bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting PARG induces tumor cell growth inhibition and antitumor immune response by reducing phosphorylated STAT3 in ovarian cancer
Authors: Martincuks Antons , Zhang Chunyan , Austria Theresa , Li Yi-Jia , Huang Rui , Lugo Santiago Nicole , Kohut Adrian , Zhao Qianqian , Borrero Rosemarie Martinez , Shen Binghui , Cristea Mihaela , Wang Edward W , Song Mihae , Rodriguez-Rodriguez Lorna , Yu Hua 
Published: April 2024

BackgroundOvarian cancer is the most lethal gynecological malignancy, with limited treatment options after failure of standard therapies. Despite the potential of poly(ADP-ribose) polymerase inhibitors in treating DNA damage response (DDR)-deficient ovarian cancer, the development of resistance and immunosuppression limit their efficacy, necessitating alternative therapeutic strategies. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) represent a novel class of inhibitors that are currently being assessed in preclinical and clinical studies for cancer treatment.MethodsBy using a PARG small-molecule inhibitor, COH34, and a cell-penetrating antibody targeting the PARG’s catalytic domain, we investigated the effects of PARG inhibition on signal transducer and activator of transcription 3 (STAT3) in OVCAR8, PEO1, andBrca1-null ID8 ovarian cancer cell lines, as well as in immune cells. We examined PARG inhibition-induced effects on STAT3 phosphorylation, nuclear localization, target gene expression, and antitumor immune responses in vitro, in patient-derived tumor organoids, and in an immunocompetentBrca1-null ID8 ovarian mouse tumor model that mirrors DDR-deficient human high-grade serous ovarian cancer. We also tested the effects of overexpressing a constitutively activated STAT3 mutant on COH34-induced tumor cell growth inhibition.ResultsOur findings show that PARG inhibition downregulates STAT3 activity through dephosphorylation in ovarian cancer cells. Importantly, overexpression of a constitutively activated STAT3 mutant in tumor cells attenuates PARG inhibitor-induced growth inhibition. Additionally, PARG inhibition reduces STAT3 phosphorylation in immune cells, leading to the activation of antitumor immune responses, shown in immune cells cocultured with ovarian cancer patient tumor-derived organoids and in immune-competent mice-bearing mouse ovarian tumors.ConclusionsWe have identified a novel antitumor mechanism underlying PARG inhibition beyond its primary antitumor effects through blocking DDR in ovarian cancer. Furthermore, targeting PARG activates antitumor immune responses, thereby potentially increasing response rates to immunotherapy in patients with ovarian cancer.
Blocking senescence and tolerogenic function of dendritic cells induced by γδ Treg cells enhances tumor-specific immunity for cancer immunotherapy
Authors: Si Fusheng , Liu Xia , Tao Yan , Zhang Yuanqin , Ma Feiya , Hsueh Eddy C , Puram Sidharth V , Peng Guangyong 
Published: April 2024

BackgroundRegulatory T (Treg) cells are a key component in maintaining the suppressive tumor microenvironment and immune suppression in different types of cancers. A precise understanding of the molecular mechanisms used by Treg cells for immune suppression is critical for the development of effective strategies for cancer immunotherapy.MethodsSenescence development and tolerogenic functions of dendritic cells (DCs) induced by breast cancer tumor-derived γδ Treg cells were fully characterized using real-time PCR, flow cytometry, western blot, and functional assays. Loss-of-function strategies with pharmacological inhibitor and/or neutralizing antibody were used to identify the potential molecule(s) and pathway(s) involved in DC senescence and dysfunction induced by Treg cells. Impaired tumor antigen HER2-specific recognition and immune response of senescent DCs induced by γδ Treg cells were explored in vitro and in vivo in humanized mouse models. In addition, the DC-based HER2 tumor vaccine immunotherapy in breast cancer models was performed to explore the enhanced antitumor immunity via prevention of DC senescence through blockages of STAT3 and programmed death-ligand 1 (PD-L1) signaling.ResultsWe showed that tumor-derived γδ Treg cells promote the development of senescence in DCs with tolerogenic functions in breast cancer. Senescent DCs induced by γδ Treg cells suppress Th1 and Th17 cell differentiation but promote the development of Treg cells. In addition, we demonstrated that PD-L1 and STAT3 signaling pathways are critical and involved in senescence induction in DCs mediated by tumor-derived γδ Treg cells. Importantly, our complementary in vivo studies further demonstrated that blockages of PD-L1 and/or STAT3 signaling can prevent γδ Treg-induced senescence and reverse tolerogenic functions in DCs, resulting in enhanced HER2 tumor-specific immune responses and immunotherapy efficacy in human breast cancer models.ConclusionsThese studies not only dissect the suppressive mechanism mediated by tumor-derived γδ Treg cells on DCs in the tumor microenvironment but also provide novel strategies to prevent senescence and dysfunction in DCs and enhance antitumor efficacy mediated by tumor-specific T cells for cancer immunotherapy.
Preclinical development of novel PD-L1 tracers and first-in-human study of [68Ga]Ga-NOTA-RW102 in patients with lung cancers
Authors: Zhang You , Cao Min , Wu Yanfei , Malih Sara , Xu Dong , Yang Erpeng , Younis Muhsin H , Lin Wilson , Zhao Haitao , Wang Cheng , Liu Qiufang , Engle Jonathan W , Rasaee Mohammad J , Guan Yihui , Huang Gang , Liu Jianjun , Cai Weibo , Xie Fang , Wei Weijun 
Published: April 2024

BackgroundThe programmed cell death protein-1 (PD-1)/programmed death receptor ligand 1 (PD-L1) axis critically facilitates cancer cells’ immune evasion. Antibody therapeutics targeting the PD-1/PD-L1 axis have shown remarkable efficacy in various tumors. Immuno-positron emission tomography (ImmunoPET) imaging of PD-L1 expression may help reshape solid tumors’ immunotherapy landscape.MethodsBy immunizing an alpaca with recombinant human PD-L1, three clones of thevariable domain of theheavy chain ofheavy-chain only antibody (VHH) were screened, and RW102 with high binding affinity was selected for further studies. ABDRW102, a VHH derivative, was further engineered by fusing RW102 with the albumin binder ABD035. Based on the two targeting vectors, four PD-L1-specific tracers ([68Ga]Ga-NOTA-RW102, [68Ga]Ga-NOTA-ABDRW102, [64Cu]Cu-NOTA-ABDRW102, and [89Zr]Zr-DFO-ABDRW102) with different circulation times were developed. The diagnostic efficacies were thoroughly evaluated in preclinical solid tumor models, followed by a first-in-human translational investigation of [68Ga]Ga-NOTA-RW102 in patients with non-small cell lung cancer (NSCLC).ResultsWhile RW102 has a high binding affinity to PD-L1 with an excellent KDvalue of 15.29 pM, ABDRW102 simultaneously binds to human PD-L1 and human serum albumin with an excellent KDvalue of 3.71 pM and 3.38 pM, respectively. Radiotracers derived from RW102 and ABDRW102 have differentin vivocirculation times. In preclinical studies, [68Ga]Ga-NOTA-RW102 immunoPET imaging allowed same-day annotation of differential PD-L1 expression with specificity, while [64Cu]Cu-NOTA-ABDRW102 and [89Zr]Zr-DFO-ABDRW102 enabled longitudinal visualization of PD-L1. More importantly, a pilot clinical trial shows the safety and diagnostic value of [68Ga]Ga-NOTA-RW102 immunoPET imaging in patients with NSCLCs and its potential to predict immune-related adverse effects following PD-L1-targeted immunotherapies.ConclusionsWe developed and validated a series of PD-L1-targeted tracers. Initial preclinical and clinical evidence indicates that immunoPET imaging with [68Ga]Ga-NOTA-RW102 holds promise in visualizing differential PD-L1 expression, selecting patients for PD-L1-targeted immunotherapies, and monitoring immune-related adverse effects in patients receiving PD-L1-targeted treatments.Trial registration numberNCT06165874.
Incomplete sensorimotor paresis after upper abdominal surgery with TEA and spinal epidural lipomatosis: a case report
Authors: Zugaj Marco Richard , Gutzeit Oliver , Mayer Victoria Louise , Ishak Basem , Gumbinger Christoph , Weigand Markus Alexander , Keßler Jens 
Published: April 2024

IntroductionThis case report documents a postoperative, incomplete sensorimotor paraparesis from thoracic vertebral body 6 (Th6) after combined anesthesia for upper abdominal surgery in a patient who had a thoracic localization of spinal epidural lipomatosis (SEL).Case presentationThe patient was treated in our clinic with a thoracic epidural catheter (TEA) for perioperative analgesia during a partial duodenopancreatectomy. Paraparetic symptoms occurred 20 hours after surgery. Initial MRI did not show bleeding, infection or spinal cord damage and the neurosurgeon consultants recommended observation. The neurological examination and the third follow-up MRI on 15th postoperative day showed ventrolateral damage of the spinal cord at level Th6. It is possible that local anesthetic compressed the spinal cord in addition to the existing lipomatosis and the thoracic kyphosis. The paraparesis improved during follow-up paraplegiologic treatment.ConclusionSo far, only two uncomplicated lumbar epidural catheter anesthesias have been described in patients who had a lumbar SEL. Epidural catheter anesthesia is a safe and effective method of pain control. But it is important to carefully identify and stratify patients with risk factors during the premedication visit. In patients who had kyphosis and thoracic localization of SEL, TEA may only be used after a risk–benefit assessment.
Fluoroscopy-guided high-intensity focused ultrasound neurotomy of the lumbar zygapophyseal joints: a prospective, open-label study
Authors: Gofeld Michael , Smith Kevin J , Bhatia Anuj , Djuric Vladimir , Leblang Suzanne , Rebhun Niv , Aginsky Ron , Miller Eric , Skoglind Brian , Hananel Arik 
Published: April 2024

ObjectiveThe objective of this study is to investigate safety and effectiveness of a fluoroscopy-guided high-intensity focused ultrasound (HIFU) system for thermal ablation of the lumbar medial branch nerves.MethodsThis dual center prospective cohort study enrolled 30 participants with lumbar zygapophyseal joint syndrome. Each participant previously had a positive response to either a single diagnostic analgesic block or radiofrequency ablation (RFA). The primary effectiveness outcome was individual responder rate, defined as a reduction of two points or more on the pain intensity numerical rating scale without an increase in opioid intake, or a reduction in opioid intake without an increase in pain at 6 months after the intervention. The primary safety outcome was procedure-related or device-related adverse events (AEs). Secondary outcome variables included MRI evidence of tissue ablation, Oswestry Disability Index, 12-Item Short Form Health Survey, Brief Pain Inventory, and Patient Global Impression of Change.ResultsThe individual responder rate was 89.7% at 2 days, 89.7% at 7 days, 72.4% at 14 days, 82.1% at 30 days, 59.3% at 90 days and 82.6% at 180 days. The average Numeric Rating Scale for pain severity decreased from 7.1 at baseline to 3.0 (N=29) after 2 days, 3.0 (N=29) after 7 days, 3.1 (N=29) after 14 days, 3.2 (N=28) after 30 days, 4.3 (N=27) after 90 days, and 3.3 (N=23) after 180 days. All participants tolerated the procedure well with no significant side effects or complications.ConclusionsFluoroscopy-guided HIFU neurotomy achieved clinical responses comparable with RFA, and there were no significant device-related or procedure-related AEs.Trial registration numberNCT04129034.
Induction of regulatory T cells and efficacy of low-dose interleukin-2 in systemic sclerosis: interventional open-label phase 1–phase 2a study
Authors: Barde François , Lorenzon Roberta , Vicaut Eric , Rivière Sébastien , Cacoub Patrice , Cacciatore Carlotta , Rosenzwajg Michelle , Daguenel-Nguyen Anne , Fain Olivier , Klatzmann David , Mekinian Arsène 
Published: April 2024

BackgroundSystemic sclerosis (SSc) is a chronic autoimmune disease, with impaired immune response, increased fibrosis and endothelial dysfunction. Regulatory T cells (Tregs), which are essential to control inflammation, tissue repair and autoimmunity, have a decreased frequency and impaired function in SSc patients. Low-dose interleukin-2 (IL-2LD) can expand and activate Tregs and has, therefore, a therapeutic potential in SSc.ObjectiveWe aimed to assess the safety and biological efficacy of IL-2LDin patients with SSc.MethodsAs part of the TRANSREG open-label phase IIa basket trial in multiple autoimmune diseases, we studied nine patients with SSc without severe organ involvement. Patients received 1 million international units (MIU)/day of IL-2 for 5 days, followed by fortnightly injections for 6 months. Laboratory and clinical evaluations were performed between baseline and month 6.ResultsAt day 8, the primary endpoint (Treg frequency) was reached with a 1.8±0.5-fold increase of Treg levels among CD4+T lymphocytes (p=0.0015). There were no significant changes in effector T cells nor in B cells. IL-2LDwas well tolerated, and no serious adverse events related to treatment occurred. There was a globally stable measurement in the modified Rodnan skin score and Valentini score at month 6. Disease activity and severity measures, the quality of life evaluated by EuroQL-5D-5L and pulmonary function test parameters remained stable during the study period.ConclusionIL-2LDat a dosage of 1 MIU/day safely and selectively activates and expands Tregs. Clinical signs remain stable during the study period. This opens the door to properly powered phase II efficacy trials investigating IL-2LDtherapeutic efficacy in SSc.
Diagnostic accuracy in axial spondyloarthritis: a systematic evaluation of the role of clinical information in the interpretation of sacroiliac joint imaging
Authors: Pohlner Tim , Deppe Dominik , Ziegeler Katharina , Proft Fabian , Protopopov Mikhail , Rademacher Judith , Rios Rodriguez Valeria , Torgutalp Murat , Braun Jürgen , Diekhoff Torsten , Poddubnyy Denis 
Published: April 2024

ObjectivesRadiography and MRI of the sacroiliac joints (SIJ) are relevant for the diagnosis and classification of patients with axial spondyloarthritis (axSpA). This study aimed to evaluate the impact of clinical information (CI) on the accuracy of imaging interpretation.MethodsOut of 109 patients referred because of suspicion of axSpA with complete imaging sets (radiographs and MRI of SIJ), 61 were diagnosed with axSpA (56%). Images were independently evaluated by three radiologists in four consecutive reading campaigns: radiographs and radiographs+MRI without and with CI including demographic data, SpA features, physical activity and pregnancy. Radiographs were scored according to the modified New York criteria, and MRIs for inflammatory and structural changes compatible with axSpA (yes/no). The clinical diagnosis was taken as reference standard. The compatibility of imaging findings with a diagnosis of axSpA (precision) before and after the provision of CI and radiologists’ confidence with their findings (0–10) were evaluated.ResultsThe precision of radiographs evaluation without versus with CI increased from 70% to 78% (p=0.008), and for radiographs+MRI from 81% to 82% (p=1.0), respectively. For CR alone, the sensitivity and specificity of radiologic findings were 51% and 94% without and 60% and 100% with CI, while, for radiographs+MRI, they were 74% and 90% vs 71% and 98%, respectively. The diagnostic confidence of radiologists increased from 5.2±1.9 to 6.0±1.7 with CI for radiographs, and from 6.7±1.6 to 7.2±1.6 for radiographs+MRI, respectively.ConclusionThe precision, specificity and diagnostic confidence of radiologic evaluation increased when CI was provided.
Recommendations for physical activity and exercise in persons living with Systemic Lupus Erythematosus (SLE): consensus by an international task force
Authors: Blaess Julien , Geneton Sophie , Goepfert Thibaut , Appenzeller Simone , Bordier Gabriel , Davergne Thomas , Fuentes Yurilis , Haglo Håvard , Hambly Karen , Kinnett-Hopkins Dominique , Su Kuei-Ying , Legge Alexandra , Li Linda , Mak Anselm , Padjen Ivan , Sciascia Savino , Sheikh Saira Z , Soriano-Maldonado Alberto , Ugarte-Gil Manuel F , Md Yusof Md Yuzaiful , Parodis Ioannis , Arnaud Laurent 
Published: April 2024

ObjectiveThis international task force aimed to provide healthcare professionals and persons living with systemic lupus erythematosus (SLE) with consensus-based recommendations for physical activity and exercise in SLE.MethodsBased on evidence from a systematic literature review and expert opinion, 3 overarching principles and 15 recommendations were agreed on by Delphi consensus.ResultsThe overarching principles highlight the importance of shared decision-making and the need to explain the benefits of physical activity to persons living with SLE and other healthcare providers. The 15 specific recommendations state that physical activity is generally recommended for all people with SLE, but in some instances, a medical evaluation may be needed to rule out contraindications. Pertaining to outdoor activity, photoprotection is necessary. Both aerobic and resistance training programmes are recommended, with a gradual increase in frequency and intensity, which should be adapted for each individual, and ideally supervised by qualified professionals.ConclusionIn summary, the consensus reached by the international task force provides a valuable framework for the integration of physical activity and exercise into the management of SLE, offering a tailored evidence-based and eminence-based approach to enhance the well-being of individuals living with this challenging autoimmune condition.
IRX4204 Induces Senescence and Cell Death in HER2-positive Breast Cancer and Synergizes with Anti-HER2 Therapy
Authors: Moyer Cassandra L. , Lanier Amanda , Qian Jing , Coleman Darian , Hill Jamal , Vuligonda Vidyasagar , Sanders Martin E. , Mazumdar Abhijit , Brown Powel H. 
Published: April 2024

Abstract

Purpose:
Rexinoids, agonists of nuclear retinoid X receptor (RXR), have been used for the treatment of cancers and are well tolerated in both animals and humans. However, the usefulness of rexinoids in treatment of breast cancer remains unknown. This study examines the efficacy of IRX4204, a highly specific rexinoid, in breast cancer cell lines and preclinical models to identify a biomarker for response and potential mechanism of action.

Experimental Design:
IRX4204 effects on breast cancer cell growth and viability were determined using cell lines, syngeneic mouse models, and primary patient-derived xenograft (PDX) tumors. In vitro assays of cell cycle, apoptosis, senescence, and lipid metabolism were used to uncover a potential mechanism of action. Standard anti-HER2 therapies were screened in combination with IRX4204 on a panel of breast cancer cell lines to determine drug synergy.

Results:
IRX4204 significantly inhibits the growth of HER2-positive breast cancer cell lines, including trastuzumab and lapatinib–resistant JIMT-1 and HCC1954. Treatment with IRX4204 reduced tumor growth rate in the MMTV-ErbB2 mouse and HER2-positive PDX model by 49% and 44%, respectively. Mechanistic studies revealed IRX4204 modulates lipid metabolism and induces senescence of HER2-positive cells. In addition, IRX4204 demonstrates additivity and synergy with HER2-targeted mAbs, tyrosine kinase inhibitors, and antibody–drug conjugates.

Conclusions:
These findings identify HER2 as a biomarker for IRX4204 treatment response and demonstrate a novel use of RXR agonists to synergize with current anti-HER2 therapies. Furthermore, our results suggest that RXR agonists can be useful for the treatment of anti-HER2 resistant and metastatic HER2-positive breast cancer.
Abstract LB084: Radiation and anti-PD-L1 synergize by stimulating a stem-like T cell population in the tumor-draining lymph node
Authors: Shen Yang , Connolly Erin , Aiello Meili , Zhou Chengjing , Song Haorui , Clark Tarralyn , Tippitak Patan , Lesinski Gregory B. , Paulos Chrystal , Schmitt Nikki , Buchwald Zachary S. 
Published: April 2024

Abstract
Radiotherapy (RT) and anti-PD-L1 synergize to enhance local and distant (abscopal) tumor control. However, clinical results in humans have been variable. With the goal of improving clinical outcomes, we investigated the underlying synergistic mechanism focusing on a TCF-1+ PD-1+ CD8+ stem-like T cell subset in the tumor-draining lymph node (TdLN). We found that RT + anti-PD-L1 induces a novel differentiation program in the TdLN stem-like population which leads to their expansion and differentiation into effector cells within the tumor. We also found that optimal synergy between RT + anti-PD-L1 is dependent on the TdLN stem-like T cell population as either blockade of TdLN egress or specific stem-like T cell depletion reduced tumor control. Together, these data demonstrate a multistep stimulation of stem-like T cells following combination therapy which is initiated in the TdLN and completed in the tumor.
Citation Format: Yang Shen, Erin Connolly, Meili Aiello, Chengjing Zhou, Haorui Song, Tarralyn Clark, Patan Tippitak, Gregory B. Lesinski, Chrystal Paulos, Nikki Schmitt, Zachary S. Buchwald. Radiation and anti-PD-L1 synergize by stimulating a stem-like T cell population in the tumor-draining lymph node [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB084.