tbuckley/cabot-search huggingface dataset:
MULTIMODAL (5-ALA, TRACTOGRAPHY AND ULTRASOUND GUIDED) AWAKE CRANIOTOMY FOR GLIOBLASTOMA: MAXIMISING SAFE SURGICAL RESECTION
Authors: Dr Susan Honeyman, Mr Sean Martin, Mr Richard Stacey, Mr Vasileios Apostolopoulos, Prof Puneet Plaha
Journal: Neuro-Oncology (2024)

Abstract AIMS Maximising the extent of surgical resection of glioblastoma is a key prognostic factor for survival. This must be balanced against avoiding neurological deﬁcit, which may delay or preclude adjuvant treatments. This is a particular challenge in eloquent tumours. Optimal surgical adjuncts to enable maximal resection of glioblastomas in eloquent brain regions, remain unclear. We present the ﬁrst series assessing the safety and eﬃcacy of multimodality image-guided, awake resection of IDH-wildtype glioblastoma, combining 5-aminolevulinic acid (5-ALA), diffusion tractography (DTI) and intraoperative ultrasound (USS). METHOD We present a single centre retrospective series of 175 patients undergoing awake craniotomy for primary resection of glioblastomas, between January 2014 and January 2023. Awake craniotomy was considered if tumours were in or adjacent to eloquent areas. Key outcomes assessed included post-operative neurological complications (classiﬁed into transient, if persisting &amp;lt;3 months and completely resolved, or permanent if persisting &amp;gt;3 months), extent of resection (EOR) and overall survival (OS). RESULTS 175 patients (103M:72F) were included, with a mean age of 58.2 years. All cases used neuronavigation, whilst 5- ALA and DTI were used in 98.9% and 97.1% of patients respectively. Intraoperative USS was used 88/175 (50.3%). Gross total resection (&amp;gt;98%) was achieved in 101/175 patients (64.7%). 83/175 patients (47.4%) experienced a post-operative neurological deﬁcit, which was temporary in 84.3% (70/83) of cases. When transient deﬁcits occurred, these were most often speech related (49/70). Subgroup analysis found left temporal tumours were highest risk for transient dysphasia (59.2%), followed by left frontal (21.7%) and left parietal (16.0%). The median percentage EOR with USS was 100%, whilst without USS was 97.8% (Wilcox, p=0.0004). CONCLUSION Patients should be counselled about the high risk of transient neurological complications following awake surgery, particularly speech deﬁcit. Multimodal image-guided surgery can maximise the extent of safe resection for glioblastoma.
MODELLING GBM RECURRENCE: THE INﬂUENCE OF PERI-LESIONAL OEDEMA AND THE DISCONNECTOME
Authors: Ms Manaal Tariq, Dr James Ruﬄe, Ms Samia Mohinta, Dr Morag Brothwell, Prof Sebastian Brandner, Prof Parashkev Nachev, Harpreet Hyare
Journal: Neuro-Oncology (2024)

Abstract AIMS Residual tumour burden after surgery in GBM patients is a prognostic imaging biomarker, often involving the area of T2 signal elevation surrounding the tumour core, histopathologically representing inﬁltrative oedema with tumour cells. We present the ﬁrst stage of a model to improve the prediction GBM recurrence by speciﬁcally investigating the peri-lesional oedema compartment. METHOD UK-wide sample of histologically proven IDHwt GBMs with MRIs at the time of diagnosis underwent state-of- the-art in-house tumour segmentation pipeline and radiomic feature extraction of whole-tumour, enhancing, non-enhancing and oedema components, and masked disconnectome map components. Of these, early GBM recurrence, within 6 months after completion of radiotherapy, was curated and distribution mapped across the brain. RESULTS 1464 patients were identiﬁed: male = 901, median age 63 years, average overall survival 597 days. The radiomic features: Compactness 1 and 2, Surface Area, Spherical Disproportion, Sphericity, and Maximum 2D Diameter column of the disconnectome-related perilesional oedema compartment were most predictive of survival outcome (p value &amp;lt;0.01). Of these, 47 patients with average overall survival 357 days and average time from end of radiotherapy to progression of 131 days were identiﬁed. CONCLUSION Our early results reveal the relationship between perilesional oedema MRI features and survival, with disconnectome-related perilesional oedema features most predictive. This suggests that extended brain network aberrations caused by gliomas may also inﬂuence tumour recurrence. Further work will focus on the development of more robust predictive models of tumour recurrence that have potential for signiﬁcant impact on surgical and radiotherapy planning.
KINOME-WIDE SYNTHETIC LETHAL SCREEN IDENTIﬁES PANK4 AS A MODULATOR OF TEMOZOLOMIDE RESISTANCE IN GLIOBLASTOMA
Authors: Dr Viviana Vella, Dr Angeliki Ditsiou, Dr Anna Chalari, Dr Murat Eravci, Dr Sarah K Wooller, Prof Teresa Gagliano, Ms Cecilia Bani, Dr Emanuela Kerschbamer, Mr Christos Karakostas, Dr Bin Xu, Dr Yongchang Zhang, Dr Frances M G Pearl, Dr Gianluca Lopez, Dr Ling Peng, Prof Justin Stebbing, Prof Apostolos Klinakis, Prof Georgios Giamas
Journal: Neuro-Oncology (2024)

Abstract AIMS Temozolomide (TMZ) represents the cornerstone of glioblastoma (GBM) therapy. However, acquisition of resistance limits its therapeutic potential. The human kinome is an undisputable source of druggable targets, still, current knowledge remains conﬁned to a limited fraction of it, with a multitude of under-investigated proteins yet to be characterised. We aimed to uncover synthetic lethal partners of TMZ in GBM that could enhance the effect of TMZ, thus improving TMZ therapy response. METHOD A kinome-wide RNAi screen was performed in a TMZ-resistant GBM cell model. A panel of several TMZ-resistant and patient-derived GBM cell lines was implemented for in vitro validation of our ﬁndings through several phenotypic assays. In vivo TMZ-resistant GBM xenografts and immunohistochemical (IHC) analysis of IDH- wildtype GBM specimens were employed to assess the clinical relevance of our ﬁndings. Tandem Mass Tag (TMT)-based quantitative proteomic studies were undertaken to elucidate the underlying mechanisms. RESULTS Following a kinome-wide RNAi screen, pantothenate kinase 4 (PANK4) was uncovered as a modulator of TMZ resistance in GBM. Validation of PANK4 across various TMZ-resistant GBM cell models, patient-derived GBM cell lines, tissue samples, as well as in vivo studies, corroborated the potential translational signiﬁcance of these ﬁndings. Moreover, PANK4 expression is induced during TMZ treatment, and its expression is associated with a worse clinical outcome. A Tandem Mass Tag (TMT)-based quantitative proteomic approach revealed that PANK4 abrogation leads to a signiﬁcant downregulation of numerous proteins with central roles in cellular detoxiﬁcation and cellular response to oxidative stress. Mechanistically, as cells undergo genotoxic stress during TMZ exposure, PANK4 depletion represents a crucial event that can lead to accumulation of intracellular reactive oxygen species (ROS) and subsequent cell death. CONCLUSION Our study provides novel insights into chemoresistance in GBM and unveils a previously unreported role for PANK4 in mediating therapeutic resistance to TMZ in GBM.
ARGININE DEPRIVATION SENSITISES GBM CELLS TO RADIATION THROUGH DOWNREGULATION OF DNA REPAIR PATHWAYS
Authors: Dr Richard Perryman, Ms Hamida Mussa, Mr Avik Ghosh, Mr Kevin O’Neill, Dr Nelofer Syed
Journal: Neuro-Oncology (2024)

Abstract AIMS Glioblastoma (GBM) is the most aggressive form of brain cancer, and therapy hasn’t changed for almost 20 years. We have previously shown that GBM tumours lack expression of argininosuccinate synthase 1 (ASS1), a key enzyme involved in arginine biosynthesis, due to promoter methylation. This renders them sensitive to systemic arginine depletion using agents such as pegylated arginine deiminase (ADI), allowing us to circumvent the issue of blood-brain-barrier (BBB) penetration. Furthermore, ADI appears to synergise with the DNA damaging agent temozolomide (TMZ), which is routinely used to treat patients with GBM. Here, we aimed to explore whether ADI can synergise with radiotherapy, and determine the mechanisms by which ADI is able to sensitise cells to DNA damaging agents. METHOD Primary GBM cell lines were treated with ADI in combination with radiation and underwent analysis using an RNA microarray, Qiagen DNA repair RT2 array, qPCR, western blotting, and proliferation assays in both 2D (SRB) and 3D (spheroid, CCK8) format. We performed orthotopic injection of primary GBM cells into the striatum of athymic nude mice, and randomised them to ADI, radiation, or the combination, plus controls. Tissue was analysed using IHC staining. RESULTS In ASS1 methylated primary GBM, treatment with ADI led to a signiﬁcant change in the expression of ~500 genes with a fold change &amp;gt;2. Gene set enrichment analysis indicated that these genes were predominantly involved in cell cycle regulation, which is closely linked to the DNA damage and repair machinery. In another ASS1 methylated primary GBM cell line, an RT2 array revealed speciﬁc downregulation of genes involved in DNA repair. qPCR and western blot validation of these changes showed a signiﬁcant decrease in the expression and protein levels of PARP1 and LIG1 with ADI treatment. CONCLUSION Arginine deprivation using ADI leads to a downregulation of PARP1 in GBM cells, sensitising them to radiotherapy.
PCV ALONE IN GRADE 2 AND GRADE 3 OLIGODENDROGLIOMA – LONG-TERM RESULTS FROM A UK TERTIARY CARE CENTRE
Authors: Dr Babusha Kalra, Dr Antonia Creak, Dr Ernest Lee, Dr Liam Welsh, Dr Francesca Solda, Dr Nicola Rosenfelder, Dr Lukasz Klobukowski
Journal: Neuro-Oncology (2024)

Abstract AIMS Oligodendroglioma is a subgroup of gliomas which affects young adults and has a favourable overall survival (OS) ranging between 31.5 to 56.6.% at 10 years. Standard management of these tumours is maximal safe resection followed by adjuvant radiotherapy and systemic chemotherapy with Procarbazine, Lomustine and Vincristine (PCV), or surveillance where appropriate. PCV alone is an option that helps defer or avoid radiotherapy and its neurocognitive side effects in a selected group of patients. Our retrospective study analyses outcomes with PCV alone in Oligodendroglioma. METHOD We screened patient records between 1999 to 2021 and identiﬁed 31 patients who had a histological diagnosis of grade 2/3 oligodendroglioma (with conﬁrmation of 1p19qcodeletion on molecular testing) and received PCV alone after surgery (biopsy/ tumour resection). RESULTS Out of 31 patients, twenty-six patients were grade 2 and ﬁve patients were grade 3 oligodendroglioma. Median age was 44 years and male: female was 15:16. Median follow up was 9.5 years. Twenty-ﬁve patients (80%) presented with seizures. 80% of patients had tumour resection &amp; twenty four patients received 5 or more cycles of PCV alone as ﬁrst-line oncological treatment. There was no signiﬁcant difference in outcomes for grade2/3 tumours. Eighteen patients (58%) had local tumour relapse. Fourteen patients (45%) underwent salvage radiotherapy. Median time to radiotherapy was 7 years. Median OS was 19.4 years and median progression free survival (PFS) was 13.3 years. 9 deaths were reported. CONCLUSION PCV chemotherapy alone is an effective adjuvant treatment option for selected patients with oligodendroglioma, with a favourable PFS and OS shown in our series. Its use may allow deferral of radiotherapy and avoidance of associated neurocognitive side effects which can have a detrimental effect of quality of life for these young patients.
PRECISE-GBM: A RADIOGENOMIC MACHINE LEARNING BASED STUDY TO IDENTIFY PREDICTIVE RADIOMICS FOR EVALUATION OF CANCER IMMUNE SIGNATURE IN IDHW GLIOBLASTOMA
Authors: Dr Prajwal Ghimire, Dr Marc Modat, Dr Thomas Booth
Journal: Neuro-Oncology (2024)

Abstract AIMS The aim of the study is to identify machine learning model based on radiological biomarkers that can predict immune status within tumor microenvironment of IDH wildtype glioblastoma. METHOD This is a retrospective multicenter machine learning based study utilizing open access anonymized matched radiogenomic data of TCGA-GBM, CPTAC, Ivy GAP and REMBRANDT datasets. REMBRANDT data acted as hold out dataset. Imaging data consisted of MRI based radiomics features extracted from deep learning based segmented tumors and transcriptomic (RNA seq/microarray) data consisted of immune scores extracted using CIBERSORTx. Outliers were identiﬁed and ﬁltered using principal component analysis. Combat and neuroCombat were utilized for data harmonization for each data type respectively. Radiomic feature selection was performed using LASSO technique with cross validation. Support vector machine (SVM) was trained and tested with 80:20 radiomics data split and a median based binary label of immune score (low and high). Validation of the trained model was performed with hold out dataset. Data query and analysis was performed using python and R statistical software. RESULTS One hundred one patients were included in the study with 15 being on the hold out set. Trained SVM model predicted the immune score label with AUC of 0.79 and balanced accuracy of 0.76 (recall 0.75, F1 score 0.75, precision 0.75) in the test data. In the holdout set, the model predicted the immune score with AUC of 0.70 with speciﬁcity of 75% in predicting the cold immune cases. The radiomic signature that acted as the label for this model were a group of ﬁrst order and second order radiomic features. CONCLUSION Radiogenomic SVM model non-invasively predicts immune status in wildtype glioblastoma microenvironment with good accuracy. This model has potential to be utilized in a prospective glioblastoma clinical trial for immunotherapy.
Alterations in the axon initial segment plasticity is involved in early pathogenesis in Alzheimer's disease
Authors: Yu Li, Han Wang, Yiming Wang, Zhiya Chen, Yiqiong Liu, Wu Tian, Xinrui Kang, Abolghasem Pashang, Don Kulasiri, Xiaoli Yang, Hung Wing Li, Yan Zhang
Journal: MedComm (2024)

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by the early presence of amyloid-β (Aβ) and hyperphosphorylated tau. Identifying the neuropathological changes preceding cognitive decline is crucial for early intervention. Axon initial segment (AIS) maintains the orderly structure of the axon and is responsible for initiating action potentials (APs). To investigate the role of AIS in early stages of AD pathogenesis, we focused on alterations in the AIS of neurons from APP/PS1 mouse models harboring familial AD mutations. AIS length and electrophysiological properties were assessed in neurons using immunostaining and patch-clamp techniques. The expression and function of ankyrin G (AnkG) isoforms were evaluated by western blot and rescue experiments. We observed a significant shortening of AIS in APP/PS1 mice, which correlated with impaired action potential propagation. Furthermore, a decrease in the 480 kDa isoform of AnkG was observed. Rescue of this isoform restored AIS plasticity and improved long-term potentiation in APP/PS1 neurons. Our study implicates AIS plasticity alterations and AnkG dysregulation as early events in AD. The restoration of AIS integrity by the 480 kDa AnkG isoform presents a potential therapeutic strategy for AD, underscoring the importance of targeting AIS stability in neurodegenerative diseases.
Controlling Cell Interactions with DNA Directed Assembly
Authors: Katelyn Mathis, Clement T. Y. Chan, Brian Meckes
Journal: Advanced Healthcare Materials (2024)

Abstract The creation of complex cellular environments is critical to mimicking tissue environments that will play a critical role in next‐generation tissue engineering, stem cell programming, and therapeutic screening. To address this growing need, techniques capable of manipulating cell–cell and cell‐material interactions are required that span single‐cell to 3D tissue architectures. DNA programmed assembly and placement of cells present a powerful technique for the bottom‐up synthesis of living microtissues for probing key questions in cell–cell and cell‐material‐driven behaviors through its refined control over placement and architecture. This review examines the current state of the art in the programming of cellular interactions with DNA and its applications spanning tissue model building, fundamental cellular biology, and cell manipulation for measurements across a host of applications.
Phototheranostic LPP‐QDs‐IR‐820 Nanocomposites for Specific NIR‐II Imaging of Lymphatic and Photothermal Therapy of Cervical Tumors
Authors: Lijun Zhu, Zhong Du, Jiabao Xiong, Hui Li, Chi Zhang, Xueliang Zhang, Nuernisha Alifu, Biao Dong
Journal: Advanced Healthcare Materials (2024)

Abstract Precise theranostics of tumors is intricately linked to the early detection and monitoring of lymph nodes (LN) and metastases, making the targeted localization of LNs essential for tumor identification. However, designing LN‐targeting probes remains a significant challenge due to issues such as lymphatic uptake, biocompatibility, and fluorescence stability. To address these challenges, near‐infrared II (NIR‐II) fluorescence probes are developed through meticulous analysis of LN physiological structure and passive targeting strategy for LN detection and tumor therapy. An LPP‐QDs‐IR‐820 nanocomposite (NCs) is engineered, comprising the IR‐820 molecules and ultrabright PbS@CdS quantum dots (QDs), which are encapsulated within a liposome‐SH‐mPEG 2000 polymer matrix. These NCs demonstrates remarkable lymphatic enrichment, facilitating real‐time tracking of LN via electrostatic repulsion and extracellular matrix effects. Importantly, the NCs exhibit negligible in vivo toxicity and high biocompatibility. The intense NIR‐II fluorescence emissions of IR‐820 and PbS@CdS QDs confer upon the NCs a high NIR‐II fluorescence quantum yield (6%). The cervical tumors and their deep microvessels are clearly observed via NIR‐II fluorescence imaging. Moreover, the photothermal properties of IR‐820 enable the NCs to achieve a photothermal conversion efficiency of 36.56%, leading to effective photothermal therapy in cervical tumor mice.
Macrophage Membrane‐Biomimetic Multi‐Layered Nanoparticles Targeting Synovial Angiogenesis for Osteoarthritis Therapy
Authors: Junyi Liao, Zhenglin Zhu, Jing Zou, Senrui Liu, Xuefeng Luo, Wei Bao, Chengcheng Du, Yiting Lei, Wei Huang
Journal: Advanced Healthcare Materials (2024)

Abstract Osteoarthritis (OA) is an inflammatory and progressive joint disease characterized by angiogenesis‐mediated sustained, chronic, and low‐grade synovitis. Anti‐angiogenesis is emerging as a strategy for attenuating OA progression, but is often compromised by poor targeted drug delivery and immune clearance. Recent studies have identified macrophages formed a “protective barrier” in the lining layer (LL) of synovium, which blocked the communication of joint cavity and sublining layer (SL) of synovium. Inspired by natural mimicry, macrophage membrane‐camouflaged drug delivery is explored to avoid immune clearance. Based on the single cell RNA sequencing, the CD34 + synovial cells are identified as “sentinel cells” for synovium angiogenesis. Consequently, CD34 antibody‐modified macrophage membrane is constructed to target new angiogenesis. Hence, a biomimetic multi‐layered nanoparticle (NP) is developed that incorporates axitinib‐loaded poly(lactic‐co‐glycolic) acid (PLGA) with CD34 antibody modified macrophage membrane (Atb@NP@Raw@CD34) to specifically deliver axitinib (Atb) to the SL and sustain inhibiting angiogenesis without immune elimination. It is found that the Atb@NP@Raw@CD34 can pass through macrophage “barrier”, specifically targeting CD34 + cells, continuously releasing Atb and anti‐angiogenesis in OA synovitis. Furthermore, in vivo data demonstrated that Atb@NP@Raw@CD34 can attenuate joint degeneration by inhibiting synovium angiogenesis‐mediated synovitis. In conclusion, local injection of Atb@NP@Raw@CD34 presents a promising approach for clinically impeding OA progression.
Nanozyme‐Shelled Microcapsules for Targeting Biofilm Infections in Confined Spaces
Authors: Hong Huy Tran, Nadasinee Jaruchotiratanasakul, Zhenting Xiang, Nil Kanatha Pandey, Min Jun Oh, Yuan Liu, Zhi Ren, Alaa Babeer, Michael J. Zdilla, David P. Cormode, Bekir Karabucak, Daeyeon Lee, Edward B. Steager, Hyun Koo
Journal: Advanced Healthcare Materials (2024)

Abstract Bacterial infections in irregular and branched confinements pose significant therapeutic challenges. Despite their high antimicrobial efficacy, enzyme‐mimicking nanoparticles (nanozymes) face difficulties in achieving localized catalysis at distant infection sites within confined spaces. Incorporating nanozymes into microrobots enables the delivery of catalytic agents to hard‐to‐reach areas, but poor nanoparticle dispersibility and distribution during fabrication hinder their catalytic performance. To address these challenges, a nanozyme‐shelled microrobotic platform is introduced using magnetic microcapsules with collective and adaptive mobility for automated navigation and localized catalysis within complex confinements. Using double emulsions produced from microfluidics as templates, iron oxide and silica nanoparticles are assembled into 100‐µm microcapsules, which self‐organize into multi‐unit, millimeter‐size assemblies under rotating magnetic fields. These microcapsules exhibit high peroxidase‐like activity, efficiently catalyzing hydrogen peroxide to generate reactive oxygen species (ROS). Notably, microcapsule assemblies display remarkable collective navigation within arched and branched confinements, reaching the targeted apical regions of the tooth canal with high accuracy. Furthermore, these nanozyme‐shelled microrobots perform rapid catalysis in situ and effectively kill biofilms on contact via ROS generation, enabling localized antibiofilm action. This study demonstrates a facile method of integrating nanozymes onto a versatile microrobotic platform to address current needs for targeted therapeutic catalysis in complex and confined microenvironments.
NIR‐Actuated Botanicals/Nanozymes Nanofibrous Membranes for Antibiotic‐Free Triple‐Synergistic Therapy Against Polymicrobial Wound Infections
Authors: Kai Dong, Wenbo Lin, Tianyu Zhu, Shuwen Sun, Chenhao Zhang, Chen Xu, Fangfang Cao, Xiaoyuan Chen
Journal: Advanced Healthcare Materials (2024)

Abstract Polymicrobial wound infection represents a significant contributor to infectious disease‐related morbidity and mortality globally. Traditionally, the management of such infection relies heavily on high doses of antibiotics, often resulting in systemic side effects and exacerbating antibiotic resistance. Consequently, there is an urgent need to develop a safe and effective platform for antibiotic‐free treatment of polymicrobial wound infections. In this study, a near‐infrared (NIR) light‐actuated nanofibrous membrane incorporating botanicals and nanozymes is presented for antibiotic‐free triple‐synergistic therapy against polymicrobial wound infections. The membrane integrates berberine hydrochloride (BBH)‐loaded hollow zinc‐doped carbon nanocubes into polyvinyl alcohol (PVA) nanofibrous membranes. Upon low‐intensity 808 nm NIR laser irradiation (0.3 W cm −2 ), the membrane achieved a controlled release of BBH and enhanced peroxidase‐like (POD‐like) enzyme activity. This NIR light‐actuated botanical/photothermal therapy (PTT)/chemodynamic therapy (CDT) system demonstrated high efficacy in eradicating methicillin‐resistant Staphylococcus aureus and Pseudomonas aeruginosa both in vitro and in vivo. Furthermore, it mitigated inflammation and promoted wound healing in polymicrobial infection wounds, highlighting its potential as a promising alternative to antibiotic‐based therapies.