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Why did my child get cancer? Clinicians have longed for a way to help answer this question. Doctors knew Hodgkin lymphoma sometimes occurs in families, but why this happens has been a mystery. Scientists at St. Jude Children’s Research Hospital have now helped solve it. The researchers studied multiple families affected by Hodgkin lymphoma and identified genetic variants linked to an increased risk of developing the disease. The findings appeared as a first edition in Blood.
Hodgkin lymphoma is a cancer of the lymphatic system (part of the immune system) that affects lymph nodes but can spread to the spleen, liver, bone marrow and lungs. As many as 7,000 new cases of the disease are diagnosed in the United States each year. Hodgkin lymphoma is the most common type of cancer in adolescents and has a five-year survival rate of 90-95%.
“We’ve never been able to tell these families anything other than its just bad luck because nobody knew why more than one family member would develop Hodgkin lymphoma,” said co-first and co-corresponding author Jamie Flerlage, M.D., St. Jude Department of Oncology. “We took on this study because understanding what is causing cancer in these families will help us to better counsel people about their chances of passing on genetic risk to their offspring, as well as help us identify novel targets that might potentially be used to create new treatments.”
Family pedigrees help reveal variants
To study Hodgkin lymphoma occurrences in families, the researchers created pedigrees, a type of diagram that reveals familial connections while tracking the incidences of cancer. The selection criteria required two or more first-degree relatives with Hodgkin lymphoma, one of whom needed to be younger than 21 years of age when diagnosed.
Scientists performed whole genome sequencing on 234 members of 36 families and identified 44 variants (33 coding and 11 noncoding) that increase the risk of developing Hodgkin lymphoma. The findings included novel gene variants that had not been previously linked to predisposition to the disease such as PAX5, GATA3, IRF7, EEF2KMT and POLR1E as well as known variants such as KDR and KLHDC8B.

Recent advances in imaging technology have made it possible to visualize intracellular dynamics, which offers a better understanding of several key biological principles for accelerating therapeutic development. Fluorescent labeling is one such technique that is used to identify intracellular proteins, their dynamics, and dysfunction. Both internal as well as external probes with fluorescent dyes are used for this purpose, although external probes can better visualize intracellular proteins as compared to the internal probes. However, their application is limited by non-specific binding to intracellular components, resulting in a low target specific signaling and higher background noise.
Recently, a fluorescent dye-labeled immunosensor known as Quenchbody (Q-body) has been successfully used to detect antigens in solutions or on the cell surface. A Q-body is essentially an antibody fragment with the ability to bind a specific antigen.
Against this backdrop, researchers from Japan and Singapore led by Prof. Hiroshi Ueda from Tokyo Institute of Technology (Tokyo Tech), Japan recently reported the applicability of Q-bodies for imaging of intracellular proteins in live cells. Their findings are now published in Chemical Science.
“Since the Q-body works as a site-specific and antigen-dependent imaging tool, we hypothesized that it will display antigen-dependent switchable fluorescence on interacting with the target protein, enabling precise visualization of intracellular dynamics. We demonstrated this by synthesizing a Q-body for p53, a tumor suppressor biomarker protein that plays an important role in DNA repair, cell division, and cell death,” explains Prof. Ueda.
The team synthesized a “double” fluorescence dye-labeled Q-body called “C11_Fab Q-body,” which displayed better sensitivity and target specificity compared to conventional probes in human cancer cells expressing p53. Since the expression of p53 increases in cancer cells, they electroporated the Q-body in several human cancer cell lines to validate their hypothesis.
Compared to a traditional probe that displayed continuous fluorescence signals even in the absence of p53, the Q-body probe displayed fluorescence signals in “fixed” cells (cells with denatured proteins to halt decomposition) expressing p53. Moreover, the Q-body probe could visualize both wild (control) and mutant type p53 in fixed cell samples.
Further, the team observed fluorescence signals with 8-fold higher intensity in live human colon cancer cell lines with p53 expression as compared to the negatives. Interestingly, the Q-body was stable in the long term, displaying fluorescence intensity changes with experimentally induced changes in p53 levels.
Flow cytometry revealed higher immunofluorescence with Q-body in cells expressing p53. Furthermore, on sorting, the ratio and fluorescence signal of these cells was significantly higher compared to the others (with or without Q body).
What are the implications of these findings? Prof. Ueda answers, “The existing techniques are unable to provide precise imaging of less abundant intracellular targets with high specificity and sensitivity. In this context, our study demonstrates the potential of Q-bodies in live cell imaging for better visualization of dynamical intracellular changes, and provides an approach for intracellular antigen-specific sorting of live cells using a Q-body.”
Going ahead, we can expect the development of many more Q-bodies for visualizing several other intracellular biomarkers, opening doors to improved cell-based therapeutic development and cancer research.
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Researchers from the National Eye Institute (NEI) have developed a gene therapy that rescues cilia defects in retinal cells affected by a type of Leber congenital amaurosis (LCA), a disease that causes blindness in early childhood. Using patient-derived retina organoids (also known as retinas-in-a-dish), the researchers discovered that a type of LCA caused by mutations in the NPHP5 (also called IQCB1) gene leads to severe defects in the primary cilium, a structure found in nearly all cells of the body. The findings not only shed light on the function of NPHP5 protein in the primary cilium, but also led to a potential treatment for this blinding condition. NEI is part of the National Institutes of Health.
“It’s so sad to see little kids going blind from early onset LCA. NPHP5 deficiency causes early blindness in its milder form, and in more severe forms, many patients also exhibit kidney disease along with retinal degeneration,” said the study’s lead investigator, Anand Swaroop, Ph.D., senior investigator at the NEI Neurobiology Neurodegeneration and Repair Laboratory. “We’ve designed a gene therapy approach that could help prevent blindness in children with this disease and one that, with additional research, could perhaps even help treat other effects of the disease.”
LCA is a rare genetic disease that leads to degeneration of the light-sensing retina at the back of the eye. Defects in at least 25 different genes can cause LCA. While there is an available gene therapy treatment for one form of LCA, all other forms of the disease have no treatment. The type of LCA caused by mutations in NPHP5 is relatively rare. It causes blindness in all cases, and in many cases it can also lead to failure of the kidneys, a condition called Senior-Løken Syndrome.
Three post-doctoral fellows, Kamil Kruczek, Ph.D., Zepeng Qu, Ph.D., and Emily Welby, Ph.D., together with other members in the research team collected stem cell samples from two patients with NPHP5 deficiency at the NIH Clinical Center. These stem cell samples were used to generate retinal organoids, cultured tissue clusters that possess many of the structural and functional features of actual, native retina. Patient-derived retinal organoids are particularly valuable because they closely mimic the genotype and retinal disease presentation in actual patients and provide a “human-like” tissue environment for testing therapeutic interventions, including gene therapies. As in the patients, these retinal organoids showed defects in the photoreceptors, including loss of the portion of the photoreceptor called “outer segments.”
In a healthy retina, photoreceptor outer segments contain light-sensing molecules called opsins. When the outer segment is exposed to light, the photoreceptor initiates a nerve signal that travels to the brain and mediates vision. The photoreceptor outer segment is a special type of primary cilium, an ancient structure found in nearly all animal cells.
In a healthy eye, NPHP5 protein is believed to sit at a gate-like structure at the base of the primary cilium that helps filter proteins that enter the cilium. Previous studies in mice have shown that NPHP5 is involved in the cilium, but researchers don’t yet know the exact role of NPHP5 in the photoreceptor cilium, nor is it clear exactly how mutations affect the protein’s function.
In the present study, researchers found reduced levels of NPHP5 protein within the patient-derived retinal organoid cells, as well as reduced levels of another protein called CEP-290, which interacts with NPHP5 and forms the primary cilium gate. (Mutations in CEP-290 constitute the most common cause of LCA.) In addition, photoreceptor outer segments in the retinal organoids were completely missing and the opsin protein that should have been localized to the outer segments was instead found elsewhere in the photoreceptor cell body.
When the researchers introduced an adeno-associated viral (AAV) vector containing a functional version of NPHP5 as a gene therapy vehicle, the retinal organoids showed a significant restoration of opsin protein concentrated in the proper location in outer segments. The findings also suggest that functional NPHP5 may have stabilized the primary cilium gate.
The study was funded by the NEI Intramural program. Patient samples were collected at the NIH Clinical Center.
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A team of Mount Sinai researchers has produced a high-resolution crystal structure of an enzyme essential to the survival of SARS-CoV-2, the virus that causes COVID-19. The discovery could lead to the design of critically needed new antivirals to combat current and future coronaviruses.
The enzyme, known as nsp14, has a crucially important region known as the RNA methyltransferase domain, which has eluded previous attempts by the scientific community to characterize its three-dimensional crystal structure. A paper describing the innovative process was published inthe September 8 online edition of Nature Structural & Molecular Biology.
“Being able to visualize the shape of the methyltransferase domain of nsp14 at high resolution gives us insights into how to design small molecules that fit into its active site, and thus inhibit its essential chemistry,” says senior author Aneel Aggarwal, PhD, Professor of Pharmacological Sciences at the Icahn School of Medicine at Mount Sinai. “With this structural information, and in collaboration with medicinal chemists and virologists, we can now design small molecule inhibitors to add to the family of antivirals that go hand-in-hand with vaccines to combat SARS-CoV-2.”
Prescription antivirals that target key enzymes of SARS-CoV-2 include nirmatrelvir for the main protease (MPro) enzyme, and molnupiravir and remdesivir for the RNA polymerase (nsp12) enzyme. Research to develop new antivirals targeting different enzymatic activities has been accelerating in laboratories around the world, and Mount Sinai’s discovery has added significantly to that effort.
“Part of what drives our work,” says Dr. Aggarwal, “is the knowledge gained from treating HIV — that you typically need a cocktail of inhibitors for maximum impact against the virus.”
The Mount Sinai team actually developed three crystal structures of nsp14, each with different cofactors, from which they identified the best scaffold for the design of antivirals for inhibiting the RNA methyltransferase activity that the enzyme enables and the virus needs to survive. According to their scheme, the antiviral would take the place of the natural cofactor S-adenosylmethionine, thus preventing the methyltransferase chemistry from occurring. The crystal structures that the team has elucidated have been made available to the public and will now serve as guides for biochemists and virologists globally to engineer these compounds.
Making the discovery possible was the ability of researchers to clear a hurdle that had prevented others in the past from creating three-dimensional crystals of the nsp14 methytransferase domain. “We employed an approach known as fusion-assisted crystallization,” explains lead author Jithesh Kottur, PhD, a postdoctoral fellow at Icahn Mount Sinai, and a crystallographer and biochemist. “It involves fusing the enzyme with another small protein that helps it to crystalize.”
Dr. Aggarwal, an internationally recognized structural biologist, underscores the importance of ongoing investigative work by researchers in his field against a virus that has led to millions of deaths globally. “The virus evolves so quickly that it can develop resistance to the antivirals now available, which is why we need to continue developing new ones,” he observes. “Because of the high sequence conservation of nsp14 across coronaviruses and their variants (meaning it does not mutate much), our study will aid in the design of broad-spectrum antivirals for both present and future coronavirus outbreaks.”

Based on findings from a new study by a Johns Hopkins Medicine-led research team, an effective means of fighting SARS-CoV-2, the virus that causes COVID-19, may be possible that circumvents the problem of waning immunity often observed when current vaccines deal with emerging COVID variants. The method uses a small molecule inhibitor (a molecule approximately 1 nanometer in size that inhibits specific interactions between proteins) called RK-33 to block the virus’s ability to take over a host cell’s “genetic manufacturing plant” and make copies of itself.
“To date, COVID-19 vaccines have relied on preventing the binding of a SARS-CoV-2 surface protein — called the spike protein — to host cells and enabling infection, but if the spike protein changes with new variants, a vaccine’s effectiveness may be weakened,” says study senior author Venu Raman, Ph.D., professor of radiology, oncology and pharmacology at the Johns Hopkins University School of Medicine. “In contrast, our study shows that RK-33’s antiviral capability is unaffected by spike protein mutations and remains consistent across four SARS-CoV-2 variants.”
The research was first posted online Aug. 25, 2022, in the journal Frontiers in Microbiology.
For several years, Raman and his colleagues have studied a protein known as DDX3 and its impact on cancer. DDX3 is a ribonucleic acid (RNA) helicase, a protein that unwinds the double-stranded RNA controlling many tumor cells, enabling the RNA’s genetic code to be read (or translated). This, in turn, leads to the creation of new cancer cells and malignant spread of the disease. Studies by Raman’s team and others have suggested that RK-33, a DDX3 inhibitor developed in the Raman laboratory, can slow down cancer progression by keeping RNA from unwinding for translation.
DDX3 protein also has been shown to help promote the infectivity of many RNA viruses, such as HIV and respiratory syncytial virus (RSV). Consequently, RK-33, the DDX3-inhibitor with great promise as a cancer fighter, is now being seriously considered for a second therapeutic function: a broad-spectrum antiviral agent.
“We know that many RNA viruses usurp the DDX3 helicase function of the host cell to facilitate their own replication,” says Raman. “When scientific studies revealed that small concentrations of RK-33 blocked replication and limited infectivity by human parainfluenza type 3 virus, RSV, dengue virus, Zika virus and West Nile virus — and potentially, HIV — our team decided to see whether RK-33 could work on SARS-CoV-2 as well.”
Along with testing RK-33’s impact on SARS-CoV-2 infectivity and reproduction, the researchers extended their study to determine if the inhibitory action observed was limited to specific variants of the virus or would be effective against multiple variants. They used RK-33 to target DDX3 in laboratory cells infected with four variants of SARS-CoV-2 — the original virus and the alpha, beta and delta variants.

Physical activity may be associated with improved outcomes for patients undergoing postoperative treatment for Stage III colon cancer.
A new study from Pennington Biomedical Research Center, published in the Journal of Clinical Oncology, assessed 1,696 patients who had undergone surgery and chemotherapy to treat Stage III colon cancer. The study examined how different types and intensity of physical activity might impact the length of time patients remained alive and disease-free. Specifically, researchers assessed the overall amount of physical activity the patients engaged in, as well as the type of activity. The researchers compared light and moderate physical activity, vigorous aerobic activity, brisk walking, and muscle-strengthening exercise.
Although many patients with colon cancer initially beat the disease, up to one-third experience cancer relapse which is often incurable. Prior to this study, it was unknown how different types and intensity of physical activity impacted disease recurrence and death in colon cancer survivors. Current clinical guidelines encourage patients to simply avoid inactivity.
“Colon cancer survivors are generally told it is best to avoid inactivity. However, many patients want specific guidance on the types of activity that can maximize their probability for cure. This study provides oncologists and their patients with specific information on exactly what type of activity will be most helpful in their goal of remaining alive and cancer free,” said Pennington Biomedical Cancer Metabolism Program Director Justin Brown, PhD, who led the study. “What we found is that larger volumes of recreational physical activity, longer durations of light- to moderate-intensity aerobic physical activity, or any vigorous-intensity aerobic physical activity were associated with the highest chances of remaining alive and cancer free. Patients should first identify a physical activity that they enjoy and then refer to the study results to determine how much of that activity is needed to achieve such a health benefit. If you enjoy the activity, you are more likely to stick with it over time.”
The study took place within an existing National Cancer Institute (NCI) trial that compared certain pharmaceutical treatments in patients who had undergone surgery to treat their colon cancer. The patients were followed for nearly six years.
“We were fortunate to be able to conduct this study as an offshoot of the NCI study. By conducting this study within the NCI trial, we eliminated many of the common limitations of prior studies to allow us to zero in on what will benefit the patient and what might not,” Brown said.
“We know that healthy lifelong habits can make a difference in cancer survivors’ overall wellness. This cutting-edge research project provides patients with very specific recommendations on how they can take back some level of control against a disease that often feels overwhelming,” said Pennington Biomedical Executive Director John Kirwan, PhD.
The journal article contains detailed charts outlining the benefits associated with the different types of physical activity and the amount per week that is ideal for achieving disease-free survival.
This work was supported by grants from the Alliance for Clinical Trials in Oncology and the National Cancer Institute of the National Institutes of Health.
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Chlamydia, the leading cause of sexually transmitted bacterial infections, evades detection and elimination inside human cells by use of a cloaking device. But Duke University researchers have grasped the hem of that invisibility cloak and now hope they can pull it apart.
To enter the cell and peacefully reproduce, many pathogenic bacteria, including Chlamydia, cloak themselves in a piece of the cell’s membrane, forming an intracellular free-floating bubble called a vacuole or, in the case of Chlamydia, an inclusion. Chlaymydia’s cloak appears to be especially effective at evading the cell’s built-in immunity, allowing the infection to last for months.
A Duke team led by graduate student Stephen Walsh and Jörn Coers, PhD, an associate professor of molecular genetics and microbiology in the Duke School of Medicine, wanted to know how the cloaking worked.
“We knew there was the potential to kill Chlamydia, but when we did experiments with the human-adapted form, Chlamydia trachomatis, it was very good at growing in human cell cultures,” Coers said. Even after the scientists used an immune stimulant to alert the cell’s defense systems of the presence of Chlamydia, nothing happened. “We said, there’s the pathogen. Our defense system should see it. Why does it not see it?”
They ran their experiments again using a mouse-adapted version of the Chlamydia bacteria in human cells to see how the cell’s immune system responded to a non-human pathogen.
“Humans, don’t get mouse Chlamydia because it evolved with mice and human Chlamydia evolved with humans,” Coers said. “So there’s this really fine-tuned adaptation that the pathogen has undergone.” The mouse version of the bacterial inclusion was readily identified and labeled for destruction in human cells.

Being vaccinated with at least two doses of Pfizer vaccines dramatically reduces most of the long-term symptoms individuals reported months after contracting COVID-19, a new study shows.
In this study, eight of the ten most-commonly reported symptoms were reported between 50 and 80% less often among individuals who received at least two doses of COVID-19 vaccine compared with those who received no doses.
The study, recently published in the Nature journal npj Vaccines, was led by Prof. Michael Edelstein, of Bar-Ilan University’s Azrieli Faculty of Medicine, in cooperation with infectious disease and IT teams at three of the Faculty’s affiliate hospitals in northern Israel: Baruch Padeh Medical Center, Ziv Medical Center and Galilee Medical Center. Paul Otiku, a PhD student at Bar-Ilan’s Azrieli Faculty, carried out most of the statistical analysis.
Nearly 3,500 adults across Israel participated in the study, carried out between July and November 2021. These individuals completed a survey available in four commonly-spoken local languages — Hebrew, Arabic, Russian and English — with a variety of questions about previous COVID-19 infection, vaccination status, and any symptoms they were experiencing.
More than half of the participants (2,447) reported no previous SARS-CoV-2 infection, while 951 were previously infected. Of those infected, 637 (67%) received at least two vaccine doses. Of the 2,447 individuals reporting no previous infection 21 (0.9%) received one dose, 1,195 (48.8%) received two doses, 744 (30.4%) received three doses, and the rest were unvaccinated (19.9%).
The researchers compared vaccinated individuals with those unvaccinated in terms of post-acute self-reported symptoms. After adjusting for factors such as age and time elapsed from infection to responding to the survey, they found that vaccination with two or more doses of the Pfizer vaccine was associated with a reduced risk of reporting the most common post-COVID symptoms. Among those in the current study group, the most common symptoms reported — fatigue, headache, weakness of limbs and persistent muscle pain — were reduced by 62%, 50%, 62%, and 66%, respectively. Other commonly-reported symptoms, such as shortness of breath, were reduced by up to 80%.
The study contributes to scarce information to date about the impact of vaccination on long COVID. “We don’t fully understand what happens in the months and years following COVID-19 in terms of physical and mental health and wellbeing,” says the study’s lead author, Prof. Michael Edelstein, of Bar-Ilan’s Azrieli Faculty. “Because long COVID seems to affect so many people it was important to us to check whether vaccines could help alleviate the symptoms. It is becoming increasingly clear that vaccines protect not just against disease but, as the results of this study suggest, against long-term, sometimes life-changing, effects of COVID-19.”
To what extent vaccines protect against long COVID remains less clear. This study is the first in an ongoing project launched by Edelstein to track a large cohort of individuals from all sectors of Israel’s diverse society to understand the impact of the vaccines on long-term quality of life, different COVID variants, and long-COVID symptoms.
This research was funded in part by the Harvey Goodstein Foundation.
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Researchers from the University of Georgiahave discovered a potential treatment for Chagas disease, marking the first medication with promise to successfully and safely target the parasitic infection in more than 50 years.
Human clinical trials of the drug, an antiparasitic compound known as AN15368, will hopefully begin in the next few years.
“I’m very optimistic,” said Rick Tarleton, corresponding author of the study and a UGA Athletic Association Distinguished Professor in the Franklin College of Arts and Sciences. “I think it has a really strong chance of being a real solution, not just a stand-in for something that works better than the drugs we currently have.”
The new drug works by targeting the parasite that causes the disease, Trypanosoma cruzi, also known as T. cruzi.
Nearly all people infected with the parasite experience flu-like symptoms such as fever, headaches and vomiting. However, after their immune response kicks in, their symptoms may subside.
But for 30% to 40% of patients, the infection can result in severe heart damage that can be both debilitating and life-threatening.

Development of medical treatment against cancer is a major research topic worldwide — but cancer often manages to circumvent the solutions found. Scientists around Tanja Weil and David Ng at the Max Planck Institute for Polymer Research (MPI-P), have now taken a closer look at the cancer’s countermeasures and aim to stop them. By disrupting the cellular components that are responsible for converting oxygen into chemical energy, they have demonstrated initial success in eliminating cells derived from untreatable metastatic cancer.
Treatment of cancer is a long-term process because remnants of living cancer cells often evolve into aggressive forms and become untreatable. Hence, treatment plans often involve multiple drug combinations and/or radiation therapy in order to prevent cancer relapse. To combat the variety of cancer cell types, modern drugs have been developed to target specific biochemical processes that are unique within each cell type.
However, cancer cells are highly adaptive and able to develop mechanisms to avoid the effects of the treatment. “We want to prevent such adaptation by invading the main pillar of cellular life — how cells breathe — that means take up oxygen — and thus produce chemical energy for growth,” says David Ng, group leader at the MPI-P.
The research team produced a synthetic drug that travels into cells where it reacts to conditions found inside and triggers a chemical process. This allows the drug’s molecules to bind together and form tiny hairs that are a thousand times thinner than human hair. “These hairs are fluorescent, so you can look at them directly with a microscope as they form,” says Zhixuan Zhou, an Alexander-von-Humboldt-fellow and first author of the paper.
The scientists monitored the oxygen consumption in different cell types and found that the hairs stop all of them from converting oxygen into ATP, a molecule that is responsible for energy delivery in cells. The process worked even for those cells derived from untreatable metastatic cancer. As a result, the cells die rapidly within four hours. After some more years of research, the scientists hope that they can develop a new method to treat up-to-now untreatable cancer.
Weil, Ng and colleagues have shown an exciting outcome under controlled laboratory culture and will continue to unravel deeper insights on the basis of how these tiny hairs prevent the conversion of oxygen to chemical energy. With further development, these objects could in the future possibly also be manipulated to control other cellular processes to address other important diseases.
They have published their results in the Journal of the American Chemical Society.
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