Month: January 2023

Study reveals how exercise turns back the clock in aging muscles

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A new study investigates how exercise can help rejuvenate aging muscles.

  • Doctors call physical exercise a “polypill,” because it can prevent and treat many of the chronic diseases that are associated with aging.
  • A new study of muscle fibers from mice and humans shows how exercise affects gene expression.
  • The exercise-induced changes “reprogram” the epigenetic expression of the fibers to a more youthful state.
  • The findings could provide leads for the development of drugs to mimic these benefits in people who are unable to exercise.

Research shows that people who exercise regularly not only strengthen their muscles but also improve their overall health, regardless of how late in life they start.

For example, recent studies have found that exercise reduces the risk of cardiovascular disease, as well as Alzheimer’s and Parkinson’s in older people.

Conversely, reductions in muscle mass and strength are associated with lower quality of life and higher mortality from all causes.

As a result of its proven ability to prevent and treat several chronic diseases at low cost, doctors have called exercise a drug-free “polypill” that can benefit nearly everyone.

“Exercise is the most powerful drug we have,” says Dr. Kevin Murach, assistant professor at the Exercise Science Research Center, University of Arkansas, Fayetteville, AR.

He believes that exercise should be considered a health-enhancing, potentially life-extending treatment, alongside medications and a healthy diet.

Scientists hope that a better understanding of how exercise rejuvenates aged muscle at a molecular level will provide clues for future anti-aging therapies.

Reprogramming muscle fibers

Exercise may turn back the clock in muscle fibers by promoting the “epigenetic reprogramming” of chromosomes in the cells’ nuclei.

EpigeneticsTrusted Source refers to how chemical changes affect the activity or “expression” of genes. For example, proteins called transcription factors can dial up the expression of particular genes when they bind to specific DNA sequences.

In 2012, Dr. Shinya Yamanaka shared the Nobel Prize for MedicineTrusted Source for his discovery that four transcription factors can revert specialized, mature cells to more youthful, flexible cells called pluripotent stem cells.

The four factors are called Oct3/4, Klf4, Sox2, and Myc, or OKSM for short.

In a new study whose results appear in The Journal of PhysiologyTrusted Source, Dr. Murach and his colleagues compared the effects of OKSM factors on gene expression in the muscle fibers of mice that had access to an exercise wheel, and mice that had no access.

In addition, they compared the effects of OKSM factors on muscle with the effects of a single transcription factor, Myc. Scientists have found that exercise induces the expression of Myc to a greater extent than the other three factors.

The researchers also investigated how exercise alone affected gene expression in muscle fibers from both mice and humans. The mice were 22 months old, which is equivalent to a human age of around 73 years.

Mice in the exercise group were free to run on an unweighted wheel for the first week, then, over the next 8 weeks, the scientists made the wheel progressively heavier by attaching magnetic weights to it.

The results suggest that exercise reprograms muscle fibers to a more youthful state through increased expression of the genes that make Yamanaka factors, in particular Myc.

Supercharged exercise response

Dr. Murach suggests that the findings may one day lead to the development of drugs that supercharge the exercise response of muscles in people who are confined to bed, or the muscles of astronauts in zero gravity.

But he dismisses the idea of a pill that boosts the expression of Myc ever replacing the need to exercise. For one thing, exercise has beneficial effects throughout the body, not just in muscle.

In addition, Myc has been linked to cancer, so there are inherent risks in artificially boosting its expression.

In their paper, the researchers also note that drugs that are gaining a popular reputation as “life-extending” may actually block some of the beneficial effects of exercise on muscle.

Dr. Murach told Medical News Today:

“Evidence suggests that ‘life-extending’ drugs such as metformin and rapamycin interfere with the positive benefits of exercise specifically in skeletal muscle.”

He said it was “not outside the realm of possibility” that the drugs could disrupt the epigenetic reprogramming of muscle that happens with exercise.

Exercises for older people

MNT asked exercise physiologists to recommend the best type of exercise for older people.

“For individuals over 70 I would highly recommend low-impact, full-body workouts with a focus on lower body and core,” advised John C. Loges, an exercise physiologist at eVOLV Strong.

“Resistance training is not only suitable but highly recommended for those in their 70s and beyond,” he said.

“The key is starting slow and progressing slowly with consistency,” he added.

“[W]alking is an activity that I recommend, along with resistance and mobility training,” advised Melissa Hendrix Wogahn, an exercise physiologist at Joy of Active Living who offers fitness and health education for older adults.

“In terms of frequency, an older adult can walk every day, assuming they have no contraindications,” she added.

She recommended strength training at least two days a week and mobility training, including stretching, every day.

Limitations of the study

The authors of the new study acknowledge that it had some limitations. For example, the type of exercise, training status, biological sex, and several other factors may affect gene expression changes associated with exercise.

In addition, they emphasize the importance of investigating the functional consequences of epigenetic reprogramming in skeletal muscle.

Soybean protein may help lower cholesterol, be as beneficial as statins

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Certain proteins in soybeans may have cholesterol-lowering effects. Lucas Ninno/Getty Images

  • Researchers studied soybeans to determine why they may have the ability to lower cholesterol.
  • The scientists studied different levels of two soybean proteins—glycinin and beta-conglycinin.
  • They noted soybeans with increased levels of beta-conglycinin compared to glycinin were better able to regulate cholesterol metabolism and inhibit fatty acid oxidation.
  • Eating soybeans with higher levels of beta-conglycinin may help to maintain healthy liver and cardiovascular function.

Since heart disease is the leadingTrusted Source cause of death in the U.S., researchers are looking for ways to reduce this number. Having high cholesterol is a risk factor for heart disease, so finding ways to improve high cholesterol is important.

Previous studiesTrusted Source have shown that eating soy can reduce the levels of LDL cholesterol—also known as “bad” cholesterol by as much as 4%.

Researchers from the University of Illinois Urbana-Champaign recently looked into different varieties of soybeans to figure out why they can lower LDL cholesterol.

The scientists found one protein in particular that provided benefits and published the study results in the journal Antioxidants.

Cholesterol and heart disease

According to MedlinePlus, cholesterol is a “waxy, fat-like substance that’s found in all the cells in your body.”

Low-density lipoprotein (LDL) cholesterol is one type that doctors consider to be “bad” cholesterol. The other cholesterol type is high-density lipoprotein (HDL) cholesterol, which doctors consider “good.”

If LDL cholesterol levels get too high, the buildup can cause plaques in the walls of your arteries. This contributes to an increased risk of developing heart disease and strokes.

As Beata Rydyger, registered nutritionist based in Los Angeles and a clinical nutritional advisor to Zen Nutrients, noted in an interview with Medical News Today:

“Cholesterol imbalances may result in cardiovascular disease or even neurodegenerative diseases and cancer.“

HDL vs. LDL cholesterol

According to the Centers for Disease Control and PreventionTrusted Source (CDC), HDL cholesterol “absorbs cholesterol in the blood and carries it back to the liver. The liver then flushes it from the body.”

Having higher levels of HDL cholesterol is a good thing and can reduce heart disease and stroke risk.

The CDCTrusted Source recommends the following cholesterol levels:

  • Total cholesterol: approximately 150 mg/dL
  • LDL cholesterol: approximately 100 mg/dL
  • HDL cholesterol: 40 mg/dL and higher in men and 50 mg/dL and higher in women

The CDC notes that high cholesterol does not typically have signs and symptoms, so it is best to have this checked by a primary health provider at annual physicals.

If someone does have high cholesterol, they can treat it with lifestyle changes (diet and exercise) or medications (statins or cholesterol absorption inhibitors).

2 LDL-lowering soy proteins

Previous research has shown the positive effect of eating more soy on people’s cholesterol levels. This new study aimed to understand the mechanism behind the findings.

They suspected this positive effect could be attributed to two proteins—glycinin and B-conglycinin.

The scientists selected 19 varieties of soybeans, each containing different levels of glycinin and B-conglycinin. The ground soybeans were defatted and studied in gastrointestinal digestion simulation experiments.

In the experiments to mimic food digestion, the defatted soybean flour was mixed with fluids and enzymes from oral, gastric, intestinal, and colonic digestion. The researchers ran the simulation using fatty cells.

After running each soybean flour variety through this process, the researchers measured how well the LDL cholesterol was absorbed.

“We measured several parameters associated with cholesterol and lipid metabolism and various other markers— proteins and enzymes—that positively or negatively affect lipid metabolism,” says study author Dr. Elvira de Meji, professor of food science at the University of Illinois Urbana-Champaign.

Soybean protein reduces lipids by half

The findings of the study supported the researchers’ hypothesis—the two proteins found in soybeans, glycinin and B-conglycinin, contribute to the cholesterol-lowering ability of soybeans.

“The soybean variety affects the protein composition and peptide release under simulated gastrointestinal conditions,” write the authors.

The protein B-conglycinin has especially good cholesterol-lowering abilities. The authors found that the peptide released from this protein “reduced HMGCR expression, the concentration of esterified cholesterol and triglycerides, the release of ANGPTL3, and the production of MDA during LDL oxidation.”

Some soybean varieties blocked the synthesis of fatty acids as well as triggered LDL absorption into the liver. This could, in theory, lead to a reduction in fatty liver disease.

“These results indicate that the intake of selected soybean varieties might regulate cholesterol and LDL homeostasis and, consequently, foster the prevention of atherosclerotic cardiovascular diseases,” write the authors.

Soybeans vs. statins

The researchers also compared the benefits of the soybean flour to Simvastatin, which is a medication used to treat high cholesterol.

The authors found that peptides from the soybean flours had a similar lipid-reducing property as Simvastatin.

“The digested soybeans’ peptides were able to reduce lipid accumulation by 50%-70%, and that’s very important. That was comparable to the statin, which reduced it by 60%,” says Dr. de Mejia.

Is soy healthy for everyone?

Dr. Jayne Morgan, cardiologist and clinical director of the Covid Task Force at the Piedmont Healthcare Corporation in Atlanta, spoke with MNT about the study.

“Soybeans have been known to lower triglycerides, total cholesterol, and LDL cholesterol, thereby possibly contributing to a healthier heart profile and becoming part of a heart-healthy lifestyle. This study further complements that,” she said.

Dr. Morgan mentioned that she would like to see studies on how soy impacts women.

“The effects of soy on estrogen, especially in menopausal women for women’s health, was not addressed, but rather a focus on different species and digestion. I would love to see information on soy and breast cancer as well. Again, more studies focused specifically on women,” said Dr. Morgan.

While the researchers tested 19 varieties of soybeans, Rydyger noted that there are more than 2,500 varieties of soybeans. This makes it difficult for people to know what they should consume to receive benefits.

“They can come in all different colors and sizes so it is important to determine if some varieties are more beneficial for heart health than others,” mentioned Rydyger.

Isabel Vazquez, registered dietician at Memorial Hermann in Houston, meanwhile, cautioned that “eating soy is not a miracle cure regarding heart health.”

“I believe in the benefits of incorporating a plant-based diet for heart health; that would also include eating a variety of plant sources like oats, nuts, and beans,” Ms. Vazquez told MNT.

FDA OKs Adjuvant Pembrolizumab for NSCLC

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Immunotherapy improved DFS versus placebo in patients regardless of PD-L1 expression

FDA APPROVED pembrolizumab (Keytruda) over a computer rendering of a transparent body with lung cancer highlighted.

The FDA has approved pembrolizumab (Keytruda) as an adjuvant therapy following surgical resection and platinum-based chemotherapy for patients with stage IB, II, or IIIA non-small cell lung cancer (NSCLC), Merck announcedopens in a new tab or window.

The approval makes pembrolizumab the only immunotherapy to be approved for NSCLC regardless of PD-L1 expression in both the adjuvant and metastatic settings, the company noted.

“While there have been many advances for patients with metastatic disease, surgery remains the typical treatment for people with stage IB, II, and IIIA non-small cell lung cancer. Unfortunately, many of these patients who undergo surgery still see their disease return,” said Roy S. Herbst, MD, PhD, deputy director and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Connecticut, in a company press release.

“Today’s approval for Keytruda offers a new, important immunotherapy treatment option for stage IB (T2a ≥4 cm), II, or IIIA patients with non-small cell lung cancer following surgery and adjuvant chemotherapy,” he continued.

Approval was based on data from the multicenter phase III KEYNOTE-091 trialopens in a new tab or window, also known as PEARLS, which involved 1,177 patients randomized 1:1 to intravenous pembrolizumab 200 mg or placebo every 3 weeks. Of these patients, 86% had received platinum-based chemotherapy following resection. The median duration of exposure to pembrolizumab was 11.7 months.

Median disease-free survival (DFS) was 58.7 months with pembrolizumab compared with 34.9 months with placebo among patients who received adjuvant platinum-based chemotherapy following surgical resection (HR 0.73, 95% CI 0.60-0.89), meeting the trial’s primary endpoint.

In an exploratory subgroup analysis of 167 patients who did not receive adjuvant chemotherapy, the HR for DFS was 1.25 (95% CI 0.76-2.05).

Overall survival results were immature at the time of analysis.

Regarding safety, Merck said adverse reactions observed in KEYNOTE-091 were largely similar to those occurring in other patients with NSCLC receiving pembrolizumab as a single agent, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%).

There were two deaths due to myocarditis.

Viagra, other ED drugs may lower cardiovascular risk in healthy men

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A new study found that erectile dysfunction drugs are linked to lower cardiovascular risk in healthy men.
Image credit: STUDIO TAURUS/Stocksy.

  • Medications to treat erectile dysfunction that contain phosphodiesterase type 5 inhibitors (PDE-5i) have wider health benefits in men with type 2 diabetes and/ or known heart conditions.
  • PDE-5i drugs include sildenafil, vardenafil, and tadalafil.
  • New research now shows that PDE-5i treatment for erectile dysfunction is linked to a significant reduction in the risk of major adverse cardiovascular events and death in healthy men.

Doctors often treat erectile dysfunction (ED) by prescribing drugs containing phosphodiesterase type 5 inhibitorsTrusted Source (PDE-5i), which reduce the amount of phosphodiesterase 5 (PDE-5) in the body.

Lack of PDE-5 increases the amount of cyclic guanosine monosulphate — a molecule that promotes the relaxation of smooth muscles in the artery walls leading to vasodilation, increased blood flow, and improved circulation.

PDE-5i drugs includeTrusted Source:

ED drugs for cardiovascular treatment

Studies on the wider impact of PDE-5i have shown that it has renoprotective (kidney protective) benefits, that it improves endothelial cell function, and reduces age-related mortality in people with type 2 diabetes.

Treatment for ED with PDE-5i after a first heart attack has also been linked to a 33%Trusted Source reduced risk of death and a 40% reduction in hospitalization with heart failure.

Separate studiesTrusted Source in men with stable coronary artery disease (CAD) associated PDE-5i treatment with lower risks of death, heart attack, and heart failure.

Until now the majority of studies have involved men with known heart conditions or type 2 diabetes. Now, new collaborative research between Huntington Medical Research Institutes and the University of California has shown thatPDE-5i may also have cardioprotective effects in healthy men.

The study appears in The Journal of Sexual Medicine.

Retrospective study

The retrospective observational study lasted for 14 years and included 72,498 men, with a diagnosis of ED, almost 24,000 of whom were receiving treatment with PDE-5i.

Pharmaceutical and medical data taken from the HealthCore Integrated Research Database highlighted men taking PDE-5 inhibitors — sildenafil, vardenafil, tadalafil, and/ or avanafil once during the study period, but not in the first 12 months.

People with previous major adverse cardiovascular events (MACE) or who had been prescribed the drugs for pulmonary hypertension were excluded from the study.

Overall mortality risk

The research team found men taking PDE-5i drugs were 13% less likely to suffer a cardiac event, this was linked to a reduction in coronary revascularisation, heart failure, and unstable angina.

Overall mortality was reduced by 25% in men exposed to PDE-5i and the team recorded a 39% lower risk of dying due to cardiovascular-related causes.

Similar reduced major adverse cardiac events (MACE) — cardiovascular-related death, hospitalization for heart attack, coronary revascularization, stroke, heart failure, and unstable angina — and mortality findings occurred in participants without CAD but with known cardiovascular disease risk factors who had been exposed to PDE-5i.

The reduction in MACE, heart attacks, and stroke was greatest in men who took the largest amount of these drugs over the study period, with a 55% reduction in MACE and a 49% reduction in overall mortality observed.

Speaking to Medical News Today, study lead author Dr. Robert A Kloner explained:

“We did find a greater benefit on MACE with higher doses. However, our study was a retrospective study and until a prospective, placebo-controlled study of various doses is performed we cannot recommend doses. In addition, we are not suggesting that PDE-5 inhibitors be used off-label. They should only be used for the treatment of ED or pulmonary hypertension, on label, at the recommended dose levels.”

Dr. Rigved Tadwalkar, a board-certified cardiologist at Providence Saint John’s Health Center in Santa Monica who was not involved in the study told MNT that prescriptions for ED medications are on the increase.

“ED medications are being increasingly prescribed ” he noted, and “taken as needed, while cardiac therapies are typically taken regularly, so the assumption is that the level of exposure to PDE5 inhibition may not be all that high.”

Subgroup findings and limitations

Men with type 2 diabetes receiving PDE-5i medication also recorded a lower incidence of MACE, as did men diagnosed with CAD but the trend was nonsignificant.

The research team explained this may be due to the small number of participants in the subgroups.

The authors also note that the retrospective nature of the study prevents them from establishing the cause of the link and that the exposure to PDE-5i is estimated from tables dispensed which may not be accurate as tablets may not have been taken or may have also been obtained from another source.

“[F]illing a medication does not necessarily equal taking the medication,” cautioned Dr. Tadwalkar.

He also commented that “[a] large possible confounding variable in this study is whether those who were taking PDE5 inhibitors could also be engaging in increased sexual activity and that the sexual activity itself was lending to the benefit, independent of the effects of the drug.”

The study did not collect information on the participants’ relationship status or levels of sexual satisfaction.

Can women benefit from PDE-5i?

This drug group was originally developedTrusted Source to treat angina, and it was only when men taking the drug for this condition reported it being easier to obtain and maintain an erection as an additional effect, that researchers investigated its role in treating erectile dysfunction.

This study did not look at the effect of the drug on women but PDE-5i is also prescribed to women for pulmonary hypertension. Could PDE-5i have similar cardioprotective potential in women?

“We did not have data on the use of PDE-5 inhibitors in women in our study, so we do not know if there is a cardioprotective effect similar to the one we saw in men with ED,” Dr. Kloner told MNT. “However, we do know that these drugs work for pulmonary hypertension and this includes women.”

“Some physicians also use these drugs to treat Raynaud’s syndrome, which also may work in women. Future studies will need to be done in which women receive placebo versus PDE-5 inhibitors and then the effect on cardiovascular events is determined,” he advised.

Dr. Tadwalkar explained that previous research has highlighted the importance of sex differences in the action of PDE-5i.

“We use PDE5 inhibitors regularly in men and women for a condition called pulmonary arterial hypertension (PAH),” he pointed out. “The use of the medication results in a reduction in pulmonary vascular tone, allowing for greater blood flow to the lungs.”

“Although not specifically confirmed, a few studies have suggested that PDE5 inhibitors may be less effective in treating PAH in women compared to men,” he cautioned. “Nonetheless, since we do give these medications to women with this condition, the hope is that it would also work in a general, at-risk population to lower rates of major adverse cardiovascular events.”

What next?

This study shows that PDE-5i is linked to lower rates of cardiovascular events in healthy men, supporting previous studies which have reported cardioprotective benefits in men with type 2 diabetes and known cardiovascular disease. The next step is the completion of randomized controlled clinical trials.

“What is needed now is a large, prospective, randomized, placebo-controlled study assessing whether these agents reduce major adverse cardiovascular events, carried out over several years,” commented Dr. Kloner.

The need for “high-quality randomized data” trials was echoed by Dr. Tadwalkar.

“The clinical implications are positive, especially since the effect sizes appear quite large,” he told us. “We have not thought of the routine use of PDE5 inhibitors in this context previously. We may be more inclined to encourage the use of these drugs in our at-risk and cardiovascular patients who decide that they want to take them, granted that no significant contraindications exist.”

However, according to Dr. Kloner, this might not be so simple.

“The problem becomes finding funding for such a study. Since most of these drugs are now generic, there will be less interest from pharmaceutical companies funding this type of study,” he explained.

Nevertheless, he is hopeful that results from these studies might encourage government funding.

“It would be great if the government (NIH) was interested. […] Perhaps some of these more recent retrospective studies that have shown very consistent and positive results will re-awaken interest in funding these drugs for new indications from various sources,” said Dr. Kloner.

MDM2 Inhibitor Breaks Through in Trial of Liposarcoma, Other Advanced Malignancies

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Intermittent dosing dramatically reduced myelosuppression that has hindered drug class

A computer rendering of MDM2 bound to tumor protein p53

Almost half of patients with advanced solid tumors or lymphomas experienced disease control with a drug that reactivates the TP53 tumor suppressor, a first-in-human study showed.

Overall, the oral murine double minute-2 (MDM2) inhibitor milademetan produced a disease control rate (DCR) of 45.8% in 107 patients, including 58.5% in a subgroup with dedifferentiated liposarcomas (DDLPS). Notably, an intermittent dosing regimen reduced the incidence of grade 3/4 toxicity by 50% or more, with no drop-off in efficacy, reported Mrinal Gounder, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues.

The improved tolerability with intermittent dosing has helped jump-start a drug class that had been stalled for a decade by myelosuppression, they noted in the Journal of Clinical Oncologyopens in a new tab or window.

“It was really the intermittent dosing that has now allowed for a resurgence of this entire class of drugs, and many drug companies are now back in the space after many major pharmaceutical companies sort of abandoned it after evaluating continuous dosing,” Gounder told MedPage Today. “Intermittent dosing is the only way forward that many companies are pursuing.”

“It really depends on the pharmacokinetics and half-life of drugs,” he added. “If somebody else is choosing to do daily dosing, that doesn’t mean they are on the wrong track. That may be appropriate for that specific drug’s pharmacology, but in general, the field is moving towards an intermittent dosing schedule.”

MDM2 and Oncogenesis

The p53 protein encoded by TP53 corrects DNA damage by multiple mechanisms, acting as a tumor suppressor in normal cells by inducing cell-cycle arrest or repair, apoptosis, or senescence. Aside from TP53 mutations, multiple other mechanisms can inactivate wild-type p53, including overexpression of MDM2 by MDM2 amplificationopens in a new tab or window or other means.

MDM2 amplification occurs in 3.5% to 7.0% of human cancers, although no specific copy-number threshold for the alteration has been determined. In DDLPS, intimal sarcomas, and certain other tumors, MDM2 amplification occurs in the absence of TP53 mutationsopens in a new tab or window, making inhibition of the MDM2 protein a logical target to support p53’s suppressive activity, Gounder and co-authors noted in the introduction to the study.

In preclinical studies, milademetan induced p53-dependent apoptosis in cancer cell lines and antitumor activity in xenograft models with wild-type p53. Gounder and colleagues reported findings from a study designed primarily to evaluate the safety and tolerability of the drug with different dosing schedules, and determine the maximum tolerated dose or recommended phase II dose (RP2D). Investigators then evaluated the RP2D and an intermittent dosing schedule in patients with liposarcomas.

They initially evaluated 21-day and 28-day dosing, then two intermittent dosing schedules — days 1-7 or days 1-3 and then 15-17. A total of 69 patients received extended or continuous dosing, and 38 were treated on intermittent schedules.

The study involved a total of 107 patients: 53 with DDLPS, 22 with melanoma, four with lymphoma, three with osteosarcoma, and 25 with miscellaneous malignancies. Two-thirds of the patients had wild-type TP53, 13 had TP53 mutations, and the rest had indeterminate or unknown mutation status. Although enrollment focused on tumors with a high prevalence of MDM2 amplification or overexpression, testing for MDM2 status was not required. Patients with TP53 mutations were excluded.

Safety, Toxicity Data

Across all dosing schedules evaluated, the most common all-grade adverse events (AEs) were nausea (72%), thrombocytopenia (60.7%), fatigue (44.9%), and anemia (35.5%). Nonhematologic AEs were generally mild or moderate, whereas the severity of hematologic AEs, particularly thrombocytopenia, was associated with dose density.

Overall, the most common grade 3/4 drug-related AEs were thrombocytopenia (29.0%), neutropenia (15.0%), and anemia (13.1%). Among patients who received the RP2D on the split intermittent dosing schedule, rates for the same AEs were 15.0%, 5.0%, and 0%. All-grade and grade 3/4 thrombocytopenia occurred in 69.6% and 36.2% of patients treated with extended-continuous dosing versus 44.7% and 15.8% with the two intermittent schedules combined.

No patients treated by intermittent dosing developed serious drug-related AEs versus 11.6% of patients who received milademetan by extended-continuous dosing.

Pharmacodynamic studies showed that levels of growth differentiation factor-15 increased with plasma concentrations of milademetan. Expression of p53, p21, and MDM2 increased in a handful of serum samples evaluable on day 8 of cycle 1.

With regard to antitumor activity in both parts of the study combined, two patients with DDLPS and one each with synovial sarcoma, small-cell lung cancer, and melanoma achieved partial responses. Additionally, 56 patients had stable disease. Response duration was not yet evaluable. Median duration of stable disease was 7.4 months, and median progression-free survival was 4.0 months.

“Despite almost two decades of research dedicated to the development of MDM2 inhibitors, none has progressed beyond early-phase clinical trials in patients with solid tumors,” the authors noted in the discussion of their findings. “The main reason for the apparent lack of progress is myelosuppression, an on-target class effect mediated by reactivation of p53.”

“In this first-in-human study of the MDM2 inhibitor milademetan, extended or continuous schedules led to unfavorable myelosuppression, particularly thrombocytopenia, as with other inhibitors in this class,” they added. “We found that intermittent dosing, allowing time for bone marrow recovery markedly reduced the occurrence and severity of thrombocytopenia and other hematologic events. Furthermore, even if toxicities occurred, patients were more likely to continue therapy with fewer dose reductions or prolonged interruptions and maintain clinical outcomes.”

Gounder said a phase III trial of the MDM2 inhibitor in DDLPS accrued its enrollment target in record time, and initial results are expected later this year. Additionally, Rain Oncology, which acquired milademetan from Daiichi Sankyo, has launched a basket trial to evaluate the MDM2 inhibitor in various tumor types associated with MDM2 amplification.

Intravesical Mitomycin in Treatment of Non-Muscle-Invasive Bladder Cancer

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Neoadjuvant instillation without TURBt is reasonable option in patients motivated to avoid invasive procedures

In recent years the management of non-muscle-invasive bladder cancer has undergone radical changes. Intravesical Bacillus Calmette-Guérin (BCG) has long been established as the therapeutic standard when superiority was demonstrated in carcinoma in situ and stage Ta urothelial cancer of the bladder. For decades after the approval of intravesical BCG, no other effective therapies were available for this disease. Valrubicin received FDA approval but had only modest efficacy and was not widely adopted or utilized. Recently, a number of novel therapies have demonstrated efficacy in BCG-failure bladder cancer such as systemic intravenous pembrolizumab, intravesical gemcitabine alternating with docetaxel, and intravesical gene therapy with nadofaragene firadenovec-vncg (Adstiladrin).

Mitomycin is an antitumor antibiotic that inhibits DNA synthesis by producing DNA cross-links that halt cell replication and eventually cause cell death. Intravesical mitomycin has long been used in the treatment of intermediate-risk superficial bladder cancer. The standard regimen involves instillations into the bladder through a catheter weekly for 6 weeks.

A recent study by Lindgren et al. evaluated a neoadjuvant intensive regimen of intravesical mitomycin instilled three times a week for 2 weeks, and compared the outcomes with the standard weekly regimen for 6 weeks. The study was conducted in patients with relapsed/recurrent NMIBC, and the majority of patients (70%) had a history of low-grade disease.

Interestingly, there was no statistically significant difference in recurrence-free survival; however, in the neoadjuvant intensive regimen group 29% of patients were able to avoid invasive procedures such as transurethral resection of bladder tumor (TURBt) as compared with the standard arm of all patients receiving TURBt followed by mitomycin instillation.

The study concludes that avoiding invasive procedures is a goal worthy of achieving in this patient population with a change in the regimen, especially as no safety risk was incurred.

Bladder cancer is a disease of the elderly. The risks of anesthesia and postoperative infections, bleeding, and hospitalizations are magnified in patients of advanced age and multiple comorbidities. The study raises an important management endpoint for clinical trial design: Decreasing the requirement for invasive procedures is an especially important goal in this patient population.

If cancer control is not compromised, then reducing the hassle, cost, and morbidity of invasive procedures is a practically useful endpoint. However, the advancement of technology has resulted in urine-based genomic tests that have reasonable sensitivity and specificity to detect relapse. The cost of these tests is considerable and maybe they would be best applied to the patients with a history of high-grade NMIBC where management would involve consideration of multiple other therapies and the risk of progression to muscle-invasive disease is substantially higher.

In conclusion, the neoadjuvant instillation of intravesical mitomycin without doing TURBt is a reasonable option to consider in patients motivated to avoid invasive procedures but committed to close cystoscopy monitoring and surveillance. Careful selection of patients with a history of low- to intermediate-grade NMIBC, and a minimum treatment-free interval of at least 2 years after intravesical BCG, is required.

For Septic Shock, Another Toss-up Between Emphasizing Vasopressors Vs Fluids

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For sepsis-induced hypotension, a restrictive fluid strategy with earlier vasopressor use didn’t impact mortality compared with liberal fluids, the CLOVERS trial showed.

The restrictive strategy had its intended effect, reducing median IV fluids administered over 24 hours by 2,134 mL in favor of more vasopressor use compared with the liberal fluids strategy among 1,563 patients refractory to initial treatment with 1 to 3 L of IV fluid, according to Nathan I. Shapiro, MD, MPH, of Beth Israel Deaconess Medical Center and Harvard Medical School in Boston.

However, all-cause, 90-day mortality before discharge home differed by less than a percentage point between the two strategies (14.0% restrictive vs 14.9% liberal fluid strategy, P=0.61), he reported at the Society of Critical Care Medicine Critical Care Congressopens in a new tab or window. The findings were simultaneously published online in the New England Journal of Medicineopens in a new tab or window.

“At the end of the day, both seem to address hypotension and neither led to a higher or lower mortality, it was the same,” he said at the late-breaking session. “Maybe future efforts need to look in other areas in order to improve mortality in sepsis beyond how to manipulate vasopressors and fluids.”

It’s been an area of controversy and uncertainty, commented Timothy Buchman, MD, PhD, of Emory University in Atlanta and a past-president of the SCCM. And whether either of the two approaches used in the trial is actually the best of all possible strategies still isn’t known, he said, “but we now can state with confidence that a little more fluid, a little more pressor, there’s probably no difference between those choices.”

The findings concurred with those of the CLASSIC trialopens in a new tab or window, in which a restrictive fluid protocol had no impact on 90-day all-cause mortality compared with a standard, more liberal fluid approach among septic shock patients already admitted to the ICU after initial resuscitation with 1 L of fluids.

One difference between the trials was patient population, with CLOVERS enrolling almost exclusively patients who presented to a hospital emergency department (ED) with sepsis (about two-thirds thereafter being admitted to the ICU), whereas most patients in CLASSIC came to the ICU from a hospital ward (34%) or the operating room (23%).

CLOVERS also excluded patients for whom the treatment approach could be clearly guided by clinical circumstances. Clinicians had to approve patient participation, so those with extremes of volume overload or volume depletion deemed not eligible for randomization would not have been enrolled, the researchers noted.

The results wouldn’t be generalizable to such patients, they added, although the enrolled population was broadly representative of patients who present to the ED with sepsis-induced hypotension.

No patient characteristics predicted better outcomes with one strategy versus another.

The Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial included 1,563 adults (age about 60; less than half female; predominantly white) seen at 60 U.S. centers who were enrolled within 4 hours of meeting criteria for sepsis-induced hypotension (<100 mm Hg systolic) refractory to initial treatment with 1 to 3 L of IV fluid. They were randomly assigned to a fluid strategy administered open label for 24 hours. The trial was stopped early for futility.

In the restrictive fluid protocol, the primary treatment prioritized vasopressors. After patients got up to 2 L of fluid, including what was given prerandomization, then the norepinephrine dose was adjusted to achieve a mean arterial pressure of at least 65 mm Hg, with a second vasopressor added if needed. Rescue fluids were given for specified indications indicative of severe intravascular volume depletion, with a preference for 500 mL boluses.

In the liberal fluid protocol, patients got an initial liter of isotonic crystalloid after randomization, then another liter if not yet volume replete based on clinical signs and if heart rate and blood pressure didn’t normalize. Additional fluid boluses were given if triggered clinically, such as due to tachycardia. If still meeting criteria, “rescue vasopressors” were allowed.

While pre-randomization strategies were similar between groups (median 2,050 mL fluid and about 20% getting vasopressors), that quickly changed after randomization. In the first 6 hours on the protocol, the restrictive group got a median of 500 mL of fluid compared with 2,300 mL in the liberal group; by 24 hours, the groups averaged 1,267 and 3,400 mL, respectively.

Vasopressors showed the same pattern, with 59% versus 37% of the patients getting them. They were also started a mean of 1.4 hours earlier and used for a mean of 4.2 hours longer over the first 24 hours in the restrictive fluids group.

Protocol adherence was nearly 100% in both groups.

None of the secondary endpoints showed an advantage to one strategy over the other, including number of days free from organ-support therapy, from renal-replacement therapy, from vasopressor use, or out of the ICU or hospital at 28 days.

Serious adverse events (AEs) likewise were similar between groups overall, although there were fewer involving fluid overload or pulmonary edema in the restrictive fluid group (both 0 vs 3 cases).

Limitations included the potential for bias in ascertainment and reporting of AEs and that “potentially important subgroups (including patients with specific coexisting conditions for which data were not collected in this trial)” were not assessed.

“Finally, we evaluated patients with sepsis-induced hypotension that was recognized early after hospital presentation,” Shapiro’s group noted. “These findings may not be generalizable to patients with delayed recognition of sepsis-induced hypotension or who are in the later phases of care.”

Device transmits radio waves with almost no power – without violating the laws of physics

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A new ultra-low-power method of communication at first glance seems to violate the laws of physics. It is possible to wirelessly transmit information simply by opening and closing a switch that connects a resistor to an antenna. No need to send power to the antenna.

Our system, combined with techniques for harvesting energy from the environment, could lead to all manner of devices that transmit data, including tiny sensors and implanted medical devices, without needing batteries or other power sources. These include sensors for smart agriculture, electronics implanted in the body that never need battery changes, better contactless credit cards and maybe even new ways for satellites to communicate.

Apart from the energy needed to flip the switch, no other energy is needed to transmit the information. In our case, the switch is a transistor, an electrically controlled switch with no moving parts that consumes a minuscule amount of power.

In the simplest form of ordinary radio, a switch connects and disconnects a strong electrical signal source – perhaps an oscillator that produces a sine wave fluctuating 2 billion times per second – to the transmit antenna. When the signal source is connected, the antenna produces a radio wave, denoting a 1. When the switch is disconnected, there is no radio wave, indicating a 0.

What we showed is that a powered signal source is not needed. Instead, random thermal noise, present in all electrically conductive materials because of the heat-driven motion of electrons, can take the place of the signal driving the antenna.

No free lunch

We are electrical engineers who research wireless systems. During the peer review of our paper about this research, published recently in Proceedings of the National Academy of Sciences, reviewers asked us to explain why the method did not violate the second law of thermodynamics, the main law of physics that explains why perpetual motion machines are not possible.

Perpetual motion machines are theoretical machines that can work indefinitely without requiring energy from any external source. The reviewers worried that if it were possible to send and receive information with no powered components, and with both the transmitter and receiver at the same temperature, that would mean that you could create a perpetual motion machine. Because this is impossible, it would imply that there was something wrong with our work or our understanding of it.

A graphic in the top half showing a horizontal cylinder on the left with a pipe extending to the right with a 90-degree bend upward connecting to an upside-down triangle with pairs of curved lines on either side, and in the bottom half the same but disconnected
Electrons that naturally move around inside a room-temperature resistor affect electrons in a connected antenna, which causes the antenna to generate radio waves. Connecting and disconnecting the antenna produces the ones and zeros of a binary signal. Zerina Kapetanovic, CC BY-ND

One way the second law can be stated is that heat will flow spontaneously only from hotter objects to colder objects. The wireless signals from our transmitter transport heat. If there were a spontaneous flow of signal from the transmitter to the receiver in the absence of a temperature difference between the two, you could harvest that flow to get free energy, in violation of the second law.

The resolution of this seeming paradox is that the receiver in our system is powered and acts like a refrigerator. The signal-carrying electrons on the receive side are effectively kept cold by the powered amplifier, similar to how a refrigerator keeps its interior cold by continuously pumping heat out. The transmitter consumes almost no power, but the receiver consumes substantial power, up to 2 watts. This is similar to receivers in other ultra-low-power communications systems. Nearly all of the power consumption happens at a base station that does not have constraints on energy use.

A simpler approach

Many researchers worldwide have been exploring related passive communication methods, known as backscatter. A backscatter data transmitter looks very similar to our data transmitter device. The difference is that in a backscatter communication system, in addition to the data transmitter and the data receiver, there is a third component that generates a radio wave. The switching performed by the data transmitter has the effect of reflecting that radio wave, which is then picked up at the receiver. An example of backscatter unpowered wireless communications.

A backscatter device has the same energy efficiency as our system, but the backscatter setup is much more complex, since a signal-generating component is needed. However, our system has lower data rate and range than either backscatter radios or conventional radios.

What’s next

One area for future work is to improve our system’s data rate and range, and to test it in applications such as implanted devices. For implanted devices, an advantage of our new method is that there is no need to expose the patient to a strong external radio signal, which can cause tissue heating. Even more exciting, we believe that related ideas could enable other new forms of communication in which other natural signal sources, such as thermal noise from biological tissue or other electronic components, can be modulated.

Finally, this work may lead to new connections between the study of heat (thermodynamics) and the study of communication (information theory). These fields are often viewed as analogous, but this work suggests some more literal connections between them.

Fossil teeth reveal how brains developed in utero over millions of years of human evolution – new research

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Fossilized bones help tell the story of what human beings and our predecessors were doing hundreds of thousands of years ago. But how can you learn about important parts of our ancestors’ life cycle – like pregnancy or gestation – that leave no obvious trace in the fossil record?

The large brains, relative to overall body size, that are a defining characteristic of our species make pregnancy and gestation particularly interesting to paleoanthropologists like me. Homo sapiens’ big skulls contribute to our difficult labor and delivery. But the big brains inside are what let our species really take off.

My colleagues and I especially wanted to know how fast our ancestors’ brains grew before birth. Was it comparable to fetal brain growth today? Investigating when prenatal growth and pregnancy became humanlike can help reveal when and how our ancestors’ brains became more like ours than like our ape relatives’.

To investigate the evolution of prenatal growth rates, we focused on the in-utero development of teeth – which do fossilize. By building a mathematical model using the relative lengths of molar teeth, we were able to track evolutionary changes in prenatal growth rates in the fossil record. Based on our model, it looks as if pregnancy and prenatal growth became more humanlike than chimplike almost 1 million years ago.

pregnant woman's silhouette against sunset on landscape
Pregnancy and delivery come with a lot of risks for parent and baby.

Gestation and the human brain

Pregnancy and gestation are important periods – they guide future growth and development and set the biological course for life.

But human pregnancy, and particularly labor and delivery, cost a lot of energy and are often dangerous. The large fetal brain requires a lot of nutrients during development. The rate of embryonic growth during gestation, also known as the prenatal growth rate, exacts a metabolic and physiological toll on the gestating parent. And the tight fit of the infant’s head and shoulders through the pelvic canal during delivery can lead to death, for both the mother and child.

As a trade-off to those potential downsides, there must be a really good reason to have such large heads. The justification is all the abilities that come along with having a big human brain. The evolution of our large brain contributed to our species’ dominance and is associated with increased use of technology and tools, creation of art and the ability to survive in diverse landscapes, among other advances.

The timing and sequence of events that led to the evolution of our large brains is entangled with the ability to find and process more resources, through the use of tools and cooperative group work, for example.

By investigating changes in prenatal growth, we are also investigating changes in how parents gathered food resources and distributed them to their offspring. These increasing resources would have also helped drive the evolution of an even bigger brain. Understanding more about when prenatal growth and pregnancy became humanlike at the same time reveals information about when and how our brains did too.

Humans have the highest prenatal growth rate of all primates living today, at 0.41 ounces/day (11.58 grams/day). Gorillas, for example, have a much larger adult body size than humans, but their prenatal growth rate is only 0.29 ounces/day (8.16 grams/day). Because more than a quarter of all human brain growth is completed during gestation, the rate of prenatal growth directly relates to how big an adult brain grows. How and when Homo sapiens‘ high prenatal growth rate evolved has been a mystery, until now.

What teeth can tell about prenatal growth

Researchers have spent centuries investigating variation in fossilized skeletal remains. Unfortunately brains – let alone gestation and prenatal growth rate – don’t fossilize.

ultrasound of a baby in utero
The developing brain of a human being gestating at 26 weeks.

But my colleagues and I started thinking about how teeth develop very, very early in utero. Your permanent adult teeth started developing long before you were born, when you were just a 20-week-old fetus. Tooth enamel is more than 95% inorganic, and the vast majority of everything we see in the vertebrate fossil record is teeth, or has teeth.

Building off this realization, we decided to investigate the relationship between prenatal growth rate, brain size and the lengths of teeth.

We measured the teeth of 608 recently living primates from skeletal collections all around the world. We compared those measurements to rates of prenatal growth that we calculated from average gestation length and mass at birth for each species. We also looked at endocranial volume – essentially how much space is inside the skull – as a proxy for brain size.

We found that the rate of prenatal growth is significantly correlated with both adult brain size and relative tooth lengths, across apes and monkeys.

Because prenatal growth is so tightly correlated with relative molar lengths, we were able to use this statistical relationship to generate a mathematical equation that predicts prenatal growth rate from teeth alone. With this equation, we can take a few molar teeth from an extinct fossil species and reconstruct exactly how fast their offspring grew during gestation.

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Using the new equation, researchers found that prenatal growth rates increased over millions of years of human and hominid evolution.

Using our new method, we then reconstructed prenatal growth rates for 13 fossil species, building a timeline of changes over the past 6 million years of human and hominid evolution. “Hominid” describes all the species on the human side of the family tree after the split about 6 million to 8 million years ago from the common ancestor we shared with chimpanzees. From our new research, we now know that prenatal growth rates increased throughout hominid evolution, reaching a humanlike rate that exceeds what we see in all other apes less than 1 million years ago.

A fully human prenatal growth rate appeared with the evolution of our species Homo sapiens only around 200,000 years ago. But other hominid species living in the past 200,000 years, such as Neanderthals, also had “human” prenatal growth rates. Which genes were involved in these changes in growth rate remains to be investigated.

Equation means teeth now reveal even more

Even with only a few teeth and some of the jaw, a trained expert can tell countless things about an extinct individual – what species it was, what kind of diet it ate, whether it competed for mates through fighting, how old it was when it died, whether or not it had any serious health issues and more.

Now, for the first time, we can add to that list knowing what pregnancy and gestation were like for that individual and other members of its species. Teeth can even indirectly hint at the emergence of human consciousness, via evolving brain size.

Interestingly, our model suggests that prenatal growth rates started increasing well before the emergence of our Homo sapiens species. We can hypothesize that having a fast prenatal growth rate was necessary for growing that big brain and evolving human consciousness and cognitive abilities.

These are the sorts of big-picture questions this research lets us start to formulate now – all from just a few teeth.

Sotorasib in KRAS p.G12C–Mutated Advanced Pancreatic Cancer

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Abstract

Background

KRAS p.G12C mutation occurs in approximately 1 to 2% of pancreatic cancers. The safety and efficacy of sotorasib, a KRAS G12C inhibitor, in previously treated patients with KRAS p.G12C–mutated pancreatic cancer are unknown.

Methods

We conducted a single-group, phase 1–2 trial to assess the safety and efficacy of sotorasib treatment in patients with KRAS p.G12C–mutated pancreatic cancer who had received at least one previous systemic therapy. The primary objective of phase 1 was to assess safety and to identify the recommended dose for phase 2. In phase 2, patients received sotorasib at a dose of 960 mg orally once daily. The primary end point for phase 2 was a centrally confirmed objective response (defined as a complete or partial response). Efficacy end points were assessed in the pooled population from both phases and included objective response, duration of response, time to objective response, disease control (defined as an objective response or stable disease), progression-free survival, and overall survival. Safety was also assessed.

Results

The pooled population from phases 1 and 2 consisted of 38 patients, all of whom had metastatic disease at enrollment and had previously received chemotherapy. At baseline, patients had received a median of 2 lines (range, 1 to 8) of therapy previously. All 38 patients received sotorasib in the trial. A total of 8 patients had a centrally confirmed objective response (21%; 95% confidence interval [CI], 10 to 37). The median progression-free survival was 4.0 months (95% CI, 2.8 to 5.6), and the median overall survival was 6.9 months (95% CI, 5.0 to 9.1). Treatment-related adverse events of any grade were reported in 16 patients (42%); 6 patients (16%) had grade 3 adverse events. No treatment-related adverse events were fatal or led to treatment discontinuation.

Conclusions

Sotorasib showed anticancer activity and had an acceptable safety profile in patients with KRAS p.G12C–mutated advanced pancreatic cancer who had received previous treatment.

Source: NEJM