Comparative Evaluation of Proton Therapy and Volumetric Modulated Arc Therapy for Brachial Plexus Sparing in the Comprehensive Reirradiation of High-Risk Recurrent Breast Cancer.

Purpose: Recurrent or new primary breast cancer requiring comprehensive regional nodal irradiation after prior radiation therapy (RT) to the supraclavicular area and upper axilla is challenging due to cumulative brachial plexus (BP) dose tolerance. We assessed BP dose sparing achieved with pencil beam scanning proton therapy (PBS-PT) and photon volumetric modulated arc therapy (VMAT).

Methods And Materials: In an institutional review board-approved planning study, all patients with ipsilateral recurrent breast cancer treated with PBS-PT re-RT (PBT1) with at least partial BP overlap from prior photon RT were identified.

Detection of COVID-19 pulmonary manifestations with radiotherapy simulation CT imaging.

COVID-19 is associated with characteristic lung CT findings. Radiotherapy simulation CT scans may reveal characteristic COVID-19 findings and identify patients with active or prior infection. We reviewed patients undergoing CT simulation at a major cancer center in an early epicenter of the COVID-19 pandemic in the United States.

Multimodal single-cell analysis reveals distinct radioresistant stem-like and progenitor cell populations in murine glioma.

Radiation therapy is part of the standard of care for gliomas and kills a subset of tumor cells, while also altering the tumor microenvironment. Tumor cells with stem-like properties preferentially survive radiation and give rise to glioma recurrence. Various techniques for enriching and quantifying cells with stem-like properties have been used, including the fluorescence activated cell sorting (FACS)-based side population (SP) assay, which is a functional assay that enriches for stem-like tumor cells.

Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis.

The development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic but not lung or bone metastatic cells.

Chromosomal instability drives metastasis through a cytosolic DNA response.

Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA.

Patterns of nodal failure after intensity modulated radiotherapy for nasopharyngeal carcinoma.

Objectives: To evaluate the sites of nodal failure (NF) of nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT).

Study Design: Retrospective chart review.

Methods: We reviewed the records of 165 patients with nonmetastatic NPC treated with IMRT between July 1998 and April 2011 at our institution.

Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area.

Brain-derived neurotrophic factor (BDNF) has a crucial role in modulating neural and behavioral plasticity to drugs of abuse. We found a persistent downregulation of exon-specific Bdnf expression in the ventral tegmental area (VTA) in response to chronic opiate exposure, which was mediated by specific epigenetic modifications at the corresponding Bdnf gene promoters. Exposure to chronic morphine increased stalling of RNA polymerase II at these Bdnf promoters in VTA and altered permissive and repressive histone modifications and occupancy of their regulatory proteins at the specific promoters.

A Role for Mitogen- and Stress-Activated Kinase 1 in L-DOPA-Induced Dyskinesia and ∆FosB Expression.

Background: Abnormal regulation of extracellular signal-regulated kinases 1 and 2 has been implicated in 3,4-dihydroxy-l-phenylalanine (L-DOPA)-induced dyskinesia (LID), a motor complication affecting Parkinson's disease patients subjected to standard pharmacotherapy. We examined the involvement of mitogen- and stress-activated kinase 1 (MSK1), a downstream target of extracellular signal-regulated kinases 1 and 2, and an important regulator of transcription in LID.

Methods: 6-Hydroxydopamine was used to produce a model of Parkinson's disease in MSK1 knockout mice and in ∆FosB- or ∆cJun-overexpressing transgenic mice, which were assessed for LID following long-term L-DOPA administration.

Chronic cocaine-regulated epigenomic changes in mouse nucleus accumbens.

Background: Increasing evidence supports a role for altered gene expression in mediating the lasting effects of cocaine on the brain, and recent work has demonstrated the involvement of chromatin modifications in these alterations. However, all such studies to date have been restricted by their reliance on microarray technologies that have intrinsic limitations.

Results: We use next generation sequencing methods, RNA-seq and ChIP-seq for RNA polymerase II and several histone methylation marks, to obtain a more complete view of cocaine-induced changes in gene expression and associated adaptations in numerous modes of chromatin regulation in the mouse nucleus accumbens, a key brain reward region.

Mathematical modeling of PDGF-driven glioblastoma reveals optimized radiation dosing schedules.

Glioblastomas (GBMs) are the most common and malignant primary brain tumors and are aggressively treated with surgery, chemotherapy, and radiotherapy. Despite this treatment, recurrence is inevitable and survival has improved minimally over the last 50 years. Recent studies have suggested that GBMs exhibit both heterogeneity and instability of differentiation states and varying sensitivities of these states to radiation.

Detection of epigenetic changes using ANOVA with spatially varying coefficients.

Identification of genome-wide epigenetic changes, the stable changes in gene function without a change in DNA sequence, under various conditions plays an important role in biomedical research. High-throughput epigenetic experiments are useful tools to measure genome-wide epigenetic changes, but the measured intensity levels from these high-resolution genome-wide epigenetic profiling data are often spatially correlated with high noise levels. In addition, it is challenging to detect genome-wide epigenetic changes across multiple conditions, so efficient statistical methodology development is needed for this purpose.

BDNF is a negative modulator of morphine action.

Brain-derived neurotrophic factor (BDNF) is a key positive regulator of neural plasticity, promoting, for example, the actions of stimulant drugs of abuse such as cocaine. We discovered a surprising opposite role for BDNF in countering responses to chronic morphine exposure. The suppression of BDNF in the ventral tegmental area (VTA) enhanced the ability of morphine to increase dopamine (DA) neuron excitability and promote reward.

Drug experience epigenetically primes Fosb gene inducibility in rat nucleus accumbens.

ΔFosB, a Fosb gene product, is induced in nucleus accumbens (NAc) and caudate-putamen (CPu) by repeated exposure to drugs of abuse such as cocaine. This induction contributes to aberrant patterns of gene expression and behavioral abnormalities seen with repeated drug exposure. Here, we assessed whether a remote history of cocaine exposure in rats might alter inducibility of the Fosb gene elicited by subsequent drug exposure.

Neurobiological sequelae of witnessing stressful events in adult mice.

Background: It is well known that exposure to severe stress increases the risk for developing mood disorders. However, most chronic stress models in rodents involve at least some form of physically experiencing traumatic events.

Methods: This study assessed the effects of a novel social stress paradigm that is insulated from the effects of physical stress.

Subregional, dendritic compartment, and spine subtype specificity in cocaine regulation of dendritic spines in the nucleus accumbens.

Numerous studies have found that chronic cocaine increases dendritic spine density of medium spiny neurons in the nucleus accumbens (NAc). Here, we used single-cell microinjections and advanced 3D imaging and analysis techniques to extend these findings in several important ways: by assessing cocaine regulation of dendritic spines in the core versus shell subregions of NAc in the mouse, over a broad time course (4 h, 24 h, or 28 d) of withdrawal from chronic cocaine, and with a particular focus on proximal versus distal dendrites. Our data demonstrate subregion-specific, and in some cases opposite, regulation of spines by cocaine on proximal but not distal dendrites.

Paternal transmission of stress-induced pathologies.

Background: There has been recent interest in the possibility that epigenetic mechanisms might contribute to the transgenerational transmission of stress-induced vulnerability. Here, we focused on possible paternal transmission with the social defeat stress paradigm.

Methods: Adult male mice exposed to chronic social defeat stress or control nondefeated mice were bred with normal female mice, and their offspring were assessed behaviorally for depressive- and anxiety-like measures.

Hippocampal-dependent antidepressant-like activity of histone deacetylase inhibition.

Chronic social defeat stress in mice significantly decreases subsequent social interactions and induces other depression-like behaviors. Here we measured and manipulated levels of acetylated histone H3 (acH3), a chromatin mark of transcriptional activation, in the hippocampus and amygdala after ten continuous days of social defeat stress in male C57/Bl6J mice. This form of social stress causes a transient increase, followed by a persistent decrease, in the levels of acH3 in hippocampus.

Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex.

Brain stimulation and imaging studies in humans have highlighted a key role for the prefrontal cortex in clinical depression; however, it remains unknown whether excitation or inhibition of prefrontal cortical neuronal activity is associated with antidepressant responses. Here, we examined cellular indicators of functional activity, including the immediate early genes (IEGs) zif268 (egr1), c-fos, and arc, in the prefrontal cortex of clinically depressed humans obtained postmortem. We also examined these genes in the ventral portion of the medial prefrontal cortex (mPFC) of mice after chronic social defeat stress, a mouse model of depression.

Serum response factor promotes resilience to chronic social stress through the induction of DeltaFosB.

The molecular mechanisms underlying stress- and drug-induced neuronal adaptations are incompletely understood. One molecule implicated in such adaptations is ΔFosB, a transcription factor that accumulates in the rodent nucleus accumbens (NAc), a key brain reward region, in response to either chronic stress or repeated exposure to drugs of abuse. The upstream transcriptional mechanisms controlling ΔFosB induction by these environmental stimuli remain elusive.

Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens.

Despite abundant expression of DNA methyltransferases (Dnmts) in brain, the regulation and behavioral role of DNA methylation remain poorly understood. We found that Dnmt3a expression was regulated in mouse nucleus accumbens (NAc) by chronic cocaine use and chronic social defeat stress. Moreover, NAc-specific manipulations that block DNA methylation potentiated cocaine reward and exerted antidepressant-like effects, whereas NAc-specific Dnmt3a overexpression attenuated cocaine reward and was pro-depressant.

CRACKing the histone code: cocaine's effects on chromatin structure and function.

Epigenetics, the nongenetic component of how chromatin structure influences gene expression, is amazingly complex, and linking how environmental stimuli can influence epigenetic 'gene programs' in specific nerve cells to ultimately control behavior is a seemingly insurmountable puzzle. Cocaine is a highly potent stimulus capable of influencing behavior for the lifetime of an organism. Not surprisingly, psychostimulant-induced epigenetic regulation of gene expression has thus been identified as key to understanding the pathology of addiction.