Ear-EEG Measures of Auditory Attention to Continuous Speech.

Auditory attention is an important cognitive function used to separate relevant from irrelevant auditory information. However, most findings on attentional selection have been obtained in highly controlled laboratory settings using bulky recording setups and unnaturalistic stimuli. Recent advances in electroencephalography (EEG) facilitate the measurement of brain activity outside the laboratory, and around-the-ear sensors such as the cEEGrid promise unobtrusive acquisition. In parallel, methods such as speech envelope tracking, intersubject correlations and spectral entropy measures emerged which allow us to study attentional effects in the neural processing of natural, continuous auditory scenes. In the current study, we investigated whether these three attentional measures can be reliably obtained when using around-the-ear EEG. To this end, we analyzed the cEEGrid data of 36 participants who attended to one of two simultaneously presented speech streams. Speech envelope tracking results confirmed a reliable identification of the attended speaker from cEEGrid data. The accuracies in identifying the attended speaker increased when fitting the classification model to the individual. Artifact correction of the cEEGrid data with artifact subspace reconstruction did not increase the classification accuracy. Intersubject correlations were higher for those participants attending to the same speech stream than for those attending to different speech streams, replicating previously obtained results with high-density cap-EEG. We also found that spectral entropy decreased over time, possibly reflecting the decrease in the listener's level of attention. Overall, these results support the idea of using ear-EEG measurements to unobtrusively monitor auditory attention to continuous speech. This knowledge may help to develop assistive devices that support listeners separating relevant from irrelevant information in complex auditory environments.

Association of circulating short chain fatty acid levels with colorectal adenomas and colorectal cancer.

BACKGROUND & AIMS: Short chain fatty acid (SCFAs) are bacterially derived metabolites suggested to have protective roles against colorectal cancer (CRC) development. However, there is sparse evidence from epidemiological studies in this context. Here, we assessed whether circulating SCFA concentrations varied in patients with colorectal adenomas (CRA) and CRC. METHODS: Levels of seven SCFAs were extracted from plasma samples and determined by gas chromatography for 213 individuals from Ireland and the Czech Republic (CRC, n = 84; CRA, n = 66; controls, n = 63). RESULTS: In the Irish CRA/CRC cohort, only levels of 2-MethylButyric acid were significantly higher in cancers compared to the adenoma and control groups (p-values = 0.016 and 0.043). Using regression analysis, we observed that levels of Acetic and Propionic acid were associated with an increased CRC risk in the Czech cohort (Odd Ratio (OR): 1.02; 95% Confidence interval (CI): 1.00-1.03; OR: 1.29; 95% CI: 1.05-1.59, respectively), while i-Valeric and Valeric acid levels were associated with a decreased cancer risk (OR: 0.92; 95% CI: 0.86-0.99; OR: 0.67; 95% CI: 0.44-1.00). In the Irish cohort, levels of SCFAs were not associated with CRC risk. CONCLUSIONS: The association with colorectal neoplasia varied between the studied SCFAs. Future studies need to confirm these findings and address the mechanism of how these acids may promote or prevent colorectal carcinogenesis.

Are They Calling My Name? Attention Capture Is Reflected in the Neural Tracking of Attended and Ignored Speech.

Difficulties in selectively attending to one among several speakers have mainly been associated with the distraction caused by ignored speech. Thus, in the current study, we investigated the neural processing of ignored speech in a two-competing-speaker paradigm. For this, we recorded the participant's brain activity using electroencephalography (EEG) to track the neural representation of the attended and ignored speech envelope. To provoke distraction, we occasionally embedded the participant's first name in the ignored speech stream. Retrospective reports as well as the presence of a P3 component in response to the name indicate that participants noticed the occurrence of their name. As predicted, the neural representation of the ignored speech envelope increased after the name was presented therein, suggesting that the name had attracted the participant's attention. Interestingly, in contrast to our hypothesis, the neural tracking of the attended speech envelope also increased after the name occurrence. On this account, we conclude that the name might not have primarily distracted the participants, at most for a brief duration, but that it alerted them to focus to their actual task. These observations remained robust even when the sound intensity of the ignored speech stream, and thus the sound intensity of the name, was attenuated.

Decoding the Attended Speaker From EEG Using Adaptive Evaluation Intervals Captures Fluctuations in Attentional Listening.

Listeners differ in their ability to attend to a speech stream in the presence of a competing sound. Differences in speech intelligibility in noise cannot be fully explained by the hearing ability which suggests the involvement of additional cognitive factors. A better understanding of the temporal fluctuations in the ability to pay selective auditory attention to a desired speech stream may help in explaining these variabilities. In order to better understand the temporal dynamics of selective auditory attention, we developed an online auditory attention decoding (AAD) processing pipeline based on speech envelope tracking in the electroencephalogram (EEG). Participants had to attend to one audiobook story while a second one had to be ignored. Online AAD was applied to track the attention toward the target speech signal. Individual temporal attention profiles were computed by combining an established AAD method with an adaptive staircase procedure. The individual decoding performance over time was analyzed and linked to behavioral performance as well as subjective ratings of listening effort, motivation, and fatigue. The grand average attended speaker decoding profile derived in the online experiment indicated performance above chance level. Parameters describing the individual AAD performance in each testing block indicated significant differences in decoding performance over time to be closely related to the behavioral performance in the selective listening task. Further, an exploratory analysis indicated that subjects with poor decoding performance reported higher listening effort and fatigue compared to good performers. Taken together our results show that online EEG based AAD in a complex listening situation is feasible. Adaptive attended speaker decoding profiles over time could be used as an objective measure of behavioral performance and listening effort. The developed online processing pipeline could also serve as a basis for future EEG based near real-time auditory neurofeedback systems.

Toward Decoding Selective Attention From Single-Trial EEG Data in Cochlear Implant Users.

Previous results showed that it is possible to decode an attended speech source from EEG data via the reconstruction of the speech envelope in normal hearing (NH) listeners. However, so far it is unknown that how the performance of such a decoder is affected by the decrease in spectral resolution and the electrical artifacts introduced by a cochlear implant (CI) in users of these prostheses. NH listeners and bilateral CI users participated in the present study. Speeches from two audio books, one uttered by a male voice and one by a female voice, were presented to NH listeners and CI users. Participants were instructed to attend to one of the two speech streams presented dichotically while a 96-channel EEG was recorded. Speech envelope reconstruction from the EEG data was obtained by training decoders using a regularized least square estimation method. Decoding accuracy was defined as the percentage of accurately reconstructed trials for each subject. For NH listeners, the experiment was repeated using a vocoder to reduce spectral resolution and simulate speech perception with a CI in NH listeners. The results showed a decoding accuracy of 80.9 % using the original sound files in NH listeners. The performance dropped to 73.2 % in the vocoder condition and to 71.5 % in the group of CI users. In sum, although the accuracy drops when the spectral resolution becomes worse, the results show the feasibility to decode the attended sound source in NH listeners with a vocoder simulation, and even in CI users, albeit more training data are needed.

Decoding Selective Attention in Normal Hearing Listeners and Bilateral Cochlear Implant Users With Concealed Ear EEG.

Electroencephalography (EEG) data can be used to decode an attended speech source in normal-hearing (NH) listeners using high-density EEG caps, as well as around-the-ear EEG devices. The technology may find application in identifying the target speaker in a cocktail party like scenario and steer speech enhancement algorithms in cochlear implants (CIs). However, the worse spectral resolution and the electrical artifacts introduced by a CI may limit the applicability of this approach to CI users. The goal of this study was to investigate whether selective attention can be decoded in CI users using an around-the-ear EEG system (cEEGrid). The performances of high-density cap EEG recordings and cEEGrid EEG recordings were compared in a selective attention paradigm using an envelope tracking algorithm. Speech from two audio books was presented through insert earphones to NH listeners and via direct audio cable to the CI users. 10 NH listeners and 10 bilateral CI users participated in the study. Participants were instructed to attend to one out of the two concurrent speech streams while data were recorded by a 96-channel scalp EEG and an 18-channel cEEGrid setup simultaneously. Reconstruction performance was evaluated by means of parametric correlations between the reconstructed speech and both, the envelope of the attended and the unattended speech stream. Results confirm the feasibility to decode selective attention by means of single-trial EEG data in NH and CI users using a high-density EEG. All NH listeners and 9 out of 10 CI achieved high decoding accuracies. The cEEGrid was successful in decoding selective attention in 5 out of 10 NH listeners. The same result was obtained for CI users.

Hearing-impaired listeners show increased audiovisual benefit when listening to speech in noise.

Recent studies provide evidence for changes in audiovisual perception as well as for adaptive cross-modal auditory cortex plasticity in older individuals with high-frequency hearing impairments (presbycusis). We here investigated whether these changes facilitate the use of visual information, leading to an increased audiovisual benefit of hearing-impaired individuals when listening to speech in noise. We used a naturalistic design in which older participants with a varying degree of high-frequency hearing loss attended to running auditory or audiovisual speech in noise and detected rare target words. Passages containing only visual speech served as a control condition. Simultaneously acquired scalp electroencephalography (EEG) data were used to study cortical speech tracking. Target word detection accuracy was significantly increased in the audiovisual as compared to the auditory listening condition. The degree of this audiovisual enhancement was positively related to individual high-frequency hearing loss and subjectively reported listening effort in challenging daily life situations, which served as a subjective marker of hearing problems. On the neural level, the early cortical tracking of the speech envelope was enhanced in the audiovisual condition. Similar to the behavioral findings, individual differences in the magnitude of the enhancement were positively associated with listening effort ratings. Our results therefore suggest that hearing-impaired older individuals make increased use of congruent visual information to compensate for the degraded auditory input.

Effects of directional sound processing and listener's motivation on EEG responses to continuous noisy speech: Do normal-hearing and aided hearing-impaired listeners differ?

OBJECTIVE: It has been suggested that the next major advancement in hearing aid (HA) technology needs to include cognitive feedback from the user to control HA functionality. In order to enable automatic brainwave-steered HA adjustments, attentional processes underlying speech-in-noise perception in aided hearing-impaired individuals need to be better understood. Here, we addressed the influence of two important factors for the listening performance of HA users - hearing aid processing and motivation - by analysing ongoing neural responses during long-term listening to continuous noisy speech. METHODS: Sixteen normal-hearing (NH) and 15 linearly aided hearing-impaired (aHI) participants listened to an audiobook recording embedded in realistic speech babble noise at individually adjusted signal-to-noise ratios (SNRs). A HA simulator was used for simulating a directional microphone setting as well as for providing individual amplification. To assess listening performance behaviourally, participants answered questions about the contents of the audiobook. We manipulated (1) the participants' motivation by offering a monetary reward for good listening performance in one half of the measurements and (2) the SNR by engaging/disengaging the directional microphone setting. During the speech-in-noise task, electroencephalography (EEG) signals were recorded using wireless, mobile hardware. EEG correlates of listening performance were investigated using EEG impulse responses, as estimated using the cross-correlation between the recorded EEG signal and the temporal envelope of the audiobook at the output of the HA simulator. RESULTS: At the behavioural level, we observed better performance for the NH listeners than for the aHI listeners. Furthermore, the directional microphone setting led to better performance for both participant groups, and when the directional microphone setting was disengaged motivation also improved the performance of the aHI participants. Analysis of the EEG impulse responses showed faster N1P2 responses for both groups and larger N2 peak amplitudes for the aHI group when the directional microphone setting was activated, but no physiological correlates of motivation. SIGNIFICANCE: The results of this study indicate that motivation plays an important role for speech understanding in noise. In terms of neuro-steered HAs, our results suggest that the latency of attentional processes is influenced by HA-induced stimulus changes, which can potentially be used for inferring benefit from noise suppression processing automatically. Further research is necessary to identify the neural correlates of motivation as an exclusive top-down process and to combine such features with HA-driven ones for online HA adjustments.

Impact of Different Acoustic Components on EEG-Based Auditory Attention Decoding in Noisy and Reverberant Conditions.

Identifying the target speaker in hearing aid applications is an essential ingredient to improve speech intelligibility. Recently, a least-squares-based method has been proposed to identify the attended speaker from single-trial EEG recordings for an acoustic scenario with two competing speakers. This least-squares-based auditory attention decoding (AAD) method aims at decoding auditory attention by reconstructing the attended speech envelope from the EEG recordings using a trained spatio-temporal filter. While the performance of this AAD method has been mainly studied for noiseless and anechoic acoustic conditions, it is important to fully understand its performance in realistic noisy and reverberant acoustic conditions. In this paper, we investigate AAD using EEG recordings for different acoustic conditions (anechoic, reverberant, noisy, and reverberant-noisy). In particular, we investigate the impact of different acoustic conditions for AAD filter training and for decoding. In addition, we investigate the influence on the decoding performance of the different acoustic components (i.e., reverberation, background noise, and interfering speaker) in the reference signals used for decoding and the training signals used for computing the filters. First, we found that for all considered acoustic conditions it is possible to decode auditory attention with a considerably large decoding performance. In particular, even when the acoustic conditions for AAD filter training and for decoding are different, the decoding performance is still comparably large. Second, when using speech signals affected by either reverberation and/or background noise there is no significant difference in decoding performance ( ) compared to when using clean speech signals as reference signals. In contrast, when using reference signals affected by the interfering speaker, the decoding performance significantly decreases. Third, the experimental results indicate that it is even feasible to use training signals affected by reverberation, background noise and/or the interfering speaker for computing the filters.

Anaerobic bacteria cultured from cystic fibrosis airways correlate to milder disease: a multisite study.

Anaerobic and aerobic bacteria were quantitated in respiratory samples across three cystic fibrosis (CF) centres using extended culture methods. Subjects aged 1-69 years who were clinically stable provided sputum (n=200) or bronchoalveolar lavage (n=55). 18 anaerobic and 39 aerobic genera were cultured from 59% and 95% of samples, respectively; 16 out of 57 genera had a ≥5% prevalence across centres.Analyses of microbial communities using co-occurrence networks in sputum samples showed groupings of oral, including anaerobic, bacteria, whereas typical CF pathogens formed distinct entities. Pseudomonas was associated with worse nutrition and F508del genotype, whereas anaerobe prevalence was positively associated with pancreatic sufficiency, better nutrition and better lung function. A higher total anaerobe/total aerobe CFU ratio was associated with pancreatic sufficiency and better nutrition. Subjects grouped by factor analysis who had relative dominance of anaerobes over aerobes had milder disease compared with a Pseudomonas-dominated group with similar proportions of subjects that were homozygous for F508del.In summary, anaerobic bacteria occurred at an early age. In sputum-producing subjects anaerobic bacteria were associated with milder disease, suggesting that targeted eradication of anaerobes may not be warranted in sputum-producing CF subjects.

Did You Listen to the Beat? Auditory Steady-State Responses in the Human Electroencephalogram at 4 and 7 Hz Modulation Rates Reflect Selective Attention.

The acoustic envelope of human speech correlates with the syllabic rate (4-8 Hz) and carries important information for intelligibility, which is typically compromised in multi-talker, noisy environments. In order to better understand the dynamics of selective auditory attention to low frequency modulated sound sources, we conducted a two-stream auditory steady-state response (ASSR) selective attention electroencephalogram (EEG) study. The two streams consisted of 4 and 7 Hz amplitude and frequency modulated sounds presented from the left and right side. One of two streams had to be attended while the other had to be ignored. The attended stream always contained a target, allowing for the behavioral confirmation of the attention manipulation. EEG ASSR power analysis revealed a significant increase in 7 Hz power for the attend compared to the ignore conditions. There was no significant difference in 4 Hz power when the 4 Hz stream had to be attended compared to when it had to be ignored. This lack of 4 Hz attention modulation could be explained by a distracting effect of a third frequency at 3 Hz (beat frequency) perceivable when the 4 and 7 Hz streams are presented simultaneously. Taken together our results show that low frequency modulations at syllabic rate are modulated by selective spatial attention. Whether attention effects act as enhancement of the attended stream or suppression of to be ignored stream may depend on how well auditory streams can be segregated.

The Right Temporoparietal Junction Supports Speech Tracking During Selective Listening: Evidence from Concurrent EEG-fMRI.

Listening selectively to one out of several competing speakers in a "cocktail party" situation is a highly demanding task. It relies on a widespread cortical network, including auditory sensory, but also frontal and parietal brain regions involved in controlling auditory attention. Previous work has shown that, during selective listening, ongoing neural activity in auditory sensory areas is dominated by the attended speech stream, whereas competing input is suppressed. The relationship between these attentional modulations in the sensory tracking of the attended speech stream and frontoparietal activity during selective listening is, however, not understood. We studied this question in young, healthy human participants (both sexes) using concurrent EEG-fMRI and a sustained selective listening task, in which one out of two competing speech streams had to be attended selectively. An EEG-based speech envelope reconstruction method was applied to assess the strength of the cortical tracking of the to-be-attended and the to-be-ignored stream during selective listening. Our results show that individual speech envelope reconstruction accuracies obtained for the to-be-attended speech stream were positively correlated with the amplitude of sustained BOLD responses in the right temporoparietal junction, a core region of the ventral attention network. This brain region further showed task-related functional connectivity to secondary auditory cortex and regions of the frontoparietal attention network, including the intraparietal sulcus and the inferior frontal gyrus. This suggests that the right temporoparietal junction is involved in controlling attention during selective listening, allowing for a better cortical tracking of the attended speech stream.SIGNIFICANCE STATEMENT Listening selectively to one out of several simultaneously talking speakers in a "cocktail party" situation is a highly demanding task. It activates a widespread network of auditory sensory and hierarchically higher frontoparietal brain regions. However, how these different processing levels interact during selective listening is not understood. Here, we investigated this question using fMRI and concurrently acquired scalp EEG. We found that activation levels in the right temporoparietal junction correlate with the sensory representation of a selectively attended speech stream. In addition, this region showed significant functional connectivity to both auditory sensory and other frontoparietal brain areas during selective listening. This suggests that the right temporoparietal junction contributes to controlling selective auditory attention in "cocktail party" situations.

Addition of 2-(ethylamino)acetonitrile group to nitroxoline results in significantly improved anti-tumor activity in vitro and in vivo.

Lysosomal cysteine peptidase cathepsin B, involved in multiple processes associated with tumor progression, is validated as a target for anti-cancer therapy. Nitroxoline, a known antimicrobial agent, is a potent and selective inhibitor of cathepsin B, hence reducing tumor progression in vitro and in vivo. In order to further improve its anti-cancer properties we developed a number of derivatives using structure-based chemical synthesis. Of these, the 7-aminomethylated derivative (compound 17) exhibited significantly improved kinetic properties over nitroxoline, inhibiting cathepsin B endopeptidase activity selectively. In the present study, we have evaluated its anti-cancer properties. It was more effective than nitroxoline in reducing tumor cell invasion and migration, as determined in vitro on two-dimensional cell models and tumor spheroids, under either endpoint or real time conditions. Moreover, it exhibited improved action over nitroxoline in impairing tumor growth in vivo in LPB mouse fibrosarcoma tumors in C57Bl/6 mice. Taken together, the addition of a 2-(ethylamino)acetonitrile group to nitroxoline at position 7 significantly improves its pharmacological characteristics and its potential for use as an anti-cancer drug.

Identifying auditory attention with ear-EEG: cEEGrid versus high-density cap-EEG comparison.

OBJECTIVE: This study presents a direct comparison of a classical EEG cap setup with a new around-the-ear electrode array (cEEGrid) to gain a better understanding of the potential of ear-centered EEG. APPROACH: Concurrent EEG was recorded from a classical scalp EEG cap and two cEEGrids that were placed around the left and the right ear. Twenty participants performed a spatial auditory attention task in which three sound streams were presented simultaneously. The sound streams were three seconds long and differed in the direction of origin (front, left, right) and the number of beats (3, 4, 5 respectively), as well as the timbre and pitch. The participants had to attend to either the left or the right sound stream. MAIN RESULTS: We found clear attention modulated ERP effects reflecting the attended sound stream for both electrode setups, which agreed in morphology and effect size. A single-trial template matching classification showed that the direction of attention could be decoded significantly above chance (50%) for at least 16 out of 20 participants for both systems. The comparably high classification results of the single trial analysis underline the quality of the signal recorded with the cEEGrids. SIGNIFICANCE: These findings are further evidence for the feasibility of around the-ear EEG recordings and demonstrate that well described ERPs can be measured. We conclude that concealed behind-the-ear EEG recordings can be an alternative to classical cap EEG acquisition for auditory attention monitoring.

Target Speaker Detection with Concealed EEG Around the Ear.

Target speaker identification is essential for speech enhancement algorithms in assistive devices aimed toward helping the hearing impaired. Several recent studies have reported that target speaker identification is possible through electroencephalography (EEG) recordings. If the EEG system could be reduced to acceptable size while retaining the signal quality, hearing aids could benefit from the integration with concealed EEG. To compare the performance of a multichannel around-the-ear EEG system with high-density cap EEG recordings an envelope tracking algorithm was applied in a competitive speaker paradigm. The data from 20 normal hearing listeners were concurrently collected from the traditional state-of-the-art laboratory wired EEG system and a wireless mobile EEG system with two bilaterally-placed around-the-ear electrode arrays (cEEGrids). The results show that the cEEGrid ear-EEG technology captured neural signals that allowed the identification of the attended speaker above chance-level, with 69.3% accuracy, while cap-EEG signals resulted in the accuracy of 84.8%. Further analyses investigated the influence of ear-EEG signal quality and revealed that the envelope tracking procedure was unaffected by variability in channel impedances. We conclude that the quality of concealed ear-EEG recordings as acquired with the cEEGrid array has potential to be used in the brain-computer interface steering of hearing aids.

Chitinase activation in patients with fungus-associated cystic fibrosis lung disease.

BACKGROUND: Chitinases have recently gained attention in the field of pulmonary diseases, particularly in asthma and chronic obstructive pulmonary disease, but their potential role in patients with cystic fibrosis (CF)-associated lung disease remains unclear. OBJECTIVE: The aim of this study was to assess chitinase activity systemically and in the airways of patients with CF and asthma compared with healthy subjects. Additionally, we assessed factors that regulate chitinase activity within the lungs of patients with CF. METHODS: Chitinase activities were quantified in serum and bronchoalveolar lavage fluid from patients with CF, asthmatic patients, and healthy control subjects. Mechanistically, the role of CF airway proteases and genetic chitinase deficiency was assessed. RESULTS: Chitinase activity was systemically increased in patients with CF compared with that in healthy control subjects and asthmatic patients. Further stratification showed that chitinase activity was enhanced in patients with CF colonized with Candida albicans compared with that in noncolonized patients. CF proteases degraded chitinases in the airway microenvironment of patients with CF. Genetic chitinase deficiency was associated with C albicans colonization in patients with CF. CONCLUSION: Patients with CF have enhanced chitinase activation associated with C albicans colonization. Therefore chitinases might represent a novel biomarker and therapeutic target for CF-associated fungal disease.

Blood basophil activation is a reliable biomarker of allergic bronchopulmonary aspergillosis in cystic fibrosis.

The diagnosis of cystic fibrosis (CF) patients with allergic bronchopulmonary aspergillosis (ABPA) is clinically challenging, due to the absence of an objective biological test. Since blood basophils play a major role in allergic responses, we hypothesised that changes in their surface activation pattern discriminate between CF patients with and without ABPA.We conducted a prospective longitudinal study (Stanford cohort) comparing basophil activation test CD203c levels by flow cytometry before and after activation with Aspergillus fumigatus allergen extract or recombinant Asp f1 in 20 CF patients with ABPA (CF-ABPA) and in two comparison groups: CF patients with A. fumigatus colonisation (AC) but without ABPA (CF-AC; n=13) and CF patients without either AC or ABPA (CF; n=12). Patients were tested every 6 months and when ill with pulmonary exacerbation. We also conducted cross-sectional validation in a separate patient set (Dublin cohort).Basophil CD203c surface expression reliably discriminated CF-ABPA from CF-AC and CF over time. Ex vivo stimulation with A. fumigatus extract or recombinant Asp f1 produced similar results within the Stanford (p<0.0001) and the Dublin cohorts. CF-ABPA patients were likelier to have elevated specific IgE to A. fumigatus and were less frequently co-infected with Staphylococcus aureus.Basophil CD203c upregulation is a suitable diagnostic and stable monitoring biomarker of ABPA in CF.

Inhibition of endopeptidase and exopeptidase activity of cathepsin B impairs extracellular matrix degradation and tumour invasion.

Cathepsin B is a lysosomal cysteine protease that is implicated in a number of physiological processes, including protein turnover in lysosomes. Changes in its expression are associated with a variety of pathological processes, including cancer. Due to the structural feature, termed the occluding loop, cathepsin B differs from other cysteine proteases in possessing both, endopeptidase and exopeptidase activity. Here we investigated the impact of both cathepsin B activities on intracellular and extracellular collagen IV degradation and tumour cell invasion using new selective synthetic inhibitors, 2-{[(8-hydroxy-5-nitroquinoline-7-yl)methyl]amino}-acetonitrile (1), 8-(4-methylpiperidin-1-yl)-5-nitroquinoline (2) and 7-[(4-methylpiperidin-1yl)methyl]-5-nitroquinolin-8-ol (3). All three compounds (5 µM) reduced extracellular degradation of collagen IV by MCF-10A neoT cells by 45-70% as determined by spectrofluorimetry and they (50 µM) attenuated intracellular collagen IV degradation by 40-60% as measured with flow cytometry. Furthermore, all three compounds (5 µM) impaired MCF-10A neoT cell invasion by 40-80% as assessed by measuring electrical impedance in real time. Compounds 1 and 3 (5 µM), but not compound 2, significantly reduced the growth of MMTV-PyMT multicellular tumour spheroids. Collectively, these data suggest that the efficient strategy to impair harmful cathepsin B activity in tumour progression may include simultaneous and potent inhibition of cathepsin B endopeptidase and exopeptidase activities.

The basophil surface marker CD203c identifies Aspergillus species sensitization in patients with cystic fibrosis.

BACKGROUND: Colonization by Aspergillus fumigatus in patients with cystic fibrosis (CF) can cause A fumigatus sensitization and/or allergic bronchopulmonary aspergillosis (ABPA), which affects pulmonary function and clinical outcomes. Recent studies show that specific allergens upregulate the surface-expressed basophil marker CD203c in sensitized subjects, a response that can be readily measured by using flow cytometry. OBJECTIVE: We sought to identify A fumigatus sensitization in patients with CF by using the basophil activation test (BAT). METHODS: Patients with CF attending Beaumont Hospital were screened for study inclusion. BAT was used to identify A fumigatus sensitization. Serologic (total and A fumigatus-specific IgE), pulmonary function, and body mass index measurements were performed. RESULTS: The BAT discriminates A fumigatus-sensitized from nonsensitized patients with CF. Persistent isolation of A fumigatus in sputum is a significant risk factor for A fumigatus sensitization. Levels of the A fumigatus-stimulated basophil activation marker CD203c inversely correlated with pulmonary function and body mass index in A fumigatus-sensitized but not nonsensitized patients with CF. Total and A fumigatus-specific IgE, but not IgG, levels are increased in A fumigatus-sensitized patients with CF and ABPA when compared with those in A fumigatus-sensitized and nonsensitized patients with CF without ABPA. Itraconazole treatment did not affect A fumigatus sensitization. CONCLUSION: Combining the BAT with routine serologic testing allows classification of patients with CF into 3 groups: nonsensitized, A fumigatus-sensitized, and ABPA. Accurate and prompt identification of A fumigatus-associated clinical status might allow early and targeted therapeutic intervention, potentially improving clinical outcomes.