Clinical Research
Abstract
Authors
Simeon I. Taylor
Abstract
Despite enormous advances in clinical genomics, idiopathic scoliosis remains an enigmatic condition with poorly understood genetic and pathophysiological underpinnings impeding molecular diagnosis and the development of targeted treatments. We performed linkage analysis, exome, genome and short- and long-read RNA sequencing in a multigenerational family affected by autosomal dominant early-onset scoliosis (EOS) with a unique pattern of spondylodysplastic elements and progressive endplate erosion and identified the LRR binding FLII interacting protein 1 gene (LRRFIP1) as the disease-causing gene. The underlying cause is a rare noncoding variant altering transcription factor binding of NR3C1 (glucocorticoid receptor) leading to changes in LRRFIP1-isoform expression. Transcriptomic changes in fibroblasts of affected individuals indicated a combination of disturbed Wnt-signaling during somitogenesis, planar cell polarity signaling and postnatal inflammatory dysregulation with clinical and molecular overlaps with Ankylosing Spondylitis and Scheuermann kyphosis. We conducted a rare variant enrichment analysis using genome data from 484,903 UK Biobank participants and found an enrichment of rare risk-increasing LRRFIP1-variants in individuals with scoliosis. Our analysis of an Lrrfip1tm1.1(KOMP)Wtsi KO mouse model showed increased prevalence of idiopathic kyphoscoliosis in Lrrfip1-deficient mice. Our work provides insights into the pathophysiology of rare and common spinal disorders and hints to potential future therapeutic approaches with selective NR3C1-inhibitors.
Authors
Tanja Frey, Elena M. Cabello, Gabriele Siegel, Carla Bello, Rike Schiller, Martina A. Trippel, Neguin Ranjbar, Paranchai Boonsawat, Stephanie E. van Gijn, Ivan Ivanovski, Michael Papik, Markus Zweier, Kan Min, Katharina Steindl, Anita Rauch
Abstract
Background. Improved understanding of the cellular mechanisms of organ transplant rejection is needed for developing targeted therapies to improve outcomes. We used digital cytometry to estimate the digital leukocyte entities (DLE) shared by rejection in biopsies of kidney, heart, lung, and liver organ transplants. Methods. We used CIBERSORTx with the LM22 leukocyte reference to estimate associations between 22 DLEs with rejection in 8422 transplant biopsies - 4898 kidney, 2361 heart, 652 lung, and 538 liver. Results. In all organs, rejection correlated with an increase in DLEs designated as classically activated macrophages and a decrease in DLEs designated regulatory T cells. T cell-mediated rejection (TCMR) was associated with a massive increase in otherwise rare T cell DLEs designated memory-activated CD4 and Tγδ, as well as follicular-helper CD4 and CD8. TCMR also had increased DLE designated plasma cells, compatible with a role for the B cell lineage in antigen presentation in TCMR. Antibody-mediated rejection (ABMR) in kidney and heart transplant biopsies correlated with increased DLEs representing activated mast cells, activated NK cells, and monocytes. Some findings were validated by single-cell/nucleus RNAseq data from kidney and liver biopsies. Conclusion. The shared correlations of DLEs with rejection in all organs - e.g. CD4ma with TCMR and activated mast cells with ABMR - suggest novel aspects of rejection. These findings can guide the search for the in vivo leukocytes that correspond with the digital entities, with potential clinical applications. Trial registration. ClinicalTrials.gov NCT01299168, NCT02670408, NCT02812290, NCT03193151. Funding. Genome Canada and a grant from Natera, Inc.
Authors
Patrick T. Gauthier, Louisa M.S. Gerhardt, Lorenz Jahn, Christian Hinze, Philip F. Halloran
Abstract
Activating mutations in FMS-like tyrosine kinase 3 (FLT3) drive aggressive acute myeloid leukemia (AML) and confer poor prognosis. Although FLT3 inhibitors have improved outcomes, their efficacy is frequently limited by microenvironment-mediated signaling and treatment-emergent resistance. XY0206 is a structurally optimized derivative of sunitinib, an inhibitor approved for multiple solid tumors. Biochemical, multi-omics, and functional analyses showed that XY0206 directly engages FLT3 and suppresses downstream STAT5, AKT, and ERK signaling, resulting in apoptosis in FLT3-ITD AML cells. Across models of FLT3-dependent resistance, XY0206 retained antileukemic activity, including in FLT3-ITD cells harboring the F691L gatekeeper mutation, a recurrent alteration conferring resistance to approved FLT3 inhibitors. In primary AML blasts and xenograft models, XY0206 exhibited enhanced antileukemic activity with favorable tolerability relative to gilteritinib. In a phase I/II trial (NCT04471064) of XY0206 monotherapy in patients with relapsed or refractory (R/R) AML, XY0206 achieved a composite complete remission rate (CRc) of 45.7% overall, with a notable 60.0% CRc rate among patients with FLT3-ITD mutations. Three of eight patients with prior FLT3 inhibitor-exposed R/R AML also achieved CRc. Together, these findings support further clinical evaluation of XY0206 as a FLT3-directed therapeutic in AML, particularly in disease settings with reduced sensitivity to existing FLT3 inhibitors.
Authors
Long Shen, Yang Yang, Chenghua Xu, Bo Jiang, Xiaoxiao Duan, Xianfeng Shao, Simeng Li, Siyi Liu, Chao Huang, Lin Song, Mingyuan Sun, Jinting Fan, Ning Wang, Dong Zhang, Youyang Fang, Lichun Kang, Yajun Jiang, Mingming Niu, Junyuan Qi, Tao Cheng, Hong Wang
Abstract
Background: Despite therapeutic advances in the early-stage triple negative breast cancer (TNBC) setting, residual disease (RD) following neoadjuvant therapy remains a key predictor of a worse prognosis and is a major obstacle to improving patient outcomes. Methods: To better characterize RD and identify survival associated features, we performed comprehensive transcriptomic profiling of 340 pre-treatment stage II/III TNBCs and 70 matched post-treatment RD samples from the randomized CALGB 40603 (Alliance) Phase 2 clinical trial. Preclinical treatment strategies mimicking RD patients were explored using Antibody Drug Conjugate (ADC) treatment in patient derived xenograft (PDX) mouse models. Results: Our study shows that prognostic genomic features measured prior to treatment may differ from prognostic features measured after treatment from RD specimens. Specifically, we identified that patients with a genomic PAM50 subtype of Basal-like in RD specimens have a poor survival outcome and their matching pre-treatment tumors are characterized by elevated chromosomal amplifications of oncogenic drivers (i.e., MYC, CDK6, and CCND1) as well as significantly reduced B- and T-cell expression features. Paired analyses of Basal-like RD and matched pre-treatment tumors reveal further lymphocyte depletion in the RD, along with lower expression of MHC class I and interferon signaling, indicating an immune-cold RD microenvironment. Treatment of a Basal-like and conventional chemotherapy-resistant PDX model, resembling Basal-like RD, with sacituzumab govitecan or trastuzumab deruxtecan produced a marked antitumor response. Conclusion: RD biology differs from pre-treatment tumors, with Basal-like subtype RD following neoadjuvant chemotherapy being immune cold and associated with poor survival. Pre-clinical modeling suggests that this high-risk group may benefit from adjuvant ADC therapy. Trial registration: ClinicalTrials.gov NCT00861705 Funding: National Cancer Institute (NCI) U10CA180821 (Alliance for Clinical Trials in Oncology) NCI U24CA176171 (Alliance for Clinical Trials in Oncology) NCI UG1CA233373 (Alliance for Clinical Trials in Oncology) NCI Breast SPORE program P50-CA058223 (CMP) Susan G. Komen SAC-160074 (CMP, PDR) Breast Cancer Research Foundation BCRF-23-127 (CMP) NCI R01-CA229409 (CMP) UNC LCCC Triple Negative Breast Cancer Center (CMP)
Authors
Patrick D. Rädler, Brooke M. Felsheim, Aranzazu Fernandez-Martinez, Adam D. Pfefferle, Michele C. Hayward, Baljit Singh, William Sikov, Lisa A. Carey, Charles M. Perou
Abstract
Gut microbiota-derived trimethylamine N-oxide (TMAO) plays a role in the pathogenesis of cardiovascular disease. The role of TMAO in the pathogenesis of atrial fibrillation (AF) remains uncertain. TMAO levels were quantified in plasma from serial subjects undergoing elective cardiac catheterizations (N=5090) and shown to independently associate with prevalent AF following adjustment for risk factors (TMAO adjusted odds ratio 1.7 [95% confidence interval 1.3-2.1]; P<0.01). Human cAMP response element modulator isoform IbΔC-X transgenic mice (CREM-IbΔC-X), a spontaneous mouse model of AF, supplemented with a TMAO diet developed AF sooner. C57BL/6J mice on and off a TMAO had more inducible AF via a transesophageal pacing study compared to chow controls. Dietary choline supplementation increased circulating TMAO levels and significantly accelerated AF onset in CREM-IbΔC-X mice (P<0.01). Iodomethylcholine (IMC), the gut microbial CutC/D inhibitor that suppresses choline→TMA(O) metabolic transformation, reduced circulating TMAO levels (P<0.0001) and choline induced AF onset (P<0.01). Cecal metagenomic analyses showed that choline supplementation induced changes in microbial communities associated with AF, while many of these changes were attenuated by IMC. Choline supplementation promoted overall adverse atrial remodeling with left atrial dilation. Optical mapping studies showed that mice supplemented with choline exhibited reduced conduction velocity, shortened action potential duration at 80% repolarization, and decreased wavelength. TMAO inhibits muscarinic receptor 2 resulting in autonomic dysfunction that promotes AF. In summary, the gut microbial metabolite TMAO, independently associated with AF risk in subjects, enhances AF in multiple AF mouse models via autonomic dysfunction, and is a therapeutic target for prevention of AF.
Authors
Selvam Arjunan, Isaiah Pemberton, Xinmin S. Li, Naseer Sangwan, Lydia Akino, Emmanuel Opoku, Dmitriy Verbovetskiy, Ina Nemet, Hyun Su Kim, Haruko Masumiya, Zeneng Wang, Joseph A. Lupica, Melissa Y. Tian, Karis Mao, Deepthi P. Mallela, Maradumane Mohan, Sarah Schumacher, Julie H. Rennison, Sathyamangla Prasad, Kenneth R. Laurita, Vamsi Chodisetty, Mina K. Chung, David R. Van Wagoner, John Barnard, Jonathan D. Smith, Oussama Wazni, Stanley L. Hazen, Robert A. Koeth
Abstract
BACKGROUND Obesity and weight loss in adults have been associated with distinct metabolome and gut microbiome features, but the extent to which those associations apply to adolescent stages remain unclear.METHODS The Pediatric Obesity Microbiome and Metabolism Study (POMMS) enrolled 220 adolescents aged 10–18 with severe obesity (OB) and 67 individuals who were healthy weight controls (HWCs). Blood, stool, and clinical measures were collected at baseline and after a 6-month obesity intervention for the OB group. Metabolomic profiling in serum using targeted quantitative mass spectrometry and microbiome profiling in stool were performed, and those features were assessed for associations with BMI, insulin resistance, and inflammation. Fecal microbiome transplants (FMT) were performed on germ-free mice using samples from both groups to assess effects on weight gain and metabolic pathways.RESULTS Adolescents with OB exhibited higher serum branched-chain amino acid (BCAA) but lower branched-chain ketoacid (BCKA) levels compared with HWC. This pattern was sex- and age-dependent and differed from adults with obesity who show elevated levels of both BCAA and BCKA. Longitudinal analysis identified metabolic and microbial features correlated with changes in health measures during the intervention. The fecal microbiomes of adolescents with OB and HWC had similar diversity but differed in membership and functional potential. FMT from both OB and HWC donors had similar effects on mouse body weight, but specific taxa were linked to weight gain in recipients of FMT.CONCLUSION Adolescents with OB have unique metabolomic adaptations and microbiome signatures compared with their HWC counterparts and adults with OB.TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03139877 (Observational Study) and NCT02959034 (Repository).FUNDING SUPPORT American Heart Association Grants: 17SFRN33670990, 20PRE35180195; National Institute of Diabetes and Digestive and Kidney Diseases Grant: R24-DK110492.
Authors
Jessica R. McCann, Chengxin Yang, Nathan A. Bihlmeyer, Runshi Tang, Tracy Truong, Wei Zhou, Jie An, Jayanth Jawahar, Olga Ilkayeva, Michael J. Muehlbauer, Zhengzheng Hu, Holly Kloos Dressman, Lisa Poppe, Joshua A. Granek, Jason W. Arnold, Lawrence A. David, Julia Oh, Pixu Shi, Pinar Gumus Balikcioglu, Svati H. Shah, Sarah C. Armstrong, Christopher B. Newgard, Patrick C. Seed, John F. Rawls
Abstract
ATR inhibition is under evaluation for treatment of high-grade serous ovarian cancer (HGSOC) to reverse acquired resistance to poly (ADP-ribose) polymerase (PARP) inhibition and to exacerbate chemotherapy-induced replicative stress. Here, we define PTEN deficiency as a predictive biomarker for response to ATR inhibition, as monotherapy and in combination with PARP inhibition or gemcitabine. In response to ATR inhibition and compared to PTEN-proficient cells, PTEN-deficient cells are prone to (1) uncoupling of DNA polymerase and helicase activities, leading to excessive single-stranded DNA and replication stress; (2) cytoplasmic sequestration of CHK1, compromising cell cycle checkpoint control with reduced compensatory effects by ATM and DNA-PK, leading to mitotic catastrophe; and (3) reduced RAD51 recruitment, exacerbating replication fork instability, also leading to lethality. Retrospective analyses demonstrate that patients with HGSOC expressing low PTEN levels experience greater clinical benefit on ATR inhibitor-based trials than those with high levels. These results justify prospective trials evaluating ATR inhibition as a therapeutic strategy for PTEN-deficient tumors.
Authors
Jie Hao, Bose Kochupurakkal, Timothy B. Branigan, Ozge Sezin Somuncu, Renyan Liu, Heta Jadhav, Alexandre Andre B.A. da Costa, Yuqing Jiao, Jenny Z. Yu, David B. Martignetti, Golbahar Sadatrezaei, Sirisha Mukkavalli, Prafulla C. Gokhale, Su-Chun Cheng, Steven J. Skates, Dimitrios Nasioudis, Panagiotis A. Konstantinopoulos, Joyce F. Liu, Stephanie L. Gaillard, Robert L. Giuntoli II, Lainie P. Martin, Janos L. Tanyi, Nawar Latif, Ian S. Heller, Fiona Simpkins, Kalindi Parmar, Alan D. D'Andrea, Geoffrey I. Shapiro
Abstract
Background. CIS43LS is a long-acting mAb that targets the Plasmodium falciparum circumsporozoite protein. A phase 2 trial showed that a single dose of CIS43LS conferred >85% sterile protection against infection in Malian adults over 6 months. Understanding the pharmacokinetics and pharmacodynamics (PK/PD) of CIS43LS is critical for the further development of CIS43LS and other anti-malaria mAbs. Methods. Using 3,777 serum samples collected from 348 trial participants over the 6-month study period, we performed a PK/PD analysis of CIS43LS that included assessments for anti-drug antibodies and target-mediated drug disposition. A two-compartment, non-linear mixed effects population PK model that evaluated demographic, anthropometric, hematologic, baseline parasitemia, and endogenous IgG and IgG1 as potential covariates was used to estimate PK parameters and serum concentrations required to achieve 80% efficacy. Results. The median CIS43LS t1/2 was 63.2 days (95%CI 59.4–67.2 days). Serum concentrations ≥64 μg/mL (95%CI 49–93 μg/mL) corresponded to ≥80% efficacy against infection over 6 months. A simulated dose of 30 mg/kg maintained serum concentrations >64 µg/mL in >97.5% of individuals for 4 months, the timeframe for the World Health Organization preferred product characteristics for anti-malaria mAbs. There was no evidence of anti-drug antibodies. Among infected individuals who received CIS43LS, no marked evidence of target-mediated drug disposition was observed. Conclusion. This study indicates that protective CIS43LS levels can be maintained over the course of a single malaria season and provides guidance for PK/PD analyses of anti-malaria mAbs in malaria-endemic populations. Trial registration. NCT04329104. Funding. National Institutes of Health and Gates Foundation.
Authors
Tuan M. Tran, Zonghui Hu, Kassoum Kayentao, Aissata Ongoiba, Sam Jones, Nada Abla, Sara A. Healy, Hamidou Cisse, Bickey H. Chang, Jeff Skinner, Leonid Serebryannyy, Sandeep R. Narpala, Robin Schlesinger, Kwang Huei Low, Rachel Kazmierski, Bob C. Lin, Joana Dias, Safiatou Doumbo, Didier Doumtabe, Anne C. Preston, Shanping Li, Mary E. Peterson, Amit Oberai, Adam D. Shandling, Joseph J. Campo, Sean C Murphy, Shinyi Telscher, Emily E. Coates, Edmund V. Capparelli, Amagana Dolo, Boubacar Traore, Robert A. Seder, Peter D. Crompton
Abstract
BACKGROUND. B cell maturation antigen (BCMA) is a key therapeutic target in multiple myeloma (MM), yet its whole-body in vivo distribution and role in disease assessment remain incompletely defined. We aimed to evaluate the safety, diagnostic performance, and clinical utility of a novel BCMA-targeted PET tracer, 68Ga-PFBC01, in patients with plasma cell disorders. METHODS. We conducted a single-center, prospective, single-arm phase I trial (ClinicalTrials.gov NCT06717113). Fifty patients underwent 68Ga-PFBC01 PET/CT, including 40 with paired 18F-FDG PET/CT for head-to-head comparison. Primary outcomes included diagnostic performance (sensitivity, specificity, PPV, NPV, and inter-reader agreement). Secondary outcomes included correlations with clinical biomarkers, treatment response assessment, impact on clinical decision-making, and safety. RESULTS.68Ga-PFBC01 PET/CT demonstrated superior diagnostic performance compared with 18F-FDG PET/CT (sensitivity 96.9% vs 84.6%; specificity 71.4% vs 60.0%). Quantitative PET-derived tumor burden correlated with M protein (R = 0.325, P = 0.026), free light chains (R = 0.340–0.437, P ≤ 0.015), soluble BCMA (R = 0.433, P = 0.050), and bone marrow plasma cells (R = 0.682, P < 0.001). Imaging findings altered clinical management in multiple cases, enabling both therapy escalation and de-escalation. Blood-pool uptake strongly correlated with soluble BCMA (R = 0.899, P < 0.001) and overall disease burden (R = 0.736, P < 0.001). No serious tracer-related adverse events were observed; two patients (4%) experienced mild events. CONCLUSION.68Ga-PFBC01 PET/CT provides biologically specific, whole-body assessment of MM, outperforming 18F-FDG and enabling integrated evaluation of tumor burden and systemic disease activity, with direct implications for clinical decision-making. TRIAL REGISTRATION. ClinicalTrials.gov NCT06717113. FUNDING. National Natural Science Foundation of China (82472018, 82402320) to Prof. Lei Kang, 82402320 to Dr. Tianyao Wang); Beijing Nova Program (20240484725) to Prof. Lei Kang; National High Level Hospital Clinical Research Funding (Interdisciplinary Research Project of Peking University First Hospital, 2024IR07, Scientific and Technological Achievements Transformation Incubation Guidance Fund Project of Peking University First Hospital, 2025CX38, 2024CX18) to Prof. Lei Kang.
Authors
Tingfei Gu, Zhao Chen, Bo Tang, Tianyao Wang, Qi Yang, Huihui Liu, Zeyin Liang, Qian Wang, Yang Zhang, Yuhua Sun, Mingyi Di, Tingting Yuan, Yongkang Qiu, Yimeng Du, Lele Song, Shengnan Wu, Wei Wang, Xiaojie Xu, Yujun Dong, Lei Kang
No posts were found with this tag.
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)