“While many studies link early childhood behavior to risk for psychopathology, the findings in our study are unique,” said Daniel Pine, M.D., a study author and chief of the NIMH Section on Development and Affective Neuroscience. “This is because our study assessed temperament very early in life, linking it with outcomes occurring more than 20 years later through individual differences in neural processes.”

Temperament refers to biologically based individual differences in the way people emotionally and behaviorally respond to the world. During infancy, temperament serves as the foundation of later personality. One specific type of temperament, called behavioral inhibition (BI), is characterized by cautious, fearful, and avoidant behavior toward unfamiliar people, objects, and situations. BI has been found to be relatively stable across toddlerhood and childhood, and children with BI have been found to be at greater risk for developing social withdrawal and anxiety disorders than children without BI.

Although these findings hint at the long-term outcomes of inhibited childhood temperament, only two studies to date have followed inhibited children from early childhood to adulthood. The current study, conducted by researchers at the University of Maryland, College Park, the Catholic University of America, Washington, D.C., and the National Institute of Mental Health, recruited their participant sample at 4 months of age and characterized them for BI at 14 months (almost two years earlier than the previously published longitudinal studies). In addition, unlike the two previously published studies, the researchers included a neurophysiological measure to try to identify individual differences in risk for later psychopathology.

The researchers assessed the infants for BI at 14 months of age. At age 15, these participants returned to the lab to provide neurophysiological data. These neurophysiological measures were used to assess error-related negativity (ERN), which is a negative dip in the electrical signal recorded from the brain that occurs following incorrect responses on computerized tasks. Error-related negativity reflects the degree to which people are sensitive to errors. A larger error-related negativity signal has been associated with internalizing conditions such as anxiety, and a smaller error-related negativity has been associated with externalizing conditions such as impulsivity and substance use. The participants returned at age 26 for assessments of psychopathology, personality, social functioning, and education and employment outcomes.

“It is amazing that we have been able to keep in touch with this group of people over so many years. First their parents, and now they, continue to be interested and involved in the work,” said study author Nathan Fox, Ph.D., of the University of Maryland Department of Human Development and Quantitative Methodology.

The researchers found that BI at 14 months of age predicted, at age 26, a more reserved personality, fewer romantic relationships in the past 10 years, and lower social functioning with friends and family. BI at 14 months also predicted higher levels of internalizing psychopathology in adulthood, but only for those who also displayed larger error-related negativity signals at age 15. BI was not associated with externalizing general psychopathology or with education and employment outcomes.

This study highlights the enduring nature of early temperament on adult outcomes and suggests that neurophysiological markers such as error-related negativity may help identify individuals most at risk for developing internalizing psychopathology in adulthood.

“We have studied the biology of behavioral inhibition over time and it is clear that it has a profound effect influencing developmental outcome,” concluded Dr. Fox.

Although this study replicates and extends past research in this area, future work with larger and more diverse samples are needed to understand the generalizability of these findings.

The study’s researchers found that low doses of the anthracycline antibiotic doxorubicin inhibit the interaction between two molecular pathways that work closely together to promote tumor growth and resistance to therapy. The targeted approach also clears the way for cancer-targeting immune cells to do their work, an unexpected and novel finding, according to the study authors.

“In low doses, doxorubicin actually stimulated the immune system, in contrast with the typical clinical doses, which were immunosuppressive, killing healthy immune cells indiscriminately,” says John M. Perry, PhD, a researcher with the Children’s Mercy Research Institute at Children’s Mercy. He completed his postdoctoral work at Stowers and is first author of the report.

The findings are the result of a decade-spanning collaborative effort among researchers at the Stowers Institute, Children’s Mercy, The University of Kansas Cancer Center and other institutions, evolving from their studies on how normal, healthy stem cells self-renew.

Early in their studies, Stowers Institute Investigator Linheng Li, PhD, and Research Specialist Xi He, MD, showed that the protein kinase Akt could enhance Wnt signaling via phosphorylating beta-catenin, thus promoting tumorigenesis in the gut. Perry further investigated the Wnt/beta-catenin and PI3K/Akt pathways in the hematopoietic (blood-forming) system. Using a mouse model with genetic modifications of the Wnt/beta-catenin and PI3K/Akt pathways, Perry found that the two pathways cooperate to drive stem cell renewal, thus resulting in excessive blood-forming stem cell production. But instead of just expanding the stem cells, the permanent activation of the pathways caused the mice also to develop leukemia. Intrigued, the researchers shifted their focus to inhibiting interaction between those same pathways to target leukemia stem cells.

Many drugs that directly target the Wnt/beta-catenin or PI3K/Akt pathways eventually fail because cancer cells evolve resistance to them, and broadly-acting chemotherapeutic drugs can have harsh side effects and systemic toxicity. The researchers collaborated with Scott Weir, PhD, and Anuradha Roy, PhD, at The University of Kansas (KU) Cancer Center, to search for an alternative among the compounds cataloged in the center’s small molecule library.

“Our idea was to find a drug with the goal of blocking the interaction between Wnt/beta-catenin and PI3K/Akt and reduce the toxicity,” says Li, who serves as liaison between Stowers and the KU Cancer Center and co-leads the center’s cancer biology research program.

The team conducted high-throughput drug screening, which showed that doxorubicin did the best job of inhibiting the interaction between the two pathways. They found that the drug’s inhibitory powers worked at low doses, which offers an advantage over administering it at high doses as a chemotherapeutic drug where it can cause lasting heart damage in some patients.

Samples collected from pediatric leukemia patients at Children’s Mercy were also central to the study. A diagnostic sample was collected from each patient before and after chemotherapy treatment to compare therapy-resistant leukemia stem cells to therapy-sensitive leukemia stem cells. Then the samples were transplanted into mice to test whether they developed leukemia and whether low-dose doxorubicin treatment improved their survival and reduced leukemia development.

“We found that mice receiving patient sample transplants with therapy-resistant leukemia stem cells rapidly developed leukemia, but low-dose doxorubicin treatment improved survival by reducing leukemia stem cells,” Perry says. “However, mice receiving patient sample transplants that did not contain therapy-resistant leukemia stem cells did not respond to low-dose doxorubicin treatment. These results showed that chemoresistant leukemia stem cells from patients could be functionally reduced with low-dose doxorubicin treatment, at least in an in vivo animal model assay.”

After successful testing in mouse models, the researchers worked with Tara Lin, MD, at the KU Cancer Center to conduct a small-scale clinical trial to test low-dose anthracycline treatment on adults with treatment-resistant acute myeloid leukemia (AML). The trial used daunorubicin, a chemotherapy drug in the same class as doxorubicin, which is widely used in treating AML. Bone marrow was collected immediately prior to treatment and again post-treatment. Half of the study participants responded to the treatment and had reduced numbers of leukemia stem cells exhibiting the Akt-activated beta-catenin biomarker.

In addition to these encouraging results, the overarching study also revealed surprising insights into immune escape — a hallmark of cancer development in which cancerous cells evade the immune system and proliferate. Mechanistically, they found that leukemia stem cells express multiple proteins known as immune checkpoints, which turn off immune responses that might otherwise recognize and eliminate leukemia stem cells. Another team member, Fang Tao, PhD, uncovered that beta-catenin binds to multiple immune checkpoint gene loci. Low-dose doxorubicin treatment reduced expression of these immune checkpoints, including PD-L1, TIM3, and CD24, which exposed otherwise resistant leukemia stem cells to immune-mediated cell killing.

Going forward, at Children’s Mercy, Perry is conducting further research to understand ways to screen other drugs that synergize with low-dose doxorubicin to kill resistant cells while reactivating anticancer immunity in pediatric patients. His team has recently launched a clinical trial on low-dose doxorubicin in pediatric patients. At Stowers, the Li Lab is investigating similar strategies for overcoming cancer therapy resistance in solid tumor cancers including breast cancer, glioblastoma, and colon cancer.

“The research holds promise as a more effective strategy to overcome cancer therapy resistance and immune escape that can be used in combination with other cancer therapies including chemotherapy, radiation, and immunotherapy for patients with leukemia and other types of cancer,” Li says.

Low-dose doxorubicin also avoids the harsh side effects of high-dose doxorubicin, potentially offering patients a better quality of life. In high doses, doxorubicin damages the heart muscle. Even when patients survive long-term, highly toxic anticancer treatments often cause long-term health problems and reduced life expectancy.

“Pediatric patients should live another half-century or more, so we need to do a better job of ensuring not only long-term survival, but healthy and productive lives,” Perry says.

The MOSAiC (Multidisciplinary drifting Observatory for the Study of Arctic Climate) research team went through extensive preparation and training for the expedition, including analyzing historic conditions. The new research shows, however, that Arctic conditions have been changing so rapidly that the past may no longer be a guide to today.

Scientists at the National Center for Atmospheric Research (NCAR) have used an ensemble of multiple climate model runs to simulate conditions along potential routes for the polar expedition, using today’s conditions in the “new Arctic.” The results suggest that thinner sea ice may carry the ship farther than would be expected compared to historical conditions and the sea ice around the ship may melt earlier than the 12-month goal. Of the 30 model runs analyzed in the new study, five (17%) showed melt-out in less than a year.

The research, published in the journal The Cryosphere, was funded by the National Science Foundation, which is NCAR’s sponsor. The study’s co-authors are from the University of Colorado Boulder and the school’s Cooperative Institute for Research in Environmental Sciences, as well as Dartmouth College and the University of Alaska Fairbanks.

The ensemble of 30 model runs used current climate conditions and reflected the breadth of ways sea ice could form, drift, and melt in a 2020 climate. The study did not incorporate 2019 ice conditions and is not a forecast of the track the ship will take over its year-long expedition.

“The whole point of MOSAiC is to understand the new Arctic and how things have changed over the last 10 years,” said Alice DuVivier, an NCAR climate scientist and lead author of the new study. “This model gives us an understanding of the range of drifting possibilities the expedition could face in the new ice regime.”

Scientists have been gathering data on Arctic sea ice extent, which can cover millions of square miles in winter, since 1979 when satellites began capturing annual changes in ice cover. “The changes in the Arctic system are so incredibly rapid that even our satellite observations from 15 years ago are unlike the Arctic today,” said Marika Holland, NCAR scientist and co-author of the study. “Now there is thinner ice, which moves more quickly, and there is less snow cover. It is a totally different ice regime.”

Going with the floe

To compare the differences between the “old Arctic” and “new Arctic,” the scientists created ice floe tracks for the expedition’s ship, a German research icebreaker called the Polarstern, using the sea ice model in the NCAR-based Community Earth System Model (CESM). First, the scientists ran 28 model tracks based on historic satellite data of sea ice conditions. Then they compared the results to 30 model tracks under the young, thin, and more seasonal Arctic ice conditions that are more reflective of recent conditions.

In these “new Arctic” conditions, the ice floes moved more quickly so their paths extend farther and varied more from each other compared to “old Arctic” paths, which include thicker sea ice and shorter, slower tracks.

Most notably, the study finds that in the seasonal Arctic scenario, 17% of the simulated tracks show the Polarstern melting out of the ice altogether, months before the October 2020 finish line. The model runs estimate July 29, 2020, as the earliest potential melt date, highlighting that the present-day Arctic has an increased risk of extreme events, such as melt-out. In contrast, none of the tracks run under the historic satellite data showed a melt-out scenario.

While the results provide additional insight into the potential outcome of MOSAiC’s path, the model runs are not a forecast of the expedition’s track, said DuVivier, who presented the study’s results to the MOSAiC science team as they prepared for the campaign. Rather, the results are a way to explore the many scenarios a ship could potentially face over the course of the journey in the current climate. “Modeling is a way to explore many worlds,” said DuVivier. “Previous experience isn’t always indicative of what is going to happen.”

By the first phase of the expedition, in fall 2019, the researchers had already encountered thin ice conditions, having initially struggled to find a thick enough ice floe to anchor the Polarstern, and experiencing storms that have challenged the expedition. According to the National Snow & Ice Data Center, the Arctic sea ice in 2019 reached the second-lowest minimum in the satellite record, meaning the expedition began under extremely low ice conditions.

Since then, the ship’s current track has been drifting farther than expected. “The model experiments from this study have comparable tracks to what the Polarstern has been experiencing in the last few months,” said DuVivier. “We are not making a prediction for the expedition, but those types of tracks melt out early in our climate model.”

Time will tell what the Polarstern’s ultimate track and destination will be, but the expedition will still provide scientists with a wealth of data. The information will ultimately be hugely beneficial for improving climate models like CESM and helping scientists understand the changes in the Arctic that future polar expeditions may go on to observe.

“This is why we need MOSAiC. Models can inform these kinds of campaigns and these campaigns are going to inform our models,” said Holland, who has her own project on the MOSAiC expedition, collecting data about snow on sea ice and upper-ocean heating that affects sea ice thickness.

“We don’t have a lot of new observations taken in this new regime, and this will be fundamental to our future understanding of the Arctic,” said Holland.