Somatic estrogen receptor α mutations that induce dimerization promote receptor activity and breast cancer proliferation
Physiologic activation of estrogen receptor α (ERα) is mediated by estradiol (E2) binding in the ligand-binding pocket of the receptor, repositioning helix 12 (H12) to facilitate binding of coactivator proteins in the unoccupied coactivator binding groove. In breast cancer, activation of ERα is often observed through point mutations that lead to the same H12 repositioning in the absence of E2. Through expanded genetic sequencing of breast cancer patients, we identified a collection of mutations located far from H12 but nonetheless capable of promoting E2-independent transcription and breast cancer cell growth. Using mac...
Source: Journal of Clinical Investigation - January 2, 2024 Category: Biomedical Science Authors: Seema Irani, Wuwei Tan, Qing Li, Weiyi Toy, Catherine Jones, Mayur Gadiya, Antonio Marra, John A. Katzenellenbogen, Kathryn E. Carlson, Benita S. Katzenellenbogen, Mostafa Karimi, Ramya Segu Rajappachetty, Isabella S. Del Priore, Jorge S. Reis-Filho, Yang Source Type: research
Cardiac noradrenergic deficiency revealed by 18F-dopamine positron emission tomography identifies preclinical central Lewy body diseases
BACKGROUND. In Lewy body diseases (LBDs) Parkinson disease (PD), and dementia with Lewy bodies (DLB), by the time parkinsonism or cognitive dysfunction manifests clinically, substantial neurodegeneration has already occurred. Biomarkers are needed to identify central LBDs in a preclinical phase, when neurorescue strategies might forestall symptomatic disease. This phase may involve catecholamine deficiency in the autonomic nervous system. We analyzed data from the prospective, observational, long-term PDRisk study to assess the predictive value of low versus normal cardiac 18F-dopamine positron emission tomography (PET), a...
Source: Journal of Clinical Investigation - January 2, 2024 Category: Biomedical Science Authors: David S. Goldstein, Courtney Holmes, Patti Sullivan, Grisel Lopez, Janna Gelsomino, Sarah Moore, Risa Isonaka, Tianxia Wu, Yehonatan Sharabi Source Type: research
Induced protein degradation for therapeutics: past, present, and future
The concept of induced protein degradation by small molecules has emerged as a promising therapeutic strategy that is particularly effective in targeting proteins previously considered “undruggable.” Thalidomide analogs, employed in the treatment of multiple myeloma, stand as prime examples. These compounds serve as molecular glues, redirecting the CRBN E3 ubiquitin ligase to degrade myeloma-dependency factors, IKZF1 and IKZF3. The clinical success of thalidomide analogs demonstrates the therapeutic potential of induced protein degradation. Beyond molecular glue degraders, several additional modalities to trigger prote...
Source: Journal of Clinical Investigation - January 2, 2024 Category: Biomedical Science Authors: Hojong Yoon, Justine C. Rutter, Yen-Der Li, Benjamin L. Ebert Source Type: research
CDKL5 regulates p62-mediated selective autophagy and confers protection against neurotropic viruses
Virophagy, the selective autophagosomal engulfment and lysosomal degradation of viral components, is crucial for neuronal cell survival and antiviral immunity. However, the mechanisms leading to viral antigen recognition and capture by autophagic machinery remain poorly understood. Here, we identified cyclin-dependent kinase–like 5 (CDKL5), known to function in neurodevelopment, as an essential regulator of virophagy. Loss-of-function mutations in CDKL5 are associated with a severe neurodevelopmental encephalopathy. We found that deletion of CDKL5 or expression of a clinically relevant pathogenic mutant of CDKL5 reduced ...
Source: Journal of Clinical Investigation - January 2, 2024 Category: Biomedical Science Authors: Josephine W. Thinwa, Zhongju Zou, Emily Parks, Salwa Sebti, Kelvin Hui, Yongjie Wei, Mohammad Goodarzi, Vibha Singh, Greg Urquhart, Jenna L. Jewell, Julie K. Pfeiffer, Beth Levine, Tiffany A. Reese, Michael U. Shiloh Source Type: research
Gasdermin C sensitizes tumor cells to PARP inhibitor therapy in cancer models
This study identifies a general marker and target for PARPi therapy and offers insights into the mechanism of PARPi function. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 2, 2024 Category: Biomedical Science Authors: Shuanglian Wang, Chiung-Wen Chang, Juan Huang, Shan Zeng, Xin Zhang, Mien-Chie Hung, Junwei Hou Source Type: research
Targeting lysine demethylase 6B ameliorates ASXL1 truncation–mediated myeloid malignancies in preclinical models
ASXL1 mutation frequently occurs in all forms of myeloid malignancies and is associated with aggressive disease and poor prognosis. ASXL1 recruits Polycomb repressive complex 2 (PRC2) to specific gene loci to repress transcription through trimethylation of histone H3 on lysine 27 (H3K27me3). ASXL1 alterations reduce H3K27me3 levels, which results in leukemogenic gene expression and the development of myeloid malignancies. Standard therapies for myeloid malignancies have limited efficacy when mutated ASXL1 is present. We discovered upregulation of lysine demethylase 6B (KDM6B), a demethylase for H3K27me3, in ASXL1-mutant le...
Source: Journal of Clinical Investigation - January 2, 2024 Category: Biomedical Science Authors: Guo Ge, Peng Zhang, Pinpin Sui, Shi Chen, Hui Yang, Ying Guo, Ivan P. Rubalcava, Asra Noor, Caroline R. Delma, Joel Agosto-Peña, Hui Geng, Edward A. Medina, Ying Liang, Stephen D. Nimer, Ruben Mesa, Omar Abdel-Wahab, Mingjiang Xu, Feng-Chun Yang Source Type: research
Leptin physiology and pathophysiology: knowns and unknowns 30 years after its discovery
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 2, 2024 Category: Biomedical Science Authors: Jeffrey S. Flier, Rexford S. Ahima Source Type: research
Solid organ transplantation: solid but not yet spectacular
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 2, 2024 Category: Biomedical Science Authors: Laurence A. Turka Source Type: research
PP2A inhibition causes synthetic lethality in BRCA2-mutated prostate cancer models via spindle assembly checkpoint reactivation
In this study, we conducted forward genetic synthetic viability screenings in Caenorhabditis elegans brc-2 (Cebrc-2) mutants and found that Ceubxn-2 inactivation rescued the viability of Cebrc-2 mutants. Moreover, loss of NSFL1C, the mammalian ortholog of CeUBXN-2, suppressed the spindle assembly checkpoint (SAC) activation and promoted the survival of BRCA2-deficient cells. Mechanistically, NSFL1C recruited USP9X to inhibit the polyubiquitination of AURKB and reduce the removal of AURKB from the centromeres by VCP, which is essential for SAC activation. SAC inactivation is common in BRCA2-deficient prostate cancer patient...
Source: Journal of Clinical Investigation - January 2, 2024 Category: Biomedical Science Authors: Jian Wang, Yuke Chen, Shiwei Li, Wanchang Liu, Xiao Albert Zhou, Yefei Luo, Zhanzhan Xu, Yundong Xiong, Kaiqi Cheng, Mingjian Ruan, Wei Yu, Xiaoman Li, Weibin Wang, Jiadong Wang Source Type: research
Getting to the heart of Lewy body disease
Early identification of neurodegenerative diseases before extensive neuronal loss or disabling symptoms have occurred is imperative for effective use of disease-modifying therapies. Emerging data indicate that central Lewy body diseases — Parkinson disease and dementia with Lewy bodies — can begin in the peripheral nervous system, opening up a therapeutic window before central involvement. In this issue of the JCI, Goldstein et al. report that cardiac 18F-dopamine positron emission tomography reveals lower activity selectively in individuals with several self-reported Parkinson disease risk factors who later develop Pa...
Source: Journal of Clinical Investigation - January 2, 2024 Category: Biomedical Science Authors: Anna E. Goodheart, Craig Blackstone Source Type: research
Building reproducible bridges to cross the “valley of death”
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 2, 2024 Category: Biomedical Science Authors: Timothy M. Errington Source Type: research
Verapamil mitigates chloride and calcium bi-channelopathy in a myotonic dystrophy mouse model
Myotonic dystrophy type 1 (DM1) involves misregulated alternative splicing for specific genes. We used exon or nucleotide deletion to mimic altered splicing of genes central to muscle excitation-contraction coupling in mice. Mice with forced skipping of exon 29 in the CaV1.1 calcium channel combined with loss of ClC-1 chloride channel function displayed markedly reduced lifespan, whereas other combinations of splicing mimics did not affect survival. The Ca2+/Cl– bi-channelopathy mice exhibited myotonia, weakness, and impairment of mobility and respiration. Chronic administration of the calcium channel blocker verapamil r...
Source: Journal of Clinical Investigation - January 2, 2024 Category: Biomedical Science Authors: Lily A. Cisco, Matthew T. Sipple, Katherine M. Edwards, Charles A. Thornton, John D. Lueck Source Type: research
Combinatorial effects of ion channel mis-splicing as a cause of myopathy in myotonic dystrophy
Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder caused by an unstable expanded CTG repeat located in the 3′-UTR of the DM1 protein kinase (DMPK) gene. The pathogenic mechanism results in misregulated alternative splicing of hundreds of genes, creating the dilemma of establishing which genes contribute to the mechanism of DM1 skeletal muscle pathology. In this issue of the JCI, Cisco and colleagues systematically tested the combinatorial effects of DM1-relevant mis-splicing patterns in vivo and identified the synergistic effects of mis-spliced calcium and chloride channels as a major contributor to DM1 s...
Source: Journal of Clinical Investigation - January 2, 2024 Category: Biomedical Science Authors: Larissa Nitschke, Thomas A. Cooper Source Type: research
A narrow T cell receptor repertoire instructs thymic differentiation of MHC class Ib–restricted CD8+ regulatory T cells
Although most CD8+ T cells are equipped to kill infected or transformed cells, a subset may regulate immune responses and preserve self-tolerance. Here, we describe a CD8 lineage that is instructed to differentiate into CD8 T regulatory cells (Tregs) by a surprisingly restricted set of T cell receptors (TCRs) that recognize MHC-E (mouse Qa-1) and several dominant self-peptides. Recognition and elimination of pathogenic target cells that express these Qa-1–self-peptide complexes selectively inhibits pathogenic antibody responses without generalized immune suppression. Immunization with synthetic agonist peptides that mobi...
Source: Journal of Clinical Investigation - January 2, 2024 Category: Biomedical Science Authors: Hye-Jung Kim, Hidetoshi Nakagawa, John Y. Choi, Xuchun Che, Andrew Divris, Qingshi Liu, Andrew E. Wight, Hengcheng Zhang, Anis Saad, Zhabiz Solhjou, Christa Deban, Jamil R. Azzi, Harvey Cantor Source Type: research
2023 American Society for Clinical Investigation Presidential AddressFrom Avicenna to ASCI: embracing the challenges and opportunities of biomedical research
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 2, 2024 Category: Biomedical Science Authors: Sohail F. Tavazoie Source Type: research
