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  • Tracking circulating tumor DNA could indicate gastroesophageal cancer treatment response

    Tracking circulating tumor DNA could indicate gastroesophageal cancer treatment response

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    Monitoring levels of DNA shed by tumors and circulating in the bloodstream could help doctors accurately assess how gastroesophageal cancers are responding to treatment, and potentially predict future prognosis, suggests a new study led by researchers at the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy.

    The study tracked minimal residual disease (the amount of cancer left following treatment) by analyzing circulating tumor DNA (ctDNA), showing how these “liquid biopsies” can provide valuable insights into treatment outcomes over time. Absence of ctDNA was seen occurring together with specific activation of T cells that are part of the immune system’s defense to recognize and fight cancer. 

    “We found that the elimination of ctDNA was a good indicator of patients’ cancer-free survival,” says Valsamo “Elsa” Anagnostou, M.D., Ph.D., senior co-author of the study and associate professor of oncology and director of the thoracic oncology biorepository at Johns Hopkins.

    Anagnostou is also leader of Precision Oncology Analytics, co-leader of the Johns Hopkins Molecular Tumor Board and co-director of the Lung Cancer Precision Medicine Center of Excellence at Johns Hopkins. “We were gratified to see tumor shrinkage at a molecular level together with the immune system flaring up and clearing the tumor,” she says.

    The findings, reported in a paper published March 19 in Nature Medicine, emerged from a clinical trial examining the safety and efficacy of two immunotherapy drugs -; nivolumab and relatlimab -;as part of pre-operative treatment for patients with operable esophageal and gastroesophageal junction cancer.

    Patients with gastroesophageal cancer who have successfully completed the standard treatment of chemoradiotherapy followed by surgery unfortunately often see a resurgence of the disease. Therefore, researchers are looking for new immunotherapy approaches, as well as more accurate ways to assess tumors’ response to treatment.

    Immunotherapy has not yet been broadly effective for patients with gastroesophageal cancer. By testing new treatments in patients prior to surgery, we can make these powerful observations linking treatment-induced molecular changes with survival outcomes, thus accelerating the development of different immunotherapy approaches for our patients.”


    Vincent Lam, M.D., senior study co-author, director of the Esophageal Cancer Research Program and an assistant professor of oncology at Johns Hopkins

    The trial included 32 patients with operable esophageal or gastroesophageal junction cancer, who received nivolumab either alone or in combination with relatlimab prior to and during their standard treatment of chemotherapy and radiation. The drugs tested are both immune checkpoint inhibitors, which prevent cancer cells from dampening the body’s anti-cancer immune response. Researchers used liquid biopsies -; tests that monitor trace levels of tumor DNA shed into the bloodstream -;at different timepoints during treatment. They also measured levels of tumor-recognizing T cells and other components of tumor-specific immune responses.

    About 40% of those in the nivolumab arm and 21.4% in the combination arm had a pathological complete response, meaning there was no evidence of cancer at the time of surgery. Over half of patients in both arms had a major pathological response, meaning less than 10% of cancer cells were remaining at the time of surgery.

    “Historically, about two-thirds of patients treated with standard chemoradiation prior to surgery are alive after two years,” Lam says. “In our study, some 72.5% of participants had no signs of cancer and 82.6% were still living after two years. Notably, patients with undetectable ctDNA at different timepoints following immunotherapy had significantly longer cancer-free survival.” 

    The findings “open the door for more personalized treatment,” says lead study author Ronan Kelly, M.D., M.B.A., chief of oncology at Baylor Scott & White Health – North Texas. Kelly was at Johns Hopkins at the time of the study. “We can either de-escalate or intensify the treatment for patients who have gone through the standard protocol,” he says. “If we see ctDNA is still there, and they don’t have robust T cell response, these are the patients who may benefit most from additional treatment.”

    The study adds to a growing collection of evidence showing the value of molecular readouts like ctDNA to assess response to therapy and guide future treatment plans. For example, another recent study from Anagnostou’s lab, along with a ctDNA-adaptive clinical trial led by Johns Hopkins investigators, showed that ctDNA clearance can predict the success of immunotherapy treatment in patients with advanced lung cancer.

    “You can imagine that liquid biopsies may be used to capture and monitor cancer spread in the body and determine tumor regression across all types of cancers and therapies. There’s ever-growing evidence to support the use of ctDNA in the full range of the cancer care continuum,” says Anagnostou. “We think it’s the future.”

    Additional study co-authors were Blair Landon, Dipika Singh, Jenna Canzoniero, Archana Balan, Russell Hales, K Ranh Voong, Richard Battafarano, Stephen Yang, Stephen Broderick, Jinny Ha, Kristen Marrone, Gavin Pereira, Nisha Rao, Aryan Borole, Katerina Karaindrou, Zineb Belcaid, James White, Suqi Ke, Eun Ji Shin, Elizabeth Thompson, Kellie Smith, Chen Hu and Josephine Feliciano of Johns Hopkins. Experts from the Allegheny Health Network Cancer Institute also contributed to the work.

    The study was supported by Bristol Myers Squibb. Translational work was supported in part by the National Institutes of Health (grants CA121113, R37 CA251447), the Cancer Research Institute, Torrey Coast Foundation GEMINI CLIP Award, the Bloomberg~Kimmel Institute for Cancer Immunotherapy, the ECOG-ACRIN Thoracic Malignancies Integrated Translational Science Center grant, the Mark Foundation for Cancer Research, and the Conquer Cancer Foundation of ASCO Career Development Award.

    Source:

    Journal reference:

    Kelly, R. J., et al. (2024). Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses. Nature Medicine. doi.org/10.1038/s41591-024-02877-z.

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  • Unmet social needs negatively impact quality of life of dementia patients and caregivers

    Unmet social needs negatively impact quality of life of dementia patients and caregivers

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    People with dementia and those who care for them should be screened for loneliness, so providers can find ways to keep them socially connected, according to experts at UC San Francisco and Harvard, who made the recommendations after finding that both groups experienced declines in social well-being as the disease progressed.

    The patients, whose average age in the study was 80, had lost their social networks as their failing memories made conversation difficult, and their family and friends grew uncomfortable. Caregivers, whose average age was 67 and included spouses, adult children and others, became isolated as their responsibilities mounted. They also grieved the loss of their relationships with the patients when those relationships were good.

    Unmet social needs negatively impact quality of life, and that can lead to health outcomes like depression and cardiovascular disease, as well as high health-care use and early death.”

    Ashwin Kotwal, M.D., assistant professor of medicine in the UCSF Division of Geriatrics, and first author of the study

    “We know from previous research that older adults with higher levels of social isolation have more than double the odds of nursing home placement,” said Kotwal, who is also affiliated with the San Francisco VA Health Medical Center. 

    The study, which appears in The Gerontologist on March 18, 2024, included information from two dozen mainly male patients with dementia, and four dozen mainly female caregivers, some of whom were recently bereaved. 

    “Participating in support groups, in which patients and their caregivers can meet separately, may be low-stress places to socialize and get advice,” said Krista Harrison, Ph.D., of the UCSF Division of Geriatrics, Global Brain Health initiative and Philip R. Lee Institute for Health Policy Studies, the study’s senior author, noting that screenings take minutes and can be done by doctors, social workers or therapists. 

    “Clinicians should discuss options like community choirs that have been tailored for patients with dementia and their caregivers,” she said. “Prior research shows that meaningful activities can be enjoyed as the disease progresses. There may be simple ways of adapting activities, like switching attendance from a place of worship to participating in a service by Zoom with a small gathering at home.” 

    The interviews were conducted for two earlier studies: Dementia Palliative Care, led by Harrison, which examined patients with mild-to-moderate dementia and their caregivers; and Music and Dementia Caregiving, led by co-author Theresa Allison, M.D., Ph.D., which looked at patients with any stage of dementia and their live-in caregivers, including those who had the assistance of professional caregivers.

    Those in good relationships have the most to lose 

    A recent UCSF-led study of married couples, in which one partner had dementia, offered a fresh twist to the current study. The researchers found partners of people with dementia who were highly satisfied with their relationships experienced more loneliness than they had previously. But those in poor-quality relationships were not impacted by their partner’s dementia, despite having higher rates of depression and loneliness overall.

    “People who are really invested in their marriage or partnership have more to lose when one partner develops dementia,” said Kotwal, the study’s senior author. “But those with lower marital quality have already lost the emotional support from the marriage that can be protective against loneliness and depression.” 

    Source:

    University of California – San Francisco

    Journal reference:

    Kotwal, A., et al. (2024) “Relationships, very quickly, turn to nothing:” Loneliness, Social Isolation, and Adaptation to Changing Social Lives Among Persons Living with Dementia and Care Partners. The Gerontologist. doi.org/10.1093/geront/gnae014.

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  • New fluid biomarker may one day detect ALS and FTD before symptoms appear

    New fluid biomarker may one day detect ALS and FTD before symptoms appear

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    Two progressively degenerative diseases, amyotrophic lateral sclerosis (ALS, commonly known as Lou Gehrig’s disease) and frontotemporal dementia (FTD, recently in the news with the diagnoses of actor Bruce Willis and talk show host Wendy Williams), are linked by more than the fact that they both damage nerve cells critical to normal functioning -; the former affecting nerves in the brain and spinal cord leading to loss of movement, the latter eroding the brain regions controlling personality, behavior and language.

    Research studies have repeatedly shown that in patients with ALS or FTD, the function of TAR DNA-binding protein 43, more commonly called TDP-43, becomes corrupted. When this happens, pieces of the genetic material called ribonucleic acid (RNA) can no longer be properly spliced together to form the coded instructions needed to direct the manufacture of other proteins required for healthy nerve growth and function. The RNA strands become riddled with erroneous code sequences called “cryptic exons” that instead affect proteins believed to be associated with increased risk for ALS and FTD development.

    Until now, it was unknown if this abnormality occurred early or late in the clinical courses of ALS and FTD. In a study in the February 2024 issue of the journal Nature Medicine (first posted online Jan. 25, 2024),Johns Hopkins Medicine researchers tell how they answered that long-pondered question.

    We developed a method for locating a specific cryptic exon-linked protein, hepatoma-derived growth factor-like 2 [HDGFL2], that is associated with the loss of TDP-43’s function. By doing so, we believe we’ve discovered a biomarker that could potentially be used to detect ALS and FTD in their earliest stages -; even before symptoms appear.”


    Philip Wong, Ph.D., senior study author, professor of pathology and neuroscience, Johns Hopkins University School of Medicine

    The hunt for the biomarker began with the researchers first identifying cryptic exon-linked proteins associated with TDP-43 function loss. Then, using fragments from those proteins known as cryptic peptides, they created monoclonal (laboratory-made) antibodies specific to each one. Placed into patient samples of blood or cerebrospinal fluid (the protective fluid that surrounds the brain and central nervous system), the monoclonal antibodies will seek and lock onto only the cryptic peptides for which they were designed, making those proteins detectable.

    “Of all the cryptic peptides for which we made monoclonal antibodies, the one that worked best was the one designed for the cryptic HDGFL2 protein,” says study lead author Katie Irwin, an M.D./Ph.D. student at the Johns Hopkins University School of Medicine. “We used that monoclonal antibody to develop an extremely sensitive detection test for the cryptic HDGFL2 protein in body fluids.”

    After validating their detection method in the lab, the researchers used it to test blood and cerebrospinal fluid samples from three different collections, encompassing people with the most common forms of familial (genetic) ALS and FTD linked to a mutation in the C9orf72 gene, sporadic (not defined as genetic) forms of ALS and FTD, and healthy controls. The collections also contained biofluid samples from patients with ALS and FTD prior to their diagnoses, meaning that the researchers could look for cryptic HDGFL2 at both presymptomatic and symptomatic stages of the diseases.

    “Our test found cryptic HDGFL2 in the presymptomatic stages of patients who were genetically predisposed to ALS and FTD, and were expected to go on to develop the diseases, giving the method credibility as a potential preclinical biomarker for predicting risk of ALS and FTD,” says Irwin. “And we discovered that the test also could detect elevated levels of cryptic HDGFL2 in fluids from people with sporadic disease cases where no family history of ALS or FTD was known.”

    Wong says that having a biomarker capable of detecting cryptic HDGFL2 in the biofluids of presymptomatic patients enables them to compare its findings to results using an established biomarker for ALS and FTD.

    “The current biomarker for ALS and FTD looks for structural components of central nervous system [brain and spinal cord] nerves called neurofilaments that are shed into the biofluids, but only after symptoms begin appearing,” explains Wong. “If we use it and our cryptic HDGFL2 biomarker to determine both presymptomatic and symptomatic ALS and FTD, we can map the course of these diseases and obtain greater insight into each of their stages.”

    Wong says that knowledge could help steer patients into clinical trials for new ALS and FTD therapies earlier and “at a time when it might truly make a difference.”

    Irwin says she and her colleagues are gathering biofluid samples from around the world from patients with FTD, genetic ALS and sporadic ALS.

    “We hope to support the effectiveness, reliability and sensitivity of our biomarker by testing it on thousands of patient samples, and once validated, encourage its use as a clinical tool,” she says. “We also plan to explore the use of our biomarker for determining the effectiveness of therapies in preclinical ALS and FTD by looking for reductions in cryptic HDGFL2 levels -; and restoration of TDP-43 function -; after treatment.”

    Along with Wong and Irwin, the members of the study team from Johns Hopkins Medicine are Kyra Bowden, Kerstin Braunstein, Koping Chang, Pei Jasin, Jonathan Ling, Abhay Moghekar, Esther Oh, Irika Sinha, Bryan Traynor and Juan Troncoso. Other team members are Dan Bartlett and Denitza Raitcheva from Biogen, James Berry and Mark Garret from Massachusetts General Hospital, and Timothy Miller from the Washington University School of Medicine in St. Louis.

    Funding for the study came from National Institutes of Health grants R01NS095969, UH3NS115608 and R33NS115161; the Robert Packard Center for ALS Research at Johns Hopkins; the Target ALS Foundation; ALS Finding a Cure; the ALS Association; U.S. Food and Drug Administration grant 1U01FD008129; the Alzheimer’s Association; the Institute for Data-Intensive Engineering and Science; the Intramural Research Program of NIH (National Institute on Aging/National Institute on Neurological Disorders and Stroke grant 1ZIAAG000933); and the Karen Toffler Charitable Trust.

    Ling and Wong are inventors on a provisional patent application submitted by The Johns Hopkins University that covers the use of TDP-43-associated cryptic exon-derived neoepitopes as biomarkers. Traynor holds patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72. Bartlett is an employee and shareholder of Biogen. At the time of the study, Raitcheva was an employee and shareholder of Biogen.

    Source:

    Journal reference:

    Irwin, K. E., et al. (2024). A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS–FTD. Nature Medicine. doi.org/10.1038/s41591-023-02788-5.

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  • Dr. Abidemi Junaid on the Groundbreaking Vagina Chip

    Dr. Abidemi Junaid on the Groundbreaking Vagina Chip

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    In this insightful interview from SLAS 2024, we talk with Dr. Abidemi Junaid, a scientist at the Hansjörg Wyss Institute for Biologically Inspired Engineering at Harvard University. Junaid spearheads the development of the human Vagina Chip, a pioneering tool designed to study host-microbiome interactions in bacterial vaginosis and pave the way for biotherapeutic development and validation.

    With a rich background in biometrics, systems biomedicine, and pharmacology, Junaid’s interdisciplinary approach has culminated in the creation of a model that closely replicates the human vaginal environment. Here, Junaid shares insights into the challenges and triumphs of simulating the female reproductive system on a chip, the implications for women’s health research, and the future of biotherapeutic strategies beyond bacterial vaginosis. 

    Firstly, please introduce yourself and outline your career to date. More specifically, please provide us with an outline of the research you are presenting on a human Vagina Chip to study host-microbiome interactions in bacterial vaginosis for biotherapeutic development and validation here at SLAS.

    My name is Abidemi Junaid, and I am a scientist at Hansjörg Wyss Institute for Biologically Inspired Engineering at Harvard University. I lead the overall effort on the advancement of preclinical testing and modeling of the human reproductive tract using organ-on-chip technology.

    The reproductive health of a woman is strongly associated with a vaginal microbiome mainly composed of Lactobacillus species. In contrast, dysbiosis decreases this population and increases the diversity of anaerobic species, including pathogens, such as Garderenella vaginalis, as seen in bacterial vaginosis (BV).

    BV increases the risk of pre-term birth, miscarriages, and the chances of acquiring sexually transmitted diseases. Various therapeutic strategies are being explored to modulate the composition of the vaginal microbiome; however, there is no human-relevant preclinical model that faithfully reproduces the vaginal epithelial microenvironment for validation of potential therapeutics.

    At SLAS, I will describe our human Vagina Chip that is lined by hormone-sensitive, primary vaginal epithelium interfaced with underlying stromal fibroblasts, which sustains a low physiological oxygen concentration in the epithelial lumen.

    The Vagina Chip allows us to study a human model of the vaginal microbiome and develop new treatments for BV and other conditions that threaten women’s health.

    Firstly, for our readers, please could you tell us more about what organ-on-a-chip technologies are, and more specifically about the benefits of the human vagina chip compared to that of an animal model?

    Organs-on-chips (OoCs) are systems containing engineered or natural miniature tissues grown inside microfluidic chips. To better mimic human physiology, the chips are designed to control cell microenvironments and maintain tissue-specific functions.

    Animal models are of limited use in research to study host-microbiota interactions in the vaginal space because of the major physiological, anatomical, and microbial differences present in these models compared to the human vagina. The Vagina Chip replicates the human vaginal tissue microenvironment including its microbiome in vitro.

    Image Credit: Love Employee/Shutterstock.comImage Credit: Love Employee/Shutterstock.com

    How does the vagina chip technology simulate the unique environment of the female reproductive system, and what are its applications in women’s health research?

    The Vagina Chip supports the growth of healthy microbiome community on-chip, which is accompanied by maintenance of epithelial cell viability, accumulation of D- and L-lactic acid, maintenance of a physiologically relevant low pH, and down regulation of proinflammatory cytokines.

    The Vagina Chip can be used to better understand interactions between the vaginal microbiome and host tissues, as well as to evaluate the safety and efficacy of live biotherapeutics products.

    What is organ-on-a-chip technology?

    Your journey from biometrics to systems biomedicine and pharmacology is quite impressive. Could you share how your diverse academic background has influenced your approach to your current research on the human Vagina Chip?

    My interdisciplinary background has allowed me to apply various elements from engineering, chemistry, and biology in the further development of the human Vagina Chip to recapitulate the human vagina for biotherapeutic studies successfully.

    During my Ph.D., I learned how to use the high-throughput human microvessels-on-chips for screening patient samples and drug discovery. I was able to use these skills for studying microbes isolated from vaginal clinical swab samples in the Vagina Chip to mimic healthy and dysbiotic conditions.

    The Vagina Chip presents a novel approach to studying bacterial vaginosis (BV). Can you describe the initial challenges you faced in replicating the complex vaginal microenvironment on a chip?

    One of the initial challenges was getting the cells that we cultured in the Vagina Chip to differentiate and become stratified just like the human vagina. We were able to solve that by using homemade differentiation media and physiologically relevant dynamic flow of media in the system.

    Learn more about vaginal dysbiosis

    The study indicates that Lactobacillus-rich live biotherapeutic products (LBPs) can alleviate dysbiotic responses without eradicating G. vaginalis. How does this finding challenge or support existing theories about BV treatment?

    In a healthy vaginal microbiota, you a have high population of L. crispatus and very low population of G. vaginalis. Since we still see a high population of G. vaginalis after treatment with the LBP in our Vagina Chip, this indicates that additional treatment is needed to reduce the population of G. vaginalis and finally reach a healthy state.

    The Vagina Chip’s ability to correlate pro-inflammatory responses with untreated BV patient samples is intriguing. How do you envision this capability impacting the future of personalized medicine for reproductive health?

    There is growing recognition that taking care of women’s health is critical for the health of all humans, but the creation of tools to study human female physiology is lagging.

    We’re hopeful that this new preclinical model will drive the development of new treatments for BV as well as new insight into female reproductive health. Furthermore, this model will allow us to study individual patients from different ethnicities and develop therapies that is specific to each of them.

    You mention that further reduction in G. vaginalis numbers might produce a greater therapeutic effect. What strategies or modifications to the Vagina Chip are being considered to investigate this hypothesis?

    One of the strategies that we are trying is to treat the dysbiotic Vagina Chip with hydroxy-metronidazole and the LBP. Hydroxy-Metronidazole is an antibiotic that is commonly used to kill G.vaginalis in BV patients.

    However, treating with hydroxy-metronidazole alone can lead to recurrent BV. We hope that with the combination of hydroxy-metronidazole and LBP there is a lower chance of recurrence.

    Given the complexity of the vaginal microbiome and its impact on women’s health, how do you see your work influencing the development and validation of other biotherapeutic strategies beyond BV?

    Various therapeutic strategies are being explored to modulate the composition of the vaginal microbiome; however, there is no human model that faithfully reproduces the vaginal epithelial microenvironment for preclinical validation of potential therapeutics or testing hypotheses about vaginal epithelium-microbiome interactions.

    The Vagina Chip is a preclinical model of the human vaginal mucosa that can be used to understand better interactions between the vaginal microbiome and host tissues, as well as to evaluate the safety and efficacy of live biotherapeutics products. This will help us to predict how successful a biotherapeutic strategy would be in clinical trials.

    Finally, as someone at the forefront of organ-on-chip technology, what advice would you give to young scientists interested in entering this field, and what do you think are the most exciting possibilities on the horizon?

    The field of organs-on-chips is very interdisciplinary. So, I advise young scientists to explore research in various scientific areas and collaborate with people with different scientific backgrounds.

    I look forward to the time when we can fully use organ-on-a-chip technology to replace animal models. Moreover, this technology will be an important tool to decide whether a therapy should go to clinical trial.

    Where can readers find more information?

    About Abidemi Junaid, Ph.D. 

    Abidemi Junaid received his B.S. in Biometrics from Zuyd University of Applied Sciences, M.S. in Biomolecular Sciences from VU University, and Ph.D. in Systems Biomedicine and Pharmacology from Leiden University. His Ph.D. work was centered around the development of high-throughput human microvessels-on-chips for studying microvascular destabilization, infectious diseases, and metabolomics.

    He also worked on integrating mechanical fluid flow and biological and environmental sensing in organs-on-chips. Altogether, this enabled him to identify the impact of patient plasma on microvessels for clinical studies. As a Scientist at the Wyss Institute, he is working on advancing preclinical testing and modeling of the human immune system using organ-on-chip technology.

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  • Nanoparticles turbocharge turmeric’s curcumin for enhanced health benefits

    Nanoparticles turbocharge turmeric’s curcumin for enhanced health benefits

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    A review article published in the journal Antioxidants provides a detailed overview of nanoparticle-based strategies to improve the bioavailability and bioactivity of curcumin.

    Study: Enhancing the Bioavailability and Bioactivity of Curcumin for Disease Prevention and Treatment. Image Credit: Microgen / ShutterstockStudy: Enhancing the Bioavailability and Bioactivity of Curcumin for Disease Prevention and Treatment. Image Credit: Microgen / Shutterstock

    Background

    Curcumin, turmeric’s main bioactive compound, is a polyphenol found in Curcuma longa roots. This compound has numerous health benefits, including anticancer, antioxidant, anti-inflammatory, anti-obesity, anti-diabetic, anti-microbial, wound-healing, and lipid-lowering properties.

    Curcumin has low bioavailability in human organs and is rapidly converted to a number of bioactive metabolites after intestinal absorption. Dried turmeric powder prepared from Curcuma longa roots contains about 2-5% of curcumin.

    Curcumin consumed through dietary sources is sufficient to impact the gut microbiota. However, due to rapid metabolism, the concentration of intact curcumin in the circulation becomes very low (sub-micromolar concentrations), which is insufficient to trigger cellular signaling and gene expression, as observed in in vitro studies with cultured cells.   

    Examples of curcumin nano-delivery systems.Examples of curcumin nano-delivery systems.

    Strategies to increase curcumin bioavailability

    Dietary curcumin is inefficiently absorbed across the intestinal epithelium and undergoes rapid metabolism and systemic elimination. In an aqueous solution with a neutral pH, the enol state of curcumin is formed, which reduces the stability of curcumin.

    Several nanoformulations have been developed to increase curcumin concentration in the circulation as well as in specific cells, tissues, and organelles. These nanoformulations have been designed to increase curcumin solubility, improve stability during gastrointestinal absorption, alter absorption routes, and inhibit detoxification enzymes using adjuvants.

    The latest generation of curcumin nanoformulations can increase free curcumin bioavailability in plasma by more than 100-fold and improve absorption, cellular uptake, permeability through the blood-brain barrier, and tissue distribution.

    Factors that improve curcumin bioavailability include composition, size, and route of administration of nanoparticles. Curcumin preparations with smaller-size nanoparticles have been found to increase bioavailability when administered orally. In contrast, larger-size nanoparticles have been found to increase bioavailability when administered intravenously.

    Curcumin nanoformulations can induce senescence in malignant and normal cells, thus effectively treating various cancer types and age-related diseases, including cardiometabolic diseases, neurodegenerative diseases, and liver, lung, and gastrointestinal diseases.

    Regarding mode of action, existing evidence indicates that curcumin acts as an antioxidant and anti-inflammatory compound to reduce the production of reactive oxygen species (ROS) and modulate cellular signaling and gene expression related to inflammatory pathways. These activities work synergistically to maintain homeostasis of cellular macromolecules (proteins, DNA, and lipids).

    These activities can be increased by incorporating curcumin in nanoparticle-based formulations, such as polymeric curcumin–bioperine–PLGA. The isomerization of curcumin to cis-trans curcumin is known to increase its ability to bind adenosine receptors. Incorporation of cis-trans curcumin into nanoformulations is considered to be a valuable strategy to increase its therapeutic efficacy against inflammatory diseases.        

    Regarding safety profile, recent clinical trials indicate that the majority of curcumin nanoformulations are well-tolerated and safe for use in humans.

    Anti-microbial activities

    Curcumin is known to exert an anti-microbial effect against both Gram-positive and Gram-negative bacteria, and this activity is beneficial for topical applications against skin infection and oral and intestinal applications. Moreover, curcumin can indirectly prevent infection by inhibiting bacterial growth in foods. 

    The anti-microbial activities of curcumin can be enhanced by incorporating it into nanoformulations. Administration of curcumin with other compounds, such as antibiotics, honey, or other polyphenols, can also increase its anti-microbial and biofilm inhibitory activities.

    Effects of curcumin nanoformulations in the gastrointestinal tract  

    Several nanotechnology-based systems, such as micelles, liposomes, exosomes, phospholipid complexes, nanoemulsions, nanostructured lipid carriers, and biopolymer nanoparticles, have been found to increase oral curcumin bioavailability.

    Nanoparticle curcumin called ‘Theracurmin’ has been found to suppress colitis in mice by modulating gut microbiota. Improvement in gut microbiota composition has also been achieved using nanobubble curcumin extract. Curcumin loaded with nanostructured lipid carriers has been found to reduce colonic inflammation in animals.

    The incorporation of curcumin in liposomes has been found to increase its anticancer activity by improving gastrointestinal absorption. Moreover, the administration of curcumin with other bioactive compounds, such as piperine and salsalate, has been found to increase curcumin bioavailability and bioactivity.

    Effects of curcumin nanoformulations in liver and adipose tissue  

    Curcumin nanoformulations with adjuvants, such as piperine and quercetin, have been found to increase its bioavailability and bioactivity significantly. Various nanotechnology-based delivery systems, such as micelles, liposomes, polymeric, metal, and solid lipid nanoparticles, have been found to increase curcumin bioavailability.

    The anti-inflammatory, antioxidant, and antifibrotic properties of curcumin make it a potential therapeutic compound for liver diseases. In liver diseases, curcumin nanoformulations have been found to increase its therapeutic efficacy by increasing curcumin solubility, bioavailability, and membrane permeability and improving its pharmacokinetics, pharmacodynamics, and biodistribution.   

    Effects of curcumin nanoformulations on the cardiovascular system   

    Curcumin encapsulated in carboxymethyl chitosan nanoparticles conjugated to a myocyte-specific homing peptide has been found to increase the cardiac bioavailability of curcumin. The formulation has also been found to improve cardiac function by reducing the expression of hypertrophy marker genes and apoptotic mediators.

    Several curcumin nanoformulations, such as hyaluronic acid-based nanocapsules, nanoparticles encapsulated in PLGA or nanoemulsion systems, have been found to increase the aqueous solubility of curcumin and subsequently prevent hypertension in animals. Similar cardio-protective effects have been observed using nanocurcumin polymer-based nanoparticles and curcumin and nisin-based polylactic acid nanoparticles. These formulations have been found to prevent myocardial damage and improve cardiac muscle functions.

    Effects of curcumin nanoformulations on the brain   

    Curcumin complexed with galactomannans has been found to have better blood-brain barrier permeability and higher efficacy in preventing neuroinflammation, anxiety, fatigue, and memory loss in both humans and animals.

    Curcumin-laden liposomes have been found to exert anti-amyloidogenic and anti-inflammatory effects in animal and cellular models of Alzheimer’s disease. Curcumin’s preventive activities against Alzheimer’s disease are associated with its ability to reduce amyloid-beta production and tau aggregation, which are major hallmarks of Alzheimer’s disease.   

    However, clinical trials involving patients with mild to moderate Alzheimer’s disease could not find any beneficial effect of curcumin in reducing disease biomarkers and improving cognitive functions.

    A recent clinical trial involving non-demented adults, on the other hand, has shown that oral curcumin treatment can improve memory and reduce amyloid and tau accumulation in the amygdala and hypothalamus.   

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  • Research provides insight into how the brain translates motivation into goal-oriented behavior

    Research provides insight into how the brain translates motivation into goal-oriented behavior

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    Hunger can drive a motivational state that leads an animal to a successful pursuit of a goal -; foraging for and finding food.

    In a highly novel study published in Current Biology, researchers at the University of Alabama at Birmingham and the National Institute of Mental Health, or NIMH, describe how two major neuronal subpopulations in a part of the brain’s thalamus called the paraventricular nucleus participate in the dynamic regulation of goal pursuits. This research provides insight into the mechanisms by which the brain tracks motivational states to shape instrumental actions.

    For the study, mice first had to be trained in a foraging-like behavior, using a long, hallway-like enclosure that had a trigger zone at one end and a reward zone at the other end, more than 4 feet distant.

    Mice learned to wait in a trigger zone for two seconds, until a beep triggered initiation of their foraging-like behavioral task. A mouse could then move forward at its own pace to the reward zone to receive a small gulp of strawberry-flavored Ensure. To terminate the trial, the mice needed to leave the reward zone and return to the trigger area, to wait for another beep. Mice learned quickly and were highly engaged, as shown by completing a large volume of trials during training.

    The researchers then used optical photometry and the calcium sensor GCaMP to continuously monitor activity of two major neuronal subpopulations of the paraventricular nucleus, or PVT, during the reward approach from the trigger zone to the reward zone, and during the trial termination from the reward zone back to the trigger zone after a taste of strawberry-flavored food. The experiments involve inserting an optical fiber into the brain just about the PVT to measure calcium release, a signal of neural activity.

    The two subpopulations in the paraventricular nucleus are identified by presence or absence of the dopamine D2 receptor, noted as either PVTD2(+) or PVTD2(–), respectively. Dopamine is a neurotransmitter that allows neurons to communicate with each other.

    We discovered that PVTD2(+) and PVTD2(–) neurons encode the execution and termination of goal-oriented actions, respectively. Furthermore, activity in the PVTD2(+) neuronal population mirrored motivation parameters such as vigor and satiety.”


    Sofia Beas, Ph.D., assistant professor in the UAB Department of Neurobiology and co-corresponding author of the study

    Specifically, the PVTD2(+) neurons showed increased activity during the reward approach and decreased activity during trial termination. Conversely, PVTD2(–) neurons showed decreased activity during the reward approach and increased activity during trial termination.

    “This is novel because people didn’t know there was diversity within the PVT neurons,” Beas said. “Contrary to decades of belief that the PVT is homogeneous, we found that, even though they are the same types of cells (both release the same neurotransmitter, glutamate), PVTD2(+) and PVTD2(–) neurons are doing very different jobs. Additionally, the findings from our study are highly significant as they help interpret contradictory and confusing findings in the literature regarding PVT’s function.”

    For a long time, the thalamic areas such as the PVT had been considered just a relay station in the brain. Researchers now realize, Beas says, that the PVT instead processes information, translating hypothalamic-derived needs states into motivational signals via projections of axons -; including the PVTD2(+) and PVTD2(–) axons -; to the nucleus accumbens, or NAc. The NAc has a critical role in the learning and execution of goal-oriented behaviors. An axon is a long cable-like extension from a neuron cell body that transfers the neuron’s signal to another neuron.

    Researchers showed that these changes in neuron activity at the PVT were transmitted to the NAc by measuring neural activity with an optical fiber inserted where the terminals of the PVT axons reach the NAc neurons. The activity dynamics at the PVT-NAc terminals largely mirrored the activity dynamics the researchers saw at the PVT neurons -; namely increased neuron activity signal of PVTD2(+) during reward approach and increased neuron activity of PVTD2(–) during trial termination.

    “Collectively, our findings strongly suggest that motivation-related features and the encoding of goal-oriented actions of posterior PVTD2(+) and PVTD2(-) neurons are being relayed to the NAc through their respective terminals,” Beas said.

    During each mouse recording session, the researchers recorded eight to 10 data samples per second, resulting in a very big dataset. In addition, these types of recordings are subject to many potential confounding variables. As such, the analysis of this data was another novel aspect of this study, through use of a new and robust statistical framework based on Functional Linear Mixed Modeling that both account for the variability of the recordings and can explore the relationships between the changes of photometry signals over time and various co-variates of the reward task, such as how quickly mice performed a trial, or how the hunger levels of the animals can influence the signal.

    One example of how researchers correlated motivation with task performance was separating the trial times into “fast” groups, two to three seconds to the reward zone from the trigger zone, and “slow” groups, nine to 11 seconds to the reward zone.

    “Our analyses showed that reward approach was associated with higher calcium signal ramps in PVTD2(+) neurons during fast compared to slow trials,” Beas said. “Moreover, we found a correlation between signal and both latency and velocity parameters. Importantly, no changes in posterior PVTD2(+) neuron activity were observed when mice were not engaged in the task, as in the cases where mice were roaming around the enclosure but not actively performing trials. Altogether, our findings suggest that posterior PVTD2(+) neuron activity increases during reward-seeking and is shaped by motivation.”

    Deficits in motivation are associated with psychiatric conditions like substance abuse, binge eating and the inability to feel pleasure in depression. A deeper understanding of the neural basis of motivated behavior may reveal specific neuronal pathways involved in motivation and how they interact. This could lead to new therapeutic targets to restore healthy motivational processes in patients.

    Co-authors with Beas in the study, “Dissociable encoding of motivated behavior by parallel thalamo-striatal projections,” are Isbah Khan, Claire Gao, Gabriel Loewinger, Emma Macdonald, Alison Bashford, Shakira Rodriguez-Gonzalez, Francisco Pereira and Mario Penzo, NIMH, Bethesda, Maryland. Beas was a post-doctoral fellow at the NIMH before moving to UAB last year.

    Support came from National Institutes of Health award K99/R00 MH126429, a NARSAD Young Investigator Award by the Brain and Behavior Research Foundation, and NIMH Intramural Research Program award 1ZIAMH002950.

    At UAB, Neurobiology is a department in the Marnix E. Heersink School of Medicine.

    Source:

    University of Alabama at Birmingham

    Journal reference:

    Beas, S., et al. (2024). Dissociable encoding of motivated behavior by parallel thalamo-striatal projections. Current Biology. doi.org/10.1016/j.cub.2024.02.037.

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  • DNA origami vaccine DoriVac paves way for personalized cancer immunotherapy

    DNA origami vaccine DoriVac paves way for personalized cancer immunotherapy

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    Therapeutic cancer vaccines are a form of immunotherapy in the making that could not only destroy cancer cells in patients, but keep a cancer from coming back and spreading. Multiple therapeutic cancer vaccines are being studied in clinical trials, but despite their promise, they are not routinely used yet by clinical oncologists to treat their patients. 

    The central ingredient of therapeutic cancer vaccines is antigens, which are preferentially produced or newly produced (neoantigens) by tumor cells and enable a patient’s immune system to search and destroy the cancerous cells. In most cases, those antigens cannot act alone and need the help of adjuvant molecules that trigger a general alarm signal in immune cells known as antigen-presenting cells (APCs). APCs internalize both antigen and adjuvant molecules and present the antigens to different types of T cells. Those T cells then launch an immediate attack against the tumor, or preserve a longer-lasting memory of the tumor for future defense.

    A cancer vaccine’s effectiveness depends on the level and duration of the “alarm” its adjuvants can ring in APCs. Previously, researchers found that delivering adjuvant and antigen molecules to APCs simultaneously using nanostructures like DNA origami can increase APC activation. However, none of these approaches systematically investigated how the number and nanoscale arrangement of adjuvant molecules affect downstream tumor-directed immunity. 

    Now, a research team at the Wyss Institute at Harvard University, Dana-Farber Cancer Institute (DFCI), Harvard Medical School (HMS), and Korea Institute of Science and Technology (KIST) has created a DNA origami platform called DoriVac, whose core component is a self-assembling square block-shaped nanostructure. To one face of the square block, defined numbers of adjuvant molecules can be attached in highly tunable, nanoprecise patterns, while the opposite face can bind tumor antigens. The study found that molecules of an adjuvant known as CpG spaced exactly 3.5 nanometers apart from each other resulted in the most beneficial stimulation of APCs that induced a highly-desirable profile of T cells, including those that kill cancer cells (cytotoxic T cells), those that cause beneficial inflammation (Th-1 polarized T cells), and those that provide a long-term immune memory of the tumor (memory T cells). DoriVac vaccines enabled tumor-bearing mice to better control the growth of tumors and to survive significantly longer than control mice. Importantly, the effects of DoriVac also synergized with those of immune checkpoint inhibitors, which are a highly successful immunotherapy that is already widely used in the clinic. The findings are published in Nature Nanotechnology.

    “DoriVac’s DNA origami vaccine technology merges different nanotechnological capabilities that we have developed over the years with an ever-deepening knowledge about cancer-suppressing immune processes,” said Wyss Core Faculty member William Shih, Ph.D., who led the Wyss Institute team together with first-author Yang (Claire) Zeng, M.D., Ph.D. “We envision that in the future, antigens identified in patients with different types of tumors could be quickly loaded onto prefabricated, adjuvant-containing DNA origami to enable highly effective personalized cancer vaccines that can be paired with FDA-approved checkpoint inhibitors in combination therapies.”

    Shih is also a Professor at HMS and DFCI’s Department of Cancer Biology and, as some of the other authors, a member of the NIH-funded cross-institutional “Immuno-engineering to Improve Immunotherapy” (i3) Center based at the Wyss. 

    DNA origami rationale

    The CpG adjuvant is a synthetic strand of DNA made up of repeated CpG nucleotide motifs that mimic the genetic material from immune cell-invading bacterial and viral pathogens. Like its natural counterparts, CpG adjuvants bind to a “danger receptor” called TLR9 in immune cells, which in turn induces an inflammatory (innate) immune response that works in concert with the antigen-induced (adaptive) immune response. 

    “We knew from previous work that to trigger strong inflammatory responses, TLR9 receptors need to dimerize and aggregate into multimeric complexes binding to multiple CpG molecules. The nanoscale distances between the CpG-binding domains in effective TLR9 assemblies revealed by structural analysis fell right into the range of what we hypothesized we could mirror with DNA origami structures presenting precisely spaced CpG molecules,” explained Zeng, who was an Instructor in Medicine at the time of the study and now is a senior scientist at DFCI and Harvard Medical School (HMS). In addition to Shih, Zeng was also mentored on the project by senior authors Ju Hee Ryu, Ph.D., a Principal Researcher at KIST, and Wyss Founding Core Faculty member David Mooney, Ph.D., who also is Professor at Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), and one of the i3 Center’s Principal Investigators. 

    Zeng and the team fabricated DoriVac vaccines in which different numbers of CpG strands were spaced at 2.5, 3.5, 5, or 7 nanometers apart from each other on one face of the square block, and a model antigen was attached to the opposite face. They protected their structures from being degraded in the body using a chemical modification method that Shih’s group had developed earlier. When internalized by different types of APCs, including dendritic cells (DCs), which orchestrate tumor-directed T cell responses, the DoriVac vaccines improved the uptake of antigens compared to controls consisting of free antigen molecules. A CpG spacing of 3.5 nanometers produced the strongest and most beneficial responses in APCs, and significantly outperformed a control vaccine containing only free CpG molecules. “We were excited to find that the DoriVac vaccine preferentially induced an immune activation state that supports anti-tumor immunity, which is what researchers generally want to see in a good vaccine,” said Zeng. 

    Besides spacing, the numbers of CpG molecules in DoriVac vaccines also mattered. The team tested vaccines containing between 12 to 63 optimally spaced CpG molecules and found that 18 CpG molecules provided the best APC activation. This meant that their approach can also help limit the dosage of CpG molecules and thus minimize commonly observed toxic side effects observed with adjuvants.

    Gained in (tumor) translation

    Importantly, these in vitro trends translated to in vivo mouse tumor models. When prophylactically injected under the skin of mice, DoriVac vaccines accumulated in the closest lymph nodes where they stimulated DCs. A vaccine loaded with a melanoma antigen prevented the growth of subsequently injected aggressive melanoma cells. While all control animals had succumbed to the cancer by day 42 of the experiment, DoriVac-protected animals all were alive. DoriVac vaccines also inhibited tumor growth in mice in which the formation of melanoma tumors was already underway, with a 3.5 nanometer spacing of 18 CpG molecules again providing maximum effects on DC and T cells, and the strongest reduction in tumor growth.

    Next, the team asked whether DoriVac vaccines could also boost immune responses produced by small “neoantigens” emerging in melanoma tumors. Neoantigens are ideal targets because they are exclusively made by tumor cells. However, they often are not very immunogenic themselves, which make highly effective adjuvants an important component in neoantigen vaccines. A DoriVac vaccine customized with four neoantigens enabled the researchers to significantly suppress growth of the tumor in mice that produced the neoantigens.

    Finally, the researchers asked whether DoriVac could synergize with immune checkpoint therapy, which reactivates T cells that have been silenced in tumors. In mice, the two therapies combined resulted in the total regression of melanoma tumors, and prevented them from growing back when the animals were exposed to the same tumor cells again four months later. The animals had built up an immune memory of the tumor. The team obtained a similar vaccination efficiency in a mouse lymphoma model.

    We think that DoriVac’s value for determining a sweet spot in adjuvant delivery and enhancing the delivery and effects of coupled antigens can pave the way to more effective clinical cancer vaccines for use in patients with a variety of cancers.”


    Yang (Claire) Zeng, M.D., Ph.D., First Author

    The team is currently translating the DoriVac platform toward its clinical application, which is supported by the study’s assessment of vaccine distribution and vaccine-directed antibodies in mice, as well as cytokines produced by immune cells in response to the vaccines in vivo. 

    “The DoriVac platform is our first example of how our pursuit of what we call Molecular Robotics – synthetic bioinspired molecules that have programmable shape and function – can lead to entirely new and powerful therapeutics. This technology opens an entirely new path for development of designer vaccines with properties tailored to meet specific clinical challenges. We hope to see its rapid translation into the clinic,” said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and Boston Children’s Hospital, and the Hansjörg Wyss Professor of Bioinspired Engineering at SEAS.

    Other authors on the study are Olivia Young, Christopher Wintersinger, Frances Anastassacos, James MacDonald, Giorgia Isinelli, Maxence Dellacherie, Miguel Sobral, Haiqing Bai, Amanda Graveline, Andyna Vernet, Melinda Sanchez, Kathleen Mulligan, Youngjin Choi, Thomas Ferrante, Derin Keskin, Geoffrey Fell, Donna Neuberg, Cathrine Wu, and Ick Chan Kwon. The study was funded by the Wyss Institute’s Validation Project and Institute Project programs, Claudia Adams Barr Program at DFCI, Korean Fund for Regenerative Medicine (award #21A0504L1), Intramural Research Program of KIST (award #2E30840), and National Institutes of Health (under the i3 Center supporting U54 grant (award #CA244726-01).

    Source:

    Wyss Institute at Harvard University

    Journal reference:

    Zeng, Y. C., et al. (2024). Fine tuning of CpG spatial distribution with DNA origami for improved cancer vaccination. Nature Nanotechnology. doi.org/10.1038/s41565-024-01615-3.

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  • Targeting a non-encoding stretch of RNA may shrink pediatric brain tumors in mice

    Targeting a non-encoding stretch of RNA may shrink pediatric brain tumors in mice

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    Targeting a non-encoding stretch of RNA may help shrink tumors caused by an aggressive type of brain cancer in children, according to new research in mice reported March 8 in Cell Reports by Johns Hopkins Kimmel Cancer Center investigators. 

    Medulloblastoma are the most common type of malignant brain cancer in children. The most aggressive and difficult-to-treat form of the disease is group 3 medulloblastoma, which is often fatal. By targeting long, noncoding genetic material called lnc-RNAs that drive the expression of cancer-causing genes, the study’s senior author, Ranjan Perera, Ph.D., director of the Center for RNA Biology at Johns Hopkins All Children’s Hospital in St. Petersburg, Florida, and his colleagues have demonstrated an innovative new approach that shrinks group 3 medulloblastoma tumors in mice. 

    “Group 3 medulloblastoma is very aggressive, and there are currently no targeted therapies,” says Perera, who has a primary affiliation in the Department of Neurosurgery, is a member of the Johns Hopkins Kimmel Cancer Center and is an associate professor of oncology at the Johns Hopkins University School of Medicine. He is also a senior scientist at the Johns Hopkins All Children’s Hospital Cancer and Blood Disorders Institute, and has a secondary affiliation with the hospital’s Institute for Fundamental Biomedical Research. “Our novel therapeutic approach based on noncoding RNA could fill an urgent need for new therapies for this devastating disease in children.” 

    RNA acts as a template for building proteins based on instructions encoded in the DNA. Until recently, scientists thought 97% of RNA was “junk” because only 3% is used to build proteins. However, scientists have realized that RNA’s nonprotein encoding stretches control gene expression. A previous study by Perera and colleagues showed that a long noncoding stretch of RNA called lnc-HLX-2-7 contributes to the growth of group 3 medulloblastoma tumors by attaching to a DNA promoter that increases expression of cancer-causing genes. Promoters are nongene coding stretches of DNA adjacent to genes that act like switches turning them on. 

    The new study provides additional details showing that lnc-HLX-2-7 specifically binds to the HLX promoter region of DNA, increasing HLX gene expression and causing the tumor to grow. HLX triggers tumor growth by binding to promoter regions for several other cancer-causing genes, increasing their expression. One gene that HLX increases expression of is MYC, which also increases the expression of several other cancer-causing genes, causing a cascade of activity that accelerates the growth of group 3 medulloblastoma tumors. 

    Perera and his team developed an intravenous treatment to block lnc-HLX-2-7 from binding to the HLX promoter to stop this cascade of cancer-gene expression. They assembled a sequence of nucleotides (called antisense oligo nucleotides), the building blocks of RNA, that can bind to the corresponding nucleotides that make up lnc-HLX-2-7, preventing it from binding to the HLX promoter in the DNA and leading to its destruction. They coated the sequence with microscopic particles called cerium oxide nanoparticles to protect the lnc-HLX-2-7 until it reaches its target. 

    When the team treated a mouse model of group 3 medulloblastoma with the experimental intravenous therapy, it reduced tumor growth by 40%–50%. Adding cisplatin, a chemotherapy drug currently used to treat medulloblastomas, alongside the new therapy caused the tumors to shrink even more and prolonged the animals’ survival. The combination therapy extended the animals’ lives by about 84 days compared with a 44-day increase in survival on lnc-HLX-2-7 alone. 

    “When you combine the two treatments, you see dramatic effects,” Perera says. 

    Perera and his colleagues will collaborate with Johns Hopkins neurosurgeons to plan studies of the therapy in humans to further test its safety and efficacy. 

    Understanding why MYC is elevated in these tumors is extremely important, and this new link to HLX provides insights that open new therapeutic possibilities.”


    Charles Eberhart, M.D., Ph.D., study co-author, Kimmel Cancer Center researcher, director of neuropathology and ophthalmic pathology and professor of oncology and pathology at the Johns Hopkins University School of Medicine

    The work was supported by the Schamroth Project, funded by Ian’s Friends Foundation, the Hough Family Foundation, the National Institutes of Health (grant P30 CA006973), the National Cancer Institute (grants 5P30CA030199, R01NS124668-01A1, and R35NS122339), and a CPRIT Scholar award from the MD Anderson Cancer Center.

    Study co-authors were Keisuke Katsushima, Kandarp Joshi, Menglang Yuan, Stacie Stapleton and George Jallo from Johns Hopkins. Other authors were from the University of Delaware; the University of Central Florida, Orlando; Institute Curie at PSL University in Paris; Texas Children’s Cancer Center, Houston; Baylor College of Medicine, Houston; and Columbia University Medical Center, New York. 

    Source:

    Journal reference:

    Katsushima, K., et al. (2024). A therapeutically targetable positive feedback loop between lnc-HLX-2-7, HLX, and MYC that promotes group 3 medulloblastoma. Cell Reports. doi.org/10.1016/j.celrep.2024.113938.

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  • Novel tool to predict a person’s risk for cardiovascular complications after bone marrow transplant

    Novel tool to predict a person’s risk for cardiovascular complications after bone marrow transplant

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    For thousands of Americans each year, a bone marrow transplant has the potential to cure diseases such as leukemias, lymphomas and immune deficiency disorders. While lifesaving, bone marrow transplants are taxing procedures that can affect various organs, including the cardiovascular system.

    With advances in medical science and improvement in protocols, more bone marrow transplants, also known as hematopoietic stem cell transplantation, are being offered to older patients, a population at greater risk of cardiovascular disease. 

    Researchers led by Michigan Medicine have not only determined the contemporary prevalence of cardiovascular complications after bone marrow transplant -; they developed a novel tool to predict a person’s risk for such problems following the procedure and help guide the pre-transplant process.

    “In the early era of bone marrow transplant, patients with heart disease were often excluded due to the cardiotoxicity of the conditioning regimens used at the time,” said Salim Hayek, M.D., adjunct professor of internal medicine-cardiology at U-M Medical School who specializes in cardio-oncology. 

    “Understanding the cardiovascular risks of modern bone marrow transplantation is crucial for selecting the right patients and to ensure that none are excluded unnecessarily. This is the first contemporary evidence that shows the risks associated with bone marrow transplant and how to assess a patient’s risk for cardiovascular complications-; which, taken together, can guide clinicians to ensure better outcomes for this procedure.”

    Cardiovascular risks after transplant 

    Hayek and his team built the Cardiovascular Registry in Bone Marrow Transplantation, known as CARE-BMT, which compiles data of patients who underwent transplant from both University of Michigan Health and Rush University. 

    In a study of over 3,300 people who had a bone marrow transplant between 2008 and 2019, 4.1% of patients experienced cardiovascular events within 100 days after the procedure, and 13.9% did so after 5 years. 

    The results are published in JACC Cardio-Oncology. 

    Rare complications

    Overall, cardiovascular complications during the hospitalization for bone marrow transplant were rare. The most common short and long term condition was atrial fibrillation, with 6.8% of patients diagnosed at the five-year mark, followed by 5.4% of patients experiencing heart failure. Severe cardiovascular complications, such as heart attack and stroke, were uncommon.

    Investigators also found that 16.4% of allogenic transplant recipients, those who received bone marrow from another donor, developed long term cardiovascular events after five years, compared to 12.1% of autologous recipients who had damaged bone marrow replaced with their own healthy blood stem cells.

    The landscape of bone marrow transplant has rapidly evolved over the last 20 years, with many improvements in the way patients are selected for and treated during bone marrow transplantation.


    Our cohort allowed us to re-evaluate the incidence of cardiovascular complications in patients who received more modern treatment.”


    Salim Hayek, M.D., adjunct professor of internal medicine-cardiology at U-M Medical School

    Patients with preexisting cardiovascular conditions, such as diabetes and coronary artery disease, were more likely to have complications in the long term but not during the transplant process. 

    “Determining who is at high and low risk of cardiovascular outcomes is crucial to help guide both the pre-transplant evaluation as well as the post-transplant management -; which is why we invested so much in creating a simple risk score that health care providers can use to identify these patients,” said first author Alexi Vasbinder, Ph.D., R.N., a post-doctoral fellow at the U-M Frankel Cardiovascular Center at the time the research was conducted. 

    Pre-bone marrow transplant risk cardiovascular score

    To develop such a tool, researchers used data from the CARE-BMT cohort. They created a simple points based risk score using clinical information that is easily accessible, including age and race, history of coronary artery disease or heart failure, and prior doses of cardiotoxic chemotherapy medications. 

    In an analysis of just over 2,400 adult patients, the final risk model, now known as the CARE-BMT risk score, identified a high risk group that accounted for over 30% of the patients. The five year cardiovascular complication rate was 31.9%; that rose to 55% at 10 years.

    The score performed equally well in allogeneic and autologous bone marrow transplant recipients, as well as in a separate cohort of over 900 patients from Rush University.

    Results are published in the Journal of the American Heart Association.

    “It’s a very simple score that can be easily calculated and implemented in any health care record,” Hayek said. 

    “This will be easy to replicate and use during evaluations before bone marrow transplant to guide referrals of high risk patients to cardiovascular specialists who can then optimize medical and lifestyle management of their conditions.”

    AHA scientific statement

    The two reports formed the basis of a scientific statement published by the American Health Association geared towards the cardiovascular management of patients undergoing bone marrow transplant. 

    The statement covers considerations during the four steps of hematopoietic stem cell transplantation : evaluation before transplant, conditioning therapy and transplant, immediate post-transplant period and long term survivorship. 

    “This innovative cardiac risk assessment tool significantly improves our ability to provide a safer path throughout treatment to our cell therapy recipients possessing cardiovascular comorbidities, which in turn will have a positive effect on long term recovery and quality of life,” said co-author John Maciejewski, M.D., Ph.D., bone marrow transplant physician at U-M Health and clinical assistant professor of internal medicine at U-M Medical School.

    Source:

    Michigan Medicine – University of Michigan

    Journal reference:

    Vasbinder, A., et al. (2023). Cardiovascular Events After Hematopoietic Stem Cell Transplant: Incidence and Risk Factors. JACC: CardioOncology. doi.org/10.1016/j.jaccao.2023.07.007.

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  • Increased stiffness in aging skin may contribute to higher rates of metastatic skin cancer

    Increased stiffness in aging skin may contribute to higher rates of metastatic skin cancer

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    Age-related changes that cause the skin to stiffen and become less elastic may also contribute to higher rates of metastatic skin cancer in older people, according to research by investigators from the Johns Hopkins Kimmel Cancer Center. 

    The study, published March 12 in Nature Aging, shows that increased stiffness in aging skin increases the release of a protein called ICAM1. Increased ICAM1 levels stimulate blood vessel growth in the tumor, helping it grow. It also makes the blood vessels “leaky,” enabling tumor cells to escape and spread throughout the body more easily. 

    As we age, the stiffness of our skin changes. That not only has physical implications, but it also has signaling implications and can lead to increases in new blood vessel growth or disruption of blood vessel function.” 


    Ashani Weeraratna, Ph.D., associate director for laboratory research at the Kimmel Cancer Center and professor of oncology at the Johns Hopkins University School of Medicine

    Melanoma is the deadliest form of skin cancer, according to the Melanoma Research Foundation. In 2024, over 200,000 Americans are expected to be diagnosed with melanoma. Older patients are more likely to get melanoma and die from it than younger patients. They experience more recurrences after treatment, and their tumors are more likely to spread, or metastasize, to other parts of the body. 

    Weeraratna’s laboratory focuses on how age-related changes help melanoma tumors spread and resist cancer therapies. Previous research by Weeraratna and her team has shown that a protein called HAPLN1 helps maintain the structure of the extracellular matrix, a network of molecules and minerals that provide structural support, to keep the skin supple. As people age, they release less HAPLN1, which causes the skin to stiffen. 

    The new study shows that reduced HAPLN1 indirectly increases ICAM1 levels by causing stiffening, which alters cellular signaling. The increase in ICAM1 contributes to angiogenesis, or the growth of new blood vessels that supply the tumors with nutrients and help them grow. The blood vessels are also leakier, making it easier for tumor cells to escape from the initial tumor site and spread to distant areas of the body. 

    Treating older mice with melanoma with drugs that block ICAM1, however, prevents these changes, shrinking their tumors and reducing metastasis, Weeraratna and her colleagues demonstrated. They are now studying ICAM1’s activities to develop more precise ways of targeting it with drugs, which might lead to new approaches to treating older people with melanoma. 

    The discoveries might also lead to new approaches to treating other age-related cancers. Previous therapies targeting growth factors that contribute to angiogenesis have failed in many tumor types, including melanoma. But ICAM1 provides a promising new target. 

    “We know that age-related angiogenesis is important in many different cancers and multiple aspects of health and disease,” says Weeraratna, who is also the E.V. McCollum Chair of Biochemistry and Molecular Biology at the Johns Hopkins Bloomberg School of Public Health and a Bloomberg Distinguished Professor. “Finding a new way to target that in different tumor types could have a big impact.” 

    Learning more about ICAM could also have important implications for understanding wound healing in older adults. Angiogenesis is essential in healing wounds not only in the skin, but also in the cardiovascular system and brain, Weeraratna says. As a result, the lab’s discoveries could have important implications for understanding age-related changes that may contribute to cardiovascular disease or strokes. 

    “Understanding angiogenesis in the context of aging is important,” she says. 

    Study co-authors were Gloria E. Marino-Bravante, Alexis E. Carey, Laura Hüser, Agrani Dixit, Vania Wang, Supeng Ding, Rahel Schnellmann, Luo Gu and Yash Chhabra of Johns Hopkins. Other authors were from the University of Pennsylvania and Duke University. 

    The study was supported in part by the National Institutes of Health (grants P01CA114046, U01CA227550 and R01CA232256 to Weeraratna). 

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