Biology subjects

Singer, T.

Publications and source records attributed to Singer, T..

3 recordsLinked to original sources

bioRxiv2021

Human immunocompetent Organs-on-Chips platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies

AbstractTraditional drug safety assessment often fails to predict complications in humans, especially when the drug targets the immune system. Here, we show the unprecedented capability of two Organs-on-Chips to evaluate the safety profile of T-cell bispecific antibodies (TCBs) targeting tumor antigens. Although promising for cancer immunotherapy, TCBs are associated with an on-target, off-tumor risk due to low levels of expression of tumor antigens in healthy tissues. We leveraged in vivo target expression and toxicity data of TCBs targeting folate receptor 1 (FOLR1) or carcinoembryonic antigen (CEA) to design and validate human immunocompetent Organs-on-Chips safety platforms. We discovered that the Lung-Chip and Intestine-Chip could reproduce and predict target-dependent TCB safety liabilities, based on sensitivity to key determinants thereof, such as target expression and antibody affinity. These novel tools broaden the research options available for mechanistic understandings of engineered therapeutic antibodies and assessing safety in tissues susceptible to adverse events.

cancer biology↗

bioRxiv2020

Contemplative mental training reduces hair glucocorticoid levels in a randomized clinical trial

ObjectiveThis study had the objective to investigate the effect of regular contemplative mental training on endocrine indices of long-term stress. MethodsAn open-label efficacy trial comprising three distinct 3-month modules targeting attention and interoception, socio-affective or socio-cognitive abilities through dyadic exercises and secularised meditation practices was designed and carried out in 332 healthy meditation-naive adults. Participants underwent the training for up to 9 months or were assigned to a retest control cohort. Chronic stress indices were assayed at four timepoints, i.e., pre-training and following each module. The main outcome measures were cortisol and cortisone concentration in hair and self-reported chronic stress ResultsN=362 initial individuals were randomized, of whom n=30 dropped out before study initiation, n=4 before first sampling and n=2 were excluded. N=99 participants did not provide hair samples. Data from three separate training cohorts revealed consistent decreases in hair cortisol and cortisone levels over the training period. This effect increased with practice frequency, was independent of training content and not associated with change in self-reported chronic stress. ConclusionsOur results point to the reduction of long-term cortisol exposure as a mechanism via which contemplative mental training may exert positive effects on practitioners health. Trial registrationClinicalTrials.gov identifier: NCT01833104

molecular biology↗

bioRxiv2020

A low-dimensional connectome manifold governs the organization and plasticity of social brain functions in humans.

The human brain scaffolds social cognitive functions, including Theory of Mind, empathy and compassion, through its functional and microstructural organization. However, it remains unclear how the learning and refinement of these skills may, in turn, shape brain function and structure. Here we studied if different types of social mental training can lead to plastic changes in brain function and microstructure. We studied a group of 332 healthy adults (197 women, 20-55 years) with repeated multimodal neuroimaging and behavioral testing. Our neuroimaging approach capitalized on the quantification of cortical functional gradients and myelin-sensitive T1 relaxometry, two emerging measures of cortical functional organization and microstructure. Longitudinal analysis indicated marked changes in intrinsic cortical function and microstructure, which varied as a function of social training content. In particular, we observed consistent differential change in function and microstructure between attention-mindfulness and socio-cognitive training in regions functionally associated with attention and interoception, including insular and parietal cortices. Conversely, socio-affective and socio-cognitive training resulted in differential microstructural changes in regions classically implicated in interoceptive and emotional processing, including insular and orbitofrontal areas, but did not result in functional reorganization. Notably, longitudinal changes in cortical function and microstructure were predictive of behavioral change in attention, compassion and perspective-taking, suggesting behavioral relevance. In sum, our work provides evidence for functional and microstructural plasticity after the training of social-interoceptive functions, and provides a causal perspective on the neural basis of behavioral adaptation in human adults.

neuroscience↗