The Combination of PARP and Topoisomerase 1 Inhibitors Improves Radiation Therapy for Ewing Sarcoma.

Although primary tumor control rates after surgery and/or radiation therapy (RT) are generally high in patients with Ewing sarcoma (EWS), those with unresectable tumors have failure rates approaching 30% and experience poorer outcomes. Additionally, although metastatic site irradiation is associated with improved survival, dose, and volume effects influence the long-term toxicity risk. Consequently, it is important to identify novel systemic agents to enhance the therapeutic ratio of RT.

Clinical proof-of-concept results with a novel TRPA1 antagonist (LY3526318) in 3 chronic pain states.

Transient receptor potential ankyrin 1 (TRPA1) is implicated in physiological and pathological nociceptive signaling, but the clinical benefit of TRPA1 antagonists in chronic pain is not clearly demonstrated. LY3526318 is an oral, potent, and selective novel TRPA1 antagonist. The Chronic Pain Master Protocol was used to evaluate the safety and efficacy of LY3526318 in 3 randomized, placebo-controlled, proof-of-concept studies in knee osteoarthritis pain (OA), chronic low back pain (CLBP), and diabetic peripheral neuropathic pain (DPNP).

Characterization of Adult Vestibular Organs in 11 CreER Mouse Lines.

Utricles are vestibular sense organs that encode linear head movements. They are composed of a sensory epithelium with type I and type II hair cells and supporting cells, sitting atop connective tissue, through which vestibular nerves project. We characterized utricular Cre expression in 11 murine CreER lines using the ROSA26 reporter line and tamoxifen induction at 6 weeks of age.

Thalamic miR-338-3p mediates auditory thalamocortical disruption and its late onset in models of 22q11.2 microdeletion.

Although 22q11.2 deletion syndrome (22q11DS) is associated with early-life behavioral abnormalities, affected individuals are also at high risk for the development of schizophrenia symptoms, including psychosis, later in life. Auditory thalamocortical (TC) projections recently emerged as a neural circuit that is specifically disrupted in mouse models of 22q11DS (hereafter referred to as 22q11DS mice), in which haploinsufficiency of the microRNA (miRNA)-processing-factor-encoding gene Dgcr8 results in the elevation of the dopamine receptor Drd2 in the auditory thalamus, an abnormal sensitivity of thalamocortical projections to antipsychotics, and an abnormal acoustic-startle response.

Spontaneous regeneration of cochlear supporting cells after neonatal ablation ensures hearing in the adult mouse.

Supporting cells in the cochlea play critical roles in the development, maintenance, and function of sensory hair cells and auditory neurons. Although the loss of hair cells or auditory neurons results in sensorineural hearing loss, the consequence of supporting cell loss on auditory function is largely unknown. In this study, we specifically ablated inner border cells (IBCs) and inner phalangeal cells (IPhCs), the two types of supporting cells surrounding inner hair cells (IHCs) in mice in vivo.

Selective ablation of pillar and deiters' cells severely affects cochlear postnatal development and hearing in mice.

Mammalian auditory hair cells (HCs) are inserted into a well structured environment of supporting cells (SCs) and acellular matrices. It has been proposed that when HCs are irreversibly damaged by noise or ototoxic drugs, surrounding SCs seal the epithelial surface and likely extend the survival of auditory neurons. Because SCs are more resistant to damage than HCs, the effects of primary SC loss on HC survival and hearing have received little attention.

Regulation of p27Kip1 by Sox2 maintains quiescence of inner pillar cells in the murine auditory sensory epithelium.

Sox2 plays critical roles in cell fate specification during development and in stem cell formation; however, its role in postmitotic cells is largely unknown. Sox2 is highly expressed in supporting cells (SCs) of the postnatal mammalian auditory sensory epithelium, which unlike non-mammalian vertebrates remains quiescent even after sensory hair cell damage. Here, we induced the ablation of Sox2, specifically in SCs at three different postnatal ages (neonatal, juvenile and adult) in mice.

Conditional gene expression in the mouse inner ear using Cre-loxP.

In recent years, there has been significant progress in the use of Cre-loxP technology for conditional gene expression in the inner ear. Here, we introduce the basic concepts of this powerful technology, emphasizing the differences between Cre and CreER. We describe the creation and Cre expression pattern of each Cre and CreER mouse line that has been reported to have expression in auditory and vestibular organs.

Outer hair cell somatic, not hair bundle, motility is the basis of the cochlear amplifier.

Sensitivity, dynamic range and frequency tuning of the cochlea are attributed to amplification involving outer hair cell stereocilia and/or somatic motility. We measured acoustically and electrically elicited basilar membrane displacements from the cochleae of wild-type and Tecta(DeltaENT/DeltaENT) mice, in which stereocilia are unable to contribute to amplification near threshold. Electrically elicited responses from Tecta(DeltaENT/DeltaENT) mice were markedly similar to acoustically and electrically elicited responses from wild-type mice.

The role of prestin in the generation of electrically evoked otoacoustic emissions in mice.

Electrically evoked otoacoustic emissions are sounds emitted from the inner ear when alternating current is injected into the cochlea. Their temporal structure consists of short- and long-delay components and they have been attributed to the motile responses of the sensory-motor outer hair cells of the cochlea. The nature of these motile responses is unresolved and may depend on either somatic motility, hair bundle motility, or both.

Prestin's role in cochlear frequency tuning and transmission of mechanical responses to neural excitation.

The remarkable power amplifier [1] of the cochlea boosts low-level and compresses high-level vibrations of the basilar membrane (BM) [2]. By contributing maximally at the characteristic frequency (CF) of each point along its length, the amplifier ensures the exquisite sensitivity, narrow frequency tuning, and enormous dynamic range of the mammalian cochlea. The motor protein prestin in the outer hair cell (OHC) lateral membrane is a prime candidate for the cochlear power amplifier [3].