10 research outputs found
Traumatic rupture of thoracic epidural capillary hemangioma resulting in acute neurologic deficit: illustrative case
BackgroundThoracic epidural capillary hemangioma is exceedingly rare, with only a few reported cases. The typical presentation usually includes chronic, progressive symptoms of spinal cord compression in middle-aged adults. To the authors' knowledge, this case is the first report in the literature of acute traumatic capillary hemangioma rupture.ObservationsA 22-year-old male presented with worsening lower extremity weakness and paresthesias after a fall onto his spine. Imaging showed no evidence of spinal fracture but revealed an expanding hematoma over 24 hours. Removal of the lesion demonstrated a ruptured capillary hemangioma.LessonsThis unique case highlights a rare occurrence of traumatic rupture of a previously unknown asymptomatic thoracic capillary hemangioma in a young adult
CDK 4/6 inhibitors for the treatment of meningioma.
Meningiomas are the most common non-metastatic brain tumors, and although the majority are relatively slow-growing and histologically benign, a subset of meningiomas are aggressive and remain challenging to treat. Despite a standard of care that includes surgical resection and radiotherapy, and recent advances in meningioma molecular grouping, there are no systemic medical options for patients with meningiomas that are resistant to standard interventions. Misactivation of the cell cycle at the level of CDK4/6 is common in high-grade or molecularly aggressive meningiomas, and CDK4/6 has emerged as a potential target for systemic meningioma treatments. In this review, we describe the preclinical evidence for CDK4/6 inhibitors as a treatment for high-grade meningiomas and summarize evolving clinical experience with these agents. Further, we highlight upcoming clinical trials for patients meningiomas, and discuss future directions aimed at optimizing the efficacy of these therapies and selecting patients most likely to benefit from their use
Cirmtuzumab (UC-961), a First-in-Class Anti-ROR1 Monoclonal Antibody: Planned Interim Analysis of Initial Phase 1 Cohorts
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Phase I Trial: Cirmtuzumab Inhibits ROR1 Signaling and Stemness Signatures in Patients with Chronic Lymphocytic Leukemia
Cirmtuzumab is a humanized monoclonal antibody (mAb) that targets ROR1, an oncoembryonic orphan receptor for Wnt5a found on cancer stem cells (CSCs). Aberrant expression of ROR1 is seen in many malignancies and has been linked to Rho-GTPase activation and cancer stem cell self-renewal. For patients with chronic lymphocytic leukemia (CLL), self-renewing, neoplastic B cells express ROR1 in 95% of cases. High-level leukemia cell expression of ROR1 is associated with an unfavorable prognosis. We conducted a phase 1 study involving 26 patients with progressive, relapsed, or refractory CLL. Patients received four biweekly infusions, with doses ranging from 0.015 to 20 mg/kg. Cirmtuzumab had a long plasma half-life and did not have dose-limiting toxicity. Inhibition of ROR1 signaling was observed, including decreased activation of RhoA and HS1. Transcriptome analyses showed that therapy inhibited CLL stemness gene expression signatures in vivo. Cirmtuzumab is safe and effective at inhibiting tumor cell ROR1 signaling in patients with CLL
Jet-Cooled Spectroscopy of the α‑Methylbenzyl Radical: Probing the State-Dependent Effects of Methyl Rocking Against a Radical Site
The
state-dependent spectroscopy of α-methylbenzyl radical
(α-MeBz) has been studied under jet-cooled conditions. Two-color
resonant two-photon ionization (2C-R2PI), laser-induced fluorescence,
and dispersed fluorescence spectra were obtained for the D<sub>0</sub>–D<sub>1</sub> electronic transition of this prototypical
resonance-stabilized radical in which the methyl group is immediately
adjacent to the primary radical site. Extensive Franck–Condon
activity in hindered rotor levels was observed in the excitation spectrum,
reflecting a reorientation of the methyl group upon electronic excitation.
Dispersed fluorescence spectra from the set of internal rotor levels
are combined with the excitation spectrum to obtain a global fit of
the barrier heights and angular change of the methyl group in both
D<sub>0</sub> and D<sub>1</sub> states. The best-fit methyl rotor
potential in the ground electronic state (D<sub>0</sub>) is a flat-topped
3-fold potential (V<sub>3</sub>″ = 151 cm<sup>–1</sup>, V<sub>6</sub>″ = 34 cm<sup>–1</sup>) while the D<sub>1</sub> state has a lower barrier (V<sub>3</sub>′ = 72 cm<sup>–1</sup>, V<sub>6</sub>′ = 15 cm<sup>–1</sup>) with Δφ = ± π/3, π, consistent with
a reorientation of the methyl group upon electronic excitation. The
ground state results are compared with calculations carried out at
the DFT B3LYP level of theory using the 6-311+GÂ(d,p) basis set, and
a variety of excited state calculations are carried out to compare
against experiment. The preferred geometry of the methyl rotor in
the ground state is <i>anti</i>, which switches to <i>syn</i> in the D<sub>1</sub> state and in the cation. The calculations
uncover a subtle combination of effects that contribute to the shift
in orientation and change in barrier in the excited state relative
to ground state. Steric interaction favors the <i>anti</i> conformation, while hyperconjugation is greater in the <i>syn</i> orientation. The presence of a second excited state close by D<sub>1</sub> is postulated to influence the methyl rotor properties. A
resonant ion-dip infrared (RIDIR) spectrum in the alkyl and aromatic
CH stretch regions was also recorded, probing in a complementary way
the state-dependent conformation of α-MeBz. Using a scheme in
which infrared depletion occurs between excitation and ionization
steps of the 2C-R2PI process, analogous infrared spectra in D<sub>1</sub> were also obtained, probing the response of the CH stretch
fundamentals to electronic excitation. A reduced-dimension Wilson
G-matrix model was implemented to simulate and interpret the observed
infrared results. Finally, photoionization efficiency scans were carried
out to determine the adiabatic ionization threshold of α-MeBz
(IP = 6.835 ± 0.002 eV) and provide thresholds for ionization
out of specific internal rotor levels, which report on the methyl
rotor barrier in the cation state
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Three-dimensional bioprinted glioblastoma microenvironments model cellular dependencies and immune interactions.
Brain tumors are dynamic complex ecosystems with multiple cell types. To model the brain tumor microenvironment in a reproducible and scalable system, we developed a rapid three-dimensional (3D) bioprinting method to construct clinically relevant biomimetic tissue models. In recurrent glioblastoma, macrophages/microglia prominently contribute to the tumor mass. To parse the function of macrophages in 3D, we compared the growth of glioblastoma stem cells (GSCs) alone or with astrocytes and neural precursor cells in a hyaluronic acid-rich hydrogel, with or without macrophage. Bioprinted constructs integrating macrophage recapitulate patient-derived transcriptional profiles predictive of patient survival, maintenance of stemness, invasion, and drug resistance. Whole-genome CRISPR screening with bioprinted complex systems identified unique molecular dependencies in GSCs, relative to sphere culture. Multicellular bioprinted models serve as a scalable and physiologic platform to interrogate drug sensitivity, cellular crosstalk, invasion, context-specific functional dependencies, as well as immunologic interactions in a species-matched neural environment