The Safety and Efficacy of Hydroxyapatite Repair of Cholesteatoma Skull Base Defects.

Objective: To investigate the possibility of hydroxyapatite as a safe and effective alternative to currently used bioavailable materials for repair of tegmen defects and labyrinthine fistulas in the setting of cholesteatoma. Study Design: Retrospective study. Setting: Tertiary-level-care hospital. Methods: Electronic medical records of patients 18+ years undergoing cholesteatoma-removal surgery between 2013 and 2022 were reviewed. Results: Twenty-two patients diagnosed with cholesteatoma who underwent repair of either a tegmen defect or labyrinthine fistula using hydroxyapatite were evaluated. There were 17 canal wall up (CWU) and 5 canal wall down (CWD) surgeries. The cholesteatoma recidivism rate was 18.2% (n = 4) and the recurrence rate was 4.5% (n = 1). To ensure that these rates were similar to cholesteatoma-removal surgeries in which hydroxyapatite was not used, a 22 age, gender, and operative technique-matched cohort was evaluated. For patients with CWU surgeries, the rate of recurrence and recidivism were identical between both cohorts (0% and 23.5%, respectively; P = 1 for both). While in CWD surgeries, there was a nonstatistically significant difference in the recurrence as there was only 1 patient with recurrence in the hydroxyapatite group (P = 1). Three (13.5%) patients in the hydroxyapatite group had a local infection and 1 (4.5%) had a subacute mastoid infection. All patients with semicircular canal fistulas had consistent bone lines on postoperative audiograms, with no worsening sensorineural hearing loss. Conclusion: In our cohort, hydroxyapatite was safe and successful in repairing skull base defects and inner-ear fistulas in the setting of cholesteatoma with a low rate of postoperative infection and no evidence of a higher rate of cholesteatoma recurrence. Further studies are needed to assess population generalizability.

Over-The-Counter Hearing Aids: Are They Safe and Effective?

OBJECTIVE: In 2022, the Food and Drug Administration established a new regulatory category for over-the-counter (OTC) hearing aids for mild to moderate hearing loss. Herein, we aim to better compare the safety and efficacy of these devices to that of prescription hearing aids. STUDY DESIGN: Comparative-effectiveness model. SETTING: Academic Audiology Center. METHODS: The safety and efficacy of prescription and OTC hearing aids was compared using the AudioScan Verifit 2 Testbox software. Three types of hearing loss (downsloping, sharp downsloping, and reverse sloping) were analyzed. Efficacy was tested at 3 volume inputs and was measured by calculating the average difference in test points (produced by the devices) and target points (estimated by the software). Safety was assessed by calculating the average difference in test points and the maximally safe hearing level (produced by the software). RESULTS: Prescription hearing aids were found to have a better safety profile by being further from the safety threshold compared to OTC devices at the 8000 Hz frequency for the 2 types of downsloping hearing loss patterns studied (48 vs 30.5 dB, P = .04; 51 vs 32.5 dB, P = .03). Prescription hearing aids also carried a statistically significant advantage at 3 test points. OTC hearing aids generally had a greater difference between test and target points. CONCLUSION: OTC and prescription hearing aids are comparably safe, though OTC hearing aids are slightly less efficacious. Further evaluation of the OTC hearing aid efficacy is warranted to ensure it provides the gain of benefit needed for different types of hearing loss.

Epidemiology and patterns of gymnastics-related head & neck trauma injuries: A NEISS database study.

OBJECTIVE: To describe the epidemiology and patterns of gymnastics-related Head & Neck trauma injuries using the NEISS database from 2001 to 2020. STUDY DESIGN AND SETTING: Cross-sectional analysis of a national database. METHODS: Gymnastics-related ED visits between 2001 and 2020 were queried from the NEISS database. Bivariate chi-squared analyses were used to compare injury demographics, location, type, and disposition. Fracture location was identified using the narrative description of each case and were divided into subtypes for further analysis. RESULTS: 1455 gymnastics-related head and neck traumatic injuries were identified. The majority were in females (65.8%). The most common presenting age group was pediatric (≤18 years) (92.7%), and the largest racial group was Caucasian (51.5%). Of all location subtypes, facial injuries were the most common presenting injury type overall (45.2%). Regarding injury types, lacerations were most common (36.8%), followed by dental injury (30.7%) and fractures (21.2%). The most common location of head and neck fractures was the nose (45.8%), followed by cervical spine (16.7%) and orbit (13.3%). The majority (95.7%) of gymnastics-related head and neck traumatic injuries presenting to the ED were treated and discharged. CONCLUSION: This study characterizes gymnastics-related head and neck injuries which is a topic that is under-studied. The findings from this study are helpful for gymnasts and those who care for them including providers, coaches and guardians, and this data may help inform future guidelines for treatment and injury prevention.

The Impact of Medical Comorbidities on Cough Improvement Following Superior Laryngeal Block.

INTRODUCTION: Chronic refractory cough is defined as cough lasting greater than 8 weeks and with an unclear etiology. Blockade of the internal branch superior laryngeal nerve (iSLN) has been shown to be safe and effective in the treatment of chronic cough. It remains unknown, however, if underlying comorbidities impact patient response to iSLN blockade. METHODS: A total of 44 patients aged 18 years and older were seen at our institution's Laryngology clinics between 2019 and 2022 and treated with iSLN blockade. Patient demographics, comorbidities, and pre- and post-treatment cough severity index (CSI) scores were collected from electronic medical records. Two-tailed independent T tests were used to compare CSI scores between groups with and without 4 underlying comorbidities: GERD, pulmonary history, smoking history, and evidence of vocal fold paresis or asymmetry on stroboscopy. RESULTS: Patients with a history of GERD or smoking and those with evidence of glottic insufficiency had similar improvements in CSI compared to those who did not (22.5 ± 26.4 vs 45.0 ± 47.1, P = .36; 32.7 ± 27.8 vs 29.0 ± 38, P = .85; 41.3 ± 18.8 vs 27.2 ± 37.7, P = .195). Patients with underlying pulmonary conditions had a significantly reduced response to iSLN blockade than did patients without underlying disease (9.85 ± 15.0 vs 47.4 ± 38.1, P = .028). CONCLUSION: Underlying lung pathology may contribute to decreased iSLN blockade efficacy in the treatment of chronic refractory cough from laryngeal hypersensitivity and its treatment is likely necessary for optimal symptom reduction. Characterizing patient comorbidity profiles can help guide patient counseling on expected treatment efficacy.

The Impact of Four Smoking Metrics on Survival After Diagnosis with HPV+ Oropharyngeal Cancer.

OBJECTIVE: While tobacco use is understood to negatively impact HPV+ oropharyngeal squamous cell carcinoma (OPSCC) outcomes, debate remains as to how this impact differs between cohorts. Multiple smoking metrics have been identified as having the greatest prognostic significance, and some recent works have found smoking to have no significant impact. Herein, we show through an analysis of four common smoking metrics that while smoking impacts overall survival (OS), it has a limited impact on recurrence-free survival (RFS) in our cohort. METHODS: We conducted a retrospective review of patients treated for HPV+ OPSCC in our health system from 2012 to 2019. Patients with metastatic disease or concurrent second primaries were excluded. Four metrics of tobacco use were assessed: current/former/never smokers, ever/never smokers, and smokers with >10 or >20 pack-year (PY) smoking histories. Our main outcomes were 3-year RFS and OS. RESULTS: Three hundred and sixty-seven patients met inclusion criteria. 37.3% of patients (137/367) were never-smokers; 13.8% of patients (51/367) were currently smoking at diagnosis and 48.8% of patients (179/367) were former smokers. No tobacco-use metric significantly impacted 3-year RFS. On univariate analysis, all smoking metrics yielded inferior OS. On multivariate analysis, current and ever smoking status significantly impacted 3-year OS. CONCLUSION: The impact of tobacco use on HPV+ OPSCC outcomes is not universal, but may instead be modulated by other cohort-specific factors. The impact of smoking may decrease as rates of tobacco use decline. LEVEL OF EVIDENCE: 3 (Cohort and case-control studies) Laryngoscope, 134:3158-3164, 2024.

Automated AJCC Restaging for Oropharyngeal Cancer Research.

With the American Joint Committee on Cancer (AJCC) 8th edition staging guidelines update, human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is now staged separately from its HPV-negative counterpart, preventing meaningful comparison of cases staged with the 7th versus 8th edition criteria. Manual restaging is time-consuming and error-prone, hindering multiyear analyses for HPV+ OPSCC. We developed an automated computational tool for re-classifying HPV+ OPSCC pathological and clinical tumor staging from AJCC 7th to 8th edition. The tool is designed to handle large data sets, ensuring comprehensive and accurate analysis of historic HPV+ OPSCC data. Validated against institutional and National Cancer Database data sets, the algorithm achieved accuracies of 100% (95% confidence interval [CI] 98.8%-100%) and 93.4% (95% CI 93.1%-93.7%), successfully restaging 326/326 and 26,505/28,374 cases, respectively. With its open-source design, this computational tool can enhance future HPV+ OPSCC research and inspire similar tools for other cancer types and subsequent AJCC editions.

A Decrease in Maternal Iron Levels Is the Predominant Factor Suppressing Hepcidin during Pregnancy in Mice.

In order to supply adequate iron during pregnancy, the levels of the iron regulatory hormone hepcidin in the maternal circulation are suppressed, thereby increasing dietary iron absorption and storage iron release. Whether this decrease in maternal hepcidin is caused by changes in factors known to regulate hepcidin expression, or by other unidentified pregnancy factors, is not known. To investigate this, we examined iron parameters during pregnancy in mice. We observed that hepatic iron stores and transferrin saturation, both established regulators of hepcidin production, were decreased in mid and late pregnancy in normal and iron loaded dams, indicating an increase in iron utilization. This can be explained by a significant increase in maternal erythropoiesis, a known suppressor of hepcidin production, by mid-pregnancy, as indicated by an elevation in circulating erythropoietin and an increase in spleen size and splenic iron uptake. Iron utilization increased further in late pregnancy due to elevated fetal iron demand. By increasing maternal iron levels in late gestation, we were able to stimulate the expression of the gene encoding hepcidin, suggesting that the iron status of the mother is the predominant factor influencing hepcidin levels during pregnancy. Our data indicate that pregnancy-induced hepcidin suppression likely occurs because of reductions in maternal iron reserves due to increased iron requirements, which predominantly reflect stimulated erythropoiesis in mid-gestation and increased fetal iron requirements in late gestation, and that there is no need to invoke other factors, including novel pregnancy factor(s), to explain these changes.

Feasibility of a Career Development Intervention for Veterans in Vocational Rehabilitation: Protocol for a Pilot Randomized Controlled Trial.

BACKGROUND: Veterans with psychiatric disorders want additional career development services to support their recovery and pursuit of meaningful employment. However, no career counseling programs have been designed for this specific population. We developed the Purposeful Pathways intervention to fill this need. OBJECTIVE: This study protocol aims to (1) evaluate the feasibility and acceptability of the Purposeful Pathways intervention for veterans living with psychiatric disorders and (2) explore preliminary clinical outcome data. METHODS: A total of 50 veterans who are participating in transitional work vocational rehabilitation services at a Veterans Affairs hospital will be randomized to either treatment as usual or the augmented treatment condition (treatment as usual plus Purposeful Pathways). Feasibility will be assessed via recruitment rates, clinician fidelity to treatment, retention rates, and acceptability of randomization procedures. Acceptability will be assessed via client satisfaction at treatment termination using quantitative and qualitative data collection. Preliminary clinical and vocational outcomes will be assessed at baseline, 6 weeks, 12 weeks (treatment termination), and a 3-month follow-up via quantitative measures assessing vocational functioning, vocational process, and mental and physical functioning. RESULTS: This pilot randomized controlled trial is beginning recruitment in June 2023 and is expected to continue through November 2025. Data collection is expected to be completed by February 2026, with full data analysis completed by March 2026. CONCLUSIONS: Findings from this study will provide information on the feasibility and acceptability of the Purposeful Pathways intervention, as well as secondary outcomes related to vocational functioning, vocational process, and mental and physical functioning. TRIAL REGISTRATION: ClinicalTrials.gov NCT04698967; https://clinicaltrials.gov/ct2/show/NCT04698967. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/47986.

Metrics for Monitoring Preoperative Optimization Programs for Total Joint Arthroplasty: A Survey of Orthopaedic Nurses.

Preoperative optimization programs are becoming more common for patients seeking total joint arthroplasty; yet, limited research has been conducted to monitor the long-term effects of these programs on patient outcomes. Our aim was to develop a set of metrics that programs can use to monitor the success of preoperative optimization programs. As part of a larger survey of orthopaedic nurses, we collected data regarding current monitoring techniques for preoperative optimization programs and the feasibility of collecting specific variables. Surgical factors such as length of stay and 30-day readmissions were most often used to monitor the success of preoperative optimization programs. Surgical factors were the most likely to be accessible using the electronic medical record. Surgical factors and patient characteristics are the most feasible components for programs to monitor in order to track the outcomes of patients participating in preoperative optimization programs.

The Use of Risk Scores in Patient Preoperative Optimization for Total Joint Arthroplasty: A Survey of Orthopaedic Nurse Navigators.

Preoperative optimization of patients seeking total joint arthroplasty is becoming more common, and risk scores, which provide an estimate for the risk of complications following procedures, are often used to assist with the preoperative decision-making process. The aim of this study was to characterize the use of risk scores at institutions that utilize nurse navigators in the preoperative optimization process. The survey included 207 nurse navigators identified via the National Association of Orthopaedic Nurses to better understand the use of risk scores in preoperative optimization and the different factors that are included in these risk scores. The study found that 48% of responding nurse navigators utilized risk scores in the preoperative optimization process. These risk scores often included patient comorbidities such as diabetes (85%) and body mass index (87%). Risk scores are commonly used by nurse navigators in preoperative optimization and involve a variety of comorbidities and patient-specific factors.

Adverse Events Associated With Bioabsorbable Nasal Implants: A MAUDE Database Analysis.

Bioabsorbable implants (eg, Latera) have recently been approved for addressing nasal valve collapse. The purpose of this study is to summarize adverse events and treatment sequelae associated with bioabsorbable nasal implants queried in the Manufacturer and User Facility Device Experience (MAUDE) database. Of the 26 device reports entered between March 2017 and April 2022, the most frequently reported complications included abscess (n = 13) and implant protrusion (n = 5). Other common symptoms reported greater than 1-year postimplantation included facial pain/discomfort (n = 3) and failure to absorb (n = 3). Management of adverse events included treatment with antibiotics (n = 9), steroid injections (n = 4), and explantation (n = 20). In 3 reports, adverse reactions required a biopsy of adjacent tissue for pathologic analysis. These findings suggest that further research is required to assess the potential long-term complications and optimize the management of bioabsorbable nasal implants. Furthermore, standardized reporting templates may improve the utility of the MAUDE database.

Multidisciplinary Stroke Pathway for Children Supported With Ventricular Assist Devices.

Mechanical circulatory support (MCS), including ventricular assist device (VAD) support, is a leading cause of stroke in children; however, existing pediatric stroke recommendations do not apply to many pediatric VAD patients. We sought to develop a multidisciplinary pathway to improve timely and effective acute stroke care and examine the early performance of the pathway in expediting stroke care. Stakeholders from pediatric heart failure, cardiac intensive care, neurology, interventional radiology, neuroradiology, neurosurgery, pharmacy, and adult VAD care convened at Stanford University in August 2017 to discuss the challenges of providing high-quality acute stroke care to children on VAD support, and to develop multidisciplinary acute stroke pathways. Stakeholders identified multiple barriers to providing timely acute stroke care to pediatric VAD patients. These include delayed recognition of stroke, and lack of clarity related to the optimal imaging technique, when to emergently reverse antithrombotic therapy (AT), pediatric indications for thrombectomy and cranial decompression, and strategies to avoid unnecessary serial CTS. Four stroke pathways were created including evaluation and management of the pediatric patient with (1) an acute neurologic change before an imaging diagnosis; (2) an arterial ischemic stroke (AIS); (3) an intracerebral hemorrhage (ICH); and (4) a subdural hematoma (SDH). With the implementation of the stroke pathway, the median time-to-first-CT image decreased by 43 minutes from 66 to 23 minutes ( P < 0.001) while the proportion with a CT within 30 minutes increased from 0% to 67% ( P < 0.001). Despite a variety of challenges, multidisciplinary consensus can be achieved on a rapid stroke management pathway for children on VAD support that addresses important barriers to timely stroke care. Although too few stoke events occurred to differentiate clinical outcomes, the time-to-first-CT image was significantly shorter after pathway implementation.

Orthopaedic Nurse Navigator Involvement in Preoperative Optimization for Total Joint Arthroplasty.

Patients seeking total joint arthroplasty frequently undergo preoperative optimization with the assistance of nurse navigators to facilitate interactions between patients, consulting services, and the orthopaedic surgical team. Given the enormous impact nurse navigator programs have on reducing postoperative complications, our aim is to characterize the involvement of nurse navigators in preoperative optimization programs across the country. We conducted a survey of nurse navigators identified through the National Association of Orthopaedic Nurses to assess the involvement of nurse navigators in the preoperative optimization process. Sixty-seven percent of responding nurse navigators were involved in preoperative optimization, including components such as heart disease (53%) and poorly controlled diabetes (52%). Orthopaedic nurse navigators are commonly involved in preoperative optimization programs for total joint arthroplasty but most of these involve gated yes/no checklists with limited established referral care pathways. Only some of the programs include standardized referrals for specific medical comorbidities.

Ornate, large, extremophilic (OLE) RNA forms a kink turn necessary for OapC protein recognition and RNA function.

Ornate, large, extremophilic (OLE) RNAs represent a class of noncoding RNAs prevalent in Gram-positive, extremophilic/anaerobic bacterial species. OLE RNAs (∼600 nt), whose precise biochemical functions remain mysterious, form an intricate secondary structure interspersed with regions of highly conserved nucleotides. In the alkali-halophilic bacterium Bacillus halodurans, OLE RNA is a component of a ribonucleoprotein (RNP) complex involving at least two proteins named OapA and OapB, but additional components may exist that could point to functional roles for the RNA. Disruption of the genes for either OLE RNA, OapA, or OapB result in the inability of cells to overcome cold, alcohol, or Mg2+ stresses. In the current study, we used in vivo crosslinking followed by OLE RNA isolation to identify the protein YbxF as a potential additional partner in the OLE RNP complex. Notably, a mutation in the gene for this same protein was also reported to be present in a strain wherein the complex is nonfunctional. The B. halodurans YbxF (herein renamed OapC) is homologous to a bacterial protein earlier demonstrated to bind kink turn (k-turn) RNA structural motifs. In vitro RNA-protein binding assays reveal that OLE RNA forms a previously unrecognized k-turn that serves as the natural binding site for YbxF/OapC. Moreover, B. halodurans cells carrying OLE RNAs with disruptive mutations in the k-turn exhibit phenotypes identical to cells lacking functional OLE RNP complexes. These findings reveal that the YbxF/OapC protein of B. halodurans is important for the formation of a functional OLE RNP complex.

Supplementation with Sucrosomial® iron leads to favourable changes in the intestinal microbiome when compared to ferrous sulfate in mice.

Iron deficiency is one of the most common nutritional deficiencies worldwide and is often treated with oral iron supplements. However, commonly used supplements, including those based on ferrous iron salts, are associated with gastrointestinal side effects and unfavorable changes in the intestinal microbiome. Sucrosomial® iron is a novel iron formulation that is effective at treating iron deficiency, and with fewer gastrointestinal side effects, yet its effect on the gut microbiome has not been examined previously. Thus, we treated mice for two weeks with diets containing either Sucrosomial® iron or ferrous sulfate as the sole iron source and examined bacterial communities in the intestine using 16S Microbial Profiling of DNA extracted from feces collected both prior to and following dietary treatment. Mice treated with Sucrosomial® iron showed an increase in Shannon diversity over the course of the study. This was associated with a decrease in the abundance of the phylum Proteobacteria, which contains many pathogenic species, and an increase in short chain fatty acid producing bacteria such as Lachnospiraceae, Oscillibacter and Faecalibaculum. None of these changes were observed in mice treated with ferrous sulfate. These results suggest that Sucrosomial® iron may have a beneficial effect on the intestinal microbiome when compared to ferrous sulfate and that this form of iron is a promising alternative to ferrous iron salts for the treatment of iron deficiency.

A Novel Ferritin-Core Analog Is a Safe and Effective Alternative to Oral Ferrous Iron for Treating Iron Deficiency during Pregnancy in Mice.

BACKGROUND: Many women enter pregnancy with iron stores that are insufficient to maintain maternal iron balance and support fetal development and consequently, often require iron supplements. However, the side effects associated with many currently available iron supplements can limit compliance. OBJECTIVE: This study aimed to test the safety and efficacy of a novel nanoparticulate iron supplement, a dietary ferritin analog termed iron hydroxide adipate tartrate (IHAT), in pregnant mice. METHODS: Female C57BL/6 mice were maintained on either an iron-deficient or a control diet for 2 wk prior to timed mating to develop iron-deficient or iron-sufficient pregnancy models, respectively. Mice from each model were then gavaged daily with 10 mg iron/kg body weight as either IHAT or ferrous sulfate, or with water only, beginning on embryonic day (E) 4.5. Mice were killed on E18.5 and maternal iron and hematological parameters were measured. The expression of genes encoding iron transporters and oxidative stress markers in the duodenum and placenta were determined, along with hepatic expression of the gene encoding the iron regulatory hormone hepcidin and fetal iron. RESULTS: Oral IHAT and ferrous sulfate were equally effective at increasing maternal hemoglobin (20.2% and 16.9%, respectively) and hepatic iron (30.2% and 29.3%, respectively), as well as total fetal iron (99.7% and 83.8%, respectively), in iron-deficient pregnant mice compared with those gavaged with water only, with no change in oxidative stress markers seen with either treatment. However, there was a significant increase in the placental expression of the oxidative stress marker heme oxygenase 1 in iron-replete pregnant mice treated with ferrous sulfate when compared with iron-replete pregnant mice gavaged with IHAT (96.9%, P <0.05). CONCLUSIONS: IHAT has proved a safe and effective alternative to oral ferrous sulfate in mice, and it has potential for treating iron deficiency in human pregnancy.

The Placental Ferroxidase Zyklopen Is Not Essential for Iron Transport to the Fetus in Mice.

BACKGROUND: The ferroxidase zyklopen (Zp) has been implicated in the placental transfer of iron to the fetus. However, the evidence for this is largely circumstantial. OBJECTIVES: This study aimed to determine whether Zp is essential for placental iron transfer. METHODS: A model was established using 8- to 12-wk-old pregnant C57BL/6 mice on standard rodent chow in which Zp was knocked out in the fetus and fetal components of the placenta. Zp was also disrupted in the entire placenta using global Zp knockout mice. Inductively coupled plasma MS was used to measure total fetal iron, an indicator of the amount of iron transferred by the placenta to the fetus, at embryonic day 18.5 of gestation. Iron transporter expression in the placenta was measured by Western blotting, and the expression of Hamp1, the gene encoding the iron regulatory hormone hepcidin, was determined in fetal liver by real-time PCR. RESULTS: There was no change in the amount of iron transferred to the fetus when Zp was disrupted in either the fetal component of the placenta or the entire placenta. No compensatory changes in the expression of the iron transport proteins transferrin receptor 1 or ferroportin were observed, nor was there any change in fetal liver Hamp1 mRNA. Hephl1, the gene encoding Zp, was expressed mainly in the maternal decidua of the placenta and not in the nutrient-transporting syncytiotrophoblast. Disruption of Zp in the whole placenta resulted in a 26% increase in placental size (P < 0.01). CONCLUSIONS: Our data indicate that Zp is not essential for the efficient transfer of iron to the fetus in mice and is localized predominantly in the maternal decidua. The increase in placental size observed when Zp is knocked out in the entire placenta suggests that this protein may play a role in placental development.

Hypoxia and hypoxia mimetics differentially modulate histone post-translational modifications.

Post-translational modifications (PTMs) to the tails of the core histone proteins are critically involved in epigenetic regulation. Hypoxia affects histone modifications by altering the activities of histone-modifying enzymes and the levels of hypoxia-inducible factor (HIF) isoforms. Synthetic hypoxia mimetics promote a similar response, but how accurately the hypoxia mimetics replicate the effects of limited oxygen availability on the levels of histone PTMs is uncertain. Here we report studies on the profiling of the global changes to PTMs on intact histones in response to hypoxia/hypoxia-related stresses using liquid chromatography-mass spectrometry (LC-MS). We demonstrate that intact protein LC-MS profiling is a relatively simple and robust method for investigating potential effects of drugs on histone modifications. The results provide insights into the profiles of PTMs associated with hypoxia and inform on the extent to which hypoxia and hypoxia mimetics cause similar changes to histones. These findings imply chemically-induced hypoxia does not completely replicate the substantial effects of physiological hypoxia on histone PTMs, highlighting that caution should be used in interpreting data from their use.

The Clinically Used Iron Chelator Deferasirox Is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases.

Fe(II)- and 2-oxoglutarate (2OG)-dependent JumonjiC domain-containing histone demethylases (JmjC KDMs) are "epigenetic eraser" enzymes involved in the regulation of gene expression and are emerging drug targets in oncology. We screened a set of clinically used iron chelators and report that they potently inhibit JMJD2A (KDM4A) in vitro. Mode of action investigations revealed that one compound, deferasirox, is a bona fide active site-binding inhibitor as shown by kinetic and spectroscopic studies. Synthesis of derivatives with improved cell permeability resulted in significant upregulation of histone trimethylation and potent cancer cell growth inhibition. Deferasirox was also found to inhibit human 2OG-dependent hypoxia inducible factor prolyl hydroxylase activity. Therapeutic effects of clinically used deferasirox may thus involve transcriptional regulation through 2OG oxygenase inhibition. Deferasirox might provide a useful starting point for the development of novel anticancer drugs targeting 2OG oxygenases and a valuable tool compound for investigations of KDM function.

Mice overexpressing hepcidin suggest ferroportin does not play a major role in Mn homeostasis.

Manganese is an essential metal that is required for a wide range of biological functions. Ferroportin (FPN), the only known cellular exporter of iron, has also been proposed to play a role in manganese export, but this relationship is incompletely understood. To investigate this in more detail in vivo, we examined the relative distributions of manganese and iron in TMPRSS6 deficient mice, which are characterized by constitutively high expression of the iron regulatory hormone hepcidin and, consequently, very low FPN levels in their tissues. Tmprss6-/- mice showed frank iron deficiency and reduced iron levels in most tissues, consistent with FPN playing an important role in the distribution of this metal, but manganese levels were largely unaffected. Associated studies using intestine-specific FPN knockout mice showed that loss of FPN significantly reduced the dietary absorption of iron, but had no effect on manganese intake. Taken together, our data suggest that FPN does not play a major role in Mn transport in vivo. They do not exclude a minor role for FPN in manganese homeostasis, nor the possibility that the transporter may be relevant at high Mn levels, but at physiological levels of this metal, other transport proteins appear to be more important.