Novel Variant in CEP250 Causes Protein Mislocalization and Leads to Nonsyndromic Autosomal Recessive Type of Progressive Hearing Loss.

Genetic hearing loss is the most common hereditary sensorial disorder. Though more than 120 genes associated with deafness have been identified, unveiled causative genes and variants of diverse types of hearing loss remain. Herein, we identified a novel nonsense homozygous variant in CEP250 (c.3511C>T; p.Gln1171Ter) among the family members with progressive moderate sensorineural hearing loss in nonsyndromic autosomal recessive type but without retinal degeneration. CEP250 encodes C-Nap1 protein belonging to the CEP protein family, comprising 30 proteins that play roles in centrosome aggregation and cell cycle progression. The nonsense variant in CEP250 led to the early truncating protein of C-Nap1, which hindered centrosome localization; heterologous expression of CEP250 (c.3511C>T) in NIH3T3 cells within cilia expression condition revealed that the truncating C-Nap1 (p.Gln1171Ter) was not localized at the centrosome but was dispersed in the cytosol. In the murine adult cochlea, Cep250 was expressed in the inner and outer hair cells. Knockout mice of Cep250 showed significant hair cell degeneration and progressive hearing loss in auditory brainstem response. In conclusion, a nonsense variant in CEP250 results in a deficit of centrosome localization and hair cell degeneration in the cochlea, which is associated with the progression of hearing loss in humans and mice.

Pain as Initial Presenting Symptom Is Associated With Delay to Seeking Medical Attention, Higher Risk of Relapse, and Shorter Survival in Patients With Early-Stage Extremity or Trunk Synovial Sarcoma.

BackgroundWhether the presenting symptom of pain vs mass impacts survival of early-stage synovial sarcoma is not known. Patients and MethodsThe authors investigated patients with early-stage extremity/trunk synovial sarcoma diagnosed from 2005 to 2017 at Kaiser Permanente Northern California for associations between the presenting symptom and survival. ResultsAmong 56 patients with early-stage extremity/trunk synovial sarcoma, median disease-free survival (DFS) was 20.3 months for the pain-only group (n = 19) vs 50.5 months for the mass ± pain group (n = 37) (p = 0.004), and median overall survival (OS) was 35.7 months vs 53.9 months (p = 0.009), respectively. Median DFS was 26.9 months for the pain ± mass group (n = 32) vs 48.6 months for the mass-only group (n = 24) (p = 0.047), whereas OS was not significantly different (49.6 vs. 53.6 months, p = 0.282). Pain at presentation was associated with a higher incidence of deep tumors and a higher risk of relapse. Cox regression model adjusting for age, sex, race, tumor location, tumor size, and wait-time to seek medical attention showed that pain at presentation was associated with 3-fold worse DFS and OS. ConclusionPain at presentation was an adverse risk factor for patients with early-stage extremity/trunk synovial sarcoma.

Overview of the Neuroprotective Effects of the MAO-Inhibiting Antidepressant Phenelzine.

Phenelzine (PLZ) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. This multifaceted drug has a number of pharmacological and neurochemical effects in addition to inhibition of MAO, and findings on these effects have contributed to a body of evidence indicating that PLZ also has neuroprotective/neurorescue properties. These attributes are reviewed in this paper and include catabolism to the active metabolite ß-phenylethylidenehydrazine (PEH) and effects of PLZ and PEH on the GABA-glutamate balance in brain, sequestration of reactive aldehydes, and inhibition of primary amine oxidase. Also discussed are the encouraging findings of the effects of PLZ in animal models of stroke, spinal cord injury, traumatic brain injury, and multiple sclerosis, as well other actions such as reduction of nitrative stress, reduction of the effects of a toxin on dopaminergic neurons, potential anticonvulsant actions, and effects on brain-derived neurotrophic factor, neural cell adhesion molecules, an anti-apoptotic factor, and brain levels of ornithine and N-acetylamino acids.

Recurrence Rate and Risk Factors of Recurrence in Benign Paroxysmal Positional Vertigo: a Single-Center Long-Term Prospective Study With a Large Cohort.

OBJECTIVE: This study aimed to assess the long-term recurrence rate and correlations between recurrence and potential risk factors in patients with benign paroxysmal positional vertigo (BPPV). DESIGN: A total of 548 consecutive patients who demonstrated typical posterior or horizontal BPPV between January 2010 and December 2012 were included in this prospective study. All patients were contacted by phone every 6 months for 5 years and were asked to revisit the clinic when they experienced positional vertigo to be reexamined for recurrence. Recurrence of BPPV was defined as having positional vertigo and nystagmus confirmed following a symptom-free period of at least 7 days after complete resolution. We assessed the 5-year recurrence rate of BPPV, and the time point of recurrence in all patients as well as the risk factors of BPPV recurrence, including the clinical characteristics, therapeutic results of BPPV, and various comorbidities. RESULTS: Among the 548 patients, 121 (22.1 %) had at least one recurrence. Of these, 78 patients (54.5%) had only one recurrence within 5 years, while 43 (45.5%) patients experienced two or more recurrences. A recurrence occurred within 1 year in 82 patients (67.8%). The Cox proportional hazard ratio analysis found that head trauma (p = 0.015), Meniere's disease (p = 0.016), the number of canalith repositioning procedures performed (p = 0.037), and the number of previous vertigo attacks (p = 0.038) were significant risk factors of BPPV recurrence as opposed to hypertension or hyperlipidemia. CONCLUSIONS: The recurrence rate of BPPV was 22.1% at 5 years after the initial treatment. About 70% of recurred patients had a recurrence within 1 year. Head trauma, ipsilateral Meniere's disease, the number of canalith repositioning procedures performed, and the number of previous vertigo attacks were significant risk factors of BPPV recurrence.

Clinical Implications of Horizontal Beating Nystagmus Induced by Dix-Hallpike Test in the Diagnosis of Horizontal Canal Benign Paroxysmal Positional Vertigo.

OBJECTIVES: The purpose of this study was to identify the diverse patterns of nystagmus during the Dix-Hallpike test (DHT) and analyze their clinical significance in horizontal canal benign paroxysmal positional vertigo (HC-BPPV). STUDY DESIGN: Retrospective medical records review. PATIENTS: Two hundred ninety-five patients diagnosed with HC-BPPV. METHODS: Various nystagmus patterns identified during the DHT in patients with HC-BPPV were analyzed. The correlation between the affected side of HC-BPPV and the direction of the horizontal beating nystagmus (HBN) during the DHT was also analyzed. RESULTS: The nystagmus pattern during the DHT in 128 patients with geotropic HC-BPPV demonstrated, direction-changing positional nystagmus on both sides in 48 (37.5%) patients, HBN toward one side in 25 (19.6%) patients, and no nystagmus in 55 (42.9%) patients. In 144 patients with apogeotropic HC-BPPV, 54 (37.5%) patients presented with direction-changing positional nystagmus on both sides, 27 (18.8%) patients presented with HBN toward one side, and 63 (43.7%) patients did not show nystagmus during the DHT. The direction of HBN provoked by the DHT was significantly correlated with the affected side in each subtype of HC-BPPV (geotropic type, p = 0.049; apogeotropic type, p = 0.040; respectively). CONCLUSION: More than half of the patients with HC-BPPV (56.6%) showed HBN during the DHT. When HBN was present during the DHT, it may provide a clue for determining the subtype and affected side in diagnosis of HC-BPPV before performing the supine roll test.

Long-term silk peptide intake promotes skeletal muscle mass, reduces inflammation, and modulates gut microbiota in middle-aged female rats.

Aging alters body composition to induce sarcopenia, particularly in women, but the mechanism remains unclear. We hypothesized that silk peptide(SP) intake could prevent an age-related decrease in muscle mass and strength in middle-aged female rats and explored the action mechanism. After the acute intake of SP and defatted soybean peptides, serum concentrations of amino acids were measured in ten middle-aged rats in each group. Forty 12-month-old female Sprague-Dawley rats were fed a high-fat and high-carbohydrate diet for 12 weeks including 0.5 g casein/kg body weight(BW)/day(Aged), 0.15 g SP plus 0.35 g casein/kg BW/day(Low-SP), 0.5 g SP/kg BW/day(High-SP), or 40 mg metformin plus 0.5 g casein/kg BW/day(Metformin). Ten rats aged 7-week old(Young) had the same treatment as the Aged-group. The body composition, grip strength, glucose metabolism, intestinal tissue morphology, and gut microbiota were also determined. After an acute consumption, total amino acids were more quickly absorbed and maintained at higher levels in SP than soybean peptides. Lean body mass(LBM) and grip strength were lower in the Aged-group than the Young and Low-SP groups, and the High-SP regimen increased these parameters as much as the Young-group. Serum concentrations and mRNA expression of TNF-α in the gastrocnemius and quadriceps muscles were higher in the Aged-group than the Young-group, whereas SP intake reduced their serum levels and skeletal muscles. Glucose and insulin tolerance indicated that insulin resistance was elevated in the Aged-group compared to the Young-group, while Low-SP and High-SP alleviated them as much as the Young-group. High-SP increased serum propionate and butyrate concentrations compared to the Aged-group. SP intake increased the relative abundance of Bacteroides and Prevotella and decreased Blautia and Clostridium in the feces. In conclusion, SP intake protects against a decrease in lean body mass and grip strength in middle-aged female rats. The protection was partly related to maintaining higher serum concentrations of total amino acids after SP consumption and decreasing inflammation and insulin resistance through gut microbiota modulation.

Therapeutic efficacy of super-high-dose steroid therapy in patients with profound sudden sensorineural hearing loss: a comparison with conventional steroid therapy.

BACKGROUND: In patients with sudden sensorineural hearing loss (SSNHL), steroid therapy is an optional treatment method, but there is controversy about its dose. OBJECTIVE: We aimed to compare the efficacy of super-high-dose steroid therapy with that of conventional steroid therapy in patients with profound SSNHL (pSSNHL). MATERIAL AND METHODS: Fifty-two patients diagnosed with pSSNHL between March 2010 and May 2017 were divided into the following groups based on their steroid regimen: a conventional steroid regimen (prednisolone at 1.0 mg/kg/day for 10 days) was applied in Group 1, and a super-high-dose steroid regimen (prednisolone at 1.5 mg/kg/day for 14 days) was applied in Group 2. The treatment outcomes were compared between the groups at 2 and 4 weeks after the initial treatment by use of Siegel's criteria. RESULTS: Of the 52 patients, 31 were classified into Group 1 and 21 into Group 2. When comparing the proportion of patients in complete or partial recovery by Siegel's criteria, the recovery rate was significantly higher in Group 2 than in Group 1 (19% vs 0%, p = .022 at 2 weeks; 35.7% vs 7.4%, p = 0.035 at 4 weeks). CONCLUSIONS AND SIGNIFICANCE: Patients with pSSNHL treated using the super-high-dose steroid regimen demonstrated better recovery rates to serviceable hearing than did those treated using the conventional steroid regimen without significant complications.

Time-resolved in situ visualization of the structural response of zeolites during catalysis.

Zeolites are three-dimensional aluminosilicates having unique properties from the size and connectivity of their sub-nanometer pores, the Si/Al ratio of the anionic framework, and the charge-balancing cations. The inhomogeneous distribution of the cations affects their catalytic performances because it influences the intra-crystalline diffusion rates of the reactants and products. However, the structural deformation regarding inhomogeneous active regions during the catalysis is not yet observed by conventional analytical tools. Here we employ in situ X-ray free electron laser-based time-resolved coherent X-ray diffraction imaging to investigate the internal deformations originating from the inhomogeneous Cu ion distributions in Cu-exchanged ZSM-5 zeolite crystals during the deoxygenation of nitrogen oxides with propene. We show that the interactions between the reactants and the active sites lead to an unusual strain distribution, confirmed by density functional theory simulations. These observations provide insights into the role of structural inhomogeneity in zeolites during catalysis and will assist the future design of zeolites for their applications.

In Situ Strain Evolution on Pt Nanoparticles during Hydrogen Peroxide Decomposition.

Fundamental understanding of structural changes during catalytic reactions is crucial to understanding the underlying mechanisms and optimizing efficiencies. Surface energy and related catalytic mechanisms are widely studied. However, the catalyst lattice deformation induced by catalytic processes is not well understood. Here, we study the strain in an individual platinum (Pt) nanoparticle (NP) using Bragg coherent diffraction imaging under in situ oxidation and reduction reactions. When Pt NPs are exposed to H2O2, a typical oxidizer and an intermediate during the oxygen reduction reaction process, alternating overall strain distribution near the surface and inside the NP is observed at the (111) Bragg reflection. In contrast, relatively insignificant changes appear in the (200) reflection. Density functional theory calculations are employed to rationalize the anisotropic lattice strain in terms of induced stress by H2O2 adsorption and decomposition on the Pt NP surface. Our study provides deeper insight into the activity-structure relationship in this system.

Double-blind randomized controlled trial on efficacy of cupulolith repositioning maneuver for treatment of apogeotropic horizontal canal benign paroxysmal positional vertigo.

Backgrounds: Although various therapeutic maneuvers have been proposed, it is still unclear which maneuver is better to treat apogeotropic horizontal canal benign paroxysmal positional vertigo (HC-BPPV).Objectives: This study aimed to assess the therapeutic efficacy of the cupulolith repositioning maneuver (CuRM) in apogeotropic HC-BPPV in comparison with the therapeutic head-shaking maneuver and modified Lempert maneuver.Materials and Method: This is double-blind randomized prospective study. Forty-nine consecutive patients diagnosed with apogeotropic HC-BPPV were allocated randomly to CuRM (n = 18), therapeutic head-shaking (n = 16), or modified Lempert maneuver (n = 15). The presence of nystagmus and vertigo on positional testing were evaluated at 30 min, on 1 day, and 1 week after treatment.Results: There were no significant differences in any clinical characteristics between the three groups at randomization. After a single trial of therapeutic maneuvers on the initial visit day, the CuRM (38.9%) and therapeutic head shaking maneuver (12.5%) did not show differences compared to modified Lempert maneuver (33.3%). The therapeutic effects on the 2nd day and at 1 week after treatment also did not differ between the three groups.Conclusions: Although the CuRM is theoretically considered to be a better therapeutic method, the therapeutic efficacy of CuRM was not statistically different compared to the other two maneuvers.

Development of a Two Triplex Real-Time Polymerase Chain Reaction for Rapid Detection of Six Carbapenemase Genes in Enterobacteriaceae.

OBJECTIVES: Carbapenem resistance is a serious clinical and public health threat. Carbapenemase can confer carbapenem resistance, and most carbapenemase genes are plasmid encoded so resistance can easily spread. In this study, we aimed to develop a novel system based on the TaqMan platform for the rapid detection of 6 clinically prevalent carbapenemase genes: Klebsiella pneumoniae carbapenemase, New Delhi metallo-ß-lactamase, oxacillinase, imipenem-hydrolyzing, Verona integron-encoded metallo-ß-lactamase, and Guiana extended-spectrum ß-lactamase. METHODS: The triplex assay was verified by testing genomic DNA of 6 carbapenemase-producing Klebsiella pneumoniae. It was validated with a blinded panel of 310 Enterobacteriaceae isolates, including 225 carbapenemase-producers and 85 non-producers, by direct colony triplex real-time polymerase chain reaction (PCR). The real-time PCR was performed using the ABI 7500 fast instrument (Applied Biosystems, CA, USA) and specific primers for each carbapenemase target were designed to include modified peptide-nucleic acid oligonucleotides. RESULTS: No amplification was detected among the negative samples. The result showed 100% concordance with the genotypes previously identified. The entire assay, including DNA extraction and real-time PCR, was completed within 2 hours. CONCLUSION: The newly developed triplex real-time PCR assay was useful for the rapid, accurate and simultaneous detection of 6 carbapenemase genes in Enterobacteriaceae, suggesting its potential to allow an early decision on the appropriate treatment, management, and prevention of the spread of resistant infections in hospitals.

Optimal reassessment time for treatment response in posterior canal benign paroxysmal positional vertigo.

OBJECTIVES/HYPOTHESIS: The present study aimed to evaluate the optimal reassessment time for treatment response in posterior canal benign paroxysmal positional vertigo (PC-BPPV) following the initial Epley maneuver. STUDY DESIGN: Prospective, single-blinded, randomized study. METHODS: One hundred eight patients with PC-BPPV agreed to participate. These patients received a single modified Epley maneuver (recommended by the 2008 American Academy of Otolaryngology-Head and Neck Surgery guidelines) daily until positional nystagmus disappeared during the Dix-Hallpike maneuver 24 hours after the treatment. Repeated Dix-Hallpike testing to reassess the treatment response was performed at 1 hour (post-1 hour), every 24 hours (post-24 hours) until the positional nystagmus resolved, 1 week (post-1 week), and 1 month (post-1 month) following the therapeutic maneuver. The difference in the resolution rates at post-1 hour and post-24 hours reassessment was analyzed, and the recurrence rates at post-1 week and post-1 month were evaluated. RESULTS: The resolution rate was 67.6% at post-1 hour, which increased to 79.6% at post-24 hours reassessment. There was a statistically significant difference in the results of the Dix-Hallpike test between post-1 hour and post-24 hours follow-up. After complete resolution, nine out of 108 patients (8.3%) demonstrated recurrence within 1 month. CONCLUSIONS: Reassessment after 24 hours following the initial Epley maneuver is more advantageous than a 1-hour follow-up in patients with PC-BPPV. This information may be helpful for clinicians in deciding the appropriate follow-up period after treatment for PC-BPPV. LEVEL OF EVIDENCE: 1b Laryngoscope, 130:496-499, 2020.

Genetic Inheritance of Late-Onset, Down-Sloping Hearing Loss and Its Implications for Auditory Rehabilitation.

OBJECTIVES: Late-onset, down-sloping sensorineural hearing loss has many genetic and nongenetic etiologies, but the proportion of this commonly encountered type of hearing loss attributable to genetic causes is not well known. In this study, the authors performed genetic analysis using next-generation sequencing techniques in patients showing late-onset, down-sloping sensorineural hearing loss with preserved low-frequency hearing, and investigated the clinical implications of the variants identified. DESIGN: From a cohort of patients with hearing loss at a tertiary referral hospital, 18 unrelated probands with down-sloping sensorineural hearing loss of late onset were included in this study. Down-sloping hearing loss was defined as a mean low-frequency threshold at 250 Hz and 500 Hz less than or equal to 40 dB HL and a mean high-frequency threshold at 1, 2, and 4 kHz greater than 40 dB HL. The authors performed whole-exome sequencing and segregation analysis to identify the genetic causes and evaluated the outcomes of auditory rehabilitation in the patients. RESULTS: There were nine simplex and nine multiplex families included, in which the causative variants were found in six of 18 probands, demonstrating a detection rate of 33.3%. Various types of variants, including five novel and three known variants, were detected in the MYH14, MYH9, USH2A, COL11A2, and TMPRSS3 genes. The outcome of cochlear and middle ear implants in patients identified with pathogenic variants was satisfactory. There was no statistically significant difference between pathogenic variant-positive and pathogenic variant-negative groups in terms of onset age, family history of hearing loss, pure-tone threshold, or speech discrimination scores. CONCLUSIONS: The proportion of patients with late-onset, down-sloping hearing loss identified with potentially causative variants was unexpectedly high. Identification of the causative variants will offer insights on hearing loss progression and prognosis regarding various modes of auditory rehabilitation, as well as possible concomitant syndromic features.

Development of a Two Triplex Real-Time Polymerase Chain Reaction for Rapid Detection of Six Carbapenemase Genes in Enterobacteriaceae

ObjectivesCarbapenem resistance is a serious clinical and public health threat. Carbapenemase can confer carbapenem resistance, and most carbapenemase genes are plasmid encoded so resistance can easily spread. In this study, we aimed to develop a novel system based on the TaqMan platform for the rapid detection of 6 clinically prevalent carbapenemase genes: Klebsiella pneumoniae carbapenemase, New Delhi metallo-β-lactamase, oxacillinase, imipenem-hydrolyzing, Verona integron-encoded metallo-β-lactamase, and Guiana extended-spectrum β-lactamase.MethodsThe triplex assay was verified by testing genomic DNA of 6 carbapenemase-producing Klebsiella pneumoniae. It was validated with a blinded panel of 310 Enterobacteriaceae isolates, including 225 carbapenemase-producers and 85 non-producers, by direct colony triplex real-time polymerase chain reaction (PCR). The real-time PCR was performed using the ABI 7500 fast instrument (Applied Biosystems, CA, USA) and specific primers for each carbapenemase target were designed to include modified peptide-nucleic acid oligonucleotides.ResultsNo amplification was detected among the negative samples. The result showed 100% concordance with the genotypes previously identified. The entire assay, including DNA extraction and real-time PCR, was completed within 2 hours.ConclusionThe newly developed triplex real-time PCR assay was useful for the rapid, accurate and simultaneous detection of 6 carbapenemase genes in Enterobacteriaceae, suggesting its potential to allow an early decision on the appropriate treatment, management, and prevention of the spread of resistant infections in hospitals.

Regulation of Diabetes: a Therapeutic Strategy for Alzheimer's Disease?

Accumulated evidence suggests that sporadic cases of Alzheimer's disease (AD) make up more than 95% of total AD patients, and diabetes has been implicated as a strong risk factor for the development of AD. Diabetes shares pathological features of AD, such as impaired insulin signaling, increased oxidative stress, increased amyloid-beta (Aß) production, tauopathy and cerebrovascular complication. Due to shared pathologies between the two diseases, anti-diabetic drugs may be a suitable therapeutic option for AD treatment. In this article, we will discuss the well-known pathologies of AD, including Aß plaques and tau tangles, as well as other mechanisms shared in AD and diabetes including reactive glia and the breakdown of blood brain barrier in order to evaluate the presence of any potential, indirect or direct links of pre-diabetic conditions to AD pathology. In addition, clinical evidence of high incidence of diabetic patients to the development of AD are described together with application of anti-diabetic medications to AD patients.

Outcomes and Predictive Factors of Electroacoustic Stimulation Rehabilitation in Children With Limited Low-Frequency Hearing.

OBJECTIVE: To evaluate the clinical feasibility and auditory benefits of hearing rehabilitation using electroacoustic stimulation (EAS) after cochlear implantation (CI) and to identify the predictive factors for successful EAS rehabilitation in children with limited low-frequency hearing. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral hospital. PATIENTS: Seventeen children (21 ears) under the age of 15 years with residual low-frequency hearing who underwent CI using hearing preservation techniques. INTERVENTION: Patients underwent CI using hearing preservation techniques, and the postoperative audiograms were obtained to evaluate the hearing preservation rate. EAS rehabilitation was applied in patients with successful low-frequency hearing preservation. OUTCOME MEASURES: Improvements in speech perception in both quiet and noise conditions were compared between the EAS mode and the CI-only mode. The predictive factors for successful EAS rehabilitation in children were analyzed. RESULTS: Functional low-frequency residual hearing less than or equal to 85 dB at 250 and 500 Hz was achieved postoperatively in six of 21 ears, and successful EAS rehabilitation was possible in nine of 21 ears. Better speech perception scores were observed in quiet conditions using the EAS mode compared with the CI-only mode, although the difference did not reach statistical significance. Significantly, better scores were observed in noise conditions with the EAS mode compared with the CI-only mode. Postoperative low-frequency pure-tone average was the only significant predictive factor of successful EAS rehabilitation. CONCLUSION: CI surgery using hearing preservation techniques with EAS rehabilitation should be performed in children, even in patients with limited residual hearing, to improve auditory outcomes.

Dissecting phenotypic responses of the druggable targetome in cancers.

Although a large amount of screening data comprising target genes and/or drugs tested against cancer cell line panels are available, different assay conditions and readouts limit the integrated analysis and batch-to-batch comparison of these data. Here, we systematically produced and analyzed the anticancer effect of the druggable targetome to understand the varied phenotypic outcomes of diverse functional classes of target genes. A library of siRNAs targeting ~4,800 druggable genes was screened against cancer cell lines under 2D and/or 3D assay conditions. The anticancer effect was simultaneously measured by quantifying cell proliferation and/or viability. Hit rates varied significantly depending on assay conditions and/or phenotypic readouts. Functional classes of hit genes were correlated with the microenvironment difference between the 2D monolayer cell proliferation and 3D sphere formation assays. Furthermore, multiplexing of cell proliferation and viability measures enabled us to compare the sensitivity and resistance responses to the gene knockdown. Many target genes that inhibited cell proliferation increased the single-cell-level viability of surviving cells, leading to an increase in self-renewal potential. In this study, combinations of parallel 2D/3D assays and multiplexing of cell proliferation and viability measures provided functional insights into the varied phenotypic outcomes of the cancer targetome.

Real-World Experiences with Pazopanib in Patients with Advanced Soft Tissue and Bone Sarcoma in Northern California.

Background: Pazopanib was approved for advanced soft tissue sarcoma as a second- or third-line therapy based on the clinical trial "Pazopanib for metastatic soft-tissue sarcoma" (PALETTE). We hypothesized that the real-world experiences may be significantly different from the clinical trial results. Methods: We analyzed the response pattern of patients with advanced soft tissue and bone sarcoma who received pazopanib treatment between 1 January 2011 and 31 October 2018 in Kaiser Permanente Northern California. Results: A total of 123 patients with 23 different histologic subtypes were assessable. One patient with low-grade fibromyxoid sarcoma obtained complete response (CR) after 2 months of treatment with pazopanib, 12 patients (9.7%) obtained partial response (PR), 34 patients (27.6%) had stable disease (SD), while 76 patients (61.8%) developed progressive disease (PD). The disease control rate (DCR) was 46.3% (CR + PR + SD). Among the 12 patients with PR, 3 had undifferentiated pleomorphic sarcoma (UPS), 4 had leiomyosarcoma (LMS), 2 had pleomorphic rhabdomyosarcoma, 1 had pleomorphic liposarcoma, 1 had dedifferentiated liposarcoma, and 1 had angiosarcoma. The median duration of response was 9 months. Two patients with Ewing's sarcoma had SD for 6 and 13 months, and two patients with osteosarcoma had SD for 6 and 9 months. Among 65 patients assessed at 8 weeks, 9 had a response, and 10 had SD. Among 104 patients assessed at 12 weeks, 12 had a response, and 26 had SD. The median progression-free survival (PFS) was approximately 3 months for all 123 cases and for patients with UPS and LMS. Conclusions: Our cohort of patients with advanced soft tissue and bone sarcoma in Northern California treated with pazopanib had diverse histologic subtypes. The response rate (CR + PR) was higher than that of the PALETTE trial, while the DCR and the median PFS were significantly lower. The observation of PR in two patients with liposarcoma and durable SD in several patients with bone sarcoma indicates that pazopanib has activity in liposarcoma and bone sarcoma.

Progressive hearing loss in vitamin A-deficient mice which may be protected by the activation of cochlear melanocyte.

Vitamin A deficiency (VAD) produces various pathologic phenotypes in humans and animals. However, evidence regarding the effect of VAD on hearing function has been inconsistent. In this study, we evaluated the effect of VAD on hearing function in two mouse models of VAD. Hearing ability was evaluated on the basis of auditory brainstem response from 3 to 20 weeks after birth in C57BL/6 (pigmented) and imprinting control region (albino) mice. The two mice strains were divided into the VAD (purified vitamin A-free diet from 7 days after pregnancy) and control (normal diet) groups. Albino VAD mice exhibited hearing loss after 6 weeks and became deaf at 18 weeks. Histological findings revealed degenerative changes in outer hair cells and neuronal loss in the spiral ganglion in albino VAD mice. In contrast, pigmented VAD mice, except those with middle-ear infection, showed no significant hearing loss. Interestingly, pigmented VAD mice exhibited melanocyte activation in the stria vascularis and upregulation of tyrosinase. Recovery of hearing after noise exposure was poorer in pigmented VAD mice than in control mice. In conclusion, complete VAD might be related to age-related or noise-induced hearing loss in mice, protection against which might involve melanocyte activation.