Article
Pediatrics
Qiyu Li, Siyuan Liu, Xuemei Ma, Jiaping Yu
Summary: This meta-analysis evaluated the effectiveness and safety of small molecule therapy in children diagnosed with cystic fibrosis (CF). The results showed that CFTR modulators can improve respiratory function, lung clearance index, sweat chloride concentration, and other aspects of function in children with CF, with comparable adverse events compared to the placebo group.
FRONTIERS IN PEDIATRICS
(2022)
Review
Pharmacology & Pharmacy
Juliana Roda, Catarina Pinto-Silva, Iris A. I. Silva, Carla Maia, Susana Almeida, Ricardo Ferreira, Guiomar Oliveira
Summary: Cystic fibrosis is a chronic disease caused by mutations in the CFTR gene, affecting over 90,000 people worldwide. New drugs targeting the molecular defect of CFTR have the potential to provide personalized treatments for patients with cystic fibrosis.
THERAPEUTIC ADVANCES IN CHRONIC DISEASE
(2022)
Article
Chemistry, Medicinal
Marc J. C. Scanio, Xenia B. Searle, Bo Liu, John R. Koenig, Robert J. Altenbach, Gregory A. Gfesser, Andrew Bogdan, Stephen Greszler, Gang Zhao, Ashvani Singh, Yihong Fan, Andrew M. Swensen, Timothy Vortherms, Arlene Manelli, Corina Balut, Wenqing Gao, Hong Yong, Michael Schrimpf, Chris Tse, Philip Kym, Xueqing Wang
Summary: Cystic fibrosis (CF) is a disease caused by mutations in both copies of the CFTR gene, with the most common mutation being the deletion of phenylalanine at position 508 of the CFTR protein. The most effective treatment for CF currently involves using a combination of CFTR correctors and potentiators. This study focuses on the identification and exploration of the structure-activity relationship of C2 correctors for CFTR, to be used in conjunction with existing C1 correctors.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Review
Pharmacology & Pharmacy
Yizi Wang, Bin Ma, Wenya Li, Peiwen Li
Summary: Triple combination therapy for cystic fibrosis patients achieves better clinical results and comparable adverse events compared to the control group.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Medicine, General & Internal
Lotte Vanherle, Darcy Lidington, Franziska E. Uhl, Saskia Steiner, Stefania Vassallo, Cecilia Skoug, Joao M. N. Duarte, Sangeetha Ramu, Lena Uller, Jean-Francois Desjardins, Kim A. Connelly, Steffen-Sebastian Bolz, Anja Meissner
Summary: Our study investigated the mechanisms that alter hippocampal neurons following myocardial infarction (MI) and explored the therapeutic potential of correcting cystic fibrosis transmembrane regulator (CFTR) as an intervention. We found that MI leads to reduced hippocampal dendrite length and spine density, which is associated with decreased neuronal CFTR expression and inflammatory responses. Blocking CFTR activity down-regulates synaptic regulator PSD-95 expression in neurons, while pharmacologically correcting CFTR expression rescues the down-regulation. Increasing hippocampal neuron CFTR expression improves MI-associated alterations in neuronal structure and memory function. These findings suggest that CFTR therapeutics can attenuate cognitive impairment in heart failure patients.
Article
Pharmacology & Pharmacy
Matthew D. Strub, Shyam Ramachandran, Dmitri Y. Boudko, Ella A. Meleshkevitch, Alejandro A. Pezzulo, Aravind Subramanian, Arthur Liberzon, Robert J. Bridges, Paul B. McCray
Summary: Cystic fibrosis is a lethal genetic disease caused by mutations in the CFTR gene, leading to misfolded proteins and degradation. Several strategies have been developed to partially correct CFTR function in vitro, but translating these interventions into therapies remains a challenge.
CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Laura Carrasco-Hernandez, Esther Quintana-Gallego, Carmen Calero, Rocio Reinoso-Arija, Borja Ruiz-Duque, Jose Luis Lopez-Campos
Summary: The role of CFTR in the pathophysiology of COPD is becoming increasingly important, with its dysfunction leading to thicker and more viscous secretions in the airway, reduced mucociliary clearance, and promotion of airway inflammation. Studying CFTR in the context of COPD pathogenesis is crucial for a comprehensive understanding of COPD's complex pathophysiology and exploring potential therapeutic approaches to address this dysfunction.
Article
Multidisciplinary Sciences
Sara Bitam, Ahmad Elbahnsi, Geordie Creste, Iwona Pranke, Benoit Chevalier, Farouk Berhal, Brice Hoffmann, Nathalie Servel, Danielle Tondelier, Aurelie Hatton, Christelle Moquereau, Melanie Faria Da Cunha, Alexandra Pastor, Agathe Lepissier, Alexandre Hinzpeter, Jean-Paul Mornon, Guillaume Prestat, Aleksander Edelman, Isabelle Callebaut, Christine Gravier-Pelletier, Isabelle Sermet-Gaudelus
Summary: The compound C407 and its derivatives correct the F508del-CFTR protein by stabilizing specific positions on the protein molecule. An analog of C407, G1, significantly improves CFTR activity by interacting more effectively with ICL4. These findings suggest new strategies for optimizing the ICL4-NBD1 interface.
SCIENTIFIC REPORTS
(2021)
Article
Biochemistry & Molecular Biology
Karol Fiedorczuk, Jue Chen
Summary: Small molecule chaperones have been widely used as therapeutics for diseases caused by protein misfolding. CFTR correctors are the most successful examples, as they can revert folding defects and are used to treat cystic fibrosis. Cryo-electron microscopy structures reveal that these correctors stabilize TMD1 of CFTR, preventing premature degradation and rescuing disease-causing mutations.
Article
Chemistry, Medicinal
Darren Le Grand, Martin Gosling, Urs Baettig, Parmjit Bahra, Kamlesh Bala, Cara Brocklehurst, Emma Budd, Rebecca Butler, Atwood K. Cheung, Hedaythul Choudhury, Stephen P. Collingwood, Brian Cox, Henry Danahay, Lee Edwards, Brian Everatt, Ulrike Glaenzel, Anne-Lise Glotin, Paul Groot-Kormelink, Edward Hall, Julia Hatto, Catherine Howsham, Glyn Hughes, Anna King, Julia Koehler, Swarupa Kulkarni, Megan Lightfoot, Ian Nicholls, Christopher Page, Giles Pergl-Wilson, Mariana Oana Popa, Richard Robinson, David Rowlands, Tom Sharp, Matthew Spendiff, Emily Stanley, Oliver Steward, Roger J. Taylor, Pamela Tranter, Trixie Wagner, Hazel Watson, Gareth Williams, Penny Wright, Alice Young, David A. Sandham
Summary: Mutations in the CFTR ion channel are linked to cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). A potential drug, icenticaftor (QBW251), has shown positive clinical results for CF and COPD patients. This study provides insights into the pathogenesis of these lung diseases and offers a novel therapeutic approach for COPD patients.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Medicine, Research & Experimental
Michael D. Kim, Charles D. Bengtson, Makoto Yoshida, Asef J. Niloy, John S. Dennis, Nathalie Baumlin, Matthias Salathe
Summary: Highly effective modulator therapies greatly improve prognosis for cystic fibrosis patients. However, not all patients with the most common F508del mutation in CFTR benefit from ETI therapy. The study found that elevated levels of active TGF-??1 in the upper airway were associated with poor response to ETI, as evidenced by low sweat chloride concentrations and lack of lung function improvements. TGF-??1 impaired the function of corrected F508del-CFTR and led to increased absorption rates of airway surface liquid and mucus hyperconcentration in vitro. Losartan reversed the negative effects of TGF-??1 and improved ASL hydration in CF airway epithelium.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
Article
Reproductive Biology
Leo Han, Mackenzie Roberts, Addie Luo, Shuhao Wei, Ov D. Slayden, Kelvin D. Macdonald
Summary: This study demonstrates the hormonal regulation of cystic fibrosis transmembrane conductance regulator (CFTR) expression in endocervical cells, both in vitro and in vivo. The researchers also showed that endocervical epithelial cells can be conditionally reprogrammed to study CFTR ion channel function. Furthermore, the study found that estrogen upregulates CFTR expression in the macaque cervix, which is blocked by cotreatment with progesterone.
BIOLOGY OF REPRODUCTION
(2022)
Article
Biochemistry & Molecular Biology
Philip R. Tedbury, Candela Manfredi, Frauke Degenhardt, Joseph Conway, Michael C. Horwath, Courtney McCracken, Adam J. Sorscher, Sandy Moreau, Christine Wright, Carolina Edwards, Jo Brewer, Jeannette Guarner, Emmie de Wit, Brandi N. Williamson, Mehul S. Suthar, Yee T. Ong, John D. Roback, David N. Alter, Jan C. Holter, Tom H. Karlsen, Nicoletta Sacchi, Manuel Romero-Gomez, Pietro Invernizzi, Javier Fernandez, Maria Buti, Agustin Albillos, Antonio Julia, Luca Valenti, Rosanna Asselta, Jesus M. Banales, Luis Bujanda, Rafael de Cid, Andre Franke, Stefan G. Sarafianos, Jeong S. Hong, Eric J. Sorscher, Annette Ehrhardt
Summary: Patients with cystic fibrosis (CF) are not highly susceptible to severe COVID-19 despite initial concerns. CFTR carrier status does not affect the severity of COVID-19 clinical outcomes. However, mortality rates are higher in control individuals compared to silent carriers of the common F508del CFTR variant, which requires further investigation. The acidic, viscous, and mucus-obstructed airways in CF patients are unfavorable for coronavirus infection.
Article
Biochemistry & Molecular Biology
Philip R. Tedbury, Candela Manfredi, Frauke Degenhardt, Joseph Conway, Michael C. Horwath, Courtney McCracken, Adam J. Sorscher, Sandy Moreau, Christine Wright, Carolina Edwards, Jo Brewer, Jeannette Guarner, Emmie de Wit, Brandi N. Williamson, Mehul S. Suthar, Yee T. Ong, John D. Roback, David N. Alter, Jan C. Holter, Tom H. Karlsen, Nicoletta Sacchi, Manuel Romero-Gomez, Pietro Invernizzi, Javier Fernandez, Maria Buti, Agustin Albillos, Antonio Julia, Luca Valenti, Rosanna Asselta, Jesus M. Banales, Luis Bujanda, Rafael de Cid, Andre Franke, Stefan G. Sarafianos, Jeong S. Hong, Eric J. Sorscher, Annette Ehrhardt
Summary: Patients with cystic fibrosis (CF) do not have a higher risk of severe COVID-19 due to CFTR carrier status, but control individuals have a higher mortality rate compared to silent carriers. The absence of functional CFTR does not affect the production of SARS-CoV-2 in airway cells, while in vitro experiments suggest that virus proliferation is dependent on features disrupted by absent CFTR in patients with CF. The acidic, viscous, and mucus-obstructed airways in CF patients are unfavorable for coronaviral infection establishment.
Article
Multidisciplinary Sciences
Melanie Faria da Cunha, Iwona Pranke, Ali Sassi, Christiane Schreiweis, Stephanie Moriceau, Dragana Vidovic, Aurelie Hatton, Mariane Sylvia Carlon, Geordie Creste, Farouk Berhal, Guillaume Prestat, Romain Freund, Norbert Odolczyk, Jean Philippe Jais, Christine Gravier-Pelletier, Piotr Zielenkiewicz, Vincent Jullien, Alexandre Hinzpeter, Franck Oury, Aleksander Edelman, Isabelle Sermet-Gaudelus
Summary: This study provides the first in vivo preclinical evidence of the efficacy of c407 in treating Cystic Fibrosis, correcting CFTR dysfunction and improving chloride conductance. Importantly, c407 was well tolerated and demonstrated no obvious toxicity after systemic administration.
SCIENTIFIC REPORTS
(2022)
Article
Gastroenterology & Hepatology
Paula Olaizola, Pui Yuen Lee-Law, Maite G. Fernandez-Barrena, Laura Alvarez, Massimiliano Cadamuro, Mikel Azkargorta, Colm J. O'Rourke, Francisco J. Caballero-Camino, Irene Olaizola, Rocio I. R. Macias, Jose J. G. Marin, Marina Serrano-Macia, Maria L. Martinez-Chantar, Matias A. Avila, Patricia Aspichueta, Diego F. Calvisi, Matthias Evert, Luca Fabris, Rui E. Castro, Felix Elortza, Jesper B. Andersen, Luis Bujanda, Pedro M. Rodrigues, Maria J. Perugorria, Jesus M. Banales
Summary: The study found that NEDDylation plays a crucial role in the development and progression of cholangiocarcinoma, inhibition of NEDDylation can suppress CCA cell proliferation and prevent tumor formation, showing potential therapeutic effects in inhibiting CCA cell growth and stroma interaction.
JOURNAL OF HEPATOLOGY
(2022)
Article
Gastroenterology & Hepatology
James J. Harding, Danny N. Khalil, Luca Fabris, Ghassan K. Abou-Alfa
Summary: Biliary tract cancers are rare gastrointestinal malignancies associated with high morbidity and mortality rates. Various treatments, including chemotherapy, precision medicine, and immunotherapy, are used in both standard-of-care and investigational settings. Recent research has shown that the combination of durvalumab with gemcitabine and cisplatin improves survival outcomes. Precision medicine is utilized in patients with specific genetic alterations, while fluoropyridine doublets are used in patients without targetable genetic alterations. Next-generation sequencing is crucial for patient care and understanding resistance mechanisms. Ongoing clinical trials seek to improve treatment standards and develop effective combination drug therapies for the future.
JOURNAL OF HEPATOLOGY
(2023)
Article
Gastroenterology & Hepatology
Massimiliano Cadamuro, Ahmad Al-Taee, Tamas A. Gonda
Summary: Cholangiocarcinoma is a deadly malignancy that is often diagnosed late due to its intrinsic characteristics and the growth pattern of cancer cells. However, early and accurate diagnosis, as well as identification of targetable changes, can potentially improve survival. Primary sclerosing cholangitis, a precursor to a minority of cholangiocarcinomas, poses particular diagnostic challenges. This article presents a comprehensive diagnostic and theranostic approach to extrahepatic cholangiocarcinoma, incorporating advanced imaging, endoscopic methods, multiple tissue sampling approaches, and molecular markers. An algorithm for sequential tool usage is also provided.
JOURNAL OF HEPATOLOGY
(2023)
Review
Cell Biology
Alessandro Gambella, Silvia Kalantari, Massimiliano Cadamuro, Marco Quaglia, Maurizio Delvecchio, Luca Fabris, Michele Pinon
Summary: The hepatocyte nuclear factor 1 beta (HNF1B) gene plays a crucial role in the development of specialized epithelia in various organs during embryogenesis. Pathogenic variants of HNF1B have been associated with a complex syndrome that mainly affects children, leading to diabetes and renal complications. However, recent studies have highlighted the importance of liver involvement, including a potential link to tumor development, expanding the understanding of HNF1B-associated disease. This review aims to provide a comprehensive analysis of the genetic, phenotypic, and clinical features of HNF1B deficiency in both pediatric and adult populations.
Article
Biochemistry & Molecular Biology
Massimiliano Cadamuro, Samantha Sarcognato, Riccardo Camerotto, Noemi Girardi, Alberto Lasagni, Giacomo Zanus, Umberto Cillo, Enrico Gringeri, Giovanni Morana, Mario Strazzabosco, Elena Campello, Paolo Simioni, Maria Guido, Luca Fabris
Summary: Metabolic syndrome (MetS) is associated with the development of intrahepatic cholangiocarcinoma (iCCA), a liver tumor. MetS iCCAs have increased deposition of osteopontin (OPN), tenascin C (TnC), and periostin (POSTN) in the extracellular matrix (ECM), which stimulates cell motility and cancer-stem-cell-like phenotype. OPN overexpression may serve as a predictive biomarker and therapeutic target for MetS iCCA.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Gastroenterology & Hepatology
Diego Calvisi, Luke Boulter, Javier Vaquero, Anna Saborowski, Luca M. Fabris, Pedro Rodrigues, Cedric E. Coulouarn, Rui Castro, Oreste Segatto, Chiara Raggi, Luc J. W. van der Laan, Guido Carpino, Benjamin Goeppert, Stephanie J. Roessler, Timothy Kendall, Matthias Evert, Ester W. Gonzalez-Sanchez, Juan Valle, Arndt Vogel, John J. Bridgewater, Mitesh J. Borad, Gregory R. Gores, Lewis Roberts, Jose J. G. B. Marin, Jesper Andersen, Domenico Alvaro, Alejandro M. Forner, Jesus Banales, Vincenzo Cardinale, Rocio I. R. Macias, Silve Vicent, Xin Chen, Chiara Braconi, Monique M. A. Verstegen, Laura Fouassier, Lewis Roberts, Alexander Scheiter, Florin M. Selaru, Katja Evert, Kirsten Utpatel, Laura Broutier, Massimiliano Cadamuro, Meritxell Huch, Robert Goldin, Sergio A. Gradilone, Yoshimasa Saito
Summary: In this Consensus Statement, experts provide recommendations on the criteria for preclinical models of cholangiocarcinoma (CCA) to increase disease understanding and develop novel therapeutic approaches.
NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY
(2023)
Article
Gastroenterology & Hepatology
Romina Fiorotto, Valeria Mariotti, Shakila Afroz Taleb, Syeda A. Zehra, Mytien Nguyen, Mariangela Amenduni, Mario Strazzabosco
Summary: In this study, researchers successfully altered the polarity of biliary organoids by culturing them in a matrix, thus creating a new organoid culture model. This model can be used to study bile transport, interactions with pathogens, epithelial permeability, cross talk with liver and immune cell types, and the effect of matrix changes on the biliary epithelium, providing important insights into the pathobiology of cholangiopathies.
HEPATOLOGY COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Paolo Rainone, Silvia Valtorta, Chiara Villa, Sergio Todde, Massimiliano Cadamuro, Gloria Bertoli, Donatella Conconi, Marialuisa Lavitrano, Rosa Maria Moresco
Summary: Breast cancer is the most common cancer in women and the second leading cause of death. Breast cancer cells show a metabolic shift towards increased glycolysis, making it an interesting target for metabolic drugs such as metformin. Recent studies have found that the antihypertensive drug syrosingopine, when combined with metformin, has a synergistic effect on various cancers. However, there is a need to develop in vivo biomarkers that can detect early clinical response.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Neurosciences
Elisa Conti, Denise Grana, Federica Angiulli, Aristotelis Karantzoulis, Chiara Villa, Romina Combi, Ildebrando Appollonio, Carlo Ferrarese, Lucio Tremolizzo
Summary: Neuroinflammation is a key mechanism in Alzheimer's disease, and this study found that oligomeric Aβ(1-42) can directly induce chemotaxis of peripheral monocytes. Interestingly, monocytes from Alzheimer's patients showed a stronger response compared to controls. TSPO was identified as a potential regulator of this process. These findings are important for future therapeutic interventions targeting monocyte motility in the central nervous system.
JOURNAL OF ALZHEIMERS DISEASE
(2023)
Article
Gastroenterology & Hepatology
Laura G. Di Pasqua, Marta Cagna, Giuseppina Palladini, Anna C. Croce, Massimiliano Cadamuro, Luca Fabris, Stefano Perlini, Luciano Adorini, Andrea Ferrigno, Mariapia Vairetti
Summary: The effects of two FXR agonists, OCA and INT-787, on hepatic levels of various proteins in a NASH model were compared. The results showed that INT-787 is superior to OCA in controlling specific cell types and clinically relevant anti-inflammatory and antifibrotic molecular mechanisms in NASH.
LIVER INTERNATIONAL
(2023)
Review
Oncology
Massimiliano Cadamuro, Luca Fabris, Xuchen Zhang, Mario Strazzabosco
Summary: Cholangiocarcinoma is an aggressive tumor with a complex tumor microenvironment, making it highly resistant to traditional chemotherapeutic drugs. The tumor microenvironment plays a crucial role in immune escape and potential therapeutic interventions.
Review
Obstetrics & Gynecology
Luisa Patane, Massimiliano Cadamuro, Gabriella Massazza, Serena Pirola, Valentina Stagnati, Chiara Comerio, Marco Carnelli, Marco Arosio, Anna Paola Callegaro, Paola Tebaldi, Elena Rigoli, Andrea Gianatti, Denise Morotti
Summary: This study described a case of second-trimester twin stillbirth in a pregnant woman with SARS-CoV-2 infection. Despite the absence of respiratory symptoms, placental and fetal markers of infection indicated the possibility of vertical transmission. Fetal autopsy also showed the development of pneumonia. These findings suggest that asymptomatic pregnant women can transmit the virus vertically and lead to severe illness.
AMERICAN JOURNAL OF OBSTETRICS & GYNECOLOGY MFM
(2022)