bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pain during prolonged sitting in subjects with patellofemoral pain in Dutch physical therapy clinics: an online questionnaire-based analysis
Authors: Ophey Martin , Frieling Sophie , Kerkhoffs Gino M M J , Tak Igor 
Published: November 2024

ObjectivesThis study aimed to describe (1) differences between subjects with patellofemoral pain (PFP) with and without pain during prolonged sitting (PDPS), (2) minimum knee flexion angle and time to onset/disappearance of PDPS and (3) differences between those with PDPS at smaller/greater flexion angles and with fast/slow onset and disappearance of PDPS.DesignPatient-reported online questionnaire.SettingPrivate physical therapy clinics in the Netherlands between May 2021 and March 2023.Participants87 participants (61 (70%) females, mean age 22.0 years (IQR 4.0), body mass index 23.1 (4.7)).Outcome measuresVisual Analogue Scale for worst pain (VAS-W) and sitting pain (VAS-W sitting), the Anterior Knee Pain Scale (AKPS), knee flexion angle to provoke PDPS and time to onset/disappearance of PDPS.Results63 of 87 (72%) participants reported PDPS. Participants with PDPS experienced bilateral symptoms of PFP more frequently (71% vs 46%, p=0.44) and scored 12 points lower on the AKPS (p<0.001). Most participants (85%) reported a minimum knee flexion angle of ≥90°, median time to PDPS onset of 16–20 min and 6–10 min for disappearance. Participants experiencing PDPS at smaller flexion angles exhibited higher VAS-W and VAS-W sitting scores (7.0 (1.0), 6.8 (1.1)) than those at greater flexion angles (5.0 (3.0), for both) (p=0.002, p=0.001). Participants with fast onset of PDPS reported higher VAS-W and VAS-W sitting scores (7.0 (2.0), 6.0 (2.0)) than those with slow onset (5.0 (3.0), 5.0 (4.0)) (p<0.001, p=0.025).ConclusionsParticipants with PDPS reported higher levels of disability than those without. PDPS was typically induced at knee flexion of ≥90°, with delayed onset/disappearance. Higher pain levels were reported by those experiencing PDPS at smaller knee flexion angles or with faster onset. Future research should explore the mechanisms of PDPS and develop targeted interventions to improve long-term outcomes.
Consensus definition of a radiologically healed fistula on magnetic resonance imaging in perianal Crohn’s disease: an international Delphi study
Authors: Anand Easan , Devi Jalpa , Joshi Shivani , Antoniou Anna , Doering Michelle , Stoker Jaap , Lung Phillip , Hart Ailsa L , Ballard David H , Deepak Parakkal , Tozer Phil 
Published: November 2024

IntroductionPerianal fistulising Crohn’s disease (pfCD) is a distinct and debilitating phenotype seen in around one-third of patients with CD. Clinical trials in pfCD are increasingly using magnetic resonance imaging (MRI) criteria as a primary endpoint, but there is heterogeneity in the radiological definition of a healed perianal fistula that currently limits our ability to perform meaningful meta-analyses of studies. Our aim is to standardise outcomes through the generation of an international consensus definition of a radiologically healed fistula.Methods and analysisThis international Delphi consensus study employs a two-part strategy.The first is a systematic review to identify a longlist of variables used to define radiological healing in pfCD. MRI-based indices used to score fistula severity and healing will be assessed for their methodological quality using Consensus-based Standards for the selection of health Measurement Instruments (COSMIN). The systematic review protocol will be conducted using COSMIN methodology and reported using Preferred Reporting Items for Systematic Reviews and Meta-Analyses.The second part will be an online Delphi consensus, guided by the results of the systematic review. Radiologists, gastroenterologists and colorectal surgeons with expertise in the management of pfCD will be invited to take part in two to three rounds of online surveys. Once an a priori threshold of >80% agreement is reached on individual radiological components used to define ‘healing’ and ‘healed’, a final meeting of key stakeholders will be organised to generate a consensus definition of a healed fistula.Ethics and disseminationThe study has been deemed exempt from a formal Research Ethics Committee review as no patients will participate directly in the consensus process, given the technical nature of the research question. The study is registered with the local R&D department (Reference RD24/007). Publication of this study will help standardise radiological endpoint measurement in clinical trials of pfCD and improve the synthesis and meta-analysis of comparative studies.PROSPERO registration numberCRD42024504334.
Managing experts’ conflicts of interest in the EU Joint Clinical Assessment
Authors: Gentilini Arianna , Parvanova Iva 
Published: November 2024

ObjectiveThis article critically evaluates the European Commission’s 2024 Implementing Regulation (IR) on conflicts of interest (COIs) management for stakeholders in the European Union (EU) Joint Clinical Assessment (JCA), with a focus on individual experts such as clinicians and patient representatives.Key findingsThe IR is the first EU-level framework to assess COIs in the context of health technology assessment (HTA). The regulation requires experts involved in the JCA to submit annual declarations of interest for both financial and non-financial interests and presents a matrix on whether these conflicts should disqualify them from participating in the joint work. We compared the IR to COIs-management approaches from other European national HTA bodies and found that the IR is closely modelled after the French guidelines. Concerns include potential over-representation of experts from a small number of countries, lack of guidance on organisational COIs, and ambiguities in how the size of financial interests are disclosed. Unclear resource allocation for enforcement could also hinder compliance.ConclusionsThe IR marks progress in EU-wide HTA collaboration, but improvements in transparency, expert diversity, and comprehensive COIs management are needed to ensure impartiality in the JCA process.
Natural killer cells are required for the recruitment of CD8+ T cells and the efficacy of immune checkpoint blockade in melanoma brain metastases
Authors: Fife Christopher , Williams Jennifer , James Fiona , Gregory Scott , Andreou Tereza , Sunderland Ashley , McKimmie Clive , Brownlie Rebecca J , Salmond Robert J , Heaton Samuel , Errington-Mais Fiona , Hadi Zarnaz , Westhead David R , Hall Marlous , Davie Alexander , Emmett Amber , Lorger Mihaela 
Published: November 2024

BackgroundBrain metastases (BrM) affect up to 60% of patients with metastatic melanoma and are associated with poor prognosis. While combined immune checkpoint blockade of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) demonstrates intracranial efficacy in a proportion of patients with melanoma, the responses are rarely durable, particularly in patients with symptomatic BrM. The brain is an immune-specialized organ and immune responses are regulated differently to the periphery.MethodsUsing our previously established two-site model of melanoma BrM with concomitant intracranial and extracranial tumors, in which clinically observed efficacy of the combined PD-1/CTLA-4 (PC) blockade can be reproduced, we here explored the role of natural killer (NK) cells in BrM, using functional studies, immunophenotyping and molecular profiling.ResultsWe demonstrate that NK cells are required for the intracranial efficacy of PC blockade. While both perforin and interferon gamma were necessary for the PC blockade-dependent control of intracranial tumor growth, NK cells isolated from intracranial tumors demonstrated only a limited cancer cell killing ability, and PC blockade did not alter the abundance of NK cells within tumors. However, the depletion of NK cells in PC blockade-treated mice led to tumor molecular profiles reminiscent of those observed in intracranial tumors that failed to respond to therapy. Furthermore, the depletion of NK cells resulted in a strikingly reduced abundance of CD8+ T cells within intracranial tumors, while the abundance of other immune cell populations including CD4+ T cells, macrophages and microglia remained unaltered. Adoptive T cell transfer experiments demonstrated that PC blockade-induced trafficking of CD8+ T cells to intracranial tumors was chemokine-dependent. In line with this, PC blockade enhanced intratumoral expression of several T cell-attracting chemokines and we observed high expression levels of cognate chemokine receptors on BrM-infiltrating CD8+ T cells in mice, as well as in human BrM. Importantly, the depletion of NK cells strikingly reduced the intratumoral expression levels of T cell attracting chemokines and vascular T cell entry receptors that were upregulated following PC blockade.ConclusionOur data demonstrate that NK cells underpin the efficacy of PC blockade in BrM by orchestrating the "responder" molecular profile in tumors, and by controlling the intratumoral abundance of CD8+ T cells through regulation of multiple key molecular mediators of T cell trafficking.
Inhibition of Cbl-b restores effector functions of human intratumoral NK cells
Authors: Tundo Sofia , Trefny Marcel , Rodić Andrijana , Grueninger Olivia , Brodmann Nicole , Börsch Anastasiya , Serger Clara , Fürst Jonas , Buchi Melanie , Buczak Katarzyna , Müller Alex T , Sach-Peltason Lisa , Don Leyla , Herzig Petra , Lardinois Didier , Heinzelmann-Schwarz Viola , Mertz Kirsten D , Hojski Aljaž , Schaeuble Karin , Laubli Heinz , Natoli Marina , Toso Alberto , Luu Thuy T , Zippelius Alfred , Romagnani Andrea 
Published: November 2024

BackgroundT cell-based immunotherapies including immune checkpoint blockade and chimeric antigen receptor T cells can induce durable responses in patients with cancer. However, clinical efficacy is limited due to the ability of cancer cells to evade immune surveillance. While T cells have been the primary focus of immunotherapy, recent research has highlighted the importance of natural killer (NK) cells in directly recognizing and eliminating tumor cells and playing a key role in the set-up of an effective adaptive immune response. The remarkable potential of NK cells for cancer immunotherapy is demonstrated by their ability to broadly identify stressed cells, irrespective of the presence of neoantigens, and their ability to fight tumors that have lost their major histocompatibility complex class I (MHC I) expression due to acquired resistance mechanisms.However, like T cells, NK cells can become dysfunctional within the tumor microenvironment. Strategies to enhance and reinvigorate NK cell activity hold potential for bolstering cancer immunotherapy.MethodsIn this study, we conducted a high-throughput screen to identify molecules that could enhance primary human NK cell function. After compound validation, we investigated the effect of the top performing compounds on dysfunctional NK cells that were generated by a newly developed in vitro platform. Functional activity of NK cells was investigated using compounds alone and in combination with checkpoint inhibitor blockade. The findings were validated on patient-derived intratumoral dysfunctional NK cells from different cancer types.ResultsThe screening approach led to the identification of a Casitas B-lineage lymphoma (Cbl-b) inhibitor enhancing the activity of primary human NK cells. Furthermore, the Cbl-b inhibitor was able to reinvigorate the activity of in vitro generated and patient-derived dysfunctional NK cells. Finally, Cbl-b inhibition combined with T-cell immunoreceptor with Ig and ITIM domains (TIGIT) blockade further increased the cytotoxic potential and reinvigoration of both in vitro generated and patient-derived intratumoral dysfunctional NK cells.ConclusionsThese findings underscore the relevance of Cbl-b inhibition in overcoming NK cell dysfunctionality with the potential to complement existing immunotherapies and improve outcomes for patients with cancer.
Adoptive transfer of membrane-restricted IL-12-TCR T cells promotes antigen spreading and elimination of antigen-negative tumor variants
Authors: Zhang Ling , Norberg Scott M , Karimipour Farrah , Davies John S , Kuznetsov Alex , Lassoued Wiem , Burnett Daniel , Homan Philip , Cam Margaret , Sinkoe Andrew , Xue Ping , Gulley James L , Hinrichs Christian S 
Published: November 2024

BackgroundAdoptive T-cell therapy has demonstrated clinical activity in B-cell malignancies, offering hope for its application to a broad spectrum of cancers. However, a significant portion of patients with solid tumors experience primary or secondary resistance to this treatment modality. Target antigen loss resulting either from non-uniform antigen expression or defects in antigen processing and presentation machinery is one well-characterized resistance mechanism. Constitutively expressed membrane-anchored interleukin-12 (caIL-12) has demonstrated enhanced antitumor activity and low systemic exposure in multiple preclinical adoptive T-cell treatment models with homogeneous tumor antigen expression. In this study, we assess the therapeutic impact of caIL-12 on target antigen-negative variants in syngeneic mouse models.MethodsTarget antigen-positive tumors were generated by transducing B16F10 melanoma cells (B16) or Lewis Lung Carcinoma cells (LLC) with a construct expressing the OVA antigen, SIINFEKL, tagged to ubiquitin (B16-U-OVA, LLC-U-OVA), while B16 or LLC tumors served as antigen-negative variants. C57BL/6J mice were subcutaneously injected with heterogeneous tumors composed of 80% B16-U-OVA and 20% B16. Bilateral tumors were established by injecting the left flank with B16-U-OVA or LLC-U-OVA tumors and the right flank injected with B16 or LLC tumors. The tumor-bearing mice then underwent 5.5 Gy total body irradiation, followed by adoptive transfer of OT-I TCR-T cells engineered with or without caIL-12.ResultsTCR-T cells (OT-I) delivered caIL-12 to the B16-U-OVA tumor sites and induced robust tumor control and survival benefits in mice bearing a heterogeneous tumor with OVA-negative variants. caIL-12 exerted its effect on OVA-negative B16 variants primarily by priming and activating endogenous antitumor CD8 T cells via antigen spreading. In addition, antigen spreading induced by OT-I-caIL-12 resulted in controlling OVA-negative tumors implanted at distant sites. This therapeutic effect required antigen-specific TCR-T cells and caIL-12 to colocalize at the tumor site, along with endogenous CD8 T cells capable of recognizing shared tumor antigens.ConclusionExpression of caIL-12 by tumor-targeting T cells demonstrated therapeutic effect against target-antigen-negative tumor variants, primarily through the induction of antigen spreading. These findings highlight the potential of caIL-12 to address challenges of antigen escape and tumor heterogeneity that may limit the efficacy of T-cell therapy against solid tumors.
Afatinib boosts CAR-T cell antitumor therapeutic efficacy via metabolism and fate reprogramming
Authors: Dai Yueyu , Liu Yue , An Lingna , Zhong Fangyuan , Zhang Xi , Lou Shifeng 
Published: November 2024

BackgroundChimeric antigen receptor T (CAR-T) cell therapy has been shown remarkable efficacy in the treatment of hematological malignancies in recent years. However, a considerable proportion of patients would experience tumor recurrence and deterioration. Insufficient CAR-T cell persistence is the major reason for relapse. Multiple strategies to enhance the long-term antitumor effects of CAR-T cells have been explored and developed. In this study, we focused on tyrosine kinase inhibitors (TKIs), which have emerged immunomodulatory potential besides direct tumoricidal effects.MethodsHere, we screened 50 approved TKIs drugs and identified that afatinib (AFA) markedly enhanced the expressing of CD62L and inhibited reactive oxygen species level in T cells. And the underlying mechanisms of AFA medicating T cells were explored by detecting signal transduction, and metabolism pattern. Furthermore, we co-cultured AFA with CAR-T cells during the preparation stage and multianalyses of differentiation characteristics, metabolic profiling, and RNA sequencing revealed that AFA induce comprehensive metabolism remodeling and fate reprogramming. Based on it, we finally identified the antitumor efficacy of AFA-pretreatment CAR-T compared with negative-control CAR-T.ResultsWe identified that AFA blocked the T-cell receptor (TCR) and phosphoinositide 3-kinase-protein kinase B-mechanistic target of rapamycin signaling pathways, induced metabolic reprogramming and modulated T-cell differentiation. When combined with CAR-T cells, AFA inhibited the exhaustion and enhanced the persistence and cytotoxicity. Our results revealed that the pretreatment of AFA enables to boost CAR-T cells with strong antitumor cytotoxicity in leukemia mouse model.ConclusionsOur study systematically demonstrated that AFA pretreatment effectively enhanced CAR-T cells antitumor performance, which presents a novel optimization strategy for potent and durable CAR-T cell therapy.
Gut microbiota in very early systemic sclerosis: the first case-control taxonomic and functional characterisation highlighting an altered butyric acid profile
Authors: Bellando-Randone Silvia , Russo Edda , Di Gloria Leandro , Lepri Gemma , Baldi Simone , Fioretto Bianca Saveria , Romano Eloisa , Ghezzi Giulio , Bertorello Sara , El Aoufy Khadija , Rosa Irene , Pallecchi Marco , Bruni Cosimo , Cei Francesco , Nannini Giulia , Niccolai Elena , Orlandi Martina , Bandini Giulia , Guiducci Serena , Bartolucci Gian Luca , Ramazzotti Matteo , Manetti Mirko , Matucci-Cerinic Marco , Amedei Amedeo 
Published: November 2024

ObjectivesIn systemic sclerosis (SSc), gastrointestinal involvement is one of the earliest events. We compared the gut microbiota (GM), its short-chain fatty acids (SCFAs) and host-derived free fatty acids (FFAs) in patients with very early diagnosis of SSc (VEDOSS) and definite SSc.MethodsStool samples of 26 patients with SSc, 18 patients with VEDOSS and 20 healthy controls (HC) were collected. The GM was assessed through 16S rRNA sequencing, while SCFAs and FFAs were assessed by gas chromatography-mass spectrometry.ResultsIn patients with VEDOSS, an increase in Bacteroidales and Oscillospirales orders and a decrease in Bacilli class,Blautia, Romboutsia, StreptococcusandTuricibactergenera was detected in comparison with HC. In patients with SSc, an elevated number of Acidaminococcaceae and Sutterellaceae families, along with a decrease of the Peptostreptococcaceae family andAnaerostipes, Blautia, RomboutsiaandTuricibactergenera was found in comparison with HC. Patients with SSc and VEDOSS had a significantly lower butyrate and higher acetate with respect to HC. In VEDOSS, an increase in Oscillospiraceae family andAnaerostipesgenus, and a decrease inAlphaproteobacteriaclass, and Lactobacillales order was identified with respect to SSc. Moreover, patients with VEDOSS exhibited higher acetate and lower valerate compared with definite SSc.ConclusionA GM dysbiosis with depletion of beneficial anti-inflammatory bacteria (especially butyrate-producing) and a significant decrease in faecal butyrate was identified in patients with VEDOSS. This early GM imbalance may foster the growth of inflammatory microbes, worsening intestinal dysbiosis and inflammation in early SSc stages. The potential butyrate administration in early disease phases might be considered as a novel therapeutic approach to mitigate gastrointestinal discomfort and progression preserving patient’s quality of life.
Fibroblast-like synoviocyte targeting antibodies are associated with failure to reach early and sustained remission or low disease activity after first-line therapy in rheumatoid arthritis
Authors: Vandormael Patrick , Fadlallah Sukayna , Ruytinx Pieter , Pues Astrid , Sleurs Ellen , Liesenborgs Jori , Joly Johan , Agten Anouk , Vandenabeele Frank , Fraussen Judith , Verschueren Patrick , Somers Veerle 
Published: November 2024

ObjectiveTo discover antibody biomarkers that can predict a lack of response to first-line therapy in rheumatoid arthritis (RA) patients.MethodsTwo RA cDNA phage display libraries were screened for novel antibodies in baseline RA sera from the Care in early RA (CareRA) trial, differentiating between patients who did or did not reach remission after first-line therapy (n=20 each). Antibody reactivity to identified University Hasselt (UH)-RA antigens was validated in baseline samples from 136 additional CareRA participants. The novel antibodies’ potential to predict failure to reach remission or low disease activity (LDA), according to the Disease Activity Score 28-joint C-reactive protein/erythrocyte sedimentation rate (DAS28CRP/ESR) and Clinical/Simplified Disease Activity Index (CDAI/SDAI), was studied by multivariate analyses. The presence of the antibody targets in RA synovial tissue and the fibroblast-like synoviocyte (FLS) cell line SW982 was determined by immunofluorescence.ResultsWe identified antibodies to 41 novel antigens. Antibodies against any of three antigens, UH-RA.305/318/329, discriminated between RA patients not reaching week (w)8 DAS28CRP remission and those that did (36% vs 13%,p=0.0031). In all patients, anti-UH-RA.305/318/329 antibody reactivity was associated with failure to reach week 8 DAS28CRP and DAS28ESR remission (OR 3.63,p=0.0031; OR 2.92,p=0.016; respectively), SDAI/CDAI sustained remission (OR 5.59,p=0.039 for both) and DAS28CRP and DAS28ESR sustained LDA (OR 3.7,p=0.009; OR 2.76,p=0.042; respectively). In rheumatoid factor/anti-citrullinated protein antibody (RF/ACPA) seronegative patients, these antibodies were strongly associated with failure to achieve week 8 DAS28CRP remission (OR 17.3,p=0.0029). Anti-UH-RA.305/329 antibodies were shown to target FLS in RA synovial tissue and SW982 cells.ConclusionWe identified three antibody biomarkers that are associated with failure to achieve remission/LDA after first-line RA therapy.