Biology subjects

Stadler, W.

Publications and source records attributed to Stadler, W..

3 recordsLinked to original sources

bioRxiv2020

PARP and PI3K inhibitor combination therapy eradicates c-MYC-driven murine prostate cancers via cGAS/STING pathway activation within tumor-associated macrophages

The majority of metastatic, castrate-resistant prostate cancer (mCRPC) patients are de novo resistant to immune checkpoint blockade (ICB), so therapeutic strategies to enhance immune-responsiveness are urgently needed. Here we performed a co-clinical trial of PARP inhibitor (PARPi) in combination with PD-1 or PDL-1 antibody in genomically unselected mCRPC patients or homologous-recombination proficient murine models, respectively, which demonstrated lack of efficacy. In contrast, PARPi in combination with PI3K inhibitor (PI3Ki), induced tumor regression via macrophage STING-dependent innate immune activation in vivo, and enhanced T-cell infiltration/activation in c-myc driven murine prostate cancer models, which was augmented by PD-L1 blockade. Ex vivo mechanistic studies revealed that PARPi-induced DNA double strand break-associated microvesicles released from tumor cells, coupled with PI3Ki-mediated c-GAS de-repression, were both required for macrophage cGAS/STING pathway activation. These data demonstrate that PARPi/PI3Ki combination triggers macrophage STING-mediated anti-cancer innate immunity, which is sufficient to induce tumor regression in ICB-refractory c-myc-driven prostate cancer. STATEMENT OF SIGNIFICANCECo-targeting of PARP and PI3K signaling pathways activates c-GAS/STING pathway within tumor-associated macrophages, thereby enhancing T cell recruitment/activation and cancer clearance in c-myc-driven murine prostate cancer models. PARPi/PI3Ki combination therapy could markedly increase the fraction of mCRPC patients responsive to ICB, independent of germline or tumor homologous recombination status.

cancer biology↗

bioRxiv2017

10-Month-Old Infants Are Sensitive To The Time Course Of Perceived Actions: Evidence From A Study Combining Eye-tracking And EEG

Research has shown that infants are able to track a moving target efficiently - even if it is transiently occluded from sight. This basic ability allows prediction of when and where events happen in everyday life. Yet, it is unclear whether, and how, infants internally represent the time course of ongoing movements to derive predictions. In this study, 10-month-old crawlers observed the video of a same-aged crawling baby that was transiently occluded and reappeared in either a temporally continuous or non-continuous manner (i.e., delayed by 500 ms vs. forwarded by 500 ms relative to the real-time movement). Eye movement and rhythmic neural brain activity (EEG) were measured simultaneously. Eye movement analyses showed that infants were sensitive to slight temporal shifts in movement continuation after occlusion. Furthermore, brain activity related to sensorimotor rather than mnemonic processing differed between observation of continuous and non-continuous movements. Early sensitivity to an actions timing may hence be explained within the internal real-time simulation account of action observation. Overall, the results support the hypothesis that 10-month-old infants are well prepared for internal representation of the time course of observed movements that are within the infants current motor repertoire.

neuroscience↗

bioRxiv2017

Visual Context Modulates Action Perception In 10-Month-Old Infants

Research on early action perception has documented infants astounding abilities in tracking, predicting, and understanding other peoples actions. Common interpretations of previous findings tend to generalize across a wide range of action stimuli and contexts. In this study, ten-month-old infants repeatedly watched a video of a same-aged crawling baby that was transiently occluded. The video was presented in alternation with videos displaying visually either dissimilar movements (i.e., distorted human, continuous object, and distorted object movements) or similar movements (i.e., delayed or forwarded versions of the crawling video). Eye-tracking behavior and rhythmic neural activity, reflecting attention (posterior alpha), memory (frontal theta), and sensorimotor simulation (central alpha), were concurrently assessed. Results indicate that, when the very same movement was presented in a dissimilar context, it was tracked at more rear parts of the target and posterior alpha activity was elevated, suggesting higher demands on attention-controlled information processing. We conclude that early action perception is not immutable but shaped by the immediate visual context in which it appears, presumably reflecting infants ability to flexibly adjust stimulus processing to situational affordances.

neuroscience↗