Article
Clinical Neurology
Gianluca D'Onofrio, Marie-Ange Delrue, Anne Lortie, Christopher Marquis, Pasquale Striano, Magdalena Jaworski, Gregor Andel, Sebastien Perreault
Summary: This study reports two patients with refractory epilepsy treated with the MEK1-2 inhibitor trametinib. Patient 1 showed a significant reduction in seizures after three months and marked clinical improvement after five months, remaining seizure-free for over six months. Patient 2 experienced an early benefit with no seizures for over three months, but seizures recurred after six months, with a rebound effect observed after trametinib discontinuation.
PEDIATRIC NEUROLOGY
(2023)
Review
Oncology
Christina Bergqvist, Pierre Wolkenstein
Summary: Early understanding of the Ras/Raf/MEK/ERK signaling pathway in cell proliferation regulation has led to the development of potent and selective MEK inhibitors, with successful applications in NF1 population. MEKi show potential as effective and well-tolerated medical treatments, with future focus on developing preclinical models and defining efficacy measurement endpoints for conducting clinical trials in non-NF1 RASopathies.
CURRENT OPINION IN ONCOLOGY
(2021)
Article
Pediatrics
George Papadopoulos, Anna Papadopoulou, Konstantina Kosma, Anastasios Papadimitriou, Vassiliki Papaevangelou, Christina Kanaka-Gantenbein, Evangelia Bountouvi, Sophia Kitsiou-Tzeli
Summary: Noonan syndrome (NS) is an autosomal dominant disorder with a mutation rate of 50% in the Greek population, mostly found in PTPN11 (32.5%), RIT1 (6%), and SOS1 (4.7%) genes. Patients with mutations have a 6.71-fold increased risk of pulmonary stenosis compared to those without mutations. PTPN11-positive patients exhibit more facial dysmorphisms while having lower neurological findings compared to patients with mutations in other genes.
EUROPEAN JOURNAL OF PEDIATRICS
(2022)
Editorial Material
Hematology
Heike L. Pahl
Summary: The identification of sentinel mutations in MPN patients, which significantly increase the risk of leukemic transformation, even when not present in leukemic cells, is a crucial advancement in understanding and managing the disease. These mutations act as early indicators of potential disease progression, similar to canaries in a coal mine.
Article
Genetics & Heredity
Alessandro Mussa, Diana Carli, Elisa Giorgio, Anna Maria Villar, Simona Cardaropoli, Caterina Carbonara, Maria Francesca Campagnoli, Paolo Galletto, Martina Palumbo, Simone Olivieri, Claudio Isella, Gregor Andelfinger, Marco Tartaglia, Giovanni Botta, Alfredo Brusco, Enzo Medico, Giovanni Battista Ferrero
Summary: This article reports a patient with severe Noonan syndrome and progressive hypertrophic cardiomyopathy treated with Trametinib, a MEK-inhibitor. The study used global RNA sequencing to study the transcriptional effects of MEK-inhibition. The findings suggest a connection between pulmonary vascular disease and the severe outcome in patients with RAF1-related Noonan syndrome, and that MEK-inhibition may not be sufficient to treat pulmonary hypertension.
Article
Cell Biology
William E. Tidyman, Alice F. Goodwin, Yoshiko Maeda, Ophir D. Klein, Katherine A. Rauen
Summary: Costello syndrome (CS) is a congenital disorder caused by mutations in the Ras/MAPK pathway, leading to hypotonia as a prominent feature. A mouse model with activating Hras(G12V) allele revealed that hypotonia in CS is primarily due to inhibition of muscle development and myofiber formation, resulting in reduced muscle mass and strength.
DISEASE MODELS & MECHANISMS
(2022)
Article
Cardiac & Cardiovascular Systems
Kimberley G. Miles, Dora Kormendine Farkas, Kristina Laugesen, Henrik Toft Sorensen, Nadine A. Kasparian, Nicolas Madsen
Summary: The incidence of mental health conditions among children with congenital heart disease (CHD) is higher than the general population, particularly among males and those with severe or single-ventricle CHD. Early intervention and mental health support may be especially important for these at-risk populations.
Article
Multidisciplinary Sciences
Shiliang Liu, Hughes Claude, Shin Jie Yong, Dunjin Chen
Summary: The rate of gastroschisis in infants conceived in winter and northern areas of residence is higher than in infants conceived in summer and southern areas. Various risk factors including winter exposure, northern area residence, hypothyroidism, substance or tobacco use, and depressive disorder were identified for gastroschisis. Maternal depression was found to be mediated by hypothyroidism and showed associations with other factors such as substance use, hypothyroidism, tobacco smoking and gestational diabetes. These findings suggest that periconceptional depression with mediation by hypothyroidism may play a causal role in offspring gastroschisis.
SCIENTIFIC REPORTS
(2023)
Review
Cell Biology
Lisa Repsold, Anna Margaretha Joubert
Summary: Platelets play a crucial role in homeostasis, thrombosis, inflammation, cancer progression, and metastasis by releasing pro-inflammatory factors to regulate immune function and inflammatory processes. Despite our understanding of platelets in these processes, the complete interrelation and extent of these processes are still not fully understood.
Article
Oncology
Mattia Garutti, Melissa Bergnach, Jerry Polesel, Lorenza Palmero, Maria Antonietta Pizzichetta, Fabio Puglisi
Summary: To date, the combination of BRAF and MEK inhibitors is commonly used for the treatment of mutated BRAF metastatic melanoma. However, there is no evidence to support the superiority of one combination over others, and safety data is limited. In this meta-analysis, we evaluated the adverse events associated with each treatment combination to provide clinicians with information for tailored patient treatment.
Article
Oncology
Diana Carli, Simona Cardaropoli, Daniele Tessaris, Paola Coppo, Roberta La Selva, Claudia Cesario, Francesca Romana Lepri, Verdiana Pullano, Martina Palumbo, Ugo Ramenghi, Alfredo Brusco, Enzo Medico, Luisa De Sanctis, Giovanni Battista Ferrero, Alessandro Mussa
Summary: Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a disease caused by somatic mosaic NRAS variants. It is characterized by melanocytic/sebaceous naevi, eye and brain malformations, and FGF23-mediated hypophosphatemic rickets. The MEK inhibitor Trametinib can effectively treat CSHS, resulting in recovery of rickets and partial regression of the phenotype.
GENES CHROMOSOMES & CANCER
(2022)
Review
Chemistry, Medicinal
Michael Stephan Bader, Sara Christina Meyer
Summary: The discovery of the activating V617F mutation in JAK2 has greatly contributed to our understanding of myeloproliferative neoplasms (MPN). JAK2 inhibitors have become a standard treatment option for certain forms of MPN and offer significant benefits for patients. However, there are still challenges to be addressed in the targeted therapy of MPN with JAK2 inhibitors, such as reducing the MPN clone and overcoming drug resistance.
Review
Biochemistry & Molecular Biology
Elina A. Beleva
Summary: Splanchnic vein thrombosis (SVT) is a relatively rare condition where thrombosis occurs in the vessels of the splanchnic basin. SVT in myelofibrosis may have a high thrombotic risk and may be more dependent on procoagulant mechanisms involving the endothelium. Better thrombotic risk stratification is needed to identify patients who may benefit from antithrombotic prophylaxis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Immunology
Daniele Cattaneo, Alessandra Iurlo
Summary: BCR-ABL1-negative myeloproliferative neoplasms have a reduced life expectancy mainly due to an increased risk of thrombo-hemorrhagic events, fibrotic progression/leukemic evolution, and infectious complications. JAK2V617F is the main driver mutation in these conditions, and JAK inhibitors, while improving symptoms and quality of life for MPN patients, may also lead to adverse events related to immune suppression or deficiency.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Pharmacology & Pharmacy
Alberto Picca, Cristina Birzu, Giulia Berzero, Paola Sanchez-Pena, Louise Gaboriau, Faustine Vidil, Timothee Lenglet, Camille Tafani, Damien Ricard, Dimitri Psimaras, Kevin Bihan
Summary: This study aimed to characterize peripheral neuropathies in patients treated with BRAF/MEK inhibitors. Two main phenotypes were observed: a length-dependent, axonal polyneuropathy and a demyelinating polyradiculoneuropathy. Prompt treatment showed variable outcomes.
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
(2022)
Article
Gastroenterology & Hepatology
Marta Alonso-Nocelo, Laura Ruiz-Canas, Patricia Sancho, Kivanc Gorgulu, Sonia Alcala, Coral Pedrero, Mireia Vallespinos, Juan Carlos Lopez-Gil, Marina Ochando, Elena Garcia-Garcia, Sara Maria David Trabulo, Paola Martinelli, Patricia Sanchez-Tomero, Carmen Sanchez-Palomo, Patricia Gonzalez-Santamaria, Lourdes Yuste, Sonja Maria Wormann, Derya Kabacaoglu, Julie Earl, Alberto Martin, Fernando Salvador, Sandra Valle, Laura Martin-Hijano, Alfredo Carrato, Mert Erkan, Laura Garcia-Bermejo, Patrick C. Hermann, Hana Algul, Gema Moreno-Bueno, Christopher Heeschen, Francisco Portillo, Amparo Cano, Bruno Sainz
Summary: LOXL2 plays an important role in pancreatic ductal adenocarcinoma (PDAC), with its loss inhibiting metastasis and prolonging overall survival, while overexpression promotes tumor growth and decreases overall survival. Macrophage-secreted OSM is an inducer of LOXL2 expression, with targeting macrophages affecting its expression and collagen fiber alignment.
Article
Biotechnology & Applied Microbiology
Katarina Pance, Josef A. Gramespacher, James R. Byrnes, Fernando Salangsang, Juan-Antonio C. Serrano, Adam D. Cotton, Veronica Steri, James A. Wells
Summary: KineTACs are modular bispecific antibodies that can degrade extracellular and cell-surface proteins. They provide a genetically encoded strategy for lysosomal delivery of target proteins, with broad or tissue-specific distribution. KineTACs offer a versatile and simple approach to modulate extracellular biology.
NATURE BIOTECHNOLOGY
(2023)
Article
Medicine, Research & Experimental
Beatriz Parejo-Alonso, Alba Royo-Garcia, Pilar Espiau-Romera, Sarah Courtois, Alvaro Curiel-Garcia, Sladjana Zagorac, Isabel Villaoslada, Kenneth P. Olive, Christopher Heeschen, Patricia Sancho
Summary: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by metastasis and chemoresistance. Targeting the ALK signaling pathway can decrease tumor formation and chemoresistance in PDAC by inhibiting pancreatic cancer stem cells.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Article
Biochemistry & Molecular Biology
Laura Clavain, Isabel Fernandez-Pisonero, Nieves Movilla, L. Francisco Lorenzo-Martin, Blanca Nieto, Antonio Abad, Rosula Garcia-Navas, Clara Llorente-Gonzalez, Manuel Sanchez-Martin, Miguel Vicente-Manzanares, Eugenio Santos, Balbino Alarcon, Jose M. Garcia-Aznar, Mercedes Dosil, Xose R. Bustelo
Summary: A study found that RRAS2 mutations discovered in human cancers have high transforming ability in cell lines, affecting adhesion, invasiveness, proliferation, and mitochondrial respiration of ovarian and breast cancer cells. These mutations also regulate gene expression programs related to cell adhesion and inflammatory/immune-related responses, and play a role in the in vivo tumorigenic activity of these cells.
Article
Oncology
Maren Stark, Marina Nicolai, Marina Tatura, Corinna U. Keber, Andreas Kaufmann, Ho-Ryun Chung, Emily P. Slater, Christopher Heeschen, Rita T. Lawlor, Aldo Scarpa, Detlef K. Bartsch, Thomas M. Gress, Stefan Bauer, Malte Buchholz
Summary: TLR7 is overexpressed in PDAC and is associated with shorter patient survival. Inhibition of TLR7 reduces cell viability in PDAC cell lines. However, global TLR7 deficiency does not affect survival or overall histopathological tumor features in PDAC mouse models.
Article
Oncology
Alejandro Hortal, Marta Lacuna, Claudia Cifuentes, Miguel Alcoceba, Xose R. Bustelo, Marcos Gonzalez, Balbino Alarcon
Summary: Overexpression of unmutated RRAS2 may contribute to the development of CLL. A SNP in the 3' untranslated region of RRAS2 mRNA is linked to higher RRAS2 overexpression and worse prognosis. A new PCR method is implemented to characterize the allele composition at the SNP position, which can be useful for predicting prognosis and response to therapy in CLL.
Review
Biochemistry & Molecular Biology
Yaru Zhao, Jiajia Tang, Ke Jiang, Shin-Yi Liu, Alexandra Aicher, Christopher Heeschen
Summary: Pancreatic cancer is a deadly disease with increasing incidence and late-stage presentation, resulting in low survival rates. The lack of specific symptoms, biomarkers, and screening tools hinders early diagnosis. Liquid biopsies have emerged as a non-invasive and repeatable method for sampling and analyzing circulating tumor cells, small extracellular vesicles, and tumor DNA. Although liquid biopsies have the potential to aid in early detection, risk stratification, and precision medicine in pancreatic cancer, they have not yet become a routine tool for clinicians. This article summarizes recent findings on the use of liquid biopsy in pancreatic cancer patients, discussing current challenges and future perspectives on this potentially powerful alternative to conventional tissue biopsies.
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER
(2023)
Review
Oncology
Qi Wang, Berina Sabanovic, Azhar Awada, Chiara Reina, Alexandra Aicher, Jiajia Tang, Christopher Heeschen
Summary: Pancreatic cancer is a deadly disease with limited treatment options due to late diagnosis. Liquid biopsies, particularly circulating tumor cells (CTCs) and their single-cell omics analysis, have the potential to detect pancreatic cancer early and provide valuable molecular insights. CTCs offer comprehensive genomic, transcriptomic, epigenetic, and proteomic information that can help understand tumor heterogeneity and track cancer features. The emerging technology of ex vivo culturing of CTCs could enable the study of individual cancers and the development of personalized treatment approaches.
EUROPEAN JOURNAL OF CANCER
(2023)
Article
Multidisciplinary Sciences
Ana Martin-Vega, Laura Ruiz-Peinado, Rocio Garcia-Gomez, Ana Herrero, Dalia de la Fuente-Vivas, Swetha Parvathaneni, Ruben Caloto, Marta Morante, Alex von Kriegsheim, Xose R. Bustelo, David B. Sacks, Berta Casar, Piero Crespo
Summary: RAS-ERK pathway signals are regulated by scaffold proteins, and it is revealed that scaffold proteins can interact with each other and undergo phosphorylation reactions. The trans-phosphorylation process participates in KSR1-regulated adipogenesis and the cytotoxicity exhibited by KSR-directed inhibitors. This finding has implications in signaling and the design of scaffold protein-aimed therapeutics.
Article
Biochemistry & Molecular Biology
Diego Romero-Miguel, Marta Casquero-Veiga, Javier Fernandez, Nicolas Lamanna-Rama, Vanessa Gomez-Rangel, Carlos Galvez-Robleno, Cristina Santa-Marta, Claudio J. Villar, Felipe Lombo, Raquel Abalo, Manuel Desco, Maria Luisa Soto-Montenegro
Summary: N-acetylcysteine (NAC) administration during pregnancy can prevent inflammation-induced brain changes and improve memory deficits in offspring. This suggests a potential role of NAC in modulating the microbiota-gut-brain axis.
Article
Microbiology
J. J. Aguilera-Correa, B. Salinas, M. Gonzalez-Arjona, D. de Pablo, P. Munoz, E. Bouza, M. J. Fernandez Acenero, J. Esteban, M. Desco, L. Cusso
Summary: This study compared structural and molecular imaging techniques to assess disease progression in a mouse model of osteomyelitis. The results showed that FDG-PET imaging was more sensitive than MRI and CT in differentiating between infection and inflammation at early stages.
MICROBIOLOGY SPECTRUM
(2023)
Article
Radiology, Nuclear Medicine & Medical Imaging
F. Arias-Valcayo, P. Galve, Joaquin L. Herraiz, J. J. Vaquero, M. Desco, J. M. Udias
Summary: In this study, a spatially-variant resolution model was incorporated into a real time iterative reconstruction code for accurate imaging of multi-animal PET studies. The spatially variant point spread function (SV-PSF) was estimated using measurements and Monte Carlo simulations, and implemented in a GPU-based reconstruction code. The method showed uniform spatial resolution and superior image quality compared to the uniform PSF model.
BIOMEDICAL PHYSICS & ENGINEERING EXPRESS
(2023)
Article
Oncology
Kamal Mandal, Gianina Wicaksono, Clinton Yu, Jarrett J. Adams, Michael R. Hoopmann, William C. Temple, Adila Izgutdina, Bonell Patino Escobar, Maryna Gorelik, Christian H. Ihling, Matthew A. Nix, Akul Naik, William H. Xie, Juwita Hubner, Lisa A. Rollins, Sandy M. Reid, Emilio Ramos, Corynn Kasap, Veronica Steri, Juan Antonio Camara Serrano, Fernando Salangsang, Paul Phojanakong, Melanie McMillan, Victor Gavallos, Andrew D. Leavitt, Aaron C. Logan, Cliona M. Rooney, Justin Eyquem, Andrea Sinz, Benjamin J. Huang, Elliot Stieglitz, Catherine C. Smith, Robert L. Moritz, Sachdev S. Sidhu, Lan Huang, Arun P. Wiita
Summary: This study explores a new strategy called structural surfaceomics for identifying and targeting cancer-specific surface protein conformations on tumor cells. The researchers successfully applied this technology to acute myeloid leukemia (AML) and identified an AML-specific target. They developed antibodies to this protein conformation and demonstrated that chimeric antigen receptor T cells can eliminate AML cells without toxicity to normal cells.
Article
Cell Biology
Marta Lacuna, Alejandro M. Hortal, Claudia Cifuentes, Tania Gonzalo, Miguel Alcoceba, Miguel Bastos, Xose R. Bustelo, Marcos Gonzalez, Balbino Alarcon
Summary: Chronic lymphocytic leukemia (CLL) is a heterogeneous hematologic malignancy. Overexpression of the RRAS2 gene and somatic mutations in its 3' untranslated region (3'UTR) are associated with CLL progression. These findings provide potential targets for therapeutic strategies and risk stratification in CLL patients.
Article
Chemistry, Multidisciplinary
Fernando Arias-Valcayo, Pablo Galve, Jose Manuel Udias, Juan Jose Vaquero, Manuel Desco, Joaquin L. Herraiz
Summary: This study investigates the optimal conditions and motion compensation methods for preclinical PET studies using awake rats with attached point sources. Monte Carlo simulations and experimental validations are performed to determine the parameters for maximum detectability without compromising image quality.
APPLIED SCIENCES-BASEL
(2023)