Photomontage of sentinel lymph node structure (red) and associated lymphangiogenesis (green) in response to circulating exosomes (gray). / Microenvironment and Metastasis Group of the CNIO.
Melanoma is the most aggressive skin cancer. According to the Spanish Society of Medical Oncology (SEOM), more than 7,000 new cases of skin melanoma are diagnosed in Spain each year. The incidence increases.
Its main risk factor is sun exposure. Ultraviolet (UV) light damages the DNA of exposed cells, generating mutations that can turn the cells into tumors.
Therefore, skin cancer is a type of tumor in which prevention is especially effective. It is important to avoid prolonged exposure to the sun and use creams with high protection. You must also be alert for new moles, and for changes in existing ones (size, color, shape, bleeding). Early diagnosis multiplies the chances of cure.
The Melanoma Group of the National Cancer Research Center (CNIO), led by Marisol Soengas, discovered a few years ago some ‘anti-defense’ proteins of the cells of this skin cancer, and are now exploring strategies to block them.Meanwhile, the Microenvironment and Metastasis Group, led by Héctor Peinado, is working on what could become one of the first treatments against its spread in its initial stages.
See metastases before they occur
To cure it, we must understand the origin and evolution of this tumor, and its ability to metastasize, that is, invade other organs. The Soengas team has managed to visualize how melanoma begins and progresses from very early stages.
One of the experimental models they have developed is the “MetAlert” system, to visualize how melanoma cells prepare dissemination routes before metastases occur. This makes it possible to identify new genes and new therapies that “turn the tumor on or off,” explains Soengas.
“With MetAlert we identified a new prometastatic protein, MIDKINE, which also has immunosuppressive effects,” he points out. “We are now developing MIDKINE inhibitors through several collaborations at the CNIO: with the Monoclonal Antibodies Unit, led by Giovanna Roncador, and the Experimental Therapies Program, directed by Joaquín Pastor.”
This research group is also interested in other proteins that degenerate the body’s defenses and, instead of attacking the tumor, promote its development.
Analysis of NGFR expression (purple) in metastatic melanoma tumor cells in the lymph node (brown). / Microenvironment and Metastasis Group of the CNIO.
Prevent the metastasis from nesting
For its part, the team led by Peinado has discovered what could become one of the first treatments against melanoma metastasis in its initial stages.
The researchers discovered a molecule that prepares the ‘nest’ in the organ in which the melanoma will reproduce, and they verified that, by blocking it, metastasis is reduced in animal models. In addition, they have found a non-toxic compound that prevents the action of this molecule, called NGFR.
Now they are preparing “a publication that presents the results of its use in combination with immunotherapy to treat melanoma,” says Peinado.
Source: CNIO and agencia Sinc
Rights: Creative Commons.
Nuevas estrategias contra el melanoma, un cáncer en el que prevenir es clave (agenciasinc.es)
]]>Scientists at the Spanish National Cancer Research Center (CNIO), in collaboration with Korean researchers, have proposed a new type of cancer predisposition genes (CPGs). The probability of developing a tumor is higher in those who inherit certain altered variants of one of these genes.
“But those 100 genes only explain about 10% of cancer cases. The vast majority of the rest may be related to mutations we don’t know about,” explains Solip Park, head of the Computational Genomics Group. Finding these other altered variants helps early detection and the development of treatments to counteract their effect.
To discover them, the experts decided to narrow the search to a group with an easily identifiable genetic profile: people carrying genes that, when altered, give rise to a hereditary disease. These are monogenic diseases, i.e. caused by the alteration of a single gene, such as muscular dystrophy or Gaucher disease.
Park, together with collaborators from several institutions in Seoul, South Korea, has discovered 103 genes in which single-gene disease-causing alterations often coexist with other cancer-predisposing alterations.
Published in the journal Genome Medicine, the study verifies that people with inherited single-gene disease mutations in these 103 genes also had a greater number of mutations implicated in cancer than the control group (healthy people).
Some of these mutations are associated with specific types of cancer, such as renal cell carcinoma, B-cell non-Hodgkin’s lymphoma, breast adenocarcinoma and medulloblastoma; others with cancer susceptibility in general. “These 103 genes whose mutations can cause Mendelian diseases may also behave as cancer predisposition genes,” Park points out.
Solip Park. / Laura M. Lombardía. CNIO
Mechanisms against cancer predisposition
The authors also analyze how defective variants of these genes promote tumor progression and cause other diseases, and point to various mechanisms of action, such as distortions in cell metabolism or immune response. Some of these are pathways that have not been considered so far in cancer, which is why they highlight the need to study them in greater depth.
They have also analyzed the PAH gene – known because some of its mutations cause the rare hereditary disease phenylketonuria, which hinders the assimilation of proteins and aspartame – in greater detail. Selected because it had the largest number of variants likely to give rise to several types of cancer, they have discovered their relationship with the PAH gene.
Reference:
Song, S., Koh, Y., Kim, S. et al. “Systematic analysis of Mendelian disease-associated gene variants reveals new classes of cancer-predisposing genes”. Genome Med (2023).
Source:SINC
]]>Nuclear staining of triple negative breast cancer cells. / Laura Pascual Reguant / Center for Genomic Regulation.
Experiments with mice reveal a potential new treatment that could transform triple-negative breast cancer into a controllable disease. Researchers from the Center for Genomic Regulation and Vall d’Hebron point out that there is still work to be done before reaching patients, but that each advance in understanding the mechanisms of this disease constitutes good news.
Researchers from the Center for Genomic Regulation and the Vall d’Hebron Institute of Oncology have shown that the simultaneous inhibition of two different proteins may represent a new strategy to confront triple negative breast cancer, the most aggressive and resistant form of breast cancer. to drugs. The findings are published today in the journal EMBO Molecular Medicine.
Breast cancer is the most diagnosed type of cancer and the fourth most common cause of cancer-related death in women, with more than two million cases worldwide and 685,000 deaths in 2020.
About one in seven (15%) of these cases are a highly aggressive form of the disease known as triple-negative breast cancer. The prognosis of this type of tumor is poor, because the disease is highly resistant to existing treatments, since its cells lack the receptors targeted by breast cancer drugs.
Recently, the LOXL2 enzyme has been shown to promote the growth of triple-negative breast cancer. A team led by Sara Sdelci, from the Center for Genomic Regulation, and Sandra Peiró, together with the Non-Colorectal Gastrointestinal Cancer Translational Research Group of the Vall d’Hebron Oncology Institute, has carried out several analyzes to evaluate the suitability of the enzyme as a biomarker to predict the success of treatments.
They found that LOXL2 expression alone predicts the outcomes of drugs that target BRD4, a cancer-promoting protein. Prompted by their findings, the researchers conducted further experiments to evaluate whether the LOXL2 and BRD4 proteins might be collaborating to help triple-negative breast cancer cells proliferate.
Several experiments demonstrated that LOXL2 interacts with a version of BRD4 within the cell nucleus. The researchers also demonstrated that this interaction changes the expression of certain genes that help the proliferation of triple-negative breast cancer cells. Inhibiting both proteins at the same time disrupted these interactions and helped slow cancer growth in cell cultures (in vitro) and in three different mouse models (in vivo).
“We have delved deeper at the molecular level to understand how triple-negative breast cancer cells grow and have discovered a new mechanism that can be exploited for therapeutic purposes. It’s exciting, because a dual-targeting strategy targeting both proteins could be combined with other treatments and transform triple negative breast cancer, from being a disease with an unfavorable prognosis to a controllable one,” says Laura Pascual Reguant, first author of the study and postdoctoral researcher at the Center for Genomic Regulation, in Barcelona.
The findings have important implications for an experimental class of drugs known as BET inhibitors, which have shown promising results in the fight against triple-negative breast cancer. BET inhibitors act by compromising the function of BRD4, but have not reached the clinic because triple-negative breast cancer cells acquire resistance to the treatment. The authors of the study believe that the simultaneous modulation of BRD4 and LOXL2 could help overcome this resistance.
The next challenge will be to find a way to safely and effectively target both proteins at the same time. One possible strategy is to combine different inhibitors. BET inhibitors are already targeting different versions of BRD4 in 30 clinical trials, five of which target triple-negative breast cancer. LOXL2 inhibitors also exist, but their safety and effectiveness in cancer treatment have not been explored. The combination of both inhibitors has not been tested.
“More work needs to be done before our findings benefit patients, but any progress in understanding the mechanisms of this highly aggressive disease is good news. As we continue to unravel the mechanisms that explain how triple-negative breast cancer proliferates , the health challenges that arise could be more manageable than we thought,” concludes Sdelci.
Reference: Sdelci, S. et al. “Interactions between BRD4S, LOXL2, and MED1 drive cell cycle transcription in triple-negative breast cancer.” EMBO Molecular Medicine (2023)
Source: CRG
]]>La enfermedad de Alzheimer es la forma más común de demencia y posiblemente representa del 60 % al 70 % de los casos de demencia neurodegenerativa.
La enfermedad de Alzheimer es un trastorno cerebral progresivo que produce disfunción neuronal y cognitiva y afecta a un alto porcentaje de personas en todo el mundo. Por esta razón resulta fundamental diagnosticarla en la etapa más temprana posible, lo que implica mejorar los sistemas de diagnóstico.
Con este trasfondo, investigadores de la Universidad Politécnica de Madrid, en el Centro de Tecnología Biomédica (CTB), y del Instituto de Investigación Sanitaria del Hospital Clínico San Carlos han llevado a cabo un estudio en el que han desarrollado un nuevo sistema y procedimiento de biodetección para medir específicamente la proteína Tau total (T-Tau) −uno de los biomarcadores más relevantes de la enfermedad de Alzheimer− en suero sanguíneo. Además, han creado un sistema de bajo coste basado en kits de diagnóstico para llevar a cabo este proceso.
La enfermedad de Alzheimer es la forma más común de demencia y posiblemente representa del 60 % al 70 % de los casos de demencia neurodegenerativa. Este trastorno, progresivo, irreversible y dependiente de la edad, posee un curso insidioso que dificulta su diagnóstico ya que los síntomas aparecen en etapas muy avanzadas de la enfermedad.
La Organización Mundial de la Salud declaró la demencia como una condición prioritaria a través del Programa de Acción para Superar las Brechas en Salud Mental debido a que tiene un impacto significativo en la calidad de vida y la independencia de las personas. Actualmente, se estima que unos 36 millones de personas en el mundo padecen esta enfermedad y, de hecho, se calcula que su incidencia se triplicará en 2050 debido, entre otras razones, al aumento de la esperanza de vida y al crecimiento de la población.
Detección precoz sin tratamientos invasivos
Uno de los métodos utilizados en la actualidad para diagnosticar la enfermedad de Alzheimer consiste en estudiar el aumento de la proteína Tau total (T-Tau) en el líquido cefalorraquídeo. Sin embargo, el líquido cefalorraquídeo es una muestra biológica invasiva, compleja, costosa y dolorosa de obtener, por lo que no permite una detección ni un seguimiento fácil de la enfermedad en los pacientes.
Diversos estudios realizados hasta el momento indican que los biomarcadores de la enfermedad de Alzheimer también se pueden encontrar en suero. Sin embargo, como señala el investigador principal del grupo de investigación de Óptica, Fotónica y Biofotónica del CTB Miguel Holgado, “el problema al que nos enfrentamos al trabajar con estas muestras es la baja concentración de las proteínas marcadoras, lo cuál hace que sean difíciles de detectar y que solo se encuentre al alcance de técnicas con un coste muy elevado”.
Para poner solución a este problema, la investigadora Ana María Martín Murillo junto con el equipo de investigadores de la UPM y del IDISSC ha desarrollado un sistema de bajo coste basado en kits de diagnóstico capaces de detectar estos niveles tan bajos establecidos en la literatura científica para su detección en suero.
El trabajo se ha llevado a cabo gracias al uso de nanopartículas específicas frente a la proteína de interés. Como resultado, “hemos conseguido por primera vez una alternativa diagnóstica relevante para detectar la proteína Tau a concentraciones exigentes”, indica Miguel Holgado.
“Esto abre la puerta a conseguir límites de detección menores que los que hemos logrado en este estudio para diagnosticar la enfermedad antes de que aparezcan los síntomas, hacerlo para otros biomarcadores relevantes de manera conjunta e incluso poder descubrir otros nuevos marcadores”, concluye el investigador.
Referencia: Miguel Holgado et al. “A New Optical Interferometric Biosensing System Enhanced with Nanoparticles for Alzheimer´s Disease in Serum”. Biosensors.
Fuente: Universidad Politécnica de Madrid y agencia Sinc
]]>Image of a skin cancer where the expression of the glucose transporter (Glut1) is seen in green, the protein pyruvate kinase 2 (PKM2) is seen in red, and DNA is seen in blue. / IBV-CIPF
A study led by the Joint Research Unit of the Valencia Biomedicine Institute (IBV-CSIC), the Higher Council for Scientific Research (CSIC) and the Príncipe Felipe Research Center (CIPF), discovers a mechanism by which cells evade chemotherapyy, not only do they survive it, but they become more aggressive.
Key to the process is protein synthesis that allows cells to adapt to the stress caused by chemotherapy. By better understanding the mechanism and characteristics of the cells that survive, we could intervene in the process by combining existing drugs, improving the effectiveness of the treatments. The work is published in the journal Signal Transduction and Targeted Therapy.
It is essential to deepen our knowledge of the mechanisms of resistance to antitumor therapies in order to improve the effectiveness of treatments. The group led by Francisco José Iborra in the Joint Research Unit of the IBV-CSIC and the CIPF studies these mechanisms of resistance to oncological therapies using cell lines derived from human tumors, which they undergo treatment and where they study the changes that have occurred in the resistant cells.
Thus, “in this study we have found that a mechanism that cells use to evade chemotherapy is a consequence of the stress response induced by chemotherapy,” explains Iborra. This response triggers protein degradation, which causes the concentration of its basic components (amino acids) to increase within the cell, inducing, in turn, protein synthesis.
As a final result, the cell reduces its size and increases protein turnover. “This last point is very important, since a high protein turnover is necessary for cellular plasticity, since cells must respond by changing their phenotype,” says the researcher.
Increase the effectiveness of chemotherapy
This study represents an important step, since it opens the possibility of designing more targeted and effective combined therapies for the treatment of cancer and, therefore, improving current treatments, increasing survival and the quality of life of patients. “We will be able to design therapies with protein synthesis inhibitors, or proteasome or autophagy inhibitors, which will increase the effectiveness of chemotherapy,” maintains the CSIC researcher.
“In our laboratory we have studied this possibility and we have observed that these combinations exert a positive synergistic effect, which suggests that this strategy could be useful in the treatment of tumors resistant to chemotherapy,” highlights the scientist. “But before moving to the clinical field, we must test these combinations in animal models,” he emphasizes.
This research has been carried out in the CIPF laboratories in Valencia, using tumor cell lines in culture of various types of tumors and computational modeling. The research has been developed with the collaboration of the National Center for Biotechnology (CNB-CSIC), the Hospital del Vinalopó (Elche) and the University of Helsinki (Finland).
Reference:
Francisco J. Iborra, et al. “Chemotherapy induces cell plasticity; “controlling plasticity increases therapeutic response.” Signal Transduction and Targeted Therapy(2023)
]]>The Clínic is the first hospital in Catalonia to opt for the robotization of the Pathological Anatomy laboratory with the installation of two AS-410M automatic cutting machines
The results obtained during the first 15,000 blocks of tissue have meant a reduction in diagnosis time of 30% and increased the maximum work capacity of the Service by 120%, allowing more patients to be treated more quickly.
Barcelona, October 31, 2023. The Pathological Anatomy laboratory at Clínic Barcelona has incorporated two AS-410M robots from Casa Álvarez to automate one of the most delicate processes in the diagnosis of biopsies, microtomy. This has allowed samples to be optimized for study and improved diagnosis time.
The Clínic thus becomes the second center in Spain to opt for the automation of this technique, with the consequent improvement in care through the optimization of processes and the reduction of time. Currently there are only 40 devices of this type in Europe and 4 of them are in Spain, two in Barcelona and two in Granada. With this addition, this service of the Biomedical Diagnostic Center (CDB) is completely automated and digitalized.
Today the new facility was presented in an event that included the participation of Dr. Josep M. Campistol, general director of the Clínic; Dr. Antoni Castells, medical director; Dr. Áurea Mira, director of the CBD; Dr. Antonio Martínez, head of the Pathological Anatomy Service; Guillermo Palanca, general director of Casa Álvarez.
Optimize tissue obtained from a biopsy
Microtomy is the technique by which thin sections of tissues included in paraffin blocks are obtained. In this way they can be studied later by microscopy for the diagnosis of different diseases. “We analyze biopsies of all types, whether for the diagnosis of oncological diseases, for transplants, the detection of infections or autoimmune diseases,” says Dr. Aurea Mira. “In many centers this technique is still manual and is done with water baths,” she adds.
The two microtomy robots perform histological sections automatically and with great precision. The cut is transferred to a slide where it is deposited and stretched and then stored in a drying chamber where it can be collected. They have the capacity to work autonomously during the night and process up to 1,000 paraffin blocks per day.
This technology allows increasing the amount of tissue available for study obtained from the biopsy to perform other tests and for research activity. On the other hand, samples with a small amount of tissue can be managed and quality and safety improves thanks to automatic identification.
A 30% reduction in sample processing time
The automation of laboratories guarantees the standardization of laboratory processes, increases the productivity of professionals and contributes to reducing diagnosis times, a
key factor for patient health. These types of devices allow a greater number of samples to be analyzed daily with more uniform and higher quality results, while avoiding routine work by technical personnel, which in many cases are repetitive physical tasks.
Since the launch of the two teams three months ago, the Pathological Anatomy Service team has determined the consistency in the depth of the cuts and the direct reduction of sample handling and processing times close to 30% compared to performing this task manually. In addition to standardization, robots expand current work capacity by up to 120%, allowing more patients to be treated in less time.
“The incorporation of this world-leading technology into our laboratory will allow us to continue offering our patients efficient care of the highest quality, which demonstrates once again our commitment to innovation as a reference hospital,” highlighted Antonio Martínez.
“We are delighted to be able to collaborate with the Clínic in the automation and robotization of its laboratory, a vital process that will allow the hospital and the professionals who work to adapt to new technological developments, incorporating new techniques and equipment, with the aim of increasing the precision and agility in the diagnosis,” says Guillermo Palanca, general director of Casa Álvarez.
]]>Scientists have tested a therapy to attack tumors with great precision using microwaves.
This therapy, which attacks tumors by intensifying radiofrequency electromagnetic fields, has achieved good results, both in simulations and in laboratory tests. The treatment would make it possible to forcefully attack tumors without affecting surrounding healthy tissues.
The work was carried out by a team of researchers headed by engineer Victor Toranzos, professor of Electromagnetism in the Electrical Engineering Career of the Faculty of Exact and Natural Sciences and Surveying of the National University of the Northeast (UNNE) in Argentina.
The treatment tested by the Toranzos team is based on hyperthermia, that is, it uses the temperature rise to eliminate a tumor or cancerous tissue. The drawback of thermal methods of this type is that their spatial accuracy leaves much to be desired. This makes it difficult to attack tumors in a very focused way without affecting surrounding healthy tissues.
Toranzos and his colleagues used microwaves to generate this hyperthermia.
Microwaves are widely used in industry, home, and medicine to produce heat. However, the distribution of heat absorption and, therefore, the temperature rise in a given volume of tissue depend on the dielectric characteristics of the materials and compounds with which they interact, as pointed out by Toranzos.
The team of researchers proposed a solution to address this problem. It consists of determining the optimal conditions with physiological aptitudes to achieve a localized microwave interaction in the surroundings of a silicon prism inserted in a medium electrically equivalent to the tissue. “The hypothesis is that this would make it possible to design a technique similar to brachytherapy but without ionizing radiation, heating mostly diseased tissue without damaging healthy tissue.”
Brachytherapy is a type of radiotherapy used to treat cancer cases. Capsules or small particles that act as a source of radiation are placed near the tumor, making it an extremely precise treatment.
During the experiment, the interaction of a linearly polarized microwave beam on a p-type doped crystalline silicon prism inserted in water was analyzed.
To test the initial hypothesis, two different paths were followed. On the one hand, the computational simulation of a system composed of a dielectric with properties similar to those of a living tissue and a doped silicon prism in which the absorption of microwave power at 2.5 GHz is studied. On the other hand, An experiment was prepared consisting of a tank with an electrolyte composed of salt water, emulating living tissue, and a silicon prism within the liquid. The time evolution of the temperature in the tank was measured, with and without the silicon prism, when the tank and its contents were exposed to microwaves generated by a magnetron of a domestic microwave oven adapted for the experiment.
Toranzos and his colleagues managed to verify temperature variations in the dielectric response in different directions depending on the aspect ratio of the prism that defines the silicon-water compound. An adequate range of frequencies for the test beam was used, according to the depth of the tissue to be treated, to overcome the limitations in the penetration distance of the proposals with metallic nanoparticles.
The simulations showed that the absorbed power can be located on a filling fraction much smaller than that occupied by the prism and in the immediate vicinity of its edges on the faces with the smallest surface.
Both in the simulation and in the experimental results, an increase from 20% to 130% in the absorbed power was observed when the flat surface of the silicon prism varies from orthogonal to parallel orientation with respect to the polarization direction of the incident beam.
These results make it possible to ensure, at least under laboratory conditions, that the temperature in the vicinity of the silicon prism is higher than the rest of the tissues exposed to microwaves. This difference can be crucial when it comes to attacking only a tumor but with the premise of not damaging healthy tissue and, therefore, improving the patient’s recovery.
(Source: Juan Monzón Gramajo / National University of the Northeast / Argentina Investiga) y Amazings® / NCYT® | (Noticiasdelaciencia.com / Amazings.com). Atacar tumores con microondas | Noticias de la Ciencia y la Tecnología (Amazings® / NCYT®)
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