The ecosystem that surrounds a tumor, also known as the tumor microenvironment, includes immune cells, tissues, blood vessels and other cells that interact with each other and with the tumor. Over time, the tumor shapes this ecosystem to its own benefit, monopolizing all of the nutrients and shielding it from immune attack. In working to understand the ecosystem’s role in cancer risk, development and treatment, researchers at The Jackson Laboratory have not only identified how two immune cells work together to fight cancer but also revealed the cascade of molecules that help coordinate this attack.
The work, led by JAX Assistant Professor Chih-Hao “Lucas” Chang, Ph.D., focuses on cytotoxic T-cells, a type of immune cell with many functions, including destroying cells infected with viruses and fighting bacterial infections and other pathogens. They also attack tumor cells. Our immune systems are able to eliminate most cancerous cells from our body before they can cause a problem. But once a tumor becomes established, cytotoxic T-cells become “exhausted” in the hostile tumor microenvironment and unable to effectively attack tumors. Chang and colleagues are investigating why these immune cells become exhausted, and potential ways to signal them back to targeting tumors.
“T-cells are excellent at identifying and attacking cells that become cancerous, but they can become exhausted in the tumor microenvironment; they can become overworked and overstimulated, while also being starved of glucose and other nutrients by tumor cells. Helping these cells to function better could improve cancer treatment strategies, particularly immunotherapies,” said Chang, whose work appears in Cancer Immunology Research.
Previous studies showed that when cytotoxic T-cells are activated, they release signaling molecules called cytokines. Chang and colleagues focused on one of these cytokines, interleukin-3 (IL-3), discovering that as a tumor grows, cytotoxic T-cells progressively lose the ability to produce IL-3 in the tumor microenvironment. Then, when Chang elevated IL-3 levels in mice bearing lymphoma or melanoma tumors, he observed strong antitumor effects.
Chang’s team further revealed that IL-3 works to mobilize basophils, a rare immune cell that can also play a role in allergies. In turn, these basophils produce another cytokine known as interleukin-4 (IL-4), which reenergizes cytotoxic T-cells, signaling them to resume detecting and destroying tumors. “Basophils have not previously been implicated in the signaling cascade for reinvigorating cytotoxic T-cells,” said Chang. “These findings are preliminary, but targeting tumor-associated basophils represents a promising avenue for enhancing antitumor immunity and improving patient outcomes.”

Increased use of blood transfusions after major traumatic brain injury could help people hospitalized in intensive care units regain greater functional independence and a better quality of life.
Six months after a major traumatic brain injury (TBI), patients who benefited from this approach regained more functional independence and had a better quality of life than those subjected to a more restrictive approach, even though the combined incidence of death and major disability was not significantly different between the two treatment groups.
This is the conclusion of an international research team led by Alexis Turgeon, professor at Université Laval, Canada Research Chair in Neurological Critical Care and Trauma, critical care physician and researcher at CHU de Québec-Université Laval, whose work is published today in the New England Journal of Medicine.
“This randomized clinical trial, initiated in 2017, was carried out in 34 hospital centres in Canada, the United Kingdom, France and Brazil. Its aim was to compare two blood transfusion strategies — one so-called restrictive and the other liberal — employed to care for people hospitalized in an intensive care unit following a TBI. These approaches differ in the degree of anemia, or the minimum hemoglobin concentration that must be present in patients’ blood before a blood transfusion can be given,” explains Professor Turgeon.
“The hemoglobin enables red blood cells to carry oxygen to the tissues and organs. Most patients hospitalized after a TBI suffer from anemia, defined as low hemoglobin concentration, which could reduce oxygen transport to the brain during a period when it is most vulnerable,” points out François Lauzier, also a professor at Université Laval and who co-led the study with Professor Dean Fergusson of the Ottawa Hospital Research Institute.
The restrictive approach consists in tolerating a low hemoglobin level before giving a transfusion, while a liberal approach aims to maintain high hemoglobin levels, thus giving more blood transfusion.
“By improving oxygen transport to the brain during the acute phase of care, it may be possible to save more nerve cells in the days following a TBI, thereby preventing additional brain damage,” says Professor Turgeon.
To conduct the study, the research team recruited 742 critically ill patients with moderate or severe TBI and anemia defined as a hemoglobin level of 10 g/decilitre or less during hospitalization. Randomly divided into two groups, these individuals were subjected to one or other of the transfusion strategies during their stay in the intensive care unit. To maintain these thresholds, the care teams administered blood transfusions whenever necessary.
Six months after TBI, the research team assessed the level of overall recovery for each group, including neurovegetative status, dependence on activities of daily living and impairments preventing resumption of activities that had been performed prior to TBI. “The combined incidence of death and major disability was not statistically different between the two groups, but seemed favouring the liberal strategy in all analyses,” says Professor Turgeon. What’s more, those treated using the liberal approach showed a higher functional independence measure and quality of life index than those treated using the restrictive approach.
“In light of the overall results of our study and considering the safety of current blood transfusions, the liberal strategy is probably the option that should be preferred in the acute phase of care to improve long-term prognosis following TBI,” concludes Professor Turgeon.

A new computational method developed by physicists at Tampere University can be used to estimate the risk of sudden cardiac death from a one-minute heart rate measurement at rest. The study was carried out in interdisciplinary collaboration between cardiology and computational physics.
Unfortunately, the first symptom of heart disease is often sudden cardiac death. It can also occur in a young and outwardly healthy person, for example, in connection with strenuous sports.
To organise preventive treatment, it is extremely important to be able to determine the risk of sudden death. Consumer devices that measure heart rate, such as commonly used smart watches, have the technical prerequisites to determine such cardiac risk factors. However, the heart rate interval analyses used thus far have not been accurate enough for this purpose.
In previous studies, the risk of sudden death has been assessed using parameters measured during a stress test, such cardiorespiratory fitness and recovery heart rate tests. Cardiorespiratory fitness refers to a person’s ability to transport oxygen to muscles and the capacity of muscle tissue to use oxygen during physical activity.
Tampere University’s researchers found that the new computational method they developed provides a significantly better estimate of the long-term risk of sudden death. Making the assessment only requires heartbeat intervals measured during one minute at rest. The finding is based on stress test data collected by the Finnish Cardiovascular Study (FINCAVAS) project from approximately 4,000 patients.
Patients with abnormal heart rate variability identified with the new method had a significantly higher incidence of sudden death compared to patients with normal heart rate characteristics. Other risk factors were also taken into account in the analysis.
The method has great potential for pre-diagnosis and the identification of high-risk patients. The method is not dependent on other measurements and could be straightforwardly integrated into, for example, a smart watch or smart ring.

“It is possible that in many previously asymptomatic individuals, who have suffered sudden cardiac death or who have been resuscitated after sudden cardiac arrest, the event would have been predictable and preventable if the emergence of risk factors had been detected in time,” says Jussi Hernesniemi, Professor of Cardiology and lead author of the study.
The new method is based on time series analysis developed by a computational physics research group led by Professor Esa Räsänen. The analysis can be used to study the interdependencies of heart rate intervals and other complex properties characteristic of different heart diseases at different time scales.
“The most interesting finding of the study is the identification of differences specifically during measurements at rest. The characteristics of heart rate intervals of high-risk patients at rest resemble those of a healthy heart during physical exertion,” says doctoral researcher Teemu Pukkila.
The development and research of the method is currently being expanded and continued with the help of databases on different heart diseases. The aim is to reliably identify not only the overall risk but also the most common heart diseases, such as heart failure, which are quite laborious to diagnose with current methods. The initial results are very promising.

Cancer genomes are the result of diverse mutation processes that have often accumulated over decades. Scientists from the German Cancer Research Center (DKFZ) and the Universities of Cambridge and Edinburgh have analyzed the molecular evolution of tumors after exposure to mutagenic chemicals. DNA lesions that persists unrepaired over several cell generations lead to sequence variations at the site of damage, the quantification of which provides insights into the kinetics and mechanisms of DNA repair. This enabled the researchers to distinguish the contribution of the triggering lesion from that of the subsequent repair in shaping the mutation pattern. These results have now been published in the journal Nature.
After DNA damage, for example by chemicals, the damaged and undamaged DNA strands are separated from each other during cell division. The cells often do not repair the DNA damage immediately; the lesions persist over several rounds of cell division. The damaged DNA can be copied by specialized enzymes known as translesion polymerases. However, these enzymes incorporate DNA building blocks (nucleotides) at random or simply skip the damaged nucleotide. The daughter cells develop different mutation profiles as a result. Researchers refer to this as “lesion segregation.” This results in complex mutation patterns in a clonal cell population such as a tumor, and can reveal which damaged DNA strand a cancer cell inherited from its “ancestors.”
Researchers led by Duncan Odom, DKFZ, Sarah Aitken, University of Cambridge and Martin Taylor, University of Edinburgh, investigated the question of how this asymmetry of DNA damage and DNA repair comes about. In particular, they wanted to clarify whether it plays a role in the mutation rate which of the two DNA strands is damaged. Despite the symmetry of both strands of the DNA ladder, they differ in many respects: only one of the strands is read into RNA, different machinery copies each of the two strands during replication, and both strands are differently accessible to repair enzymes.
The team used a mouse model to investigate how diethylnitrosamine damages liver cells and ultimately causes liver cancer. The substance damages the genetic material by chemically bonding with a base. Experts refer to such stable attachments as small DNA adducts. For their current study, the researchers examined 237 tumors from 98 mice and analyzed over seven million mutations.
Contrary to expectations, they found no significant differences in the mutation rates of the two strands of DNA (leading and lagging strand) despite their replication being performed by different processes. They went on to show that on encountering damage, both processes recruit the same damage bypass machinery with the same efficiency.
This stands in stark contrast to the asymmetric strand tolerance of the much more space-consuming UV light-induced adducts and gives new insight into how cells deal with the DNA damage caused by smoking and cancer treatments.
The accumulation of several different mutations at the site of persistently unrepaired DNA lesions can be used to measure the efficiency of repair processes — in the entire genome and with a resolution of single nucleotides.
The researchers found that the mutations induced by DNA damage are largely shaped by the influence of DNA accessibility on repair efficiency rather than where damage occurs.
Finally, they reveal specific genomic conditions that actively drive cancer-promoting mutagenesis by impairing the reliability of a specific repair mechanism called “nucleotide excision repair.”
Duncan Odom, one of the senior authors of the study, summarizes: “Our results shed light on how strand-asymmetric mechanisms of DNA damage generation, tolerance and repair underlie the evolution of the cancer genome.”

A viral gene therapy developed by University at Buffalo researchers has reversed some brain abnormalities in infant mice with FOXG1 syndrome, a significant step toward one day treating children with this severe neurodevelopmental disorder.
This mediated delivery of the FOXG1 gene via adeno-associated virus 9 (AAV9) is detailed in a study published June 5 in Molecular Therapy Methods & Clinical Development. A postnatal injection of the therapy in day-old mice rescued a wide range of abnormalities, the study found, including in parts of the brain responsible for language, memory and social interaction.
“Our findings highlight the efficacy of AAV9-based gene therapy as a viable treatment strategy for FOXG1 syndrome and potentially other neurodevelopmental disorders with similar brain malformations,” says Soo-Kyung Lee, PhD, Empire Innovation Professor and Om P. Bahl Endowed Professor in the UB Department of Biological Sciences, College of Arts and Sciences, who led the study along with her husband, Jae Lee, PhD, professor in the department. “This research asserts the therapeutic relevance of our approach in postnatal stages, which is a critical time frame for intervention.”
The Lees’ teenage daughter, Yuna, was diagnosed with FOXG1 syndrome at the age of 2. The researchers have since established themselves as leading experts on the disorder and are the principal investigators of UB’s FOXG1 Research Center (FRC). The center, which launched earlier this year, as well as this recent study, are supported by the FOXG1 Research Foundation.
The study was co-led by Kathrin Meyer, PhD, principal investigator at Nationwide Children’s Hospital in Columbus, Ohio. Other contributions represent the University of Pennsylvania and Samsung Medical Center in Seoul, South Korea.
Reversing structural abnormalities
A master regulator gene, FOXG1 is one of the most important genes for early brain development and its impairment can result in profound brain structure abnormalities.

The Lees previously established that the FOXG1 gene and protein remain active in mice after birth, so they wondered if restoring FOXG1 levels could reverse some of the abnormalities associated with FOXG1 syndrome.
These abnormalities include failure to fully develop the corpus callosum, the bundle of nerves that connect the brain’s two hemispheres and help integrate sensory and motor information with social interaction, executive function and language.
It’s thought that correcting the corpus callosum postnatally would be extremely difficult given that it develops before birth, but, when injected into mice postnatally, the Lee team’s viral gene therapy reconnected the callosal axons and restored the callosal nerves, substantially recovering the corpus callosum.
The therapy also increased the size of the dentate gyrus, the primary gateway for input formation into the rest of the hippocampus that is crucial for memory. This is one of only a few areas of the brain that continues to produce new neurons as mammals age into adulthood, making it a crucial target for postnatal treatments.
In addition, the therapy rescued areas of the brain related to signal speed between neurons.
Oligodendrocytes are the cells primarily responsible for myelination, the process of insulating nerves so they can transmit information rapidly. Brains with FOXG1 often have high numbers of oligodendrocyte precursor cells (OPC) yet delayed myelination.
According to the study, the therapy normalized the number of OPCs while restoring myelination.
The study provides a solid foundation for advancing the gene therapy toward human clinical trials, researchers said.
“We are thrilled by the full rescue of brain structure abnormalities observed in our mouse model through this study. It marks a significant step forward in our research. With these promising results, we are eager to advance this AAV9 compound towards human clinical trials, hopeful that we can extend these breakthroughs to benefit children with FOXG1 syndrome.”

The reason why targeted treatment for non-small cell lung cancer fails to work for some patients, particularly those who have never smoked, has been discovered by researchers from UCL, the Francis Crick Institute and AstraZeneca.
The study, published in Nature Communications, shows that lung cancer cells with two particular genetic mutations are more likely to double their genome, which helps them to withstand treatment and develop resistance to it.
In the UK, lung cancer is the third most common type of cancer and the leading cause of cancer death. Around 85% of patients with lung cancer have non-small cell lung cancer (NSCLC), and this is the most common type found in patients who have never smoked. Considered separately, ‘never smoked’ lung cancer is the fifth most common cause of cancer death in the world.
The most common genetic mutation found in NSCLC is in the epidermal growth factor receptor gene (EGFR), which enables cancer cells to grow faster. It is found in about 10-15% of NSCLC cases in the UK, particularly in patients who have never smoked.
Survival rates vary depending on how advanced the cancer is, with only around a third of patients with Stage IV NSCLC and an EGFR mutation surviving for up to three years.
Lung cancer treatments that target this mutation, known as EGFR inhibitors, have been available for over 15 years. However, while some patients see their cancer tumours shrink with EGFR inhibitors, other patients, particularly those with an additional mutation in the p53 gene (which plays a role in tumour suppression), fail to respond and experience far worse survival rates. But scientists and clinicians have so far been unable to explain why this is the case.
To find the answer, the researchers re-analysed data from trials of the newest EGFR inhibitor, Osimertinib, developed by AstraZeneca. They looked at baseline scans and first follow-up scans taken a few months into treatment for patients with either EGFR-only or with EGFR and p53 mutations.

The team compared every tumour on the scans, far more than were measured in the original trial. They found that for patients with just the EGFR mutations, all tumours got smaller in response to treatment. But for patients with both mutations, while some tumours had shrunk others had grown, providing evidence of rapid drug resistance. This pattern of response, when some but not all areas of a cancer are shrinking in response to a drug treatment within an individual patient, is known as a ‘mixed response’ and is a challenge for oncologists caring for patients with cancer.
To investigate why some tumours in these patients might be more prone to drug resistance, the team then studied a mouse model with both the EGFR and p53 mutation. They found that within resistant tumours in these mice, far more cancer cells had doubled their genome, giving them extra copies of all their chromosomes.
The researchers then treated lung cancer cells in the lab, some with just the single EGFR mutation and some with both mutations, with an EGFR inhibitor. They found that within five weeks of exposure to the drug, a significantly higher percentage of cells with both the double mutation and double genomes had multiplied into new drug-resistant cells.
Professor Charles Swanton, from UCL Cancer Institute and the Francis Crick Institute, said: “We’ve shown why having a p53 mutation is associated with worse survival in patients with non-smoking related lung cancer, which is the combination of EGFR and p53 mutations enabling genome doubling. This increases the risk of drug-resistant cells developing through chromosomal instability.”
Non-small cell lung cancer patients are already tested for EGFR and p53 mutations, but there is currently no standard test to detect the presence of whole genome doubling. The researchers are already looking to develop a diagnostic test for clinical use.
Dr Crispin Hiley, from UCL Cancer Institute and a Consultant Clinical Oncologist at UCLH, said: “Once we can identify patients with both EGFR and p53 mutations whose tumours display whole genome doubling, we can then treat these patients in a more selective way. This might mean more intensive follow up, early radiotherapy or ablation to target resistant tumours, or early use of combinations of EGFR inhibitors, such as Osimertinib, with other drugs including chemotherapy.”
This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK, the UK Medical Research Council, and Wellcome.

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The hospital backlog in England has gone up slightly over the past month, latest NHS figures show.

11 minutes agoGetty ImagesLong waits for cancer care are becoming routine across the UK with nearly half of all specialist cancer centres experiencing delays most weeks, the Royal College of Radiologists (RCR) has said.

Momentary shifts in mood, even those lasting just a matter of seconds, profoundly alter the brain’s response to pleasurable experiences in people with bipolar disorder, finds a new study by UCL researchers.
Previous research shows that mood can make us experience events in more positive or negative light — irrespective of having bipolar disorder. When we are in a good mood, we are drawn to viewing things more favourably — causing the good mood to rollover and gain momentum.
Equally, when we are upset we get drawn into perceiving bad outcomes as even worse, causing us to remain upset or get even more upset.
This “momentum” in mood can bias how we perceive events and the decisions we make.
Co-lead author, Dr Liam Mason (UCL Psychology & Language Sciences) said: “Imagine going to a new restaurant for the first time. If you happen to be in a fantastic mood, you’re likely to perceive the experience as being even better than it actually is.”
However, the new study published in Biological Psychiatry Global Open Science, found that people with bipolar disorder are more prone to this mood bias. The researchers have also discovered the connections in the brain that drive this mood bias effect.
For the new study, the researchers investigated what happens in the brains of people with bipolar disorder while playing a computerised Roulette game in which they experienced good and bad outcomes.

The researchers used a technique called functional Magnetic Resonance Imaging (fMRI) to scan the brains of 21 participants with bipolar disorder and 21 control participants while playing the game. This allowed them to track the neural responses of participants during moments of winning and losing. They measured the extent to which these “reward signals” in the brain were influenced by micro mood fluctuations over a matter of seconds.
To achieve this, the researchers used a computational model to quantify the mood momentum experienced by participants based on recent outcomes. They assessed whether, during periods of upward momentum (a series of wins), the brain was extra responsive to subsequent wins, and vice-versa for periods of negative momentum.
The team observed heightened neural activity in the anterior insula, an area of the brain linked to transient mood states, during periods of upward momentum in both control participants and participants diagnosed with bipolar disorder.
However, only participants with bipolar disorder exhibited a more pronounced influence of this momentum on their perception of subsequent wins and losses, as the researchers observed heightened activation in their striatum, a brain region that responds to pleasurable experiences.
Importantly, the researchers also highlighted that the amount of communication between these two regions — striatum and anterior insula — was reduced in participants with bipolar disorder.
Co-lead author Dr Hestia Moningka (UCL Psychology & Language Sciences) said: “In the control group, insula and striatum are both firing up in union, suggesting that participants were better able to keep their ‘mood in mind’ when perceiving rewards in the task.

“Meanwhile, participants with bipolar disorder showed the opposite; when there was higher momentum, they were less able to set this aside from how exciting they found the rewards to be.”
The researchers believe that these findings may help to explain why people with bipolar disorder can get stuck in a ‘vicious cycle’ where their mood escalates, and sometimes causes them to take bigger risks than usual.
Dr Moningka said: “We think these findings could help us one day move beyond existing interventions which aim to regulate mood often at the cost of dampening down exciting experiences.
“Instead, new interventions that help people with bipolar disorder to better decouple their mood from their perception and decisions is an avenue we are looking into.”