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The model’s development is described in the January issue of the journal Stem Cell Reports. NEI is part of the National Institutes of Health.
“This ‘disease-in-a-dish’ system will help us understand how the absence of pigment in albinism leads to abnormal development of the retina, optic nerve fibers, and other eye structures crucial for central vision,” said Aman George, Ph.D., a staff scientist in the NEI Ophthalmic Genetics and Visual Function Branch, and the lead author of the report.
OCA is a set of genetic conditions that affects pigmentation in the eye, skin, and hair due to mutation in the genes crucial to melanin pigment production. In the eye, pigment is present in the retinal pigment epithelium (RPE), and aids vision by preventing the scattering of light. The RPE is located right next to the eye’s light-sensing photoreceptors and provides them nourishment and support. People with OCA lack pigmented RPE and have an underdeveloped fovea, an area within the retina that is crucial for central vision. The optic nerve carries visual signals to the brain.
People with OCA have misrouted optic nerve fibers. Scientists think that RPE plays a role in forming these structures and want to understand how lack of pigment affects their development.
“Animals used to study albinism are less than ideal because they lack foveae,” said Brian P. Brooks, M.D., Ph.D., NEI clinical director and chief of the Ophthalmic Genetics and Visual Function Branch. “A human stem cell model that mimics the disease is an important step forward in understanding albinism and testing potential therapies to treat it.”
To make the model, researchers reprogrammed skin cells from individuals without OCA and people with the two most common types of OCA (OCA1A and OCA2) into pluripotent stem cells (iPSCs). The iPSCs were then differentiated to RPE cells. The RPE cells from OCA patients were identical to RPE cells from unaffected individuals but displayed significantly reduced pigmentation.
The researchers will use the model to study how lack of pigmentation affects RPE physiology and function. In theory, if fovea development is dependent on RPE pigmentation, and pigmentation can be somehow improved, vision defects associated with abnormal fovea development could be at least partially resolved, according to Brooks.
“Treating albinism at a very young age, perhaps even prenatally, when the eye’s structures are forming, would have the greatest chance of rescuing vision,” said Brooks. “In adults, benefits might be limited to improvements in photosensitivity, for example, but children may see more dramatic effects.”
The team is now exploring how to use their model for high-throughput screening of potential OCA therapies.
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Materials provided by NIH/National Eye Institute. Note: Content may be edited for style and length.

Research led by scientists at the Jonsson Comprehensive Cancer Center (JCCC) at UCLA provides new insights into molecular “crosstalk” in pancreas cancer cells, identifying vulnerabilities that could provide a target for therapeutic drugs already being studied in several cancers. This interdisciplinary research was led by a team of JCCC investigators, Dr. Caius Radu, an expert in cancer cell metabolism, and Dr. Timothy Donahue, a pancreas cancer surgeon and an expert in pancreas cancer biology.
“Pancreatic ductal adenocarcinoma, which is highly resistant to current therapies, is expected to become the second most common cause of cancer-related deaths in the United States within this decade,” said senior author Caius Radu, MD, a researcher at Jonsson Comprehensive Cancer Center at UCLA and Professor in the Department of Molecular and Medical Pharmacology at UCLA. “Results of this study increase our understanding of the inflammatory microenvironment within these tumors and suggest targeted pharmacological strategies that could be employed to leverage this hallmark feature of pancreas cancer by current treatments.”
The preclinical research, using tumor cells from patients and cell line-derived xenograft tumors, was published online at Cell Reports on Jan. 11. It centers on STING-driven type I interferon, an immune system signaling molecule that impairs cancer cell proliferation in lab studies but tends to have the opposite effect in clinical practice, where tumor cells adapt to them and often become resistant to treatment with radiation, chemotherapy and immune checkpoint blockade. Interferons are produced in immune and other cells, including some types of cancer cells.
“We determined that a subset of PDAC tumors exhibit an intrinsic interferon response that has not been modeled by standard cell culture conditions. Using several advanced techniques, we found that interferon signaling causes the tumor cells to rely on a specific signaling pathway for survival. However, if we inhibit a protein called ATR, which plays an important role in this signaling pathway, we can cause catastrophic damage to the cancer cells’ DNA and induce programmed cell death,” said Evan Abt, a postdoctoral researcher in Dr. Radu’s lab and co-first author of the article with Thuc Le, adjunct assistant professor in Molecular and Medical Pharmacology, and Amanda Dann, MD, a resident in surgery at the UCLA David Geffen School of Medicine.
Results suggest that new small molecule drugs that inhibit ATR and are being studied for treatment of several cancers, including PDAC, could be used in combination with interferon “amplification” to thwart the tumor cells’ ability to escape.
The researchers defined a series of molecular interactions leading to a cascade of intracellular events. Through its influence on several genes, interferon alters the metabolic processes supporting the foundation of the cancer cells’ DNA, reducing the supply of biochemical building blocks needed for the DNA to survive. To compensate, the cancer cells rely on a signaling pathway – the replication stress response signaling pathway – that can enable threatened DNA to survive, largely through the influence of ATR.
Dr. Donahue said one potential intervention deserving further exploration, according to results of the study, therapy that activates another signaling pathway, called STING.
“STING activation induces interferon signaling in PDAC cells and triggers ATR activation,” he said. “This strategy would enhance the attack brought about through interferon signaling while preventing escape through the collateral pathway by shutting it down with ATR-inhibiting drugs.”

A common stereotype for an “older adult” might include early-bird specials, dentures and tickets to the matinee show.
A new Northwestern Medicine study that analyzed 20 years of fatal opioid overdose data in adults 55 and older paints a much different picture. Between 1999 and 2019, opioid-related overdose deaths increased exponentially in U.S. adults ages 55 and older, from 518 deaths in 1999 to 10,292 deaths in 2019: a 1,886% increase.
“Many of us think drug misuse is a problem of the young. However, older adults are experiencing an explosion in fatal opioid overdoses,” said Maryann Mason, an associate professor of emergency medicine at Northwestern University Feinberg School of Medicine.
The findings will be published Jan. 11 in JAMA Network Open.
“Many are Baby Boomers who, in their youth, were using recreational drugs and, unlike in previous generations, they’ve continued using into their older age,” said senior author Lori Post, the Buehler Professor of Geriatric Medicine and professor of emergency medicine and medical social sciences at Feinberg. “That sort of flies in the face of our stereotypes of the ‘older adult.’ We don’t think of them as recreational drug users, but it’s a growing problem.”
In the 20-year span, 79,893 people in the U.S. aged 55 to 80 died by opioid overdose, with about half being between 55 and 64 years old, Mason said. The annual overall death rate per 100,000 people 55 years and up ranged from a low of 0.9 in 1999 to a high of 10.7 in 2019 and increased annually from 2000 on, the study found.

Scientists with the USF Genomics program and Center for Global Health and Infectious Disease Research have taken a significant step in providing the people of Rwanda the scientific tools they need to help address mental health issues that stemmed from the 1994 genocides of the Tutsi ethnic group.
In a first of its kind study, Professors Monica Uddin and Derek Wildman of the College of Public Health looked at the entire genomes of Tutsi women who were pregnant and living in Rwanda at the time of the genocide and their offspring and compared their DNA to other Tutsi women pregnant at the same time and their offspring, who were living in other parts of the world.
In the study published in Epigenomics, they found that the terror of genocide was associated with chemically modifications to the DNA of genocide-exposed women and their offspring. Many of these modifications occurred in genes previously implicated in risk for mental disorders such as PTSD and depression. These findings suggest that, unlike gene mutations, these chemical “epigenetic” modifications can have a rapid response to trauma across generations.
“Epigenetics refers to stable, but reversible, chemical modifications made to DNA that help to control a gene’s function,” Uddin said. “These can happen in a shorter time frame than is needed for changes to the underlying DNA sequence of genes. Our study found that prenatal genocide exposure was associated with an epigenetic pattern suggestive of reduced gene function in offspring.”
The team, which includes Clarisse Musanabaganwa, a visiting scholar from the University of Rwanda and her colleagues, came to their conclusion following the review of DNA from blood samples from 59 individuals — about half exposed personally or exposed in utero to the genocide. Exposure is defined as being impacted by genocide-related trauma, such as rape or evading capture, witnessing murder or serious attack with a weapon and seeing dead and mutilated bodies.
The novel study is part of a larger consortium, the Human, Heredity & Health in Africa (H3), which is funded by the National Institutes of Health. It’s an effort to empower scientists in Africa in genomics, increasing their independence and ability to build the infrastructure needed to enhance genetic studies across the continent, and ultimately better capture data on the human genome across the world.
“The Rwandan people who are in this study and community as a whole really want to know what happened to them because there’s a lot of PTSD and other mental health disorders in Rwanda and people want answers as to why they’re experiencing these feelings and having these issues,” Wildman said.
While this study looks specifically at the impact of the 1994 Rwandan genocide, it supports previous studies that show what occurs during pregnancy when one is a fetus can have long-term impacts — many symptoms not appearing until later in life. Such evidence proves the need to enhance efforts to protect the safety and emotional and psychological wellbeing of pregnant women.
Researchers point out that individuals who were in utero during the genocide are starting to have children of their own and they hope to soon look at whether or not that trauma has had an epigenetic impact on the third generation. They’re now awaiting a new, larger batch of DNA samples to find out how trauma can impact risk for specific mental health disorders, like PTSD.
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Materials provided by University of South Florida (USF Innovation). Note: Content may be edited for style and length.

Researchers at Penn Medicine have discovered a new, more effective method of preventing the body’s own proteins from treating nanomedicines like foreign invaders, by covering the nanoparticles with a coating to suppress the immune response that dampens the therapy’s effectiveness.
When injected into the bloodstream, unmodified nanoparticles are swarmed by elements of the immune system called complement proteins, triggering an inflammatory response and preventing the nanoparticles from reaching their therapeutic targets in the body. Researchers have devised some methods to reduce this problem, but the Penn Medicine team, whose findings are published in Advanced Materials, has invented what may be the best method yet: coating nanoparticles with natural suppressors of complement activation.
Nanoparticles are tiny capsules, typically engineered from proteins or fat-related molecules, that serve as delivery vehicles for certain types of treatment or vaccine — usually those containing RNA or DNA. The best-known examples of nanoparticle-delivered medicines are mRNA vaccines against COVID-19.
“It turned out to be one of those technologies that just works right away and better than anticipated,” said study co-senior author Jacob Brenner, MD, PhD, an associate professor of Pulmonary Medicine in the Division of Pulmonary, Allergy, and Critical Care.
The Complement Problem
Therapies based on RNA or DNA generally need delivery systems to get them through the bloodstream into target organs. Harmless viruses often have been used as carriers or “vectors” of these therapies, but nanoparticles are increasingly considered safer alternatives. Nanoparticles also can be tagged with antibodies or other molecules that make them hone in precisely on targeted tissues.

Acute myeloid leukemia (AML) is an aggressive cancer of white blood cells with few effective targeted therapies available to treat it. Cold Spring Harbor Laboratory (CSHL) Professor Christopher Vakoc and former graduate student Sofya Polyanskaya found that AML cells rely on a previously little-known protein called SCP4 for survival. Their discovery points to a potential new therapeutic approach for this disease.
SCP4 is a phosphatase, a type of protein that regulates cell activity by taking phosphates off other proteins. Another type of protein called a kinase puts those phosphates back on. The number of phosphates added to or subtracted from a protein — its phosphorylation level — determines its activity. Polyanskaya discovered that SCP4 could pair with either one of two similar kinases called STK35 and PDIK1L. AML cells appear to need the phosphatase and kinases to work together to survive; turning off the gene that produces SCP4 kills the cancer cells.
Polyanskaya was surprised to find only 12 papers in the scientific literature that even mention SCP4. Of those papers, none discussed a role for these proteins in cancer. She says:
“When you encounter something that was never previously studied in the context of cancer or hasn’t been understood at all, it’s very interesting.”
The researchers think SCP4 may control an important metabolic pathway on which AML cells depend. Drugs directed against SCP4 could starve and kill the cancer cells while allowing other healthy blood cells to grow. Fortunately, other phosphatases have been successfully targeted by drugs before.
Polyanskaya admits that deciding to study SCP4 was risky. But now that its important role in AML cells has been discovered, Polyanskaya says, “Other researchers can use this system and tweak some other things to really try and pinpoint the exact pathway. This work underscores the importance of fundamental research for discovering future therapies.”
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A study published today in Cell Reports reveals important insights into the molecular mechanisms that underpin the body’s natural defences against the development of skin cancer. The findings offer new clues into the behaviour of skin cancer at the cellular level, paving the way for potential new therapeutic targets to treat the disease.
“We found that the protein CSDE1 coordinates a complex chain of events that enable senescence in skin cells, significantly slowing down their function without causing death,” says Rosario Avolio, first author of the study and postdoctoral researcher at the CRG at the time of submission. “The resulting cells act as a firewall against cancer, suppressing the formation of tumours.”
Researchers led by Fátima Gebauer at the Centre for Genomic Regulation (CRG) carried out the study by collecting keratinocytes from mice, the most abundant type of skin cell in the epidermis. Keratinocytes can give rise to various types of skin cancer including basal and squamous cell carcinomas, two of the most frequently occurring forms of all human cancers.
The group experimentally introduced genes that drive the formation of cancer, which induced the cells into a state of senescence. They found that when levels of CSDE1 were depleted, cells could not undergo senescence and became immortalised, a necessary step in the development of cancer.
Further experiments revealed that when CSDE1-depleted cells were implanted under the skin of mice, they started forming malignant tumours. The authors found this striking because every treated mouse developed squamous cell carcinomas within 15 to 20 days, highlighting the importance of CSDE1 in tumour suppression.
The researchers discovered that CSDE1 promotes tumour suppression through two different mechanisms. CSDE1 induces the cell to secrete a cocktail of cytokines and enzymes that force the cell to enter a state of permanent growth arrest. CSDE1 also stops the synthesis of YBX1, a protein previously known to promote tumour growth and aggressiveness.
According to the authors, the findings of the study are surprising because CSDE1 has been previously linked to driving the formation of cancers, not suppressing them. Previous studies from the same group led by Dr. Gebauer found that CSDE1 promotes the formation of metastases in melanoma, a less common but the most aggressive type of skin cancer. Other studies have shown CSDE1 is linked to tumour proliferation in many types of cancer.
“CSDE1 is very much the ‘Dr. Jekyll and Mr. Hyde’ of proteins. It has an unpredictable dual nature depending on what type of cell and tissue it’s found in,” explains Dr. Gebauer, acting co-coordinator of the Gene Regulation, Stem Cells and Cancer research programme at the CRG and senior author of the study. “We do not know why this protein causes cancer in some cases and suppresses them in others. Exploring the root cause of this will have important implications for the discovery of new, more personalized cancer treatments.”
CSDE1 is an RNA-binding protein, a type of protein that monitors RNA, often as soon as they’re made with the potential to significantly change their function. One possible theory that explains why CSDE1 behaves differently is that normal skin cells or tumours each have slightly different variants of the protein which affect the wider molecular machinery in different ways.
The study is one of the few to examine the role of RNA-binding proteins in establishing cell senescence, which is an important new frontier in cancer research. “It was long thought that RNA-binding proteins are universal molecules that cells use for general housekeeping, and that they cannot be targeted therapeutically. It is becoming increasingly clear that this is not true, and that this emerging field is critical for understanding human disease,” concludes Dr. Gebauer.
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The global burden of Chronic Obstructive Pulmonary Disease (COPD), a group of common lung conditions that affects more than 300* million people, could be significantly reduced with a simple health assessment, concludes a large-scale international study led by UCL researchers.
COPD includes serious lung conditions, such as emphysema and chronic bronchitis, and is the world’s third leading cause of morbidity with more than three million deaths a year. The greatest burden on COPD is in low- and middle-income countries (LMIC), which account for around 90% of COPD related deaths. Globally, COPD has also been a major risk factor associated with Covid-19 outcomes.
In high-income countries, COPD is typically caused by smoking tobacco and is diagnosed using a spirometer, where an individual blows into a device that measures how much air a person can breathe out in one forced breath. Diagnosis is straightforward and symptoms can be effectively treated.
However, in LMICs the primary cause of COPD is more varied and includes household air pollution in the form of biomass smoke for cooking and heating; other causes include impaired lung growth, chronic asthma and post-tuberculosis lung damage. And diagnosis in LMICs is hindered as spirometry — the ‘gold-standard’ for diagnosing COPD — is often not available. There is a shortage of clinicians needed to perform and interpret the tests, therefore rolling these out is costly. As a result, COPD is commonly undiagnosed in LMICs.
In the new study, published in JAMA, researchers found that people at high-risk of COPD could be identified in 7-8 minutes using either a questionnaire on its own or a questionnaire combined with a Peak Expiratory Flow (PEF) assessment, a low-cost device that tests how fast a person can exhale.
Explaining the study, Principal Investigator Professor John Hurst (UCL Division of Medicine) said: “Chronic Obstructive Pulmonary Disease is one of the world’s major public health issues, causing both individual and economic harm: there is a clear and pressing need to find better ways to identify people early, in all manner of settings.

In normal cells, electrical voltage patterns provide a blueprint for orderly growth. But with cancer, the opposite happens. Marked by a breakdown in the normal electrical patterns generated by the cells, they lose their specialized functions, start expanding into a tumor and spreading into and disrupting the function of other tissues — metastasis. As of yet, there are no clinically available treatments that specifically target the process of metastasis, which remains the leading cause of death in cancer patients.
Now researchers at Tufts University have found that manipulating voltage patterns in tumor cells using ion channel blockers already FDA-approved as treatments for other diseases can in fact significantly reduce tumor cell invasion in a dish and metastasis in an animal model of breast cancer.
The discovery, published in eBioMedicine, showed that drugs already approved for other conditions can slow or stop metastasis could lead to an expedited path to approval for the treatment of cancer.
“This is very much an unexplored, but highly opportunistic strategy for the treatment of cancer,” said Madeleine Oudin, Tiampo Family Assistant Professor of biomedical engineering at Tufts University School of Engineering and corresponding author of the study. “Ion channels, which regulate the bioelectrical properties of cells, are the second-most common target for existing pharmaceuticals, so we have a relatively large set of ready-to-use drugs that could be repurposed for cancer therapy.”
To test their therapeutic strategy, the Tufts research team focused on triple-negative breast cancer (TNBC), a subtype of the disease which accounts for approximately 15% of all breast cancer cases. The likelihood of metastasis for TNBC is greater than all other subtypes of breast cancer, and because TNBC is associated with a poor five-year prognosis, scientists are focusing efforts on counteracting it.
The researchers were able to show that manipulating the voltage properties of breast cancer cells can have a significant effect on their progression to metastasis, reducing the number of metastatic sites in mouse lungs by about 50%.

A research team of LKS Faculty of Medicine, The University of Hong Kong (HKUMed) has successfully repurposed an approved drug ifenprodil, a vasodilator, to be used in combination with the FDA-approved first-line drug sorafenib for hepatocellular carcinoma (HCC) treatment. This study leveraged on their CombiGEM-CRISPR v2.0 screening platform1 to expedite the search among the many possible drug combinations to inhibit druggable targets in the genome for treating HCC. The findings are now published in Cancer Research.
Liver cancer is the sixth most common cancer and the third leading cause of cancer related death worldwide. Despite the promising initial response to molecularly targeted therapies, tumours are often susceptible to developing drug resistance. It is no exception for sorafenib, the mainstay of treatment for HCC, and the available treatment options are very limited. Drug combination is a strategy for expanding options for cancer treatment to reduce the risk of drug resistance and tumour relapse that often arises in standalone treatment. The simplicity and precision of CRISPR-Cas9 that uses guide ribonucleic acids (RNAs) to knockout any genes in the genome make it a great tool to identify targets for potential drug discovery and development.
Utilising the screening platform of CombiGEM-CRISPR v2.0 to generate multiplexable gene knockouts, this study rapidly characterised the survival of cancer cells following dual-genetic knockouts in a pool of cells linked with DNA barcodes specifying the types of genetic alterations they carry. Instead of using conventional drug screening array that requires handling of numerous independent multi-wells, this platform only requires a simple experimental setup as the number of DNA barcodes carried by a large population of cells grown in the same culture dish could be counted in high volume via high-throughput sequencing technologies. Through screening genes and their combinations from which hits can be translated directly into drug combinations using existing drugs, non-conventional drugs and drug combinations could be discovered and repurposed for treating cancers.
Through a combinatorial CRISPR-Cas9 screen focusing on a set of druggable targets of which their expressions are upregulated in HCC cancer stem cells, the HKUMed research team identified two combinations harbouring a common target known as NMDAR1 and its paired targets are two kinases (FLT4 and FGFR3) of which both their corresponding drug inhibitor is the first line sorafenib. Specifically, genetically ablation of the identified gene combinations inhibits HCC cells’ growth and self-renewal ability. Based on The Cancer Genome Atlas database, the research team also unveiled the clinical significance of NMDAR1 in HCC, where HCC patients with low level of NMDAR1 expression show better survival outcomes.
The team also revealed the enhanced inhibition effect of the corresponding drug combination and their underlying molecular mechanisms. Co-administration of ifenprodil and sorafenib remarkably reduced the cell growth and stemness in multiple HCC cell lines, patient-derived organoids and tumour xenograft models. Additionally, the team also showed that the upregulation of unfolded protein response, triggering of cell-cycle arrest, and downregulation of genes associated with WNT-signaling and stemness could account for the enhanced effects of the drug combination.
Ifenprodil has been used as a vasodilator in countries including Japan and France with known safety history in humans. Combined with the first line sorafenib, the HKUMed research team has successfully demonstrated this two-drug regimen profoundly suppressed HCC cells’ growth and self-renewal ability.
‘Successful drug repurposing saves the cost and time that otherwise would be needed for developing new therapeutic agents with uncertain efficacy and safety profile. It also increases the chance of clinical translation of the findings from bench to bedside as the identified drug combination could be readily tested in future trials for treating HCC. Our work has identified a potentially useful drug combination to be further tested for the treatment of HCC patients from approved drugs, which could possibly save or prolong patients’ life,’ said Dr Stephanie Ma, Associate Professor of the School of Biomedical Sciences, HKUMed, who co-led the study.
‘The application of the CombiGEM-CRISPR v2.0 platform has broadened our scope in search for effective combinations of actionable targets and approved/repurposed drugs for HCC in a rapid and simple manner, and could be extended to other cancers and diseases,’ added Dr Alan Wong Siu-lun, Assistant Professor of the School of Biomedical Sciences, HKUMed, who co-led the research.
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