MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 15, 2024 Category: Biomedical Science Authors: Yao Zhan, Jun Guo, William Yang, Christophe Goncalves, Tomasz Rzymski, Agnieszka Dreas, Eliza Żyłkiewicz, Maciej Mikulski, Krzysztof Brzózka, Aniela Golas, Yan Kong, Meng Ma, Fan Huang, Bonnie Huor, Qianyu Guo, Sabrina Daniela da Silva, Jose Torres, Yu Source Type: research
Endothelial HIF-2α regulates murine pathological angiogenesis and revascularization processes
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 15, 2024 Category: Biomedical Science Authors: Nicolas Skuli, Amar J. Majmundar, Bryan L. Krock, Rickson C. Mesquita, Lijoy K. Mathew, Zachary L. Quinn, Anja Runge, Liping Liu, Meeri N. Kim, Jiaming Liang, Steven Schenkel, Arjun G. Yodh, Brian Keith, M. Celeste Simon Source Type: research
Infantile hemangioma: the common and enigmatic vascular tumor
Infantile hemangioma (IH) is a benign vascular tumor that occurs in 5% of newborns. The tumor follows a life cycle of rapid proliferation in infancy, followed by slow involution in childhood. This unique life cycle has attracted the interest of basic and clinical scientists alike as a paradigm for vasculogenesis, angiogenesis, and vascular regression. Unanswered questions persist about the genetic and molecular drivers of the proliferating and involuting phases. The beta blocker propranolol usually accelerates regression of problematic IHs, yet its mechanism of action on vascular proliferation and differentiation is unclea...
Source: Journal of Clinical Investigation - April 15, 2024 Category: Biomedical Science Authors: Annegret Holm, John B. Mulliken, Joyce Bischoff Source Type: research
Reduced incretin effect precedes diabetes development following duodenopancreatectomy in individuals without diabetes
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 15, 2024 Category: Biomedical Science Authors: Gianfranco Di Giuseppe, Laura Soldovieri, Gea Ciccarelli, Pietro Manuel Ferraro, Giuseppe Quero, Francesca Cinti, Umberto Capece, Simona Moffa, Enrico Celestino Nista, Antonio Gasbarrini, Andrea Mari, Sergio Alfieri, Vincenzo Tondolo, Alfredo Pontecorvi, Source Type: research
A murine model of hnRNPH2-related neurodevelopmental disorder reveals a mechanism for genetic compensation by Hnrnph1
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 15, 2024 Category: Biomedical Science Authors: Ane Korff, Xiaojing Yang, Kevin O’Donovan, Abner Gonzalez, Brett J.W. Teubner, Haruko Nakamura, James Messing, Fen Yang, Alexandre F. Carisey, Yong-Dong Wang, Tushar Patni, Heather Sheppard, Stanislav S. Zakharenko, Yuh Min Chook, J. Paul Taylor, Hong J Source Type: research
68Ga-FAPI PET imaging monitors response to combined TGF-βR inhibition and immunotherapy in metastatic colorectal cancer
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 15, 2024 Category: Biomedical Science Authors: Ke Li, Wei Liu, Hang Yu, Jiwei Chen, Wenxuan Tang, Jianpeng Wang, Ming Qi, Yuyun Sun, Xiaoping Xu, Ji Zhang, Xinxiang Li, Weijian Guo, Xiaoling Li, Shaoli Song, Shuang Tang Source Type: research
Polyomavirus-positive Merkel cell carcinoma: the beginning of the beginning
Merkel cell carcinoma (MCC) is an aggressive, fast-growing, highly metastatic neuroendocrine skin cancer. The Merkel cell polyomavirus (MCPyV) is an oncogenic driver in the majority of MCC tumors. In this issue of the JCI, Hansen and authors report on their tracking of CD8+ T cells reactive to MCPyV T antigen (T-Ag) in the peripheral blood of 26 patients with MCC who were undergoing frontline anti–programmed cell death protein-1 (anti–PD-1) immunotherapy. They discovered unique T cell epitopes and used the power of bar-coded tetramers to portray immune checkpoint inhibitor–induced immunogenicity as a predictor of cli...
Source: Journal of Clinical Investigation - April 15, 2024 Category: Biomedical Science Authors: Michael K. Wong, Cassian Yee Source Type: research
Complement C3 and marginal zone B cells promote IgG-mediated enhancement of RBC alloimmunization in mice
Administration of anti-RhD immunoglobulin (Ig) to decrease maternal alloimmunization (antibody-mediated immune suppression [AMIS]) was a landmark clinical development. However, IgG has potent immune-stimulatory effects in other settings (antibody-mediated immune enhancement [AMIE]). The dominant thinking has been that IgG causes AMIS for antigens on RBCs but AMIE for soluble antigens. However, we have recently reported that IgG against RBC antigens can cause either AMIS or AMIE as a function of an IgG subclass. Recent advances in mechanistic understanding have demonstrated that RBC alloimmunization requires the IFN-α/-β ...
Source: Journal of Clinical Investigation - April 15, 2024 Category: Biomedical Science Authors: Arijita Jash, Thomas Pridmore, James B. Collins, Ariel M. Hay, Krystalyn E. Hudson, Chance John Luckey, James C. Zimring Source Type: research
Protein aggregates containing wild-type and mutant NOTCH3 are major drivers of arterial pathology in CADASIL
Loss of arterial smooth muscle cells (SMCs) and abnormal accumulation of the extracellular domain of the NOTCH3 receptor (Notch3ECD) are the 2 core features of CADASIL, a common cerebral small vessel disease caused by highly stereotyped dominant mutations in NOTCH3. Yet the relationship between NOTCH3 receptor activity, Notch3ECD accumulation, and arterial SMC loss has remained elusive, hampering the development of disease-modifying therapies. Using dedicated histopathological and multiscale imaging modalities, we could detect and quantify previously undetectable CADASIL-driven arterial SMC loss in the CNS of mice expressi...
Source: Journal of Clinical Investigation - April 15, 2024 Category: Biomedical Science Authors: Nicolas Dupré, Florian Gueniot, Valérie Domenga-Denier, Virginie Dubosclard, Christelle Nilles, David Hill-Eubanks, Christelle Morgenthaler-Roth, Mark T. Nelson, Céline Keime, Lydia Danglot, Anne Joutel Source Type: research
T antigen–specific CD8+ T cells associate with PD-1 blockade response in virus-positive Merkel cell carcinoma
Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer primarily induced by Merkel cell polyomavirus, which is driven by the expression of the oncogenic T antigens (T-Ags). Blockade of the programmed cell death protein-1 (PD-1) pathway has shown remarkable response rates, but evidence for therapy-associated T-Ag–specific immune response and therapeutic strategies for the nonresponding fraction are both limited. We tracked T-Ag–reactive CD8+ T cells in peripheral blood of 26 MCC patients under anti-PD1 therapy, using DNA-barcoded pMHC multimers, displaying all peptides from the predicted HLA ligandome of the on...
Source: Journal of Clinical Investigation - April 15, 2024 Category: Biomedical Science Authors: Ulla Kring Hansen, Candice D. Church, Ana Micaela Carnaz Simões, Marcus Svensson Frej, Amalie Kai Bentzen, Siri A. Tvingsholm, Jürgen C. Becker, Steven P. Fling, Nirasha Ramchurren, Suzanne L. Topalian, Paul T. Nghiem, Sine Reker Hadrup Source Type: research
Ectopic expression of the transcription factor ONECUT3 drives a complex karyotype in myelodysplastic syndromes
This study revealed that ONECUT3 promoted chromosomal instability by transcriptional activation of INCENP and CDCA8, suggesting potential prognostic and therapeutic roles for targeting high-risk MDS patients with a CK. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 15, 2024 Category: Biomedical Science Authors: Yingwan Luo, Xiaomin Feng, Wei Lang, Weihong Xu, Wei Wang, Chen Mei, Li Ye, Shuanghong Zhu, Lu Wang, Xinping Zhou, Huimin Zeng, Liya Ma, Yanling Ren, Jie Jin, Rongzhen Xu, Gang Huang, Hongyan Tong Source Type: research
A BMP-controlled metabolic/epigenetic signaling cascade directs midfacial morphogenesis
Craniofacial anomalies, especially midline facial defects, are among the most common birth defects in patients and are associated with increased mortality or require lifelong treatment. During mammalian embryogenesis, specific instructions arising at genetic, signaling, and metabolic levels are important for stem cell behaviors and fate determination, but how these functionally relevant mechanisms are coordinated to regulate craniofacial morphogenesis remain unknown. Here, we report that bone morphogenetic protein (BMP) signaling in cranial neural crest cells (CNCCs) is critical for glycolytic lactate production and subseq...
Source: Journal of Clinical Investigation - April 15, 2024 Category: Biomedical Science Authors: Jingwen Yang, Lingxin Zhu, Haichun Pan, Hiroki Ueharu, Masako Toda, Qian Yang, Shawn A. Hallett, Lorin E. Olson, Yuji Mishina Source Type: research
Neutralizing IFN-γ autoantibodies are rare and pathogenic in HLA-DRB1*15:02 or 16:02 individuals
CONCLUSION These findings suggest that nAIGAs are isolated and that their penetrance in HLA-DRB1*15:02 or 16:02 individuals is low, implying that they may be triggered by rare germline or somatic variants. In contrast, the risk of mycobacterial disease in patients with nAIGAs is high, confirming that these nAIGAs are the cause of EM disease.FUNDING The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI095983 and U19AIN1625568), the National Center for Advancing Translati...
Source: Journal of Clinical Investigation - April 15, 2024 Category: Biomedical Science Authors: Jessica N. Peel, Rui Yang, Tom Le Voyer, Adrian Gervais, Jérémie Rosain, Paul Bastard, Anish Behere, Axel Cederholm, Aaron Bodansky, Yoann Seeleuthner, Clément Conil, Jing-Ya Ding, Wei-Te Lei, Lucy Bizien, Camille Soudee, Mélanie Migaud, Masato Ogishi Source Type: research
Hyperactive STAT5 hijacks T cell receptor signaling and drives immature T cell acute lymphoblastic leukemia
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T cell cancer. Mutations in IL7R have been analyzed genetically, but downstream effector functions such as STAT5A and STAT5B hyperactivation are poorly understood. Here, we studied the most frequent and clinically challenging STAT5BN642H driver in T cell development and immature T cell cancer onset and compared it with STAT5A hyperactive variants in transgenic mice. Enhanced STAT5 activity caused disrupted T cell development and promoted an early T cell progenitor–ALL phenotype, with upregulation of genes involved in T cell receptor (TCR) signaling, ev...
Source: Journal of Clinical Investigation - April 15, 2024 Category: Biomedical Science Authors: Tobias Suske, Helena Sorger, Gabriele Manhart, Frank Ruge, Nicole Prutsch, Mark W. Zimmerman, Thomas Eder, Diaaeldin I. Abdallah, Barbara Maurer, Christina Wagner, Susann Schönefeldt, Katrin Spirk, Alexander Pichler, Tea Pemovska, Carmen Schweicker, Dani Source Type: research
VHL loss reprograms the immune landscape to promote an inflammatory myeloid microenvironment in renal tumorigenesis
Clear cell renal cell carcinoma (ccRCC) is characterized by dysregulated hypoxia signaling and a tumor microenvironment (TME) highly enriched in myeloid and lymphoid cells. Loss of the von Hippel Lindau (VHL) gene is a critical early event in ccRCC pathogenesis and promotes stabilization of HIF. Whether VHL loss in cancer cells affects immune cells in the TME remains unclear. Using Vhl WT and Vhl-KO in vivo murine kidney cancer Renca models, we found that Vhl-KO tumors were more infiltrated by immune cells. Tumor-associated macrophages (TAMs) from Vhl-deficient tumors demonstrated enhanced in vivo glucose consumption, phag...
Source: Journal of Clinical Investigation - April 15, 2024 Category: Biomedical Science Authors: Melissa M. Wolf, Matthew Z. Madden, Emily N. Arner, Jackie E. Bader, Xiang Ye, Logan Vlach, Megan L. Tigue, Madelyn D. Landis, Patrick B. Jonker, Zaid Hatem, KayLee K. Steiner, Dakim K. Gaines, Bradley I. Reinfeld, Emma S. Hathaway, Fuxue Xin, M. Noor Tan Source Type: research
