The award supports a mechanistic research project rather than a clinical trial or an evaluation of an intervention for pregnant people. Investigators will focus on acid, base and salt components used in newer-generation e-cigarette products. Gestational exposure will be delivered through advanced vaping exposure systems designed to mimic patterns of human use. The study will examine how these compounds affect pulmonary immune development, including neutrophils, macrophages, natural killer cells and alveolar epithelial cells. Researchers will also use neonatal viral infection models to evaluate whether changes in fetal immune development are associated with greater susceptibility to respiratory viral infection after birth.

Preliminary findings cited by the research team indicate that prenatal exposure to the selected e-cigarette compounds can disrupt innate immune pathways in the fetal lung. The affected pathways include viral sensing, type I interferon signaling and neutrophil-related immune responses. In the laboratory models examined in those preliminary studies, the changes differed between male and female offspring and were associated with increased susceptibility to neonatal viral infection. These observations provide the scientific basis for the grant-supported investigation. The announcement does not establish how extensively the same effects occur in human pregnancy, the magnitude of any effects in people or whether a particular commercial e-cigarette product has been shown to cause the outcomes observed in the models.

The five-year project is organized around three aims. First, researchers will define how gestational exposure to e-cigarette components affects fetal lung immune cells, including their development and characteristics. Second, the team will use single-cell RNA sequencing, advanced computational modeling and machine- and deep-learning approaches to identify gene networks and signaling pathways disrupted by exposure. Third, researchers will test whether postnatal treatment with interferon beta can improve antiviral responses and disrupted gene networks in newborns exposed to e-cigarette components during pregnancy. The final aim is explicitly experimental: the announcement describes a test to be conducted in the project’s models and does not report that a treatment has already proved effective.

Several complementary techniques will be used to examine the exposed fetal lungs and neonatal immune responses. Spectral flow cytometry, confocal imaging and single-cell RNA sequencing are among the methods named in the project description, alongside computational modeling and machine- and deep-learning approaches. These techniques will support the investigation of immune-cell populations, gene networks and signaling pathways affected by the selected aerosol components. Neonatal viral infection models will provide the setting for testing functional antiviral responses and evaluating the postnatal interferon-beta experiment. The grant announcement does not provide results from these methods because the five-year program is newly funded.

A major feature of the investigation is its focus on biological sex as a determinant of fetal immune programming. Early data from the Ramadoss laboratory indicate that male and female fetal organs can respond differently to gestational e-cigarette exposure, suggesting that the consequences of prenatal vaping may not be uniform across offspring. The researchers plan to assess whether changes in pulmonary immune cells, affected signaling pathways and vulnerability to neonatal viral infection vary according to sex. By examining these differences, the project seeks to identify sex-specific mechanisms of immune disruption rather than assume that the same developmental processes are affected equally in all offspring.

The planned postnatal interferon-beta experiment is intended to test whether some functional consequences of prenatal exposure can be modified after birth. Researchers will determine whether administering interferon beta to newborns in the experimental models can improve their antiviral responses and address disrupted gene networks. A favorable result would indicate that at least part of the altered immune response could be modified in that experimental setting. It would not establish that interferon beta is effective or safe for human newborns, nor would it demonstrate that the approach prevents respiratory viral infection in people. The study’s broader purpose is to investigate biological mechanisms and identify possibilities for subsequent work.

The project brings together reproductive biology, pregnancy research, environmental health, fetal development, immunology, virology and computational analysis. Its scope is preclinical: it uses pregnancy models, controlled aerosol-delivery systems, laboratory immune analyses and neonatal infection models to examine how prenatal exposures may shape later immune function. Translation to human health would require additional evidence, including whether the relevant exposures and biological pathways are comparable in human pregnancy and whether findings from the models apply to infants. The announcement presents the work as potentially relevant to future counseling, prevention strategies and interventions, but it does not report clinical findings or establish a specific clinical recommendation.

Ramadoss, a professor of obstetrics and gynecology and director of the C.S. Mott Center for Human Growth and Development’s Pregnancy and Environment Division, will serve as lead principal investigator. Rodriguez-Garcia, an associate professor of biochemistry, microbiology and immunology, will serve as a multiple principal investigator. The Mott Center, where the researchers are based, conducts multidisciplinary work in reproductive biology, pregnancy, fetal development, cancer, environmental health and the developmental origins of disease. The award also reflects broader institutional interest in how environmental conditions during pregnancy can influence child health and development.

Ultimately, the study aims to clarify how prenatal exposure to e-cigarette aerosols changes the fetal lung immune environment and whether those changes help explain later susceptibility to respiratory viral infection. Its combination of controlled exposure models, cellular and transcriptomic analysis, computational approaches, sex-specific comparisons and a postnatal immune-treatment test is intended to identify mechanisms that could later inform more targeted approaches to protecting infants. For now, the available evidence consists of a grant announcement and preliminary laboratory observations cited by the investigators. The funded work has not yet established the scale, mechanism or human relevance of any effect, and the interferon-beta question remains a planned experiment rather than a demonstrated clinical result.

Subject of Research: Prenatal e-cigarette exposure, fetal lung immune development and neonatal respiratory viral susceptibility

Article Title: New $2.4 million NIH study will explore exposures of e-cigarettes before birth and future health implications

Article References: New $2.4 million NIH study will explore exposures of e-cigarettes before birth and future health implications. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: prenatal vaping, e-cigarette aerosols, fetal lung immunity, neonatal infection, antiviral response, type I interferon, single-cell RNA sequencing, sex-specific biology, preclinical models, NIH grant, million, will

Researchers at The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute developed the approach. Its first component is an antibody-drug conjugate, or ADC, targeting CD276, a protein on the surface of some cancer cells. The second component is cmLumiOpto, a gene therapy that disrupts mitochondria, the structures that produce energy for cells. The ADC links an antibody to an anticancer drug: the antibody recognizes CD276 on a cancer cell and carries the drug to it, potentially limiting damage to healthy cells. CmLumiOpto attacks through a separate mechanism by targeting mitochondria and interfering with the energy supply that cancer cells need to survive.

Triple-negative breast cancer, commonly abbreviated TNBC, does not have estrogen or progesterone receptors and does not have high levels of the HER2 protein. Many breast cancer drugs work by targeting one of these features, so fewer targeted treatments are available for TNBC. The cancer is also more likely to spread and return after treatment, which can lead to poorer long-term survival. The new study examined whether a CD276-targeted ADC could work against TNBC that had spread and whether adding mitochondrial disruption would improve the results. The authors’ central hypothesis was that cancer cells might be more vulnerable when simultaneously attacked through a cell-surface target and their energy supply.

Across both metastatic TNBC models, the combination produced greater reductions in cancer-cell viability, slower tumor growth and less spread than either the CD276-targeted ADC or cmLumiOpto used alone. These findings extend earlier preclinical work in which the team developed antibodies targeting CD276 and used them to construct antibody-drug conjugates. Those earlier treatments reduced the amount of cancer in preclinical models of TNBC and non-small cell lung cancer. The current experiment provides evidence that adding a mitochondrial-disrupting treatment may improve the activity of a CD276-targeted ADC in metastatic TNBC models, although the reported results remain limited to experimental systems.

Corresponding author Xiaoguang “Margaret” Liu, a professor in Ohio State University’s College of Engineering and a member of the cancer center’s Translational Therapeutics Program, described the results as an early step. She said the approach could become a more effective treatment with fewer side effects than current options only if it continues to work in laboratory studies and clinical trials. Senior co-author Lufang Zhou, a professor of surgery and biomedical engineering, said the lower-dose findings warrant further study because reducing treatment exposure could help limit dose-related side effects, but that possibility requires experimental evaluation. The researchers also identified unresolved questions about optimal doses and schedules, long-term safety, possible adverse effects and whether tumors might stop responding. More laboratory research is required before the combination can advance to clinical trials, with additional funding and a commercial partner identified as next steps. Separately, development of the licensed CD276-targeted ADC is moving forward through studies and manufacturing preparation intended to support a future clinical trial application.

Subject of Research: Preclinical evaluation of a CD276-targeted antibody-drug conjugate combined with cmLumiOpto for metastatic triple-negative breast cancer.

Article Title: ‘Smart bomb’ combination attacks triple-negative breast cancer in preclinical study

Article References: ‘Smart bomb’ combination attacks triple-negative breast cancer in preclinical study. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: triple-negative breast cancer, antibody-drug conjugate, CD276, cmLumiOpto, mitochondrial disruption, gene therapy, preclinical models, metastatic cancer, tumor growth, cancer-cell targeting, Smart, bomb

The study, led by Alexandra McCarron and colleagues at Adelaide University and the Women’s and Children’s Hospital in South Australia and published in Gene Therapy, set out to answer a question that has real clinical consequences. Cystic fibrosis is caused by mutations in the CFTR gene, which encodes a chloride channel on the surface of airway cells. Highly effective modulator drugs have transformed care for many patients, but roughly ten percent of people with cystic fibrosis carry nonsense variants that produce no CFTR protein at all, making pharmaceutical rescue impossible. Others cannot tolerate the drugs or derive no measurable benefit. For these patients, gene-addition therapy, delivering functional CFTR genetic material directly to the airways, remains one of the few credible paths to slowing lung disease.

Clinical translation, however, has repeatedly disappointed. Every cystic fibrosis gene therapy product tested in humans to date has stalled at Phase I or II trials, failing to meet predefined efficacy endpoints despite strong preclinical performance. The researchers argue that a key reason may be the inadequacy of the preclinical models themselves. Commonly used rodent models of cystic fibrosis do not develop the severe, muco-obstructive, infected lung disease seen in patients, so candidate therapies are routinely validated under conditions that bear little resemblance to the target organ. Infections are a particularly glaring omission, since chronic Pseudomonas aeruginosa colonization, embedded in biofilms within viscous sputum, defines advanced cystic fibrosis lung disease and is strongly linked to hospitalization and early death.

Earlier work supports the concern that infection matters. Adenoviral vector transfer was halved in Pseudomonas-infected mice, and adeno-associated virus transfer was impeded in mice infected with either Bordetella bronchiseptica or Pseudomonas. Yet the picture is not uniform: in one study, the liposomal reagent lipofectamine was completely blocked by infection while a VSV-G pseudotyped lentiviral vector and PEI/DNA polyplexes retained their efficacy. The lesson, the researchers note, is that every vector, pseudotype and serotype must be tested individually under infected-lung conditions.

To do this properly, the team exploited two tools they had developed previously. The first was a pair of cystic fibrosis rat models, generated by CRISPR/Cas9 gene editing, which unlike mice display many features of the human disease but, importantly, do not spontaneously develop lung infections. The second was a method for establishing a localized, chronic Pseudomonas infection by delivering bacteria embedded in agarose beads directly into the right main bronchus through a miniature bronchoscope. The beads immobilize the bacteria and prevent their clearance, producing a persistent infection with robust inflammation and tissue remodeling, while confining the disease to one lung to minimize mortality risk.

The experimental design was a 2 x 2 factorial study: wild-type or CFTR knockout rats, each receiving either Pseudomonas-laden or sterile beads, with ten animals per group. Seven days after infection was established, the researchers delivered a lentiviral vector pseudotyped with the vesicular stomatitis virus glycoprotein, or VSV-G, carrying a luciferase reporter gene under the EF1α promoter. This vector platform has appealing properties for lung therapy: it transduces dividing and non-dividing cells, integrates stably into the host genome for long-term expression, and elicits comparatively little immune response. Because VSV-G enters cells through the low-density lipoprotein receptor, which sits on the basolateral surface of airway epithelial cells behind tight junctions, the team first applied a small dose of lysophosphatidylcholine, a lipid that transiently opens those junctions and gives the vector access to the cell layer.

Bioluminescence imaging at seven days after vector delivery produced the study’s first key finding: there was no significant difference in gene expression between infected and non-infected animals, regardless of genotype. The inflamed, bacteria-colonized lung had not impeded the vector at all. Histology confirmed that the infection was doing real damage, with widespread alveolar consolidation, mucus plugging of airways, goblet cell hyperplasia, perivascular inflammatory cuffs and proliferation of bronchus-associated lymphoid tissue in both wild-type and CF rats, yet the vector still got through.

The second imaging time point delivered the surprise. By day 14, bioluminescence in the sterile-bead control animals had fallen 136-fold from its day 7 level, whereas in infected animals the decline was only about seven-fold. A statistically significant interaction between infection status and time confirmed that infection genuinely attenuated the loss of transgene expression. The researchers propose a plausible mechanism: infection injures the airway epithelium, further disrupting tight junctions beyond what the lysophosphatidylcholine achieves, and thereby grants the vector enhanced access to the basal stem cell niche. Because injured lungs actively repair themselves, gene-modified progenitor cells may then proliferate and differentiate to replace damaged cells, carrying the transgene into daughter cells more effectively than in the quiescent, intact airways of healthy controls. Notably, the magnitude of the decline did not correlate with bacterial load, suggesting the infected environment itself, rather than the number of bacteria, modifies expression persistence.

The findings also carry reassurance on safety. Critics have worried that opening tight junctions in an infected lung could let bacteria escape into the bloodstream, but spleen cultures showed no dissemination, no procedure-related deaths occurred, and the animals tolerated repeated bronchoscopic interventions well. This is also the first study to use a cystic fibrosis animal model to test how infection affects gene transfer. CF rats carried about forty times more bacteria than wild-type rats on average, an unsurprising observation given that compromised mucociliary clearance and defective CFTR-mediated bacterial uptake are hallmarks of the disease, though high variability kept the difference short of statistical significance.

The study has caveats the authors acknowledge candidly. The agarose bead model, while producing authentic inflammation and remodeling, does not replicate the polymicrobial, true-biofilm infections of human cystic fibrosis lungs, and it may be severe enough to mask genotype-dependent differences. Only one vector, one luciferase reporter and one time window were tested, and luciferase, an intracellular enzyme, is a simpler protein than CFTR, whose folding, trafficking and membrane insertion could be far more vulnerable to infection-induced cellular stress. Follow-up beyond day 14 would establish whether the infection-induced advantage endures. Even so, the message is consequential: chronic bacterial infection, long viewed as a fundamental barrier, does not impair lentiviral gene transfer and may even help expression persist. The real obstacles to clinical success in cystic fibrosis gene therapy may lie elsewhere, and each candidate vector, particularly for the modulator-ineligible patients most likely to have advanced lung disease, deserves evaluation under infected-lung conditions before it reaches the clinic.

Subject of Research: Effect of chronic Pseudomonas aeruginosa lung infection on lentiviral vector gene transfer in cystic fibrosis rat models

Article Title: Chronic lung infection does not impair lentiviral vector gene transfer in a cystic fibrosis rat model

Article References: McCarron, A., Reyne, N., Boog, B., Cmielewski, P., & Donnelley, M. (2026). Chronic lung infection does not impair lentiviral vector gene transfer in a cystic fibrosis rat model. Gene Therapy. https://doi.org/10.1038/s41434-026-00652-y

Image Credits: AI Generated

DOI: 10.1038/s41434-026-00652-y

Keywords: cystic fibrosis, gene therapy, lentiviral vector, Pseudomonas aeruginosa, CFTR, VSV-G, lung infection, bioluminescence imaging, airway epithelium, preclinical models, gene transfer, inflammation

The review, led by Samruddhi Kaknale and Varnitha Manikantan of Symbiosis Medical College for Women in Pune, India, together with collaborators at Symbiosis School of Biological Sciences, Karunya Institute of Technology and Sciences, and Manipal Institute of Technology Bengaluru, systematically maps the pathobiology of infant neuroblastoma, the mechanics of CRISPR/Cas9 targeting, and the nanocarrier platforms that might deliver the editing machinery safely in vivo. The authors are careful to frame the work as an investigational hypothesis rather than an established clinical application, noting that direct evidence in infant neuroblastoma remains limited and that most findings come from general neuroblastoma models, non-cancer models, or adult cancers that should not be interpreted as proof of efficacy in infants.

At the heart of the therapeutic concept lie two molecular hallmarks: MYCN amplification and activating ALK mutations. MYCN is a potent transcription factor that drives proliferation, suppresses apoptosis, and propels tumor progression, and its amplification is an established adverse prognostic feature associated with advanced stage, rapid growth, and poor outcome. ALK mutations, meanwhile, produce constitutive kinase activity that fuels oncogenic signaling. Because these alterations define the biology of high-risk disease, they represent the most attractive targets for precision gene editing, offering a shift from broad cytotoxic chemotherapy toward highly selective molecular intervention.

The CRISPR/Cas9 system itself is elegantly simple in principle. It consists of the Cas9 nuclease and a single guide RNA, a synthetic chimeric RNA containing a scaffold for Cas9 binding and a 20-nucleotide spacer complementary to the target DNA. For the commonly used Streptococcus pyogenes Cas9, target recognition requires a 5′-NGG-3′ protospacer-adjacent motif. Once directed to its genomic address, Cas9 induces a targeted double-strand break that the cell repairs through endogenous mechanisms. The predominant pathway, non-homologous end joining, is error-prone and typically generates small insertions or deletions that frameshift and inactivate the target gene, a powerful strategy for knocking out oncogenes such as MYCN or ALK. The less frequent homology-directed repair pathway uses a homologous DNA template and can, in principle, correct specific point mutations, such as activating ALK variants, with meticulous precision.

Recent advances have refined this toolkit further. Base editors harness a catalytically impaired Cas9 fused to a deaminase to convert single nucleotides directly, for example C to T or A to G, without double-strand breaks. Prime editors combine nCas9 with reverse transcriptase and a prime editing guide RNA to direct templated insertions, deletions, and all twelve possible base-to-base conversions, offering search-and-replace capabilities that reduce the risk of indels and chromosomal rearrangements. The review notes that direct evidence for base or prime editing in neuroblastoma remains limited, marking these approaches as avenues for future investigation rather than validated options.

Preclinical evidence, however, is already compelling in cell lines and animal models. High-throughput CRISPR screens have identified genetic dependencies in neuroblastoma, including a reliance on the PRC2 components EZH2, EED, and SUZ12 in MYCN-amplified models. Direct knockout of MYCN and ALK in various neuroblastoma cell lines has produced significant reductions in cell proliferation, inhibition of tumor growth in vitro and in vivo, and induction of apoptosis. CRISPR interference targeting the MYCN promoter has effectively repressed MYCN expression and suppressed neuroblastoma cell growth, while knockout of uPAR, a gene linked to cellular invasion, has inhibited invasive phenotypes, suggesting the technology can also blunt metastasis by targeting genes involved in tumor cell motility.

Yet the review is unflinching about the obstacles. Delivering Cas9 and its guide RNA into a sufficient percentage of tumor cells in vivo remains the central challenge, complicated by the large size, negative charge, immunogenicity, and degradation susceptibility of CRISPR cargoes. The Cas9 protein, derived from bacteria, can elicit innate and adaptive immune responses that clear edited cells or render subsequent treatments unproductive, and preexisting adaptive immunity to Cas9 proteins has been identified in humans. Off-target editing persists despite improvements in guide RNA design and high-fidelity Cas9 variants, and achieving uniform editing efficiency across a heterogeneous solid tumor microenvironment, with poor penetration and variable cellular uptake, is extraordinarily difficult. For infants, whose expected lifespans stretch across decades, persistent Cas9 activity, potential germline exposure, chromosomal rearrangements, large deletions, structural variants, and long-term effects in normal tissues demand careful assessment and lifelong follow-up before any clinical translation.

Nanoparticle delivery systems emerge as the leading candidates to surmount these barriers. Lipid nanoparticles, the most clinically advanced platform and the technology behind successful mRNA vaccines, typically comprise ionizable lipids, helper lipids like cholesterol and phospholipids, and PEGylated lipids. Ionizable lipids are positively charged at acidic pH but neutral at physiological pH, facilitating nucleic acid complexing and endosomal escape after cellular uptake, while PEGylated lipids preserve systemic circulation by preventing rapid elimination by the reticuloendothelial system. Delivery of Cas9 mRNA with sgRNA allows transient protein expression, minimizing off-target effects and immune activation associated with prolonged Cas9 activity, whereas pre-formed Cas9 ribonucleoproteins offer reduced immunogenicity and faster editing onset but are more complicated to encapsulate due to their size.

Polymeric and inorganic nanocarriers expand the design space. Biodegradable polymers such as PLGA, PEG, chitosan, and dendrimers can encapsulate CRISPR components with adjustable degradation and sustained release, and PLGA’s capacity to safeguard sensitive payloads makes it widely used for surface functionalisation aimed at neuroblastoma cell targeting. Gold nanoparticles are biocompatible and easily functionalized for direct conjugation with Cas9 and sgRNA, with photothermal applications, while magnetic nanoparticles enable magnetic targeting and MRI tracking, and mesoporous silica nanoparticles provide high loading, controlled release, and rigid protection of CRISPR cargo. For the minority of patients with CNS involvement or relapse, blood-brain barrier penetration strategies, including receptor-mediated transcytosis via ligands binding the transferrin, insulin, or low-density lipoprotein receptors, cell-penetrating peptides like TAT and R8, and focused ultrasound combined with microbubbles to transiently and locally disrupt the barrier, are being explored, though the review cautions that enhanced permeability does not necessarily indicate efficient nanoparticle delivery to the brain and may increase the risk of unintended CNS exposure and neurotoxicity.

The authors conclude that robust preclinical validation in relevant in vitro and in vivo models, including organoids, patient-derived xenografts, and orthotopic systems that precisely mimic the human disease, is essential for determining efficacy, characterizing biodistribution, evaluating off-target effects, and establishing a preliminary safety profile. Ethical and regulatory considerations add further complexity, as infants lack capacity for informed consent, requiring parents or legal guardians to decide in the child’s best interests amid the potentially irreversible nature of genomic modification. Future work should prioritize more selective nanoparticles, gene-editing tools with high precision and minimal off-target effects, and internationally harmonised regulatory frameworks for paediatric applications. With sustained interdisciplinary collaboration, the convergence of nanoparticle delivery and CRISPR/Cas9 precision may ultimately enable safer and more effective therapies for infants with neuroblastoma, though the review emphasizes that current evidence remains predominantly preclinical and is not yet sufficient to establish the optimal nanoparticle or CRISPR technique for infant neuroblastoma.

Subject of Research: Nanoparticle-enabled CRISPR/Cas9 gene editing as a potential therapy for infant neuroblastoma

Article Title: Precision gene editing in infant neuroblastoma: a review of nanoparticle: enabled CRISPR/Cas9 therapies

Article References: Kaknale, S., Ranjan, A., Enoch, I. V. M. V., Vyas, A., & Manikantan, V. (2026). Precision gene editing in infant neuroblastoma: a review of nanoparticle: enabled CRISPR/Cas9 therapies. Molecular Biology Reports, 53(1), Article 1725. https://doi.org/10.1007/s11033-026-12916-2

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12916-2

Keywords: infant neuroblastoma, CRISPR/Cas9, nanoparticles, lipid nanoparticles, gene therapy, MYCN, ALK, drug delivery, paediatric oncology, base editing, prime editing, preclinical models

The case for better models begins with melanoma biology itself. Melanoma arises from pigment-producing melanocytes, and its development is typically initiated by ultraviolet radiation-induced DNA damage that, when repaired incorrectly, produces oncogenic mutations in key regulatory genes. Activating mutations in the BRAF and NRAS proto-oncogenes drive constitutive activation of the MAPK signaling pathway, which governs cell proliferation, differentiation, and survival. Simultaneously, loss of function in tumor suppressor genes such as CDKN2A, PTEN, and TP53 disrupts cell-cycle control, apoptosis, and genomic stability. Beyond genetics, the tumor microenvironment, populated by stromal cells, tumor-infiltrating immune cells, and tumor-associated blood vessels, plays decisive roles in tumor growth, immune evasion, and metastatic spread. Any model that hopes to predict how a patient will respond to therapy must somehow reproduce this intricate biological landscape.

Current treatments illustrate why predictive models matter so much. Surgical resection remains the cornerstone for early-stage disease, while advanced melanoma is treated with immune checkpoint inhibitors and targeted therapies. Anti-CTLA-4 antibodies block inhibitory signaling between T-cells and antigen-presenting cells, unleashing T-cell activation, cytokine release, and tumor infiltration. Anti-PD-1 and PD-L1 agents prevent the co-inhibitory ligand-receptor interaction that otherwise dampens T-cell responses. In BRAF-mutant tumors, small-molecule inhibitors such as vemurafenib and dabrafenib are combined with downstream MEK inhibitors like trametinib and cobimetinib to suppress MAPK signaling, reducing proliferation and inducing apoptosis. Yet despite these advances, intrinsic and acquired resistance to both targeted and immune-based therapies keeps melanoma a pressing public health problem, and the drugs that succeed in flat cultures or mice frequently fail in patients.

Three-dimensional bioprinting has emerged as one of the most promising strategies to close this translation gap. In this approach, a bioink, a mixture of living cells suspended in biocompatible hydrogel biomaterials, is deposited layer by layer according to a pre-determined computer-aided design, building melanoma constructs that more closely resemble skin tissue architecture and better capture clinical heterogeneity. The hydrogels provide structural support, protect cells during printing, and allow the incorporation of multiple cell types, including melanoma cells, fibroblasts, keratinocytes, endothelial cells, and immune cells, to mimic the tumor microenvironment. Several printing technologies are in use, including laser-assisted, inkjet-based, stereolithography-based, and extrusion-based bioprinting. Pneumatic extrusion bioprinting has become the most widely adopted because of its accessibility, cost-effectiveness, and capacity to replicate tissue complexity, while digital light processing offers the added benefit of fabricating complex structures with high resolution. Importantly, the technology also aligns with the principles of replacement, reduction, and refinement in animal research and opens the door to personalized, patient-specific tumor models.

The field has already produced impressive demonstrations. Organotypic melanoma spheroid skin models built from primary keratinocytes and fibroblasts combined with metastatic melanoma spheroids have shown epidermal differentiation, basal lamina formation, and necrotic cores that mimic human disease. High-throughput drug screening on NRAS-mutant and multicomponent melanoma spheroids has identified candidate inhibitors such as daunorubicin hydrochloride and pyrvinium pamoate. Patient-derived organoids from melanoma brain metastases, cutaneous tumors, and mucosal melanoma have preserved key histological features and mutational profiles and responded to agents including dabrafenib plus trametinib and temozolomide. Microfluidic melanoma-on-a-chip systems have distinguished carboplatin-responsive from carboplatin-resistant tumors, and bioprinted constructs have recreated vascular-lymphatic interactions to study metastasis. More recently, bioprinted A375 melanoma constructs have been validated for apoptotic cell death analysis using flow cytometry, showing compatibility with quantitative mechanistic assays used in preclinical research.

Yet the du Plessis team’s central argument is that the bottleneck has shifted from building the models to measuring what happens inside them. Most biochemical and molecular techniques used to assess cell viability, proliferation, drug efficacy, and toxicity, including luminescence, colorimetric, and fluorometric assays, microscopy, flow cytometry, quantitative polymerase chain reaction, and SDS-PAGE, were optimized for cells growing in flat monolayers. Applied to dense, multilayered 3D matrices, they often yield inconsistent or misleading results because of matrix interference, diffusion limitations, and uneven cell distribution. Bioprinted constructs frequently exceed 500 micrometers in thickness, and diffusion barriers restrict reagent penetration to deep layers, which can cause an underestimation of viable cells in the interior and lead to incorrect drug potency predictions and misinterpretation of pharmacodynamic behavior. Variability in construct size, shape, and cell number further complicates comparisons and can skew potency estimates between studies.

The printing process itself adds another layer of complexity. Pneumatic extrusion bioprinting damages cells through mechanical shear forces, whereas digital light processing inflicts radiative stress from light exposure and chemical stress from photoinitiators. Bioink compatibility with melanoma cells is not guaranteed either, because both bioink composition and printing conditions can alter proliferation, spheroid morphology, migration, and cell-matrix interactions even when viability is maintained. Studies of printable hydrogels such as alginate/hyaluronic acid/gelatin and pectin-nanocellulose composites have improved rheology, printability, and short-term viability of A375 melanoma cells, but these outcomes are formulation- and bioprinter-specific, meaning the same bioink may need re-optimization when transferred to different printers, extrusion parameters, or crosslinking methods. The authors call for systematic validation of identical formulations across multiple bioprinting platforms to establish true reproducibility.

Apoptosis, the regulated form of cell death that most anti-cancer drugs aim to trigger, presents its own analytical puzzles. The intrinsic, or mitochondrial, pathway is controlled by pro- and anti-apoptotic Bcl-2 family proteins that increase mitochondrial outer membrane permeability and release factors such as cytochrome c, which activates caspase-9. The extrinsic pathway is death-receptor mediated, with Fas ligand and tumor necrosis factor-alpha binding their receptors and activating caspase-8, both routes converging on effector caspase-3. Melanoma cells evade apoptosis through dysregulated Bcl-2 family proteins, overexpression of inhibitor of apoptosis proteins, and rewired pro-survival signaling through heat shock proteins. Accurately quantifying drug-induced apoptosis therefore requires comparable cell numbers or construct sizes, and the context-dependence of apoptotic signaling, shaped by cell-cell interactions, cell-matrix adhesion, biomechanical cues, and gradients of oxygen, nutrients, and drugs, is precisely what 2D cultures fail to represent. Notably, the effect of different bioprinting technologies on apoptotic signaling in melanoma remains underexplored, with current evidence limited mainly to extrusion-based systems.

Each analytical workaround carries trade-offs. Non-destructive colorimetric and fluorescence assays such as MTT, MTS, CellTiter-Glo, and resazurin-based methods preserve construct integrity but tend to return only an average response across a cell population, losing crucial biological information, and dye diffusion through the hydrogel matrix can dilute signals and distort viability readings. Destructive methods like flow cytometry require dissolving the construct into a single-cell suspension but offer rapid, quantitative, multi-parametric analysis of individual cells within heterogeneous populations, making them attractive for high-throughput drug screening. Fluorescence and confocal microscopy suffer from poor imaging depth because refractive index differences in heterogeneous hydrogels scatter light, a problem addressed through physical sectioning, tissue clearing, and refractive-index-matched hydrogels. Immunolabelling can be unreliable in thick matrices where antibodies diffuse poorly, producing weak or false-negative staining in deeper layers. Histology remains a gold standard for validating tissue structure and diagnostic markers, while lysate-based assays such as Western blotting and RT-qPCR can be biased by inefficient lysis of cells embedded in dense, highly crosslinked matrices.

The authors conclude that 3D bioprinted melanoma models genuinely represent physiologically relevant platforms capable of mimicking architectural complexity, cellular heterogeneity, and clinically relevant drug responses, but that the assays used to evaluate drug efficacy and toxicity must be re-optimized, standardized, and validated for hydrogel-embedded constructs. As high-throughput screening generates ever more parameters, the field will also need sophisticated data storage, automated analysis, miniaturization, and increasingly artificial intelligence and machine learning, all of which remain constrained by the absence of regulatory and global standards. Solving this analysis bottleneck, the researchers argue, will determine whether bioprinted melanoma models fulfill their potential to accelerate drug discovery, improve toxicity testing, and ultimately deliver safer, more effective treatments to patients battling one of medicine’s most aggressive cancers.

Subject of Research: Analytical challenges in drug efficacy and toxicity screening using 3D bioprinted melanoma models

Article Title: Challenges in drug efficacy and toxicity screening with 3D bioprinted melanoma models

Article References: du Plessis, L. H., Myeza, N., Gouws, C., Kotzé, A. F., & Nieto, D. (2026). Challenges in drug efficacy and toxicity screening with 3D bioprinted melanoma models. Frontiers in Cell Death, 5, Article 1821035. https://doi.org/10.3389/fceld.2026.1821035

Image Credits: AI Generated

DOI: 10.3389/fceld.2026.1821035

Keywords: 3D bioprinting, melanoma, drug screening, apoptosis, tumor microenvironment, bioinks, hydrogels, flow cytometry, cell viability assays, skin cancer, drug resistance, preclinical models

Medulloblastoma arises in the cerebellum and comprises four major molecular subgroups: WNT, SHH, Group 3, and Group 4. While WNT tumors have an excellent prognosis and SHH tumors can sometimes be addressed with inhibitors of the sonic hedgehog pathway, Group 3 and Group 4 remain stubbornly resistant to targeted approaches. Children with these tumors typically receive maximal surgery, craniospinal irradiation, and multi-agent chemotherapy. Although survival rates have improved over decades, the intensity of treatment leaves many survivors with lasting cognitive, endocrine, and developmental damage. This therapeutic gap is precisely what motivated the St. Jude and KiTZ collaboration: if no drugs exist for these subgroups, the field must first discover what the tumors cannot live without.

The biological logic behind the search lies in epigenetics. Epigenetic regulation refers to the layer of control that determines which genes are switched on or off without altering the underlying DNA sequence. The principal players are chemical marks deposited on histones, the protein spools around which DNA is wound. Distinct histone modifications, such as methylation and acetylation at specific amino acid positions, act as signposts that recruit or repel the molecular machinery of transcription. Because epigenetic deregulation that disrupts normal brain development has long been suspected of driving medulloblastoma formation, mapping the exact histone modification landscape of patient tumors promised to reveal where that control breaks down, and which proteins might be holding the broken system together.

Delivering that map required an effort of unusual scale for a rare pediatric cancer. The team performed the largest analysis of its kind in medulloblastoma, profiling 52 primary patient samples drawn from all four major subgroups, with multiple samples per subgroup to ensure that subgroup-specific signals could be distinguished from individual tumor quirks. They measured six distinct histone post-translational modifications and used chromatin state, the functional packaging configuration of the genome, as a readout of epigenetic activity. The resulting dataset, made publicly available through a web portal so that other investigators can mine it, constitutes a comprehensive community resource. The researchers deliberately designed the resource to help the field move beyond cataloging mutations toward identifying functional dependencies.

The search for strong subgroup-specific signals quickly paid off. The team detected a recurrent, aberrant epigenetic signature shared by Group 3 and Group 4 tumors, an unexpected convergence given that these subgroups differ in their genomic features and presumed cells of origin. When the researchers asked which chromatin-modifying protein could account for the signature, KDM2B emerged as the leading candidate. First author Ran Tao, PhD, of the St. Jude Department of Developmental Neurobiology described the progression: after identifying the signature, the team spent years investigating how KDM2B controls tumor growth and working through the underlying molecular mechanisms. KDM2B is highly expressed in Group 3 and Group 4 tumors, and its abundance marks it as a defining feature of these high-risk disease categories.

Functionally, KDM2B proved to be a genuine dependency rather than a passive passenger. In preclinical models, genetic removal of the KDM2B gene or pharmacologically oriented degradation of the protein suppressed tumor growth and extended survival. Corresponding author Paul Northcott, PhD, director of the St. Jude Center of Excellence in Neuro-Oncology Sciences and a member of the Department of Developmental Neurobiology, summarized the finding: select medulloblastoma groups require KDM2B to grow, which gives the field a potential future therapeutic opportunity to selectively suppress the growth of Group 3 and Group 4 tumors while sparing normal tissue. The selectivity is the crucial point, because an ideal pediatric target should be dispensable in healthy cells but indispensable in the tumor.

The project itself has a long history that illustrates how cancer genomics matures over time. Northcott traced its origins to his postdoctoral years, when early sequencing of medulloblastoma genomes revealed an enrichment of alterations in chromatin-modifying genes, a signal that at the time had no obvious therapeutic exploitation. Almost fifteen years later, with modern epigenomic profiling tools and the infrastructure to study dependencies, that old signal could finally be pursued to its mechanistic roots. The trajectory underscores a broader lesson in pediatric oncology: discoveries from large-scale sequencing projects often take years, sometimes decades, before they translate into actionable biology, and sustained investment in data generation and model systems is what makes such translation possible.

KDM2B itself is not the end of the story, and perhaps not even the easiest drug target. The mechanistic studies showed that KDM2B exerts its growth-promoting influence by recruiting Polycomb repressive complexes, a family of protein assemblies that modify chromatin to silence genes. Recognizing this downstream dependency, the team looked for additional vulnerabilities among the complexes themselves. Data from The Pediatric Cancer Dependencies Accelerator, a multi-institutional initiative involving the Broad Institute, Dana-Farber Cancer Institute, and St. Jude, indicated that removing these Polycomb complexes in medulloblastoma cell lines also slows cancer growth. This downstream angle matters clinically because drugging a complex can be more tractable than drugging a single regulatory protein.

Two Polycomb-related findings stand out for their therapeutic implications. First, PRC2, one of the Polycomb repressive complexes, is already being investigated as a drug target in other pediatric cancers, which lends external validation to the strategy and suggests that existing medicinal chemistry and clinical experience could be adapted for medulloblastoma trials. Second, the study identified PRC1.1 as a previously unrecognized potential therapeutic target for Group 3 and Group 4 medulloblastoma, adding a novel candidate to a therapeutic landscape that previously held none. Together, these findings reframe the problem: targeting KDM2B directly, or disrupting the Polycomb pathways it recruits, provides at least three distinct intervention points against tumors that have historically been treated with one-size-fits-all regimens.

The researchers emphasize that the public dataset is as much a product of the study as the KDM2B discovery itself. By characterizing the medulloblastoma chromatin landscape in unprecedented detail and making it freely explorable, the team hopes that other laboratories will mine the resource for additional subgroup-specific signatures and dependencies. Northcott framed the ambition plainly: the characterization identified a potential vulnerability in subgroups that still lack targeted therapy, and he hopes others will explore the data to make further discoveries and, collectively, find new therapeutic targets for subgroups with poor prognosis. For the children diagnosed with Group 3 and Group 4 medulloblastoma each year, the study converts fifteen years of accumulated genomic insight into a concrete biological target, a set of downstream pathway candidates, and a roadmap for developing the selective treatments that this high-risk population has long awaited.

Subject of Research: KDM2B dependency in Group 3 and Group 4 medulloblastoma epigenetics

Article Title: KDM2B revealed as a selective dependency in high-risk medulloblastoma subgroups

Article References: KDM2B revealed as a selective dependency in high-risk medulloblastoma subgroups. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: medulloblastoma, KDM2B, epigenetics, histone modifications, Polycomb repressive complexes, Group 3 medulloblastoma, Group 4 medulloblastoma, pediatric brain tumor, targeted therapy, chromatin regulation, PRC2, preclinical models

The research team, led by Marta Boffa and Francesca Zoratto of the Istituto Superiore di Sanità in Rome together with Mauro Pettorruso of the G. d’Annunzio University of Chieti-Pescara, set out to answer a question that has long hovered over the neuromodulation field. Does rTMS push the brain along a single, common path of adaptation, or does it recruit distinct mechanisms depending on the baseline state of neural circuits? To find out, they compared three groups of male rats: a non-depressed control group of socially housed Wistar rats, a treatment-responsive depression model created by prolonged social isolation in otherwise ordinary Wistar rats, and a model of treatment-resistant depression built from Wistar-Kyoto rats exposed to both social isolation and a four-week chronic mild stress protocol involving rotating stressors such as cage tilting, food and water deprivation, soiled bedding, and stroboscopic illumination.

The treatment-resistant model is critical to the study’s design. Most preclinical rTMS research has relied on depression models that respond to standard antidepressants, which limits how well the findings translate to the treatment-resistant patients who actually receive the therapy in clinics. The Wistar-Kyoto strain under chronic mild stress, by contrast, is unresponsive to classic antidepressant drugs but has been shown in earlier work to react to esketamine, electroconvulsive therapy, and deep brain stimulation, making it a far better stand-in for the human condition the therapy targets.

The stimulation protocol itself was engineered to mirror clinical practice as closely as rodent anatomy allows. Using a rat-specific cooled coil and a commercial stimulator, the team delivered high-frequency stimulation at 10 hertz, 110 percent of resting motor threshold, in trains of 40 pulses, amounting to 1,600 pulses per session across eight consecutive days and a total of 12,800 pulses aimed bilaterally at the frontal cortex. Notably, the animals were awake and unanesthetized during stimulation, gently held under the coil, with sham groups receiving identical handling and noise exposure. Behavioral testing began one day after the final session and again fourteen days later, spanning tests of anhedonia, motivation, helplessness, and anxiety-like behavior, including the sucrose consumption, novelty-suppressed feeding, splash, forced swim, open-field, and elevated plus maze tests.

The behavioral results split cleanly along phenotype lines. In the treatment-responsive isolation model, active rTMS improved multiple domains: the rats moved more in the forced swim test, froze less in the open field, and entered the open arms of the elevated plus maze earlier and spent more time there, indicating reduced anxiety. In the treatment-resistant model, the effects were narrower but still real. Treated rats approached food faster in the novelty-suppressed feeding test and, in the splash test, a significantly higher proportion of actively stimulated TRD animals engaged in self-grooming, a proxy for motivation and self-care that is often collapsed in severe depressive states. Neither model showed changes in sucrose consumption, and most behavioral gains faded by the two-week follow-up, suggesting the protocol produced adaptations that may need maintenance sessions to persist.

The neuroendocrine data added a second layer of divergence. Active stimulation lowered basal plasma corticosterone, the rodent equivalent of the human stress hormone cortisol, only in the treatment-responsive model. In the treatment-resistant rats, corticosterone stayed flat even though select behaviors improved. This dissociation matters because dysregulation of the hypothalamic-pituitary-adrenal axis is central to depression’s pathophysiology and has been linked in clinical work to whether patients respond to neuromodulation. The findings imply that behavioral recovery in treatment-resistant brains can proceed independently of stress-hormone normalization, possibly reflecting reduced neuroendocrine flexibility or altered stress-feedback regulation as features of the resistant state itself.

The most consequential results emerged at the molecular level, sixteen days after the final stimulation session, when detectable behavioral effects had largely subsided. In the prefrontal cortex of treatment-resistant rats, active rTMS significantly increased expression of both Bdnf, the gene encoding brain-derived neurotrophic factor, and Cnr1, the gene encoding the CB1 cannabinoid receptor, with large effect sizes. BDNF signaling is a cornerstone of activity-dependent synaptic remodeling and antidepressant action, while the endocannabinoid system regulates stress adaptation and synaptic plasticity through control of excitatory and inhibitory neurotransmission. Neither gene was significantly elevated in the treatment-responsive or control groups, and the hippocampus showed essentially no changes except a reduction of Bdnf in controls, pointing to a marked regional specificity for the stimulated cortical area.

Perhaps the most intriguing observation was a correlation. Across the treatment-resistant group, prefrontal Bdnf and Cnr1 expression were strongly and positively correlated, an association driven entirely by the actively stimulated animals and absent in sham-treated ones and in the other models. Because the endocannabinoid and BDNF systems are known to interact bidirectionally in regulating synaptic plasticity and stress responses, the authors interpret this pattern as coordinated engagement of plasticity-related pathways specifically in the treatment-resistant phenotype. Correlation cannot establish causation, and the absence of matched short-term molecular samples means the team cannot say whether these gene changes accompanied the behavioral improvements or emerged afterward. Still, the finding suggests that late, persistent cortical molecular adaptations outlasted the visible behavioral response rather than simply mirroring it.

Taken together, the study argues that rTMS does not switch on a single biological program across depressive conditions. In treatment-responsive brains, recovery tracked neuroendocrine normalization and broader behavioral improvement; in treatment-resistant brains, selective gains in motivation and self-care ran in parallel with a coordinated, prefrontal engagement of neurotrophic and endocannabinoid machinery. The authors acknowledge a key limitation: only male rats were studied, a significant gap given well-established sex differences in depressive phenotypes and HPA-axis regulation, and female subjects remain underrepresented in preclinical rTMS research broadly. Even so, the work lays groundwork for a more refined clinical vision, in which stimulation protocols are matched not just to symptoms but to the underlying neurobiological state of the patient’s brain. If phenotype-informed, mechanism-guided neuromodulation can be validated in humans, the heterogeneous and often frustrating response rates of rTMS in treatment-resistant depression may become less a mystery and more a matter of matching the right biological lever to the right brain.

Subject of Research: Phenotype-dependent behavioral, neuroendocrine, and molecular responses to repetitive transcranial magnetic stimulation in rat models of treatment-responsive and treatment-resistant depression

Article Title: Depressive phenotype shapes behavioral, neuroendocrine and molecular responses to repetitive transcranial magnetic stimulation in preclinical models of depression

Article References: Boffa, M., Spalletti, S., Martella, F., Cerri, C., Feliciani, B., Inserra, A., De Risio, L., Di Lorenzo, G., Martinotti, G., D’Addario, C., Pettorruso, M., & Zoratto, F. (2026). Depressive phenotype shapes behavioral, neuroendocrine and molecular responses to repetitive transcranial magnetic stimulation in preclinical models of depression. Frontiers in Molecular Neuroscience, 19, Article 1939025. https://doi.org/10.3389/fnmol.2026.1939025

Image Credits: AI Generated

DOI: 10.3389/fnmol.2026.1939025

Keywords: rTMS, treatment-resistant depression, BDNF, endocannabinoid system, neuroplasticity, prefrontal cortex, corticosterone, HPA axis, preclinical models, chronic mild stress, neuromodulation, Cnr1

The core of the argument rests on a technical point that distinguishes addiction from most of psychiatry. Conditions such as schizophrenia or major depression involve subjective experiences, including hallucinations, delusions or pervasive low mood, that cannot be meaningfully reproduced in laboratory animals. Substance use disorders are different. The essential behavioral features of addiction, from escalating drug intake to compulsive seeking despite negative consequences, can be modeled with remarkable fidelity in rodents. This makes the disorder a kind of Rosetta stone for psychiatric neuroscience, allowing researchers to interrogate the same behaviors in mice, in rats and in human patients, and to test mechanistic hypotheses across species with a precision that few other brain diseases permit.

Central to this modeling effort are operant drug self-administration paradigms, the workhorse techniques of preclinical addiction research. In these setups, an animal learns to perform an action, typically pressing a lever or poking a nose into a port, to receive a dose of a drug such as cocaine, heroin or a cannabinoid agonist. Over decades, researchers have refined these procedures so that they now capture the core diagnostic criteria laid out in the DSM-5, the standard manual used by clinicians to diagnose psychiatric illness. Animals can be tested for persistence of seeking behavior, for the motivation driving escalating effort to obtain drugs, for compulsive intake that continues even when the drug is paired with punishment, and for relapse-like reinstatement of seeking after prolonged abstinence. Each of these measures maps onto a criterion that a psychiatrist would recognize in a patient, giving the models genuine face validity.

These paradigms have already paid substantial scientific dividends. By combining self-administration with genetic, pharmacological and neurobiological tools, researchers have identified neural circuits and molecular targets that underlie the addictive process for a range of substances, including opioids, cocaine and cannabis, and have even extended the framework to non-drug compulsions such as food addiction. Work on the opioid receptor system, long championed by Kieffer and her collaborators, exemplifies how preclinical genetics can illuminate the molecular machinery of reward and dependence. The commentary emphasizes that this accumulated mechanistic knowledge represents a genuine asset, a detailed map of the brain’s addiction circuitry that, in principle, should be brimming with candidate therapeutic targets.

Yet the translation from that map to medicine has been disappointing, and the authors are candid about the scale of the shortfall. For several substance use disorders, no approved medications exist at all. Stimulant use disorder, involving cocaine and methamphetamine, stands as a particularly glaring example, with decades of preclinical promise failing to yield a single regulatory-approved pharmacotherapy. Even where medications do exist, such as methadone and buprenorphine for opioid use disorder or naltrexone for alcohol dependence, they help only a subset of patients, and relapse rates remain high across the board. The pipeline from target discovery to approved drug, which in other therapeutic areas has produced steady if incremental progress, has repeatedly stalled for addiction.

The commentary identifies a specific technical culprit behind these failures: poor predictive validity in preclinical models. A model may faithfully reproduce the outward signs of addiction, but if a compound that reduces drug seeking in a rat fails to reduce craving or relapse in a human, the model has not predicted the clinical outcome. Part of the problem, the authors suggest, lies in how candidate compounds are selected for clinical trials. When the choice of which molecule to advance rests on behavioral endpoints in animals that only loosely correspond to the human condition, the odds of clinical success are stacked against the field from the start. Improving the alignment between what is measured in the animal and what matters in the patient is therefore framed as the single most important methodological priority.

One of the most promising tools for achieving that alignment is rodent functional magnetic resonance imaging, an emerging technique that the commentary highlights as a potential game changer. Human neuroimaging studies have generated a rich literature on how addiction alters brain activity, from disrupted prefrontal control systems to hypersensitive reward circuits, but those findings have been difficult to connect to mechanistic work in animals because the two research traditions measured different things. Rodent fMRI changes that calculus. By scanning the brains of rats and mice during task performance, researchers can now look for activity signatures that match those observed in human patients, creating a common biomarker language across species. A neural signal that appears in addicted humans and can be reproduced, manipulated and mechanistically dissected in rodents becomes far more credible as a target for drug development than a behavioral endpoint alone.

The authors argue that such cross-species biomarkers could also open the door to personalized medicine in addiction treatment. If robust imaging or molecular markers can be identified that predict which patients will respond to a given intervention, clinicians could move beyond the current trial-and-error approach and match treatments to individuals. This vision depends, however, on a genuinely bidirectional flow of information. Clinical observations, including patterns of treatment response, relapse triggers and heterogeneity among patients, must inform the design of preclinical experiments, just as laboratory findings must be validated in patient populations. Translational research in this framing is not a one-way pipeline from animal to human but a continuous loop in which each side sharpens the hypotheses of the other.

Achieving that loop, the commentary contends, will require more than good intentions from individual laboratories. The authors call for institutional and policy-level support for translational addiction research, including funding structures that reward cross-disciplinary collaboration between preclinical neuroscientists and clinical psychiatrists, and training that equips researchers to work fluently on both sides of the divide. The commentary itself is a product of such collaboration, bringing together a hospital psychiatry department, an Inserm neuroscience unit in Strasbourg and a neuropharmacology laboratory in Barcelona, with support from the National Institutes of Health and the European Commission’s painFACT project. The authors suggest that this kind of integrated structure, rather than isolated excellence in either preclinical or clinical research, is what the field needs to accelerate innovation.

The stakes of getting this right are difficult to overstate. Substance use disorders impose an enormous burden of disease, disability and death worldwide, and the opioid crisis has only sharpened the urgency of developing new treatments. The commentary’s message is ultimately one of cautious optimism grounded in methodological realism. The tools to understand addiction at a mechanistic level already exist and have been refined over decades; animal models now mirror the diagnostic core of the human disorder; and new technologies such as rodent fMRI promise to knit the preclinical and clinical pictures together. What has been missing, the authors argue, is the systematic, bidirectional translation that converts this knowledge into biomarkers, validated targets and, finally, medications that work for patients. Closing that gap, they conclude, is not merely desirable but essential if the next generation of people affected by substance use disorders is to receive better care than the last.

Subject of Research: Translational research approaches for understanding and treating substance use disorders

Article Title: The need for translational research to advance the understanding of substance use disorders

Article References: Lalanne, L., Darcq, E., Kieffer, B. L., Durpoix, A., & Maldonado, R. (2026). The need for translational research to advance the understanding of substance use disorders. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08909-1

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08909-1

Keywords: translational research, substance use disorders, addiction, preclinical models, operant self-administration, DSM-5, rodent fMRI, biomarkers, drug development, personalized medicine, neuroscience, psychiatry

To understand why the target is unusual, it helps to look at the immunology of the disease. Psoriasis is a chronic autoimmune skin disorder affecting roughly two percent of the global population, and about thirty percent of those patients go on to develop psoriatic arthritis, a condition that combines joint inflammation, pain, and progressive structural damage. Both diseases are driven primarily by CD4-positive T cells, the immune cells whose fate is dictated by the cytokine environment they encounter. One of the most influential of these signals is TGF-beta, a molecule with a famously dual personality: it can push naive T cells toward Th17 cells, potent drivers of inflammation, or toward regulatory T cells, or Tregs, which restrain autoimmunity and protect tissue. In psoriasis and psoriatic arthritis, this balance tips sharply toward Th17 cells, while the protective regulatory arm underperforms.

Most existing therapies attack the downstream consequences of that imbalance rather than the balance itself. Tumor necrosis factor inhibitors and antibodies against the IL-17 axis have transformed treatment for many patients, but the study’s authors note that roughly thirty-five to forty percent of people with psoriatic arthritis fail to reach a minimum level of efficacy with these drugs, and resistance emerges over time in others. Blocking BAMBI offers a conceptually different approach. BAMBI is a pseudoreceptor, a membrane-bound protein that lacks an intracellular signaling domain and acts as a decoy that modulates signaling by the TGF-beta and related pathways. By inhibiting BAMBI with an antibody, the researchers aimed to enhance the signaling that favors regulatory T cell differentiation, thereby rebuilding the immune system’s own brakes instead of merely blocking its accelerators.

The antibody itself, hB101.37, is a humanized monoclonal antibody, meaning its protein framework has been engineered to resemble human antibodies closely enough to minimize the risk that a patient’s immune system will reject it as foreign. The team evaluated its therapeutic effect in three preclinical mouse models: an imiquimod-induced model of psoriasis, an IL-21-induced model of the skin disease, and a mannan-induced model of psoriatic arthritis. These models reproduce key features of the human conditions, from scaly skin inflammation to joint swelling, and are standard tools for testing whether a candidate biologic can plausibly work in patients before any clinical trial begins.

The results were striking on several fronts. Treatment with hB101.37 reduced disease in both the psoriasis and psoriatic arthritis models, confirming efficacy across the spectrum of the disease. Flow cytometry analyses of immune cells from treated animals showed that the antibody reduced the population of pro-inflammatory Th17 cells while promoting differentiation toward the regulatory T cell lineage, exactly the rebalancing effect the researchers had predicted from the mechanism. In molecular terms, the team traced the effect to activation of the Smad2/3 pathway, the canonical intracellular signaling route downstream of the TGF-beta receptor, which they assessed by western blot. In other words, blocking the decoy receptor BAMBI allowed the genuine TGF-beta signal to flow more freely into the Smad pathway, steering T cell fate toward tolerance.

Perhaps the most commercially and clinically significant comparison in the study is head-to-head with an established drug class. The researchers report that anti-BAMBI therapy showed potentially greater clinical efficacy in psoriasis than anti-IL-17A monoclonal antibodies, one of the most successful modern treatments for the disease. If that advantage translates to humans, it would represent a meaningful advance for the many patients whose disease is incompletely controlled by IL-17 blockade. Because the antibody works upstream of the IL-17 axis, reshaping the T cell populations that generate inflammatory cytokines in the first place, it could also, in principle, address multiple inflammatory pathways simultaneously rather than a single mediator.

Safety is where many promising immunomodulators stumble, and the Spanish team devoted considerable effort to characterizing the antibody’s preclinical safety profile. They performed histological and immunofluorescence analyses of murine tissues, measured inflammatory markers by ELISA and gene expression by quantitative PCR, and, notably, conducted transthoracic echocardiography after chronic administration of the antibody to assess cardiac function. Cardiac monitoring matters because TGF-beta family signaling is implicated in fibrosis and remodeling in multiple organs, so any therapy that perturbs this pathway must demonstrate that it does not provoke cardiovascular or structural toxicity. According to the authors, the preclinical phase confirmed the safety profile of the therapeutic antibody, an essential green light for moving toward clinical development.

The work also extended beyond mice. The researchers examined the effects of hB101.37 on human CD4-positive T cells in vitro, isolating the cells from buffy coat samples of anonymous healthy donors provided by the Blood and Tissue Bank of Cantabria under ethics committee approval. Demonstrating that the antibody can modulate T cell differentiation in human cells, not just in engineered mouse models, strengthens the translational case considerably, since species differences in cytokine biology frequently derail therapies that look spectacular in rodents. The animal studies were conducted under the approval of the University of Cantabria’s Institutional Laboratory Animal Care and Use Committee and in accordance with European directives on animal welfare.

The research is the product of a collaboration that blends a small biotechnology company with academic immunology groups. Inhibitec Anticuerpos, based in Santander, developed the antibody, and several of its scientists are coauthors, while the University of Cantabria’s molecular biology and pharmacology departments and the CSIC-affiliated biomedicine institute contributed the disease models and mechanistic analyses. The work was funded by a constellation of Spanish public agencies, including the Centro para el Desarrollo Tecnológico Industrial, the Ministry of Science, Innovation and Universities, SODERCAN, and the Government of Cantabria, along with the United States National Psoriasis Foundation, reflecting the international interest in new psoriasis therapeutics. The authors note a conflict of interest: Ramón Merino is a cofounder and stockholder of Inhibitec, and several coauthors are company employees, with the company holding a license for a patent application covering monoclonal antibodies against BAMBI for inflammatory diseases.

Caveats remain. The findings are preclinical, generated in mouse models and human cells in culture, and the antibody has not yet been tested in patients, where questions of dosing, immunogenicity, long-term safety, and real-world efficacy will ultimately be decided. The published version of the paper was shared early as an accepted manuscript and remains subject to final editorial edits. Still, the study offers something the psoriasis field has lacked: a genuinely new point of intervention that does not simply block another inflammatory cytokine but instead reprograms the T cell balance itself, boosting the regulatory arm of immunity while shrinking the inflammatory one. For the large minority of patients with psoriatic arthritis who do not respond to TNF or IL-17 blockers, and for whom drug resistance looms over even successful treatments, a first-in-class antibody that teaches the immune system to regulate itself is a development worth watching closely as it advances toward the clinic.

Subject of Research: Development of a humanized anti-BAMBI monoclonal antibody for the treatment of psoriasis and psoriatic arthritis

Article Title: Humanized anti-BAMBI monoclonal antibody as a novel therapeutic strategy for psoriatic arthritis

Article References: Perez-Adrian, P., Romero, D., Cappitelli, V., Gallego, F., Ruso-Julve, F., Calvo, M., Garcia, R., Puyalto, A., Gomez, I., Merino, D., Gil-de-Gomez, L., Merino, R., & Casado-Medrano, V. (2026). Humanized anti-BAMBI monoclonal antibody as a novel therapeutic strategy for psoriatic arthritis. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09038-5

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09038-5

Keywords: psoriasis, psoriatic arthritis, BAMBI, monoclonal antibody, Th17 cells, regulatory T cells, TGF-beta, immunotherapy, biologics, Smad2/3 pathway, preclinical models, autoimmune disease

Mesenchymal stem cells, or MSCs, are adult stromal cells typically harvested from bone marrow, adipose tissue, umbilical cord or amniotic membrane. They secrete anti-inflammatory signals, modulate immune responses and home to sites of injury, which explains their popularity across regenerative medicine. What has become increasingly clear over the past decade is that these cells do not act in isolation. The trillions of microbes inhabiting the intestine communicate with the immune system through microbial metabolites, barrier integrity and immune cell trafficking, and growing evidence links gut dysbiosis to conditions ranging from inflammatory bowel disease to hypertension. The Malaysian team set out to map whether MSC therapy consistently corrects that dysbiosis, and whether the microbial shifts could plausibly mediate the therapeutic effects observed in animal models.

The quantitative picture that emerged is one of heterogeneity rather than a single unifying signature. Of the 27 studies reporting alpha-diversity, a measure of how many species and how evenly they are distributed within a single sample, 11 found an increase after MSC treatment, three found a decrease, 11 reported no significant difference, and two described a change without a clear direction. Beta-diversity, which compares the composition of entire microbial communities between groups, was assessed in 27 studies and likewise showed between-group differences that varied widely across disease models, cell sources and delivery routes. In other words, there is no universal microbial restoration pattern triggered by MSC infusion; the gut responds differently depending on the disease context, the tissue origin of the cells and the experimental design.

One of the most closely watched microbial metrics in cardiometabolic research is the ratio of Firmicutes to Bacteroidetes, two dominant bacterial phyla whose balance has been linked to obesity, metabolic syndrome and blood pressure regulation. Only four studies in the review quantified this ratio, and even here the results split: three reported a lower ratio after MSC intervention while one reported a higher one. This inconsistency matters because much of the hypertension-microbiome literature leans on such coarse taxonomic markers. The review’s authors argue that simply counting bacterial taxa is not enough, and that enrichment of bacteria known to produce short-chain fatty acids, metabolites with well-documented vasodilatory and anti-inflammatory properties, cannot substitute for directly measuring those metabolites themselves.

That measurement gap is one of the review’s most important findings. Only three of the 31 studies directly quantified short-chain fatty acids, and just five used direct metabolomics or targeted bile-acid profiling. Short-chain fatty acids such as acetate, propionate and butyrate act on G-protein coupled receptors on immune and vascular cells, and clinical trials have shown that boosting their production with a resistant starch prebiotic can lower blood pressure in untreated hypertensive patients. Bile acids and indole derivatives such as indole propionic acid have similarly been implicated in blood pressure control through immune and vagal signalling pathways. Yet in most MSC studies, the metabolic layer of the gut-microbiome axis went unmeasured, leaving the mechanistic chain from cell therapy to microbial change to host benefit largely speculative.

The immune dimension was far better covered, with 27 studies assessing inflammatory or immune outcomes and 18 examining gut-barrier integrity. Here the evidence was more coherent: MSC therapy frequently reduced pro-inflammatory markers, rebalanced T-helper 17 and regulatory T cell populations, and improved intestinal permeability, the leakiness that allows bacterial lipopolysaccharide to enter circulation and drive the low-grade endotoxemia associated with cardiovascular disease. Studies in colitis models showed that human umbilical cord MSCs restored microbial diversity, increased immunoglobulin A secretion and modulated the microbiota-SCFA-immune axis. Work in graft-versus-host disease demonstrated that human amniotic MSCs protected mice in a manner dependent on the intestinal microbiome, and even fecal microbiota transplantation from MSC-treated mice could transfer protective anti-inflammatory effects to recipients with acute lung injury.

So where does hypertension fit in? The connection is biologically plausible: gut dysbiosis has been reproducibly documented in hypertensive humans and animal models, microbial metabolites influence vascular tone and sympathetic activity, and MSCs are known to modulate both inflammation and the microbiota. But the preclinical evidence assembled in this review falls short of closing the loop. Of the 31 studies included, only one used a pulmonary hypertension model, in which MSC therapy reversed gut microbiota changes in hypoxia-induced mice, and not a single study directly evaluated systemic hypertension. No trial has yet tested whether MSC-mediated microbial modulation lowers blood pressure in a hypertensive animal model, let alone in patients. The review is explicit that the current preclinical evidence does not establish an antihypertensive effect.

The review also delivers a methodological caution that extends well beyond the hypertension question. Of the 310 risk-of-bias judgements made using the SYRCLE tool for animal studies, 74.5 percent were rated unclear and only 25.5 percent were rated low risk, reflecting widespread deficiencies in reporting randomization, blinding and allocation concealment. Moreover, even where microbial and host changes occurred in parallel, the studies generally did not demonstrate causal mediation, meaning it remains unknown whether the microbiota changes actually caused the therapeutic benefit or merely accompanied it. Distinguishing correlation from causation will require carefully designed experiments, such as microbiota transfer from treated to untreated animals, metabolite supplementation and germ-free or antibiotic-treated controls, applied specifically to blood pressure endpoints.

What the review does establish is a credible biological foundation for the next phase of research. MSC-associated gut microbiota modulation is real, reproducible across many disease contexts and mechanistically intertwined with immune regulation and barrier repair. The authors suggest that targeted mechanistic investigation, ideally with standardized cell manufacturing under good manufacturing practice conditions, consistent culture media and direct metabolite measurement, could clarify whether the microbiome is a genuine therapeutic mediator or an epiphenomenon. If the microbiota does prove to be a mediator, combination strategies that pair cell therapy with prebiotics or engineered metabolite production could amplify cardiovascular benefit. Until then, the tantalizing idea that a stem cell infusion could quiet inflammation through the gut and ease hypertension remains exactly that: a well-grounded hypothesis awaiting its decisive experiment.

Subject of Research: Mesenchymal stem cell therapy and gut microbiota modulation in preclinical disease models with implications for hypertension

Article Title: Mesenchymal stem cell therapy and gut microbiota modulation in preclinical disease models: a systematic review with implications for hypertension

Article References: Kumereshwaran, D. D., Kuppusamy, S. G., Lokanathan, Y., Rajamanikam, A., & Govindaraju, K. (2026). Mesenchymal stem cell therapy and gut microbiota modulation in preclinical disease models: a systematic review with implications for hypertension. Molecular Biology Reports, 53(1), Article 1632. https://doi.org/10.1007/s11033-026-12782-y

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12782-y

Keywords: mesenchymal stem cells, gut microbiota, hypertension, short-chain fatty acids, dysbiosis, systematic review, preclinical models, microbiome, inflammation, gut barrier, SCFA, immunomodulation