September 28, 2023 — With the end of pandemic-era federal support that provided free school breakfasts and lunches for all, experts worry that kids who continue to need free meals will face increasing stigma.

During the pandemic, the federal government made school breakfasts and lunches free for two years and increased meal reimbursements to schools for the third year. When this support ended in July, nine states made universal free school meals permanent; in the rest of the country, only students from households at or up to 130% of the federal poverty level can eat for free, while those from households making slightly higher incomes qualify for reduced prices. But many families struggle to pay for even the discounted meals. According to experts quoted in a September 25, 2023, Civil Eats article, this can lead to their children being shamed.

Schools will feed a child even if he or she can’t pay, but this results in debt accruing. Prior to the pandemic, some schools used tactics that embarrassed children who couldn’t pay for their meals, such as sending them home with bills or serving them obviously cheaper food. While fewer districts have resumed these practices, they haven’t gone away, Juliana Cohen, adjunct professor of nutrition at Harvard T.H. Chan School of Public Health, said in the article.

Students who qualify for free school lunches based on their household income may also feel stigmatized, Cohen said. For example, they may worry about being seen with a “free school lunch” form that brands them as different from their peers.

Cindy Leung, assistant professor of public health nutrition at Harvard Chan School, said in the article that the shame, anger, and loneliness experienced by kids who are food insecure is a form of toxic stress that can be harmful to their mental health.

The stigma around free school meals can be so strong that children don’t want to eat them. Research led by Cohen found that 42% of families eligible for free or reduced-price meals said that their child would be less likely to eat a school meal unless it was free for all students. Evidence from the past few years suggests that if that stigma is taken away, more kids will eat a school meal.

“There is so much movement in this area,” Leung said. “Not only are we providing all children nutrients, but universal free school meals reduce the stigma of who’s accessing school meals. There’s no more lunch shaming. So, how can we leverage this momentum?”

Read the Civil Eats article: Without Federal School-Meal Support, Lunch Shaming May Be Back on the Menu

Learn more

The free school lunch paradox (Harvard Public Health)

September 28, 2023 – Scientists are trying to learn more about the long-term health impacts of microplastics—tiny plastic particles in the environment that result from the disposal and breakdown of consumer products and industrial waste.

A September 21 article in Discover noted that the tiny plastic particles are everywhere, including in our bodies. The particles have been found in blood, baby poop, placentas, breastmilk, and in lung tissue, according to the article. A 2019 report found that people in the U.S. consume from 39,000 to 52,000 particles of microplastics every year. Some research has linked the particles with lung inflammation, shortness of breath, and a higher risk of lung cancer.

Mary Johnson, principal research scientist in Harvard T.H. Chan School of Public Health’s Department of Environmental Health, told Discover that vulnerable communities are particularly impacted by microplastics.

“In general, vulnerable populations are at even greater risk of the negative health impacts from the production, use and degradation of plastics,” she said. She noted that a 2021 United Nations report about global plastics pollution showed that Indigenous communities have been displaced for oil extraction, that water supplies in low-income communities have been contaminated, and that predominantly Black communities near oil refineries in the South have suffered health problems.

Read the article: Microplastics Are Everywhere. What Are They Doing to Our Health?

September 27, 2023 – Cancer rates are increasing in people below the age of 50, a trend that could be driven by obesity and other factors, according to experts.

For the past 30 years or so, over a dozen types of cancers have become more common in younger people, according to Timothy Rebbeck, Vincent L. Gregory, Jr. Professor of Cancer Prevention at Harvard T.H. Chan School of Public Health, who was one of several guests interviewed in a September 15 story on WBUR’s “On Point.” The types of cancers span multiple organ systems and include colorectal, breast, and kidney cancers, he said.

Rebbeck explained that the trend could be related to increasing rates of obesity, since the condition has been associated with early-onset cancers. Other potential factors include exposure to environmental toxins and eating Western diets, which contain high amounts of processed foods, red meat, and sugar.

Listen to or read the WBUR story: Why are cancer rates rising among young people?

Learn more

Lifestyle changes may be driving higher cancer rates in people under 50 (Harvard Chan School news)

September 22, 2023 – The bad news: COVID cases have been ticking up.

The good news: Those old COVID tests you have around the house are probably still good; businesses should know how to pivot if infections keep climbing; and, overall, current COVID conditions aren’t nearly as bad as they were even a year ago.

COVID tests

The Food and Drug Administration has been extending expiration dates for some over-the-counter COVID test kits, based on new data from manufacturers. In a September 6 Wall Street Journal article, Rachael Piltch-Loeb, research scientist in the Department of Biostatistics and a fellow in the EPREP (Emergency Preparedness Research Evaluation & Practice) Program at Harvard T.H. Chan School of Public Health, said, “It’s important for people to understand that the reason those expirations existed in the first place is we didn’t have information, just based on the rapid development of testing, on how long the pieces of test were good for. It’s important to check into whether or not the expiration has been updated.”

Check out the FDA text expiration date database to see if your at-home tests are still good.

Business readiness

Even if COVID cases increase, businesses now have more than three years of pandemic-related experience under their belts. “We have tools at our disposal to mitigate the consequences of COVID-19 on the population,” Piltch-Loeb said in a September 13 BBC article. “Businesses have adapted to working in different disease environments … The way work is done has changed for the majority of the workforce.” She said that companies have established remote-work policies and crisis plans, and, in some cases, have updated or added sick leave and parental leave policies. She noted, however, that the situation may be different for essential workers and people in frontline jobs.

‘New normal’

Experts acknowledge that COVID spikes are troubling. The virus still poses a grave threat to those who are immunocompromised and it can trigger long COVID in some. Bill Hanage, associate professor of epidemiology and associate director of the Center for Communicable Disease Dynamics at Harvard Chan School, said in a September 10 STAT article that as of mid-September there had been roughly 100,000 COVID deaths, with 3.5 months still left to go in the year.

“And yet, by comparison with what’s happened in the past, [COVID] is so much better,” he added. “And I think we need to hold in our heads the fact that those things are both true.”

Read the Wall Street Journal article: Your Expired At-Home Covid-19 Tests May Still Work

Read the BBC article: Are businesses ready for another wave of Covid-19 cases?

Read the STAT article: Amid another rise in cases, Covid’s new normal has set in

September 22, 2023 – Hair products sold in neighborhoods that are poorer or that have a higher percentage of residents of color were more likely to contain higher levels of hazardous chemicals than products sold in predominantly white and affluent areas, according to a study from researchers at Harvard T.H. Chan School of Public Health.

The study, published September 13 in Environmental Health Perspectives, was led by Marissa Chan, a doctoral candidate in the Department of Environmental Health. Other Harvard Chan School co-authors included Shivani Parikh, Derek Shyr, Gary Adamkiewicz, and Tamarra James-Todd.

The researchers looked at more than 14,000 shampoos, conditioners, and relaxers sold in 50 stores in eight Boston neighborhoods, identifying each product’s hazard score according to the Environmental Working Group’s Skin Deep Cosmetics Database. They found that 12.2% of hair products available in Roxbury, a lower-income community of color, and 11.4% of hair products available in Mission Hill, a lower-income community, had high hazard scores. But in Beacon Hill, a more affluent neighborhood with more white residents, 7.9% had high hazard scores.

Interviewed in a September 13 segment on WCVB Boston, Chan said that personal care products are notable sources of exposure to endocrine-disrupting chemicals, which have been found to interfere with the body’s hormone system and have been linked with reproductive health issues such as early menstruation, breast cancer, and pregnancy problems.

Watch or read the WCVB story: Hair product safety linked to neighborhood, race, Boston scientists say

Learn more

Op-ed: How to achieve ‘beauty justice’ for Black people (Harvard Chan School news)

When beauty causes harm (Harvard Chan School news)

September 20, 2023 – The harmful effects of alcohol can be potentially lowered by prioritizing healthy habits, according to experts.

Drinking alcohol has been linked to cancer, cardiovascular disease, and other conditions. However, drinking in moderation—no more than two drinks a day for men or one drink a day for women—can still be part of a healthy lifestyle, said Eric Rimm, professor in the Department of Epidemiology at Harvard T.H. Chan School of Public Health and one of several experts quoted in a September 12 New York Times article.

While there are no guaranteed ways to offset the effects of alcohol, Rimm suggested taking healthy actions including exercising regularly to support the immune system, being mindful of extra calories from alcoholic beverages, and seeing a doctor for annual checkups.

Read the New York Times article: I Drink Alcohol Regularly. What Can I Do to Mitigate the Risks?

September 19, 2023 – Two faculty members from Harvard T.H. Chan School of Public Health are among 19 from across Harvard selected to receive support from the Salata Institute Seed Grant Program, launched in April to fund interdisciplinary research in climate and sustainability.

This is the first cohort of awards from the Seed Grant Program, which is supported by a gift from the Troper Wojcicki Foundation.

Stéphane Verguet, associate professor of global health, is principal investigator of a project that will provide evidence for governments to use in decarbonizing their healthcare systems.

And K. “Vish” Viswanath, Lee Kum Kee Professor of Health Communication, is co-principal investigator of a project on effectively communicating the benefits of climate action.

Read a Harvard Gazette article: 14 projects confronting climate change win Salata Institute grants

Read a Harvard Crimson article: Harvard Salata Institute Funds 14 New Climate Research Projects Through Seed Grant Program

September 19, 2023 – People who tend to stay up late have a higher risk of developing diabetes than those who rise early, a new study found.

The study, published September 12 in the Annals of Internal Medicine, found that night owls are 72% more likely than early birds to develop diabetes. Following nearly 64,000 nurses from 2009–2017, researchers found that those who reported that they were night owls tended to have poorer diets, unhealthy weight, and were less physically active. But even after researchers adjusted for lifestyle factors such as diet, exercise, and smoking status, night owls still were 19% more likely to develop diabetes than non-night owls, suggesting that genetic factors may be involved. Co-authors of the article included Harvard Chan School’s Marta Guasch-Ferré, adjunct associate professor of nutrition, and Eva Schernhammer, adjunct professor of epidemiology, as well as colleagues from Harvard Medical School and Brigham and Women’s Hospital.

An accompanying editorial by other Harvard Chan researchers—Kehuan Lin, doctoral student in the Department of Epidemiology; Mingyang Song, associate professor of clinical epidemiology and nutrition; and Edward Giovannucci, professor of nutrition and epidemiology—suggested the need for further research on the connections between a person’s chronotype—their preference for earlier or later sleep timing—their lifestyle, and their diabetes risk.

Read an article in HealthDay: ‘Night Owls’ Are Often Less Healthy, Upping Diabetes Risk

September 19, 2023 – In June 2022, the U.S. Supreme Court’s decision in the case of Dobbs v. Jackson overturned the constitutional right to abortion, leading many states to pass laws that restricted abortion access. In the months following the decision, more people traveled to Massachusetts—a state with few restrictions—to access abortion care, according to a study by researchers at Harvard T.H. Chan School of Public Health, Planned Parenthood League of Massachusetts, and Harvard Medical School.

“It was hard to predict before Dobbs what the impact would be, in part because the Dobbs decision affected such a large number of people,” said study author Elizabeth Janiak, assistant professor in the Department of Social and Behavioral Sciences, in a September 6 Boston Globe article. “It’s been 50 years since we’ve had this number of people in the US not have access. How people would decide where to go was an open question.”

The researchers looked at the number of abortions performed at Planned Parenthood clinics in Massachusetts from July to October 2022. They found that the overall number of abortions increased by 6.2%. In particular, the number of out-of-state patients was 37.5% higher than expected. Furthermore, the out-of-state patients received more financial help from charitable organizations than before the court decision.

“Even though there’s been a surge of people wanting to support this care, there is a huge surge in need,” Janiak said.

Other Harvard Chan School researchers involved with the study were Brianna Keefe-Oates, PhD candidate and Rose Service Learning Fellow, and Jarvis Chen, senior lecturer on social and behavioral sciences.

Read the Boston Globe article: Number of out-of-state travelers seeking abortions at Mass. Planned Parenthood grew 37% after Dobbs

Read the study: Use of Abortion Services in Massachusetts After the Dobbs Decision Among In-State vs Out-of-State Residents

September 14, 2023—“Mindful eating”—the practice of taking time to consciously experience, enjoy, and express gratitude for a meal—offers myriad health benefits, according to Harvard T.H. Chan School of Public Health’s Lilian Cheung.

Cheung, lecturer on nutrition and Director of Mindfulness Research and Practice in the Department of Nutrition, was featured on the September 11 episode of NPR’s Life Kit podcast. Cheung offered five tips for listeners to eat mindfully:

1. Take at least 20 minutes to eat your meal
2. Put your phone and other technology away while eating
3. Engage your senses while eating—notice things like smells and textures
4. Portion out snacks to help prevent mindless munching
5. Make sure you’re chewing well—for the sake of both mindfulness and digestion

Mindful eating “encourages us to make choices that are satisfying and nourishing to the body,” Cheung said. “And as we become more aware of our eating habits, we can take steps toward behavior that will benefit not only ourselves, but also our environment.”

Listen to the Life Kit episode: Scarfing down your food? Here’s how to slow down and eat more mindfully

Irritable bowel syndrome (IBS) and bladder pain syndrome/interstitial cystitis (BPS/IC) are comorbid visceral pain disorders seen commonly in women with unknown etiology and limited treatment options and can involve visceral organ cross-sensitization. Calcitonin gene-related peptide (CGRP) is a mediator of nociceptive processing and may serve as a target for therapy. In three rodent models, we employed a monoclonal anti-CGRP F(ab’)₂ to investigate the hypothesis that visceral organ cross-sensitization is mediated by abnormal CGRP signaling. Visceral organ cross-sensitization was induced in adult female rats via transurethral infusion of protamine sulfate (PS) into the urinary bladder or infusion into the colon of trinitrobenzene sulfonic acid (TNBS). Colonic sensitivity was assessed via the visceromotor response to colorectal distension (CRD). Bladder sensitivity was assessed as the frequency of abdominal withdrawal reflexes to von Frey filaments applied to the suprapubic region. PS- or TNBS-induced changes in colonic and bladder permeability were investigated in vitro via quantification of transepithelial electrical resistance (TEER). Peripheral administration of an anti-CGRP F(ab’)₂ inhibited PS-induced visceral pain behaviors and colon hyperpermeability. Similarly, TNBS-induced pain behaviors and colon and bladder hyperpermeability were attenuated by anti-CGRP F(ab’)₂ treatment. PS into the bladder or TNBS into the colon significantly increased the visceromotor response to CRD and abdominal withdrawal reflexes to suprapubic stimulation and decreased bladder and colon TEER. These findings suggest an important role of peripheral CGRP in visceral nociception and organ cross-sensitization and support the evaluation of CGRP as a therapeutic target for visceral pain in patients with IBS and/or BPS/IC.

Previous studies show ATP-sensitive potassium (K_ATP) channel openers can reduce hypersensitivity associated with chronic pain models in rodents, and reduce morphine tolerance. Many agonists of K_ATP channels are not soluble in physiologically relevant vehicles, requiring adaptation for clinical use. This study compared the antinociceptive activity of novel K_ATP channel targeting prodrugs, CKLP1, CKLP2, and CF3-CKLP. These prodrugs are activated by endogenous alkaline phosphatase enzymes present in the peripheral and central nervous systems. Analgesic capabilities of intrathecally injected prodrugs were tested in rodent models of spinal nerve ligation (SNL) and complete Freund’s adjuvant (CFA) as models for neuropathic and inflammatory pain, respectively. CKLP1 and CKLP2 significantly increased mechanical paw withdrawal thresholds 1–2 hours after intrathecal administration in the SNL model, but all three prodrugs were able to attenuate hypersensitivity up to 7 days after CFA treatment. The reduction of opioid tolerance and opioid-induced hypersensitivity in mice treated chronically with morphine was significantly reduced in CKLP1 and CKLP2 treated animals. Prodrug cleavage was confirmed in mouse spinal cords using liquid chromatography. These studies may aid in the further development of K_ATP channel prodrugs for use in treatments of chronic pain, opioid tolerance, and withdrawal.

Myeloproliferative neoplasms (MPNs) are hematologic malignancies that result from acquired driver mutations in hematopoietic stem cells (HSCs), causing overproduction of blood cells and an increased risk of thrombohemorrhagic events. The most common MPN driver mutation affects the JAK2 gene (JAK2^V617F). Interferon alpha (IFNα) is a promising treatment against MPNs by inducing a hematologic response and molecular remission for some patients. Mathematical models have been proposed to describe how IFNα targets mutated HSCs, indicating that a minimal dose is necessary for long-term remission. This study aims to determine a personalized treatment strategy. First, we show the capacity of an existing model to predict cell dynamics for new patients from data that can be easily obtained in clinic. Then, we study different treatment scenarios in silico for three patients, considering potential IFNα dose-toxicity relations. We assess when the treatment should be interrupted depending on the response, the patient’s age, and the inferred development of the malignant clone without IFNα. We find that an optimal strategy would be to treat patients with a constant dose so that treatment could be interrupted as quickly as possible. Higher doses result in earlier discontinuation but also higher toxicity. Without knowledge of the dose-toxicity relationship, trade-off strategies can be found for each patient. A compromise strategy is to treat patients with medium doses (60–120 μg/week) for 10–15 years. Altogether, this work demonstrates how a mathematical model calibrated from real data can help build a clinical decision-support tool to optimize long-term IFNα therapy for MPN patients.

Clinical trials assessing the impact of radiotherapy (RT) in combination with DNA damage response pathway inhibitors (DDRis) and/or immune checkpoint blockade are currently ongoing. However, current methods for optimizing dosage and schedule are limited. A mathematical model was developed to capture the impacts of RT in combination with DDRi and/or anti–PD-L1 [immune checkpoint inhibitor (ICI)] on tumor immune interactions in the MC38 syngeneic tumor model. The model was fitted to datasets that assessed the impact of RT in combination with the DNA protein kinase inhibitor (DNAPKi) AZD7648. The model was further fitted to datasets from studies that were used to assess both RT/ICI combinations as well as RT/ICI combinations followed by concurrent administration of the poly ADP ribose polymerase inhibitor (PARPi) olaparib. Nonlinear mixed-effects modeling was performed followed by internal validation with visual predictive checks (VPC). Simulations of alternative dosage regimens and scheduling were performed to identify optimal candidate dosage regimens of RT/DNAPKi and RT/PARPi/ICI. Model fits and VPCs confirmed a successful internal validation for both datasets and demonstrated very small differences in the median, lower, and upper percentile values of tumor diameters between RT/ICI and RT/PARPi/ICI, which indicated that the triple combination of RT/PARPi/ICI at the given dosage and schedule does not provide additional benefit compared with ICI in combination with RT. Simulation of alternative dosage regimens indicated that lowering the dosage of ICI to between 2 and 4 mg/kg could induce similar benefits to the full dosage regimen, which could be of translational benefit.

The ataxia-telangiectasia and Rad3-related (ATR) inhibitor ceralasertib and the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib have shown synergistic activity, in vitro, in the FaDu ATM-knockout cell line. It was found that combining these drugs with lower doses and for shorter treatment periods induced greater or equal toxicity in cancer cells than using either as a single agent. Here, we developed a biologically motivated mathematical model governed by a set of ordinary differential equations, considering the cell cycle–specific interactions of olaparib and ceralasertib. By exploring a range of different possible drug mechanisms, we have studied the effects of their combination as well as which drug interactions are the most prominent. After careful model selection, the model was calibrated and compared with relevant experimental data. We have used this developed model further to investigate other doses of olaparib and ceralasertib in combination, which can be potentially helpful in exploring optimized dosage and delivery.

Glioblastoma is the most common and deadly primary brain tumor in adults. All glioblastoma patients receiving standard-of-care surgery-radiotherapy-chemotherapy (i.e., temozolomide (TMZ)) recur, with an average survival time of only 15 months. New approaches to the treatment of glioblastoma, including immune checkpoint blockade and oncolytic viruses, offer the possibility of improving glioblastoma outcomes and have as such been under intense study. Unfortunately, these treatment modalities have thus far failed to achieve approval. Recently, in an attempt to bolster efficacy and improve patient outcomes, regimens combining chemotherapy and immune checkpoint inhibitors have been tested in trials. Unfortunately, these efforts have not resulted in significant increases to patient survival. To better understand the various factors impacting treatment outcomes of combined TMZ and immune checkpoint blockade, we developed a systems-level, computational model that describes the interplay between glioblastoma, immune, and stromal cells with this combination treatment. Initializing our model to spatial resection patient samples labeled using imaging mass cytometry, our model’s predictions show how the localization of glioblastoma cells, influence therapeutic success. We further validated these predictions in samples of brain metastases from patients given they generally respond better to checkpoint blockade compared with primary glioblastoma. Ultimately, our model provides novel insights into the mechanisms of therapeutic success of immune checkpoint inhibitors in brain tumors and delineates strategies to translate combination immunotherapy regimens more effectively into the clinic.

In situ clinical measurement of receptor occupancy (RO) is challenging, particularly for solid tumors, necessitating the use of mathematical models that predict tumor receptor occupancy to guide dose decisions. A potency metric, average free tissue target to initial target ratio (AFTIR), was previously described based on a mechanistic compartmental model and is informative for near-saturating dose regimens. However, the metric fails at clinically relevant subsaturating antibody doses, as compartmental models cannot capture the spatial heterogeneity of distribution faced by some antibodies in solid tumors. Here we employ a partial differential equation (PDE) Krogh cylinder model to simulate spatiotemporal receptor occupancy and derive an analytical solution, a mechanistically weighted global AFTIR, that can better predict receptor occupancy regardless of dosing regimen. In addition to the four key parameters previously identified, a fifth key parameter, the absolute receptor density (targets/cell), is incorporated into the mechanistic AFTIR metric. Receptor density can influence equilibrium intratumoral drug concentration relative to whether the dose is saturating or not, thereby influencing the tumor penetration depth of the antibody. We derive mechanistic RO predictions based on distinct patterns of antibody tumor penetration, presented as a global AFTIR metric guided by a Thiele Modulus and a local saturation potential (drug equivalent of binding potential for positron emissions tomography imaging) and validate the results using rigorous global and local sensitivity analysis. This generalized AFTIR serves as a more accurate analytical metric to aid clinical dose decisions and rational design of antibody-based therapeutics without the need for extensive PDE simulations.

As pharmaceutical development moves from early-stage in vitro experimentation to later in vivo and subsequent clinical trials, data and knowledge are acquired across multiple time and length scales, from the subcellular to whole patient cohort scale. Realizing the potential of this data for informing decision making in pharmaceutical development requires the individual and combined application of machine learning (ML) and mechanistic multiscale mathematical modeling approaches. Here we outline how these two approaches, both individually and in tandem, can be applied at different stages of the drug discovery and development pipeline to inform decision making compound development. The importance of discerning between knowledge and data are highlighted in informing the initial use of ML or mechanistic quantitative systems pharmacology (QSP) models. We discuss the application of sensitivity and structural identifiability analyses of QSP models in informing future experimental studies to which ML may be applied, as well as how ML approaches can be used to inform mechanistic model development. Relevant literature studies are highlighted and we close by discussing caveats regarding the application of each approach in an age of constant data acquisition.

Ras-GTPase-activating protein (SH3 domain)-binding proteins (G3BP) are RNA binding proteins that play a critical role in stress granule (SG) formation. SGs protect critical mRNAs from various environmental stress conditions by regulating mRNA stability and translation to maintain regulated gene expression. Recent evidence suggests that G3BPs can also regulate mRNA expression through interactions with RNA outside of SGs. G3BPs have been associated with a number of disease states, including cancer progression, invasion, metastasis, and viral infections, and may be useful as a cancer therapeutic target. This review summarizes the biology of G3BP including their structure, function, localization, role in cancer progression, virus replication, mRNA stability, and SG formation. We will also discuss the potential of G3BPs as a therapeutic target.

We have previously shown that a bona fide aryl hydrocarbon receptor (AhR) agonist, cinnabarinic acid (CA), protects against alcohol-induced hepatocyte apoptosis via activation of a novel AhR target gene, stanniocalcin 2 (Stc2). Stc2 translates to a secreted disulfide-linked hormone, STC2, known to function in cell development, calcium and phosphate regulation, angiogenesis, and antiapoptosis—albeit the comprehensive mechanism by which the CA-AhR-STC2 axis confers antiapoptosis is yet to be characterized. In this study, using RNA interference library screening, downstream antiapoptotic molecular signaling components involved in CA-induced STC2-mediated protection against ethanol-induced apoptosis were investigated. RNA interference library screening of kinases and phosphatases in Hepa1 cells and subsequent pathway analysis identified mitogen-activated protein kinase (MAPK) signaling as a critical molecular pathway involved in CA-mediated protection. Specifically, phosphorylation of ERK1/2 was induced in response to CA treatment without alterations in p38 and JNK signaling pathways. Silencing Stc2 in Hepa1 cells and in vivo experiments performed in Stc2^–/– (Stc2 knockout) mice, which failed to confer CA-mediated protection against ethanol-induced apoptosis, showed abrogation of ERK1/2 activation, underlining the significance of ERK1/2 signaling in CA-STC2–mediated protection. In conclusion, activation of ERK1/2 signaling in CA-driven AhR-dependent Stc2-mediated protection represents a novel mechanism of protection against acute alcohol-induced apoptosis.

Mechanistic modeling can be used to describe the time course of vaccine-induced humoral immunity and to identify key biologic drivers in antibody production. We used a six-compartment mechanistic model to describe a 20-week time course of humoral immune responses in 56 non-human primates (NHPs) elicited by vaccination with Ad26.COV2.S according to either a single-dose regimen (1 x 10¹¹ or 5 x 10¹⁰ viral particles [vp]) or a two-dose homologous regimen (5 x 10¹⁰ vp) given in an interval of 4 or 8 weeks. Humoral immune responses were quantified by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike–specific binding antibody concentrations as determined by spike protein–enzyme-linked immunosorbent assay. The mechanistic model adequately described the central tendency and variability of binding antibody concentrations through 20 weeks in all vaccination arms. The estimation of mechanistic modeling parameters revealed greater contribution of the antibody production mediated by short-lived cells as compared with long-lived cells in driving the peak response, especially post second dose when a more rapid peak response was observed. The antibody production mediated by long-lived cells was identified as relevant for generating the first peak and for contributing to the long-term time course of sustained antibody concentrations in all vaccination arms. The findings contribute evidence on the key biologic components responsible for the observed time course of vaccine-induced humoral immunity in NHPs and constitute a step toward defining immune biomarkers of protection against SARS-CoV-2 that might translate across species.