tbuckley/cabot-search huggingface dataset:
Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models
Authors: Svena Verma, Sadna Budhu, Inna Serganova, Lauren Dong, Levi M Mangarin, Jonathan F Khan, Mamadou A Bah, Anais Assouvie, Yacine Marouf, Isabell Schulze, Roberta Zappasodi, Jedd D Wolchok, Taha Merghoub
Journal: Journal of Clinical Investigation (2024)

Tumor reliance on glycolysis is a hallmark of cancer. Immunotherapy is more effective in controlling glycolysis-low tumors lacking lactate dehydrogenase (LDH) due to reduced tumor lactate efflux and enhanced glucose availability within the tumor microenvironment (TME). LDH inhibitors (LDHi) reduce glucose uptake and tumor growth in preclinical models, but their impact on tumor-infiltrating T cells is not fully elucidated. Tumor cells have higher basal LDH expression and glycolysis levels compared with infiltrating T cells, creating a therapeutic opportunity for tumor-specific targeting of glycolysis. We demonstrate that LDHi treatment (a) decreases tumor cell glucose uptake, expression of the glucose transporter GLUT1, and tumor cell proliferation while (b) increasing glucose uptake, GLUT1 expression, and proliferation of tumor-infiltrating T cells. Accordingly, increasing glucose availability in the microenvironment via LDH inhibition leads to improved tumor-killing T cell function and impaired Treg immunosuppressive activity in vitro. Moreover, combining LDH inhibition with immune checkpoint blockade therapy effectively controls murine melanoma and colon cancer progression by promoting effector T cell infiltration and activation while destabilizing Tregs. Our results establish LDH inhibition as an effective strategy for rebalancing glucose availability for T cells within the TME, which can enhance T cell function and antitumor immunity.
Wider recognition and greater understanding of postinfectious, antibiotic-refractory Lyme arthritis
Authors: Allen C Steere, Jacob E Lemieux
Journal: Journal of Clinical Investigation (2024)

Lyme disease, caused by Borrelia burgdorferi (Bb), can progress to Lyme arthritis (LA). While most patients with LA respond successfully to antibiotic therapy, a small percentage fail to improve, a condition known as antibiotic-refractory Lyme arthritis (ARLA). While T cell responses are known to drive ARLA, molecular mechanisms for ARLA remain unknown. In this issue of the JCI, Dirks et al. isolated disease-specific Th cells from patients with ARLA residing in Germany. A distinct TCR-β motif distinguished ARLA from other rheumatic diseases. Notably, the TCR-β motif was linked predominantly to HLA-DRB1*11 or 13 alleles, which differed from alleles in patients from North America. It also mapped primarily to T peripheral helper (Tph) cells, as opposed to classical Th1 cells. These findings provide a roadmap explaining how T cell responses necessary for control of an infection can, despite antibiotic therapy, drive a disadvantageous T cell response, resulting in a postinfectious, inflammatory arthritis.
Single-cell analysis of breast cancer metastasis reveals epithelial-mesenchymal plasticity signatures associated with poor outcomes
Authors: Juliane Winkler, Weilun Tan, Catherine Mm Diadhiou, Christopher S McGinnis, Aamna Abbasi, Saad Hasnain, Sophia Durney, Elena Atamaniuc, Daphne Superville, Leena Awni, Joyce V Lee, Johanna H Hinrichs, Patrick S Wagner, Namrata Singh, Marco Y Hein, Michael Borja, Angela M Detweiler, Su-Yang Liu, Ankitha Nanjaraj, Vaishnavi Sitarama, Hope S Rugo, Norma Neff, Zev J Gartner, Angela Oliveira Pisco, Andrei Goga, Spyros Darmanis, Zena Werb
Journal: Journal of Clinical Investigation (2024)

Metastasis is the leading cause of cancer-related deaths. It is unclear how intratumor heterogeneity (ITH) contributes to metastasis and how metastatic cells adapt to distant tissue environments. The study of these adaptations is challenged by the limited access to patient material and a lack of experimental models that appropriately recapitulate ITH. To investigate metastatic cell adaptations and the contribution of ITH to metastasis, we analyzed single-cell transcriptomes of matched primary tumors and metastases from patient-derived xenograft models of breast cancer. We found profound transcriptional differences between the primary tumor and metastatic cells. Primary tumors upregulated several metabolic genes, whereas motility pathway genes were upregulated in micrometastases, and stress response signaling was upregulated during progression. Additionally, we identified primary tumor gene signatures that were associated with increased metastatic potential and correlated with patient outcomes. Immune-regulatory control pathways were enriched in poorly metastatic primary tumors, whereas genes involved in epithelial-mesenchymal transition were upregulated in highly metastatic tumors. We found that ITH was dominated by epithelial-mesenchymal plasticity (EMP), which presented as a dynamic continuum with intermediate EMP cell states characterized by specific genes such as CRYAB and S100A2. Elevated expression of an intermediate EMP signature correlated with worse patient outcomes. Our findings identified inhibition of the intermediate EMP cell state as a potential therapeutic target to block metastasis.
GLP-1R–positive neurons in the lateral septum mediate the anorectic and weight-lowering effects of liraglutide in mice
Authors: Zijun Chen, Xiaofei Deng, Cuijie Shi, Haiyang Jing, Yu Tian, Jiafeng Zhong, Gaowei Chen, Yunlong Xu, Yixiao Luo, Yingjie Zhu
Journal: Journal of Clinical Investigation (2024)

Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, is approved for obesity treatment, but the specific neuronal sites that contribute to its therapeutic effects remain elusive. Here, we show that GLP-1 receptor–positive (GLP-1R–positive) neurons in the lateral septum (LSGLP-1R) play a critical role in mediating the anorectic and weight-loss effects of liraglutide. LSGLP-1R neurons were robustly activated by liraglutide, and chemogenetic activation of these neurons dramatically suppressed feeding. Targeted knockdown of GLP-1 receptors within the LS, but not in the hypothalamus, substantially attenuated liraglutide's ability to inhibit feeding and lower body weight. The activity of LSGLP-1R neurons rapidly decreased during naturalistic feeding episodes, while synaptic inactivation of LSGLP-1R neurons diminished the anorexic effects triggered by liraglutide. Together, these findings offer critical insights into the functional role of LSGLP-1R neurons in the physiological regulation of energy homeostasis and delineate their instrumental role in mediating the pharmacological efficacy of liraglutide.
Revisiting sex as a biological variable in hypertension research
Authors: Michael J Ryan, John S Clemmer, Roy O Mathew, Jessica L Faulkner, Erin B Taylor, Justine M Abais-Battad, Fiona Hollis, Jennifer C Sullivan
Journal: Journal of Clinical Investigation (2024)

Half of adults in the United States have hypertension as defined by clinical practice guidelines. Interestingly, women are generally more likely to be aware of their hypertension and have their blood pressure controlled with treatment compared with men, yet hypertension-related mortality is greater in women. This may reflect the fact that the female sex remains underrepresented in clinical and basic science studies investigating the effectiveness of therapies and the mechanisms controlling blood pressure. This Review provides an overview of the impact of the way hypertension research has explored sex as a biological variable (SABV). Emphasis is placed on epidemiological studies, hypertension clinical trials, the genetics of hypertension, sex differences in immunology and gut microbiota in hypertension, and the effect of sex on the central control of blood pressure. The goal is to offer historical perspective on SABV in hypertension, highlight recent studies that include SABV, and identify key gaps in SABV inclusion and questions that remain in the field. Through continued awareness campaigns and engagement/education at the level of funding agencies, individual investigators, and in the editorial peer review system, investigation of SABV in the field of hypertension research will ultimately lead to improved clinical outcomes.
Increased risk of kidney failure in patients with genetic kidney disorders
Authors: Mark D Elliott, Natalie Vena, Maddalena Marasa, Enrico Cocchi, Shiraz Bheda, Kelsie Bogyo, Ning Shang, Francesca Zanoni, Miguel Verbitsky, Chen Wang, Victoria Kolupaeva, Gina Jin, Maayan Sofer, Rafael Gras Pena, Pietro A Canetta, Andrew S Bomback, Lisa M Guay-Woodford, Jean Hou, Brenda W Gillespie, Bruce M Robinson, Jon B Klein, Michelle N Rheault, William E Smoyer, Larry A Greenbaum, Larry B Holzman, Ronald J Falk, Afshin Parsa, Simone Sanna-Cherchi, Laura H Mariani, Matthias Kretzler, Krzysztof Kiryluk, Ali G Gharavi
Journal: Journal of Clinical Investigation (2024)

BACKGROUNDIt is unknown whether the risk of kidney disease progression and failure differs between patients with and without genetic kidney disorders.METHODSThree cohorts were evaluated: the prospective Cure Glomerulonephropathy Network (CureGN) and 2 retrospective cohorts from Columbia University, including 5,727 adults and children with kidney disease from any etiology who underwent whole-genome or exome sequencing. The effects of monogenic kidney disorders and APOL1 kidney-risk genotypes on the risk of kidney failure, estimated glomerular filtration rate (eGFR) decline, and disease remission rates were evaluated along with diagnostic yields and the impact of American College of Medical Genetics secondary findings (ACMG SFs).RESULTSMonogenic kidney disorders were identified in 371 patients (6.5%), high-risk APOL1 genotypes in 318 (5.5%), and ACMG SFs in 100 (5.2%). Family history of kidney disease was the strongest predictor of monogenic disorders. After adjustment for traditional risk factors, monogenic kidney disorders were associated with an increased risk of kidney failure (hazard ratio [HR] = 1.72), higher rate of eGFR decline (-3.06 vs. 0.25 mL/min/1.73 m2/year), and lower risk of complete remission (odds ratioNot achieving CR = 5.25). High-risk APOL1 genotypes were associated with an increased risk of kidney failure (HR = 1.67) and faster eGFR decline (-2.28 vs. 0.25 mL/min/1.73 m2), replicating prior findings. ACMG SFs were not associated with personal or family history of associated diseases, but were predicted to impact care in 70% of cases.CONCLUSIONSMonogenic kidney disorders were associated with an increased risk of kidney failure, faster eGFR decline, and lower rates of complete remission, suggesting opportunities for early identification and intervention based on molecular diagnosis.TRIAL REGISTRATIONNA.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases grants U24DK100845 (formerly UM1DK100845), U01DK100846 (formerly UM1DK100846), U01DK100876 (formerly UM1DK100876), U01DK100866 (formerly UM1DK100866), U01DK100867 (formerly UM1DK100867), U24DK100845, DK081943, RC2DK116690, 2U01DK100876, 1R01DK136765, 5R01DK082753, and RC2-DK122397; NephCure Kidney International; Department of Defense Research Awards PR201425, W81XWH-16-1-0451, and W81XWH-22-1-0966; National Center for Advancing Translational Sciences grant UL1TR001873; National Library of Medicine grant R01LM013061; National Human Genome Research Institute grant 2U01HG008680.
Cancer therapy–related salivary dysfunction
Authors: Cristina Paz, Annemarie Glassey, Abigail Frick, Sarah Sattar, Nicholas G Zaorsky, Grace C Blitzer, Randall J Kimple
Journal: Journal of Clinical Investigation (2024)

Salivary gland dysfunction is a common side effect of cancer treatments. Salivary function plays key roles in critical daily activities. Consequently, changes in salivary function can profoundly impair quality of life for cancer patients. We discuss salivary gland anatomy and physiology to understand how anticancer therapies such as chemotherapy, bone marrow transplantation, immunotherapy, and radiation therapy impair salivary function. We discuss approaches to quantify xerostomia in the clinic, including the advantages and limitations of validated quality-of-life instruments and approaches to directly measuring salivary function. Current and emerging approaches to treat cancer therapy-induced dry mouth are presented using radiation-induced salivary dysfunction as a model. Limitations of current sialagogues and salivary analogues are presented. Emerging approaches, including cellular and gene therapy and novel pharmacologic approaches, are described.
Mapping the transcriptional evolution of human metastatic breast cancer
Authors: Melissa Q. Reeves
Journal: Journal of Clinical Investigation (2024)

Many aspects of breast cancer metastasis remain poorly understood, despite its clinical importance. In this issue of the JCI, Winkler et al. have applied an elegant patient-derived xenograft (PDX) model to map the transcriptomes of single cells in matched primary tumors and lung metastases across 13 breast cancer PDX models. They identified distinct transcriptional changes associated with metastatic evolution in lowly and highly metastatic primary tumors. Furthermore, by classifying the "epithelial-mesenchymal plasticity" (EMP) state of single cells, they revealed that considerable EMP heterogeneity exists among primary and metastatic human breast cancer cells. However, the EMP profile of a tumor does not change substantially upon metastasis. These findings give an unprecedentedly detailed view into the transcriptional heterogeneity and evolution of metastatic human breast cancer.
Itm2a expression marks periosteal skeletal stem cells that contribute to bone fracture healing
Authors: Wenhui Xing, Heng Feng, Bo Jiang, Bo Gao, Jiping Liu, Zaiqi Xie, Yazhuo Zhang, Xuye Hu, Jun Sun, Matthew B Greenblatt, Bo O Zhou, Weiguo Zou
Journal: Journal of Clinical Investigation (2024)

The periosteum contains skeletal stem/progenitor cells that contribute to bone fracture healing. However, the in vivo identity of periosteal skeletal stem cells (P-SSCs) remains unclear, and membrane protein markers of P-SSCs that facilitate tissue engineering are needed. Here, we identified integral membrane protein 2A (Itm2a) enriched in SSCs using single-cell transcriptomics. Itm2a+ P-SSCs displayed clonal multipotency and self-renewal and sat at the apex of their differentiation hierarchy. Lineage-tracing experiments showed that Itm2a selectively labeled the periosteum and that Itm2a+ cells were preferentially located in the outer fibrous layer of the periosteum. The Itm2a+ cells rarely expressed CD34 or Osx, but expressed periosteal markers such as Ctsk, CD51, PDGFRA, Sca1, and Gli1. Itm2a+ P-SSCs contributed to osteoblasts, chondrocytes, and marrow stromal cells upon injury. Genetic lineage tracing using dual recombinases showed that Itm2a and Prrx1 lineage cells generated spatially separated subsets of chondrocytes and osteoblasts during fracture healing. Bone morphogenetic protein 2 (Bmp2) deficiency or ablation of Itm2a+ P-SSCs resulted in defects in fracture healing. ITM2A+ P-SSCs were also present in the human periosteum. Thus, our study identified a membrane protein marker that labels P-SSCs, providing an attractive target for drug and cellular therapy for skeletal disorders.
Adeno-associated virus–based gene therapy treats inflammatory kidney disease in mice
Authors: Guochao Wu, Shuya Liu, Julia Hagenstein, Malik Alawi, Felicitas E Hengel, Melanie Schaper, Nuray Akyüz, Zhouning Liao, Nicola Wanner, Nicola M Tomas, Antonio Virgilio Failla, Judith Dierlamm, Jakob Körbelin, Shun Lu, Tobias B Huber
Journal: Journal of Clinical Investigation (2024)

Adeno-associated virus (AAV) is a promising in vivo gene delivery platform showing advantages in delivering therapeutic molecules to difficult or undruggable cells. However, natural AAV serotypes have insufficient transduction specificity and efficiency in kidney cells. Here, we developed an evolution-directed selection protocol for renal glomeruli and identified what we believe to be a new vector termed AAV2-GEC that specifically and efficiently targets the glomerular endothelial cells (GEC) after systemic administration and maintains robust GEC tropism in healthy and diseased rodents. AAV2-GEC-mediated delivery of IdeS, a bacterial antibody-cleaving proteinase, provided sustained clearance of kidney-bound antibodies and successfully treated antiglomerular basement membrane glomerulonephritis in mice. Taken together, this study showcases the potential of AAV as a gene delivery platform for challenging cell types. The development of AAV2-GEC and its successful application in the treatment of antibody-mediated kidney disease represents a significant step forward and opens up promising avenues for kidney medicine.
Recruitment of CXCR4+ type 1 innate lymphoid cells distinguishes sarcoidosis from other skin granulomatous diseases
Authors: Satish Sati, Jianhe Huang, Anna E. Kersh, Parker Jones, Olivia Ahart, Christina Murphy, Stephen M. Prouty, Matthew L. Hedberg, Vaibhav Jain, Simon G. Gregory, Denis H. Leung, John T. Seykora, Misha Rosenbach, Thomas H. Leung
Journal: Journal of Clinical Investigation (2024)

Sarcoidosis is a multiorgan granulomatous disease that lacks diagnostic biomarkers and targeted treatments. Using blood and skin from patients with sarcoid and non-sarcoid skin granulomas, we discovered that skin granulomas from different diseases exhibit unique immune cell recruitment and molecular signatures. Sarcoid skin granulomas were specifically enriched for type 1 innate lymphoid cells (ILC1s) and B cells and exhibited molecular programs associated with formation of mature tertiary lymphoid structures (TLSs), including increased CXCL12/CXCR4 signaling. Lung sarcoidosis granulomas also displayed similar immune cell recruitment. Thus, granuloma formation was not a generic molecular response. In addition to tissue-specific effects, patients with sarcoidosis exhibited an 8-fold increase in circulating ILC1s, which correlated with treatment status. Multiple immune cell types induced CXCL12/CXCR4 signaling in sarcoidosis, including Th1 T cells, macrophages, and ILCs. Mechanistically, CXCR4 inhibition reduced sarcoidosis-activated immune cell migration, and targeting CXCR4 or total ILCs attenuated granuloma formation in a noninfectious mouse model. Taken together, our results show that ILC1s are a tissue and circulating biomarker that distinguishes sarcoidosis from other skin granulomatous diseases. Repurposing existing CXCR4 inhibitors may offer a new targeted treatment for this devastating disease.
Metabolic benefits afforded by estradiol and testosterone in both sexes: clinical considerations
Authors: Franck Mauvais-Jarvis, Sarah H Lindsey
Journal: Journal of Clinical Investigation (2024)

Testosterone (T) and 17β-estradiol (E2) are produced in male and female humans and are potent metabolic regulators in both sexes. When E2 and T production stops or decreases during aging, metabolic dysfunction develops and promotes degenerative metabolic and vascular disease. Here, we discuss the shared benefits afforded by E2 and T for metabolic function human females and males. In females, E2 is central to bone and vascular health, subcutaneous adipose tissue distribution, skeletal muscle insulin sensitivity, antiinflammatory immune function, and mitochondrial health. However, T also plays a role in female skeletal, vascular, and metabolic health. In males, T's conversion to E2 is fundamental to bone and vascular health, as well as prevention of excess visceral adiposity and the promotion of insulin sensitivity via activation of the estrogen receptors. However, T and its metabolite dihydrotestosterone also prevent excess visceral adiposity and promote skeletal muscle growth and insulin sensitivity via activation of the androgen receptor. In conclusion, T and E2 are produced in both sexes at sex-specific concentrations and provide similar and potent metabolic benefits. Optimizing levels of both hormones may be beneficial to protect patients from cardiometabolic disease and frailty during aging, which requires further study.
Unhealthy visceral fat is associated with improved efficacy of immunotherapy in endometrial cancer
Authors: Matthew L Steinhauser
Journal: Journal of Clinical Investigation (2024)

Obesity is a known driver of endometrial cancer. In this issue of the JCI, Gómez-Banoy and colleagues investigated a cohort of patients with advanced endometrial cancer treated with immune checkpoint inhibitors targeting the interaction between programmed cell death receptor-1 (PD-1) and its ligand (PD-L1). Notably, a BMI in the overweight or obese range was paradoxically associated with improved progression-free and overall survival. A second paradox emerged from CT analyses of visceral adipose tissue, viewed as an unhealthy fat depot in most other contexts, the quantity of which was also associated with improved treatment outcomes. Though visceral adiposity may have value as a biomarker to inform personalized treatment strategies, of even greater impact would be if a therapeutic strategy emerges from the future identification of adipose-derived mediators of this putative anticancer immune-priming effect.
Somatic RAP1B gain-of-function variant underlies isolated thrombocytopenia and immunodeficiency
Authors: Marta Benavides-Nieto, Frédéric Adam, Emmanuel Martin, Charlotte Boussard, Chantal Lagresle-Peyrou, Isabelle Callebaut, Alexandre Kauskot, Christelle Repérant, Miao Feng, Jean-Claude Bordet, Martin Castelle, Guillaume Morelle, Chantal Brouzes, Mohammed Zarhrate, Patricia Panikulam, Nathalie Lambert, Capucine Picard, Damien Bodet, Jérémie Rouger-Gaudichon, Patrick Revy, Jean-Pierre de Villartay, Despina Moshous
Journal: Journal of Clinical Investigation (2024)

The ubiquitously expressed small GTPase Ras-related protein 1B (RAP1B) acts as a molecular switch that regulates cell signaling, cytoskeletal remodeling, and cell trafficking and activates integrins in platelets and lymphocytes. The residue G12 in the P-loop is required for the RAP1B-GTPase conformational switch. Heterozygous germline RAP1B variants have been described in patients with syndromic thrombocytopenia. However, the causality and pathophysiological impact remained unexplored. We report a boy with neonatal thrombocytopenia, combined immunodeficiency, neutropenia, and monocytopenia caused by a heterozygous de novo single nucleotide substitution, c.35G>A (p.G12E) in RAP1B. We demonstrate that G12E and the previously described G12V and G60R were gain-of-function variants that increased RAP1B activation, talin recruitment, and integrin activation, thereby modifying late responses such as platelet activation, T cell proliferation, and migration. We show that in our patient, G12E was a somatic variant whose allele frequency decreased over time in the peripheral immune compartment, but remained stable in bone marrow cells, suggesting a differential effect in distinct cell populations. Allogeneic hematopoietic stem cell transplantation fully restored the patient's hemato-immunological phenotype. Our findings define monoallelic RAP1B gain-of-function variants as a cause for constitutive immunodeficiency and thrombocytopenia. The phenotypic spectrum ranged from isolated hematological manifestations in our patient with somatic mosaicism to complex syndromic features in patients with reported germline RAP1B variants.