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  • BMJ  (5)
  • 1
    Online Resource
    Online Resource
    Associated genetic variants and potential pathogenic mechanisms of brain arteriovenous malformation
    BMJ ; 2023
    In:  Journal of NeuroInterventional Surgery Vol. 15, No. 6 ( 2023-06), p. 572-578
    Details
    In: Journal of NeuroInterventional Surgery, BMJ, Vol. 15, No. 6 ( 2023-06), p. 572-578
    Abstract: The pathogenic mechanism of brain arteriovenous malformation (bAVM) is poorly understood. A growing body of evidence indicates that genetic factors play crucial roles in bAVM. This study examined genetic variants associated with bAVM through quantitative synthesis and qualitative description of literature. Methods Five databases were searched to gather potentially relevant articles published up to January 2022. STATA 14.0 software was used for statistical analyses. Pooled odds ratios and 95% confidence intervals were calculated with random effect models, and heterogeneity was assessed using the Cochran Q test and quantified with the I 2 test. Sensitivity and publication bias were analyzed to test the robustness of the associations. Variants identified in only one study or with great heterogeneity were not suitable for pooling association analysis, and therefore a qualitative systematic review was performed. Results In total, 30 papers were included in a systematic review involving 4709 cases and 7832 controls, where 17 papers were in a meta-analysis. A suggested association of bAVM was observed with ACVRL1 rs2071219 in the additive model and CDKN2B-AS1 rs1333040 in the recessive and additive models. Other variants of genes that could not be analyzed were summarized by qualitative description. These genes were mostly involved in bone morphogenic protein/transforming growth factor beta (BMP/TGF-β), vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR), and RAS-mitogen activated protein kinase (MAPK) signaling and inflammation. Conclusions According to our meta-analysis, ACVRL1 rs2071219 and CDKN2B-AS1 rs1333040 were potentially associated with bAVM. Multiple pathological signaling pathways could affect disease development. Future studies should aim to determine the interaction of candidate genes with environmental risk factors and to elucidate detailed mechanisms of action of variants and genes. 1
    Type of Medium: Online Resource
    ISSN: 1759-8478 , 1759-8486
    URL: Article
    DOI: 10.1136/neurintsurg-2022-018776
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 2506028-4
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  • 2
    Online Resource
    Online Resource
    Hepatic haemangiomas: possible association with IL-17
    BMJ ; 2012
    In:  Journal of Clinical Pathology Vol. 65, No. 2 ( 2012-02), p. 146-151
    Details
    In: Journal of Clinical Pathology, BMJ, Vol. 65, No. 2 ( 2012-02), p. 146-151
    Type of Medium: Online Resource
    ISSN: 0021-9746 , 1472-4146
    URL: Article
    DOI: 10.1136/jclinpath-2011-200365
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2012
    detail.hit.zdb_id: 2028928-5
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  • 3
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    Haemorrhage risk of brain arteriovenous malformation during pregnancy and puerperium
    BMJ ; 2023
    In:  Stroke and Vascular Neurology Vol. 8, No. 4 ( 2023-08), p. 307-317
    Details
    In: Stroke and Vascular Neurology, BMJ, Vol. 8, No. 4 ( 2023-08), p. 307-317
    Abstract: This study aimed to assess whether pregnancy and puerperium were associated with the risk of brain arteriovenous malformation (bAVM) haemorrhage. Methods A retrospective review was conducted in Xiangya Hospital, Central South University from January 2012 to December 2021. A case–crossover design was adopted to calculate the incidence density of bAVM-related haemorrhage among female patients in risk (pregnancy and puerperium) and control (non-pregnancy and non-puerperium) periods, according to four scenarios observed in different populations (scenario I: patients with haemorrhagic bAVM of all ages; scenario II: patients with haemorrhagic bAVM of all ages, with at least one previous pregnancy; scenario III: patients with haemorrhagic bAVM who are of reproductive age (15–45 years); scenario IV: patients with haemorrhagic bAVM of reproductive age (15–45 years), with at least one previous pregnancy. Next, a comprehensive literature aggregation (up to April 2022) was performed for evidence synthesis. Results Among the 311 female patients with haemorrhagic bAVM, a significant haemorrhage risk during pregnancy and puerperium was found in Scenarios I (relative risk [RR], 2.08; 95% CI, 1.28 to 3.39), II (RR, 3.21; 95% CI, 1.95 to 5.31) and IV (RR, 2.92; 95% CI, 1.73 to 4.93); however, a suggestive risk was found in scenario III (RR, 1.62; 95% CI, 0.99 to 2.67). Evidence synthesis revealed a consistent haemorrhage risk among patients of all ages (RR, 3.15; 95% CI, 1.93 to 5.15) and those of reproductive age (RR, 1.29; 95% CI, 0.89 to 1.86). Conclusion Compared with most previous studies, a higher but relatively moderate risk for bAVM-related haemorrhage was identified during pregnancy and puerperium. Individualised prevention and treatment strategies should be preferred when neurosurgeons make clinical decisions.
    Type of Medium: Online Resource
    ISSN: 2059-8688 , 2059-8696
    URL: Article
    DOI: 10.1136/svn-2022-001921
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 2847692-X
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  • 4
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    Online Resource
    Generation of a safe and efficacious llama single-domain antibody fragment (vHH) targeting the membrane-proximal region of 4-1BB for engineering therapeutic bispecific antibodies for cancer
    BMJ ; 2021
    In:  Journal for ImmunoTherapy of Cancer Vol. 9, No. 6 ( 2021-06), p. e002131-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 9, No. 6 ( 2021-06), p. e002131-
    Abstract: The discovery of checkpoint inhibitors towards cytotoxic T-lymphocyte protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) has been revolutionary for the treatment of cancers. These therapies have only offered an average of 20%–30% response rates across the tumor spectrum and the combination of agonists towards the tumor-necrosis superfamily members, such as 4-1BB and CD40, has shown potent efficacy in preclinical studies; however, these agonists have exhibited high degrees of toxicity with limited efficacy in human trials. In this study, we have generated a single-domain antibody towards a unique epitope of 4-1BB that limits its potential on-target toxicity while maintaining sufficient potency. This 4-1BB binder is ideal for use in the engineering of multispecific antibodies to localize 4-1BB activation within the tumor microenvironment, as shown here by a anti-PD-L1/4-1BB bispecific candidate (PM1003). Methods To determine the functional activity of the 4-1BB- and PD-L1-binding elements of PM1003, in vitro luciferase reporter and primary cell assays were used to test the potency of programmed cell death 1 ligand 1 (PD-L1) blockade and PD-L1-mediated 4-1BB activation via cross-bridging. X-ray crystallography was conducted to resolve the binding epitopes of the respective binding arms, and accurate binding kinetics were determined using standard affinity measurement techniques. Human 4-1BB and/or PD-L1 knock-in mice were used in cancer models for testing the in vivo antitumor efficacy of PM1003, and safety was evaluated further. Results PM1003 shows potent activation of 4-1BB and blockade of PD-L1 in cell-based assays. 4-1BB activation was exerted through the bridging of PD-L1 on target cells and 4-1BB on effector cells. No PD-L1-independent activation of 4-1BB was observed. Through X-ray crystallography, a unique binding epitope in the cysteine-rich domain 4 (CRD4) region was resolved that provides high potency and potentially low on-target toxicity as determined by primary immune cell assays and toxicity evaluation in vivo . Conclusions A unique single-domain antibody was discovered that binds to the CRD4 domain of 4-1BB. When incorporated into a 4-1BB/PD-L1 bispecific (PM1003), we have shown the potent inhibition of PD-L1 activity with 4-1BB agonism upon cross-bridging with PD-L1 in vitro . Antitumor activity with minimal toxicity was found in vivo . Thus, PM1003 is a uniquely differentiating and next generation therapeutic agent for cancer therapy.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2020-002131
    Language: English
    Publisher: BMJ
    Publication Date: 2021
    detail.hit.zdb_id: 2719863-7
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  • 5
    Online Resource
    Online Resource
    895 Discovery of a safer 4–1BB agonist by targeting a membrane-proximal epitope combined with bispecific-mediated cross-bridging
    BMJ ; 2021
    In:  Journal for ImmunoTherapy of Cancer Vol. 9, No. Suppl 2 ( 2021-11), p. A939-A939
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 9, No. Suppl 2 ( 2021-11), p. A939-A939
    Abstract: Checkpoint inhibitors towards cytotoxic T-lymphocyte protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have paved the way for a new frontier of anti-cancer therapies that modulate our pre-existing immune system to fight against malignancies. 4-1BB is a tumor-necrosis superfamily member expressed on NK and T cells, that acts as a co-stimulatory receptor to improve effector/memory responses towards tumors. Early efforts have focused on the generation of agonist antibodies towards 4-1BB that relied on Fc-mediated cross-linking to cluster and induce receptor downstream signaling, but has led to liver- and immune-related toxicities. We have discovered a PD-L1 x 4-1BB bispecific that exhibits conditional agonist activity in the presence of PD-L1 with better safety features. Methods vHH binders to PD-L1 and 4-1BB were generated from immune libraries derived from camelids and selected via yeast display. Antibody screening was carried out by protein-protein interaction analysis and cell-based binding. Target-related activity was confirmed using luciferase reporter assays. Primary immune cells were also tested for T cell activation via the detection of IL-2 and IFNg secretion. PD-L1-mediated 4-1BB activation via cross-bridging was carried out using target cells expressing PD-L1 co-cultured with effector cells. X-ray crystallography was conducted to resolve the binding sites of both the anti-PD-L1 and anti-4-1BB vHHs. Both tumor efficacy and safety assessment were tested in human knockin mice. Results The 4-1BB binder of PM1003 was found to interact with the CRD4 domain of 4-1BB, as determined by X-ray crystallography. Binding to this domain does not affect the binding between 4-1BB and its ligand 4-1BBL. The anti-PD-L1 vHH binds to an epitope on PD-L1 that overlaps with the binding region of PD-1, and is thus effective in disrupting the interaction between PD-1 and PD-L1. Using luciferase reporter assays and primary cell assays we found the PM1003 could activate 4-1BB in the context of PD-L1-mediated cross-bridging. Data from human 4-1BB and PD-L1 knockin mice also showed that PM1003 could effectively control tumor growth without observing any toxicity signals. Conclusions PM1003 is a safe and efficacious bispecific antibody that blocks PD-L1 and concurrently activates 4-1BB receptor. An antibody with mild activity was selected directed against the CRD4 domain of 4-1BB to elicit effective potency while minimizing potential toxicity issues. This was reflected in our results. Thus, PM1003 is a potential next generation therapeutic antibody in the IO space that combines and synergizes two independent signaling pathways to control tumor growth.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2021-SITC2021.895
    Language: English
    Publisher: BMJ
    Publication Date: 2021
    detail.hit.zdb_id: 2719863-7
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