tbuckley/cabot-search huggingface dataset:
AB0439 COMBINING PROMS TO DETECT DISEASE FLARE IN RHEUMATOID ARTHRITIS AND PSORIATIC ARTHRITIS IN A CLINICAL FEASIBLE WAY
Authors: A. E. M. Looijen, S. V. J. Snoeck Henkemans, A. H. M. Van der Helm – van Mil, J. J. Luime, M. R. Kok, I. Tchetverikov, M. Vis, P. H. P. De Jong
Journal: Annals of the Rheumatic Diseases (2024)
OP0162 THE TEMPORAL MORTALITY TREND IN SEROPOSITIVE AND SERONEGATIVE RHEUMATOID ARTHRITIS - A DANISH POPULATION-BASED COHORT STUDY
Authors: F. F. Lauritzen, B. G. Soussi, K. S. Duch, S. Kristensen, A. S. Mortensen, L. Dreyer
Journal: Annals of the Rheumatic Diseases (2024)
POS1083 UNBIASED ANALYSIS OF KNEE CARTILAGE THICKNESS CHANGE OVER THREE YEARS POST-TREATMENT WITH SPRIFERMIN VS. PLACEBO – A POST-HOC ANALYSIS FROM THE PHASE II FORWARD STUDY
Authors: F. Eckstein, A. Wisser, S. Maschek, W. Wirth, C. Ladel, A. R. Bihlet, C. Knight, K. Somberg, L. Zhao
Journal: Annals of the Rheumatic Diseases (2024)
OP0019 INCIDENCE AND RISK FACTORS FOR NEW ONSET INTERSTITIAL LUNG DISEASE IN SYSTEMIC SCLEROSIS: INSIGHTS FROM AN ANALYSIS OF THE EUSTAR COHORT
Authors: C. Bruni, L. Petelytska, A. Velauthapillai, L. Tofani, E. Hachulla, U. Müller-Ladner, E. Siegert, Y. Allanore, G. Riemekasten, C. Bergmann, R. Bečvář, K. Solanki, B. Anic, S. Rednic, B. Stamenković, M. Vonk, J. K. De Vries-Bouwstra, A. M. Hoffmann-Vold, M. Matucci-Cerinic, O. Distler
Journal: Annals of the Rheumatic Diseases (2024)
AB0515 RELATION AND IMPACT OF SEROPOSITIVITY ON ANKLE AND FOOT PATHOLOGIES IN RHEUMATOID ARTHRITIS: AN ULTRASOUND-BASED STUDY
Authors: M. G. Abdelzaher, S. Finzel, A. Abdelsalam, A. F. Enein, N. Abdelsalam
Journal: Annals of the Rheumatic Diseases (2024)
AB0459 BASELINE (BL) DEMOGRAPHICS AND DISEASE CHARACTERISTICS BY MENOPAUSAL STATUS AND SEX IN PATIENTS FROM A PHASE 2 TRIAL OF DEUCRAVACITINIB, A FIRST-IN-CLASS, ORAL, SELECTIVE, ALLOSTERIC TYROSINE KINASE 2 INHIBITOR, IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS (PsA)
Authors: L. Eder, R. Koti, M. J. Colombo, M. Nowak, S. Dahan
Journal: Annals of the Rheumatic Diseases (2024)
POS0589 EHR DEFINED BASELINE RA-SUBSETS CHARACTERISED BY LOCALISED JOINT INVOLVEMENT DIFFERENTIALLY ASSOCIATE WITH GENETIC RISK AND CLINICAL OUTCOMES BEYOND BASELINE
Authors: T. D. Maarseveen, M. P. Maurits, S. Böhringer, N. Steinz, S. A. Bergstra, B. M. Boxma-De Klerk, A. H. M. Van der Helm – Van Mil, C. F. Allaart, M. J. T. Reinders, T. Huizinga, E. B. Van Den Akker, R. Knevel
Journal: Annals of the Rheumatic Diseases (2024)
AB0258 CLINICAL AND SEROLOGICAL CHARACTERIZATION OF PATIENTS WITH IDIOPATHIC INFLAMMATORY MYOPATHIES
Authors: P. Martinez Calabuig, J. J. Fragío Gil, R. González-Mazarío, S. Moner Marín, L. Salvador Maicas, M. L. Sanmartín Martínez, A. Sierra Rivera, A. Rueda Cid, J. J. Lerma Garrido, C. Molina Almela, C. Campos Fernández
Journal: Annals of the Rheumatic Diseases (2024)
POS1281 CLINICAL CHARACTERISTICS OF ANTI-SYNTHETASE SYNDROME: ANALYSIS FROM THE CLASS PROJECT
Authors: S. Faghihi-Kashani, A. Yoshida, F. Bozan, G. Zanframundo, D. Rozza, A. Loganathan, E. Dourado, G. Sambataro, I. Bauer-Ventura, S. Bae, D. Lim, D. Rivero Gallegos, Y. Yamano, A. Selva-O’callaghan, A. Mammen, C. A. Scirè, C. Montecucco, C. V. Oddis, D. Fiorentino, F. Bonella, F. Miller, I. E. Lundberg, J. Schmidt, J. Rojas-Serrano, M. Hudson, M. Kuwana, M. Á. González-Gay, N. Mchugh, T. J. Corte, T. Doyle, V. Werth, R. Aggarwal, L. Cavagna
Journal: Annals of the Rheumatic Diseases (2024)
AB0410 COMPARISON OF ON-LABEL TREATMENT PERSISTENCE IN REAL-WORLD PATIENTS WITH PSORIATIC ARTHRITIS RECEIVING GUSELKUMAB VERSUS SUBCUTANEOUS TNF INHIBITORS
Authors: N. J. Shiff, J. A. Walsh, I. Lin, R. Zhao, L. Morrison, B. Emond, L. H. Yu, S. Schwartzbein, P. Lefebvre, D. Pilon, S. D. Chakravarty, P. J. Mease
Journal: Annals of the Rheumatic Diseases (2024)
POS0588 COGNITIVE IMPAIRMENT IS ASSOCIATED WITH HIGH INFLAMMATORY ACTIVITY IN PATIENTS WITH RHEUMATOID ARTHRITIS
Authors: F. Ortiz-Márquez, A. Garcia Studer, P. Borregón-Garrido, T. Ramírez-García, P. Cabezudo-García, N. Mena-Vázquez
Journal: Annals of the Rheumatic Diseases (2024)
AB0520 METHOTREXATE MAINTENANCE IN RHEUMATOID ARTHRITIS, TWO YEARS AFTER INITIATION OF A FIRST TARGETED THERAPY: RESULTS FROM THE PROSPECTIVE STRATEGE2 STUDY
Authors: C. Gaujoux-Viala, E. Dernis, E. Senbel, H. Herman-Demars, J. Becker, A. Courbeyrette, R. M. Flipo
Journal: Annals of the Rheumatic Diseases (2024)
AB0384 CANCER IMMUNOTHERAPY REVEALED NON-EXACERBATING EFFECT ON PATIENTS WITH AUTOIMMUNE RHEUMATIC DISEASES: A RETROSPECTIVE COHORT STUDY
Authors: P. H. Tsai, Y. F. Fang, Y. F. Chen, Y. C. Wang, C. H. Hsieh
Journal: Annals of the Rheumatic Diseases (2024)
POS0721 CCN1 IS A NOVEL THERAPEUTIC TARGET FOR REDUCING STRUCTURAL DAMAGE IN RHEUMATOID ARTHRITIS: DEMONSTRATION FROM 2 PRECLINICAL MODELS
Authors: J. Avouac, M. Lesturgie, V. Gonzalez, A. Cauvet, F. Tilotta, Y. Allanore
Journal: Annals of the Rheumatic Diseases (2024)
AB0458 DEUCRAVACITINIB, A SELECTIVE, ALLOSTERIC TYROSINE KINASE 2 INHIBITOR, IN ACTIVE PSA: ASSESSMENT OF DIRECT AND INDIRECT IMPACT ON PAIN AND FATIGUE OUTCOMES BY MEDIATION ANALYSIS IN A PHASE 2 CLINICAL TRIAL
Authors: P. J. Mease, L. Eder, A. Ogdie, A. Deodhar, S. Banerjee, Y. M. Jou, M. Nowak, T. Lehman, V. Strand
Journal: Annals of the Rheumatic Diseases (2024)
AB0409 IMPROVEMENT IN PAIN-ASSOCIATED BIOMARKERS WITH DEUCRAVACITINIB, A FIRST-IN-CLASS, ORAL, SELECTIVE, ALLOSTERIC TYROSINE KINASE 2 INHIBITOR, IN PATIENTS WITH PSORIATIC ARTHRITIS (PsA) IN A DOUBLE-BLIND PHASE 2 STUDY (IM011-084)
Authors: P. J. Mease, C. T. Ritchlin, L. Gao, P. Schafer, M. Nowak, I. M. Catlett, J. Liu
Journal: Annals of the Rheumatic Diseases (2024)
AB0510 UNVEILING THE REAL-WORLD IMPACT OF UPADACITINIB – DOES CLINICAL REMISSION MIRROR THE PATIENT’S PERSPECTIVE ON RHEUMATOID ARTHRITIS?
Authors: T. Witte, U. Kiltz, F. Haas, E. Riechers, D. Adolf, U. Prothmann, K. Famulla, A. Rössler, K. Götz, K. Krüger
Journal: Annals of the Rheumatic Diseases (2024)
POS0962 UNRAVELING THE IMPACT OF EARLY DISEASE MANAGEMENT ON RADIOLOGIC OUTCOME IN PSORIATIC ARTHRITIS
Authors: G. H. Koc, M. R. Kok, S. V. J. Snoeck Henkemans, J. J. Luime, I. Tchetverikov, J. H. Van der Kaap, P. Baudoin, P. Kok, Y. Goekoop-Ruiterman, J. Bijsterbosch, M. Van Oosterhout, L. A. Korswagen, R. J. E. M. Dolhain, M. Vis
Journal: Annals of the Rheumatic Diseases (2024)
POS0979 REAL-WORLD DISEASE BURDEN BY ARTICULAR INVOLVEMENT AMONG PATIENTS WITH PSORIATIC ARTHRITIS IN THE COREVITAS PSORIATIC ARTHRITIS/SPONDYLOARTHRITIS REGISTRY
Authors: P. J. Mease, C. D. Saffore, X. Ye, P. Nakasato, M. Kelleman, N. Middaugh, K. Ho, A. Ogdie
Journal: Annals of the Rheumatic Diseases (2024)
POS0644 IMPACT OF CHRONIC INFLAMMATION ON BODY COMPOSITION IN RHEUMATOID ARTHRITIS PATIENTS
Authors: A. Garcia Studer, F. Ortiz-Márquez, P. Borregón-Garrido, R. Redondo-Rodriguez, S. Manrique-Arija, N. Mena-Vázquez
Journal: Annals of the Rheumatic Diseases (2024)
POS0645 NAILFOLD VIDEOCAPILLAROSCOPY AS MARKER OF MICROVASCULAR STATUS IN RHEUMATOID ARTRITIS MAY ALSO IDENTIFY THE CONCOMITANT PRESENCE OF OVERLAP SYNDROMES
Authors: T. Vojinovic, R. Campitiello, A. Pinelli, F. Lalli, E. Gotelli, C. Pizzorni, A. Sulli, V. Smith, M. Cutolo
Journal: Annals of the Rheumatic Diseases (2024)
OP0063 GLUCOCORTICOID INDUCED OSTEOPOROSIS: PROPHYLAXIS HABITS IN PATIENTS TREATED WITH HIGH-DOSE PREDNISONE
Authors: A. Naranjo, J. Falcón, M. M. Plasencia, F. De la Nuez, J. Moreno, S. Ojeda
Journal: Annals of the Rheumatic Diseases (2024)
A platform to deliver single and bi-specific Cas9/guide RNA to perturb genes in vitro and in vivo
Authors: Yi-Jia Li, Sheng-Hsuan Chien, Rui Huang, Andreas Herrmann, Qianqian Zhao, Pei-Chuan Li, Chunyan Zhang, Antons Martincuks, Nicole Lugo Santiago, Katherine Zong, Piotr Swiderski, Ross A. Okimoto, Mihae Song, Lorna Rodriguez, Stephen J. Forman, Xiuli Wang, Hua Yu
Journal: Molecular Therapy (2024)

Although CRISPR-Cas9 technology is poised to revolutionize the treatment of diseases with underlying genetic mutations, it faces some significant issues limiting clinical entry. They include low-efficiency in vivo systemic delivery and undesired off-target effects. Here, we demonstrate, by modifying Cas9 with phosphorothioate-DNA oligos (PSs), that one can efficiently deliver single and bi-specific CRISPR-Cas9/guide RNA (gRNA) dimers in vitro and in vivo with reduced off-target effects. We show that PS-Cas9/gRNA-mediated gene knockout preserves chimeric antigen receptor T cell viability and expansion in vitro and in vivo. PS-Cas9/gRNA mediates gene perturbation in patient-derived tumor organoids and mouse xenograft tumors, leading to potent tumor antitumor effects. Further, HER2 antibody-PS-Cas9/gRNA conjugate selectively perturbs targeted genes in HER2+ ovarian cancer xenografts in vivo. Moreover, we created bi-specific PS-Cas9 with two gRNAs to target two adjacent sequences of the same gene, leading to efficient targeted gene disruption ex vivo and in vivo with markedly reduced unintended gene perturbation. Thus, the cell-penetrating PS-Cas9/gRNA can achieve efficient systemic delivery and precision in gene disruption. Although CRISPR-Cas9 technology is poised to revolutionize the treatment of diseases with underlying genetic mutations, it faces some significant issues limiting clinical entry. They include low-efficiency in vivo systemic delivery and undesired off-target effects. Here, we demonstrate, by modifying Cas9 with phosphorothioate-DNA oligos (PSs), that one can efficiently deliver single and bi-specific CRISPR-Cas9/guide RNA (gRNA) dimers in vitro and in vivo with reduced off-target effects. We show that PS-Cas9/gRNA-mediated gene knockout preserves chimeric antigen receptor T cell viability and expansion in vitro and in vivo. PS-Cas9/gRNA mediates gene perturbation in patient-derived tumor organoids and mouse xenograft tumors, leading to potent tumor antitumor effects. Further, HER2 antibody-PS-Cas9/gRNA conjugate selectively perturbs targeted genes in HER2+ ovarian cancer xenografts in vivo. Moreover, we created bi-specific PS-Cas9 with two gRNAs to target two adjacent sequences of the same gene, leading to efficient targeted gene disruption ex vivo and in vivo with markedly reduced unintended gene perturbation. Thus, the cell-penetrating PS-Cas9/gRNA can achieve efficient systemic delivery and precision in gene disruption.
POS0966 PSORIATIC ARTHRITIS PATIENT PROFILES ARE DIFFERENT BETWEEN RANDOMISED CONTROLLED TRIALS OF BIOLOGICAL DISEASE-MODIFYING ANTIRHEUMATIC DRUGS AND A REAL-WORLD STUDY OVER THE SAME TIMEFRAME (PSABIO) - A LITERATURE REVIEW WITH META-ANALYSIS
Authors: G. Alle, C. López-Medina, S. Siebert, F. Lavie, W. Noel, J. S. Smolen, L. Gossec
Journal: Annals of the Rheumatic Diseases (2024)
POS1057 DXA EVALUATION OF BONE FRAGILITY 2 YEARS AFTER BARIATRIC SURGERY IN PATIENTS WITH OBESITY
Authors: M. Fauny, M. Halin, E. Allado, L. Brunaud, C. Nomine-Criqui, E. Albuisson, I. Chary Valckenaere, D. Quilliot, D. Loeuille
Journal: Annals of the Rheumatic Diseases (2024)
POS1304 SAFETY AND EFFECTIVENESS OF RITUXIMAB TAPERING IN IDIOPATHIC INFLAMMATORY MYOPATHIES: REAL-WORLD DATA FROM A MONOCENTRIC STUDY
Authors: S. Stano, M. Fornaro, L. Coladonato, V. Spedicato, M. Capodiferro, D. Catamerò, F. Cacciapaglia, F. Iannone
Journal: Annals of the Rheumatic Diseases (2024)
Blockade of glucose-6-phosphate dehydrogenase induces immunogenic cell death and accelerates immunotherapy
Authors: Motoki Nakamura, Tetsuya Magara, Maki Yoshimitsu, Shinji Kano, Hiroshi Kato, Keisuke Yokota, Katsuhiro Okuda, Akimichi Morita
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Enhanced glucose metabolism has been reported in many cancers. Glucose-6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme involved in the pentose phosphate pathway, which maintains NADPH levels and protects cells from oxidative damage. We recently found that low G6PD expression correlates with active tumor immunity. However, the mechanism involving G6PD and tumor immunity remained unclear. Methods We conducted in vitro studies using G6PD-knocked down malignant melanoma cells, pathway analysis using the GEO dataset, in vivo studies in combination with immune checkpoint inhibitors (ICIs) using a mouse melanoma model, and prognostic analysis in 42 melanoma patients and 30 lung cancer patients who were treated with ICIs. Results Inhibition of G6PD, both chemically and genetically, has been shown to decrease the production of NADPH and reduce their oxidative stress tolerance. This leads to cell death, which is accompanied by the release of high mobility group box 1 and the translocation of calreticulin to the plasma membrane. These findings suggested that inhibiting G6PD can induce immunogenic cell death. In experiments with C57BL/6 mice transplanted with G6PD-knockdown B16 melanoma cells and treated with anti-PD-L1 antibody, a significant reduction in tumor size was observed. Interestingly, inhibiting G6PD in only a part of the lesions increased the sensitivity of other lesions to ICI. Additionally, out of 42 melanoma patients and 30 lung cancer patients treated with ICIs, those with low G6PD expression had a better prognosis than those with high G6PD expression (p=0.0473; melanoma, p=0.0287; lung cancer). Conclusion G6PD inhibition is a potent therapeutic strategy that triggers immunogenic cell death in tumors, significantly augmenting the efficacy of immunotherapies.
POS0967 REAL-WORLD USE OF UPADACITINIB AND IMPACT ON MINIMAL DISEASE ACTIVITY IN PATIENTS WITH OLIGO- OR POLY-ARTICULAR PSORIATIC ARTHRITIS: DATA FROM THE UPJOINT STUDY
Authors: S. G. Werner, I. Schwarze, X. Baraliakos, M. Fiene, J. Walter, L. Bessette, H. Allard-Chamard, M. C. Laliberté, T. Girard, K. Jeromin, N. Baschuk, A. Hueber
Journal: Annals of the Rheumatic Diseases (2024)
Prophylactic IL-23 blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy
Authors: Mingyi Ju, Jiaojiao Zhang, Zhuoyuan Deng, Minjie Wei, Lianghua Ma, Ting Chen, Lin Zhao
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Immune-related adverse events (irAEs), characterized by targeted inflammation, occur in up to 60% of patients with melanoma treated with immune checkpoint inhibitors (ICIs). Evidence proved that the baseline peripheral blood profiles of patients at risk for severe irAEs development paralleled clinical autoimmunity. Interleukin (IL)-23 blockade with risankizumab is recommended for cases that are suffering from autoimmune disease, such as autoimmune colitis. However, currently, the role of IL-23 in irAEs onset and severity remains poorly understood. Methods The pro-inflammatory cytokines most associated with severe irAEs onset were identified by retrospective analysis based on GSE186143 data set. To investigate the efficacy of prophylactic IL-23 blockade administration to prevent irAEs, refer to a previous study, we constructed two irAEs murine models, including dextran sulfate sodium salt (DSS)-induced colitis murine model and a combined-ICIs-induced irAEs murine model. To further explore the applicability of our findings, murine models with graft-versus-host disease were established, in which Rag2 −/− Il2rg −/− mice were transferred with human peripheral blood mononuclear cells and received combined cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1) treatment. Human melanoma cells were xenografted into these mice concomitantly. Results Here we show that IL-23 was upregulated in the serum of patients suffering from irAEs after dual anti-CTLA-4 and anti-PD-1 treatment, and increased as a function of irAEs severity. Additionally, Augmented CD4 + Tems may preferentially underlie irAEs onset. Treating mice with anti-mouse IL-23 antibody concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, preserves antitumor efficacy. Moreover, in xenografted murine models with irAEs, prophylactic blockade of human IL-23 using clinically available IL-23 inhibitor (risankizumab) ameliorated colitis, hepatitis and lung inflammation, and moreover, immunotherapeutic control of tumors was retained. Finally, we also provided a novel machine learning-based computational framework based on two blood-based features—IL-23 and CD4 + Tems—that may have predictive potential for severe irAEs and ICIs response. Conclusions Our study not only provides clinically feasible strategies to dissociate efficacy and toxicity in the use of combined ICIs for cancer immunotherapy, but also develops a blood-based biomarker that makes it possible to achieve a straightforward and non-invasive, detection assay for early prediction of irAEs onset.
Reply to Francesco Montorsi, Francesco Montorsi, Pietro Scilipoti, Alessandro Viti, Alfonso Santangelo, Giuseppe Rosiello, and Marco Moschini’s Letter to the Editor re: Jeremy Yuen-Chun Teoh, Cheung-Hing Cheng, Chiu-Fung Tsang, et al. Transurethral En Bloc Resection Versus Standard Resection of Bladder Tumour: A Randomised, Multicentre, Phase 3 Trial. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2024.04.015
Authors: Jeremy Yuen-Chun Teoh, Peter Ka-Fung Chiu, Chi-Hang Yee, Chi-Fai Ng
Journal: European Urology (2024)
Camptothecin multifunctional nanoparticles effectively achieve a balance between the efficacy of breast cancer treatment and the preservation of intestinal homeostasis
Authors: Qingya Liu, Yun Yang, Meng Pan, Kun Shi, Dong Mo, Yicong Li, Meng Wang, Linfeng Guo, Zhiyong Qian
Journal: Bioactive Materials (2024)

Camptothecin (CPT) exhibits potent antitumor activity; however, its clinical application is limited by significant gastrointestinal adverse effects (GAEs). Although the severity of GAEs associated with CPT derivatives has decreased, the incidence rate of these adverse effects has remained high. CPT multifunctional nanoparticles (PCRHNs) have the potential to increase the efficacy of CPT while reducing side effects in major target organs; however, the impact of PCRHNs on the GAEs from CPT remains uncertain. Here, we investigated the therapeutic effects of PCRHNs and different doses of CPT and examined their impacts on the intestinal barrier and the intestinal microbiota. We found that the therapeutic efficacy of PCRHNs + Laser treatment was superior to that of high-dose CPT, and PCRHNs + Laser treatment also provided greater benefits by helping maintain intestinal barrier integrity, intestinal microbiota diversity, and intestinal microbiota abundance. In summary, compared to high-dose CPT treatment, PCRHNs + Laser treatment can effectively balance therapeutic effects and GAEs. A high dose of CPT promotes the enrichment of the pathogenic bacteria
Age-related alveolar bone maladaptation in adult orthodontics: finding new ways out
Authors: Yunfan Zhang, Jiale Yan, Yuning Zhang, Hao Liu, Bing Han, Weiran Li
Journal: International Journal of Oral Science (2024)

Abstract Compared with teenage patients, adult patients generally show a slower rate of tooth movement and more pronounced alveolar bone loss during orthodontic treatment, indicating the maladaptation of alveolar bone homeostasis under orthodontic force. However, this phenomenon is not well-elucidated to date, leading to increased treatment difficulties and unsatisfactory treatment outcomes in adult orthodontics. Aiming to provide a comprehensive knowledge and further inspire insightful understanding towards this issue, this review summarizes the current evidence and underlying mechanisms. The age-related abatements in mechanosensing and mechanotransduction in adult cells and periodontal tissue may contribute to retarded and unbalanced bone metabolism, thus hindering alveolar bone reconstruction during orthodontic treatment. To this end, periodontal surgery, physical and chemical cues are being developed to reactivate or rejuvenate the aging periodontium and restore the dynamic equilibrium of orthodontic-mediated alveolar bone metabolism. We anticipate that this review will present a general overview of the role that aging plays in orthodontic alveolar bone metabolism and shed new light on the prospective ways out of the impasse.
Gingipain from Porphyromonas gingivalis causes insulin resistance by degrading insulin receptors through direct proteolytic effects
Authors: Fen Liu, Bofeng Zhu, Ying An, Zhifei Zhou, Peiying Xiong, Xuan Li, Yang Mi, Tongqiang He, Faming Chen, Buling Wu
Journal: International Journal of Oral Science (2024)

Abstract Periodontitis is a critical risk factor for the occurrence and development of diabetes. Porphyromonas gingivalis may participate in insulin resistance (IR) caused by periodontal inflammation, but the functional role and specific mechanisms of P. gingivalis in IR remain unclear. In the present study, clinical samples were analysed to determine the statistical correlation between P. gingivalis and IR occurrence. Through culturing of hepatocytes, myocytes, and adipocytes, and feeding mice P. gingivalis orally, the functional correlation between P. gingivalis and IR occurrence was further studied both in vitro and in vivo. Clinical data suggested that the amount of P. gingivalis isolated was correlated with the Homeostatic Model Assessment for IR score. In vitro studies suggested that coculture with P. gingivalis decreased glucose uptake and insulin receptor (INSR) protein expression in hepatocytes, myocytes, and adipocytes. Mice fed P. gingivalis tended to undergo IR. P. gingivalis was detectable in the liver, skeletal muscle, and adipose tissue of experimental mice. The distribution sites of gingipain coincided with the downregulation of INSR. Gingipain proteolysed the functional insulin-binding region of INSR. Coculture with P. gingivalis significantly decreased the INSR–insulin binding ability. Knocking out gingipain from P. gingivalis alleviated the negative effects of P. gingivalis on IR in vivo. Taken together, these findings indicate that distantly migrated P. gingivalis may directly proteolytically degrade INSR through gingipain, thereby leading to IR. The results provide a new strategy for preventing diabetes by targeting periodontal pathogens and provide new ideas for exploring novel mechanisms by which periodontal inflammation affects the systemic metabolic state.
l-[5-11C]Glutamine PET imaging noninvasively tracks dynamic responses of glutaminolysis in non-alcoholic steatohepatitis
Authors: Yiding Zhang, Lin Xie, Masayuki Fujinaga, Yusuke Kurihara, Masanao Ogawa, Katsushi Kumata, Wakana Mori, Tomomi Kokufuta, Nobuki Nengaki, Hidekatsu Wakizaka, Rui Luo, Feng Wang, Kuan Hu, Ming-Rong Zhang
Journal: Acta Pharmaceutica Sinica B (2024)

Inhibiting glutamine metabolism has been proposed as a potential treatment strategy for improving non-alcoholic steatohepatitis (NASH). However, effective methods for assessing dynamic metabolic responses during interventions targeting glutaminolysis have not yet emerged. Here, we developed a positron emission tomography (PET) imaging platform using L-[5-11C]glutamine ([11C]Gln) and evaluated its efficacy in NASH mice undergoing metabolic therapy with bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a glutaminase 1 (GLS1) inhibitor that intervenes in the first and rate-limiting step of glutaminolysis. PET imaging with [11C]Gln effectively delineated the pharmacokinetics of L-glutamine, capturing its temporal-spatial pattern of action within the body. Furthermore, [11C]Gln PET imaging revealed a significant increase in hepatic uptake in methionine and choline deficient (MCD)-fed NASH mice, whereas systemic therapeutic interventions with BPTES reduced the hepatic avidity of [11C]Gln in MCD-fed mice. This reduction in [11C]Gln uptake correlated with a decrease in GLS1 burden and improvements in liver damage, indicating the efficacy of BPTES in mitigating NASH-related metabolic abnormalities. These results suggest that [11C]Gln PET imaging can serve as a noninvasive diagnostic platform for whole-body, real-time tracking of responses of glutaminolysis to GLS1 manipulation in NASH, and it may be a valuable tool for the clinical management of patients with NASH undergoing glutaminolysis-based metabolic therapy.