Pan-cancer analysis reveals CCL5/CSF2 as potential predictive biomarkers for immune checkpoint inhibitors.

BACKGROUND: Currently, there are no optimal biomarkers available for distinguishing patients who will respond to immune checkpoint inhibitors (ICIs) therapies. Consequently, the exploration of novel biomarkers that can predict responsiveness to ICIs is crucial in the field of immunotherapy. METHODS: We estimated the proportions of 22 immune cell components in 10 cancer types (6,128 tumors) using the CIBERSORT algorithm, and further classified patients based on their tumor immune cell proportions in a pan-cancer setting using k-means clustering. Differentially expressed immune genes between the patient subgroups were identified, and potential predictive biomarkers for ICIs were explored. Finally, the predictive value of the identified biomarkers was verified in patients with urothelial carcinoma (UC) and esophageal squamous cell carcinoma (ESCC) who received ICIs. RESULTS: Our study identified two subgroups of patients with distinct immune infiltrating phenotypes and differing clinical outcomes. The patient subgroup with improved outcomes displayed tumors enriched with genes related to immune response regulation and pathway activation. Furthermore, CCL5 and CSF2 were identified as immune-related hub-genes and were found to be prognostic in a pan-cancer setting. Importantly, UC and ESCC patients with high expression of CCL5 and low expression of CSF2 responded better to ICIs. CONCLUSION: We demonstrated CCL5 and CSF2 as potential novel biomarkers for predicting the response to ICIs in patients with UC and ESCC. The predictive value of these biomarkers in other cancer types warrants further evaluation in future studies.

Auditory-motor adaptation is reduced in adults who stutter but not in children who stutter.

Previous studies have shown that adults who stutter produce smaller corrective motor responses to compensate for unexpected auditory perturbations in comparison to adults who do not stutter, suggesting that stuttering may be associated with deficits in integration of auditory feedback for online speech monitoring. In this study, we examined whether stuttering is also associated with deficiencies in integrating and using discrepancies between expected and received auditory feedback to adaptively update motor programs for accurate speech production. Using a sensorimotor adaptation paradigm, we measured adaptive speech responses to auditory formant frequency perturbations in adults and children who stutter and their matched nonstuttering controls. We found that the magnitude of the speech adaptive response for children who stutter did not differ from that of fluent children. However, the adaptation magnitude of adults who stutter in response to auditory perturbation was significantly smaller than the adaptation magnitude of adults who do not stutter. Together these results indicate that stuttering is associated with deficits in integrating discrepancies between predicted and received auditory feedback to calibrate the speech production system in adults but not children. This auditory-motor integration deficit thus appears to be a compensatory effect that develops over years of stuttering.

Auditory feedback control in adults who stutter during metronome-paced speech I. Timing Perturbation.

PURPOSE: This study determined whether adults who stutter (AWS) exhibit deficits in responding to an auditory feedback timing perturbation, and whether external timing cues, which increase fluency, attenuate any disruptions due to altered temporal auditory feedback. METHODS: Fifteen AWS and sixteen adults who do not stutter (ANS) read aloud a multisyllabic sentence either with normal pacing or with each syllable paced at the rate of a metronome. On random trials, an auditory feedback timing perturbation was applied, and timing responses were compared between groups and pacing conditions. RESULTS: Both groups responded to the timing perturbation by delaying subsequent syllable boundaries, and there were no significant differences between groups in either pacing condition. Furthermore, no response differences were found between normally paced and metronome-paced conditions. CONCLUSION: These findings are interpreted as showing that 1) AWS respond normally to pure timing perturbations, and 2) metronome-paced speech has no effect on online speech timing control as assessed in the present experiment.

Focal manipulations of formant trajectories reveal a role of auditory feedback in the online control of both within-syllable and between-syllable speech timing.

Within the human motor repertoire, speech production has a uniquely high level of spatiotemporal complexity. The production of running speech comprises the traversing of spatial positions with precisely coordinated articulator movements to produce 10-15 sounds/s. How does the brain use auditory feedback, namely the self-perception of produced speech sounds, in the online control of spatial and temporal parameters of multisyllabic articulation? This question has important bearings on the organizational principles of sequential actions, yet its answer remains controversial due to the long latency of the auditory feedback pathway and technical challenges involved in manipulating auditory feedback in precisely controlled ways during running speech. In this study, we developed a novel technique for introducing time-varying, focal perturbations in the auditory feedback during multisyllabic, connected speech. Manipulations of spatial and temporal parameters of the formant trajectory were tested separately on two groups of subjects as they uttered "I owe you a yo-yo." Under these perturbations, significant and specific changes were observed in both the spatial and temporal parameters of the produced formant trajectories. Compensations to spatial perturbations were bidirectional and opposed the perturbations. Furthermore, under perturbations that manipulated the timing of auditory feedback trajectory (slow-down or speed-up), significant adjustments in syllable timing were observed in the subjects' productions. These results highlight the systematic roles of auditory feedback in the online control of a highly over-learned action as connected speech articulation and provide a first look at the properties of this type of sensorimotor interaction in sequential movements.

Auditory feedback control in adults who stutter during metronome-paced speech II. Formant Perturbation.

PURPOSE: Prior work has shown that Adults who stutter (AWS) have reduced and delayed responses to auditory feedback perturbations. This study aimed to determine whether external timing cues, which increase fluency, resolve auditory feedback processing disruptions. METHODS: Fifteen AWS and sixteen adults who do not stutter (ANS) read aloud a multisyllabic sentence either with natural stress and timing or with each syllable paced at the rate of a metronome. On random trials, an auditory feedback formant perturbation was applied, and formant responses were compared between groups and pacing conditions. RESULTS: During normally paced speech, ANS showed a significant compensatory response to the perturbation by the end of the perturbed vowel, while AWS did not. In the metronome-paced condition, which significantly reduced the disfluency rate, the opposite was true: AWS showed a significant response by the end of the vowel, while ANS did not. CONCLUSION: These findings indicate a potential link between the reduction in stuttering found during metronome-paced speech and changes in auditory motor integration in AWS.

Improvement of the fast simulation of gamma-gamma density well logging measurement.

The fast modeling of gamma-gamma density well logging is essential for the inversion techniques of formation properties, which is usually carried out jointly with other logging measurements such as electrical logging. It also can help to adjust the initial geological model in real time during geosteering. The Monte Carlo method is the foremost numerical technique to simulate gamma-gamma density logging measurement. But due to its slow speed, it is not sufficient for inversion or real-time forward modeling. An algorithm to achieve the fast simulation of density logging response is introduced. In the algorithm, a new approximation model is proposed to enable accurate forward modeling of density logging with better efficiency. The Monte Carlo simulation method is utilized as a benchmark to validate the performance of the fast simulation method. The density logging responses under vertical and high-angle well conditions are simulated. The results of the fast simulation show a good agreement with the Monte Carlo simulations in vertical and high-angle wells. In addition, the comparison of density imaging data also confirmed the accuracy of the fast simulation method.

The Neural Circuitry Underlying the "Rhythm Effect" in Stuttering.

Purpose Stuttering is characterized by intermittent speech disfluencies, which are dramatically reduced when speakers synchronize their speech with a steady beat. The goal of this study was to characterize the neural underpinnings of this phenomenon using functional magnetic resonance imaging. Method Data were collected from 16 adults who stutter and 17 adults who do not stutter while they read sentences aloud either in a normal, self-paced fashion or paced by the beat of a series of isochronous tones ("rhythmic"). Task activation and task-based functional connectivity analyses were carried out to compare neural responses between speaking conditions and groups after controlling for speaking rate. Results Adults who stutter produced fewer disfluent trials in the rhythmic condition than in the normal condition. Adults who stutter did not have any significant changes in activation between the rhythmic condition and the normal condition, but when groups were collapsed, participants had greater activation in the rhythmic condition in regions associated with speech sequencing, sensory feedback control, and timing perception. Adults who stutter also demonstrated increased functional connectivity among cerebellar regions during rhythmic speech as compared to normal speech and decreased connectivity between the left inferior cerebellum and the left prefrontal cortex. Conclusions Modulation of connectivity in the cerebellum and prefrontal cortex during rhythmic speech suggests that this fluency-inducing technique activates a compensatory timing system in the cerebellum and potentially modulates top-down motor control and attentional systems. These findings corroborate previous work associating the cerebellum with fluency in adults who stutter and indicate that the cerebellum may be targeted to enhance future therapeutic interventions. Supplemental Material https://doi.org/10.23641/asha.14417681.

Adaptive auditory feedback control of the production of formant trajectories in the Mandarin triphthong /iau/ and its pattern of generalization.

In order to test whether auditory feedback is involved in the planning of complex articulatory gestures in time-varying phonemes, the current study examined native Mandarin speakers' responses to auditory perturbations of their auditory feedback of the trajectory of the first formant frequency during their production of the triphthong /iau/. On average, subjects adaptively adjusted their productions to partially compensate for the perturbations in auditory feedback. This result indicates that auditory feedback control of speech movements is not restricted to quasi-static gestures in monophthongs as found in previous studies, but also extends to time-varying gestures. To probe the internal structure of the mechanisms of auditory-motor transformations, the pattern of generalization of the adaptation learned on the triphthong /iau/ to other vowels with different temporal and spatial characteristics (produced only under masking noise) was tested. A broad but weak pattern of generalization was observed; the strength of the generalization diminished with increasing dissimilarity from /iau/. The details and implications of the pattern of generalization are examined and discussed in light of previous sensorimotor adaptation studies of both speech and limb motor control and a neurocomputational model of speech motor control.

Changes of serum trace elements in early stage trauma and its correlation with injury severity score.

BACKGROUND: Severe trauma can cause secondary multiple organ dysfunction syndrome and death. The absolute and relative concentrations of trace elements in both critical care and conventional treatment, which can lead to acute trace element deficiency, constitute an important mechanism of multiple organ dysfunction syndrome (MODS)/multiple organ failure (MOF). METHODS: We investigated the changes in serum Cu, Zn, and Fe in early stage trauma of patients with the high injury severity score (ISS) and correlated the change in trace elements with ISS. Blood samples were collected within an hour of admittance and the patients were scored according to ISS. We collected clinical data records and ISS score values, and determined serum Fe, Zn, and Cu by inductively coupled plasma mass spectrometry. RESULTS: Compared with the control group, the serum Zn and Fe values of trauma patients were decreased. There was no significant difference in serum Cu between the patients and the control group. In the trauma group, the serum Zn and Fe were lower than that of the minor injury group, and the difference of Cu concentration was not statistically significant. CONCLUSIONS: Serum Zn and Fe levels in patients with multiple trauma fractures were significantly different than those in the normal group, suggesting that Zn and Fe need to be monitored in the early stage of trauma.

Psychophysics of reading with a limited number of pixels: towards the rehabilitation of reading ability with visual prosthesis.

Psychophysics of reading with limited numbers of pixels has received increasing attention as the envisioned visual prosthesis offers a possibility to restore some useful reading ability to the blind through the pixelized vision it generates. This paper systematically studied how several important parameters of pixelized vision affect reading performance. A closed-circuit television reading platform with digital image processing capacities was developed to convert images of printed text into pixelized patterns made up of discrete dots. Reading rates in six normally sighted subjects were measured under different combinations of pixel number, window width, and angular subtense of pixel array. The results showed that reading is possible with as few as 6 x 6 binary pixels, at 15 words/min. It was also found that for a given array of pixels, maximum reading rates occur at a specific medium window width, due to a tradeoff between window width and character sampling resolution. It was also observed that pixelized reading exhibits more significant scale dependence than normal vision. Reading rates were decreased by increasing the angular subtense of the pixel array while keeping other parameters fixed. We hope these results will be helpful to the design of visual prosthesis for the rehabilitation of reading abilities.

Decreased Cerebellar-Orbitofrontal Connectivity Correlates with Stuttering Severity: Whole-Brain Functional and Structural Connectivity Associations with Persistent Developmental Stuttering.

Persistent developmental stuttering is characterized by speech production disfluency and affects 1% of adults. The degree of impairment varies widely across individuals and the neural mechanisms underlying the disorder and this variability remain poorly understood. Here we elucidate compensatory mechanisms related to this variability in impairment using whole-brain functional and white matter connectivity analyses in persistent developmental stuttering. We found that people who stutter had stronger functional connectivity between cerebellum and thalamus than people with fluent speech, while stutterers with the least severe symptoms had greater functional connectivity between left cerebellum and left orbitofrontal cortex (OFC). Additionally, people who stutter had decreased functional and white matter connectivity among the perisylvian auditory, motor, and speech planning regions compared to typical speakers, but greater functional connectivity between the right basal ganglia and bilateral temporal auditory regions. Structurally, disfluency ratings were negatively correlated with white matter connections to left perisylvian regions and to the brain stem. Overall, we found increased connectivity among subcortical and reward network structures in people who stutter compared to controls. These connections were negatively correlated with stuttering severity, suggesting the involvement of cerebellum and OFC may underlie successful compensatory mechanisms by more fluent stutterers.

Responses to Intensity-Shifted Auditory Feedback During Running Speech.

PURPOSE: Responses to intensity perturbation during running speech were measured to understand whether prosodic features are controlled in an independent or integrated manner. METHOD: Nineteen English-speaking healthy adults (age range = 21-41 years) produced 480 sentences in which emphatic stress was placed on either the 1st or 2nd word. One participant group received an upward intensity perturbation during stressed word production, and the other group received a downward intensity perturbation. Compensations for perturbation were evaluated by comparing differences in participants' stressed and unstressed peak fundamental frequency (F0), peak intensity, and word duration during perturbed versus baseline trials. RESULTS: Significant increases in stressed-unstressed peak intensities were observed during the ramp and perturbation phases of the experiment in the downward group only. Compensations for F0 and duration did not reach significance for either group. CONCLUSIONS: Consistent with previous work, speakers appear sensitive to auditory perturbations that affect a desired linguistic goal. In contrast to previous work on F0 perturbation that supported an integrated-channel model of prosodic control, the current work only found evidence for intensity-specific compensation. This discrepancy may suggest different F0 and intensity control mechanisms, threshold-dependent prosodic modulation, or a combined control scheme.

Impaired timing adjustments in response to time-varying auditory perturbation during connected speech production in persons who stutter.

Auditory feedback (AF), the speech signal received by a speaker's own auditory system, contributes to the online control of speech movements. Recent studies based on AF perturbation provided evidence for abnormalities in the integration of auditory error with ongoing articulation and phonation in persons who stutter (PWS), but stopped short of examining connected speech. This is a crucial limitation considering the importance of sequencing and timing in stuttering. In the current study, we imposed time-varying perturbations on AF while PWS and fluent participants uttered a multisyllabic sentence. Two distinct types of perturbations were used to separately probe the control of the spatial and temporal parameters of articulation. While PWS exhibited only subtle anomalies in the AF-based spatial control, their AF-based fine-tuning of articulatory timing was substantially weaker than normal, especially in early parts of the responses, indicating slowness in the auditory-motor integration for temporal control.

Diffusion imaging of cerebral white matter in persons who stutter: evidence for network-level anomalies.

Deficits in brain white matter have been a main focus of recent neuroimaging studies on stuttering. However, no prior study has examined brain connectivity on the global level of the cerebral cortex in persons who stutter (PWS). In the current study, we analyzed the results from probabilistic tractography between regions comprising the cortical speech network. An anatomical parcellation scheme was used to define 28 speech production-related ROIs in each hemisphere. We used network-based statistic (NBS) and graph theory to analyze the connectivity patterns obtained from tractography. At the network-level, the probabilistic corticocortical connectivity from the PWS group were significantly weaker than that from persons with fluent speech (PFS). NBS analysis revealed significant components in the bilateral speech networks with negative correlations with stuttering severity. To facilitate comparison with previous studies, we also performed tract-based spatial statistics (TBSS) and regional fractional anisotropy (FA) averaging. Results from tractography, TBSS and regional FA averaging jointly highlight the importance of several regions in the left peri-Rolandic sensorimotor and premotor areas, most notably the left ventral premotor cortex (vPMC) and middle primary motor cortex, in the neuroanatomical basis of stuttering.

Weak responses to auditory feedback perturbation during articulation in persons who stutter: evidence for abnormal auditory-motor transformation.

Previous empirical observations have led researchers to propose that auditory feedback (the auditory perception of self-produced sounds when speaking) functions abnormally in the speech motor systems of persons who stutter (PWS). Researchers have theorized that an important neural basis of stuttering is the aberrant integration of auditory information into incipient speech motor commands. Because of the circumstantial support for these hypotheses and the differences and contradictions between them, there is a need for carefully designed experiments that directly examine auditory-motor integration during speech production in PWS. In the current study, we used real-time manipulation of auditory feedback to directly investigate whether the speech motor system of PWS utilizes auditory feedback abnormally during articulation and to characterize potential deficits of this auditory-motor integration. Twenty-one PWS and 18 fluent control participants were recruited. Using a short-latency formant-perturbation system, we examined participants' compensatory responses to unanticipated perturbation of auditory feedback of the first formant frequency during the production of the monophthong [ε]. The PWS showed compensatory responses that were qualitatively similar to the controls' and had close-to-normal latencies (∼150 ms), but the magnitudes of their responses were substantially and significantly smaller than those of the control participants (by 47% on average, p<0.05). Measurements of auditory acuity indicate that the weaker-than-normal compensatory responses in PWS were not attributable to a deficit in low-level auditory processing. These findings are consistent with the hypothesis that stuttering is associated with functional defects in the inverse models responsible for the transformation from the domain of auditory targets and auditory error information into the domain of speech motor commands.

Encoding intensity in ventral cochlear nucleus following acoustic trauma: implications for loudness recruitment.

Loudness recruitment, an abnormally rapid growth of perceived loudness with sound level, is a common symptom of sensorineural hearing loss. Following acoustic trauma, auditory-nerve rate responses are reduced, and rate grows more slowly with sound level, which seems inconsistent with recruitment (Heinz et al., J. Assoc. Res. Otolaryngol. 6:91-105, 2005). However, rate-level functions (RLFs) in the central nervous system may increase in either slope or saturation value following trauma (e.g., Salvi et al., Hear. Res. 147:261-274, 2000), suggesting that recruitment may arise from central changes. In this paper, we studied RLFs of neurons in ventral cochlear nucleus (VCN) of the cat after acoustic trauma. Trauma did not change the general properties of VCN neurons, and the usual VCN functional classifications remained valid (chopper, primary-like, onset, etc.). After trauma, non-primary-like neurons, most noticeably choppers, exhibited elevated maximum discharge rates and steeper RLFs for frequencies at and near best frequency (BF). Primary-like neurons showed the opposite changes. To relate the neurons' responses to recruitment, rate-balance functions were computed; these show the sound level required to give equal rates in a normal and a traumatized ear and are analogous to loudness balance functions that show the sound levels giving equal perceptual loudness in the two ears of a monaurally hearing-impaired person. The rate-balance functions showed recruitment-like steepening of their slopes in non-primary-like neurons in all conditions. However, primary-like neurons showed recruitment-like behavior only when rates were summated across neurons of all BFs. These results suggest that the non-primary-like, especially chopper, neurons may be the most peripheral site of the physiological changes in the brain that underlie recruitment.