The Paradoxical Roles of Inflammation during PD-1 Blockade in Cancer.

Recent studies have reported paradoxical roles of inflammation in tumor immunity triggered by PD-1 checkpoint antibody (Ab) blockade. Here, we elaborate on this controversy and propose a new perspective that might help understand this paradox. Since inflammatory cytokines and PD-1 blockade are known to target different subsets of exhausted CD8+ T cells, we propose that the timing at which anti-PD-1 Ab therapy and cytokine modulation occur might determine the fate of exhausted CD8+ T cells and perhaps, the clinical outcome of immunotherapeutic modalities.

The role of prosody in infants' preference for speech: A comparison between speech and birdsong.

Speech preferences emerge very early in infancy, pointing to a special status for speech in auditory processing and a crucial role of prosody in driving infant preferences. Recent theoretical models suggest that infant auditory perception may initially encompass a broad range of human and nonhuman vocalizations, then tune in to relevant sounds for the acquisition of species-specific communication sounds. However, little is known about sound properties eliciting infants' tuning-in to speech. To address this issue, we presented a group of 4-month-olds with segments of non-native speech (Mandarin Chinese) and birdsong, a nonhuman vocalization that shares some prosodic components with speech. A second group of infants was presented with the same segment of birdsong paired with Mandarin played in reverse. Infants showed an overall preference for birdsong over non-native speech. Moreover, infants in the Backward condition preferred birdsong over backward speech whereas infants in the Forward condition did not show clear preference. These results confirm the prominent role of prosody in early auditory processing and suggest that infants' preferences may privilege communicative vocalizations featured by certain prosodic dimensions regardless of the biological source of the sound, human or nonhuman.

Linking vestibular, tactile, and somatosensory rhythm perception to language development in infancy.

First experiences with rhythm occur in the womb, with different rhythmic sources being available to the human fetus. Among sensory modalities, vestibular, tactile, and somatosensory perception plays a crucial role in early processing. However, a limited number of studies so far have specifically focused on VTS rhythms in language development. The present work investigated VTS rhythmic abilities and their role in language acquisition through two experiments with 45 infants (21 females, sex assigned at birth; M age = 661.6 days, SD = 192.6) with middle/high socioeconomic status. Specifically, 37 infants from the original sample completed Experiment 1, assessing VTS rhythmic abilities through a vibrotactile tool for music perception. In Experiment 2, linguistic abilities were evaluated in 40 participants from the same cohort, specifically testing phonological and prosodic processing. Discrimination abilities for rhythmic and linguistic stimuli were inferred from changes in pupil diameter to contingent visual stimuli over time, through a Tobii X-60 eye-tracker. The predictive effect of VTS rhythmic abilities on linguistic processing and the developmental changes occurring across ages were explored in the 32 infants who completed both Experiments 1 and 2 by means of generalized, additive and linear, mixed-effect models. Results are discussed in terms of cross-sensory (i.e., haptic to hearing) and cross-domain (i.e., music to language) effects of rhythm on language acquisition, with implications for typical and atypical development.

Antitumor activity of human hydatid cyst fluid in a murine model of colon cancer.

This study evaluates the antitumor immune response induced by human hydatic cyst fluid (HCF) in an animal model of colon carcinoma. We found that anti-HCF antibodies were able to identify cell surface and intracellular antigens in CT26 colon cancer cells. In prophylactic tumor challenge experiments, HCF vaccination was found to be protective against tumor formation for 40% of the mice (P = 0.01). In the therapeutic setting, HCF vaccination induced tumor regression in 40% of vaccinated mice (P = 0.05). This vaccination generated memory immune responses that protected surviving mice from tumor rechallenge, implicating the development of an adaptive immune response in this process. We performed a proteomic analysis of CT26 antigens recognized by anti-HCF antibodies to analyze the immune cross-reactivity between E. granulosus (HCF) and CT26 colon cancer cells. We identified two proteins: mortalin and creatine kinase M-type. Interestingly, CT26 mortalin displays 60% homology with E. granulosus hsp70. In conclusion, our data demonstrate the capacity of HCF vaccination to induce antitumor immunity which protects from tumor growth in an animal model. This new antitumor strategy could open new horizons in the development of highly immunogenic anticancer vaccines.

The pupil collaboration: A multi-lab, multi-method analysis of goal attribution in infants.

The rise of pupillometry in infant research over the last decade is associated with a variety of methods for data preprocessing and analysis. Although pupil diameter is increasingly recognized as an alternative measure of the popular cumulative looking time approach used in many studies (Jackson & Sirois, 2022), an open question is whether the many approaches used to analyse this variable converge. To this end, we proposed a crowdsourced approach to pupillometry analysis. A dataset from 30 9-month-old infants (15 girls; Mage = 282.9 days, SD = 8.10) was provided to 7 distinct teams for analysis. The data were obtained from infants watching video sequences showing a hand, initially resting between two toys, grabbing one of them (after Woodward, 1998). After habituation, infants were shown (in random order) a sequence of four test events that varied target position and target toy. Results show that looking times reflect primarily the familiar path of the hand, regardless of target toy. Gaze data similarly show this familiarity effect of path. The pupil dilation analyses show that features of pupil baseline measures (duration and temporal location) as well as data retention variation (trial and/or participant) due to different inclusion criteria from the various analysis methods are linked to divergences in findings. Two of the seven teams found no significant findings, whereas the remaining five teams differ in the pattern of findings for main and interaction effects. The discussion proposes guidelines for best practice in the analysis of pupillometry data.

The intracellular cation channel TMEM176B as a dual immunoregulator.

Characterizing immune regulatory pathways is critical to understand physiological and pathophysiological processes as well as to identify novel immunotherapeutic targets. The cation channel TMEM176B has emerged in the last years as a potential new immunoregulatory player and pharmacological target. Here, we review how expression data, clinical associations of genetic variants and functional studies support a dual role for TMEM176B in regulating immune responses. Thus, TMEM176B can inhibit effector immune responses in some settings whereas it may also promote immunity by supporting antigen presentation in others. We also discuss a potential role for TMEM176B in regulating type 2 and 3 immunity and comment recent data on modulation of DC biology and inflammasome activation as well as CD8+ T cell responses. Understanding the role of TMEM176B in immunity is critical to propose rational pharmacological approaches targeting this channel.

PD-1/PD-L1 blockade abrogates a dysfunctional innate-adaptive immune axis in critical ß-coronavirus disease.

Severe COVID-19 is associated with hyperinflammation and weak T cell responses against SARS-CoV-2. However, the links between those processes remain partially characterized. Moreover, whether and how therapeutically manipulating T cells may benefit patients are unknown. Our genetic and pharmacological evidence demonstrates that the ion channel TMEM176B inhibited inflammasome activation triggered by SARS-CoV-2 and SARS-CoV-2-related murine ß-coronavirus. Tmem176b-/- mice infected with murine ß-coronavirus developed inflammasome-dependent T cell dysfunction and critical disease, which was controlled by modulating dysfunctional T cells with PD-1 blockers. In critical COVID-19, inflammasome activation correlated with dysfunctional T cells and low monocytic TMEM176B expression, whereas PD-L1 blockade rescued T cell functionality. Here, we mechanistically link T cell dysfunction and inflammation, supporting a cancer immunotherapy to reinforce T cell immunity in critical ß-coronavirus disease.

An Integrated Perspective on Spatio-Temporal Attention and Infant Language Acquisition.

Efficiency in the early ability to switch attention toward competing visual stimuli (spatial attention) may be linked to future ability to detect rapid acoustic changes in linguistic stimuli (temporal attention). To test this hypothesis, we compared individual performances in the same cohort of Italian-learning infants in two separate tasks: (i) an overlap task, measuring disengagement efficiency for visual stimuli at 4 months (Experiment 1), and (ii) an auditory discrimination task for trochaic syllabic sequences at 7 months (Experiment 2). Our results indicate that an infant's efficiency in processing competing information in the visual field (i.e., visuospatial attention; Exp. 1) correlates with the subsequent ability to orient temporal attention toward relevant acoustic changes in the speech signal (i.e., temporal attention; Exp. 2). These results point out the involvement of domain-general attentional processes (not specific to language or the sensorial domain) playing a pivotal role in the development of early language skills in infancy.

Attentional engagement during syllable discrimination: The role of salient prosodic cues in 6- to 8-month-old infants.

Prosodic cues drive speech segmentation and guide syllable discrimination. However, less is known about the attentional mechanisms underlying an infant's ability to benefit from prosodic cues. This study investigated how 6- to 8-month-old Italian infants allocate their attention to strong vs. weak syllables after familiarization with four repeats of a single CV sequence with alternating strong and weak syllables (different syllables on each trial). In the discrimination test-phase, either the strong or the weak syllable was replaced by a pure tone matching the suprasegmental characteristics of the segmental syllable, i.e., duration, loudness and pitch, whereas the familiarized stimulus was presented as a control. By using an eye-tracker, attention deployment (fixation times) and cognitive resource allocation (pupil dilation) were measured under conditions of high and low saliency that corresponded to the strong and weak syllabic changes, respectively. Italian learning infants were found to look longer and also to show, through pupil dilation, more attention to changes in strong syllable replacement rather than weak syllable replacement, compared to the control condition. These data offer insights into the strategies used by infants to deploy their attention towards segmental units guided by salient prosodic cues, like the stress pattern of syllables, during speech segmentation.

The unique role of novel linguistic labels on the disengagement of visual attention.

Do novel linguistic labels have privileged access to attentional resources compared to non-linguistic labels? This study explores this possibility through two experiments with a training and an attentional overlap task. Experiment 1 investigates how novel label and object-only stimuli influence resource allocation and disengagement of visual attention. Experiment 2 tests the impact of linguistic information on visual attention by comparing novel tones and labels. Because disengagement of attention is affected both by the salience of the perceptual stimulus and by the degree of familiarity with the stimulus to be disengaged from, we compared pupil size variations and saccade latency under different test conditions: (a) consistent with (i.e., identical to) the training; (b) inconsistent with the training (i.e., with an altered feature), and (c) deprived of one feature only in Experiment 1. Experiment 1 indicated a general consistency advantage (and deprived disadvantage) driven by linguistic label-object pairs compared to object-only stimuli. Experiment 2 revealed that tone-object pairs led to higher pupil dilation and longer saccade latency than linguistic label-object pairs. Our results suggest that novel linguistic labels preferentially impact the early orienting of attention.

Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation.

Although immune checkpoint blockers have yielded significant clinical benefits in patients with different malignancies, the efficacy of these therapies is still limited. Here, we show that disruption of transmembrane protein 176B (TMEM176B) contributes to CD8+ T cell-mediated tumor growth inhibition by unleashing inflammasome activation. Lack of Tmem176b enhances the antitumor activity of anti-CTLA-4 antibodies through mechanisms involving caspase-1/IL-1ß activation. Accordingly, patients responding to checkpoint blockade therapies display an activated inflammasome signature. Finally, we identify BayK8644 as a potent TMEM176B inhibitor that promotes CD8+ T cell-mediated tumor control and reinforces the antitumor activity of both anti-CTLA-4 and anti-PD-1 antibodies. Thus, pharmacologic de-repression of the inflammasome by targeting TMEM176B may enhance the therapeutic efficacy of immune checkpoint blockers.

The perception of the illness and the self-efficacy in the management of emotions in cardiac patients.

Cardiac rehabilitation is the sum of psychological, physical and social treatments that are offered to cardiac patients to maintain or regain an active position in society. This study wants to evaluate changes in the perception of the illness and in the self-efficacy of the management of positive and negative emotions in patients who went through cardiac rehabilitation. Sixty-seven patients (20 females, 47 males) were selected within the cardiac rehabilitation unit in the Hospital of Cittadella (Italy). Illness Perception Questionnaire - revised version and the Scale for the self-efficacy of the management of positive and negative emotions were submitted at the beginning and at the end of the rehabilitation program. One-way analyses-of-variance were performed to evaluate different answers in questionnaires between pre- and post-evaluation, and to explore gender differences. A significant change was found in the perception of duration of illness, perceived as permanent and longer after the cardiac rehabilitation program. Furthermore, at the end of the cardiac rehabilitation program men perceived the illness more chronic than women, even if they are less worried and anxious. Intensive cardiac rehabilitation has a great emotional impact on cardiac patients, influencing their perception and management of the illness. Working on emotions, through psychological groups, helps patients change their beliefs by offering them a different perspective to approach the illness.

Pro-inflammatory Ca++-activated K+ channels are inhibited by hydroxychloroquine.

Antimalarials have demonstrated beneficial effects in Systemic Lupus Erithematosus and Rheumatoid Arthritis. However, the mechanisms and the molecular players targeted by these drugs remain obscure. Although hydroxychloroquine (HCQ) is a known ion channel inhibitor, this property has not been linked to its anti-inflammatory effects. We aimed to study whether HCQ inhibits pro-inflammatory ion channels. Electrophysiology experiments demonstrated that HCQ inhibited Ca++-activated K+ conductance in THP-1 macrophages in a dose-dependent manner. In macrophages, ATP-induced K+ efflux plays a key role in activating the NLRP3 inflammasome. ATP-induced IL-1beta secretion was controlled by the KCa1.1 inhibitor iberiotoxin. NS1619 and NS309 (KCa1.1 and KCa3.1 activators respectively) induced the secretion of IL-1beta. This effect was inhibited by HCQ and also by iberiotoxin and clotrimazol (KCa3.1 inhibitor), arguing against off-target effect. In vitro, HCQ inhibited IL-1beta and caspase 1 activation induced by ATP in a dose-dependent manner. HCQ impaired K+ efflux induced by ATP. In vivo, HCQ inhibited caspase 1-dependent ATP-induced neutrophil recruitment. Our results show that HCQ inhibits Ca++-activated K+ channels. This effect may lead to impaired inflammasome activation. These results are the basis for i) a novel anti-inflammatory mechanism for HCQ and ii) a new strategy to target pro-rheumatic Ca++-activated K+ channels.