‘Magic carpet’ guides cells to self-organize in 3D

During morphogenesis—the process by which living organisms take shape—cells collectively position themselves in specific ways, leading to the development of tissues and organs. Being able to recreate aspects of these processes in vitro would be a huge step forward in the field of tissue engineering.

Now, a team of researchers at Yale has created a cell-driven environment, paving the way toward realizing morphogenesis in the laboratory—an advance that could lead to innovations in tissue regeneration, disease models, wound dressings, hygiene products, and other applications.

The results are published in Advanced Materials.

Prof. Yimin Luo, who led the study, explains that in living organisms, cells collectively align themselves to create the microstructures in our bodies, and then these microstructures align to create larger structures.

“Unfortunately, it’s very difficult to reproduce structures like this in a petri dish because the petri dish has no order,” said Luo, assistant professor of mechanical engineering. “You can’t manipulate where you want them to align. It’s quite difficult to get them to align collectively.”

The Luo lab, though, figured out a way to get the cells to collectively align in both 2-dimensional and 3-dimensional environments, and control the force generation process of the cells on the engineered tissue.

While scientists have previously managed to do so in 2D environments, creating a 3D environment for cells has been a challenge. Luo chalks that up to “two things that are at odds with each other.” On the one hand, you can create an environment with “rails”—structures to guide the cells into assembly, a method that researchers have used previously. But that restricts the cells to 2-dimensional movements.

“So you want something to guide the assembly, but then also decouple it from what’s been assembled,” she said. “And it turned out that it’s really difficult to do in 3D.”

To that end, Luo and her research team created what she calls a “magic carpet,” that is, they fabricated a self-organizing, cell-laden environment made from liquid crystal-templated hydrogel fibers and biodegradable collagen.

They also used a photopatterning system that they designed and built in the Luo laboratory. Photopatterning is a technique traditionally used to create specific patterns of liquid crystal mesogens—and, by extension, hydrogel fibers—but not cells directly.

However, researchers can indirectly influence cell alignment by using photopatterning to guide the alignment of the hydrogel fibers (the “magic carpet” the cells sit on). This alignment can propagate into the 3D, thereby enabling the formation of patterned, tissue-like structures.

The approach allowed them to program the collective forces exerted by the cells, resulting in predefined macroscopic shape changes in the cell-laden matrix. For instance, Luo and her team were able to program the collective alignment of cells to shape the collagen matrix into a square, and then transition that to the shape of a diamond.

“So we thought that this might be the first step to self-actuating artificial tissues,” Luo said.

By demonstrating precise control of collective cell orientation, the Luo lab has shown that this very complex environment and the bio-chemo-mechanical dynamics of the cells that inhabit it can be captured in vitro.

Further, the method they developed is accessible, cost-effective, and versatile. That means it can be readily adopted by laboratories in multiple disciplines, paving the way for numerous innovations in medicine and other fields.

WuXi Biologics Reports Completion of First Commercial PPQ Campaign at 15,000 L Production Line

WuXi Biologics completed the first commercial project Process Performance Qualification (PPQ) campaign for its three sets of 5,000 L single-use bioreactors (SUBs) in the second drug substance line of its MFG20 facility at the Hangzhou site in China.

The accomplishment not only marks a “significant breakthrough” as Asia’s first 5,000 L drug substance scale-up line utilizing SUBs, but also demonstrates the company’s capabilities in single-use technology (SUT) application for large-scale production, said Chris Chen, PhD, CEO of WuXi Biologics.

According to Chen, WuXi Biologics’ process technologies have been able to achieve demonstrable PPQ outcomes. Protein production costs per gram were reduced by nearly 70%, while advanced mass transfer technology delivered a 20% increase in protein yield per batch.

In 2024, the company commissioned three 5,000 L single-use bioreactors, its largest operational SUBs to date, and the systems achieved a commercial-scale engineering run within the same year. Integrated with four existing 2,000 L single-use technology production lines at the same facility, the site’s total capacity is elevated from 8,000 L to 23,000 L, added Chen.

“Over the past six years, by leveraging continuous process innovation, the company has applied SUT manufacturing in over 300 batches of scaled production ranging from 4,000 L to 16,000 L across multiple facilities, achieving a 99% production success rate over the past three years,” he continued. “Single-use technology manufacturing can attain COGs comparable to stainless-steel systems, while being the more eco-friendly approach, and it provides clients with greater flexibility and a wider range of options for patients worldwide.”

New Strategy Enhances CRISPR Editing Efficiency for Therapeutic Use

While CRISPR-mediated gene editing has led to powerful advances across biology, medicine, and agriculture, challenges persist in optimizing the editing efficiency of enzymes, such as the widely used Cas9 nuclease. This is especially true in therapeutic use cases, where the goal is to attain high rates of editing via a relatively low and transient enzyme dose.

In a new study published in the April 2025 issue of The CRISPR Journal titled, “Hairpin Internal Nuclear Localization Signals in CRISPR-Cas9 Enhance Editing in Primary Human Lymphocytes,” researchers from the Innovative Genomics Institute (IGI) at the University of California (UC), Berkeley, present a strategy to improve editing efficiency in human immune cells for therapeutic applications by leveraging new constructs for nuclear localization signal (NLS) sequences.

“Efficient CRISPR enzyme production is essential for translation. This is one element that allowed the rapid clinical evaluation of Casgevy, the world’s first genome editing drug. Unfortunately, this aspect tends to be overlooked in the basic research performed in academia,” said Ross Wilson, PhD, assistant adjunct professor of molecular and cell biology at UC Berkeley, who led the new study.

“Our work aimed to close this gap by finding a way to increase NLS density while maintaining the capacity for high-yield production. We think this should be a win-win for clinical use,” Wilson told GEN.

Engineered variants of CRISPR enzymes with diverse NLS sequences have shown success in promoting nuclear localization and efficient DNA editing. The study applied a new approach that installed hairpin internal nuclear localization signal sequences (hiNLS) at selected sites within the backbone of CRISPR-Cas9. This approach contrasts with the widely adopted strategy of incorporating terminally fused NLS sequences.

The study evaluated the genome editing activity of hiNLS constructs using two delivery methods for ribonucleoprotein (RNP) enzymes: electroporation, a basis for several clinical trials, and peptide-enabled RNP delivery, a hardware-free, nonviral approach which the authors view as a proxy for other in vivo delivery technologies.

RNP is appealing for therapeutic use because it is inherently transient, which minimizes off-target editing and risk of immune response. Due to RNP’s 1–2 day half-life, the enzyme must quickly reach the nucleus so that it can induce editing before it is metabolized by the cell, thereby explaining the impact of NLS density on editing efficiency.

Wilson team’s results showed that hiNLS Cas9 variants effectively improved editing efficiency in human primary T cells compared with constructs with terminally fused NLS sequences. They found enhanced knockout efficiencies for beta-2-microglobulin (B2M), a protein crucial in antigen presentation and immune response, and T cell receptor alpha chain (TRAC), a key immune signaling protein.

The authors stated that the versatility demonstrated across different target genes highlights the robustness and potential translational impact of these hiNLS constructs. Additionally, hiNLS constructs can be produced with high purity and yield compared to their terminally fused counterparts, thereby supporting manufacturing scalability.

Wilson stated that prior work performed in the lab of his IGI colleague, CRISPR Nobel laureate, Jennifer Doudna, PhD, has shown that increased NLS density has improved the ability of Cas9 to self-deliver into cells. As a result, his team is in the process of evaluating hiNLS Cas9 for its capacity to self-deliver into various clinically relevant contexts. Wilson said he is “optimistic” that this could be an added benefit of these constructs beyond what has been reported to date.

Exploring the Mutational Landscape of Colorectal Cancer

Researchers from Japan report that they have characterized gene mutations in colorectal cancer (CRC) tumors with high tumor mutation burden that lack mutations in the major oncogenes. Their findings highlight alternate site-specific mechanisms of CRC development that can guide treatment selection, according to the scientists.

The mutational landscape of CRC is well characterized, revealing key pathogenic genetic abnormalities that drive carcinogenesis and disease progression. Moreover, a stepwise colorectal carcinogenesis model has been proposed wherein normal epithelial cells transition to adenoma (noncancerous tumor) and then to carcinoma (cancerous tumor) as they sequentially acquire genetic mutations.

Mutations in APC, TP53, KRAS, and PIK3CA genes have been frequently reported in CRC patients and have been shown to drive tumor formation. However, the frequency of these mutations varies with the location of the tumor: APC and TP53 mutations are more frequent in left-sided colon cancer, whereas KRAS mutations are more frequent in right-sided colon cancer.

Recently implicated in tumor development

Additionally, the location of the tumor also influences its morphology, immune cell filtration, prognosis, metastasis, and treatment response, suggesting that mechanisms underlying tumor development are likely site-specific.

Recently, BRAF mutations have been implicated in the development of tumors with a low frequency of APC, TP53, KRAS, and PIK3CA mutations. These tumors are known to develop via alternate genetic and epigenetic mechanisms, also known as the “serrated pathway.” An alternate carcinogenesis model based on BRAF mutations, microsatellite instability (MSI), and CpG island methylator phenotype status has been proposed, although the underlying mechanisms remain unknown.

To bridge this gap, investigators led by Hideyuki Saya, MD, PhD, director of the Oncology Innovation Center, Fujita Health University, Japan, analyzed CRC tumors with high tumor mutation burden (TMB) to characterize BRAF-associated mutations and decipher their role in the carcinogenesis of tumors lacking major driver oncogenes.

Further insight into their work is shown in a study titled “Mutational Analysis of TMB-High Colorectal Cancer: Insights into Molecular Pathways and Clinical Implications,” which was published in Cancer Science. Saya explained, “We observed that CRCs arising in the right and left colon differ in both their oncogenic mechanisms and biological characteristics. As a result, treatment approaches should also differ. Genome analysis for each cancer type can guide treatment selection and help improve the outcomes of patients with CRC.”

The scientists performed targeted exome sequencing using tumor samples obtained from 150 patients with CRC. They used a proprietary in-house cancer genome analysis system and assessed the type and frequencies of gene mutations based on TMB, MSI, and tumor site. Fourteen tumors were classified as TMB-high.

Notably, 12 out of 14 tumors were located in the right colon and had a high BRAF mutation frequency and high MSI. Further, a high TMB was significantly associated with higher age and MSI-high status.

Additionally, mutations in DNA damage response transducers, such as ATM and POLE, and mismatch repair pathway genes MSH2 and MSH6, were frequent and significantly associated with a high TMB. Mutational signature analysis revealed that these mutations likely precede BRAF mutations associated with the activation of the serrated pathway, suggesting their potential role in early carcinogenesis.

While TMB-high tumors did not harbor APC, TP53, or KRAS mutations, the analysis revealed mutations in genes for pathways related to these key oncogenes, including mutations in receptor tyrosine kinase (RTK)-RAS pathway genes, BRAF, phosphatidylinositol 3-kinase (PI3K) pathway genes, PTEN, and NOTCH pathway genes; these mutations likely contribute to tumor survival and maintenance.

Overall, these findings suggest that TMB-high CRC tumors likely arise from a heterogeneous population of cells that harbors numerous gene mutations distinct from the driver oncogenes. The researchers speculate that these TMB-high tumors rely on alternate gene mutations that may respond well to targeted treatments and immunotherapies.

“Currently, cancer genome analysis is performed only for a subset of cancer patients,” said Saya. “However, in the future, it could well become a standard test for all cancers to better understand their genomic characteristics and devise appropriate treatment strategies.”

The team is now optimizing the in-house cancer genome analysis system to integrate it into the diagnosis of CRC and tailor treatments based on genetic mutations. In the long term, these efforts could pave the way to several advancements in precision oncology.

Multi-Zonal Liver Organoids Replicate Human Organs, Improve Injury Survival in Rodents

Scientists from Cincinnati Children’s Hospital Medical Center and their collaborators have used human stem cells to develop liver organoids that faithfully replicate key zones observed in human livers. Furthermore, when the organoids were transplanted into immunodeficient rats whose liver-bile duct systems had been disconnected, their survival rates nearly doubled. Details are published in a new Nature paper aptly titled, “Multi-zonal liver organoids from human pluripotent stem cells.”

Organoids that faithfully replicate the human liver are an essential tool for scientists who study the organ’s biology and disease. “There [is] outstanding hepatocyte diversity and associated functional orchestrations in the human liver that do not exist in rodents,” said Takanori Takebe, MD, PhD, the study’s corresponding author. “This new system paves the way for studying, and eventually treating, a wide range of otherwise fatal liver disorders.”

The paper provides details on how the new organoids were developed, and how they function—including data from single-cell RNA sequencing. More research is needed to fully understand how the organoids match up with natural human organ development. Additionally, the scientists are working to develop chemical methods for triggering zonal development in the new organoids rather than relying on gene editing. This would make it more practical to study disease development and drug responses at a personal level.

In the short term, these multi-zonal liver organoids will help scientists shed new light on diseases like diabetes, drug-induced liver injury, alcohol-related liver disease, and viral hepatitis. And it could also help accelerate the development of therapies that restore liver health. For example, the organoids could be used to study and make more accurate predictions about drug metabolism and toxicity in humans.

Longer-term, for people on waiting lists for liver transplantation, this study moves the scientific community one step closer to “growing” replacement organs using patients’ own tissue instead of relying on organ donation. Currently, more than 9,000 Americans are registered on waiting lists to receive a liver transplant, according to the federal Organ Procurement and Transplantation Network. Every year, an estimated 2,000 people die on waiting lists, while far more people never become eligible.

With these results, “we have taken a significant step forward at growing liver tissue in the lab that accurately mimic[s] human liver function,” said Aaron Zorn, PhD, co-director of Cincinnati Children’s Center for Stem Cell and Organoid Medicine. “While human liver organoid transplantation remains at least several years away, in the lab, these special tissues may help us find ways to prevent people from ever needing a liver transplant.”

Bypassing Size Constraints, Scientists Use CD36 Protein to Deliver Bulky PROTACs

Scientists from Duke University School of Medicine, the University of Texas (UT) Health Science, and the University of Arkansas have found a way to improve the uptake of proteolysis targeting chimeras (PROTACs) by cancer cells. Details are provided in a new Cell paper titled, “CD36-mediated endocytosis of proteolysis-targeting chimeras.”

PROTACs are small molecules that use the ubiquitin-proteasome system to remove unwanted proteins. They are a promising class of cancer-fighting drugs, but there are challenges with getting them into cells due to their large size. The new method that the researchers are proposing uses the CD36 protein, which is abundant in the body and found on the surface of cells, in the intestine, skin, lungs, eyes, and even some brain cells.

Instead of tweaking drug molecules to help them slip through cell membranes via passive diffusion, the scientists used a strategy called chemical endocytic medicine chemistry, which relies on the process of endocytosis. By designing drugs to use the CD36 pathway, researchers were able to deliver 7.7 to 22.3 times more of the drug inside cancerous cells. This change makes the treatments up to 23 times more potent, according to the researchers. Furthermore, data from mouse studies showed that the enhanced uptake led to stronger tumor suppression without making the drugs harder to dissolve or less stable.

This approach could impact future efforts to design drugs once considered too big to work. “It could rescue many drugs that were previously considered unusable due to poor absorption and turn them into clinically useful treatments for diseases,” said study author Hui-Kuan Lin, PhD, a cancer biology researcher and professor in the pathology department at Duke University School of Medicine.

The strategy is proving particularly useful for PROTACs, which are typically between 700 and 1,000 Dalton (Da). In this study, the researchers tested PROTACs that were over 1,000 Da. Despite their size, the modified PROTACs not only entered cells more efficiently but also showed greater tumor-fighting power, all while maintaining their stability and solubility.

“This was completely unexpected in the research field,” said study author Hong-yu Li, PhD, professor of medicinal chemistry and chemical biology in the pharmacology department at UT-San Antonio. Scientists have long thought that “molecules this large couldn’t cross membranes effectively, since the endocytic cellular uptake of chemical compounds was unknown. We identified CD36 as a protein for uptake and optimized drugs, better engaging with CD36 to internalize these drugs to more efficiently reach the target protein.”

Several companies are developing PROTACs to treat cancer, neurodegenerative diseases like Parkinson’s, and other conditions. For now, the findings reported in this paper will need to undergo further testing and evaluation in clinical trials before the strategy can be used in patient therapies.

Using two newly developed types of reasoning tests, a team of researchers at UCL and UCLH has identified key brain regions that are essential for logical thinking and problem-solving. The results will help to increase our understanding of how the human brain supports reasoning skills that enable us to comprehend, draw conclusions, and deal with new and novel problems. Findings from the study, which involved patients with unilateral focal frontal or posterior lesions, and healthy controls, could also have significant clinical applications, the researchers suggested, as the two new tests can help identify cognitive impairments that would otherwise go undetected.

“Our findings show a close connection between the right frontal brain network involved in reasoning and the right frontal brain network essential for fluid intelligence (our ability to solve problems without prior experience),” said Lisa Cipolotti, FMedSci, a professor at UCL Queen Square Institute of Neurology and Department of Neuropsychology, UCLH, and senior author of the team’s published paper in Brain. “This suggests that a common area of the brain plays a critical role in both reasoning and fluid intelligence.”

Cipolotti and colleagues reported on their work in a paper titled, “A right frontal network for analogical and deductive reasoning.” The paper’s lead and corresponding author is Joseph Mole, PhD, DClinPsy, CPsychol, at UCL Queen Square Institute of Neurology and Department of Neuropsychology, UCLH.

“Reasoning skills are central to many of humanity’s greatest intellectual endeavors: mathematics, philosophy, and science, to name but a few,” the authors wrote. “Two of the most well-studied types of reasoning are analogical reasoning (AR) and deductive reasoning (DR).” However, they pointed out, our understanding of the relationship between reasoning abilities and their neuroanatomical basis remains “surprisingly limited.”

Analogical reasoning is the process of identifying similarities between relationships and is held to underpin our ability to solve problems by transferring information from one set of relationships to another. Deductive reasoning, in contrast, is the ability to derive a logical conclusion from a set of premises that are held to be true. This form of reasoning is thought to be critical for solving problems with determinate solutions, as well as identifying when solutions cannot be determined.

To determine which brain areas are necessary for a certain ability, researchers study patients with brain lesions that may be caused by stroke or brain tumors. This approach, known as “lesion-deficit mapping,” is the most powerful method for localizing function in the human brain. However, studying brain injuries can be difficult and time-consuming because researchers need a large number of patients with specific brain damage. This kind of damage can affect how a person thinks, feels, or moves. However, very few research centers have access to enough patients to conduct these studies effectively.

As a result, previous studies have mainly relied on functional imaging (fMRI) techniques in healthy individuals. However, these results can sometimes be misleading as they provide correlational rather than causal evidence. As the authors pointed out, “An important caveat of fMRI techniques is that they cannot reliably differentiate regions activated in the exercise of a cognitive ability from those necessary for it.”

For their newly reported study, the researchers used lesion-deficit mapping to investigate 247 patients with unilateral focal brain lesions in either the left or right frontal (front) or posterior (back) regions of the brain. An additional 81 healthy individuals served as controls. “Lesion studies on patients with focal, unilateral, brain damage, caused by pathologies such as brain tumor or stroke, offer a unique opportunity to further our understanding of the neurocognitive architecture underpinning reasoning,” the investigators noted. “In contrast to studies using functional neuroimaging, focal lesion studies provide causal—rather than correlational—evidence.”

For their reported study, and to assess the reasoning skills of the participants, the researchers developed two new tests. One is a verbal deductive reasoning task—a type of puzzle where participants are asked to find relationships between words to solve problems—which included questions such as: “If Sarah is smarter than Diana and Sarah is smarter than Heather, is Diane smarter than Heather?”

The other is a nonverbal analogical reasoning task—a type of puzzle where participants are asked to use pictures, shapes, or numbers to figure out logical patterns and solve problems—with questions such as, “Which set of numbers is 1,2,3 most similar to—5,6,7 or 6,5,7?”

The test results showed that people with damage to the right frontal lobe had a much harder time on both tests compared to those with damage in other areas. These individuals made about 15% more mistakes than the other patients and healthy individuals. The results of their behavioral and neuroimaging analyses converged to implicate a right frontal network in analogical reasoning test (ART) and deductive reasoning test (DRT) performance, the team noted. “Combining detailed analysis of performance on novel reasoning tests with graph-based lesion-deficit mapping in a large cohort has provided novel insights into the neural basis of reasoning.”

Mole said, “Our study explores how the front right part of the brain helps people think and solve new problems. It also shows that our two new tests can help detect reasoning problems in individuals with brain damage, improving diagnosis and treatment.” Added Cipolotti, “By combining a detailed cognitive investigation in a large sample of brain-damaged patients with advanced lesion mapping techniques—developed by professor Parashkev Nachev and his team at the UCL Queen Square Institute of Neurology—we have deepened our understanding of the complex and, so far, poorly understood, neural structures underlying human reasoning.”

The researchers believe that their findings could have significant clinical implications, as the two new tests can help identify cognitive impairments that would otherwise go undetected. “Our findings imply that a right frontal network is critical for aspects of AR and DR,” they stated. “They also suggest that the ART and DRT are promising new tests, capable of evaluating reasoning abilities and identifying right frontal lobe dysfunction.”

With further validation and implementation, the team aims to make their new reasoning tests widely available in the NHS, addressing an unmet need for tools specifically designed for assessing right frontal lobe dysfunction. “Our findings suggest that the ART and DRT may provide useful information in clinical practice,” they stated. “To date, only a very small number of clinical tests have been shown capable of detecting right frontal lobe dysfunction. Translating the ART and DRT into clinical practice may address this unmet need. Notably, both tests also lack ceiling effects: an issue that applies to many existing neuropsychological tests.”

Long-Read Sequencing Pinpoints Genetic Basis for Psychiatric Diagnosis in Pediatric Case

Researchers at Rady Children’s Institute for Genomic Medicine (RCIGM) in San Diego have successfully applied long-read genome sequencing to reveal the genetic underpinnings of complex psychiatric conditions in a 17-year-old patient, showcasing the potential of this advanced technology for clinical diagnosis and future gene therapies.

In the recent study, “Long-Read Genome Sequencing in Clinical Psychiatry: RFX3 Haploinsufficiency in a Hospitalized Adolescent With Autism, Intellectual Disability, and Behavioral Decompensation,” published in the American Journal of Psychiatry, researchers utilized the PacBio Revio platform, a long-read sequencing technology, to pinpoint the diagnosis of RFX3 haploinsufficiency syndrome in an adolescent with autism spectrum disorder and intellectual disability.

While testing children for genetic disorders, a percentage of young patients are found to have variants of uncertain significance that short-read sequencing is unable to decipher. That’s where long-read sequencing can shed some light. RCIGM clinicians have used this technology to understand and diagnose pediatric patients. Stephen Kingsmore, PhD, the RCIGM president and CEO, is well known in the genomics field for leading long-read studies on rare disease diagnostics.

Aaron D. Besterman, MD, a child psychiatrist and genetics researcher at RCIGM who co-authored the new study, told GEN that this was part of a larger project that primarily used short-read sequencing to study children with neurodevelopmental disorders. “The goal of this study was really to better characterize and understand who these kids are exactly,” Besterman said. Reaching a confirmed diagnosis can be a big step to improving the outcomes for these young patients.

A tale of two platforms

Investigators must face several considerations when choosing between long-read platforms for clinical diagnostics, particularly when cataloging complex structural variants.

Jonathan Sebat, PhD, director of the Verge Center at the University of California, San Diego, and a co-author of the study, told GEN that the team selected PacBio over the other major long-read sequencing platform, produced by the U.K.’s Oxford Nanopore (ONT). After weighing the pros and cons of both platforms, the team decided to use PacBio to maximize accuracy, Sebat said.

“Both technologies are progressing rapidly. They are quite complementary and are often used in combination,” Sebat said. “Historically, PacBio has had an advantage in terms of the accuracy of the sequencing reads. ONT has the ability to generate much longer reads, which is very useful for assembling the reads into a complete genome.”

“ONT has also made improvements to its sequencing accuracy so both platforms are strong contenders for eventually becoming a first-line comprehensive genetic test.”

Through PacBio sequencing, the San Diego team uncovered a complex arrangement with both deletions and duplications in the RFX3 gene, ultimately leading to a loss of function. This allowed them to categorize the variant and make a more certain and accurate diagnosis in the teenage patient.

The long view: Sequencing toward the future

The successful diagnosis provided significant relief for the patient’s family, delivering answers after years of uncertainty. Beyond personal closure, genetic insights from long-read sequencing also open avenues for community support, reproductive counseling, gene therapy, and tailored medical management strategies.

“The last important piece of this is medical management,” Besterman added. Through long-read sequencing, Besterman believes that a few cases in the study have the potential to uncover genes associated with autism and other medical conditions, which could prevent other patients from a diagnostic odyssey.

Despite its promising outcomes, the broader clinical adoption of long-read sequencing faces several barriers. The relatively high cost, limited accessibility, and the need for extensive medical genetics training among clinicians are currently holding back widespread use.

“I think it’s important that the general psychiatry field start to become more familiar with this technology because it will become more and more common and can play a very important role in making diagnoses that are not possible through any other means,” stated Besterman.

Looking ahead, the researchers emphasize the importance of integrating long-read sequencing into broader diagnostic pipelines, not as a replacement for short-read methods but as a powerful complement for cases where other tools fall short.

“Long-read sequencing is certainly the type of diagnostic technology that’s going to play a huge role in precision medicine moving forward. I think there will also be a lot of integration with other omics platforms and technology,” said Besterman. Instead of solely focusing on genetics, the integration of transcriptomics and proteomics, among others, with clinical data to inform diagnoses, should be considered.

As clinical implementation grows, the case from RCIGM underscores the importance of continued investment and innovation in genomic technologies, highlighting a hopeful path forward for complex psychiatric conditions previously considered diagnostically elusive.

Circulating Tumor DNA Test May Help Predict Melanoma Recurrence

A study led by scientists at NYU Langone Health and its Perlmutter Cancer Center has shown that monitoring blood levels of DNA fragments shed by dying tumor cells may accurately predict skin cancer recurrence. The team’s research, involving adult melanoma patients in a Phase III clinical trial (COMBI-AD) found that approximately 80% of stage III melanoma patients who had detectable levels of circulating tumor DNA (ctDNA) before they started treatment to suppress their tumors went on to experience recurrence.

This ctDNA method works by focusing on the most common mutations in the genetic code in melanoma cells. The mutated DNA spills into the surrounding blood as the cells break down. The team’s study results also indicated that the disease returned more than four times faster in this group of individuals than in those with no detectable levels of the biomarker, and that the higher their levels, the faster the cancer returned.

“Our findings suggest that circulating tumor DNA tests could help oncologists identify which melanoma patients are most likely to respond well to therapy,” said Mahrukh Syeda, a research scientist in the Ronald O. Perlman Department of Dermatology at NYU Grossman School of Medicine. “In the future, such assessments may be used routinely in the clinic to help guide treatment decisions.”

Lead author Syeda and colleagues reported their findings in The Lancet Oncology, in a paper titled: “Clinical validation of droplet digital PCR assays in detecting BRAFV600-mutant circulating tumor DNA as a prognostic biomarker in patients with resected stage III melanoma receiving adjuvant therapy (COMBI-AD): a biomarker analysis from a double-blind, randomized Phase III trial.”

In stage III melanoma, which is among the most aggressive forms of skin cancer, tumor cells have spread from the skin to nearby lymph nodes. After those lymph nodes are surgically removed recurrence can be hard to spot using common imaging methods like X-rays and CT scans, fuelling the search for other ways to detect cancer activity early on.

According to Syeda, swiftly tracking treatment progress and the ability to spot signs of cancer growth could be helpful in a disease as dangerous as melanoma, which is notoriously difficult to treat once it spreads to other body parts. Early feedback from a ctDNA analysis might save lives, she suggested. Cell-free, ctDNA is an established measure of minimal residual disease (MRD) the authors noted, but isn’t utilized in melanoma management. “The discovery of cell-free, circulating tumor DNA (ctDNA) as a direct, albeit imperfect, measurement of tumor burden opens new possibilities for monitoring MRD and tailoring therapies accordingly.”

Previous research has shown that ctDNA tests accurately trace the progression of colorectal and breast cancers, among others. In addition, in 2021, Syeda and colleagues found that higher levels of ctDNA in those with stage IV melanoma, which has spread throughout the body, were linked to lower chances of survival. They also found that changes in ctDNA measurements during treatment could be used to identify patients with better or worse chances of survival.

Their newly reported study is, they suggested, the largest to date to assess ctDNA as a predictor for recurrence in patients with stage III melanoma. The research involved nearly 600 men and women who had participated in an earlier clinical trial for stage III melanoma. Using droplet digital PCR assays to test blood samples the team compared ctDNA measurements to clinical evidence of cancer recurrence. Their statistical analysis accounted for factors other than tumor shedding that could affect recurrence, such as sex, age, and type of therapy.

Among the findings, the the resulting data showed that assessing ctDNA levels was as good or better at predicting recurrence than other experimental tests that examine a tumor itself, such as those that measure immune activity within a group of cancer cells. “We showed that detection of post-resection, pretreatment ctDNA, which was present in 13% of patients, identified a group at high risk of early recurrence, and that the risk increased sharply with increasing ctDNA quantities,” they wrote. “In multivariable prognostic models, ctDNA concentrations were a more robust predictor of survival outcome than tumor substage, and tissue-based measures of IFNG gene expression and tumor mutational burden. These tumor-based markers were previously identified as promising candidates to stratify patients into low risk and high risk of recurrence.”

“Unlike standard, tissue-based analyses of tumor cells, which can only suggest the likelihood of recurrence, circulating tumor DNA tests provide a clear, direct measure of the disease itself and can tell us outright that melanoma has returned,” said co-senior study author and dermatologist David Polsky, MD, PhD, who is the Alfred W. Kopf, M.D., Professor of Dermatologic Oncology in the Ronald O. Perelman Department of Dermatology.

Polsky also cautioned that in some cases, cancer still recurred even though the patient had received a negative ctDNA test before starting therapy. To address this, the authors next plan to improve the sensitivity of their test, commented Polsky, a professor at NYU Grossman School of Medicine’s Department of Pathology. The team also intends to explore, in a clinical setting, whether using the biomarker to make treatment decisions can indeed improve patients’ chances of survival and quality of life.

“Droplet digital PCR measurements of ctDNA to assess minimal residual disease before adjuvant targeted therapy and during follow-up can identify patients at high risk of early recurrence,” they concluded. They suggested that additional studies using ctDNA measurements to guide therapeutic interventions might lead to improvements in the management of resected stage III melanoma. “Moving forward, newer ctDNA detection approaches using whole-genome sequencing-based analysis are likely to show greater clinical sensitivity than the current technologies to detect MRD in patients with resected melanoma,” they further stated.

In an associated Commentary, Saskia M Wilting, PhD, and Astrid AM van der Veldt, MD, PhD, at the department of medical oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, noted that the study by Syeda and colleagues adds to existing evidence for the independent prognostic value of post-surgical detection of ctDNA. “In our view, these results underline the importance of implementing ctDNA-based prognostic estimates as a stratification factor in future clinical trials,” Wilting and van der Veldt stated. “Although none of the currently available ctDNA tests are perfect, we should remember the quote by Voltaire that sometimes “perfect is the enemy of good.” Otherwise, waiting for the perfect ctDNA test will prevent us from implementing already available, ctDNA-based improvements into the clinical management of today’s patients.”

Cyprumed and MSD Agree to Develop Oral Peptide Formulations and CDMO Meribel Pharma Solutions Launches

Cyprumed and MSD signed a nonexclusive license and option agreement to develop oral formulations of MSD’s peptides using Cyprumed’s innovative drug delivery technology.

MSD gains nonexclusive global rights to Cyprumed’s oral peptide delivery platform for an undisclosed number of targets. The agreement also grants MSD the option to exclusively license Cyprumed’s technology for use with individual targets.

Cyprumed will be eligible to receive up to $493 million in upfront, development, regulatory, and net sales milestones associated with the approval of any products under the collaboration. Cyprumed may receive additional payments if MSD exercises its exclusive license option.

MSD will be responsible for the research, development, manufacturing, and commercialization of any product utilizing the Cyprumed delivery technology under the agreement.

“Our drug delivery technology has the potential to unlock new opportunities in peptide therapeutics. Continuing this collaboration with MSD to develop our innovative tablet formulations for additional targets is a great validation of our technology,” said Florian Föger, PhD, CEO of Cyprumed.

“We look forward to collaborating with the Cyprumed team to leverage their technology to help advance our macrocyclic peptide development efforts,” added Allen C. Templeton, vice president, pharmaceutical sciences, MSD Research Laboratories.

New CDMO launches

Meribel Pharma Solution, a new mid-size CDMO, has launched with an integrated network across Europe. The firm has ten manufacturing sites and three drug development services sites, situated across France, Spain, and Sweden, following the acquisition of Synerlab Group, a CDMO, and seven European manufacturing facilities from Recipharm last year.

The company, which has expertise in oral solid dose manufacturing, semi-solid dosage formulations, and sterile drug products, has established centers of excellence in drug development, lyophilization, preservative-free multidose technologies, and flexible stick-pack and sachet production.

“There is a gap in the market for a niche-player, mid-sized CDMO that’s focused, agile, and dedicated to solving complex challenges, and we are well positioned to fulfill this unmet need,” said Bruce Vielle, CEO. “We have invested heavily in the latest technologies and expanded our capacity to meet the evolving needs of our customers.”

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