tbuckley/cabot-search huggingface dataset:
Central conducting lymphatic anomaly: from bench to bedside
Authors: Luciana Daniela Garlisi Torales, Benjamin A Sempowski, Georgia L Krikorian, Kristina M Woodis, Scott M Paulissen, Christopher L Smith, Sarah E Sheppard
Journal: Journal of Clinical Investigation (2024)

Central conducting lymphatic anomaly (CCLA) is a complex lymphatic anomaly characterized by abnormalities of the central lymphatics and may present with nonimmune fetal hydrops, chylothorax, chylous ascites, or lymphedema. CCLA has historically been difficult to diagnose and treat; however, recent advances in imaging, such as dynamic contrast magnetic resonance lymphangiography, and in genomics, such as deep sequencing and utilization of cell-free DNA, have improved diagnosis and refined both genotype and phenotype. Furthermore, in vitro and in vivo models have confirmed genetic causes of CCLA, defined the underlying pathogenesis, and facilitated personalized medicine to improve outcomes. Basic, translational, and clinical science are essential for a bedside-to-bench and back approach for CCLA.
VHL governs m6A modification and PIK3R3 mRNA stability in clear cell renal cell carcinomas
Authors: Hyemin Lee, Li Zhuang, Boyi Gan
Journal: Journal of Clinical Investigation (2024)

N6-Methyladenosine (m6A), a prevalent posttranscriptional modification, plays an important role in cancer progression. Clear cell renal cell carcinoma (ccRCC) is chiefly associated with the loss of the von Hippel-Lindau (VHL) gene, encoding a component of the E3 ubiquitin ligase complex. In this issue of the JCI, Zhang and colleagues unveiled a function of VHL beyond its canonical role as an E3 ubiquitin ligase in regulating hypoxia-inducible factors (HIFs). It also governed m6A modification by orchestrating the assembly of m6A writer proteins METTL3 and METTL14, thereby stabilizing PIK3R3 mRNA. Mechanistically, PIK3R3 contributed to p85 ubiquitination, which restrained PI3K/AKT signaling and consequently impeded ccRCC growth in cell and mouse models. This discovery provides potential treatment targets in VHL-deficient ccRCCs.
MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma
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, Yutian Cai, Ivan Topisirovic, Jie Su, Krikor Bijian, Moulay A. Alaoui-Jamali, Sidong Huang, Fabrice Journe, Ghanem E. Ghanem, Wilson H. Miller, Sonia V. del Rincón
Journal: Journal of Clinical Investigation (2024)
Capillary malformations
Authors: Adrienne M Hammill, Elisa Boscolo
Journal: Journal of Clinical Investigation (2024)

Capillary malformation (CM), or port wine birthmark, is a cutaneous congenital vascular anomaly that occurs in 0.1%-2% of newborns. Patients with a CM localized on the forehead have an increased risk of developing a neurocutaneous disorder called encephalotrigeminal angiomatosis or Sturge-Weber syndrome (SWS), with complications including seizure, developmental delay, glaucoma, and vision loss. In 2013, a groundbreaking study revealed causative activating somatic mutations in the gene (GNAQ) encoding guanine nucleotide-binding protein Q subunit α (Gαq) in CM and SWS patient tissues. In this Review, we discuss the disease phenotype, the causative GNAQ mutations, and their cellular origin. We also present the endothelial Gαq-related signaling pathways, the current animal models to study CM and its complications, and future options for therapeutic treatment. Further work remains to fully elucidate the cellular and molecular mechanisms underlying the formation and maintenance of the abnormal vessels.
A murine model of hnRNPH2-related neurodevelopmental disorder reveals a mechanism for genetic compensation by Hnrnph1
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 Joo Kim
Journal: Journal of Clinical Investigation (2024)
Infantile hemangioma: the common and enigmatic vascular tumor
Authors: Annegret Holm, John B Mulliken, Joyce Bischoff
Journal: Journal of Clinical Investigation (2024)

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 unclear. Some IHs fail to respond to beta blockers and regrow after discontinuation. Side effects occur and long-term sequelae of propranolol treatment are unknown. This poses clinical challenges and raises novel questions about the mechanisms of vascular overgrowth in IH.
Endothelial HIF-2α regulates murine pathological angiogenesis and revascularization processes
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
Journal: Journal of Clinical Investigation (2024)
68Ga-FAPI PET imaging monitors response to combined TGF-βR inhibition and immunotherapy in metastatic colorectal cancer
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
Journal: Journal of Clinical Investigation (2024)
Von Hippel Lindau tumor suppressor controls m6A-dependent gene expression in renal tumorigenesis
Authors: Cheng Zhang, Miaomiao Yu, Austin J Hepperla, Zhao Zhang, Rishi Raj, Hua Zhong, Jin Zhou, Lianxin Hu, Jun Fang, Hongyi Liu, Qian Liang, Liwei Jia, Chengheng Liao, Sichuan Xi, Jeremy M Simon, Kexin Xu, Zhijie Liu, Yunsun Nam, Payal Kapur, Qing Zhang
Journal: Journal of Clinical Investigation (2024)

N6-Methyladenosine (m6A) is the most abundant posttranscriptional modification, and its contribution to cancer evolution has recently been appreciated. Renal cancer is the most common adult genitourinary cancer, approximately 85% of which is accounted for by the clear cell renal cell carcinoma (ccRCC) subtype characterized by VHL loss. However, it is unclear whether VHL loss in ccRCC affects m6A patterns. In this study, we demonstrate that VHL binds and promotes METTL3/METTL14 complex formation while VHL depletion suppresses m6A modification, which is distinctive from its canonical E3 ligase role. m6A RNA immunoprecipitation sequencing (RIP-Seq) coupled with RNA-Seq allows us to identify a selection of genes whose expression may be regulated by VHL-m6A signaling. Specifically, PIK3R3 is identified to be a critical gene whose mRNA stability is regulated by VHL in a m6A-dependent but HIF-independent manner. Functionally, PIK3R3 depletion promotes renal cancer cell growth and orthotopic tumor growth while its overexpression leads to decreased tumorigenesis. Mechanistically, the VHL-m6A-regulated PIK3R3 suppresses tumor growth by restraining PI3K/AKT activity. Taken together, we propose a mechanism by which VHL regulates m6A through modulation of METTL3/METTL14 complex formation, thereby promoting PIK3R3 mRNA stability and protein levels that are critical for regulating ccRCC tumorigenesis.
T antigen–specific CD8+ T cells associate with PD-1 blockade response in virus-positive Merkel cell carcinoma
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
Journal: Journal of Clinical Investigation (2024)

Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer primarily induced by Merkel Cell Polyomavirus, 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 non-responding 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 oncoproteins, covering 33 class-I haplotypes. We observed a broad T-cell recognition of T-Ags, including identification of 20 novel T-Ag-derived epitopes. Broadening of the T-Ag recognition profile and increased T-cell frequencies during therapy were strongly associated with clinical response and prolonged progression-free survival. T-Ag-specific T cells could be further boosted and expanded directly from peripheral blood using artificial antigen-presenting scaffolds, even in patients with no detectable T-Ag-specific T cells. These T cells provided strong tumor rejection capacity while retaining a favorable phenotype for adoptive cell transfer. These findings demonstrate that T-Ag-specific T cells are associated with the clinical outcome to PD-1 blockade and that Ag-presenting scaffolds can be used to boost such responses.
Complement C3 and marginal zone B cells promote IgG-mediated enhancement of RBC alloimmunization in mice
Authors: Arijita Jash, Thomas Pridmore, James B Collins, Ariel M Hay, Krystalyn E Hudson, Chance John Luckey, James C Zimring
Journal: Journal of Clinical Investigation (2024)

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 receptor (IFNAR) and is inhibited by the complement C3 protein. Here, we demonstrate the opposite for AMIE of an RBC alloantigen (IFNAR is not required and C3 enhances). RBC clearance, C3 deposition, and antigen modulation all preceded AMIE, and both CD4+ T cells and marginal zone B cells were required. We detected no significant increase in antigen-specific germinal center B cells, consistent with other studies of RBC alloimmunization that show extrafollicular-like responses. To the best of our knowledge, these findings provide the first evidence of an RBC alloimmunization pathway which is IFNAR independent and C3 dependent, thus further advancing our understanding of RBCs as an immunogen and AMIE as a phenomenon.
Hyperactive STAT5 hijacks T cell receptor signaling and drives immature T cell acute lymphoblastic leukemia
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, Daniel Pölöske, Emina Hubanic, Dennis Jungherz, Tony Andreas Müller, Myint Myat Khine Aung, Anna Orlova, Ha Thi Thanh Pham, Kerstin Zimmel, Thomas Krausgruber, Christoph Bock, Mathias Müller, Maik Dahlhoff, Auke Boersma, Thomas Rülicke, Roman Fleck, Elvin Dominic de Araujo, Patrick Thomas Gunning, Tero Aittokallio, Satu Mustjoki, Takaomi Sanda, Sylvia Hartmann, Florian Grebien, Gregor Hoermann, Torsten Haferlach, Philipp Bernhard Staber, Heidi Anne Neubauer, Alfred Thomas Look, Marco Herling, Richard Moriggl
Journal: Journal of Clinical Investigation (2024)

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, even in absence of surface TCR. Importantly, TCR pathway genes were overexpressed in human T-ALL and mature T cell cancers and activation of TCR pathway kinases was STAT5 dependent. We confirmed STAT5 binding to these genes using ChIP-Seq analysis in human T-ALL cells, which were sensitive to pharmacologic inhibition by dual STAT3/5 degraders or ZAP70 tyrosine kinase blockers in vitro and in vivo. We provide genetic and biochemical proof that STAT5A and STAT5B hyperactivation can initiate T-ALL through TCR pathway hijacking and suggest similar mechanisms for other T cell cancers. Thus, STAT5 or TCR component blockade are targeted therapy options, particularly in patients with chemoresistant clones carrying STAT5BN642H.
Oncotherapy resistance explained by Darwinian and Lamarckian models
Authors: Yogen Saunthararajah
Journal: Journal of Clinical Investigation (2024)

Cell and antibody therapies directed against surface molecules on B cells, e.g., CD19-targeting chimeric antigen receptor T cells (CD19 CAR-T), are now standard for patients with chemorefractory B cell acute lymphoblastic leukemias and other B cell malignancies. However, early relapse rates remain high. In this issue of the JCI, Aminov, Giricz, and colleagues revealed that leukemia cells resisting CD19-targeted therapy had reduced CD19 but also low CD22 expression and were sensitive to Bruton's tyrosine kinase and/or MEK inhibition. Overall, their observations support the evolution of resistance following a Lamarckian model: the oncotherapy directly elicits adaptive, resistance-conferring reconfigurations, which are then inherited by daughter cells as epigenetic changes. The findings prompt reflection also on the broader role of epigenetics in decoupling of replication from lineage differentiation activation by the B cell lineage master transcription factor hub. Such oncogenesis and resistance mechanisms, being predictable and epigenetic, offer practical opportunities for intervention, potentially non-cross-resistant and safe vis-à-vis present cytotoxic and CAR-T treatments.
Mitovesicles secreted into the extracellular space of brains with mitochondrial dysfunction impair synaptic plasticity
Authors: Pasquale D’Acunzo, Elentina K. Argyrousi, Jonathan M. Ungania, Yohan Kim, Steven DeRosa, Monika Pawlik, Chris N. Goulbourne, Ottavio Arancio, Efrat Levy
Journal: Molecular Neurodegeneration (2024)

Abstract Background Hypometabolism tied to mitochondrial dysfunction occurs in the aging brain and in neurodegenerative disorders, including in Alzheimer’s disease, in Down syndrome, and in mouse models of these conditions. We have previously shown that mitovesicles, small extracellular vesicles (EVs) of mitochondrial origin, are altered in content and abundance in multiple brain conditions characterized by mitochondrial dysfunction. However, given their recent discovery, it is yet to be explored what mitovesicles regulate and modify, both under physiological conditions and in the diseased brain. In this study, we investigated the effects of mitovesicles on synaptic function, and the molecular players involved. Methods Hippocampal slices from wild-type mice were perfused with the three known types of EVs, mitovesicles, microvesicles, or exosomes, isolated from the brain of a mouse model of Down syndrome or of a diploid control and long-term potentiation (LTP) recorded. The role of the monoamine oxidases type B (MAO-B) and type A (MAO-A) in mitovesicle-driven LTP impairments was addressed by treatment of mitovesicles with the irreversible MAO inhibitors pargyline and clorgiline prior to perfusion of the hippocampal slices. Results Mitovesicles from the brain of the Down syndrome model reduced LTP within minutes of mitovesicle addition. Mitovesicles isolated from control brains did not trigger electrophysiological effects, nor did other types of brain EVs (microvesicles and exosomes) from any genotype tested. Depleting mitovesicles of their MAO-B, but not MAO-A, activity eliminated their ability to alter LTP. Conclusions Mitovesicle impairment of LTP is a previously undescribed paracrine-like mechanism by which EVs modulate synaptic activity, demonstrating that mitovesicles are active participants in the propagation of cellular and functional homeostatic changes in the context of neurodegenerative disorders.
Treating Alzheimer’s disease using nanoparticle-mediated drug delivery strategies/systems
Authors: Aryan Kia Roghani, Ricardo Isaiah Garcia, Ali Roghani, Aananya Reddy, Sachi Khemka, Ruhananhad P. Reddy, Vasanthkumar Pattoor, Michael Jacob, P. Hemachandra Reddy, Ujala Sehar
Journal: Ageing Research Reviews (2024)
Pearl-Appearing “Pseudohypopyon” in a Child: Exclude Malignancy
Authors: Nan Zhou, Dongjun Li, Wenbin Wei
Journal: Ophthalmology (2024)

A 5-year-old boy was found to have "leukocoria" and was referred for evaluation. Slit-lamp photography (A, B) showed multiple pearl-like, white cysts as "pseudohypopyon" in the anterior chamber with associated neovascularization. Ultrasound biomicroscopy (C) confirmed a medium reflective solid iridociliary mass with intratumoral cystic areas that proved on enucleation to be a nonteratoid malignant medulloepithelioma (D, hematoxylin and eosin ×40). The patient had no signs of tumor recurrence or metastases after 5 years of follow-up.
The key role of altered tubule cell lipid metabolism in kidney disease development
Authors: Lauren E Lee, Tomohito Doke, Dhanunjay Mukhi, Katalin Susztak
Journal: Kidney International (2024)

Kidney epithelial cells have very high energy requirements, which are largely met by fatty acid oxidation. Complex changes in lipid metabolism are observed in patients with kidney disease. Defects in fatty acid oxidation and increased lipid uptake, especially in the context of hyperlipidemia and proteinuria, contribute to this excess lipid build-up and exacerbate kidney disease development. Recent studies have also highlighted the role of increased de novo lipogenesis in kidney fibrosis. The defect in fatty acid oxidation causes energy starvation. Increased lipid uptake, synthesis, and lower fatty acid oxidation can cause toxic lipid build-up, reactive oxygen species generation, and mitochondrial damage. A better understanding of these metabolic processes may open new treatment avenues for kidney diseases by targeting lipid metabolism.
Validation Study for the N Descriptor of the Newly Proposed Ninth Edition of the TNM Staging System Proposed by the International Association for the Study of Lung Cancer
Authors: In Ha Kim, Geun Dong Lee, Sehoon Choi, Hyeong Ryul Kim, Yong-Hee Kim, Dong Kwan Kim, Seung-Il Park, Jae Kwang Yun
Journal: Journal of Thoracic Oncology (2024)
Corrigendum to “Imeglimin improves systemic metabolism by targeting brown adipose tissue and gut microbiota in obese model mice” [Metabolism 153 (April 2024) 155796]
Authors: Motoharu Awazawa, Maya Matsushita, Ikumi Nomura, Naoki Kobayashi, Miwa Tamura-Nakano, Yuriko Sorimachi, Keiyo Takubo, Kohjiro Ueki
Journal: Metabolism (2024)
VHL loss reprograms the immune landscape to promote an inflammatory myeloid microenvironment in renal tumorigenesis
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 Tantawy, Scott M. Haake, Eric Jonasch, Alexander Muir, Vivian L. Weiss, Kathryn E. Beckermann, W. Kimryn Rathmell, Jeffrey C. Rathmell
Journal: Journal of Clinical Investigation (2024)

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, phagocytosis, and inflammatory transcriptional signatures, whereas lymphocytes from Vhl-KO tumors showed reduced activation and a lower response to anti-programmed cell death 1 (anti-PD-1) therapy in vivo. The chemokine CX3CL1 was highly expressed in human ccRCC tumors and was associated with Vhl deficiency. Deletion of Cx3cl1 in cancer cells decreased myeloid cell infiltration associated with Vhl loss to provide a mechanism by which Vhl loss may have contributed to the altered immune landscape. Here, we identify cancer cell-specific genetic features that drove environmental reprogramming and shaped the tumor immune landscape, with therapeutic implications for the treatment of ccRCC.
Machine-learning analysis reveals an important role for negative selection in shaping cancer aneuploidy landscapes
Authors: Juman Jubran, Rachel Slutsky, Nir Rozenblum, Lior Rokach, Uri Ben-David, Esti Yeger-Lotem
Journal: Genome biology (2024)

Abstract Background Aneuploidy, an abnormal number of chromosomes within a cell, is a hallmark of cancer. Patterns of aneuploidy differ across cancers, yet are similar in cancers affecting closely related tissues. The selection pressures underlying aneuploidy patterns are not fully understood, hindering our understanding of cancer development and progression. Results Here, we apply interpretable machine learning methods to study tissue-selective aneuploidy patterns. We define 20 types of features corresponding to genomic attributes of chromosome-arms, normal tissues, primary tumors, and cancer cell lines (CCLs), and use them to model gains and losses of chromosome arms in 24 cancer types. To reveal the factors that shape the tissue-specific cancer aneuploidy landscapes, we interpret the machine learning models by estimating the relative contribution of each feature to the models. While confirming known drivers of positive selection, our quantitative analysis highlights the importance of negative selection for shaping aneuploidy landscapes. This is exemplified by tumor suppressor gene density being a better predictor of gain patterns than oncogene density, and vice versa for loss patterns. We also identify the importance of tissue-selective features and demonstrate them experimentally, revealing KLF5 as an important driver for chr13q gain in colon cancer. Further supporting an important role for negative selection in shaping the aneuploidy landscapes, we find compensation by paralogs to be among the top predictors of chromosome arm loss prevalence and demonstrate this relationship for one paralog interaction. Similar factors shape aneuploidy patterns in human CCLs, demonstrating their relevance for aneuploidy research. Conclusions Our quantitative, interpretable machine learning models improve the understanding of the genomic properties that shape cancer aneuploidy landscapes.