Loss of TLE3 promotes the mitochondrial program in beige adipocytes and improves glucose metabolism.

Prolonged cold exposure stimulates the recruitment of beige adipocytes within white adipose tissue. Beige adipocytes depend on mitochondrial oxidative phosphorylation to drive thermogenesis. The transcriptional mechanisms that promote remodeling in adipose tissue during the cold are not well understood. Here we demonstrate that the transcriptional coregulator transducin-like enhancer of split 3 (TLE3) inhibits mitochondrial gene expression in beige adipocytes. Conditional deletion of TLE3 in adipocytes promotes mitochondrial oxidative metabolism and increases energy expenditure, thereby improving glucose control. Using chromatin immunoprecipitation and deep sequencing, we found that TLE3 occupies distal enhancers in proximity to nuclear-encoded mitochondrial genes and that many of these binding sites are also enriched for early B-cell factor (EBF) transcription factors. TLE3 interacts with EBF2 and blocks its ability to promote the thermogenic transcriptional program. Collectively, these studies demonstrate that TLE3 regulates thermogenic gene expression in beige adipocytes through inhibition of EBF2 transcriptional activity. Inhibition of TLE3 may provide a novel therapeutic approach for obesity and diabetes.

Minimum information for reporting on the TEER (trans-epithelial/endothelial electrical resistance) assay (MIRTA).

Standard information reporting helps to ensure that assay conditions and data are consistently reported and to facilitate inter-laboratory comparisons. Here, we present recommendations on minimum information for reporting on the TEER (trans-epithelial/endothelial electrical resistance) assay (MIRTA). The TEER assay is extensively used to evaluate the health of an epithelial/endothelial cell culture model and as an indicator of the potential toxicity of a test substance. This publication is the result of an international collaboration─called the RespTox (Respiratory Toxicity) Collaborative─through which twelve laboratories shared their protocols for assessing the barrier function of respiratory epithelial cells using the TEER assay following exposure to substances. The protocols from each laboratory were reviewed to identify general steps for performing the TEER assay, interlaboratory differences between steps, the rationale for differences, whether these differences impact results or cross-laboratory comparisons between TEER measurements. While the MIRTA recommendations are focused on respiratory epithelial cell systems, these recommendations can be adapted for other cell systems that form barriers. The use of these recommendations will support data transparency and reproducibility, reduce challenges in data interpretation, enable cross-laboratory comparisons, help assess study quality, and facilitate the incorporation of the TEER assay into national and international testing guidance.

Cancer survivors treated with platinum-based chemotherapy affected by ototoxicity and the impact on quality of life: a narrative synthesis systematic review.

Objective: To identify any change in quality of life (QoL) caused by chemotherapy-induced toxicities, such as hearing loss and tinnitus, to provide information in order to improve services and aid clinicians in their decision-making. Design: This systematic review followed the preferred reporting items for systematic reviews and meta-analysis (PRISMA) checklist. The search terms were cancer, platinum-based chemotherapy, ototoxicity and "quality of life". Titles and abstracts, followed by full texts, were screened by two independent researchers. The relevant data were extracted and quality analysis was performed using the NIH Quality Assessment Tool. Study sample: About 308 titles and abstracts were screened, and 27 full-text articles were screened. Ten articles representing 11 studies were included in the review. Study design included cross-sectional studies, randomised control trials and longitudinal studies. Results: Diagnostic criteria consisted of audiograms, questionnaires and patient complaints. The study quality ranged from 21.43% to 85.71%. Overall results found that those treated with cisplatin had more hearing loss and tinnitus than those treated with other therapies. Furthermore, those with hearing loss and tinnitus were more likely to have a lower QoL. Conclusions: There is an urgent need to standardise diagnostics when investigating ototoxicity and its effect on QoL, particularly for research into risk factors, prevention and management.

The long-term impacts of hearing loss, tinnitus and poor balance on the quality of life of people living with and beyond cancer after platinum-based chemotherapy: a literature review.

PURPOSE: To elucidate the long-term impacts of hearing loss, tinnitus and balance in people living with and beyond cancer (LWBC) treated with platinum-based chemotherapy (PBCT). METHODS: A literature search was conducted between March and June 2022 using PubMed, Web of Science and Google Scholar. Full-text papers in English were included. Articles explored the impacts of hearing loss, tinnitus and balance and discussed them in the context of treatment. If PBCT was used in conjunction with other treatments, the article was included. There were no constraints on age, cancer type, publication date, location, study design or data type. Sixteen studies and two reviews were included. RESULTS: Hearing loss and tinnitus can cause communication difficulties and subsequent social withdrawal. There were deficits in cognition, child development and educational performance. Employment and the ease of everyday life were disrupted by hearing loss and tinnitus, whereas poor balance interfered with walking and increased the risk of falls. Depression and anxiety were related to ototoxicity. Most notable were the differing mindsets experienced by adults LWBC with ototoxicity. There was evidence of inadequate monitoring of ototoxicity by clinicians and a lack of communication between clinicians and patients about ototoxicity as a side effect. CONCLUSIONS: Ototoxicity has a negative long-term impact on multiple areas of life for adults and children LWBC. This can compromise their quality of life. IMPLICATIONS FOR CANCER SURVIVORS: Increased awareness, monitoring and education surrounding these issues may lead to earlier intervention and better management of ototoxicity, enhancing the quality of life of people LWBC.

The impact of chemotherapy-induced inner ear damage on quality of life in cancer survivors: a qualitative study.

PURPOSE: This study aimed to explore the burden of inner ear damage (ototoxicity) on adults living with and beyond cancer treated with chemotherapy and  the impact on their quality of life (QoL). Furthermore, this study aimed to explore patient awareness surrounding chemotherapy-induced inner ear damage, known as ototoxicity, and assess what support they had been offered. METHODS: Participants were adults who had undergone chemotherapy, recruited from cancer clinics, charities and social media. Using semi-structured interviews and fieldnotes, an inductive thematic analysis was used to develop key themes surrounding this topic. RESULTS: Twenty participants from the UK were interviewed. Two key themes were developed from the thematic analysis, cancer-related QoL and ototoxicity-related QoL, with each one including 5 subthemes. Subthemes consisted of impact of ototoxicity, hearing, tinnitus, clinical experience, audiological assessments, and impact of treatment, cancer and chemotherapy, other toxicities, information and patient reflections. CONCLUSIONS: Ototoxicity can have a negative impact on QoL, specifically on social life and the fear of hearing loss and/or tinnitus worsening. There are opportunities for increased awareness by patients and clinicians, including improved information sources, and hearing monitoring not only for those undergoing platinum-based chemotherapy but many others surviving after treatment for cancer. IMPLICATIONS FOR CANCER SURVIVORS: Better monitoring of hearing and information about ototoxicity during chemotherapy could potentially reduce the fear of the symptoms of ototoxicity worsening. Furthermore, hearing monitoring would facilitate the detection of hearing loss at early stages of survivorship, which would facilitate earlier access to clinical interventions and longer term counselling.

Mitochondrial pyruvate carrier is required for optimal brown fat thermogenesis.

Brown adipose tissue (BAT) is composed of thermogenic cells that convert chemical energy into heat to maintain a constant body temperature and counteract metabolic disease. The metabolic adaptations required for thermogenesis are not fully understood. Here, we explore how steady state levels of metabolic intermediates are altered in brown adipose tissue in response to cold exposure. Transcriptome and metabolome analysis revealed changes in pathways involved in amino acid, glucose, and TCA cycle metabolism. Using isotopic labeling experiments, we found that activated brown adipocytes increased labeling of pyruvate and TCA cycle intermediates from U13C-glucose. Although glucose oxidation has been implicated as being essential for thermogenesis, its requirement for efficient thermogenesis has not been directly tested. We show that mitochondrial pyruvate uptake is essential for optimal thermogenesis, as conditional deletion of Mpc1 in brown adipocytes leads to impaired cold adaptation. Isotopic labeling experiments using U13C-glucose showed that loss of MPC1 led to impaired labeling of TCA cycle intermediates. Loss of MPC1 in BAT increased 3-hydroxybutyrate levels in blood and BAT in response to the cold, suggesting that ketogenesis provides an alternative fuel source to compensate. Collectively, these studies highlight that complete glucose oxidation is essential for optimal brown fat thermogenesis.

Exploring the Experiences of Cancer Patients With Chemotherapy-Induced Ototoxicity: Qualitative Study Using Online Health Care Forums.

BACKGROUND: Many cancer patients and survivors experience permanent and life-debilitating effects, such as ototoxicity, from treatment. Ototoxicity manifests as high-frequency hearing loss and tinnitus, which can have a detrimental effect on the quality of life (QoL) of those affected. Currently, there is little information and support offered to these patients who experience ototoxicity, potentially leading to many being undiagnosed and untreated. OBJECTIVE: The aim of this study was to explore the extent of ototoxic side effects, such as hearing loss and tinnitus, and their impact on cancer patients following chemotherapy treatment. Secondary objectives included detecting the time periods of onset and duration of the ototoxicity and identifying what support was available to this population. METHODS: Posts from publicly available online forums were thematically analyzed using the guidelines by Braun and Clarke. A coding manual was iteratively developed to create a framework for the analysis of the ototoxicity experience among the cancer population. RESULTS: A total of 9 relevant online forums were identified, consisting of 86 threads and 570 posts from 377 members. Following the bottom-up thematic analysis, 6 major themes were identified: nature of ototoxicity, time of experienced ototoxicity, information on ototoxicity, quality of life, therapies, and online social support. CONCLUSIONS: There was a significant number of reports expressing concerns about the lack of information on the risk of ototoxicity. More support for those suffering is needed; for example, improved interdepartmental communication between oncology and audiology services could optimize patient care. Patients should also be encouraged to communicate with their health care professionals about their ototoxicity and relay how their QoL is impacted by ototoxicity when accessing support. Tinnitus was the most common concern and was associated with distress. Hearing loss was less common; however, it was associated with fear and employment issues. Those who reported preexisting conditions were fearful about worsening their condition as their QoL was already impacted.

A Feasibility Study of Restorative Yoga Versus Vigorous Yoga Intervention for Sedentary Breast and Ovarian Cancer Survivors.

Yoga has been shown to improve cancer survivors' quality of life, yet regular yoga practice is a challenge for those who are sedentary. We conducted a pilot randomized controlled study to assess feasibility and adherence of two types of yoga intervention among sedentary cancer survivors. Sedentary breast and ovarian cancer survivors were randomized to practice either restorative yoga (minimal physical exertion, Group R) or vigorous yoga (considerable physical exertion, Group V) in three 60-minute supervised sessions a week for 12 weeks, followed by 12 weeks of home practice. Accrual, adherence, and attendance rates were assessed. Of the 226 eligible patients, 175 (77%) declined to participate in the study, citing time commitment and travel as the most common barriers. Forty-two subjects consented to participate in the study. Of the 35 participants who began the intervention (20 in Group R and 15 in Group V), adherence rate (percentage remaining in the study at week 12) was 100% and 87%, respectively. Rate of adequate attendance (more than 66% of the scheduled supervised sessions) was 85% and 73%, respectively. Rate of completion of the home practice period was 85% and 77%, respectively. In this study, sedentary cancer survivors were able to adhere to a long-term, regular yoga regimen. The rate of adequate attendance was higher for restorative yoga. Future studies for sedentary patients should focus on reducing time commitment and travel requirements to improve recruitment, and on using restorative yoga as a more feasible intervention for this population.

Vestibulotoxicity Associated With Platinum-Based Chemotherapy in Survivors of Cancer: A Scoping Review.

Background: Cochleotoxicity following the treatment with platinum-based chemotherapy is well documented. The potential for vestibulotoxicity is still unclear. This scoping review examined the extent of current research literature, summarized research findings and identified research gaps regarding vestibular-related adverse effects associated with platinum-based chemotherapy in survivors of cancer. Methods: Inclusion criteria followed the PICO principles: Participants, adult, and pediatric cancer patients of any cancer type; Intervention, platinum-based chemotherapy (such as cisplatin, carboplatin, and oxaliplatin); Control, none or any; Outcomes, vestibular-related adverse effects. English language articles published since 1978 were retrieved. Seventy-five eligible studies were identified from a systematic literature search, and relevant data were charted, collated, and summarized. Results: Testing for vestibulotoxicity predominately featured functional evaluation of the horizontal semicircular canal using the caloric and rotational tests. The rate of abnormal vestibular function test results after chemotherapy administration varied from 0 to 50%. The results of objective testing did not always correspond to patient symptoms. There is tentative support for patients with pre-existing loss of vestibular function to be more likely to experience vestibular toxicity after dosing with cisplatin. Conclusions: A number of studies reported significant evidence of vestibular toxicities associated with platinum-based chemotherapy, especially cisplatin. This scoping review emphasizes that vestibular toxicity needs more attention and comprehensive evaluation. Specifically, studies that analyse cumulative dose of platinum-based chemotherapy, affected sites of lesion in vestibular end organs, and the correlation and temporal patterns of cochlear and vestibular toxicity are needed.

Transabdominal cerclage after comprehensive evaluation of women with previous unsuccessful transvaginal cerclage.

OBJECTIVE: The purpose of this study was to assess the outcome after transabdominal-cerclage placement during pregnancy in women with previous unsuccessful transvaginal cerclage. STUDY DESIGN: We conducted a retrospective case series that described pregnancy outcome in women who were treated with transabdominal cerclage between 1994 and 2006. RESULTS: Seventy-five women with negative evaluation for recurrent pregnancy loss and > or = 1 previous unsuccessful transvaginal cerclage procedures were treated with transabdominal cerclage. The median gestational age at the time of cerclage placement was 13 weeks, and the median gestational age at delivery was 36 weeks. Seventy-two women delivered after 24 weeks of gestation, and 3 women delivered < or = 24 weeks of gestation. The fetal-salvage after transabdominal cerclage was 96%. CONCLUSION: Our findings suggest that, in women with a history of > or = 1 failed transvaginal cerclage, transabdominal cerclage is an effective procedure.

Academic difficulty and program-level variables predict performance on the National Physical Therapy Examination for licensure: a population-based cohort study.

BACKGROUND: Several factors have been shown to influence first-time pass rates on the National Physical Therapy Examination (NPTE). It is unclear to what extent academic difficulty experienced by students in a physical therapist education program may affect NPTE pass rates. The effects of institutional status (public or private) and Carnegie Classification on NPTE pass rates also are unknown. OBJECTIVE: The aim of this study was to quantify the odds of failure on the NPTE for students experiencing academic difficulty and for institutional status and Carnegie Classification. DESIGN: This investigation was a retrospective population-based cohort study. METHODS: Quota sampling was used to recruit a random sample of 20 professional physical therapist education programs across the United States. Individual student demographic, preadmission, and academic performance data were collected, as were data on program-level variables and data indicating pass/fail performance on the NPTE. A generalized linear mixed-effects logistic regression model was used to adjust for confounding factors and to describe relationships among the key predictor variables-academic difficulty, institutional status, and Carnegie Classification-and the dependent variable, NPTE performance. RESULTS: Academic difficulty during a student's professional training was an independent predictor for NPTE failure. The odds of students who had academic difficulty (relative to students who did not experience academic difficulty) failing the NPTE were 5.89 (95% confidence interval=4.06-8.93). The odds of NPTE failure also varied depending on institutional status and Carnegie Classification. LIMITATIONS: The findings related to Carnegie Classification and institutional status should be considered preliminary. CONCLUSIONS: Student performance on the NPTE was influenced by multiple factors, but the most important, potentially modifiable risk factor for poor NPTE performance likely is academic difficulty during professional training.

Gain of allelic gene expression for IGF-II occurs frequently in Barrett's esophagus.

The IGF-II gene normally exhibits genomic imprinting, a DNA modification that allows the expression of only one of the two inherited alleles. With loss of imprinting, there is a gain of allelic gene expression (GOAGE) due to IGF-II being expressed by both alleles. GOAGE for IGF-II has been demonstrated in a number of malignancies and in normal epithelia surrounding malignancies, but not in epithelia without associated neoplasia. We hypothesized that nonneoplastic Barrett's epithelium might have GOAGE for IGF-II that could facilitate its progression to neoplasia. Endoscopic biopsies were obtained from metaplastic esophageal, normal gastric, and normal duodenal epithelia from 43 patients with Barrett's esophagus. Genomic DNA were analyzed using PCR followed by ApaI restriction enzyme digestion or allele-specific PCR to identify an ApaI polymorphism of IGF-II. cDNA from patients with the ApaI polymorphism were analyzed for IGF-II GOAGE using exon connection PCR, followed by a secondary nested PCR and ApaI restriction enzyme digestion. We found that 13 (30%) of 43 samples of Barrett's metaplasia contained the ApaI polymorphism and were thus informative for IGF-II, and sufficient material was available for GOAGE analysis in 9 of those 13 cases. GOAGE for IGF-II was demonstrated in five (56%) of those nine cases. All patients with GOAGE in Barrett's metaplasia also demonstrated GOAGE in the gastric and duodenal epithelia. In contrast, patients without GOAGE in Barrett's metaplasia also had no GOAGE in their gastric and duodenal epithelia. We conclude that in patients with Barrett's esophagus, GOAGE for IGF-II is found frequently in the metaplastic esophageal epithelium as well as in normal gastric and duodenal epithelia.

Acid increases proliferation via ERK and p38 MAPK-mediated increases in cyclooxygenase-2 in Barrett's adenocarcinoma cells.

Cyclooxygenase-2 (COX-2) has been linked to neoplastic progression in Barrett's esophagus. Acid exposure has been shown both to activate the MAPK pathways and to increase COX-2 protein expression in Barrett's metaplasia, but it is not known whether these effects are interrelated. We hypothesized that acid-induced activation of the MAPK pathways mediates an increase in COX-2 expression in Barrett's esophagus, and we tested this hypothesis in a Barrett's-associated adenocarcinoma cell line (SEG-1). We exposed SEG-1 cells to acidic or neutral media in the presence and absence of two MAPK inhibitors: U-0126 (an ERK inhibitor) or SB-203580 (a p38 inhibitor). We quantitated COX-2 protein levels using an enzyme immunometric assay and COX-2 mRNA levels using real-time PCR. We also determined how acid affects the activity of the COX-2 promoter and mRNA stability. Compared with SEG-1 cells exposed to neutral media, acid-exposed cells exhibited a 2.8-fold increase in COX-2 mRNA levels within 30 min. Both U-0126 and SB-203580 attenuated the acid-induced increase in COX-2 mRNA. Acid significantly increased COX-2 protein expression and promoter activity, and both of these effects were abolished by treatment with U-0126 and SB-203580. Acid exposure also stabilized COX-2 mRNA levels, an effect that was abolished by U-0126 but not by SB-203580. We conclude that acid increases COX-2 expression through activation of the MAPK pathways. Acid-induced activation of both ERK and p38 causes a significant increase in COX-2 promoter activity, and acid-activated ERK stabilizes COX-2 mRNA. These findings suggest potential mechanisms whereby acid reflux might promote carcinogenesis in Barrett's esophagus.