Tag: Medicine

Brain metastases are one of the deadliest forms of cancer metastasis, with grave survival rates of less than one year in many cases. The incidence of brain metastases has been increasing in recent years and developing better therapeutic strategies for brain metastasis is an urgent need. In a new study from Tel Aviv University, researchers identified and characterized a new mechanism that facilitates the formation of brain metastases and found that impairing this mechanism significantly reduced the development of brain metastases in lab models.

“The findings establish LCN2 as a new prognostic marker and a potential therapeutic target.” Prof. Neta Erez

On the Radar: LCN2

The research was led by Prof. Neta Erez, head of the laboratory for the biology of tumors from the Department of Pathology at the Sackler Faculty of Medicine, and members of her team: Omer Adler, Yael Zeit, and Noam Cohen, in collaboration with Prof. Shlomit Yust Katz from Rabin Medical Center (Beilinson Hospital) and Prof. Tobias Pukrop from Regensburg Hospital, Germany. The study was supported by the Melanoma Research Alliance (MRA), the Cancer Biology Research Center at Tel Aviv University, the Personalized Medicine Program of the Israel Science Foundation (ISF IPMP) and the German Cancer Research Foundation (DFG), and was published in the journal Nature Cancer.

In this new study, the researchers show that Lipocalin-2 (LCN2) [a protein which in humans is encoded by the LCN2 gene] is a key factor in inducing neuroinflammation in the brain. Moreover, the researchers found that high LCN2 levels in patients’ blood and brain metastases from several types of cancer are associated with disease progression and reduced survival.

LCN2 is a secreted protein that functions in the innate immune system and was originally discovered due to its ability to bind iron molecules and as part of the inflammatory process in fighting bacterial infection. LCN2 is produced by a large variety of cells and was shown to be involved in multiple cancer-related processes.

“Our findings reveal a previously unknown mechanism, mediated by LCN2, which reveals a central role for the mutual interactions between immune cells recruited to the brain (granulocytes) and brain glial cells (astrocytes) in promoting inflammation and in the formation of brain metastases. The findings establish LCN2 as a new prognostic marker and a potential therapeutic target,” says Prof. Neta Erez.

“In blood and tissue samples from patients with brain metastases from three types of cancer, blood LCN2 levels were correlated with disease progression and with shorter survival, which positions LCN2 as a potential prognostic marker for brain metastases.” Prof. Neta Erez

LCN2 as a Predictive Marker for Brain Metastases

The researchers used models of melanoma and breast cancer brain metastases to reveal the mechanism by which neuroinflammation is activated in the metastatic niche in the brain.

“We show that signals secreted into the blood from the primary tumor stimulate pro-inflammatory activation of astrocytes in the brain. The astrocytes promote the recruitment of inflammatory cells from the bone marrow (granulocytes) into the brain, and they in turn become a main source of signaling by LCN2,” explains Prof. Erez.

“We demonstrated the importance of LCN2 for the development of metastases by genetically inhibiting its expression in mice, which resulted in a significant decrease in neuroinflammation and reduced brain metastases. Moreover, in blood and tissue samples from patients with brain metastases from three types of cancer, blood LCN2 levels were correlated with disease progression and with shorter survival, which positions LCN2 as a potential prognostic marker for brain metastases.”

Prof. Erez adds: “We analyzed the LCN2 protein levels in the blood and cerebrospinal fluid (CSF) of mice with brain metastases and found that LCN2 levels increased greatly in mice with melanoma and breast cancer metastases compared to healthy mice. Importantly – an increase in blood LCN2 preceded the detection of brain metastases by MRI. Furthermore, the mice in which LCN2 levels were very high developed brain metastases later, further establishing LCN2 as a predictive marker for brain metastases.”

The researchers also examined whether LCN2 is elevated in the blood of melanoma patients at the time of initial diagnosis, and whether it can be a prognostic factor. The findings indicated that patients with melanoma had significantly higher levels of LCN2 in their blood compared to samples from healthy individuals. Strikingly, patients who developed brain metastases displayed significantly higher levels of LCN2 even before the diagnosis of the metastases, and high levels of LCN2 in the blood correlated with worse survival.

“We have identified a new mechanism in which LCN2 mediates the communication between immune cells from the bone marrow and supporting cells in the brain, activates inflammatory mechanisms and thus helps the progression of metastatic disease in the brain, and demonstrated its importance. The functional and prognostic aspects of LCN2 that we have identified in brain metastases in mouse models as well as in cancer patients suggest that targeting LCN2 may be an effective therapeutic strategy to delay or prevent the recurrence of brain metastases,” summarizes Prof. Erez.

Researchers at Tel Aviv University identified a new genetic risk factor for the complex eye disease AMD (Age-related Macular Degeneration), a leading cause for loss of eyesight at an advanced age. For the first time, the researchers identified proteins that play a key role in the development and functioning of the tissue affected by the disease, found their exact sites in the genome, and discovered the connection between variations in these genomic regions and the risk for AMD. The researchers: “The new discovery enhances our understanding of the previously unknown function of genomic regions outside the genes. The method we applied may enable the deciphering of additional genetic mechanisms involved in various complex genetic diseases.”

“Comparative studies have identified whole genomic regions that are probably related to the disease but were unable to pinpoint any specific feature in these regions and define it as a risk factor. Our study addressed this problem.” Prof. Ran Elkon

Decoding Mechanisms of a Complex Disease

The study was led by Prof. Ruth Ashery-Padan and Prof. Ran Elkon and their research teams, Mazal Cohen Gulkar, Naama Mesika, Ahuvit David, and May Eshel, from the Department of Human Molecular Genetics and Biochemistry at the Sackler Faculty of Medicine and the Sagol School of Neuroscience at Tel Aviv University. The paper was published in PLOS Biology.

Prof. Ashery-Padan explains that “one of the greater challenges in genetic research today is decoding the genetic mechanisms of complex diseases caused by a combination of several different genetic and environmental factors (rather than an identifiable defect in a single gene). Diabetes, bowel diseases, and various mental illnesses are just a few examples. In our study we chose to focus on AMD, which causes degeneration of the central retina – a major cause of loss of vision at an advanced age in developed countries.”

Prof. Elkon adds: “AMD has a significant genetic component. Studies comparing the genomes of people with and without AMD (as well as a range of other complex genetic diseases) have found differences in several genomic regions, probably associated with risk factors for the disease. However, these differences were not detected in any specific gene, but rather in the extensive regions that stretch between the genes, whose functions and modes of operation are still largely unknown. In fact, comparative studies have identified whole genomic regions that are probably related to the disease but were unable to pinpoint any specific feature in these regions and define it as a risk factor. Our study addressed this problem.”

The study focused on the cells of a layer of tissue called retinal pigmented epithelium (RPE), which supports photoreceptors in the retina, and is essential for their initial development as well as their survival throughout an individual’s lifetime. According to the researchers, this tissue is affected right from the earliest stages of AMD.

Prof. Ruth Ashery-Padan

“Our findings provide new insight into a previously unsolved issue: the functions and mode of operation of genomic sequences located outside the genes, and how they are involved in complex genetic diseases.” Prof. Ruth Ashery-Padan

Novel Research Methodology

“First, we wanted to understand the genetic mechanism that activates and regulates the specific activity of pigmented epithelium cells,” says Prof. Ashery-Padan. “Through a series of experiments, knocking down different proteins in both a mouse model and human cells, we identified two key proteins, LHX2 and OTX2, which together dictate the expression of many genes unique to this tissue. The proteins act as transcriptional activators – binding to specific regulatory sites in the genome to determine which genes will be expressed in a particular cell.”

The next challenge was mapping the precise locations of the two proteins in the genome. The researchers used the innovative technology ChIP-seq – a DNA sequencing method that identifies binding sites where proteins bind to the DNA.

“We found that the binding sites of the two proteins were quite close to each other,” explains Prof. Elkon. “Moreover, these same sites had previously been identified as related to risk factors for AMD (namely, sequences that showed differences between people with and without AMD). We assume that due to changes in DNA sequences in these genomic regions, transcriptional proteins cannot easily find and bind with their binding sites. This reduces the expression of the nearby gene regulated by the transcriptional proteins, which encodes an ion channel known as important to eye function. The decrease in the gene’s activity affects the entire tissue, increasing the risk for development of AMD.”

Prof. Ashery-Padan sums up the study: “In our study we identified two proteins related to risk factors for the complex genetic eye disease AMD. In addition, for the first time, we were able to map the exact genomic sites of these proteins and found that they operate in a region previously identified as related to risk factors for AMD. Our findings provide new insight into a previously unsolved issue: the functions and mode of operation of genomic sequences located outside the genes, and how they are involved in complex genetic diseases. We believe that our novel research methodology will enable the identification and mapping of many other genetic mechanisms related to AMD and other complex genetic diseases.”

A new study examined the pain perception among people with autism and found that they experience pain at a higher intensity than the general population and are less adaptable to the sensation. This finding is contrary to the prevalent belief that people with autism are supposedly ‘indifferent to pain’. The researchers expressed the hope that the findings of their study will lead to more appropriate treatment on the part of medical staff, caregivers, and parents toward people with autism, who do not always express the experience of pain in the usual way.

The study was funded by the Israel Science Foundation and was led by four researchers: Dr. Tami Bar-Shalita of the Sackler Faculty of Medicine at Tel Aviv University who initiated the study, Dr. Yelena Granovsky of the Technion and Rambam Medical Center, and Prof. Irit Weissman-Fogel and Prof. Eynat Gal of the University of Haifa. This study constitutes a framework for the theses of PhD students Tzeela Hofmann and Mary Klingel-Levy, and three articles based on it have already been published or approved for publishing. The present study has been published in the prestigious PAIN journal.

“We know that self-harm could stem from attempts to suppress pain, and it could be that [people with autism] hurt themselves to activate, unconsciously, a physical mechanism of ‘pain inhibits pain’.” Dr. Tami Bar-Shalita

Self-harm Not Proof of Indifference to Pain

“Approximately 10% of the general population suffer from sensory modulation dysfunction, which means sensory hypersensitivity at a level that compromises normal daily functioning and quality of life. These people have difficulty, for example, ignoring or adapting to buzzing or flickering of fluorescent lights, humming of air conditioners or fans, or the crunching of popcorn by someone sitting next to them in the cinema,” explains Dr. Bar-Shalita.

“In previous studies in the lab we found that these people suffer from pain more than those without sensory modulation dysfunction. Since it is known that sensory modulation dysfunction occurs in   people with autism at a rate of 70-90%, it constitutes a criterion for diagnosing autism, and is associated with its severity. We were interested in exploring pain perception in autism, so we asked: do people with autism hurt more than the general population? This question was hardly studied in the lab before we got started.”

According to the researchers, for many years the prevalent opinion was that ‘people with autism hurt less’ or that they were ‘indifferent to pain’. Actually, ‘indifference to pain’ is one of the characteristics presented in the current diagnostic criteria of autism.

The proof of this was, supposedly, their tendency to inflict pain on themselves by self-harm. 

Dr. Bar-Shalita: “this assumption is not necessarily true. We know that self-harm could stem from attempts to suppress pain, and it could be that they hurt themselves to activate, unconsciously, a physical mechanism of ‘pain inhibits pain’.”

“The results of our study indicate that in most cases, the sensitivity to pain of people with autism is higher than that of most of the population, while at the same time they are unsuccessful at effectively suppressing painful stimuli.” Dr. Tami Bar-Shalita

Dr. Tami Bar-Shalita

Contributing to Advancement of Personalized Treatment

This study is a laboratory pain study approved by the ethics committee of the academic institutions and Rambam Medical Center. The study included 52 adults with high-functioning autism (HFA) and normal intelligence – hitherto the largest reported sample in the world in studies on pain among people with autism. The study made use of psychophysical tests to evaluate pain, commonly used in the area of pain study. These methods examine the link between stimulus and response, while the researcher, using a computer, controls the duration and intensity of stimulus and the examinee is asked to rank the intensity of the pain felt by him on a scale of 0 to 100.

The findings have proven beyond doubt that people with autism hurt more. Furthermore, their pain suppression mechanism is less effective.

The researchers conducted a variety of measurements, aimed among other things at examining whether the hypersensitivity to pain derives from a sensitized nervous system or from suppression of mechanisms that are supposed to enable adjustment and, over time, reduce the response to the stimulus. They found that in the case of people with autism, it is a combination of the two: an increase of the pain signal along with a less effective pain inhibition mechanism.

Dr. Bar-Shalita concludes: “our study constituted a comprehensive, in-depth study of the intensity of pain experienced by people with autism. The prevalent belief was that they are supposedly ‘indifferent to pain’, and there are reports that medical and other professional staff treated them accordingly. The results of our study indicate that in most cases, the sensitivity to pain of people with autism is higher than that of most of the population, while at the same time they are unsuccessful at effectively suppressing painful stimuli. We hope that our findings will benefit the professionals and practitioners handling this population and contribute to the advancement of personalized treatment.”

In additional articles soon to be published, the researchers have examined the brain activity of people with autism during pain stimuli, and sub-groups within this population concerning their perception of pain.

You see them stroll around in the hospitals’ toughest wards with their red noses, colorful clothes, and unwavering smiles, spreading laughter and cheerfulness wherever they go. They are the medical clowns: trained professionals whose goal is to change the hospital environment through humor. 

A new study tested and categorized the skills of medical clowns and found that their importance goes far beyond contributing to a patient’s good mood. The researchers identified 40 different skills of medical clowns, including establishing an emotional connection and creating a personal relationship with the patient, expressing the patient’s frustrations and difficulties to the medical staff, increasing the patient’s motivation to adhere to medical treatment, distracting the patient from pain, and creating a joyful atmosphere.

Medical clowns working alongside other therapists (Photo: The Dream Doctors Project, Medical Clowning in Action)

Not Just for Entertainment Purposes

The research was conducted under the leadership of Prof. Orit Karnieli-Miller, with Dr. Lior Rosenthal, both from the Department of Medical Education at TAU’s Sackler Faculty of Medicine, in collaboration with Ms. Orna Divon-Ophir, Dr. Doron Sagi, Prof. Amitai Ziv and Ms. Liat Pessach-Gelblum from the Israel Center for Medical Simulation (MSR). The study was published in Qualitative Health Research, a leading journal in the field of health.

The researchers show that not only do medical clowns help the patients and their family members, but also the medical team and the achievement of treatment goals.

Through use of different communication skills, clowns make it easier for the patient to cooperate with various treatments. The medical clowns work in a team with other therapists, know how to intervene and help whenever an argument or crisis should arise to advance treatment.

“From the moment they enter the room, the clowns form a bond with the patients, strengthen them, and give them power and status within the medical system.” Prof. Orit Karnieli-Miller. 

Decoding their “Secret Magic”

Studies conducted throughout the years have shown the clowns’ positive influence on the hospital environment through humor, as well as helping patients deal with pain. However, no studies have empirically mapped the skills they use and their therapeutic goals to help understand their “secret magic.” In addition, there was a lack of broad understanding of how clowns can help children, teenagers, and their parents in various challenging situations of distress and difficulty, as well as how they can help patients and medical teams achieve treatment goals. This lack of appreciation of the potential benefits of utilizing the services of medical clowns meant that patients and medical teams would occasionally be reluctant to cooperate with them.

As part of the new study, the researchers focused on qualitative, in-depth systematic identification of the skills of medical clowns through observation and analysis of their actions in challenging encounters with adolescents, parents, and medical staff.

Medical clowns help patients and medical teams achieve treatment goals (Photo: The Dream Doctors Project, Medical Clowning in Action)

The team analyzed videotaped sessions of medical clowns in various simulated situations and conducted in-depth interviews with expert medical clowns. The researchers identified 40 different skills used by the medical clowns to achieve four therapeutic goals:

1) building a relationship and connecting to the needs and desires of the patients

2) dealing with emotions and difficulties

3) increasing the patient’s motivation to adhere to the treatment plan

4) increasing the patient’s sense of control and providing encouragement to patients

The clowns examined in the study were trained and recruited by the “Dream Doctors Project”, a non-profit association that employs medical clowns as part of the paramedical system in Israeli hospitals, and trains them to work within multi-disciplinary teams. The Tel Aviv University researchers collaborated with the Israel Center for Medical Simulation (MSR), which created a simulation-based workshop focused on developing the skills of experienced medical clowns.

“From the moment they enter the room, the clowns form a bond with the patients, strengthen them, and give them power and status within the medical system,” explains Prof. Karnieli-Miller. “They do this through an initial connection to the patients’ voice, and even to the patients’ reluctance to implement therapeutic recommendations – an emotional connection that often results in the patient changing their position and cooperating with the medical staff.”

Providing the patient with an increased sense of control and courage to face their challenges (Photo: The Dream Doctors Project, Medical Clowning in Action)

According to Prof. Karnieli-Miller the medical system is hierarchical, and it is not always easy for patients to navigate. Therefore, one of the skills of medical clowns is to place themselves in the lowest position in the medical setting. By doing so, they empower the patients by giving them a sense of power and control, including the choice of whether to allow the clown to enter the room as well as to dictate the nature of the patient’s role vis-à-vis that of the clown. This provides the patient with an increased sense of control and courage to face their challenges.

The researchers emphasize that the clowns are very aware of the emotional difficulty associated with staying in a hospital and dealing with an illness. To help deal with these issues, the clowns sometimes distract the patient by using props, humor, and imagination. Other skills include allowing the patient to direct their frustrations towards them, away from medical staff or parents.

Depending on the situation the clowns may also use a comforting touch, soothing music, empathetic listening, or a reinforcing statement to provide an environment where the patient feels comfortable to express their feelings. A patient’s ability to gain legitimacy is important and is strengthened by the clowns.

Prof. Orit Karnieli-Miller

“Mapping the skills and goals of the medical clowns improves their understanding of their role and may help other health professionals appreciate their work methods and the benefits of incorporating these methods into their own practices when faced with similar challenges” Prof. Orit Karnieli-Miller.

Learning from Medical Clowns’ Methods

“Mapping the skills and goals of the medical clowns improves their understanding of their role and may help other health professionals appreciate their work methods and the benefits of incorporating these methods into their own practices when faced with similar challenges,” adds Prof. Karnieli-Miller.

“This research is important because it allows the clowns to enhance their training program and refine their diverse skills to achieve the various therapeutic goals appropriate for different patients, as well as helping health professionals collaborate with the medical clowns. If professionals in the healthcare field gain a clear understanding of how and when to cooperate with the medical clowns, they will be able to help patients overcome challenges, and at the same time they may be more tolerant of the clowns’ ‘disruption’ of the hospital care regimen. This appreciation of the clowns’ contribution will provide the clowns with the time and space to connect with patients and help and encourage patients to become more active participants in their treatment plan,” she concludes.