, according to new research conducted in mouse models.

The research was led by an international team of scientists from Harvard Medical School, Boston Children’s Hospital and the Austrian Academy of Sciences’ Institute of Molecular Biotechnology and was published Aug. 31 in Science Translational Medicine.

Considering the addiction risk tied to opioid painkillers, there’s an urgent need for new non-opioid painkillers, particularly for patients with chronic pain.

The research team had previously discovered that sensory neurons produce a metabolite known as BH4 that can drive chronic pain. Higher concentrations of BH4 were tied to increased pain sensitivity and persistence. Based on these findings, the team decided to launch their new research by targeting the BH4 pathway.

The researchers conducted a phenotypic screen of 1,000 FDA-approved medications to identify ones that reduce BH4 levels in pain neurons. They linked previously observed painkilling effects of several drugs—including clonidine, a sedative and antihypertensive drug—to the BH4 pathway.

The screening unveiled an unexpected molecular link between the BH4 pathway and EGFR/KRAS signaling, a pathway involved in multiple cancers. In fact, EGFR and KRAS are thought to be the most frequently mutated genes in lung cancer.

Blocking EGFR/KRAS signaling decreased pain sensitivity by reducing BH4 levels, according to the new findings. EGFR/KRAS signaling also increased expression of GCH1, an important enzyme in the BH4 pathway that contributes to neuropathic pain. So it also turned out that blocking EGFR inhibited GCH1 and was tied to pain relief.

“The same triggers that drive tumor growth appear to be also involved in setting the path to chronic pain, often experienced by cancer patients. We also know that sensory nerves can drive cancer, which could explain the vicious circuit of cancer and pain,” said co-corresponding author Josef Penninger, IMBA group leader and founding director, in a press release. “Understanding these cross-talks is therefore not only critical for cancer treatments but might also help to improve the quality of life for cancer patients towards less pain.”

The researchers went a step further, deleting GCH1 in some of the mice with KRAS-driven lung cancer. They found that those mice developed fewer tumors and survived longer.

GCH1/BH4 acts downstream of KRAS to drive lung cancer—presenting itself as a common signaling pathway for chronic pain and lung cancer, as well as a potentially druggable target. However, not a lot is known about regulating GCH1 expression for nerve injury or if it could be used as an analgesic.

The phenotypic screen also led the team to a separate discovery: fluphenazine, an antipsychotic drug that has been used to treat schizophrenia, blocks the BH4 pathway in injured nerves. The effective fluphenazine dose used in the mouse model is similar to the low end of doses safely indicated for schizophrenia in humans.

https://www.fiercebiotech.com/research/scientists-uncover-link-between-chronic-pain-lung-cancer-and-druggable-pathway-both

FDA lets Curis resume enrollment for part of phase 1/2 leukemia study

 Curis has received another spark of hope as the FDA lets the biotech resume enrollment for a part of its phase 1/2 study assessing emavusertib in patients with leukemia.

In April 2022, the FDA placed a partial clinical hold on the study—dubbed TakeAim Leukemia and examining emavusertib in patients with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome—after a patient death spurred a review. A week later, the agency slapped a separate partial hold on the biotech’s TakeAim Lymphoma study examining the same drug but in patients with relapsed or refractory B-cell malignancies.

The partial holds came so the FDA could investigate the safety and efficacy of emavusertib—an IRAK4 kinase inhibitor—following an information request about the death of an AML patient who experienced rhabdomyolysis and other conditions. Rhabdomyolysis—the breakdown of skeletal muscle—is a known dose-limiting toxicity of emavusertib.

Curis received some good news Aug. 18 when the FDA lifted the partial hold on its lymphoma trial. Curis and the FDA agreed on a strategy for rhabdomyolysis identification and management as well as on the enrollment of at least nine more patients at the 200-mg dose level of emavusertib in combination with Imbruvica. 

Now, the FDA is letting Curis resume patient enrollment in the phase 1a portion of TakeAim Leukemia, according to an Aug. 30 release. The biotech intends to enroll at least nine more patients at the 200-mg dose level of emavusertib, which has an FDA orphan-drug tag in AML.

Before lifting the enrollment restriction, the FDA reviewed additional data from Curis about the risk of rhabdomyolysis along with the company's strategy for using lab measurements to identify the condition and manage it if detected. 

The partial hold remains in place for the combination therapy phase (phase 1b) of TakeAim Leukemia, in which Curis was evaluating doses of emavusertib with azacitidine or the AbbVie-Genentech drug Venclexta. The trial’s expansion phase (phase 2a) is also still under a partial hold. Both holds will remain in place until phase 1a is completed and the FDA greenlights the next phases.

"We are pleased to announce the results of the FDA's review and to have addressed potential concerns about the identification and management of rhabdomyolysis," said James Dentzer, president and CEO of Curis. "We are working with our clinical sites to quickly resume enrollment of additional patients."

https://www.fiercebiotech.com/biotech/fda-sparks-hope-curis-lets-biotech-resume-enrollment-part-phase-12-leukemia-study

$5.53B: Olympus, PerkinElmer sell lab equipment businesses to private equity

 Medical and life sciences manufacturer Olympus is selling Evident, its lab instrument subsidiary, to a private equity firm for $3.08 billion, Chemical & Engineering News reported Sept. 1.

Bain Capital's acquisition of the lab equipment business comes less than one month after PerkinElmer said it would sell its name and analytical assets to private equity firm New Mountain Capital for $2.45 billion, the report said. Olympus will look to focus on its medical endoscopes and other therapeutic lines.

Evident sells microscopes, X-ray fluorescence analyzers and other optical instruments, and industrial endoscopes and related inspection equipment, the report said.

https://www.beckershospitalreview.com/lab/5-53b-olympus-perkinelmer-sell-lab-equipment-businesses-to-private-equity.html

Data For Newly Authorized COVID-19 Boosters Based On Mice, Not Humans

 by Zachary Stieber via The Epoch Times (emphasis ours),

The preclinical data for the just-authorized COVID-19 booster shots are based on just mice, not humans, because U.S. authorities believe waiting for human trial data would have made the updated boosters outdated.

The data for Pfizer’s booster was based on just 8 mice, Pfizer scientists told the U.S. Food and Drug Administration’s (FDA) vaccine advisory panel in June. The data for Moderna’s booster was based on 16 to 20 mice, some of which received the original booster, according to a presentation slated to be delivered to the U.S. Centers for Disease Control and Prevention’s (CDC) advisory panel on Sept. 1.

The mice data show “substantial increases against all Omicron sublineages including BA.4/5 as well as the reference strain with the BA.4/5- modified vaccines,” Kena Swanson, Pfizer’s vice president for vaccine research and development, told the FDA panel.

BA.4 and BA.5 are both subvariants of the Omicron variant of the virus that causes COVID-19.

Both Moderna and Pfizer developed boosters containing parts of the original COVID-19 virus and the BA.1 subvariant, but the FDA after the June meeting asked the vaccine makers to switch out the BA.1 component for a component targeting BA.4 and BA.5, the latter of which is the dominant strain in the United States.

The FDA declined to require human trial data for authorization, and granted authorization for both updated boosters on Aug. 31.

The mice data “demonstrate that these vaccines successfully evoke an immune response in the same way previous versions of the vaccine have,” Dr. Peter Marks, a top FDA vaccine official, told reporters on a call.

CDC Director Dr. Rochelle Walensky also signaled support for the path.

“If we wait for those data to emerge in human data, not just mice data, we will be using what I would consider to be a potentially outdated vaccine,” Walensky said on “Conversations on Health Care” during a segment broadcast on Aug. 29.

Unprecedented

Dr. Monica Gandhi, a professor of medicine at University of California, San Francisco, said that she thinks the updated booster “has the potential to increase antibodies in humans to the circulating subvariant (mainly BA.5 at this point), but to be fair, we need to note that we only have data in mice of increased antibodies at this point.”

“We do not have human data on this new booster, either antibody data or clinical data. However, there is biological plausibility that these updated boosters will curb cases by increasing antibodies as we enter the winter,” Gandhi told The Epoch Times in an email.

Gandhi recommends all Americans 65 and older, or others who are immunocompromised, get the updated booster, especially in those who received their most recent shot more than 6 months ago, citing recent papers on vaccine effectiveness.

The FDA is advising all Americans 12 and older to get the updated booster just two months after their latest shot.

John Moore, a vaccine expert at Weill Cornell Medicine, told USA Today before the authorizations that relying on mouse data “would be unprecedented in my knowledge and would certainly raise eyebrows,” but told The Epoch Times in an email on Thursday that he’s not concerned about safety.

“It’s still the same vaccine, just with a small tweak. The same strategy is used every year to adjust the composition of the standard flu vaccines. I’d draw an analogy to getting a new paint job on your car—that would not trigger the need for a full-service check into all the safety features. However, I think many members of the public may be concerned—particularly ones who have listened to the lies from anti-vaxxers,” he added, using a pejorative for people concerned about vaccine side effects and waning effectiveness.

https://www.zerohedge.com/covid-19/data-newly-authorized-covid-19-boosters-based-mice-not-humans

What’s in the New 401(k) Retirement Bills

 Retirement plans could see some major changes if proposed new legislation is approved by Congress. “They have so many bills,” says Ed Slott, president and founder of Ed Slott and Company. “Some people call the whole batch SECURE 2.0. There’s an EARN Act (Enhancing American Retirement Now). One is the Retirement Protection Act. There’s a bunch of different acts here.”

These retirement bills would:

• Increase the maximum annual contribution for retirement accounts by $4,000.
• Increase the age when you must begin required minimum distributions.
• Require automatic enrollment and escalation for employer-sponsored plans.
• Increase the amount for the catch-up provision for those 50 and older.
• Allow employers to help those who are burdened with student debt save for retirement.

Many of the changes are intended to encourage employees to prepare for retirement. “For the most part, what they're trying to do is get people really to save,” says Eric Bond, a wealth advisor with Bond Wealth Management in Long Beach California. "They feel that people don't have enough money in their retirement accounts.”
Here's a look at some of the proposed changes to retirement accounts.

Increase the Annual Contribution Limit for Retirement Accounts by $4,000

The annual limit for tax-deductible contributions for people under 50 is currently $6,000 for an individual retirement account and $20,500 for a 401(k). “Basically, they're proposing raising the limit for one year, and I say they're proposing because this may go nowhere. Whether it's a Roth IRA or the traditional IRA, the proposal is to increase the contribution limit by $4,000 to $10,000," Slott says. "The 401(k) contribution limit would move up to $24,500, which is a lot you could put in, if you have the money.”

Increase the Age for Required Minimum Distributions

Money typically goes into traditional retirement accounts tax deferred, but you have to take distributions and pay the taxes in retirement. It was required that participants begin withdrawals at age 70 1/2. The SECURE Act raised the required minimum distribution age to 72. Now the House has passed SECURE 2.0, which would increase the age for RMDs to 73 in 2022 and 75 in 2032. However, it must still be passed by the Senate and signed by the president before it would become law.

The formula that sets the amount of your required minimum distribution considers life expectancy. “Now that we're living longer, it makes sense to start it later,” Bond says. “People who need it take it anyway. People who don't need it keep deferring it and deferring it. The whole goal of the IRA is to make sure people in retirement have enough (savings) throughout their lifetime."

Increase the Catch-Up Provision for People Age 50 and Over

There are several proposals to allow increased catch-up contributions to retirement accounts. Catch-up provisions permit people 50 and older to catch up on saving for retirement during their peak earning years. The catch-up contribution limits for 2022 are $6,500 for 401(k)s and $1,000 for IRAs.

Some proposed legislation would allow people between ages 62 and 64 to put an additional $10,000 into retirement accounts via the catch-up provision. However, the money would not be tax-deferred, making it a Roth contribution. A separate Senate bill limits the new catch-up contributions to those ages 60 to 63. “They're all over the place,” Slott says. “They're not even in agreement with the House and Senate yet. That's why I say that Congress is thinking about these things, but they really haven't solidified everything.”

Automatic Enrollment and Escalation in 401(k) Plans

Employees might increasingly be automatically enrolled in workplace retirement accounts. “They really want to have the employers create these 401(k) plans for the employees and automatically enroll them in it starting at 3%,” Bond says. “If you make it mandatory, the only way they cannot be part of it is for them to opt out of it.”

A 401(k) Match for Student Loan Payments

If you have student loan debt and an employer-sponsored retirement plan, one proposal will allow your employer to match your monthly payment up to a certain amount and put that directly into your 401(k). “They don’t want people to say they can't save because they have a student loan,” Bond says.

These legislative proposals are not current law and are subject to change. “It hasn't come together yet," Slott says. “The bottom line is more people will be able to put more away for their retirement, especially older people who need to catch up.”

https://money.usnews.com/money/retirement/401ks/articles/whats-in-the-new-401k-retirement-bills

Profit From America’s Healthcare Bloat

 It’s no secret America has one of the least-efficient healthcare systems in the world, far outspending other wealthy countries for poorer results. The high cost of everything from medical procedures to cancer drugs often gets much of the blame.

But just as bad are the incentives baked into it. Most wealthy countries have government-controlled health systems that encourage doctors to keep costs down by directing patients to less invasive approaches at first. America’s works the opposite way.

In the US, everyone from your primary-care doctor to your cardiologist has an incentive to make you consume as much healthcare as possible, from the prescription drug you could do without to the expensive surgical procedure you might be able to avoid through physical therapy.

But the incentives might be starting to change, ever so gradually, creating an opportunity for a host of companies, Among them are those helping doctors make the shift, like Privia Health Group Inc. PRVA 0.71% and Agilon Health Inc. AGL 0.24%

Others, like Oak Street Health Inc., Cano Health Inc. and CareMax Inc., also invest and operate medical centers that focus on value-based care.

The trend started with the country’s largest insurer—the government. Due to provisions in the Affordable Care Act, Medicaid has been pushing providers to adopt the approach, which seeks to reward the doctor for keeping a patient healthy, instead of just encouraging more volume, known as a fee-for-service model. Commercial insurers such as UnitedHealth Group, the nation’s largest, are also pushing to shift medical providers to this model.

We are still in the early stages, with more than 70% of provider revenue tied to fee-for-service arrangements, according to Gist Healthcare. But analysts including Ryan Daniels at William Blair see value-based care expanding in the coming decade as pressure to reduce healthcare costs grows.

“We believe a movement of financial and quality risk to providers is the best means to address the cost and quality issues that are present in healthcare today,” analysts led by Mr. Daniels wrote in a recent report.

The changes might gradually help turn the tide on healthcare costs, but for medical providers they are a big headache. Realigning a large medical practice to a new business model can be cumbersome. Doctors go to school to treat patients, not to deal with revamping their actuarial models or upgrading their IT systems. Some groups wind up partnering, or selling themselves to a larger business like UnitedHealth Group Inc.’s Optum, which can help move providers to value-based care. Others who choose to remain independent are turning to companies like Privia or Agilon, which focuses on the Medicare population.

“When doctors go to medical school they don’t learn about the technology stack, the revenue cycle or reimbursement models,” says Parth Mehrotra, Privia’s president and chief operating officer. “We’re stepping in to handle those things so doctors can actually practice medicine.”

Most of Privia’s providers are still using a fee-for-service model, but the company aims to convert a growing portion of them to value-based care over time. Analysts expect Privia’s practice collections, a measure of revenue, to grow from $1.6 billion in 2021 to $2.7 billion in 2023, according to data compiled by FactSet, Privia’s shares have outperformed the broader market, rising 55% this year.

There are risks to that growth, of course. For Privia, one particular challenge is that it is pitching its services to independent doctors who could just sell their practices to a company such as Optum, for instance.

Industry watchers have been talking about the shift to value-based care for years and the pace has been slow but undeniable. Instead of just hoping to cash in on the next high-price drug or device, investors can also make money from wringing the excess out of America’s pricey healthcare complex.

https://netionaldastak.com/profit-from-americas-healthcare-bloat/

Recycling Greenhouse Gases

 Wherever the production of harmful greenhouse gases cannot be prevented, they should be converted into something useful: this approach is called "carbon capture and utilisation". Special catalysts are needed for this. Until now, however, the problem has been that a layer of carbon quickly forms on these catalysts - this is called "coking" - and the catalyst loses its effect. At TU Wien, a new approach was taken: tiny metallic nanoparticles were produced on perovskite crystals through special pre-treatment. The interaction between the crystal surface and the nanoparticles then ensures that the desired chemical reaction takes place without the dreaded coking effect.

Dry reforming: Greenhouse gases become synthesis gas

Carbon dioxide (CO2) and methane are the two human-made greenhouse gases that contribute most to climate change. Both gases often occur in combination, for example in biogas plants. "So-called methane dry reforming is a method that can be used to convert both gases into useful synthesis gas at the same time," says Prof. Christoph Rameshan from the Institute of Materials Chemistry at TU Wien. "Methane and carbon dioxide are turned into hydrogen and carbon monoxide - and it is then relatively easy to produce other hydrocarbons from them, right up to biofuels."

The big problem here is the stability of the catalysts: "The metal catalysts that have been used for this process so far tend to produce tiny carbon nanotubes," explains Florian Schrenk, who is currently working on his dissertation in Rameshan's team. These nanotubes deposit as a black film on the surface of the catalyst and block it.

Perovskite crystals as the key to success

The TU Wien team has now created a catalyst with fundamentally different properties: "We use perovskites, which are crystals containing oxygen, which can be doped with various metal atoms," says Christoph Rameshan. "You can insert nickel or cobalt, for example, into the perovskite – metals that have also been used in catalysis before."

A special pre-treatment of the crystal with hydrogen at around 600 °C allows the nickel or cobalt atoms to migrate to the surface and form nanoparticles there. The size of the nanoparticles is crucial: Success has been achieved with nanoparticles with a diameter of 30 to 50 nanometres. The desired chemical reaction then takes place on these tiny grains, but at the same time the oxygen contained in the perovskite prevents the formation of carbon nanotubes.

"We were able to show in our experiments: If you choose the right size of nanoparticles, no carbon film is created – coking is no longer a danger," says Florian Schrenk. "Moreover, the nanoparticles are stable, the structure of the catalyst does not change, it can be used permanently."

Important building block for tomorrow's bio-refinery

The novel perovskite catalysts could be used wherever methane and carbon dioxide are produced simultaneously - this is often the case when dealing with biological substances, for example in biogas plants. Depending on the selected reaction temperature, one can influence the composition of the resulting synthesis gas. In this way, the further processing of climate-damaging greenhouse gases into valuable products could become an important building block for a sustainable circular economy.

Original publication

F. Schrenk et al., Impact of nanoparticle exsolution on dry reforming of methane: Improving catalytic activity by reductive pre-treatment of perovskite-type catalysts, Applied Catalysis B: Environmental, 318, 121886 (2022).

https://www.tuwien.at/en/tu-wien/news/news/recycling-fuer-treibhausgase