Publications by authors named "Daniel Y Zhang"

Brain arteriovenous malformations (AVMs) are vascular lesions characterized by abnormal connections between parenchymal arteries and veins, bypassing a capillary bed, and forming a nidus. Brain AVMs are consequential as they are prone to rupture and associated with significant morbidity. They can broadly be subdivided into hereditary vs.

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Patient-derived tumor organoids have been leveraged for disease modeling and preclinical studies but rarely applied in real time to aid with interpretation of patient treatment responses in clinics. We recently demonstrated early efficacy signals in a first-in-human, phase 1 study of dual-targeting chimeric antigen receptor (CAR)-T cells (EGFR-IL13Rα2 CAR-T cells) in patients with recurrent glioblastoma. Here, we analyzed six sets of patient-derived glioblastoma organoids (GBOs) treated concurrently with the same autologous CAR-T cell products as patients in our phase 1 study.

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Introduction: For many therapeutic drugs, including antiretroviral drugs used to treat people living with HIV-1 (PLWH), we have little data on the potential effects on the developing human brain due to limited access to tissue and historical constraints on the inclusion of pregnant populations in clinical trials. Human induced pluripotent stem cells (iPSCs) offer a new avenue to gain insight on how drugs may impact human cell types representative of the developing central nervous system. To prevent vertical transmission of HIV and promote the health of pregnant PLWH, antiretroviral therapy must be initiated and/or maintained throughout pregnancy.

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Objective: Frailty is recognized as an important predictor of neurointerventional outcomes. MRI-guided focused ultrasound (MRgFUS) thalamotomy is a treatment option for patients with refractory essential tremor (ET) and tremor-dominant Parkinson's disease (TdPD). The aim of this study was to evaluate whether frailer MRgFUS thalamotomy patients had worse tremor outcomes or more complications.

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  • Glioblastoma is a challenging brain cancer that often resists standard immunotherapy, but Botensilimab, a specialized antibody, has shown potential in treating this type of cancer.
  • In preclinical studies, a mouse version of Botensilimab demonstrated effectiveness when used alone or with doxorubicin combined with ultrasound techniques, leading to significant immune responses in treatment-resistant glioblastoma.
  • Results indicated that this combination therapy not only effectively targeted and reduced tumor-associated immune cells but also fostered a strong infiltration of harmful T cells, achieving a remarkable cure rate in mice and suggesting promising implications for human treatments.
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  • Most drugs struggle to effectively treat glioblastoma (GBM) due to limited penetration across the blood-brain barrier, which makes their efficacy low.
  • This study utilizes low-intensity pulsed ultrasound (LIPU) combined with microbubbles (MB) to temporarily open the blood-brain barrier, significantly increasing the delivery of liposomal doxorubicin and PD-1 blocking antibodies (aPD-1) in both human and animal models.
  • Results show that this method improves drug concentrations, enhances immune responses in cells, and contributes to long-term survival in GBM mouse models, highlighting its potential for improving GBM treatments.
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  • Glioblastoma (GBM) is an aggressive brain tumor that is resistant to treatment and often recurs after therapy, with surgery, radiation, and chemotherapy being the primary treatment options.
  • Despite research into new therapies like immunotherapy and targeted treatments, progress has been limited due to challenges in creating accurate models that mimic the tumor's complexity.
  • Recent advances include 3D organoid systems that replicate GBM biology, offering new insights and potential for improved therapeutic strategies, although retaining the tumor microenvironment remains a significant challenge.
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  • Glioblastoma (GBM) is a lethal brain cancer that infiltrates the brain and can form synapses with neurons, contributing to its progression.
  • This study used a rabies virus tracing technique to show that human GBM cells transplanted into mice integrate quickly into various neuronal circuits and receive diverse synaptic inputs, including neuromodulatory signals.
  • Activation of the acetylcholine receptor CHRM3 in GBM cells was found to trigger invasive behavior and increased survival, suggesting that synaptic connections play a crucial role in enhancing tumor aggressiveness.
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Background: Deep brain stimulation (DBS) surgery is an effective treatment for movement disorders. Introduction of intracranial air following dura opening in DBS surgery can result in targeting inaccuracy and suboptimal outcomes. We develop and evaluate a simple method to minimize pneumocephalus during DBS surgery.

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Background: Recurrent gliomas are therapeutically challenging diseases with few treatment options available. One area of potential therapeutic vulnerability is the presence of targetable oncogenic fusion proteins.

Methods: To better understand the clinical benefit of routinely testing for fusion proteins in adult glioma patients, we performed a retrospective review of 647 adult patients with glioma who underwent surgical resection at our center between August 2017 and May 2021 and whose tumors were analyzed with an in-house fusion transcript panel.

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Background: Low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU-MB) can be used to open the blood-brain barrier. We aimed to assess the safety and pharmacokinetics of LIPU-MB to enhance the delivery of albumin-bound paclitaxel to the peritumoural brain of patients with recurrent glioblastoma.

Methods: We conducted a dose-escalation phase 1 clinical trial in adults (aged ≥18 years) with recurrent glioblastoma, a tumour diameter of 70 mm or smaller, and a Karnofsky performance status of at least 70.

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  • The study investigates how intrinsic tumor-cell mechanisms, specifically kinases, allow glioblastoma (GBM) cells to evade detection by CD8 T cells, highlighting checkpoint kinase 2 (Chek2) as a key player.
  • An in vivo CRISPR screen identified Chek2 as crucial for tumor cell escape, and its inhibition, along with PD-1 or PD-L1 blockade, improves survival in preclinical glioma models.
  • The research shows that reducing Chek2 enhances antigen presentation and T-cell activation while analysis of human GBMs shows an inverse relationship between Chek2 expression and immune responsiveness, suggesting it as a potential target for improving immune checkpoint therapies in GBM.
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Introduction: Magnetic resonance-guided focused ultrasound (MRgFUS) represents an incisionless treatment option for essential or parkinsonian tremor. The incisionless nature of this procedure has garnered interest from both patients and providers. As such, an increasing number of centers are initiating new MRgFUS programs, necessitating development of unique workflows to optimize patient care and safety.

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Increasing evidence implicates the critical roles of various epitranscriptomic RNA modifications in different biological processes. Methyltransferase METTL8 installs 3-methylcytosine (mC) modification of mitochondrial tRNAs in vitro; however, its role in intact biological systems is unknown. Here, we show that Mettl8 is localized in mitochondria and installs mC specifically on mitochondrial tRNA in mouse embryonic cortical neural stem cells.

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Immature dentate granule cells (imGCs) arising from adult hippocampal neurogenesis contribute to plasticity and unique brain functions in rodents and are dysregulated in multiple human neurological disorders. Little is known about the molecular characteristics of adult human hippocampal imGCs, and even their existence is under debate. Here we performed single-nucleus RNA sequencing aided by a validated machine learning-based analytic approach to identify imGCs and quantify their abundance in the human hippocampus at different stages across the lifespan.

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Purpose: Paclitaxel (PTX) is one of the most potent and commonly used chemotherapies for breast and pancreatic cancer. Several ongoing clinical trials are investigating means of enhancing delivery of PTX across the blood-brain barrier for glioblastomas. Despite the widespread use of PTX for breast cancer, and the initiative to repurpose this drug for gliomas, there are no predictive biomarkers to inform which patients will likely benefit from this therapy.

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Pseudouridine is the most abundant yet unexplored RNA modification in glioblastoma. Cui and coworkers find that PUS7, a pseudouridine depositing enzyme, promotes tumor growth and can be targeted by small molecule inhibitors. Mechanistically, PUS7 modifies tRNAs, reduces TYK2 translation, and downregulates a proliferation-restricting interferon-STAT1 pathway in glioblastoma.

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Tumor heterogeneity is a key reason for therapeutic failure and tumor recurrence in glioblastoma (GBM). Our chimeric antigen receptor (CAR) T cell (2173 CAR T cells) clinical trial (NCT02209376) against epidermal growth factor receptor (EGFR) variant III (EGFRvIII) demonstrated successful trafficking of T cells across the blood-brain barrier into GBM active tumor sites. However, CAR T cell infiltration was associated only with a selective loss of EGFRvIII+ tumor, demonstrating little to no effect on EGFRvIII tumor cells.

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Purpose: The blood-brain barrier (BBB) inhibits adequate dosing/penetration of therapeutic agents to malignancies in the brain. Low-intensity pulsed ultrasound (LIPU) is a safe therapeutic method of temporary BBB disruption (BBBD) to enhance chemotherapeutic delivery to the tumor and surrounding brain parenchyma for treatment of glioblastoma.

Experimental Design: We investigated if LIPU could enhance therapeutic efficacy of anti-PD-1 in C57BL/6 mice bearing intracranial GL261 gliomas, epidermal growth factor receptor variant III (EGFRvIII) chimeric antigen receptor (CAR) T cells in NSG mice with EGFRvIII-U87 gliomas, and a genetically engineered antigen-presenting cell (APC)-based therapy producing the T-cell attracting chemokine CXCL10 in the GL261-bearing mice.

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  • Human brain organoids, specifically arcuate organoids (ARCOs), have been created from human induced pluripotent stem cells to study the hypothalamic arcuate nucleus and its development.
  • Single-cell RNA sequencing of these organoids shows significant diversity in cellular makeup and highlights a distinct molecular signature related to the human arcuate nucleus.
  • ARCOs derived from Prader-Willi syndrome patients demonstrate abnormal differentiation and inflammatory responses, making them valuable models for exploring hypothalamic development and related diseases.
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  • * Researchers found that while neurons and astrocytes were only lightly infected, choroid plexus epithelial cells were significantly affected, leading to cell death and signs of inflammation.
  • * The findings support using human induced pluripotent stem cell-derived brain organoids to further explore how SARS-CoV-2 infects brain cells and the resulting dysfunction, potentially aiding in developing treatment strategies.
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Immunotherapy has revolutionized the treatment of many tumors. However, most glioblastoma (GBM) patients have not, so far, benefited from such successes. With the goal of exploring ways to boost anti-GBM immunity, we developed a B cell-based vaccine (BVax) that consists of 4-1BBL+ B cells activated with CD40 agonism and IFNγ stimulation.

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