Publisher Health

At any time, most cancer patients are receiving a treatment that does not significantly benefit them while enduring bodily and financial toxicity. Aiming to guide each patient to the most optimal treatment, precision medicine has been expanding from genetic mutations to other drivers of clinical outcome. There has been a concerted effort to create “avatars” of patient tumors for testing and selecting therapies before administering them into patients.
A recently published Cancer Cell paper, which represents several National Cancer Institute consortia and includes key opinion leaders from both the research and clinical sectors in the United States and Europe, laid out the vision for next-generation, functional precision medicine by recommending measures to enable 3D patient tumor avatars (3D-PTAs) to guide treatment decisions in the clinic. According to Dr. Xiling Shen, the corresponding author of this article and the chief scientific officer of the Terasaki Institute for Biomedical Innovation, the power of 3D-PTAs, which include patient-derived organoids, 3D bioprinting, and microscale models, lie in their accurate real-life depiction of a tumor with its microenvironment and their speed and scalability to test and predict the efficacy of prospective therapeutic drugs. To fully realize this aim and maximize clinical accuracy, however, many steps are needed to standardize methods and criteria, design clinical trials, and incorporate complete patient data for the best possible outcome in personalized care.
The use of such tools and resources can involve a great variety of materials, methods, and handling of data, however, and to ensure the accuracy and integrity for any clinical decision making, major efforts are needed to aggregate, standardize, and validate the uses of 3D-PTAs. Attempts by the National Cancer Institute’s Patient-Derived Models of Cancer Consortium and other groups have initiated official protocol standardizations, and much work needs to be done.
The authors emphasize that in addition to unifying and standardizing protocols over a widespread number of research facilities, there must be quantification using validated software pipelines, and information must be codified and shared amongst all the research groups involved. They also recommend that more extensive and far-reaching clinical patient profile be compiled, which encompass every facet of a patient’s history, including not only medical, but demographic information as well; these are important factors in patient outcome. To achieve standardization in this regard, regulatory infrastructure provided by the National Institutes of Health and other institutes and journals must also be included to allow reliable global data sharing and access.
Clinical trials are also a major part of the 3D-PTA effort, and to date, studies have been conducted to examine clinical trial workflows and turnaround times using 3D-PTA. The authors advise innovative clinical trial designs that can help with selecting patients for specific trials or custom treatments, especially when coupled with the patient’s clinical and demographic information.
Combining these patient omics profiles with information in 3D-PTA functional data libraries can be facilitated by well-defined computational pipelines, and the authors advocate the utilization of relevant consortia, such as NCI Patient-Derived Model of Cancer Program, PDXnet, Tissue Engineering Collaborative, and Cancer Systems Biology Centers as well as European research infrastructure such as INFRAFRONTIER, EuroPDX)
Integrating data from existing 3D-PTA initiatives, consortia, and biobanks with omics profiles can bring precision medicine to a new level, providing enhanced vehicles for making optimum choices among approved therapeutic drugs, as well as investigational, alternative, non-chemotherapeutic drugs. It can also provide solutions for patients experiencing drug resistance and expand opportunities for drug repurposing.
“The integration of the 3D-PTA platform is a game-changing tool for oncological drug development,” said Ali Khademhosseini, Director and CEO for the Terasaki Institute for Biomedical Innovation. “We must combine it in a robust fashion with existing cancer genomics to produce the most powerful paradigm for precision oncology.”

A new study finds that antibodies produced in the nose decline nine months after COVID-19 infection, while antibodies found in the blood last at least a year.
Antibodies in the nasal fluid (known as immunoglobulin A, or IgA) provide first-line defence against COVID-19 by blocking SARS-CoV-2 virus when it first enters the respiratory tract. These antibodies are very effective at preventing the virus from entering cells and causing infection.
However, the investigators found that the nasal antibodies were only present in those recently infected and were particularly short-lived against the Omicron variant, compared to earlier variants.
These new findings — which are published in eBioMedicine — may explain why people who have recovered from COVID are at risk of reinfection, and especially with Omicron and its subvariants.
The study also found that vaccination is very effective in creating and boosting antibodies in the blood, which prevent severe disease, but had very little effect on nasal IgA levels.
First author of the study, Dr Felicity Liew, from the National Heart and Lung Institute at Imperial College London, said: “Before our study, it was unclear how long these important nasal antibodies lasted. Our study found durable immune responses after infection and vaccination, but these key nasal antibodies were shorter-lived than those in the blood. While blood antibodies help to protect against disease, nasal antibodies can prevent infection altogether. This might be an important factor behind repeat infections with the SARS-CoV-2 virus and its new variants.”
The researchers note that studies that directly study these nasal antibodies and reinfections are needed to confirm their results.

Smell loss is one of the most prevalent symptoms of long Covid according to a new study from the University of East Anglia.
New research published today reveals that almost a third of long Covid patients suffer persistent smell loss, with almost a fifth experiencing loss of taste.
The team say that Christmas in particular can be a difficult time for people who have lost their sense of smell and taste — who will be missing out smells like the Christmas tree and mulled wine, or being able to taste their Christmas dinner, mince pies and chocolates.
The research team investigated the prevalence of long Covid, and particularly ear, nose and throat related symptoms such as smell loss and parosmia — where people experience strange and often unpleasant smell distortions.
Lead researcher Prof Carl Philpott, from UEA’s Norwich Medical School, said: “Long Covid is a complex condition that develops during or after having covid, and it is classified as such when symptoms continue for more than 12 weeks.
“Symptoms include headache, myalgia, fatigue and loss of taste and smell. Parosmia can persist for months after initial infection, alongside brain fog and memory loss.

Researchers have designed and synthesized analogs of a new antibiotic that is effective against multidrug-resistant bacteria, opening a new front in the fight against these infections.
Antibiotics are vital drugs in the treatment of a number of bacterial diseases. However, due to continuing overuse and misuse, the number of bacteria strains that are resistant to multiple antibiotics is increasing, affecting millions of people worldwide. The development of new antibacterial compounds that target multiple drug resistant bacteria is also an active field of research so that this growing issue can be controlled.
A team led by Professor Satoshi Ichikawa at Hokkaido University has been working on the development of new antibacterials. Their most recent research, published in the journal Nature Communications, details the development of a highly effective antibacterial compound that is effective against the most common multidrug-resistant bacteria.
The team worked on a class of antibacterial compounds called sphaerimicins. These compounds block the function of a protein in the bacteria called MraY. MraY is essential for the replication of bacteria and plays a role in the synthesis of the bacterial cell wall; it is also not a target of currently available commercial antibiotics.
“Sphaerimicins are biological compounds, and have very complex structures,” explained Ichikawa, a corresponding author of the study. “We set out to design analogs to this molecule that would be easier to manufacture while also becoming more effective against MraY, thus increasing its antibacterial activity. The drug we designed was effective against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE), two of the more common multi-drug resistant bacteria.”
The team analysed structures of sphaerimicin A by molecular modelling assisted by calculation, and designed and synthesized two analogs of sphaerimicin, SPM1 and SPM2. These analogs were found to be effective against Gram positive bacteria.
They then determined the structure of SPM1 bound to MraY. By studying this structure and comparing it to that of related antibacterial agents, they determined how to further simplify the molecules. They were successful in developing a simpler analog, SPM3, whose activity was similar to SPM1.
In addition to their effectiveness against MRSA and VRE, the SPMs were also effective against Mycobacterium tuberculosis, the bacteria that causes tuberculosis — and which has multidrug-resistant strains.
“Our most significant contribution is the construction of the core skeleton of sphaerimicin, which can be used to develop more antibacterial agents that target MraY and hence multidrug resistant strains. Sphaerimicin is most promising as MraY is also present in Gram negative bacteria,” Ichikawa concluded. Future work will include optimisation of the currently developed SPM molecules, and the development of sphaerimicin-containing antibiotic combinations to target a wider range of bacteria.
Story Source:
Materials provided by Hokkaido University. Note: Content may be edited for style and length.

A large-scale study by the Swiss Tropical and Public Health Institute (Swiss TPH) and partners has found that rectal artesunate (RAS) has no beneficial effect on the survival of young children with severe malaria when used as an emergency treatment in resource-constrained settings. The study, which took place under real-world conditions in three African countries, concludes that the use of RAS is unlikely to reduce malaria deaths unless underlying health system weaknesses are addressed. The results could have implications on current WHO guidelines. A viewpoint about these findings was published today in The Lancet Infectious Diseases.
Rectal artesunate (RAS), a promising antimalarial drug, proves ineffective at saving the lives of young children suffering from severe malaria, according to the results of a new study conducted by the Swiss Tropical and Public Health Institute (Swiss TPH) and partners. A viewpoint about these findings was published today in The Lancet Infectious Diseases.
The study, which investigated a large-scale roll-out of RAS in the DR Congo, Nigeria and Uganda, found that when used as an emergency treatment under real-world conditions, RAS did not improve the odds of survival for young children with severe malaria. “Our findings point to a very inconvenient but important issue,” said Manuel Hetzel, Professor of Epidemiology at Swiss TPH and first author of the publication. “We found that the overall management of severe malaria cases is so poor, that adding a single product does not seem to make a positive difference. Our focus must be on investment in improving existing health systems instead of relying on individual interventions.”
The observational study, which included 6,200 severely ill children under the age of 5 years, found that in some instances, the children who received RAS were more likely to die than those who did not. “RAS was previously shown to have a beneficial effect if it is followed by adequate post-referral care at a hospital, which raised hopes in the malaria community,” added Hetzel. “But more often than not, children do not finish the entire treatment due to lack of transportation to hospitals, cost of transport and treatment, or poor quality of care at hospitals.” Pre-referral treatment with RAS is the administration of a single suppository by a community health worker or in a remote health facility as an emergency treatment, in order to bridge the time until a child is admitted to a hospital where comprehensive post-referral care is available. Post-referral care for severe malaria includes treatment with an injectable antimalarial, followed by a full oral course of artemisinin-based combination therapy (ACT), plus antibiotics and measures to manage potential complications.
Current recommendation by the WHO
The current WHO guidance on using RAS as pre-referral treatment is based on a randomised controlled trial that took place between 2000 and 2006 in Ghana, Tanzania and Bangladesh. The trial offered limited guidance on introducing RAS at scale. “Under real-life conditions, many factors influence whether an individual is appropriately treated and cured, which is why interventions that work well in a controlled trial may not always fulfil their potential in real life.” said Phyllis Awor, co-investigator of the study at the Makerere University School of Public Health in Uganda. Based on the results of this new study, the WHO issued an Information Note in October 2021 recommending that countries either delay scale-up until further guidance on the safe implementation of RAS is made available, or urgently review the conditions under which it is currently being used. At present, the current WHO guidelines on RAS are under review by a team of WHO-appointed experts.
“The real-world evidence generated in our study should be taken into consideration before pushing for a large-scale roll-out of pre-referral RAS in systems that do not have a functioning continuum of care,” said Hetzel. “Without a comprehensive approach that acknowledges the complex realities faced by caregivers and health workers in remote, underserved areas, children will continue to die from malaria, and promising interventions such as RAS will fail to meet their full potential.”
Story Source:
Materials provided by Swiss Tropical and Public Health Institute. Note: Content may be edited for style and length.

A probiotic bacterium called Lacticaseibacillus rhamnosus HA-114 prevents neurodegeneration in the C. elegans worm, an animal model used to study amyotrophic lateral sclerosis (ALS).
That’s the finding of a new study at Canada’s CHUM Research Centre (CRCHUM) led by Université de Montréal neuroscience professor Alex Parker and published in the journal Communications Biology.
He and his team suggest that the disruption of lipid metabolism contributes to this cerebral degeneration, and show that the neuroprotection provided by HA-114, a non-commercial probiotic, is unique compared to other strains of the same bacterial family tested.
“When we add it to the diet of our animal model, we notice that it suppresses the progression of motor neuron degeneration,” said Parker, the study’s lead author. “The particularity of HA-114 resides in its fatty acid content.”
By enabling the transmission of signals to muscles so that they contract, motor neurons, which are nerve cells, allow us to move our body at will.
People with ALS see a gradual deterioration of their motor neurons. This makes them lose their muscular ability, to the point of total paralysis, with an average life expectancy of only 3 to 5 years after diagnosis.

Both hot and cold environments trigger a stress response in the human body and can lead to cardiovascular problems. Physiologist Justin Lawley from the Department of Sport Science at the University of Innsbruck and colleagues have recently investigated both factors in scientific studies. The results, which were published in the Journals Scientific Reports and Experimental Physiology, are especially interesting in light of the current multiple global crises.
The climate and energy crises are currently among the greatest challenges of our time and are having a direct physical effect on people’s health. For example, the climate crisis is causing more frequent, longer and more intense heat waves, which are responsible for more deaths than natural disasters. Moreover, the energy crisis is causing a rise in energy costs and forcing many households to heat their homes less often or not at all.
The physiological responses to a simulated heat wave and cold ambient temperatures have now been investigated by Justin Lawley, together with his research group, the Laboratory of Exercise and Environmental Physiology, and international scientists in two studies — the focus was on the cardiovascular system. “In both studies, we replicated real-world environmental temperatures the body might be exposed to and were able to show physiological responses that could help explain known seasonal variations in cardiovascular deaths,” explains Lawley.
Heat study
As part of the Horizon 2020 Heat Shield project, Lawley’s group collaborated with colleagues from Slovenia to examine how heat waves affect the health of industrial workers. Seven male participants spent nine consecutive regular workdays in a controlled laboratory setting.
On the first and last three days, normal summer temperatures for Central European conditions ranged from 25.1 to 25.7 degrees during work and 21.8 to 22.8 degrees during rest periods. Days four through six represented the heat wave; during this period, researchers created ambient temperatures between 35.2 and 35.8 degrees during work periods and 25.5 to 27.1 degrees during rest periods including while sleeping at night. During the entire study, participants completed daily tasks to simulate typical industrial work.

In our bones, specialized cells called osteoblasts are responsible for building up bone substance. A team of researchers led by scientists from the DKFZ-Hector Cancer Institute at the University Medical Center Mannheim* and the University Medical Center Hamburg Eppendorf has now identified an enzyme that controls the activity of osteoblasts. An agent that inhibits the activity of this enzyme reduced cancer-related bone loss and the number of bone metastases in multiple myeloma and in lung and breast cancer models in mice.
Bones appear to be durable and solid. But appearances are deceptive: in fact, bone tissue is in a constant state of remodeling. Bone-degrading osteoclasts and bone-building osteoblasts ensure a fine balance in the healthy organism.
But this balance is occasionally disturbed: in osteoporosis, bone resorption takes over, so that fractures and deformities can occur. Bone metastases, which occur in the course of many cancers, are also often caused by bone resorption processes. This is also true for multiple myeloma, which originates and spreads in the bone marrow.
“Once they have penetrated the bone, many cancer cells secrete substances that suppress bone formation by osteoblasts. Patients often suffer greatly from painful bone metastases and fractures frequently occur,” says Sonja Loges from the DKFZ-Hector Cancer Institute at the University Medical Center Mannheim*.
So far, drugs are available that inhibit bone resorption by osteoclasts. However, Loges and her colleague Isabel Ben Batalla believe that agents that promote bone formation by osteoblasts are also medically necessary. To identify such substances, the researchers first had to find out which signaling pathways control osteoblast activity.
In this investigation, the team identified in mouse osteoblasts the two enzymes MERTK and Typo3, so-called receptor tyrosine kinases, which regulate bone production. The function of the two enzymes was studied in mice in whose osteoblasts either one or the other receptor tyrosine kinase was genetically switched off. The result: If MERTK was inactivated, the bone mass of the animals increased. Without Typo3, on the other hand, it decreased.
This result was an indication that the activity of MERTK in osteoblasts could also contribute to the cancer-related inhibition of bone formation.
MERTK inhibitor boosts bone formation
The small-molecule agent R992 inhibits MERTK activity. “R992 gave us a tool to test whether inhibiting MERTK could slow cancer-induced bone loss,” says Janik Engelmann, first author of the study from the University Medical Center Hamburg-Eppendorf and the DKFZ-Hector Cancer Institute. When healthy mice were treated with R992, their osteoblast numbers increased and the animals’ bone mass increased. Treatment with R992 also reduced bone loss and the number of bone metastases in mouse models with myeloma, lung cancer and breast cancer cell lines.
The agent R992 is not approved as a drug. To potentially study the effects of MERTK blockade in patients, Sonja Loges’ team at the German Cancer Research Center is currently developing an antibody that specifically blocks the function of MERTK. “Bone metastases affect a great many cancer patients. Osteoporosis is also a common disease. A drug that counteracts the fatal bone loss could therefore benefit a great many sufferers. We are therefore investing in further research into the role of MERTK as a therapeutic target in pathological bone loss.”
* The DKFZ-Hector Cancer Center at the University Medical Center Mannheim is a cooperation of the German Cancer Research Center (DKFZ), the Medical Faculty Mannheim of the University of Heidelberg and the University Hospital Mannheim.

Mothers drank alcohol less frequently as the COVID-19 pandemic progressed, according to a small study of Ohio women, but another result was more concerning to researchers.
Findings showed that the number of drinks per day increased for moms later in the pandemic, raising concerns that mothers may have been more likely to binge when they did drink.
“The COVID-19 pandemic was especially stressful for parents, as they juggled working from home and taking care of their children,” said Bridget Freisthler, co-author of the study and professor of social work at The Ohio State University.
“Our study gives a glimpse on how some mothers used alcohol to cope as the pandemic went on.”
Freisthler conducted the study with Jennifer Price Wolf, associate professor of social work at San Jose State University. Their study was published recently in the journal Alcohol and Alcoholism.
The researchers recruited 266 mothers in central Ohio for a study on parenting during April-May 2020 when Ohio was under stay-at-home orders for the pandemic. Participants, who all had children between 2 and 12 years of age, were recruited via social media and word-of-mouth, so it was not a random sample.

Blinding eye diseases like macular degeneration, diabetic retinopathy, and glaucoma are accompanied by the death of neurons in the retina that leads to blindness.
Although several strategies are being investigated for restoring sight to the people who are blind, including using stem cells from the body to regenerate retinal neurons lost to injury or disease. While regenerative stem cells have not been identified in the adult human retina, they have been found in zebrafish.
Experts at U-M Medical School are investigating how cells called Muller glial cells, responsible for regenerating a damaged zebrafish retina, acquire stem cell properties with the hope of eventually developing techniques to encourage human retinas to regenerate.
Building on their work that identified the cells, a new study reported in Proceedings of the National Academy of Science, led by postdoctoral fellow Sumitra Mitra, Ph.D., and research lab specialist Sulochana Devi, Ph.D., in the lab of Daniel Goldman, Ph.D., investigates whether cells other than dying neurons influence Muller glia’s regenerative response.
Interestingly, these cells are present in both the zebrafish and human retina, and in both species, they contribute to retinal structure and homeostasis; however, only in zebrafish do these cells respond to retinal neurodegeneration by adopting stem cell properties that allow them to regenerate retinal neurons.
With the new study, they discovered a Vegf-Notch signaling system that is activated in the injured retina and connects Muller glia with immune cells and cells lining blood vessels. Importantly, they found that each of these cell types contributes to the gene expression changes necessary for Muller glial cell reprogramming and acquisition of stem cell properties.
Interestingly, this signaling system is not found in mammals and thus, might help explain why the human retina does not regenerate.
This work was funded by the Gilbert Family Foundation Vision Restoration Initiative and the NEI.
Story Source:
Materials provided by Michigan Medicine – University of Michigan. Original written by Kelly Malcom. Note: Content may be edited for style and length.