Biology subjects

Piazza, G.

Publications and source records attributed to Piazza, G..

4 recordsLinked to original sources

bioRxiv2026

Indomethacin exerts both cyclooxygenase inhibition-dependent and independent mechanisms to enhance chemo-immunotherapy in mice

Nonsteroidal anti-inflammatory drugs (NSAIDs) primarily act by inhibiting cyclooxygenases (COX1 and COX2), thereby reducing production of the proinflammatory mediator prostaglandin E2 (PGE2). Because PGE2 is a critical driver of cancer progression and tumor immune evasion, this has motivated interest in combining NSAIDs with chemotherapy or immunotherapy for cancer treatment. However, since COX and PGE2 levels vary across tumor types, it remains unclear whether tumor PGE2 abundance solely dictates tumor response to NSAID-based therapies. Here, we investigated the therapeutic potential of indomethacin (Indo), a prototypical NSAID, in combination with cyclophosphamide (CTX), a widely used chemotherapeutic agent with immunostimulatory properties. Metronomic administration of Indo significantly enhanced the antitumor efficacy of CTX in multiple murine tumor models exhibiting variable COX2 and PGE2 levels, including CT26, MC38, 4T1 and A20. The antitumor effects of CTX+Indo required CD8 T cells and T-cell trafficking from tumor-draining lymph nodes and were further potentiated by anti-PD-1 blockade. Single-cell RNA sequencing (scRNA-seq) revealed that responsive CT26 tumors exhibited a reprogrammed tumor immune microenvironment (TIME), marked by increased effector CD8 T-cell infiltration, reduced immunosuppressive myeloid populations, and enhanced interferon signaling in tumor cells. Importantly, Indo retained therapeutic benefit following CTX even in tumors incapable of producing PGE2, demonstrating a critical contribution of COX-independent mechanisms, particularly inhibition of tumor-intrinsic oncogenic RAS signaling, to the enhanced efficacy of the CTX+Indo combination. Collectively, our results provide strong preclinical rationale for leveraging the COX/PGE2 and RAS dual inhibitory capacities of NSAIDs to enhance the efficacy of chemotherapy and immunotherapy.

immunology↗

bioRxiv2025

No Risky Bets: The Brain Avoids All-In Predictions During Naturalistic Multitalker Listening

Listeners daily adapt to new talkers, yet how acoustic variability challenges the brains predictive mechanisms during speech processing remains unclear. Here, we used EEG and Temporal Response Function to examine neural responses to continuous speech narrated by a single talker (Single), enabling stable acoustic model formation, or multiple talkers (Multi), introducing acoustic uncertainty. We assessed whether talker variability influences phoneme recognition and predictive processing, indexed by neural responses to phonemes, phonemic and semantic surprisal. In the Multi condition, responses to phonemes increased but responses to phonemic surprisal decreased, indicating greater speech perception demands and weaker phonemic predictions. Conversely, semantic surprisal responses were stronger, suggesting increased reliance on lexical-semantic predictions. These findings reveal a trade-off in the brains predictive mechanisms, where acoustic uncertainty reduces lower-level phonemic anticipation but promotes higher-level semantic prediction. Adaptive processing underscored the brains ability to dynamically adjust predictions across linguistic levels, promoting speech comprehension in variable environments. SignificanceHumans attend to many different talkers daily, switching between them apparently without any effort. This stems from the brains ability to construct adaptive, probabilistic models of speech. In this study, we provide novel evidence that predictions in language comprehension are sensitive to acoustic uncertainty. Specifically, under conditions of increased acoustic uncertainty, listeners rely more on bottom-up information in phoneme recognition and reduce the anticipation of phonemic information. This is accompanied by enhanced semantic prediction, suggesting that listeners compensate for acoustic uncertainty by increasing reliance on higher-level contextual representations. This flexible approach allows for robust comprehension, highlighting the brains capacity to dynamically adjust its predictive processing to accommodate varying acoustic environments. TeaserTalker-driven acoustic uncertainty reduces phoneme predictions but boosts semantic inference.

neuroscience↗

bioRxiv2024

Are you talking to me? How the choice of speech register impacts listeners' hierarchical encoding of speech.

Speakers accommodate their speech to meet the needs of their listeners, producing different speech registers. One such register is Foreigner-Directed Speech (FDS), which is the way native speakers address non-native listeners, typically characterized by features such as slow speech rate and phonetic exaggeration. Here, we investigated how register impacts the cortical encoding of speech at different levels of language integration. Specifically, we tested the hypothesis that enhanced comprehension of FDS compared with Native-Directed Speech (NDS) involves more than just a slower speech rate, influencing speech processing from acoustic to semantic levels. Electroencephalography (EEG) signals were recorded from Spanish native listeners, who were learning English (L2 learners), and English native listeners (L1 listeners) as they were presented with audio-stories. Speech was presented in English in three different speech registers: FDS, NDS and a control register (Slow-NDS) which is slowed down version of NDS. We measured the cortical tracking of acoustic, phonological, and semantic information with a multivariate temporal response function analysis (TRF) on the EEG signals. We found that FDS promoted L2 learners cortical encoding at all the levels of speech and language processing considered. First, FDS led to a more pronounced encoding of the speech envelope. Second, phonological encoding was more refined when listening to FDS, with phoneme perception getting closer to that of L1 listeners. Finally, FDS also enhanced the TRF- N400, a neural signature of lexical expectations. Conversely FDS impacted acoustic but not linguistic speech encoding in L1 listeners. Taken together, these results support our hypothesis that FDS accommodates speech processing in L2 listeners beyond what can be achieved by simply speaking slowly, impacting the cortical encoding of sound and language at different abstraction levels. In turn, this study provides objective metrics that are sensitive to the impact of register on the hierarchical encoding of speech, which could be extended to other registers and cohorts.

neuroscience↗

bioRxiv2023

The contribution of early language exposure to the cortical tracking of speech

Cortical tracking of speech is relevant for the development of speech perception skills. However, no study to date has explored whether and how cortical tracking of speech is shaped by accumulated language experience, the central question of this study. In 35 bilingual children (6 y.o.) with considerably bigger experience in one language, we collected electroencephalography data while they listened to continuous speech in their two languages. Cortical tracking of speech was assessed at acoustic-temporal and lexico-semantic levels. Children showed more robust acoustic-temporal tracking in the least experienced language, and more sensitive cortical tracking of semantic information in the most experienced language. Additionally, and only for the most experienced language, acoustic-temporal tracking was specifically linked to phonological abilities, and lexico-semantic tracking to vocabulary knowledge. Our results indicate that accumulated linguistic experience is a relevant maturational factor for the cortical tracking of speech at different levels during early language acquisition.

neuroscience↗