IGFBP3 promotes esophageal cancer growth by suppressing oxidative stress in hypoxic tumor microenvironment.

Insulin-like growth factor binding protein 3 (IGFBP3), a hypoxia-inducible gene, regulates a variety of cellular processes including cell proliferation, senescence, apoptosis and epithelial-mesenchymal transition (EMT). IGFBP3 has been linked to the pathogenesis of cancers. Most previous studies focus upon proapoptotic tumor suppressor activities of IGFBP3. Nevertheless, IGFBP3 is overexpressed in certain cancers including esophageal squamous cell carcinoma (ESCC), one of the most aggressive forms of squamous cell carcinomas (SCCs). The tumor-promoting activities of IGFBP3 remain poorly understood in part due to a lack of understanding as to how the tumor microenvironment may influence IGFBP3 expression and how IGFBP3 may in turn influence heterogeneous intratumoral cell populations. Here, we show that IGFBP3 overexpression is associated with poor postsurgical prognosis in ESCC patients. In xenograft transplantation models with genetically engineered ESCC cells, IGFBP3 contributes to tumor progression with a concurrent induction of a subset of tumor cells showing high expression of CD44 (CD44H), a major cell surface receptor for hyaluronic acid, implicated in invasion, metastasis and drug resistance. Our gain-of-function and loss-of-function experiments reveal that IGFBP3 mediates the induction of intratumoral CD44H cells. IGFBP3 cooperates with hypoxia to mediate the induction of CD44H cells by suppressing reactive oxygen species (ROS) in an insulin-like growth factor-independent fashion. Thus, our study sheds light on the growth stimulatory functions of IGFPB3 in cancer, gaining a novel mechanistic insight into the functional interplay between the tumor microenvironment and IGFBP3.

Hypoxia induces IGFBP3 in esophageal squamous cancer cells through HIF-1α-mediated mRNA transcription and continuous protein synthesis.

Insulin-like growth factor binding protein (IGFBP)-3 regulates cell proliferation and apoptosis in esophageal squamous cell carcinoma (ESCC) cells. We have investigated how the hypoxic tumor microenvironment in ESCC fosters the induction of IGFBP3. RNA interference experiments revealed that hypoxia-inducible factor (HIF)-1α, but not HIF-2α, regulates IGFBP3 mRNA induction. By chromatin immunoprecipitation and transfection assays, HIF-1α was found to transactivate IGFBP3 through a novel hypoxia responsive element (HRE) located at 57 kb upstream from the transcription start site. Metabolic labeling experiments demonstrated hypoxia-mediated inhibition of global protein synthesis. 7-Methyl GTP-cap binding assays suggested that hypoxia suppresses cap-dependent translation. Experiments using pharmacological inhibitors for mammalian target of rapamycin (mTOR) suggested that a relatively weak mTOR activity may be sufficient for cap-dependent translation of IGFBP3 under hypoxic conditions. Bicistronic RNA reporter transfection assays did not validate the possibility of an internal ribosome entry site as a potential mechanism for cap-independent translation for IGFBP3 mRNA. Finally, IGFBP3 mRNA was found enriched to the polysomes. In aggregate, our study establishes IGFBP3 as a direct HIF-1α target gene and that polysome enrichment of IGFBP3 mRNA may permit continuous translation under hypoxic conditions.

[Three-channeled aortic dissection; report of a case].

The formation of 2 adjacent lumens is rarely observed in aortic dissection. We report herein a case of ruptured 3-channeled aortic dissection in a short time of hospitalization. A 58-year-old man who had been followed up for aortic dissection (Stanford type B) was admitted to Kumamoto National Hospital with an abdominal pain and a lumbago. A computed tomography (CT) revealed that a 3-channeled aortic dissection from the aortic arch to the right common iliac artery. An intramural hematoma was generated in the abdominal aorta and the left kidney was not enhanced. We initially adopted conservative therapies. But on the next day, he suddenly complained a severe back pain and died. At autopsy, the thoracic aorta was found to have ruptured into the mediastinum, and massive hematoma was formed.

[Total aortic arch replacement for distal aortic arch aneurysm with adhered left lung: report of a case].

A 76-year-old man with a history of pleuritis and a cerebral infarct underwent a total arch replacement for an aneurysm of the distal aortic arch. Computed tomography revealed a true aneurysm having a maximum diameter of 70 mm as well as pleural thickening and calcification. Total arch replacement with selective cerebral perfusion was performed through median sternotomy and left thoracotomy. The myocardial ischemic time was shortened by reperfusion from the right axillary artery after the anastomosis of the proximal ascending aorta and the brachiocephalic artery. After the other branches of the arch were anastomosed, a distal anastomosis through the left thoracotomy was then performed using the pull-through method, enabling minimal decortication of the adhered lung. Our surgical procedure for distal arch aneurysm with adhered lung involves the addition of a left thoracotomy, but the reduction in the myocardial ischemic time and lung injury are of benefit.

Effects of speech babble on transient evoked otoacoustic emissions in normal-hearing adults.

The results of transient evoked otoacoustic emissions (TEOAEs) have been found to be adversely affected by noise. However, there are few investigations into the specific effect of background noise on TEOAEs. The purpose of the present study was to determine the effects of increasing levels of speech babble and the recording method on TEOAEs using the ILO88 Otodynamics instrumentation. Subjects were 30 normal-hearing adults (15 males and 15 females), aged between 18 and 32 years. TEOAE recordings were obtained from both ears of each subject under five different levels of speech babble delivered via a loudspeaker in sound field using both the default and Quickscreen methods of data collection. The results indicated that both the whole-wave reproducibility (WWR) and mean signal-to-noise ratio (MSNR), averaged across frequencies from about 2 to 4 kHz, decreased with increasing speech babble levels. The results also showed that the Quickscreen mode was less susceptible to noise than the default mode. The pass percentage, using either WWR > or = 50 percent or an MSNR > or = 3 dB as a pass criterion, also decreased with increasing speech babble levels. Furthermore, the findings indicated that the use of the WWR pass criterion resulted in a high failure rate under high levels of speech babble. In contrast, the MSNR pass criterion was robust to speech babble levels of up to 70 dBA in the Quickscreen mode and 65 dBA in the default setting. The clinical implications of these findings, as applied to non-sound-treated environments, are discussed.

The effect of high-pass filtering on TEOAE in 2-month-old infants.

The aim of the present study was to investigate the effect of high-pass filtering on TEOAE obtained from 2-month-old infants as a function of filter cut-off frequency, activity states and pass/fail status of infants. Two experiments were performed. In Experiment 1, 100 2-month-old infants (200 ears) in five activity states (asleep, awake but peaceful, sucking a pacifier, feeding, restless) were tested by use of TEOAE technology. Five different filter conditions were applied to the TEOAE responses post hoc. The filter conditions were set at 781 Hz (default setting), 1.0, 1.2, 1.4 and 1.6 kHz. Results from this experiment showed that TEOAE parameters such as whole-wave reproducibility (WR) and signal-to-noise ratio (SNR) at 0.8 kHz and 1.6 kHz, changed as a function of the cut-off frequency. The findings suggest that the 1.6 kHz and 1.2 kHz filter conditions are optimal for WR and SNR pass/fail criteria, respectively. Although all infant recordings appeared to benefit from the filtering, infants in the noisy states seemed to benefit the most. In Experiment 2, the high-pass filtering technique was applied to 23 infants (35 ears) who apparently failed the TEOAE tests on initial screening but were subsequently awarded a pass status based on the results from a follow-up auditory brainstem response (ABR) assessment. The findings showed a significant decrease in noise contamination of the TEOAE with a corresponding significant increase in WR. With high-pass filtering at 1.6 kHz, 21/35 ears could be reclassified into the pass category.

Outcomes of transient evoked otoacoustic emission testing in 6-year-old school children: a comparison with pure tone screening and tympanometry.

OBJECTIVES: (1) To establish test performance measures for Transient Evoked Otoacoustic Emission testing of 6-year-old children in a school setting; (2) To investigate whether Transient Evoked Otoacoustic Emission testing provides a more accurate and effective alternative to a pure tone screening plus tympanometry protocol. METHODS: Pure tone screening, tympanometry and transient evoked otoacoustic emission data were collected from 940 subjects (1880 ears), with a mean age of 6.2 years. Subjects were tested in non-sound-treated rooms within 22 schools. Receiver operating characteristics curves along with specificity, sensitivity, accuracy and efficiency values were determined for a variety of transient evoked otoacoustic emission/pure tone screening/tympanometry comparisons. RESULTS: The Transient Evoked Otoacoustic Emission failure rate for the group was 20.3%. The failure rate for pure tone screening was found to be 8.9%, whilst 18.6% of subjects failed a protocol consisting of combined pure tone screening and tympanometry results. In essence, findings from the comparison of overall Transient Evoked Otoacoustic Emission pass/fail with overall pure tone screening pass/fail suggested that use of a modified Rhode Island Hearing Assessment Project criterion would result in a very high probability that a child with a pass result has normal hearing (true negative). However, the hit rate was only moderate. Selection of a signal-to-noise ratio (SNR) criterion set at > or =1 dB appeared to provide the best test performance measures for the range of SNR values investigated. Test performance measures generally declined when tympanometry results were included, with the exception of lower false alarm rates and higher positive predictive values. The exclusion of low frequency data from the Transient Evoked Otoacoustic Emission SNR versus pure tone screening analysis resulted in improved performance measures. CONCLUSIONS: The present study poses several implications for the clinical implementation of Transient Evoked Otoacoustic Emission screening for entry level school children. Transient Evoked Otoacoustic Emission pass/fail criteria will require revision. The findings of the current investigation offer support to the possible replacement of pure tone screening with Transient Evoked Otoacoustic Emission testing for 6-year-old children. However, they do not suggest the replacement of the pure tone screening plus tympanometry battery.

Distortion-product otoacoustic emissions in schoolchildren: effects of ear asymmetry, handedness, and gender.

The present study examined effects of ear asymmetry, handedness, and gender on distortion-product otoacoustic emissions (DPOAEs) obtained from schoolchildren. A total of 1003 children (528 boys and 475 girls), with a mean age of 6.2 years (SD = 0.4, range = 5.2-7.9 years), were tested in a quiet room at their schools using the GSI-60 DPOAE system. A distortion-product (DP)-gram was obtained for each ear, with f2 varying from 1.1 to 6.0 kHz and the ratio of f2/f1 at 1.21. The signal-to-noise ratios (SNRs) (DPOAE amplitude minus the mean noise floor) at the tested frequencies 1.1, 1.5, 1.9, 2.4, 3.0, 3.8, 4.8, and 6.0 kHz were measured. The results revealed a small but significant difference in SNR between ears, with right ears showing a higher mean SNR than left ears at 1.9, 3.0, 3.8, and 6.0 kHz. At these frequencies, the difference in mean SNR between ears was less than 1 dB. A significant gender effect was also found. Girls exhibited a higher SNR than boys at 3.8, 4.8, and 6.0 kHz. The difference in mean SNR, as a result of the gender effect, was about 1 to 2 dB at these frequencies. There was no significant difference in mean SNR between left-handed and right-handed children for all tested frequencies.

[Coefficients between TEOAEs and DPOAEs in infants].

OBJECTIVE: To investigate the coefficients of TEOAEs and DPOAEs based on various pass/fail criteria. METHOD: Thirty-six Australia infants were tested (age range: 1-6 months) using both TEOAE and DPOAE. Cohen's Kappa (K) were used to analyze different criteria. RESULT: There is a significant low agreement in the screening outcomes between TEOAEs and DPOAEs, and different criteria for TEOAEs. CONCLUSION: The findings from the study of coefficients among commonly used screening pass/fail criteria suggested that there is no simple relationship among them. The possible reasons for weak agreement were discussed.

Paediatric hearing screening in the community: a comparison of outcomes from transient evoked and distortion product otoacoustic emission measures.

The present study aimed to compare TEOAE screening outcomes based on different pass/fail criteria and the outcomes from TEOAE and DPOAE measures in children. For the purpose of the study, the subjects were divided into two age groups: group 1 (n = 36; mean age 2.7 months, SD 1.2), and group 2 (n = 29; mean age 37.5 months, SD 16.3). Results indicated that the agreement of screening outcomes between pass/fail criteria for the TEOAE measure and between TEOAE and DPOAE measures was significantly lower for the younger group than for the older group. The greater variability in the younger age group could be partly attributed to the higher physiological noise produced by young infants. Irrespective of the pass/fail criteria used, the findings of the present study suggest that the OAE outcomes for children with weak OAEs or OAEs obscured by excessive noise were most variable.

Transient evoked otoacoustic emissions in 6-year-old school children: a normative study.

Great potential has recently been demonstrated for the application of transient evoked otoacoustic emissions (TEOAEs) in screening the hearing of school-aged children. The present study aimed to describe the range of TEOAE values obtained from a large cohort of 6-year-old children in school settings. Results indicated significant sex and ear asymmetry effects on signal-to-noise ratio, response, whole wave reproducibility, band reproducibility and noise levels. A prior history of ear infections was also shown to influence response level, whole wave reproducibility and band reproducibility. The sex, ear and history specific normative data tables derived may contribute to future improvements in the accuracy of hearing screening for 6-year-old school children.

Measuring the understanding of sentences by hearing-impaired children: comparison with connected discourse ratings.

Measuring the understanding of connected speech by hearing-impaired children is desirable if an appropriate rehabilitative or special educational program is to be implemented or monitored. This study was undertaken to explore the potential of a Cantonese version of the Helen sentence test as a measure of understanding connected speech by a group of 54 mildly to profoundly hearing-impaired children, and to compare the results from this sentence test with those achieved by the same children on a connected discourse test. The effects of two different hearing aid frequency responses and two noise conditions on the results from both tests were also examined. Findings from the present study revealed that the Helen sentence test could be successfully adapted for use with Cantonese-speaking hearing-impaired children in Hong Kong. When compared to the connected discourse test, the modified Helen test produced significantly higher scores and was more sensitive to changes in noise level, especially for the severely and profoundly hearing-impaired children.

Combined thoracic aortic or upper digestive tract resection for lung cancer and malignant mediastinal tumor.

OBJECTIVE: We studied possible indications and combined resection in patients with lung cancer and mediastinal tumors requiring combined thoracic aortic or upper digestive tract resection. METHODS: Ten patients with lung cancer and malignant mediastinal tumors (9 men and 1 woman aged 39 to 72 years; mean: 60.5) underwent combined aortic or upper digestive tract resection. RESULTS: Five--3 [corrected] with primary lung cancer, 1 with thymic cancer, and 1 with liposarcoma--, underwent combined aortic resection. In 2 each, lung cancer and malignant mediastinal tumor had infiltrated the thoracic aorta. The remaining case of lung cancer was complicated by aortic aneurysm in the distal arch. Cardiopulmonary bypass was conducted in 4, and selective cerebral perfusion in 2. Three patients are alive after 11, 22, and 61 months without disease recurrence. Those undergoing combined upper digestive tract resection all had lung cancer, with 4 having tumors infiltrating the esophagus or corpus ventriculi. The remaining patient had both lung and esophageal cancer. The patient treated with combined corpus ventriculi resection has survived 24 months and the patient treated with combined esophageal resection has survived 12 months without disease recurrence. The 1-year survival rate was 60%, 2-year 23%, and 3-year 23%. Prognosis was generally poor with the longest survival 13 months with N2 lung cancer. CONCLUSIONS: In combined resection due to malignant mediastinal tumor, T4N0-1 lung cancer, or diseases such as aortic aneurysm, prognosis can be expected to improve. Despite the often poor prognosis in T4N2 lung cancer, surgical intervention may be indicated to avoid complications due to tumor invasion and to lengthen survival and improve quality of life.

Transient evoked otoacoustic emissions in two-month-old infants: a normative study.

Researchers have recently reported the effects of age, sex, ear asymmetry, and subject's activity status on transient evoked otoacoustic emissions (TEOAEs). The present study aimed to expand upon such reports by describing the characteristics of TEOAE spectra obtained from a cohort of 607 two-month-old infants in community child health clinics. Results indicated significant sex, ear and activity state effects on the signal:noise ratio, response, whole wave and band reproducibility values. These findings suggest the need for TEOAE normative data to be expressed as a function of sex, ear, and activity state of infants. These characteristics of TEOAE spectra may shape future investigations into appropriate pass fail criteria for two-month-old infants.

Otoacoustic emission criteria for neonatal hearing screening.

Transient evoked otoacoustic emission measures are gaining acceptance as a technique in new-born hearing screening. At present a wide variety of pass-fail screening criteria are used in otoacoustic emission screening programs. In a study of 100 special care neonates and 35 well, full term babies, a number of screening criteria were examined for sensitivity and specificity characteristics when compared to a standard auditory brainstem response protocol. Results indicate that, for normal and special care neonates with a gestational age at test of 38-41 weeks, high sensitivity ( > 80%) could be obtained when a pass-fail criterion involving analysis of emission reproducibility, or emission reproducibility and emission response level, was set. Sensitivity was reduced for special care neonates who fell outside this age range. Specificity was found to be relatively low overall (always < 65%) and may relate to clinical factors in special care neonates not investigated in this study.

Otoacoustic emission findings in Rett syndrome.

Rett syndrome is a neurologic disorder affecting mainly females after a seemingly normal 6 to 18 months of life. The resulting developmental disabilities include apparent dementia and loss of acquired language, social skills, and purposeful hand use. The present investigation assessed 10 individuals with Rett syndrome and a control group matched for age and sex. The present study aimed to determine the clinical feasibility of obtaining otoacoustic emissions (OAEs) from the Rett syndrome group and to compare the characteristics of the transient evoked and distortion-product OAEs obtained from the two subject groups. Results indicated that OAE evaluation is a clinically feasible method of assessing individuals with Rett syndrome. The Rett syndrome group had less robust OAEs, especially in the higher frequencies, when compared to the control group. Seven of the Rett syndrome group were identified as having reduced or absent OAEs in at least one ear. These findings suggest a need for hearing screening at an early age and monitoring of hearing on a regular basis.

Effects of background noise on click-evoked otoacoustic emissions.

OBJECTIVE: To investigate the effect of increased levels of background noise on click-evoked otoacoustic emission (CEOAE) recordings and to compare the effectiveness of the default CEOAE program with the QuickScreen CEOAE program in increased levels of noise, using an Otodynamics ILO88 recording device. DESIGN: The right ears of 40 young adult women with normal hearing were assessed using CEOAEs under four different noise conditions and with two different methods of data collection. The noise conditions were in quiet, 50 dB A, 55 dB A, and 60 dB A of white noise. Data were collected at each noise level in the default mode and also using the ILO88 QuickScreen program. RESULTS: There was a significant change in a number of important CEOAE output parameters with increased noise. In the default mode, mean whole wave reproducibility was 89.2% in quiet but declined to 85% with 50 dB A of white noise, 65% at 55 dB A and 20% at 60 dB A. The QuickScreen program proved more robust to the effects of noise than the default. In that mode, mean whole wave reproducibility was 91.7% in quiet, 92.5% with 50 dB A of white noise, 82.5% at 55 dB A and 45% at 60 dB A. CONCLUSIONS: The findings of the study indicate ambient noise levels for accurate CEOAE recording should not exceed 50 to 55 dB A of noise and alternatives to the default program should be considered in non-sound-treated situations.

Infant hearing screening: a comparison of two techniques.

Hearing screening programs for Australian children are known to have poor coverage in many areas. In addition, only a minority of children are screened for hearing loss before 2 years of age. However, early detection of hearing loss and early treatment are generally considered very important to successful rehabilitation outcomes. Traditional methods of screening infants have limitations with their accuracy in detecting children with hearing loss. This study compared the results obtained with a traditional questionnaire approach to screening and a newer objective technique involving otoacoustic emission measures. Poor correlation was found between pass rates for the two techniques, suggesting that the questionnaire approach is not an accurate screening method for detecting infant hearing loss. With further development, otoacoustic emission testing holds promise as an objective alternative hearing screening procedure.

Feasibility of community-based hearing screening using transient evoked otoacoustic emissions.

This study investigated the feasibility of obtaining transient evoked otoacoustic emissions for hearing screening purposes from infants and children at seven child health clinics. Factors affecting the outcomes of the community hearing screening program were examined. The subject group comprised 2305 children aged two weeks to 11 y 11 mon. Many children were attending the clinics for initial immunisation at two months of age. While there were no exclusion criteria for the 1305 young infants tested who were in this category, all other children were screened only upon receipt of a referral from clinic nurses. Results indicated that 182 children (7.9%) did not complete the screening for both ears within the time constraint (usually 15 min) of a child health clinic visit. Three hundred and sixty-two children (15.7%) failed the first screening. Of the 226 children who returned for a second screening test, separated from the first by at least two weeks, 121 children failed. With parents' consent, 107 children (4.6% of all participants) were referred for diagnostic or medical assessment. Subsequently, 77 out of 94 children who received audiological or medical assessment were found to have some degree of hearing impairment. The majority of positive screening results were associated with middle ear disorder. The results suggest that TEOAE screening has potential as a technique in the community health setting but improvements in instrumentation are required to reduce 'could not test' cases and to separate probable conductive hearing loss from cases likely to have other disorders.