Cholinergic neuron-to-glioblastoma synapses in a human iPSC-derived co-culture model.

Glioblastoma (GBM) integrates extensively into brain-wide neuronal circuits; however, neuron-tumor interactions have largely been studied with glutamatergic neurons in animal models. The role of neuromodulatory circuits for GBM biology in all-human cell systems remains unclear. Here, we report a co-culture system employing patient-derived GBM organoids and human induced pluripotent stem cell (hiPSC)-derived cholinergic neurons.

Incidence and Outcomes of Brain Metastasis in Pleural Mesothelioma in the Era of Immunotherapy.

Introduction: Immunotherapy (IO) has reported efficacy in pleural mesothelioma (PM). Brain metastases (BMs) in PM are rare; thus, surveillance brain imaging is not included in the guidelines. We evaluated the incidence of BM by treatment type.

Methotrexate-associated Peripheral Neuropathy on 18F-FDG PET/CT and MRI Masquerading as Neurolymphomatosis.

A 53-year-old woman with primary central nervous system lymphoma with vitreal involvement presented with upper extremity weakness, pain, and contractures following methotrexate infusion. Electromyography showed mononeuropathies of the upper extremities, suspicious for neurolymphomatosis versus vasculitis. An 18F-FDG PET CT indicated neurolymphomatosis, while an MRI of the bilateral forearms demonstrated intramuscular fluid collections, suspicious for abscesses or infarcts.

Brain-wide neuronal circuit connectome of human glioblastoma.

Glioblastoma (GBM) infiltrates the brain and can be synaptically innervated by neurons, which drives tumour progression. Synaptic inputs onto GBM cells identified so far are largely short range and glutamatergic. The extent of GBM integration into the brain-wide neuronal circuitry remains unclear.

Technical Feasibility and Safety of Transpedicular Thoracic Partial Corpectomy Using Biportal Endoscopic Technique: A Novel Approach for Separation Surgery in Spinal Metastatic Disease.

Bony metastases frequently involve the spinal column, most commonly the thoracic spine. Surgical interventions in spinal metastatic disease are palliative and effective in providing diagnoses, reducing pain, and maintaining ambulatory function through neural element decompression and improving axial pain and posture through spinal column stabilization. Surgeons must weigh the benefits of surgery against fragility and limited life expectancy in patients with cancer.

Patient-derived glioblastoma organoids as real-time avatars for assessing responses to clinical CAR-T cell therapy.

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.

Cellular signaling impacts upon GABAergic cortical interneuron development.

The development and maturation of cortical GABAergic interneurons has been extensively studied, with much focus on nuclear regulation transcription factors. While these seminal events are critical for the establishment of interneuron developmental milestones, recent studies on cellular signaling cascades have begun to elucidate some potential contributions of cell signaling during development. Here, we review studies underlying three broad signaling families, mTOR, MAPK, and Wnt/beta-catenin in cortical interneuron development.

LiCl treatment leads to long-term restoration of spine maturation and synaptogenesis in adult Tbr1 mutants.

Background: Tbr1 encodes a T-box transcription factor and is considered a high confidence autism spectrum disorder (ASD) gene. Tbr1 is expressed in the postmitotic excitatory neurons of the deep neocortical layers 5 and 6. Postnatally and neonatally, Tbr1 conditional mutants (CKOs) have immature dendritic spines and reduced synaptic density.

Autism risk gene POGZ promotes chromatin accessibility and expression of clustered synaptic genes.

Deleterious genetic variants in POGZ, which encodes the chromatin regulator Pogo Transposable Element with ZNF Domain protein, are strongly associated with autism spectrum disorder (ASD). Although it is a high-confidence ASD risk gene, the neurodevelopmental functions of POGZ remain unclear. Here we reveal the genomic binding of POGZ in the developing forebrain at euchromatic loci and gene regulatory elements (REs).

and control mouse pallial interneuron fate and maturation through neuropsychiatric disease gene regulation.

() and transcription factors (TFs) have compensatory roles in repressing somatostatin (SST) interneuron (IN) production in medial ganglionic eminence (MGE) secondary progenitors in mice. and conditional deletion (cDKO) decreases the survival of MGE-derived cortical interneurons (CINs) and changes their physiological properties. Herein, we show that (1) and are positively regulated by and to drive IN morphological maturation; (2) and promote expression which specifies parvalbumin (PV) INs; (3) , and are candidate markers of immature PV hippocampal INs (HIN).

Enhancing WNT Signaling Restores Cortical Neuronal Spine Maturation and Synaptogenesis in Tbr1 Mutants.

Tbr1 is a high-confidence autism spectrum disorder (ASD) gene encoding a transcription factor with distinct pre- and postnatal functions. Postnatally, Tbr1 conditional knockout (CKO) mutants and constitutive heterozygotes have immature dendritic spines and reduced synaptic density. Tbr1 regulates expression of several genes that underlie synaptic defects, including a kinesin (Kif1a) and a WNT-signaling ligand (Wnt7b).

deletion results in depletion of the transcription factor and a specific loss of parvalbumin cortical interneurons.

Neurofibromatosis 1 (NF1) is caused by mutations in the gene, which encodes the protein, neurofibromin, an inhibitor of Ras activity. Cortical GABAergic interneurons (CINs) are implicated in NF1 pathology, but the cellular and molecular changes to CINs are unknown. We deleted mouse from the medial ganglionic eminence, which gives rise to both oligodendrocytes and CINs that express somatostatin and parvalbumin.

Tsc1 represses parvalbumin expression and fast-spiking properties in somatostatin lineage cortical interneurons.

Medial ganglionic eminence (MGE)-derived somatostatin (SST)+ and parvalbumin (PV)+ cortical interneurons (CINs), have characteristic molecular, anatomical and physiological properties. However, mechanisms regulating their diversity remain poorly understood. Here, we show that conditional loss of the Tuberous Sclerosis Complex (TSC) gene, Tsc1, which inhibits the mammalian target of rapamycin (MTOR), causes a subset of SST+ CINs, to express PV and adopt fast-spiking (FS) properties, characteristic of PV+ CINs.

Mafb and c-Maf Have Prenatal Compensatory and Postnatal Antagonistic Roles in Cortical Interneuron Fate and Function.

Mafb and c-Maf transcription factor (TF) expression is enriched in medial ganglionic eminence (MGE) lineages, beginning in late-secondary progenitors and continuing into mature parvalbumin (PV) and somatostatin (SST) interneurons. However, the functions of Maf TFs in MGE development remain to be elucidated. Herein, Mafb and c-Maf were conditionally deleted, alone and together, in the MGE and its lineages.

Neonatal Tbr1 Dosage Controls Cortical Layer 6 Connectivity.

An understanding of how heterozygous loss-of-function mutations in autism spectrum disorder (ASD) risk genes, such as TBR1, contribute to ASD remains elusive. Conditional Tbr1 deletion during late mouse gestation in cortical layer 6 neurons (Tbr1 mutants) provides novel insights into its function, including dendritic patterning, synaptogenesis, and cell-intrinsic physiology. These phenotypes occur in heterozygotes, providing insights into mechanisms that may underlie ASD pathophysiology.

The AAA + ATPase Thorase is neuroprotective against ischemic injury.

Neuronal preconditioning in vitro or in vivo with a stressful but non-lethal stimulus leads to new protein expression that mediates a profound neuroprotection against glutamate excitotoxicity and experimental stroke. The proteins that mediate neuroprotection are relatively unknown and under discovery. Here we find that the expression of the AAA + ATPase Thorase is induced by preconditioning stimulation both in vitro and in vivo.

Endografting under Assistance of Transapical Body Floss Through-and-Through Wiring Technique and Rapid Ventricular Pacing for an Ascending Aortic Tuberculous Pseudoaneurysm.

Background: To demonstrate an ascending aortic tuberculosis pseudoaneurysm successfully treated with endografts under assistance of trans-apical body floss wiring technique and rapid ventricular pacing support.

Method And Result: A 77-year-old woman with a non-healing anteromedial chest wound presented with sudden hypotension and hemoptysis. The computed tomography (CT) scan revealed a 9-cm-diameter pseudoaneurysm of ascending aorta, with sternal erosion close to the wound.

High-Content Genome-Wide RNAi Screen Reveals as a Key Mediator of Neuronal Cell Death.

Neuronal loss caused by ischemic injury, trauma, or disease can lead to devastating consequences for the individual. With the goal of limiting neuronal loss, a number of cell death pathways have been studied, but there may be additional contributors to neuronal death that are yet unknown. To identify previously unknown cell death mediators, we performed a high-content genome-wide screening of short, interfering RNA (siRNA) with an siRNA library in murine neural stem cells after exposure to -methyl--nitroso-'-nitroguanidine (MNNG), which leads to DNA damage and cell death.